Decision of the Council of the Eurasian Economic Commission dated 03.11.2016 N 78 (as amended on 20.10.2023)
"On the Rules for the Registration and Expertise of Medicines for Medical Use"
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Note to the document
The version comes into effect on 20.12.2023.
The amendments introduced by the Decision of the EEC Council dated 20.10.2023 N 114 (as amended on 24.11.2023) entered into force on 20 December 2023.
Document title
Decision of the Council of the Eurasian Economic Commission dated 03.11.2016 N 78
(as amended on 20.10.2023)
"On the Rules for Registration and Expertise of Medicines for Medical Use"
COUNCIL OF THE EURASIAN ECONOMIC COMMISSION
DECISION
of November 3, 2016 N 78
ON THE RULES
OF REGISTRATION AND EXPERTISE OF MEDICINES
FOR MEDICAL USE
List of amending documents
(as amended by decisions of the Council of the Eurasian Economic Commission
dated 14.06.2018 N 55, dated 30.01.2020 N 9, dated 23.12.2020 N 128,
dated 05.03.2021 N 14, dated 23.04.2021 N 34, dated 17.03.2022 N 36,
dated 23.09.2022 N 141, dated 22.05.2023 N 60, dated 20.10.2023 N 114
In accordance with Article 7 of the Agreement on Uniform Principles and Rules for the Circulation of Medicines within the Eurasian Economic Union dated December 23, 2014, paragraph 84 of Appendix No. 1 to the Regulations of the Eurasian Economic Commission, approved by Decision of the Supreme Eurasian Economic Council dated December 23, 2014 No. 98, and Decision of the Supreme Eurasian Economic Council dated December 23, 2014 No. 108 "On the implementation of the Agreement on Uniform Principles and Rules for the Circulation of Medicines within the Eurasian Economic Union", the Council of the Eurasian Economic Commission decided:
a) registration, confirmation of registration (re-registration), amendments to the registration dossier and other procedures related to the registration of medicinal products for medical use, stipulated by the legislation of the Member States of the Eurasian Economic Union (hereinafter referred to as the Member States, the Union) and not completed by the authorized bodies of the Member States before January 1, 2016, shall be carried out in accordance with the legislation of the Member States;
b) until July 1, 2021 (in the Russian Federation - until December 31, 2020), at the applicant's discretion, registration of a medicinal product may be carried out either in accordance with the Rules or in accordance with the legislation of a Member State. In this case, medicinal products registered in accordance with the legislation of a Member State are allowed to circulate only in the territory of the Member State whose authorized body issued the registration certificate;
(as amended by the decision of the Council of the Eurasian Economic Commission dated 23.12.2020 N 128)
c) the validity of registration certificates of medicinal products submitted for registration (expert work for the purpose of registration) in accordance with the legislation of the Member States before July 1, 2021, may be extended in accordance with the legislation of the Member States, but not later than until December 31, 2025. At the same time, changes to the registration dossiers of such medicinal products, formed in accordance with the legislation of the Member States, are carried out in accordance with the legislation of the Member States no later than December 31, 2025;
(as amended by decisions of the Council of the Eurasian Economic Commission of 23.12.2020 N 128, of 05.03.2021 N 14)
d) medicinal products registered in accordance with the legislation of the Member States must be brought into compliance with the requirements of international treaties and acts constituting the law of the Union by December 31, 2025;
e) registration certificates of medicinal products issued in accordance with the legislation of the Member States are valid until their expiration date, but not later than December 31, 2025.
3. Member States, by December 31, 2016:
a) approve the amount of fees (duties) or other mandatory payments provided for by the Rules, taking into account the complexity of the procedures and the volume of work performed in the reference state and the states of recognition, including during:
registration of a medicinal product;
confirmation of registration (re-registration) of a medicinal product;
bringing the registration dossier of a medicinal product into line with the requirements of international treaties and acts constituting the law of the Union;
b) determine the bodies (organizations) authorized to carry out registration, confirmation of registration (re-registration), amendments to the registration dossier and other procedures related to the registration of medicinal products for medical use provided for by the Rules, and inform the Eurasian Economic Commission thereof.
4. This Decision shall enter into force after 10 calendar days from the date of entry into force of the Protocol signed on December 2, 2015, on the accession of the Republic of Armenia to the Agreement on uniform principles and rules for the circulation of medicines within the Eurasian Economic Union dated December 23, 2014, but not earlier than after 10 calendar days from the date of official publication of this Decision.
Members of the Council of the Eurasian Economic Commission:
From the Republic of Armenia
V. GABRIELYAN From the Republic of Belarus
V. MATYUSHEVSKY From the Republic of Kazakhstan
A. MAMIN From the Kyrgyz Republic
O. PANKRATOV From the Russian Federation
I. SHUVALOV
Approved by the Decision of the Council
of the Eurasian Economic Commission
dated November 3, 2016 N 78
RULES FOR REGISTRATION AND EXPERTISE OF MEDICINES FOR MEDICAL USE
dated 14.06.2018 N 55, dated 30.01.2020 N 9, dated 05.03.2021 N 14,
dated 23.04.2021 N 34, dated 17.03.2022 N 36, dated 23.09.2022 N 141,
dated 22.05.2023 N 60, dated 20.10.2023 N 114
I. General Provisions
1. These Rules determine the procedure for registration, confirmation of registration (re-registration), amendments to the registration dossier and examination of medicinal products for medical use in order to form a common market for medicinal products within the Eurasian Economic Union (hereinafter referred to as the Union), as well as other procedures related to the registration of medicinal products for medical use (hereinafter referred to as registration-related procedures), including:
a) bringing the registration dossier of a medicinal product registered under the national procedure in the Member States of the Union (hereinafter referred to as the Member States) into compliance with these Rules (hereinafter referred to as bringing into compliance with the requirements of the Union);
(subparagraph "a" as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 N 114)
b) suspension and cancellation of registration of medicinal products or restriction of the use of a medicinal product;
c) issuance of duplicates of the registration certificate of a medicinal product.
2. The requirements of these Rules shall apply to developers and manufacturers of medicinal products, holders of registration certificates for medicinal products, their authorized representatives, and authorized bodies (expert organizations) of the Member States in the field of circulation of medicinal products.
3. The requirements of these Rules shall not apply to:
a) medicinal products that are intended for use in military operations, emergency situations, for the prevention and treatment of diseases and injuries resulting from exposure to chemical, biological, and radiation factors, developed on the instructions of state authorities of the Member States authorized in the field of security and defense, and the circulation of which is regulated by the legislation of the Member States;
a) medicinal products that are intended for use in emergency situations, the threat of their occurrence or the occurrence of emergency situations, for the prevention and treatment of diseases and injuries that pose a danger to others, resulting from exposure to chemical, biological, and radiation factors, the circulation of which is regulated by the legislation of the Member States;
(paragraph "a.1" introduced by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
b) veterinary medicinal products, the circulation of which is regulated by other acts that are part of the law of the Union.
4. Medicinal products intended for circulation on the common market of medicinal products within the Union or on the territory of one of the Member States are subject to registration in accordance with these Rules.
5. The following are not subject to registration within the Union:
a) medicinal products manufactured in pharmacies;
b) pharmaceutical substances;
c) medicinal products intended for preclinical and clinical trials;
d) medicinal products imported by individuals for personal use;
e) radiopharmaceutical medicinal products manufactured directly in medical organizations in the manner established by the authorized bodies of the Member States;
(as amended by the Decision of the Council of the Eurasian Economic Commission of 17.03.2022 N 36)
f) medicinal products not intended for sale in the customs territory of the Union;
g) samples of medicinal products intended for registration and standard samples;
h) medicinal products intended for use as exhibition samples.
5.1. In the cases and in the manner stipulated by the legislation of the Member States, it is allowed to provide patients with and use them with unregistered medicinal products. Such medicinal products include, among other things:
medicines imported into a Member State to provide medical care for vital indications of a specific patient or to provide medical care to a limited group of patients with a rare and (or) particularly severe pathology, on the basis of a conclusion (permit document) issued by the authorized body of the Member State;
high-tech medicinal products manufactured on a non-standardized (non-routine) basis and used in the territory of the same Member State in a hospital for the purpose of fulfilling an individual medical prescription for a medicinal product specially produced for an individual patient.
(as amended by the decision of the Council of the Eurasian Economic Commission of 22.05.2023 N 60)
The production of such high-tech medicinal products is permitted by the authorized body of the Member State. Member States are obliged to ensure the equivalence of the requirements for the traceability of series and batches of medicinal products established by the legislation of the Member States and for pharmacovigilance in accordance with the acts of the Union bodies.
(as amended by the decision of the Council of the Eurasian Economic Commission dated 22.05.2023 N 60)
(clause 5.1 introduced by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
6. If a medicinal product is recognized as an orphan drug in the territories of all or several Member States in accordance with the legislation of the Member States, such medicinal product shall be registered in accordance with Sections V and VII or Sections VI and VII of these Rules, as well as in accordance with the requirements of Section 16 of Part III of Appendix No. 1 to these Rules.
If a medicinal product is not recognized as an orphan drug in the territory of any Member State in accordance with the legislation of that State, such medicinal product shall be registered in that State in accordance with the requirements of Subsection I of Section V of these Rules and Appendix No. 1 to these Rules.
If a medicinal product is intended for the treatment of an orphan disease included in the lists maintained in accordance with the legislation of an individual Member State, the registration of such medicinal product in the reference State in accordance with these Rules for the purpose of placing the medicinal product on the market of that State only (national registration procedure) shall be carried out in accordance with Sections V and VII or Sections VI and VII of these Rules, as well as in accordance with the provisions of Section 16 of Part III of Appendix No. 1 to these Rules.
(paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
7. It is prohibited to register medicinal products with different qualitative compositions of active substances under one trade name.
8. It is permitted to register one medicinal product with different trade names in different Member States in the following cases:
a) the use of the proposed trade name may be contrary to legal and moral norms or otherwise does not take into account national cultural and (or) linguistic characteristics;
b) the intellectual property rights to the trade name in the form of a trademark belong to a person other than the person who submitted the application for registration of the medicinal product (hereinafter referred to as the applicant) or the holder of the registration certificate, and the applicant or the holder of the registration certificate cannot provide a corresponding license agreement granting the right to use the trademark;
c) the medicinal product was registered under different trade names in accordance with the legislation of the Member States before December 31, 2020.
9. Registration of a medicinal product, confirmation of registration (re-registration), amendments to the registration dossier, as well as procedures related to registration, are carried out by authorized bodies.
10. The examination of the medicinal product shall be carried out by an expert organization determined in accordance with the legislation of the Member State.
11. The authorized bodies and expert organizations shall ensure the confidentiality of the information contained in the registration dossier of the medicinal product in the process of registration and examination of medicinal products, including the information contained in the closed part of the master file for the active pharmaceutical substance.
The Eurasian Economic Commission (hereinafter referred to as the Commission) and the Expert Committee on Medicines (hereinafter referred to as the Expert Committee) shall ensure the confidentiality of the information contained in the registration dossier of the medicinal product obtained in the course of their activities.
12. The applicant, in accordance with the legislation of the Member State, shall bear the costs of registration, confirmation of registration (re-registration), amendments to the registration dossier and examination of medicinal products, procedures related to registration, as well as for conducting inspections to determine compliance with the requirements of good pharmaceutical practices initiated in connection with the implementation of the said procedures.
13. The applicant shall not be reimbursed for the expenses specified in paragraph 12 of these Rules, except in cases where the applicant submits an application to withdraw an application for registration, confirmation of registration (re-registration), amendments to the registration dossier of a medicinal product prior to the start of the examination (issuance of an assignment for the examination or conclusion of an agreement for the examination) or other cases stipulated by the legislation of the Member States.
(paragraph 13 as amended by the decision of the Council of the Eurasian Economic Commission dated 05.03.2021 N 14)
14. The authorized body (expert organization) of the reference state, upon receipt of an application for registration, confirmation of registration (re-registration), amendments to the registration dossier and procedures related to registration, assigns it a unique number generated using the integrated information system of the Union (hereinafter referred to as the integrated system), and communicates it to the applicant.
15. The authorized body (expert organization) of a Member State shall submit information related to the implementation of registration, confirmation of registration (re-registration), amendments to the registration dossier, as well as procedures related to registration, to the authorized bodies (expert organizations) of other Member States, as well as to the Commission using the integrated system by the application number in accordance with the procedure for the formation and maintenance of a single register of registered medicines of the Union (hereinafter referred to as the single register).
(as amended by the decision of the Council of the Eurasian Economic Commission dated 05.03.2021 N 14)
The authorized body (expert organization) of the reference state, no later than 5 working days from the date of submission of the registration dossier by the applicant in electronic form, provides access to the information in the registration dossier at the request of the authorized bodies (expert organizations) of the states of recognition through the use of the integrated system.
If the Commission needs to provide access to a regulatory document on the quality of a medicinal product using the integrated system, the authorized bodies (expert organizations) of the Member States shall send a corresponding written request to the Commission containing information on the laboratories implementing quality control and the experts who need to be granted such access.
(paragraph introduced by the decision of the Council of the Eurasian Economic Commission of 22.05.2023 N 60)
If it is necessary to restrict access to a regulatory document on quality previously provided by the Commission, the authorized bodies (expert organizations) of the Member States shall send a corresponding written request to the Commission indicating information on the laboratories implementing quality control and the experts whose access to the document needs to be restricted.
16. Based on the results of registration of a medicinal product, the authorized body of each Member State that has registered the medicinal product shall issue a registration certificate for the medicinal product confirming the fact of its registration.
17. The registration certificate of a medicinal product shall be issued in a uniform form and in accordance with the rules for filling out the registration certificate of a medicinal product for medical use in accordance with Appendix No. 17 to these Rules by the authorized body that registered the medicinal product.
In case of loss or damage of the registration certificate of a medicinal product, at the request of the holder of the registration certificate for the issuance of a duplicate of the registration certificate of the medicinal product, the authorized body that issued this registration certificate shall issue a duplicate thereof, executed in accordance with the rules for completion according to Appendix No. 17 to these Rules.
18. The validity period of the registration certificate for a medicinal product registered for the first time in the reference state is 5 years. Upon expiration of the specified period, an indefinite registration certificate of the medicinal product shall be issued, subject to confirmation of its registration (re-registration). In cases related to pharmacovigilance issues, the authorized body may re-issue the registration certificate with a validity period of 5 years based on the results of confirmation of registration (re-registration).
(as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
The validity period of the registration certificate for a medicinal product registered under the conditional registration procedure is determined taking into account the provisions of subsection VII.III of section VII of these Rules.
(paragraph introduced by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
For a medicinal product registered in accordance with the legislation of a member state for 5 years or more, an unlimited registration certificate is issued if the medicinal product is intended to be circulated on the market of only that member state.
(as amended by the decision of the Council of the Eurasian Economic Commission of 20.10.2023 N 114)
A registration certificate for a medicinal product registered in accordance with the legislation of the Member States specified in the application for bringing it into compliance with the requirements of the Union and registered for 5 years or more on the market of the reference state shall be issued for an unlimited period as part of the procedure for bringing it into compliance with the requirements of the Union in accordance with Section XIII of these Rules.
In this case, in the cases specified in paragraphs three and four of this clause, as part of the procedure for bringing it into compliance with the requirements of the Union, the authorized body (expert organization) of the reference state may establish one or more additional requirements in accordance with paragraph 116 of these Rules, and in such a case a registration certificate shall be issued with a validity period of 5 years.
(paragraph introduced by decision of the Council of the Eurasian Economic Commission dated 20.10.2023 N 114)
II. Definitions
19. For the purposes of these Rules, the following concepts are used:
"allergen" - any medicinal product intended to identify or induce a specific acquired change in the immunological response to a substance that causes an allergy;
"safety of a medicinal product (benefit-risk ratio)" - an assessment of the positive therapeutic effects of a medicinal product in relation to the risks associated with its use (the concept of risk includes any risk associated with the quality, safety or effectiveness of a medicinal product in relation to the health of a patient or the population);
"biosimilar medicinal product (bioanalogue, biosimilar medicinal product, biosimilar)" - a biological medicinal product that contains a version of the active substance of a registered biological original (reference) drug and for which similarity (similarity) has been demonstrated on the basis of comparative studies with the reference drug in terms of quality, biological activity, efficacy and safety; "biological availability (bioavailability)" - the rate and extent to which the active substance or its active part of the molecule from the dosage form is absorbed and becomes available at the site of action;
"biological equivalence (bioequivalence)" - the absence of significant differences in the rate and extent to which the active substance or active moiety of the active substance molecule of pharmaceutical equivalents or pharmaceutical alternatives becomes available at its site of action when administered at the same molar dose under similar conditions in a properly designed study;
"biological medicinal product" - a medicinal product whose active substance is produced or isolated from a biological source and for the description of the properties and quality control of which a combination of biological and physicochemical methods of analysis with an assessment of the production process and methods for its control is necessary;
"generic medicinal product" - a medicinal product that has the same quantitative and qualitative composition of active substances and the same dosage form as the original medicinal product, and whose bioequivalence to the original medicinal product is confirmed by appropriate bioavailability studies. Different salts, esters, isomers, mixtures of isomers, complexes or derivatives of an active substance are considered to be the same active substance if their safety and efficacy do not differ significantly. Different immediate-release oral dosage forms are considered to be the same dosage form for the purposes of bioavailability studies;
"radionuclide generator" - any system containing a fixed primary radionuclide from which secondary radionuclides are formed, which are extracted by elution or other means and used in a radiopharmaceutical medicinal product;
"hybrid medicinal product" - a medicinal product that does not fall under the definition of a generic medicinal product if its bioequivalence cannot be confirmed using bioavailability studies, and also if the active substance(s), indications for use, dosage, dosage form or route of administration have changed in this medicinal product compared to the original medicinal product;
"homeopathic medicinal product" - a medicinal product manufactured using homeopathic technology using homeopathic raw materials in accordance with the requirements of the Pharmacopoeia of the Union or, in their absence, in accordance with the requirements of homeopathic pharmacopeias;
"state of recognition" - a member state in which a medicinal product is registered (is registered) with an examination, including an assessment of the expert report on the assessment of the safety, efficacy and quality of the medicinal product prepared by the reference state;
"data from real clinical practice" - data related to the patient's health status and (or) the process of providing medical care, obtained from various sources;
(paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
"holder of the registration certificate" - a legal entity in whose name the registration certificate for a medicinal product has been issued and which is responsible for the safety, efficacy and quality of the medicinal product;
"evidence obtained on the basis of real clinical practice data" - clinical evidence regarding the use and potential benefit or risk of using a medicinal product, obtained on the basis of collecting and analyzing real clinical practice data;
"unified register of registered medicinal products of the Union" - a common information resource formed within the framework of an integrated system and containing information on medicinal products registered or having undergone other procedures related to registration in accordance with these Rules;
"applicant" - a legal entity authorized to submit an application for registration, confirmation of registration (re-registration), amendments to the registration dossier of medicinal products, other procedures related to registration, and responsible for the accuracy of the information contained in the documents submitted by it and the data of the registration dossier;
"immunological medicinal product (immunobiological medicinal product)" - a medicinal product intended to form active or passive immunity, or to diagnose the presence of immunity, or to diagnose (develop) a specific acquired change in the immunological response to allergenic substances;
"instructions for medical use (package insert)" - a document approved by the authorized body of a member state in accordance with the acts of the Union bodies, containing information for the consumer and accompanying the medicinal product in the package;
"quality of a medicinal product" - a set of properties and characteristics of a pharmaceutical substance and a medicinal product, ensuring their compliance with the intended purpose in accordance with the requirements of the acts of the Union bodies;
"critical remark" - an expert's remark that the data submitted in the registration dossier by the applicant do not confirm the quality and (or) effectiveness of the registered medicinal product for medical use or indicate that the benefit-risk ratio for the medicinal product is unacceptable and the risk of harm to human health due to taking the medicinal product exceeds the effectiveness of using such a medicinal product, which makes its registration impossible;
(paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 N 60)
"dosage form" - the state of a medicinal product corresponding to the methods of its administration and use and ensuring the achievement of the desired effect;
"medicinal plant materials" - fresh or dried plants, algae, fungi or lichens, or parts thereof, whole or crushed, used for the production of medicinal products;
"a medicinal product with well-studied medical use" - a medicinal product whose active substance has been well studied in the course of medical use, while its efficacy and acceptable degree of safety are recognized, confirmed by detailed bibliographic references to published data on post-registration and (or) epidemiological studies, and at least 10 years have passed from the date of the first systematic and documented use of the active substance (active substances) of this medicinal product in at least 3 Member States;
"herbal medicinal product" - a medicinal product containing as active components exclusively medicinal plant materials and (or) herbal pharmaceutical substance (substances);
"international nonproprietary name" - the name of the active substance recommended by the World Health Organization;
"minor remark" - an expert's remark that the documents submitted in the registration dossier on the quality, safety and efficacy of a medicinal product deviate from the requirements of the relevant acts of the Union bodies in the field of circulation of medicinal products, which cannot lead to a risk of harm to human health due to taking the medicinal product;
(paragraph introduced by the decision of the Council of the Eurasian Economic Commission dated 22.05.2023 N 60)
"normative document on quality" - a document that establishes requirements for the quality control of a medicinal product (containing a specification and description of analytical methods and tests or references to them, as well as the relevant acceptance criteria for the specified quality indicators, etc.) based on the conducted examination of the medicinal product, approved by the authorized body upon registration, confirmation of registration (re-registration), amendments to the registration dossier and bringing the registration dossier into line with the requirements of the Union and is intended to control the quality of the medicinal product in the post-registration period on the territory of the Union;
(as amended by the decision of the Council of the Eurasian Economic Commission of 23.04.2021 N 34)
"general characteristics of a medicinal product" - a document approved by the authorized body of a member state, in accordance with acts of the Union bodies, containing information for healthcare professionals on the safe and effective use of a medicinal product;
"common (group) name" - the name of a medicinal product that does not have an international nonproprietary name, or a combination of medicinal products, used to combine them into a group under a single name based on the same qualitative composition of active ingredients;
"original medicinal product" - a medicinal product with a new active ingredient, which was the first to be registered and placed on the world pharmaceutical market on the basis of a dossier containing the results of full preclinical (non-clinical) and clinical studies confirming its quality, safety and effectiveness;
"orphan (rare) medicinal product" - a medicinal product intended for diagnostics, etiopathogenetic or pathogenetic treatment (treatment aimed at the mechanism of disease development) of rare (orphan) diseases, the incidence of which does not exceed the officially determined level in the Member State;
"representative of the holder of the registration certificate" - a legal entity registered in accordance with the legislation of the Member State, or a separate subdivision of a legal entity located in the territory of the Member State and authorized by the holder of the registration certificate to perform actions related to the circulation of medicinal products in the territory of the Member State;
"manufacturer of medicinal products" - an organization carrying out activities for the production of medicinal products and having a permit (license) for such activity, issued by the authorized body of the manufacturing country;
"radiopharmaceutical medicinal product" - a medicinal product containing in a ready-to-use state one or more radionuclides (radioactive isotopes) as an active substance or as part of the active substance;
"plant pharmaceutical substance" - a product obtained from medicinal plant raw materials as a result of stages of the production process using such methods as extraction, distillation, pressing, fractionation, purification, concentration, fermentation, as well as grinding of medicinal plant raw materials to a given degree. Such substances include tinctures, extracts, essential oils, squeezed juices and processed extracts, medicinal plant raw materials ground to a given degree or powdered. Such substances do not include whole medicinal plant raw materials, as well as medicinal plant raw materials subjected to mechanical processing by the manufacturer (cutting, grinding, pressing, sifting, separation, etc.); (as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 N 60)
"registration dossier" - a set of documents (including an application), executed in accordance with these Rules, submitted for carrying out procedures related to the registration, confirmation of registration (re-registration) of a medicinal product;
"registration certificate of a medicinal product" - a document of a uniform form issued by an authorized body, confirming the fact of registration of a medicinal product and constituting permission for its medical use in the territory of a member state;
"registration number" - a code designation assigned to a medicinal product upon registration in the territory of a member state;
"registration of a medicinal product" - the process of obtaining permission for medical use of a medicinal product in the territories of one or more member states, carried out in accordance with these Rules;
"reference state" - a member state that prepares an expert report on the assessment of the safety, efficacy and quality of a medicinal product based on an examination of the medicinal product in accordance with these Rules;
"reference medicinal product" - a medicinal product that is used as a comparison drug and is a standard by which the properties of a medicinal product are determined (standardized);
"risks associated with the use of a medicinal product" - any risks associated with the quality, safety or efficacy of a medicinal product in relation to the health of patients or the population, or risks leading to an undesirable impact on the environment;
"specification" - a list of quality indicators, references to analytical methods and tests and standards that represent numerical (quantitative) limits, ranges and other criteria for the specified quality indicators;
"standard sample" - an identified homogeneous substance or mixture of substances intended for use in chemical, physical and biological studies in which its properties are compared with the properties of the medicinal product under study, and possessing a degree of purity sufficient for the appropriate use;
"trade name of a medicinal product" - the name under which a medicinal product is registered;
"pharmaceutical substance (active pharmaceutical substance)" - a medicinal product intended for the production and manufacture of medicinal products;
"expert report on the assessment of safety, efficacy and quality (expert assessment report)" - a document containing the results of the examination of the safety, efficacy and quality of a medicinal product and a conclusion on the possibility (or impossibility) of its registration, confirmation of registration (re-registration), amendments to the registration dossier, bringing it into compliance with the requirements of the Union, prepared by an expert organization of the reference state;
"efficacy of a medicinal product" - a set of characteristics that ensure the achievement of a prophylactic, diagnostic or therapeutic effect or the restoration, correction or modification of a physiological function.
III. General principles of registration of medicinal products
20. Registration of medicinal products may be carried out at the request of the applicant in accordance with the mutual recognition procedure or the decentralized registration procedure.
(as amended by the decision of the Council of the Eurasian Economic Commission of 17.03.2022 N 36)
21. The mutual recognition procedure is carried out:
a) by the reference state in accordance with these Rules for the purpose of circulation of the medicinal product on the market of this state only (national registration procedure);
b) in the states of recognition - at the request of the applicant after registration of the medicinal product in the reference state under the mutual recognition procedure. Simultaneous initiation of the mutual recognition procedure in several recognition states is allowed.
22. The decentralized registration procedure is carried out simultaneously by several Member States to which an application for registration of a medicinal product has been submitted, with the choice of the reference state.
23. The applicant shall independently select the reference state and, if necessary, the state of recognition when submitting an application for registration of a medicinal product.
The applicant has the right to withdraw his/her application at any time before the end of the registration procedure for a medicinal product by notifying in writing the authorized body of the member state where the application is being considered of the withdrawal.
(paragraph introduced by the decision of the Council of the Eurasian Economic Commission dated 05.03.2021 N 14)
In the event of withdrawal of the application, the authorized body of the member state where the application is being considered shall cease its consideration on the merits and return to the applicant the originals of the documents and (or) information submitted with the application.
24. Only one state may act as a reference state.
25. The requirements for the documents and data of the registration dossier in the format of a general technical document submitted for registration of a medicinal product are established by Appendices No. 1 - 5 to these Rules.
26. Prior to filing an application for registration of a medicinal product, authorized bodies or expert organizations of the Member States may, at the request of the applicant, conduct scientific and pre-registration consultations in accordance with the legislation of the Member States, on issues related to the conduct of analytical tests, preclinical and clinical studies (trials), aspects of the registration procedure, including issues related to the qualification, type of application for registration of a medicinal product in order to determine the volume of documents and data of the registration dossier, with respect to the completeness of the registration dossier, the format for submitting the application and registration dossier, the need to provide samples of the medicinal product, standard samples, materials, specific reagents, consumables necessary for conducting a laboratory examination of quality in the expert organization or as designated by it, and on other issues.
27. In the event that, during the registration procedures, confirmation of registration (re-registration), amendments to the registration dossier or procedures related to registration, the authorized body or expert organization of the reference state identifies facts that cast doubt on the reliability of the information provided by the applicant in the registration dossier in relation to the preclinical (non-clinical) studies (trials) of medicinal products and clinical studies (trials) of medicinal products or the production of a medicinal product, including the production of a pharmaceutical substance or the organization of a pharmacovigilance system, the pharmaceutical inspectorate of this state shall initiate an inspection for compliance with the requirements of the relevant good pharmaceutical practices. Such inspections may also be initiated in the cases specified in paragraphs 31, 33, 35, 37 - 39 of these Rules. The responsibility for the timely initiation of relevant unscheduled inspections, if necessary, lies with the authorized body of the reference state.
28. The production of medicinal products must comply with the Rules of Good Manufacturing Practice of the Eurasian Economic Union.
29. When submitting an application for registration, confirmation of registration (re-registration), or bringing a medicinal product into compliance with the Union requirements, the applicant must submit as part of the registration dossier a valid document confirming compliance with the Union good manufacturing practice requirements, the manufacturing site (manufacturing sites) producing the finished dosage form and issuing quality control of the medicinal product submitted for registration, confirmation of registration (re-registration), or bringing it into compliance with the Union requirements.
With respect to the manufacturing site (manufacturing sites) of the medicinal product, the applicant, instead of a document confirming compliance with the Union good manufacturing practice requirements, has the right to submit, before the expiration of its validity, a document confirming compliance with the good manufacturing practice requirements issued to the manufacturer of the medicinal product by the authorized body of the Member States, the manufacturing site (manufacturing sites) of the medicinal product producing the finished dosage form and issuing quality control.
(as amended by decisions of the Council of the Eurasian Economic Commission of 14.06.2018 N 55, of 23.04.2021 N 34)
30. If it is impossible to submit a valid document confirming the compliance of the production site (production sites) of the medicinal product with the requirements of good manufacturing practice of the Union, the applicant, when submitting an application for registration of the medicinal product or for bringing it into compliance with the requirements of the Union before December 31, 2024, instead of this document, shall submit the following documents and information:
(as amended by decisions of the Council of the Eurasian Economic Commission of 14.06.2018 N 55, of 23.04.2021 N 34, of 22.05.2023 N 60)
a) valid documents confirming the compliance of the production site (production sites) carrying out the production of the finished dosage form and the release quality control of the medicinal product with the requirements of good manufacturing practice, issued to the manufacturer of the medicinal product by an authorized body of the country - manufacturer of the medicinal product;
b) a copy of the report on the results of the last inspection of the production site (production sites at the production stages), carried out by the authorized body of the country of manufacture and (or) another authorized body over the past 3 years;
c) information on the results of all inspections of this production site (production sites) for compliance with the requirements of good manufacturing practice, carried out over the past 3 years;
d) information on complaints regarding the quality of medicinal products manufactured at this production site (production sites), over the past 3 years;
d) consent to conduct a pharmaceutical inspection for compliance with the requirements of good manufacturing practice of the Union;
e) a copy of the main dossier (master file) of the production site (production sites).
31. The reference state, on the basis of the documents submitted by the applicant, specified in paragraph 30 of these Rules, taking into account the assessment of possible risks, makes a decision on the need to conduct an unscheduled pharmaceutical inspection for compliance with the requirements of good manufacturing practice of the Union during the registration procedures for the medicinal product or on the inclusion of an inspection of the production site (production sites) where the medicinal product applied for registration or for bringing into compliance with the requirements of the Union is manufactured, including, if necessary, the pharmaceutical substance, in the plan for conducting inspections in the first 3 years after completion of the registration procedures.
32. In the event of documentary justification by the authorized body of the reference state of the impossibility of conducting an unscheduled inspection of the production site (production sites) of the medicinal product by the reference state during the registration procedures for the medicinal product, the applicant has the right, in agreement with the reference state, to apply to one of the Member States with an application for an inspection of this production site (production sites) for compliance with the requirements of good manufacturing practice of the Union. In the event of a written refusal by the authorized bodies of the recognition states to conduct an unscheduled inspection of the production site(s) of the medicinal product, the authorized body of the reference state is obliged to organize and conduct an unscheduled inspection within the timeframe for conducting registration procedures in relation to the medicinal product.
33. The decision on the need to conduct an unscheduled pharmaceutical inspection for compliance with the requirements of good manufacturing practice of the Union shall be made by the authorized body of the reference state in the process of implementing:
a) the registration procedure - for medicinal products manufactured at sites that manufacture finished dosage forms and undergo release quality control that have not previously been inspected by the authorized body (organization) of at least one Member State;
b) the procedure for bringing into compliance with the requirements of the Union - for medicinal products previously registered in the Member States, in the event of indicating (introducing, changing) a production site (production sites) that have not previously been inspected by the authorized body (organization) of at least one Member State.
34. Preclinical safety studies of medicinal products are conducted in accordance with the requirements of the rules of good laboratory practice of the Union approved by the Commission.
Clinical trials of medicinal products are conducted in accordance with the requirements of the rules of good clinical practice of the Union approved by the Commission.
35. Preclinical safety studies of medicinal products conducted in non-Union member states shall be considered in the course of examination of medicinal products, provided that they are planned, conducted and described in the preclinical study report in accordance with the requirements of good laboratory practice equivalent to the Union requirements (or not lower).
Clinical studies of medicinal products conducted in non-Union member states shall be considered in the course of examination of medicinal products, provided that they are planned, conducted and described in the clinical study report in accordance with the requirements of good clinical practice equivalent to the Union requirements (or not lower), as well as the principles of the World Medical Association Declaration of Helsinki "Ethical Principles for Medical Research Involving Human Subjects".
During the examination of a medicinal product, the authorized body of the reference state has the right to appoint an unscheduled inspection for compliance with the rules of good laboratory practice of the Union in the event of:
identification during the examination of the medicinal product of facts that cast doubt on the reliability of the results obtained during the preclinical studies;
identification of questionable (implausible or contradictory from a medical and biological point of view) research results;
the presence of other circumstances stipulated by the rules for conducting pharmaceutical inspections approved by the Commission.
36. When registering a medicinal product, reports on the clinical trials conducted, included in module 5 of its registration dossier, are considered during the examination if one of the following conditions is met:
clinical trials were conducted in accordance with the legislation of the Member States and on their territory before 1 January 2016 (based on the date of the last visit of the last patient (volunteer)) or continued to be conducted as of 1 January 2016 (with the recruitment of patients (volunteers) into the study completed);
clinical trials were conducted partially or completely in the territories of the countries of the region of the International Conference on Harmonization of Technical Requirements for Registration of Medicinal Products for Human Use (ICH) before January 1, 2016 (according to the date of the last visit of the last patient), on the basis of which the medicinal product was registered in the territories of the countries of the region of the International Conference on Harmonization of Technical Requirements for Registration of Medicinal Products for Human Use (ICH);
clinical trials initiated after January 1, 2016, were conducted in accordance with international treaties and acts constituting the law of the Union, while at least one of the clinical trials was conducted fully or partially (in relation to the data obtained from the subjects of the study) in the territory of the Union.
If the requirements specified in the second to fourth paragraphs of this clause are not met, before filing an application for registration of a medicinal product, the applicant shall conduct clinical trials (at least one trial at the discretion of the applicant and in agreement with the authorized body) in whole or in part on the territory of the Union or, when conducting an examination of the registration dossier, an unscheduled inspection of one of the clinical centers in which the clinical trial was conducted shall be appointed by decision of the authorized body. The provisions of this clause shall not apply to orphan medicinal products.
37. The authorized body of the reference state, on the basis of the documents and information submitted by the applicant and taking into account the assessment of possible risks, makes a decision on the need (or lack of need) to conduct an unscheduled inspection of clinical trials of the medicinal product, including bioequivalence studies, during the registration of the medicinal product for compliance with the requirements of good clinical practice of the Union or to include an inspection of the clinical trial in the plan for inspections in the first 3 years after registration of the medicinal product. In this case, a scheduled inspection is carried out in at least one research center in accordance with the rules for conducting pharmaceutical inspections approved by the Commission.
38. The decision on the need to conduct an unscheduled inspection of a clinical trial for compliance with the requirements of good clinical practice of the Union (or for compliance with the requirements of good laboratory practice of the Union - in relation to applicable points) is made by the authorized body based on a comprehensive assessment of the following factors:
lack of information on approval by an independent ethics committee of the clinical trial;
identification of violations in obtaining informed consent or information provided to research subjects;
(as amended by the decision of the Council of the Eurasian Economic Commission dated 30.01.2020 N 9)
the presence of issues related to the administrative structure of the clinical trial (absence or ambiguity of information);
the presence of significant amendments not reflected in the protocol during the study in accordance with the rules of good clinical practice approved by the Commission;
the absence or insufficiency of information in the protocol and report on the clinical trial describing the determination of indicators of efficacy and (or) safety (regarding the selection, identification, processing of clinical samples, conditions of quantitative determination);
the presence of information on the exclusion of these research subjects from statistical analysis without justification;
identification of facts that cast doubt on the reliability of the information presented in the registration dossier regarding a clinical trial of a medicinal product (unjustified or unclear differences in the efficacy and safety endpoints in the clinical trial protocol and report; inconsistency, inaccuracy or incompleteness of data recording, protocol changes not taken into account in other clinical trial documents, a large number of missing values that could affect the statistical power of the study);
implausibility or inconsistency of clinical data (contradictory results compared with known results of other studies, low frequency of reports of cases of serious adverse reactions and (or) implausible data in favor of the study drug compared with the results of other researchers or other studies, questionable (implausible or contradictory) results from a medical and biological point of view between studies or between study centers);
critical dependence (justification of the efficacy and safety of the drug, as well as the benefit-risk ratio) on the results of only one study or studies on a small sample of subjects; the medicinal product is intended for use by a wide population (e.g. vaccines and other medicinal products that are intended for simultaneous use by large groups of the population);
high probability of ethical issues (participation in the study of vulnerable groups of the population: children, persons with cognitive impairment, patients with diseases that have no alternative therapy, institutionalized patients, etc. in accordance with the requirements of the rules of good clinical practice approved by the Commission);
conducting a clinical trial in a clinical center in a geographical region where the level of requirements for conducting clinical trials is lower than those established within the Union;
availability of information from authorized bodies of states that are not members of the Union regarding problems with compliance with the requirements of good clinical practice by the research center or sponsor;
the presence of circumstances stipulated by the rules for conducting pharmaceutical inspections approved by the Commission.
If there are doubts about the quality of the medicinal product and comparator drugs, including placebo, used in the clinical trial, a decision is made to conduct a pharmaceutical inspection of the production site of this medicinal product for compliance with the requirements of good manufacturing practice of the Union.
(as amended by the {HYPERLINK(«https://docs.eaeunion.org/documents/401/6507/»;»Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36»})
39. The decision on the need to conduct an unscheduled inspection in relation to the results of bioequivalence studies shall be made by the authorized body, taking into account the requirements of paragraphs 37 and 38 of these Rules, based on a comprehensive assessment of the following factors:
a) submission of unreasonably homogeneous (heterogeneous) bioequivalence study data;
b) discrepancy between the number of missing (outlier) values and the expected values for a given active substance or type of measurement;
c) implausibility (inconsistency) of the presented clinical, statistical or analytical data;
d) presence of conflicting results of studies regarding pharmacokinetic parameters or interindividual (intraindividual) variability.
40. An unscheduled inspection of the pharmacovigilance system of the registration certificate holder as part of the registration procedure for a medicinal product shall be carried out in cases stipulated by the rules of good pharmacovigilance practice approved by the Commission.
IV. General principles of examination of medicinal products
41. Examination of medicinal products is carried out to obtain a scientific assessment of the quality, safety and efficacy of medicinal products and the benefit-risk ratio of medicinal products and may include:
a) assessment of documents and information submitted by the applicant in the registration dossier of the medicinal product (assessment of the dossier);
b) conducting laboratory tests for compliance with the requirements of the regulatory document on quality and verification of analytical quality control methods;
c) preparation by the reference state of an expert report on the assessment of the medicinal product;
d) assessment by the state of recognition of the expert report on the assessment, taking into account the documents and information contained in the registration dossier of the medicinal product.
42. The main principles of conducting examination of medicinal products during registration are:
a) independence and legal protection of experts in the exercise of their professional activities;
b) mandatory compliance with the requirements of the legislation of the Member States, international treaties and acts constituting the law of the Union;
c) a scientific approach, completeness, comprehensiveness and objectivity of studies of the objects of examination, ensuring the validity of the results of the examination in accordance with documented accepted criteria of acceptability;
d) competence and high professional level of expert organizations and experts;
e) systematic organization of examination of medicinal products and its methodological support;
f) orientation to the world level of development of science and technology, norms and rules of technical and public safety;
g) publicity of the results of the examination, subject to the preservation of state, official and commercial secrets in accordance with the legislation of the Member States, international treaties and acts constituting the law of the Union.
43. When developing, conducting preclinical (non-clinical) and clinical studies (tests) of a medicinal product, its production, implementing pharmacovigilance and preparing documents provided for the registration procedure, confirmation of registration (re-registration), amendments to the registration dossier or other procedures related to registration, developers, manufacturers and holders of registration certificates of medicinal products and their authorized persons must comply with the legislation of the Member States, international treaties and acts constituting the law of the Union, and also be guided by optimal approaches, the implementation of which will ensure the fulfillment of such requirements and which are set out, among other things, in decisions and recommendations adopted by the Commission. In the event of non-compliance with these recommendations, the applicant must provide a justification for the admissibility of the chosen approach from the point of view of ensuring the quality, efficacy and safety of the medicinal product. The justification provided must be assessed during the examination of medicinal products.
44. The examination of a medicinal product shall not be interrupted for the period of unscheduled pharmaceutical inspections for compliance with the requirements of good practices of the Union (manufacturing, laboratory, clinical, pharmacovigilance), but the final expert assessment report may be drawn up by the authorized body (expert organization) of the reference state only taking into account the results of unscheduled pharmaceutical inspections (if they are carried out). The said inspections must be carried out within a period not exceeding 180 calendar days from the date of the authorized body's decision to initiate the inspection.
45. For medicinal products that require additional safety monitoring in accordance with the requirements of good pharmacovigilance practice of the Union, the general characteristics of the medicinal product for medical use (hereinafter referred to as the SmPC) and the instructions for medical use of the medicinal product (package leaflet) (hereinafter referred to as the instructions for medical use) must include the relevant wording and notes in accordance with the requirements for the instructions for medical use of the medicinal product and the general characteristics of the medicinal product for medical use approved by the Commission.
V. Procedure for registration and examination of medicinal products under the mutual recognition procedure
V.I. Registration and examination of a medicinal product
in the reference state
46. The period for registration and examination of a medicinal product in the reference state must not exceed 140 working days from the date of filing an application for registration of a medicinal product until the date of issue of the registration certificate.
(as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
47. In order to register a medicinal product, the applicant shall submit the following documents and materials to the authorized body (expert organization) of the reference state:
an application in the form established by Appendix No. 2 to these Rules, on paper or in the form of an electronic document signed with an electronic digital signature (electronic signature) in accordance with the legislation of the member state in which such application is submitted (hereinafter referred to as the electronic signature);
documents confirming payment of the fee (duty) for registration and examination of the medicinal product in the case and in the manner established by the legislation of the reference state on paper or in the form of electronic documents signed with an electronic signature;
registration dossier in accordance with Appendices N 1 - 5 to these Rules on electronic media in the form of a set of electronic documents;
samples of medicinal products.
Samples of medicinal products, standard samples of active pharmaceutical ingredients and related impurities, specific reagents and other materials necessary for testing samples of medicinal products specified in paragraph five of this clause shall be submitted in agreement with the expert organization.
Samples of medicinal products, specific reagents and other materials shall be submitted in quantities agreed upon with the expert organization and required to conduct no more than 3-fold analysis in accordance with the requirements of the regulatory document on the quality of medicinal products or other specifications included in the registration dossier, within the time period agreed upon by the authorized body (expert organization), which is not included in the general time period for examination and registration of the medicinal product.
Samples, specific reagents and other materials shall not be submitted if it is impossible to conduct tests in the expert organization due to:
difficult availability of samples of medicinal products, standard samples, specific reagents and other materials (including when they are classified as orphan, high-tech, radiopharmaceutical, narcotic, psychotropic or intended for the treatment of high-cost nosologies due to their high cost);
(as amended by decisions of the Council of the Eurasian Economic Commission of 17.03.2022 N 36, of 22.05.2023 N 60)
impossibility of complying with the conditions for transporting the said samples to the territory of a member state and (or) storing them;
(as amended by decision of the Council of the Eurasian Economic Commission of 17.03.2022 N 36)
lack of special equipment and consumables in the expert organization;
and other reasons by decision of the authorized body (expert organization) in the event of force majeure circumstances or circumstances beyond the control of the parties, including in connection with the specifics of production and quality control of the medicinal product.
In accordance with the requirements of the legislation of a member state, the documents specified in paragraphs two through four of this clause may be submitted using electronic document management without additional submission of relevant documents and information on paper, signed and (or) certified by the electronic signature of the applicant, in the cases provided for by these Rules.
48. In the cases specified in paragraphs eight through eleven of clause 47 of these Rules, laboratory tests are carried out in the quality control laboratory of the manufacturer of the medicinal product in the presence of representatives of the expert organization or in a contract laboratory used by the manufacturer in the presence of representatives of the expert organization.
In cases where it is impossible to conduct laboratory tests in the quality control laboratories of the manufacturer of the medicinal product or contract laboratories used by the manufacturer (under conditions of the threat of occurrence, occurrence and elimination of an emergency situation and (or) in the event of a threat of the spread of diseases that pose a danger to others, diseases and injuries resulting from exposure to unfavorable natural, chemical, biological, radiation factors, in which the presence of a representative of an expert organization is not possible, or in other circumstances (for example, related to the specifics of the production and quality control of a specific medicinal product of the categories specified in paragraphs eight to eleven of clause 47)), in agreement with the authorized body (expert organization), the quality examination is carried out on the basis of the manufacturer's documentation (manufacturer's analysis protocols), including using remote interaction tools, including audio or video communication.
49. Expertise of a medicinal product in the reference state includes:
a) assessment of the completeness, completeness and correctness of execution of documents submitted in the registration dossier;
b) assessment of documents and information submitted by the applicant in the registration dossier of the medicinal product for safety, efficacy and quality;
c) conducting laboratory tests for compliance with the requirements of the regulatory document on the quality and reproducibility of the declared quality control methods carried out in accredited testing laboratories;
d) initiation, if necessary, of a pharmaceutical inspection in the cases established by these Rules;
e) preparation by the reference state of an expert report on the assessment of the medicinal product.
50. The authorized body (expert organization) of the reference state shall, within 10 working days from the date of filing the application for registration, evaluate the completeness, completeness and correctness of the documents submitted in the registration dossier before sending the registration dossier materials for examination. The applicant shall be given no more than 90 working days, not included in the period of registration and examination of the medicinal product, to submit materials missing from the registration dossier, based on the comments of the authorized body (expert organization) of the reference state.
The applicant's response shall be assessed within a period not exceeding 5 working days from the date of receipt of the applicant's response.
51. The authorized body (expert organization) of the reference state rejects the application for registration of a medicinal product in the event of failure to submit the registration dossier materials based on the comments of the authorized body (expert organization) of the reference state and (or) failure to confirm payment of the fee (duty) for registration and examination of the medicinal product in the cases and in the manner established by the legislation of the reference state.
52. When registering and/or examining a medicinal product, the authorized body and/or expert organization of the reference state shall have the right to send the applicant a written and/or electronic request for missing additional information, necessary explanations or clarifications of documents and data submitted in the registration dossier (including proposals to amend the summary of product characteristics, instructions for medical use, layouts of the medicinal product packaging, regulatory documentation on quality or other documents of the registration dossier). After the first request, subsequent requests are allowed only if additional questions arise regarding the information submitted by the applicant in response to the previous request.
The examination, which includes the stages specified in subparagraphs "b" - "d" of paragraph 49 of these Rules, shall be carried out within a period not exceeding 105 working days from the date of assessment of the completeness, completeness and correctness of the execution of the documents submitted in the registration dossier or from the date of receipt by the expert organization of the relevant assignment for the examination.
(paragraph introduced by decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
53. The period for the applicant to submit a response to the request specified in paragraph 52 of these Rules shall not exceed 90 working days from the date of receipt of the request.
(as amended by decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
54. If necessary, based on the relevant justification of the applicant, the period established in paragraph 53 of these Rules may be extended by the authorized body (expert organization) of the reference state. The total period for responding to requests shall not exceed 180 working days.
55. The time for the applicant to submit documents at the request of the authorized body or expert organization during the examination of the medicinal product is not included in the period for the examination and registration of the medicinal product.
56. If the applicant fails to submit the requested documents and information within the specified period, the examination and registration of the medicinal product shall be terminated. The authorized body (expert organization) shall notify the applicant of the decision taken in writing and (or) electronically within 14 working days from the date of this decision.
57. The request of the authorized body (expert organization) of the reference state must be transmitted to the applicant in electronic form via telecommunication channels and shall be considered received after 1 working day from the date of its sending.
(clause 57 as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
58. The decision to initiate an unscheduled pharmaceutical inspection for compliance with good pharmaceutical practices of the Union may be taken by the authorized body (expert organization) of the reference state no later than 70 working days from the date of filing the application for registration.
In the event of a decision to initiate an unscheduled pharmaceutical inspection, the authorized body (expert organization) of the reference state sends the applicant a request on the need to organize an inspection (indicating the reasons for initiation and references to acts of the Union bodies). The response to this request is submitted within the time period specified in paragraphs 53 and 54 of these Rules.
An unscheduled pharmaceutical inspection with the submission of a report on the inspection must be carried out within a period not exceeding the registration period of the medicinal product (within 180 working days from the date of the decision by the relevant authorized body or expert organization to initiate the inspection).
An unscheduled pharmaceutical inspection is organized by the applicant in accordance with the rules for conducting pharmaceutical inspections.
In the event that a pharmaceutical inspection is included in the inspection plan in accordance with paragraph 31 of these Rules, the preparation of the report is completed without taking into account the inspection results.
(clause 58 as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
59. In order to prepare an expert assessment report, the expert organization of the reference state has the right, if necessary, to draw up expert reports on quality aspects, assessment of a new active substance contained in a medicinal product, assessment of the registration dossier for the active substance, preclinical, clinical aspects according to the forms in accordance with Appendices No. 6 - 9, 11 and 22. If the expert organization has carried out the relevant tests, a laboratory test report is drawn up, which must contain information in accordance with Appendix No. 12. The form of the laboratory test report is established by the expert organization in accordance with the legislation of the Member States.
Based on the results of the examination of the registration dossier of a reproduced or hybrid medicinal product, the expert organization of the reference state shall, if necessary, draw up expert reports in the forms provided for in Appendices No. 8, 11 and 22 to these Rules, and, if necessary, draw up a laboratory test protocol containing the information specified in Appendix No. 12 to these Rules. The form of the laboratory test protocol shall be established by the expert organization in accordance with the legislation of the Member States.
(clause 59 as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
60. Based on the results of the examination of the medicinal product, the expert organization of the reference state shall draw up a final expert report on the assessment of the medicinal product submitted for registration, including an assessment of the explanations received from the applicant, documents and information submitted in response to a request from the expert organization or authorized body, in the form according to Appendix No. 16 to these Rules.
61. Expert reports on quality aspects, preclinical, clinical aspects, and the final expert assessment report shall be prepared in accordance with Appendices No. 13-15 and 23 to these Rules.
62. The expert assessment report must be updated by the expert organization of the reference state when new information appears that is important for assessing the quality, safety, or efficacy of the medicinal product and may affect the benefit-risk ratio of the medicinal product, as part of the procedure for making changes to the registration dossier.
63. If, based on the results of the examination of the medicinal product, the authorized body of the reference state makes a positive decision on registration of the medicinal product, the authorized body of the reference state, within a period not exceeding 10 working days:
a) issues to the applicant a registration certificate for the medicinal product in the form in accordance with Appendix No. 17 to these Rules, the approved SmPC, instructions for medical use, a regulatory document on quality, packaging layouts, an expert assessment report (if necessary, the applicant is issued the approved SmPC, instructions for medical use and packaging layouts of the medicinal product in the official language of the reference state), an agreed risk management plan (if necessary);
b) places information about the medicinal product and the active pharmaceutical substances included in its composition in a single register with the attached approved summary of product characteristics, instructions for medical use, packaging layouts, quality regulatory document, as well as the final expert assessment report compiled in accordance with Appendix No. 16 to these Rules, after the removal of confidential data and data on experts, an agreed risk management plan (if necessary) in accordance with the procedure for the formation and maintenance of a single register.
63.1. A decision based on the results of the examination of the medicinal product shall be made by the authorized body of the reference state within a period not exceeding 10 working days from the date of signing the expert assessment report.
(clause 63.1 was introduced by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
64. The authorized body of the reference state refuses to register a medicinal product based on the results of the examination in the following cases:
a) the ratio of the expected benefit to the possible risks associated with the use of the medicinal product is not favorable;
b) the effectiveness of the medicinal product is not confirmed by the information provided by the applicant;
c) the quality of the medicinal product is not confirmed;
d) the proposed quality control methods and techniques are not reproducible;
e) the applicant has provided false information;
f) the results of the appointed inspection during the registration of the medicinal product do not confirm compliance with the proper pharmaceutical practices of the Union;
g) the applicant has not submitted the documents and information requested by the authorized body (organization) within the specified time period.
(subparagraph "g" introduced by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
65. If the authorized body of the reference state decides to refuse to register a medicinal product, the authorized body (expert organization) of the reference state shall notify the applicant thereof electronically and (or) in writing within 10 working days from the date of such decision.
V.II. Registration and examination of a medicinal product under the mutual recognition procedure in the state (states) of recognition
66. After registration of a medicinal product in the reference state, the applicant may initiate registration in other Member States selected by the applicant as recognition states under the mutual recognition procedure by submitting to the authorized bodies (expert organization) of such Member States:
an application for registration of a medicinal product under the mutual recognition procedure on paper or in the form of an electronic document signed with an electronic signature, in the form according to Appendix No. 2 to these Rules;
(as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
documents confirming payment of the fee (duty) for registration and examination of the medicinal product in the case and in the manner established by the legislation of the recognition state, on paper or in the form of electronic documents;
(as amended by the Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
module 1 of the registration dossier on an electronic medium in the form of electronic documents (including updated documents related exclusively to the state of recognition). In the cover letter, the applicant is obliged to provide information on all changes made to the registration dossier if they were initiated before the date of filing the application for registration in the state of recognition (indicating the application numbers and attaching copies of the decisions (conclusions) of the authorized body of the reference state).
If there are relevant requirements in the legislation of the member state, the summary of product characteristics, instructions for medical use and packaging layouts of the medicinal product in the official language of the state of recognition are submitted.
The application cannot be submitted to the states of recognition before the date of completion of the procedures for making changes initiated in the reference state (if any). After the registration procedure has been initiated in the recognition states and until it has been completed in the recognition states in which this procedure has been initiated, the applicant may not initiate the procedure for making changes in the reference state, with the exception of urgent changes related to safety.
(paragraph introduced by the Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
When submitting urgent changes related to safety in the reference state, the applicant is obliged to notify the authorized body (expert organization) of the recognition state carrying out the recognition procedure of this fact within 24 hours.
In accordance with the requirements of the legislation of a member state, the documents specified in paragraphs two through four of this clause may be submitted using electronic document management without additional submission of relevant documents and information on paper, signed and (or) certified by the electronic signature of the applicant, in cases stipulated by these Rules.
66.1. It is allowed to make changes to the registration dossier of a registered medicinal product in the reference state in accordance with Appendices No. 19 and 20 to these Rules before the date of initiation of the mutual recognition procedure in the state (states) of recognition. In this case, an updated expert report on the results of the changes (if applicable) must be submitted to the state of recognition by the reference state. At the applicant's discretion, it is allowed to initiate the mutual recognition procedure simultaneously in several recognition states.
(paragraph 66.1 was introduced by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
67. The authorized body (expert organization) of the reference state, at the request of the applicant, within a period not exceeding 5 working days from the date of receipt of this request, provides access for the authorized bodies (expert organizations) of the recognition states to the registration dossier of the medicinal product and the expert assessment report through an integrated system using additional documents and information submitted by the applicant in response to requests from the authorized body (expert organization) of the reference state.
68. Registration of a medicinal product in the state of recognition, in the absence of disagreements between the authorized bodies of this Member State and the reference State and in the presence of an opinion on the possibility of recognizing the expert assessment report, is carried out no later than 60 working days from the date of receipt by the expert organization of access to all versions (sequences) of the electronic registration dossier, on the basis of which the reference State prepared the expert assessment report, and to the approved expert assessment report.
69. Examination of a medicinal product under the mutual recognition procedure in the states of recognition is carried out within a period not exceeding 40 working days from the date of receipt of access to the expert assessment report, by:
consideration of the application, documents and information presented in the registration dossier, current (taking into account changes made to the registration dossier, if any) in the reference State at the time of filing the application in the states of recognition;
review of the expert assessment report prepared by the expert organization of the reference state, updated in the reference state at the time of filing the application in the recognition states.
The expert organization of the recognition state notifies the authorized body of the recognition state and the applicant of receiving the specified access in full within 1 working day from the date of its receipt.
The applicant is notified of the start of the examination in electronic form via telecommunication channels. The notification is considered received after 1 working day from the date of its sending (or publication in the applicant's personal account).
(clause 69 as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
70. The authorized body (expert organization) of the state of recognition, within 10 working days from the date of filing the application, rejects the application for registration of a medicinal product under the mutual recognition procedure in the event of non-compliance of the application with the requirements of these Rules and (or) failure to confirm payment of the fee (duty) for registration and examination of the medicinal product in the cases and in the manner stipulated by the legislation of the state of recognition, or makes a decision to begin the examination specified in clause 69 of these Rules.
71. When registering a medicinal product under the mutual recognition procedure, the authorized body (expert organization) of the state of recognition, no later than 30 working days after receiving access to the expert assessment report, if necessary, sends a request to the applicant and to the authorized body (expert organization) of the reference state in the form according to Appendix No. 18 to these Rules.
The request of the authorized body (expert organization) of the state of recognition to the applicant may be submitted to the authorized representative of the applicant in person against signature, sent by registered mail or transmitted electronically via telecommunication channels. If this request is sent by registered mail, it is considered received after 6 calendar days from the date of sending the registered letter. If the request is sent via telecommunication channels, it shall be deemed received after 1 calendar day from the date of its sending.
A request from an authorized body (expert organization) of the state of recognition to an authorized body of the reference state shall be sent using the integrated system.
72. The applicant shall send a response to the request to the authorized body (expert organization) of the state of recognition within a period not exceeding 90 working days. The period for the applicant's response to the request is not included in the total period for the examination and registration of the medicinal product. The authorized body (expert organization) of the state of recognition shall, within 5 working days from the date of receipt of the applicant's response, provide the authorized body (expert organization) of the reference state with access to it through the integrated system.
73. If the applicant fails to submit the documents and information requested by the authorized body (expert organization) of the state of recognition within the established period, the examination and registration of the medicinal product in this state of recognition shall be terminated.
If the authorized body of the reference state fails to submit the documents and information requested by the authorized body (expert organization) of the state of recognition within 100 working days, a conclusion shall be drawn up on the impossibility of recognizing the expert assessment report prepared by the reference state.
The said report shall be sent by the state of recognition for consideration by the Expert Committee.
74. The applicant shall be notified of the decision taken by the authorized body and (or) expert organization (in electronic and (or) paper form) within 10 working days from the date of the decision.
75. The authorized body (expert organization) of the state of recognition, based on the results of the examination of the medicinal product, within 5 working days from the date of completion of the examination specified in paragraph 69 of these Rules, using the integrated system, sends to the authorized body (expert organization) of the reference state a conclusion on the possibility or impossibility of recognizing the expert assessment report prepared by the reference state. The authorized body of the reference state communicates the received conclusion to the applicant in electronic form via telecommunication channels and makes a decision on the possibility or impossibility of recognizing the expert assessment report prepared by the reference state. (paragraph 75 as amended by the Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
76. If, based on the results of the examination of the medicinal product, the authorized body of the state of recognition makes a positive decision on registration of the medicinal product, the authorized body of the state of recognition, no later than 5 working days:
a) issues to the applicant a registration certificate of the medicinal product in the form according to Appendix No. 17 to these Rules, as well as the approved summary of product characteristics, instructions for medical use, packaging layouts in the official language of the state of recognition, if there are relevant requirements in the legislation of the state of recognition;
b) approves the regulatory document on quality issued by the reference state;
c) places information about the medicinal product and its active pharmaceutical ingredients in the unified register with the attached approved summary of product characteristics, instructions for medical use, packaging layouts, and an agreed risk management plan (if necessary) in accordance with the procedure for forming and maintaining the unified register.
(as amended by the decision of the Council of the Eurasian Economic Commission of 30.01.2020 N 9)
77. The registration certificate of a medicinal product shall be issued by the authorized body of the state of recognition with the validity period of the registration certificate established by the reference state.
78. Registration of a medicinal product registered in accordance with these Rules in other Member States not specified in the initial application for registration as recognition states, as well as in states that joined the Union after registration of the medicinal product, shall be carried out in accordance with the mutual recognition procedure based on the consideration of the current version of the expert assessment report prepared by the expert organization of the reference state.
79. If it is impossible to recognize the expert assessment report prepared by the expert organization of the reference state, the authorized body (expert organization) of the recognition state shall send to the authorized body (expert organization) of the reference state, other recognition states participating in the registration procedure of the medicinal product, the applicant and the Expert Committee a conclusion on the impossibility of recognizing this expert assessment report, indicating the following reasons:
b) the applicant has not proven the efficacy of the medicinal product;
c) the quality of the medicinal product has not been confirmed;
d) the applicant has submitted inaccurate information;
e) based on the results of the appointed inspection during the registration period of the medicinal product, a non-compliance with the proper pharmaceutical practices of the Union is revealed, which is critical.
80. The Expert Committee, within a period not exceeding 60 calendar days from the date of receipt of the conclusion of the authorized body of the state of recognition on the impossibility of recognizing the expert assessment report prepared by the expert organization of the reference state, shall carry out the procedure for considering disagreements in accordance with the procedure established by the Commission.
81. The authorized body of the state of recognition shall refuse to register a medicinal product if, based on the results of the examination of the medicinal product and after the procedure for settling disagreements in the Expert Committee, it has decided that the data presented in the expert assessment report cannot be recognized as sufficient to confirm the quality and (or) effectiveness, and (or) a favorable benefit-risk ratio of the medicinal product, as well as if the applicant fails to submit within the prescribed period the documents and information requested by the authorized body (expert organization) of the state of recognition.
If, after the dispute resolution procedure has been carried out in the Expert Committee, it has made a unanimous decision that the data presented in the expert assessment report can be recognized as sufficient to confirm the quality and (or) effectiveness and (or) a positive benefit-risk ratio of the medicinal product, the authorized body of the state of recognition, no later than 15 working days from the date of receipt of the decision of the Expert Committee:
makes a decision to recognize the expert assessment report prepared by the expert organization of the reference state;
issues to the applicant a registration certificate for a medicinal product in the form according to Appendix N 17 to these Rules, as well as an approved general characteristic of the medicinal product, instructions for medical use, packaging layouts in the official language of the state of recognition, if there are relevant requirements in the legislation of the state of recognition;
coordinates the regulatory document on quality issued by the reference state;
posts information about the medicinal product and the active pharmaceutical substances included in its composition in a single register with the attached approved general characteristics of the medicinal product, instructions for medical use, packaging layouts, an agreed risk management plan (if necessary) in accordance with the procedure for the formation and maintenance of a single register.
82. In the event of disagreements between authorized bodies regarding the recognition of the expert assessment report and their consideration by the Expert Committee, the authorized body of the state of recognition that made a positive decision on the recognition of the expert assessment report prepared by the expert organization of the reference state issues a registration certificate, approved summary of product characteristics, instructions for medical use, packaging layouts and agrees on a risk management plan (if necessary), a regulatory document on quality until the decision of the Expert Committee. At the request of the applicant, the issuance of a registration certificate by the authorized body of such a recognition state may be suspended until the disagreements between the authorized bodies of other recognition states and the reference state are resolved.
The registration certificate issued in such cases is valid in the territory of this recognition state.
VI. Procedure for registration and examination
under the decentralized procedure in the reference state
and recognition states
83. For the purpose of registering a medicinal product under the decentralized procedure, the applicant shall select the reference state and recognition states.
84. The duration of the decentralized procedure for registration and examination of a medicinal product shall not exceed 140 working days from the date of filing an application for registration of a medicinal product until the date of issuance of a registration certificate in the reference state and shall not exceed 50 working days in the recognition states participating in the decentralized procedure.
(clause 84 as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
85. The registration procedure under the decentralized procedure consists of the following stages, carried out simultaneously:
a) registration and examination of the medicinal product in the reference state;
(subparagraph "a" as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
b) consideration of the expert assessment report prepared by the expert organization of the reference state, in the states of recognition.
(subparagraph "b" as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
86. For the purpose of registering a medicinal product, the applicant shall submit the following documents to the authorized body (expert organization) of the reference state:
an application for registration of a medicinal product on paper or in the form of an electronic document signed with an electronic signature, in the form in accordance with Appendix No. 2 to these Rules;
documents confirming payment of the fee (duty) for registration and examination of the medicinal product in the case and manner established by the legislation of the reference state, on paper or in the form of electronic documents;
registration dossier in accordance with Appendices No. 1 - 5 to these Rules on electronic media in the form of a set of electronic documents;
Samples of medicinal products, standard samples of active pharmaceutical substances and related impurities, specific reagents and other materials necessary for testing the samples specified in paragraph five of this clause shall be submitted in agreement with the expert organization.
Samples, specific reagents and other materials shall be submitted in quantities agreed upon with the expert organization, necessary for conducting no more than a 3-fold analysis in accordance with the requirements of the regulatory document on the quality of medicinal products within the time period agreed upon by the authorized body (expert organization) and not included in the general time period for examination and registration of the medicinal product.
In accordance with the requirements of the legislation of a member state, the documents specified in paragraphs 2 - 4 of this clause may be provided in the form of electronic document management without additional submission of relevant documents and information on paper, signed and (or) certified by the electronic signature of the applicant, in the cases provided for by these Rules.
87. In the case specified in paragraph eight of clause 86 of these Rules, laboratory tests are carried out in the quality control laboratory of the manufacturer of the medicinal product or in a contract laboratory used by the manufacturer, in the presence of representatives of the expert organization.
In the event that it is impossible to conduct laboratory tests in the manufacturer's quality control laboratories or contract laboratories used by the manufacturer (under conditions of a threat of occurrence, occurrence and elimination of an emergency situation and (or) in the event of a threat of the spread of diseases posing a danger to others, diseases and injuries resulting from exposure to unfavorable natural, chemical, biological, radiation factors, in which the presence of a representative of an expert organization is not possible, or in other circumstances (for example, related to the specifics of the production and quality control of a specific medicinal product related to the categories specified in paragraphs eight to twelve of clause 86 of these Rules)), in agreement with the authorized body (expert organization) of the reference state, the quality examination is carried out on the basis of the manufacturer's documentation (manufacturer's analysis protocols), including using remote interaction tools, including audio or video communication. (paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
88. Within 14 working days from the date of submission of documents to the authorized body (expert organization) of the reference state, the applicant shall submit to the authorized bodies (expert organizations) of the states of recognition:
an application on paper or in the form of an electronic document signed with an electronic signature, in the form in accordance with Appendix No. 2 to these Rules;
module 1 of the registration dossier on electronic media in the form of a set of electronic documents;
documents confirming payment of the fee (duty) for registration and examination in the case and manner established in accordance with the legislation of the state of recognition in the form of electronic documents.
If there are relevant requirements in the legislation of a member state, the summary of product characteristics, instructions for medical use and layouts of the packaging of the medicinal product shall be submitted in the official language of the state of recognition.
In accordance with the requirements of the legislation of a member state, the submission of the documents specified in paragraphs two through four of this clause may be carried out using electronic document management without additional submission of relevant documents and information on paper, signed and (or) certified by the electronic signature of the applicant, in the cases stipulated by these Rules.
89. Expertise of a medicinal product in the reference state under the decentralized registration procedure includes:
a) assessment of the completeness, completeness and correctness of the submitted documents of the registration dossier;
b) assessment of the documents and data submitted by the applicant in the registration dossier of the medicinal product for safety, efficacy and quality;
e) preparation of an expert report on the assessment of the medicinal product by the reference state.
90. Expertise of a medicinal product in the states of recognition under the decentralized registration procedure is carried out by reviewing:
a) the application, documents and data of the registration dossier;
b) the expert assessment report prepared by the reference state.
91. The authorized body (expert organization) of the reference state, within 10 working days from the date of filing the application for registration, shall assess the completeness, completeness and correctness of the submitted documents of the registration dossier before sending the materials of the registration dossier for examination. The applicant shall be given no more than 90 working days, not included in the period of registration and examination of the medicinal product, to submit missing materials of the registration dossier at the request of the authorized body (expert organization) of the reference state. (as amended by the Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
The request of the authorized body (expert organization) of the reference state must be transmitted to the applicant in electronic form via telecommunication channels and is considered received after 1 calendar day from the date of its sending.
The assessment of the applicant's response is carried out within a period not exceeding 5 working days from the date of receipt of the applicant's response.
The authorized body (expert organization) of the reference state, no later than 14 working days from the date of completion of the assessment of the completeness and completeness of the submitted materials of the registration dossier, provides access to the registration dossier of the medicinal product to the authorized bodies (expert organizations) of the recognition states participating in the procedure for decentralized registration of the medicinal product through the use of an integrated system or notifies of the rejection of the application in the manner established by paragraph 92 of these Rules.
The examination, which includes the stages specified in subparagraphs "b" - "d" of paragraph 89 of these Rules, shall be carried out within a period not exceeding 105 working days from the date of assessment of the completeness, completeness and correctness of execution of the documents submitted in the registration dossier, or from the date of receipt by the expert organization of the relevant assignment for the examination.
92. The authorized body (expert organization) of the reference state rejects the application for registration of a medicinal product in the event of failure to submit within the specified time period the documents and materials of the registration dossier based on the comments of the authorized body (expert organization) of the reference state and (or) failure to confirm payment of the fee (duty) for registration and examination of the medicinal product in the cases and in the manner established by the legislation of the reference state, and informs the applicant and the authorized bodies (expert organizations) of the states of recognition through the integrated system within no more than 5 working days from the date of the decision.
93. When registering and examining a medicinal product, the authorized body (expert organization) of the reference state has the right to send the applicant a written and/or electronic request for the submission of missing additional information, necessary explanations or clarifications concerning the submitted documents and data of the registration dossier (including proposals to amend the summary of product characteristics, instructions for medical use, layouts of the medicinal product packaging, regulatory document on quality or other documents of the registration dossier). (as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
94. The authorized body (expert organization) of the reference state, within 60 working days from the date of commencement of the examination, shall send to the authorized bodies (expert organizations) of the recognition states copies of reports with the wording of comments in the form in accordance with Appendices No. 6 - 8 to these Rules or a preliminary assessment report in the form in accordance with Appendix No. 11 to these Rules or copies of requests to the applicant.
The examination in the reference state shall be suspended until the day of receipt from all recognition states participating in the procedure of additional comments or information on agreement with the preliminary report or request of the reference state.
In the event of an examination of the registration dossier of a reproduced or hybrid medicinal product, the authorized body (expert organization) of the reference state, within 60 working days from the date of commencement of the examination, shall send to the authorized bodies (expert organizations) of the states of recognition copies of reports with the wording of comments and requests to the applicant in the form in accordance with Appendices No. 8 and 22 to these Rules or a preliminary assessment report in the form in accordance with Appendix No. 11 to these Rules, or copies of requests to the applicant.
If there are any additional comments addressed to the applicant, the authorized body (expert organization) of the state of recognition, no later than 30 working days from the date of receipt of the preliminary assessment report of the reference state, sends requests to the authorized body (expert organization) of the reference state, which, within 20 working days from the date of receipt of the last request from the state of recognition or information on consent with the preliminary report of the reference state, forms a single request and sends it to the applicant in accordance with paragraph 93 of these Rules.
From the date of sending comments to the applicant, further examination is suspended. After the first request, subsequent requests are allowed only if additional questions arise regarding the data provided by the applicant in response to the previous request.
95. The period for the applicant to submit a response to the specified request shall not exceed 90 working days. The procedures for sending requests and submitting responses shall be established by the requirements of the legislation of the member states.
If necessary, based on the relevant application of the applicant, the deadline for responding to a request may be extended by the authorized body of the reference state. The general deadline for responding to requests shall not exceed 180 working days.
96. The total period for the applicant to submit responses to requests from the authorized body (expert organization) during the registration procedure shall not exceed 180 working days.
The time for the applicant to submit documents at the request of the authorized body (expert organization) during the examination of a medicinal product shall not be included in the time frame for the examination and registration of the medicinal product.
97. After the applicant submits responses to requests to the authorized body (expert organization) of the reference state, the examination shall be resumed.
98. If the applicant fails to submit the documents and materials requested by the authorized body (expert organization) within the specified time frame, the examination and registration of the medicinal product shall be terminated. The authorized body (expert organization) shall notify the applicant and authorized bodies (expert organizations) of the decision taken within 14 working days from the date of adoption of such decision in written and/or electronic form.
99. The decision to initiate an unscheduled pharmaceutical inspection for compliance with good pharmaceutical practices of the Union may be taken by the authorized body (expert organization) of the reference state no later than 70 working days from the date of filing the application for registration.
In the event of a decision to initiate an unscheduled pharmaceutical inspection, the authorized body (expert organization) of the reference state sends the applicant a request on the need to organize an inspection with a detailed indication of the reasons for the initiation and references to the acts of the Union bodies.
An unscheduled pharmaceutical inspection with the submission of a report on the inspection carried out must be carried out within a period not exceeding the registration period of the medicinal product (within 180 working days from the date of the decision by the relevant authorized body to initiate the inspection).
In the event that pharmaceutical inspection is included in the inspection plan in accordance with paragraph 31 of these Rules, the preparation of the report shall be completed without taking into account the inspection results.
(paragraph 99 as amended by the Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
100. Interaction between authorized bodies (expert organizations) when sending requests to the applicant shall be carried out electronically in the form in accordance with Appendix N 18 to these Rules using the tools of the integrated system.
101. In the absence of additional comments from any recognition state regarding the examination of a medicinal product (submission of comments, results of consideration of the preliminary assessment report), this recognition state shall provide the reference state with information that it agrees with the conclusion (including comments, if applicable) contained in the preliminary assessment report in accordance with paragraph 94 of these Rules.
(paragraph 101 as amended by the Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
102. Written consultations between the authorized bodies (expert organizations) of the reference state and the states of recognition, if necessary, shall be carried out electronically using the tools of the integrated system.
103. In order to prepare the final expert assessment report, the expert organization of the reference state has the right, if necessary, to draw up expert reports on quality aspects, assessment of a new active substance contained in a medicinal product, assessment of the registration dossier for the active substance, preclinical, clinical aspects according to the forms provided for in Appendices No. 6 - 9, 11 and 22 to these Rules. If the expert organization has carried out the relevant tests, a laboratory test report shall be drawn up, which must contain the mandatory information provided for in Appendix No. 12 to these Rules. The form of the laboratory test protocol is established by the expert organization in accordance with the legislation of the Member States. (as amended by the decision of the Council of the Eurasian Economic Commission of 22.05.2023 N 60)
Based on the results of the examination of the registration dossier of a reproduced or hybrid medicinal product, the expert organization of the reference state, if necessary, draws up expert reports in the forms provided for in Appendices No. 8, 10 and 22 to these Rules, and, if necessary, draws up a laboratory test protocol containing the information provided for in Appendix No. 12 to these Rules. The form of the laboratory test protocol is established by the expert organization in accordance with the legislation of the Member States.
(as amended by the decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
Expert reports on quality aspects, preclinical, clinical aspects, the final expert report on the assessment are drawn up in accordance with the instructions provided in Appendices No. 13 - 15 and 23 to these Rules.
The final expert report on the assessment of the reference state is drawn up in the form according to Appendix No. 16 to these Rules.
104. No later than 90 working days from the date of filing an application for registration, the authorized body (expert organization) of the reference state may send to the recognition states and the applicant a draft final expert assessment report in the form in accordance with Appendix No. 16 to these Rules together with the applicant's responses to inquiries, a draft general characteristics of the medicinal product, a draft instruction for medical use (package insert), a draft packaging layout, a draft regulatory document on quality, and, if necessary, a draft risk management plan.
If the expert organization of the reference state has prepared a negative draft final expert assessment report and a decision has been made to refuse registration in accordance with paragraph 114 of these Rules, the examination and registration of the medicinal product shall be terminated. The authorized body (expert organization) shall notify the applicant of the decision taken within 14 working days from the date of such decision in written and (or) electronic form with the specified final expert assessment report attached.
If the expert organization of the reference state has prepared a positive draft of the final expert assessment report, it shall be reviewed by the authorized bodies (expert organizations) of the recognition states.
105. In the absence of comments from the authorized bodies (expert organizations) of the recognition states or after their withdrawal in accordance with paragraph 106 of these Rules, the authorized body (expert organization) of the reference state and the recognition states shall complete the procedure for examining the medicinal product within 10 working days (the 117th working day from the date of filing the application for registration).
106. If there are comments from the authorized bodies (expert organizations) of the states of recognition on the draft final expert assessment report, the draft summary of product characteristics, the draft instructions for medical use, the draft packaging layouts or the draft regulatory document on quality, the draft risk management plan (if necessary), the authorized bodies (expert organizations) of the states of recognition, if necessary, consult with the authorized body (expert organization) of the reference state or states of recognition in electronic form within 10 working days in the form in accordance with Appendix No. 18 to these Rules (the 110th working day from the date of filing the application for registration).
(as amended by Decisions of the Council of the Eurasian Economic Commission of 30.01.2020 N 9, of 17.03.2022 N 36)
107. In the event of any unresolved disagreements within the framework of mutual consultations, the authorized body (expert organization) of the state of recognition, within a period not exceeding 10 working days from the date of receipt of the final expert report on the assessment of the reference state, taking into account the conditions of paragraph 106 of these Rules, using the means of the integrated system, shall send a conclusion on the impossibility of recognizing the expert report on the assessment prepared by the expert organization of the reference state, with a justification for the reasons for the negative decision to the authorized body (expert organization) of the reference state and the states of recognition, as well as to the Expert Committee, including on paper.
108. The Expert Committee, within a period not exceeding 60 calendar days from the date of sending by the states of recognition of the conclusion on the impossibility of recognizing the positive expert report on the assessment prepared by the expert organization of the reference state, shall carry out the procedure for settling disagreements in accordance with the procedure established by the Commission. If the disagreements between the authorized bodies of the reference state and the recognition states regarding the recognition of the expert assessment report are resolved, they shall proceed to the completion of the examination procedure and the procedure for issuing final documents in accordance with paragraphs 105 and 109-113 of these Rules.
If the disagreements between the authorized bodies of the reference state and the recognition states regarding the recognition of the expert assessment report are not resolved, the authorized bodies of the reference state and the recognition states that have made a positive decision to recognize the expert assessment report shall proceed to the completion of the examination procedure and the procedure for issuing final documents in accordance with paragraphs 105 and 109-113 of these Rules. At the request of the applicant, the issuance of a registration certificate by the authorized bodies of such member states may be suspended until the disagreements between the authorized bodies of other recognition states and the reference state are resolved.
109. The authorized bodies (expert organizations) of the reference state and recognition states that have made a positive decision based on the results of the examination on the possibility of registering a medicinal product in accordance with paragraphs 105 and 108 of these Rules, shall proceed to the procedure for issuing final documents within a period of no more than 20 working days. (paragraph 109 as amended by the decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
110. No later than 20 working days from the date of the authorized body's positive decision on registration:
a) the authorized body of the reference state issues to the applicant a registration certificate for the medicinal product in the form in accordance with Appendix No. 17 to these Rules, the approved SmPC, instructions for medical use, quality regulatory document, packaging layouts, expert assessment report (if necessary, the applicant is issued the approved SmPC, instructions for medical use and packaging layouts of the medicinal product in the official language of the reference state), and, if necessary, an agreed risk management plan;
b) the authorized bodies of the states of recognition issue to the applicant registration certificates of the medicinal product in the form in accordance with Appendix No. 17 to these Rules, approved SmPC, instructions for medical use, packaging layouts in the official languages of the states of recognition (if there are relevant requirements in the legislation of the member states), and, if necessary, an agreed risk management plan.
111. The authorized bodies of the reference state and the states of recognition shall post information on the registration of the medicinal product and the active pharmaceutical substances included in it in a single register with the attached approved summary of product characteristics, instructions for medical use, packaging layouts, quality regulatory document, as well as the final expert assessment report compiled in accordance with Appendix No. 16 to these Rules, after the removal of confidential data and data on experts, a summary of the agreed risk management plan (if necessary) in accordance with the procedure for the formation and maintenance of a single register.
112. The registration certificate of the medicinal product shall be issued by the authorized body of the state of recognition with the validity period of the registration certificate established by the authorized body of the reference state.
113. The expert assessment report shall be updated by the reference state when new information emerges that is important for assessing the quality, safety or efficacy of the medicinal product as part of the procedure for amending the registration dossier.
114. The authorized body of the reference state shall refuse registration under the decentralized procedure in the following cases:
b) the efficacy of the medicinal product is not confirmed by the data submitted by the applicant;
e) the applicant has submitted inaccurate information;
f) the results of the appointed inspection during the registration of the medicinal product do not confirm compliance with good pharmaceutical practices of the Union;
g) the applicant has not submitted a response to the request sent in accordance with paragraph 94 of these Rules within the prescribed time limit.
115. The authorized body of the recognition state shall not recognize the expert assessment report prepared by the expert organization of the reference state, and thereby refuse registration under the decentralized procedure if, based on the results of the examination of the registration dossier of the medicinal product and after the dispute resolution procedure in the Expert Committee, it has decided that the data presented in the expert assessment report cannot be recognized as sufficient to confirm the quality and (or) effectiveness and (or) favorable benefit-risk ratio of the medicinal product.
VII. Establishment of Post-Registration Measures
(as amended by Decision of the Council of the Eurasian Economic Commission
of March 17, 2022, No. 36)
VII.I. Registration of a Medicinal Product with the Establishment of
Additional Requirements
116. The authorized body (expert organization) of the reference state may establish one or more of the following additional requirements for a medicinal product during its registration and related procedures:
inclusion of certain measures in the risk management system to ensure the safe use of the medicinal product;
conducting post-registration safety studies of the medicinal product;
establishing additional requirements for the registration of the medicinal product and the reporting of suspected adverse reactions;
conducting post-registration studies of the medicinal product's efficacy, and, if necessary, studies of various aspects of the medicinal product's efficacy that cannot be studied prior to marketing;
other conditions or restrictions for the safe and effective use of the medicinal product in accordance with the requirements of the Good Pharmacovigilance Practice Rules of the Eurasian Economic Union.
The established conditions and restrictions, as well as the deadlines for their fulfillment, are specified in the registration certificate, the unified register, the summary of product characteristics, and the instructions for medical use.
117. The authorized body (expert organization) of the reference state may revoke the registration certificate of a medicinal product if the registration certificate holder fails to comply with additional requirements established by the authorized body (expert organization) of the reference state with respect to the medicinal product during its registration and the implementation of registration-related procedures in accordance with paragraph 116 of these Rules.
118. A condition for registration and confirmation of registration (re-registration) of a medicinal product by the authorized body (expert organization) may be the obligation for the registration certificate holder to conduct:
a) post-registration safety studies of the medicinal product if there are concerns regarding the risks associated with the use of the medicinal product. If the risks relate to more than one medicinal product, the authorized bodies of Member States shall facilitate joint post-registration safety studies by registration certificate holders of such medicinal products;
b) post-registration efficacy studies of the medicinal product if the understanding of the disease or clinical methodology indicate that previous efficacy assessments require significant revision.
119. The Marketing Authorization Holder has the right to submit a written explanation on paper or as an electronic document signed with an electronic signature in response to the introduction of the obligation stipulated by paragraph 118 of these Rules, within 90 business days from the date of receipt of the corresponding notification from the authorized body (expert organization) regarding the introduction of the obligation.
120. Based on the written explanation submitted by the Marketing Authorization Holder for the medicinal product in accordance with paragraph 119 of these Rules, the authorized body (expert organization) must waive or confirm the obligation to conduct the studies specified in paragraph 118 of these Rules within 20 business days. If the obligation is confirmed, the terms of registration of the medicinal product (by including the relevant provisions) and the risk management systems must be amended.
VII.II. Registration of the medicinal product
in exceptional cases
120.1. In exceptional cases, after consultation with the applicant, registration may be granted subject to certain conditions, in particular those concerning the safety of the medicinal product, notification of authorized bodies of Member States of each incident related to its use, and the measures taken.
Registration may be granted if the applicant can demonstrate that they are unable to provide comprehensive data on the efficacy and safety of the medicinal product under normal conditions of use due to objective, verifiable reasons, which must correspond to one of the grounds set out in Section 11 of Appendix No. 1 to these Rules.
The continued presence of a medicinal product subject to the procedures described in this paragraph on the Union market shall be subject to a reassessment of such conditions, conducted annually by the authorized body (expert organization) of the reference Member State, with the preparation of an expert report on the assessment of the medicinal product.
The procedural details for the application of this paragraph are set out in Appendix No. 25 to these Rules.
VII.III. Conditional Registration of a Medicinal Product
120.2. If the need to address unmet medical needs for medicinal products intended for the treatment, prevention, or diagnosis of serious (severe) disabling or life-threatening diseases is justified, registration may be granted prior to the submission of comprehensive clinical data, as required by Section 5 of Appendix No. 1 to these Rules, at the time of filing the registration application, provided that the benefit of earlier market availability of the medicinal product in question outweighs the risk associated with the lack of comprehensive data. In cases of urgent need for such medicinal products, their registration may be granted without the provision of comprehensive preclinical or biopharmaceutical data.
120.3. For the purposes of this subsection, "unmet medical need" means a condition for which there is no approved, authorized, and recognized effective diagnostic, prophylactic, or therapeutic method in the Union, or for which the use of a medicinal product submitted for conditional registration would offer a significant advantage over a diagnostic, prophylactic, or therapeutic method already approved by competent authorities.
120.4. Conditional registration may only be granted if the benefit-risk ratio of the medicinal product is positive and if the applicant is likely to be able to provide comprehensive missing data on the safety, efficacy, and quality of the medicinal product after the conditional registration procedure.
120.5. Conditional registration must be accompanied by the fulfillment by the marketing authorization holder of special conditions. These special conditions and the deadline for their fulfillment as conditions of registration shall be established by the competent authority of the Member State and shall be subject to annual assessment by this competent authority.
120.6. Under the special conditions specified in paragraph 120.5, the holder of a marketing authorization issued in accordance with this section must be required to complete ongoing studies or conduct new studies to confirm a positive benefit-risk balance.
120.7. The SmPC and instructions for medical use (package insert) must clearly state that the medicinal product has been registered subject to the special conditions specified in paragraph 120.5 of these Rules.
120.8. Registration issued in accordance with this section is valid for one year and requires confirmation of registration (re-registration) with an annual reassessment of the benefit-risk balance.
120.9. If the special conditions specified in paragraph 120.5 of these Rules are met, the authorized body of the Member State may, upon application by the marketing authorization holder and after receiving a positive opinion from the expert organization, issue a marketing authorization valid for 5 years and subject to renewal in accordance with Section VIII of these Rules.
120.10. A description of the procedures, criteria, and requirements for registration in accordance with this Section is provided in Appendix No. 26 to these Rules.
VII.IV. Accelerated Expertise of Medicinal Products
120.11. 120.11. Accelerated expert evaluation of medicinal products applies to:
orphan medicinal products;
medicinal products intended exclusively for use by minors;
Medicinal products of particular importance to public health, in particular, in the absence of effective methods of providing medical care in Member States, as determined by the Expert Committee on Medicinal Products based on an application from the authorized body of the Member State in which the applicant has submitted an application regarding the particular importance of the medicinal product prior to the submission of the registration application.
The registration and expert review period for a medicinal product in the reference state must not exceed 100 working days from the date of submission of the application for registration of the medicinal product to the date of issuance of the registration certificate.
The procedure for reviewing an application for accelerated expert review of a medicinal product is provided in Appendix No. 27 to these Rules.
VII.V. General Provisions
120.12. The authorized body (expert organization) of the reference state shall act in accordance with the provisions of Section X of these Rules in the event of the marketing authorization holder's failure to comply with additional requirements or obligations established by the authorized body (expert organization) of the reference state with respect to the medicinal product in question during its registration and the implementation of registration-related procedures, in accordance with the provisions of this section.
VIII. Confirmation of Registration (Re-registration)
of a Medicinal Product
121. The date of confirmation of registration (re-registration) of a medicinal product for all Member States in which the medicinal product is registered is determined by the date of registration of the medicinal product in the reference Member State under the mutual recognition procedure or decentralized procedure.
For medicinal products that are not recognized as orphan products in the territory of any Member State in accordance with its legislation, the date of confirmation of registration (re-registration) is determined by the date of registration of the medicinal product in that Member State under the mutual recognition procedure.
122. Confirmation of registration (re-registration) is carried out based on a reassessment of the benefit-risk ratio, conducted by the authorized body (expert organization) of the reference Member State, with the preparation of an expert report on the assessment of the medicinal product.
The assessment of a medicinal product during registration confirmation (re-registration) in the Member States is carried out by:
reviewing the application, documents, and data from the registration dossier;
reviewing the expert assessment report prepared by the reference Member State.
During the registration confirmation (re-registration) procedure for a medicinal product, its circulation within the Union is permitted.
123. The applicant shall submit applications for registration confirmation (re-registration) to all Member States in which the medicinal product is registered.
The applicant has the right to withdraw their application at any time before the completion of the registration confirmation (re-registration) procedure for a medicinal product by notifying in writing the authorized body of the Member State in which the application is being considered.
(paragraph introduced by Decision No. 14 of the Council of the Eurasian Economic Commission dated 05.03.2021)
If an application is withdrawn, the authorized body of the Member State in which the application is being considered shall cease its consideration on the merits and return the original documents and/or information submitted with the application to the applicant. (paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 05.03.2021 No. 14)
124. If the holder of a registration certificate for a medicinal product fails to submit an application for confirmation of registration (re-registration) before the expiration of the registration certificate, the registration certificate for the medicinal product shall be deemed invalid.
125. The procedure for confirmation of registration (re-registration) shall not exceed 80 working days from the date of submission of the application for confirmation of registration (re-registration) in the reference state and 50 working days in each of the recognition states participating in the procedure.
(paragraph 125 as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
126. An application for confirmation of registration (re-registration) of a medicinal product shall be submitted no earlier than 140 working days before the expiration of the registration certificate for the medicinal product in the reference state, but no later than the expiration date of the registration certificate.
(as amended by Decision of the Council of the Eurasian Economic Commission of 17.03.2022 No. 36)
127. In order to confirm the registration (re-registration) of a medicinal product, the applicant shall submit the following documents to the authorized body (expert organization) of the reference state:
a) an application for registration (re-registration) of a medicinal product on paper or as an electronic document signed with an electronic signature, in the form in accordance with Appendix No. 2 to these Rules;
(subparagraph "a" as amended by Decision of the Council of the Eurasian Economic Commission of 17.03.2022 No. 36)
b) documents confirming payment of the fee (duty) for confirmation of registration (re-registration) and examination in the case and according to the procedure established in accordance with the legislation of the reference state, on paper or in the form of an electronic document;
(as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
c) Modules 1 and 2 of the registration dossier, prepared in accordance with Appendices No. 1–5 to these Rules, on electronic media; If an application is submitted to confirm the registration of a medicinal product based on documents from a registration dossier brought into compliance with the requirements of the Union and subject to the post-registration period obligations stipulated by Section VII of these Rules, at the request of the authorized body (expert organization), the applicant may additionally submit documents from Modules 1 and 3, as well as Modules 4 and 5 (if necessary), that were not previously submitted in the registration dossier;
(as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
d) In accordance with the requirements of the legislation of a Member State, the submission of the documents specified in subparagraphs "a" - "c" of this paragraph may be carried out using electronic document management without the additional submission of the relevant documents and information on paper, signed and/or certified by the electronic signature of the applicant, in cases stipulated by these Rules.
(subparagraph "d" introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
128. The authorized body (expert organization) of the reference state, within a period not exceeding 5 working days from the date of submission by the applicant of the documents specified in paragraph 127 of these Rules, shall provide the authorized bodies (expert organizations) of the recognition states with access to the registration dossier of the medicinal product using the tools of the integrated system.
The authorized bodies (expert organizations) of the recognition states shall receive the registration dossier of the medicinal product using the tools of the integrated system.
129. No later than 14 working days from the date of submission of the application for confirmation of registration (re-registration) in the reference state, the applicant shall submit the following documents to the authorized body (expert organization) of each recognition state:
a) an application on paper or in the form of an electronic document signed with an electronic signature, in the established form in accordance with Appendix No. 2 to these Rules;
(subparagraph "a" as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
b) documents confirming payment of the fee (duty) for confirmation of registration (re-registration) and examination in the case and according to the procedure established in accordance with the legislation of the recognition states, on paper or in the form of an electronic document;
c) Module 1 of the registration dossier, on electronic media in the form of electronic documents;
d) if the legislation of a Member State provides for the relevant requirements, the summary of product characteristics, instructions for medical use, and packaging layouts of the medicinal product shall also be submitted in the official language of the State of recognition;
e) in accordance with the requirements of the legislation of a Member State, the submission of the documents specified in subparagraphs "a" - "d" of this paragraph may be carried out using electronic document management without the additional submission of relevant documents and information on paper, signed and/or certified by the electronic signature of the applicant, in cases stipulated by these Rules.
(Subparagraph "d" introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
130. The authorized body (expert organization) of the reference state, within 10 business days from the date of filing an application for confirmation of registration (re-registration), shall assess the completeness, completeness, and correctness of the submitted registration dossier documents before sending the registration dossier materials for expert review. The applicant shall be given no more than 90 business days, not included in the period for confirmation of registration (re-registration) and expert review of the medicinal product, to submit missing registration dossier materials based on the comments of the authorized body (expert organization) of the reference state.
The request from the authorized body (expert organization) to the applicant must be transmitted electronically via telecommunications channels and is considered received after 1 day from the date of its submission.
(paragraph introduced by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
The applicant's response will be assessed within 5 business days from the date of receipt of the applicant's response (paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36)
131. The authorized body (expert organization) of the reference state shall reject an application for confirmation of registration (re-registration) of a medicinal product in cases of failure to submit missing materials from the registration dossier in response to previously submitted comments within the prescribed timeframe and (or) failure to confirm payment of the fee (duty) for confirmation of registration (re-registration) and examination of the medicinal product in the cases and in the manner established by the legislation of the reference state, as well as in connection with a violation of the deadline for filing an application for confirmation of registration (re-registration) specified in paragraph 126 of these Rules, and shall notify the authorized bodies (expert organizations) of the states of recognition and the applicant thereof in writing and (or) electronically.
132. Within 30 working days of the commencement of the subject matter examination or receipt of the relevant assignment to conduct the examination, the authorized body (expert organization) of the reference State shall prepare a preliminary expert report containing comments in the form specified in Appendix No. 11 to these Rules, or a draft request to the applicant, and shall send it using the integrated system to the authorized bodies (expert organizations) of the recognition States.
The examination in the reference State shall be suspended until the day additional comments or information on agreement with the preliminary report or request of the reference State are received from all recognition States participating in the procedure. (paragraph 132 as amended by Decision N 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
133. In the event of disagreement with the conclusions presented in the preliminary expert assessment report of the reference state regarding the benefit-risk ratio of the medicinal product, or in the presence of a request from the authorized bodies (expert organizations) of the states of recognition to amend the summary of product characteristics, instructions for medical use, packaging layouts of the medicinal product or other documents of the registration dossier, the authorized body (expert organization) of the state of recognition, no later than 20 working days from the date of receipt by the authorized body (expert organization) of the reference state of the preliminary expert assessment report, using the means of the integrated system, sends a corresponding substantiated request to the authorized body (expert organization) of the reference state.
(as amended by Decision N 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
134. During the consideration by the authorized bodies (expert organizations) of the recognition states of the preliminary expert assessment report prepared by the expert organization of the reference state, the consideration by the authorized bodies (expert organizations) of the reference state of requests from the authorized bodies (expert organizations) of the recognition states and the consideration by the authorized bodies (expert organizations) of the recognition states of the final expert assessment report prepared by the expert organization of the reference state, consultations may be carried out between the authorized bodies (expert organizations) of the member states participating in the procedure, using the means of the integrated system within the time period specified in paragraph 133 of these Rules, in the form in accordance with Appendix No. 18 to these Rules in order to agree on the final expert assessment report to be prepared by the expert organization of the reference state based on the results of the procedure.
(clause 134 as amended by the decision of the Council of the Eurasian Economic Commission of 17.03.2022 N 36)
135. During the registration confirmation (re-registration) and expert examination of a medicinal product, the authorized body (expert organization) of the reference state may, no later than 10 business days from the date of receipt of additional comments from the authorized bodies (expert organizations) of the states of recognition or information on agreement with the preliminary expert report prepared by the reference state, send the applicant, in written and/or electronic form, a consolidated request for missing additional information, necessary clarifications, or clarifications regarding the submitted documents and data in the registration dossier (including proposals for amendments to the general characteristics of the medicinal product, instructions for medical use, medicinal product packaging layouts, quality regulatory documents, or other documents in the registration dossier).
(as amended by Decision of the Council of the Eurasian Economic Commission dated March 17, 2022, No. 36)
The applicant's deadline for submitting a response to this request shall not exceed 90 business days. The time required for the applicant to submit documents requested by the authorized body (expert organization) of the reference state during the confirmation (re-registration) and expert examination of a medicinal product is not included in the timeframe for the confirmation (re-registration) and expert examination of the medicinal product.
(as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
The expert organization of the reference state shall, as part of the expert examination of the medicinal product, review the applicant's response and prepare a final expert report in accordance with Appendix No. 16 to these Rules within no more than 20 business days.
If the applicant fails to submit the requested documents and data within the specified timeframe, the expert examination and confirmation of registration (re-registration) of the medicinal product shall be terminated. The authorized body (expert organization) of the reference state shall notify the authorized bodies (expert organizations) of the recognizing states and the applicant of the decision taken within 14 working days from the date of such decision in written and/or electronic form.
136. Based on the results of the medicinal product examination, the authorized body (expert organization) of the reference state shall prepare and approve a final expert assessment report in accordance with the form set out in Appendix No. 16 to these Rules. This report shall be sent, using the integrated system, to the authorized bodies (expert organizations) of all recognizing states participating in the procedure for confirming the registration (re-registration) of the medicinal product. The expert assessment report shall be prepared in accordance with Appendices No. 13-15 and 23 to these Rules.
(Clause 136 as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36)
137. The authorized body (expert organization) of the state of recognition, based on the results of the examination of the medicinal product, within a period not exceeding 20 working days from the date of receipt of the final expert report on the assessment of the reference state, shall prepare, approve, and, using the tools of the integrated system, send to the authorized body (expert organization) of the reference state a conclusion on the possibility or impossibility of recognizing the expert report on the assessment of the reference state in the form in accordance with Appendix No. 18 to these Rules.
138. Proposals from authorized bodies (expert organizations) of the reference state and recognition states to amend the summary of product characteristics, instructions for medical use, packaging layouts of the medicinal product, or other registration dossier documents, if the applicant agrees with them, cannot serve as grounds for refusing to confirm the registration (re-registration) of the medicinal product.
139. If, based on the results of the expert assessment of the medicinal product in the reference state, it is established that the benefit-risk ratio is assessed positively and the registration dossier, taking into account the amendments made, meets the established requirements:
a) the authorized body (expert organization) of the reference state, within a period of no more than 10 working days from the date of receipt of the expert assessment report, issues to the applicant an indefinite registration certificate for the medicinal product in the form in accordance with Appendix No. 17 to these Rules, the approved SmPC, instructions for medical use, a regulatory document on quality, packaging layouts of the medicinal product, the expert assessment report (as well as the approved SmPC, instructions for medical use, and packaging layouts of the medicinal product in the official language of the reference state, if this requirement is present in the legislation of the Member State) and, if necessary, an agreed risk management plan;
(as amended by decisions of the Council of the Eurasian Economic Commission of 30.01.2020 No. 9, of 17.03.2022 No. 36)
b) the authorized bodies of the states of recognition, within a period of no more than 10 working days from the date of receipt of the expert assessment report, issue to the applicant perpetual registration certificates for the medicinal product in the form in accordance with Appendix No. 17 to these Rules, as well as, if necessary, approved summary of product characteristics, instructions for medical use, and packaging layouts for the medicinal product in the official language of the states of recognition, if there are relevant requirements in the legislation of these states;
c) the authorized bodies of the member states participating in the registration confirmation (re-registration) procedure, within no more than 10 working days from the date of receipt of the expert assessment report, post the necessary information about the medicinal product and its active pharmaceutical ingredients in the unified register, along with a summary of the agreed risk management plan (if necessary).
(as amended by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No 36)
140. If it is impossible to recognize the expert assessment report prepared by the expert organization of the reference state, the authorized body (expert organization) of the recognizing state shall send in electronic and/or paper form a conclusion on the impossibility of recognizing this expert report, along with the justification for the decision taken by the authorized body (expert organization) of the reference state and the recognizing states participating in the procedure for confirming the registration (re-registration) of the medicinal product, to the applicant and the Expert Committee within the time period specified in paragraph 137 of these Rules.
141. The Expert Committee, within a period not exceeding 60 calendar days from the date of receipt of the conclusion of the authorized body of the recognizing state on the impossibility of recognizing the expert assessment report of the reference state, shall carry out the procedure for considering the disagreements in accordance with the procedure established by the Commission.
The authorized body of the Member State of recognition shall refuse to confirm the registration (re-registration) of a medicinal product if, following the examination of the medicinal product and the dispute resolution procedure conducted by the Expert Committee, it is determined that the expert assessment report prepared by the expert organization of the reference state cannot be recognized by the authorized body (expert organization) of the Member State of recognition for the reasons specified in paragraph 146 of these Rules.
142. When confirming the registration (re-registration) of a medicinal product, the authorized body (expert organization) of the Member State shall analyze the compliance of the registration certificate holder with the conditions related to the registration of the medicinal product set forth in Section VII of these Rules, if these obligations were applied to this registration certificate holder. If new data on the safety and efficacy of the medicinal product is identified, the authorized body may amend the registration conditions and/or introduce new conditions.
During the assessment of the registration dossier of a medicinal product in the process of confirming the registration (re-registration) of a medicinal product by the authorized bodies (expert organizations) of the Member States, the fulfillment by the holder of the registration certificate of the obligations to maintain information on the medicinal product up-to-date in the light of current scientific knowledge is checked, taking into account the conclusions based on the results of assessments and recommendations of the authorized body (expert organization).
143. If the authorized body (expert organization) of the reference state finds during the examination of the medicinal product during confirmation of its registration (re-registration) that the obligations specified in paragraph 142 of these Rules have not been fulfilled for objective reasons and amendments to the registration dossier of the medicinal product are required, then after the reference state has adopted a positive conclusion on confirmation of registration (re-registration) of the medicinal product, the regulatory document on quality, the summary of product characteristics, instructions for medical use and the risk management plan (if applicable) should be updated by initiating the relevant procedure for amending the registration dossier by the registration certificate holder within a period not exceeding 120 working days from the date of sending a request by the authorized body (expert organization) of the reference state on the need to amend the registration dossier.
144. The authorized body (expert organization) of the reference state may allow amendments to the registration dossier of a Type I medicinal product in accordance with Appendix No. 19 to these Rules when confirming the registration (re-registration) of the medicinal product, in order to avoid the need to submit an additional application for amendments to the registration dossier.
145. Based on pharmacovigilance data, as well as taking into account the circumstances specified in paragraphs 143 and 144 of these Rules, when confirming the registration (re-registration) of a medicinal product, the authorized body of the reference state, following the results of an expert examination of the medicinal product, may decide to issue a registration certificate with a validity period of 5 years, with the need for subsequent confirmation of registration (re-registration) upon expiration of the specified validity period of the registration certificate.
146. The grounds for refusal to confirm (re-register) a medicinal product by the authorized body of the reference state and for the authorized body of the state to recognize the expert assessment report are:
a) the persistence of the following serious health risks associated with the use of the medicinal product at the time of confirmation of registration (re-registration):
a proven unfavorable benefit-risk ratio or a demonstrated lack of therapeutic efficacy when the conditions of use of the medicinal product described in the approved SmPC are met;
facts established based on pharmacovigilance data indicating an unfavorable benefit-risk ratio (including a significant excess of the reporting frequency of certain adverse reactions compared to the data specified in the approved SmPC);
a discrepancy between the qualitative and quantitative composition of the medicinal product and the declared one, or repeated discrepancies in the quality of the medicinal product during its circulation on the Union market with the declared one at the time of its registration;
inaccurate or out-of-date data in the registration dossier accompanying the application for confirmation of registration (re-registration);
b) failure by the registration certificate holder to address concerns or to respond within the allotted time to questions that arose during the examination of the medicinal product;
c) failure by the registration certificate holder to fulfill pharmacovigilance obligations or obligations under the conditional registration procedure.
IX. Amendments to the registration dossier
of a registered medicinal product
147. Following registration of a medicinal product in the reference state, the marketing authorization holder must make any amendments to the registration dossier of the registered medicinal product (hereinafter referred to as "amendments") that may be necessary to ensure that the production and quality control of the medicinal product comply with current generally accepted scientific methods.
Such amendments must be approved by the authorized body of the Member State in which the medicinal product is registered (or this authorized body must be notified of them in accordance with the approved procedure). Amendments to the registration dossier of a medicinal product must be initiated by the applicant through the authorized body (expert organization) of the same reference state that registered the medicinal product.
Amendments to the registration dossier of a medicinal product registered under the mutual recognition procedure in the reference state are permitted prior to the commencement of the recognition procedure in the designated states in accordance with paragraph 66.1 of these Rules.
148. The Marketing Authorization Holder is obliged to notify the authorized body of the Member State of any new information that may require amendments to the documents and data contained in the marketing authorization for the medicinal product.
The Marketing Authorization Holder must promptly notify the authorized body of the Member State of any prohibition or restriction on the medical use of the medicinal product imposed by the authorized bodies of any state where the medicinal product is marketed, and of all other information that may impact the benefit-risk assessment of the medicinal product. The information must include both positive and negative results of clinical trials or other studies (including those containing evidence obtained based on real-world clinical practice data) for all indications and in all patient groups, regardless of their inclusion in the registration dossier, as well as data on the use of the medicinal product if such use does not comply with the registration conditions.
149. The Marketing Authorization Holder must ensure that the information on the medicinal product complies with current scientifically based medical standards, including expert opinions and recommendations of authorized bodies in the field of medicinal product circulation in other countries.
150. To ensure continuous assessment of the benefit-risk balance of a registered medicinal product, the authorized body of a Member State (including at the request of an expert organization) has the right to request from the Marketing Authorization Holder for the registered medicinal product data confirming that the benefit-risk balance of the registered medicinal product remains favorable. The Marketing Authorization Holder (MAH) is obligated to submit the necessary materials to this authorized body (expert organization) as soon as possible, but no later than 20 business days from the date of receipt of the relevant request.
The authorized body of a member state (including at the request of an expert organization) has the right to request a copy of the pharmacovigilance system master file from the MAH for a registered medicinal product. The MAH must submit the corresponding copy within 10 business days from the date of receipt of this request.
151. Amendments to the registration dossier of a registered medicinal product must not alter the positive benefit-risk balance of the medicinal product.152. Amendments to the registration dossier of a registered medicinal product are made in accordance with the classification of amendments made to the registration dossier of a registered medicinal product and the rules for making them in accordance with Appendices No. 19 and 20 to these Rules. The review of amendments to the registration dossier of medicinal products is carried out in accordance with Appendix No. 20 to these Rules.
The applicant has the right to withdraw their application at any time before the end of the procedure for amending the registration dossier of a registered medicinal product by notifying the authorized body of the Member State in which the application is being reviewed of the withdrawal in writing.
If an application is withdrawn, the authorized body of the Member State where the application is being considered shall cease its consideration on the merits and return the original documents and/or information submitted with the application to the applicant.
An expert report on the assessment of changes to the registration dossier of a medicinal product shall be prepared by the expert organization of the reference State based on the results of this assessment in accordance with Appendix No. 21 to these Rules in the event of Type I changes, with the exception of administrative changes.
(paragraph introduced by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
To make a decision on the possibility of introducing an administrative change to the registration dossier, the applicant must, along with the application for this change, submit, in hard copy or electronic form, confirmation from the authorized body (expert organization) of the reference state that the corresponding version (sequence) of the registration dossier is valid and attached to the electronic registration dossier.
Following the results of the expert organization's review of Type II changes in the reference state, if the requested change is approved, the expert assessment report must be updated in accordance with Appendix No. 16 to these Rules.
Following the review of Type II amendments by the expert organization of the reference state, in the event of disapproval of the proposed amendment, information containing the experts' reasoned position is sent to the authorized body.
In order to update information on the medicinal product based on the review of Type II amendments made to the registration dossier of the medicinal product, brought into compliance with the requirements of the Union, the expert organization of the reference state may establish one or more additional requirements in the final expert report on the assessment of the medicinal product in accordance with Clause 116 of these Rules.
(paragraph introduced by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
153. If the authorized body (expert organization) approves amendments to the registration dossier of a medicinal product, the applicant shall be issued a new registration certificate under the previous number for the remaining validity period of the medicinal product registration if the amendments affect the information and data of the registration certificate. A record of each amendment made shall be made in the unified register, indicating its details and the section of the dossier to which the amendment was made.
154. If amendments to the registration dossier of a medicinal product occur 90 calendar days or less before the expiration of the registration certificate, amendments may be made during the examination of the medicinal product upon confirmation of its registration (re-registration).
155. When making changes to the registration dossier of a medicinal product registered under the mutual recognition procedure, the applicant must submit to the authorized body (expert organization) of the reference state a list of the dates of filing the relevant applications for amendments to the registration dossier of the medicinal product in the recognition states and documents confirming payment of the fee (duty) for making changes to the registration dossier of the medicinal product (and its expert examination, if necessary) in the cases and according to the procedure established by the legislation of the recognition states, indicating the procedure numbers for making changes in accordance with Appendix No. 19 to these Rules that were carried out in the recognition states.
When changing the registration certificate holder in all or several (one) Member States that have registered the medicinal product, the applicant shall submit to the authorized body (expert organization) of these Member States an application for amendments in accordance with Appendix No. 2 to these Rules and the relevant documents from Module 1 of the registration dossier.
In accordance with the requirements of the legislation of a Member State, the documents specified in this paragraph may be submitted using electronic document management without the additional submission of relevant documents and information on paper, signed and/or certified by the applicant's electronic signature, in cases stipulated by these Rules.
156. When conducting an expert examination of a medicinal product and introducing changes to the registration dossier of the medicinal product, the expert organization and the authorized body of the reference state have the right to send the applicant a written and/or electronic request for missing additional information, necessary explanations, or clarifications concerning the submitted documents and data in the registration dossier (including proposals for amendments to the summary of product characteristics, instructions for medical use, medicinal product packaging layouts, quality regulatory document, or other documents of the registration dossier).
The applicant's response to this request must be submitted within 90 business days. The time required for the applicant to submit documents requested by the authorized body or expert organization during the amendment and review process for the medicinal product is not included in the review and amendment process.
If the applicant fails to submit the requested documents and data within the specified timeframe, the review and amendment process for the medicinal product's registration dossier will be terminated. The authorized body (expert organization) will notify the applicant of the decision made within 14 business days of the date of such decision in written and/or electronic form.
157. When amendments are made to the registration dossier in terms of amendments to the instructions for medical use of a medicinal product, the authorized body shall approve and issue new instructions for medical use to the applicant.
158. In the event of confirmation of registration (re-registration) of a medicinal product or amendments being made to the registration dossier, manufacture of the medicinal product is permitted for 180 calendar days from the date of confirmation of registration (re-registration) or amendments being made to the registration dossier in accordance with the information contained in the registration dossier documents of the medicinal product, until the date of confirmation of registration (re-registration) or amendments being made, with the exception of:
urgent safety restrictions introduced by the registration certificate holder or the authorized body, in accordance with paragraph 4.1.4 of Appendix No. 19 to these Rules;
A decision by a Member State's authorized body on the impossibility of further production of a medicinal product in accordance with previously approved (agreed upon) documents and information in the registration dossier.
The import, simultaneous sale, and medical use of a medicinal product are permitted until the expiration of its expiration date (shelf life), consistent with the documents and information in the registration dossier before and after amendments, provided this does not conflict with the requirements of the Union's good pharmacovigilance practice rules approved by the Commission.
(Clause 158 as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
X. Suspension, revocation (cancellation) of a registration
certificate, or restriction of use, or amendment of the terms of a registration
certificate
159. The authorized body shall suspend the registration certificate or restrict the use of a medicinal product in the following cases:
there are documented facts of discrepancy between the qualitative and quantitative composition of released batches of the medicinal product and the declared composition;
the medicinal product is dangerous (causes serious or irreparable harm to human health (the justification for the seriousness or irreparability of the harm to health must be supported by an expert opinion of the authorized body (expert organization) with reference to documentary evidence));
an unfavorable benefit-risk ratio has been proven or documented insufficient therapeutic efficacy of the medicinal product has been identified under the conditions of its use described in the approved SmPC;
a positive benefit-risk ratio has not been confirmed during the reassessment of the benefit-risk ratio, conducted annually by the authorized body (expert organization) in accordance with paragraph 117 of these Rules;
the registration dossier contains inaccurate documents and data;
The manufacturer failed to correct the nonconformities in production and control methods identified during the inspection, as stated in the registration dossier, within the timeframes agreed upon with the authorized body (expert organization);
The registration certificate holder has failed to fulfill its pharmacovigilance obligations;
The registration certificate holder has failed to fulfill its obligations in accordance with paragraphs 116 and 118 of these Rules, as established by the authorized body (expert organization).
In cases of suspension of the registration certificate, as specified in paragraphs two through four of this paragraph, the authorized body (expert organization) shall send the registration certificate holder a request to amend the relevant documents of the registration dossier, specifying the deadline for compliance.
160. The decision to revoke (cancel) the registration certificate of a medicinal product and to exclude the medicinal product from the Unified Register shall be made by the authorized body (expert organization) in the event of:
a) the filing by the holder of the registration certificate of the medicinal product or a legal entity authorized by the holder of the registration certificate of the medicinal product of an application to cancel the registration of the medicinal product;
b) the failure of the holder of the registration certificate of the medicinal product to comply with the requirements of the authorized body (expert organization) specified in paragraphs two through nine of clause 159 of these Rules;
c) the submission by the authorized body (expert organization) of a conclusion on the failure of the holder of the registration certificate to eliminate the nonconformities in production and control methods identified during the inspection, as declared in the registration dossier, within the prescribed timeframe.
161. In the cases specified in paragraphs 159 and 160 of these Rules, the authorized bodies of Member States shall take appropriate measures (actions) to ensure that the supply of the medicinal product is stopped and that the medicinal product is withdrawn from circulation.
162. In exceptional cases, for a limited period of time, the authorized body may permit the circulation of a medicinal product whose sale is prohibited or which has been withdrawn from the market, exclusively for its controlled use in patients who used this medicinal product for vital indications.
(as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17 March 2022)
XI. Conditions for the circulation of medicinal products in Member States
163. Medicinal products registered in accordance with these Rules and included in the unified register shall be sold within the Union within the Member States in which they are registered.
164. Medicinal products registered in Member States that have not been brought into compliance with Union requirements shall be sold after December 31, 2025, within the territory of that Member State until the expiration of their expiration date (shelf life).
165. Medicinal products whose registration certificates have expired may be sold in Member States until the expiration of their expiration date (shelf life), if they were manufactured before the expiration of their registration certificate.
XII. Obligations of Marketing Authorization Holders
166. The Marketing Authorization Holder shall promptly provide complete information upon request from the authorized body of any Member State in which the medicinal product is registered.
167. The Marketing Authorization Holder shall notify the authorized body of the Member State of the planned cessation of production or sale of the medicinal product on the Union market, stating the reasons, at least 60 calendar days prior to such cessation of production or sale.
168. In the event of a change of Marketing Authorization Holder in the Reference State or the State of Recognition, the new Marketing Authorization Holder shall provide documentary justification for such change (transfer) and confirmation of the ability to interact with Marketing Authorization Holders in other Member States to ensure the proper performance of all Marketing Authorization Holder duties.
169. During the validity period of a registration certificate for a medicinal product issued for an unlimited period, the benefit-risk ratio shall be periodically assessed based on pharmacovigilance, as well as to update information on the medicinal product (taking into account the conclusions of the assessment results and recommendations of the authorized body (expert organization) of the Member State or the Expert Committee).
(Clause 169 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
XIII. Procedure for bringing the registration dossier of a medicinal product registered under the rules of a Member State into compliance with the requirements of the Union
(as amended by Decision No. 36 of the Council of the Eurasian Economic Commission of 17 March 2022)
170. Registration dossiers of medicinal products registered in Member States must be brought into compliance with Union requirements by December 31, 2025, in accordance with this procedure.
171. Bringing a registration dossier into compliance with Union requirements includes submitting the registration dossier documents for the registered medicinal product in the format of a common technical document in accordance with Appendix No. 1 to these Rules.
When initiating the procedure for bringing the medicinal product into compliance with the requirements of the Union, the applicant shall submit to the authorized body (expert organization) of the reference state a written confirmation that the documents and data contained in the submitted updated registration dossier in the format of a common technical document correspond in their content to the data of the registration dossier of the medicinal product registered in the Member State(s) and do not contain changes to the registration dossier that affect the quality, efficacy, safety or benefit-risk ratio of the medicinal product, in the form of a document "For the attention of experts" provided for in paragraph 1.0 of Appendix No. 1 to these Rules.
(as amended by decisions of the Council of the Eurasian Economic Commission of 23.04.2021 No. 34, of 17.03.2022 No. 36, of 20.10.2023 No. 114)
Bringing the registration dossier into line with the requirements of the Union in terms of bringing draft packaging layouts, general characteristics of the medicinal product, instructions for medical use (package insert), and regulatory documents on quality into line with the acts of the Commission is not considered a change requiring a reassessment of the benefit-risk ratio, and is not a change affecting the conformity of the content of the registration dossier data being brought into line with the requirements of the Union with the content of the registration dossier data of the registered medicinal product.
(paragraph introduced by Decision No. 34 of the Council of the Eurasian Economic Commission dated 23.04.2021)
In accordance with the requirements of the legislation of a Member State, the documents specified in the first and second paragraphs of this clause may be submitted using electronic document management without the additional submission of relevant documents and information on paper, signed and/or certified by the applicant's electronic signature, in cases stipulated by these Rules.
172. When bringing the medicinal product into compliance with Union requirements, the applicant may simultaneously amend the registration dossier of the registered medicinal product. In this case, the procedure for making such amendments and assessing the dossier for compliance with acts within the law of the Union shall be carried out in accordance with Appendices No. 19 and 20 to these Rules.
The list of amendments that may be introduced by the applicant concurrently with the harmonisation with Union requirements, in accordance with this paragraph, is specified in Appendix VI to Appendix No. 19 to these Rules and contains unclassified Type IB amendments. The authorized body (expert organization) of the reference state has the right to review the amendments introduced concurrently within the timeframes stipulated for the harmonisation with Union requirements procedure.
Upon completion of the harmonisation procedure for the registration dossier in the reference state with Union requirements, the applicant may make procedural amendments in accordance with Appendices No. 19 and 20 to these Rules prior to the initiation of the mutual recognition procedure in the state(s) of recognition (prior to the submission of the relevant application to the authorized body (expert organization) of the recognition states).
173. The procedure for bringing a medicinal product's registration dossier into compliance with Union law shall not exceed 70 working days from the date of submission of the relevant application for bringing the registration dossier into compliance with Union law.
174. If a medicinal product is registered in more than one Member State, the applicant shall select one of them as the reference state, to whose authorized body (expert organization) the applicant shall submit the application, documents, and registration dossier data in accordance with paragraph 175 of these Rules. If the authorized body (expert organization) of the reference state makes a positive decision to bring the medicinal product's registration dossier into compliance with the acts included in Union law, the procedure for bringing the medicinal product's registration dossier into compliance in the recognition states shall be carried out according to the mutual recognition of registration model, in accordance with the procedures specified in paragraphs 66–82 of these Rules.
Amendments to the registration dossier of a registered medicinal product in the reference state are permitted in accordance with Appendices No. 19 and 20 to these Rules prior to the initiation of the mutual recognition procedure in the state(s) of recognition.
Simultaneous initiation of the mutual recognition procedure in several states of recognition is permitted.
175. To bring the registration dossier of a medicinal product into compliance with the requirements of the Union and to continue circulation of the medicinal product in the territories of the Member States in which it is registered, the applicant shall submit to the authorized body (expert organization) of the reference state in which the medicinal product is registered:
an application on paper or as an electronic document signed with an electronic signature, in the form set out in Appendix No. 2 to these Rules;
documents confirming payment of the fee (duty) for bringing the medicinal product into compliance with the requirements of the Union in the cases and according to the procedure established in accordance with the legislation of the recognition states, on paper or as an electronic document;
modules 1-3 of the registration dossier of the medicinal product on electronic media and/or in the form of electronic documents in accordance with Appendices No. 1-5 to these Rules.
In this case, Module 2 of the registration dossier may be presented in the form of overview sections with the necessary updates of changes (in the form of appendices) in the corresponding sections 2.3 - 2.5 of Module 2 of the registration dossier.
If there are differences in the registration dossier of a medicinal product, based on which the medicinal product is registered in different Member States, in dosages and manufacturing sites, the applicant shall provide updated information on the existing differences and their justification in Module 1 of the registration dossier in the form of a document "For the Information of Experts" as provided for in paragraph 1.0 of Appendix No. 1 to these Rules.
If there are different manufacturing sites, comparative studies must be submitted to the authorized body (expert organization) of the Member State.
If there are differences in the indications for use, dosages, and routes of administration of a medicinal product in different Member States, the applicant shall provide updated information on the existing differences and their justifications in Sections 2.4 and 2.5 of Module 2 of the medicinal product registration dossier, and shall provide reports on the relevant studies in Modules 4 and/or 5 of the medicinal product registration dossier.
In accordance with the requirements of the legislation of a Member State, the submission of the documents specified in paragraphs two through four of this clause may be carried out using an electronic document management system without the need to submit the relevant documents and information on paper, signed and/or certified by the applicant's electronic signature.
Data from preclinical and clinical studies conducted in accordance with the requirements of the legislation of the Member States are presented in modules 4 and 5 of the registration dossier of the medicinal product (without the mandatory alignment of reports on preclinical (non-clinical) studies and clinical studies (tests) of the medicinal product with the rules for the preparation of such reports established by acts of the Union bodies) in the form of relevant reports.
The applicant has the right to withdraw their application at any time prior to the completion of the harmonisation procedure with Union requirements by notifying the authorized body of the Member State where the application is being reviewed in writing.
In the event of withdrawal of the application, the authorized body of the Member State where the application is being reviewed shall cease consideration of the application on the merits and return the original documents and/or information submitted with the application to the applicant.
When conducting an expert review of the registration dossier of a medicinal product as part of the harmonisation procedure with Union requirements, if the required data are missing from Modules 4 and 5 of the registration dossier of the medicinal product, or if new relevant safety information on the medicinal product is available following the review, the authorized body (expert organization) of the reference state may impose additional obligations on the registration certificate holder, as provided for in Section VII of these Rules (including a limited (urgent) validity period of the registration certificate). (Clause 175 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
175(1). If a medicinal product is registered in one Member State and is intended for circulation only within its territory, the applicant may submit, in the official language(s) of that Member State or in another language (if so provided for by the legislation of that Member State), without translation into Russian (if Russian is not the official language of that Member State), only Modules 1–3 of the registration dossier of the medicinal product (in electronic form in accordance with Appendices Nos. 1–5 to these Rules).
Module 2 of the registration dossier of the medicinal product shall be submitted in the form of summaries (Sections 2.3–2.5), with updated changes included as an appendix to the original documents of the registration dossier.
If documents from Modules 4 and 5 of the registration dossier of a medicinal product are available, the applicant has the right to submit them as part of the registration dossier of the medicinal product without submitting Sections 2.4 and 2.5 of Module 2 of the registration dossier of the medicinal product. The authorized body (expert organization) has the right to request documents from Modules 4 and 5 of the registration dossier upon request. (Clause 175(1) as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
176. The authorized body (expert organization) of the reference Member State shall assess the completeness, completeness, and correctness of the submitted documents of the registration dossier of the medicinal product within 10 working days before sending the registration dossier materials for expert review. The applicant is given no more than 90 working days, outside the expert review period, to submit missing materials from the medicinal product registration dossier based on comments from the authorized body (expert organization) of the reference state. (as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
The authorized body (expert organization) of a Member State shall reject an application to bring the registration dossier of a medicinal product into compliance with Union requirements in the event of failure to submit missing materials from the registration dossier of the medicinal product in response to comments from the authorized body (expert organization) of the reference State and/or failure to confirm payment of the fee (duty) for bringing the registration dossier of the medicinal product into compliance with Union requirements in the cases and according to the procedure established by the legislation of the reference State.
The authorized body's (expert organization's) request to the applicant must be transmitted electronically via telecommunications channels and is considered received one calendar day after the date of its submission. (paragraph introduced by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
The applicant's response shall be assessed within five working days from the date of receipt of the applicant's response. (paragraph introduced by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
The examination specified in this clause shall be carried out within a period not exceeding 45 working days from the date of the assessment of the completeness, completeness, and correctness of the documents submitted in the registration dossier, or from the date the expert organization receives the relevant assignment to conduct the examination. (paragraph introduced by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
177. When conducting an expert examination of a medicinal product during the procedure for bringing the medicinal product's registration dossier into compliance, the authorized body (expert organization) of the reference state may send the applicant a written and/or electronic request for additional information, necessary clarifications, or clarifications regarding the submitted documents and data in the medicinal product's registration dossier (including proposals for amendments to the summary of product characteristics, instructions for medical use, medicinal product packaging layouts, quality regulatory documents, or other documents in the registration dossier).
After the initial request, subsequent requests are permitted only if additional questions arise regarding the information provided by the applicant in response to the previous request. The total response time for requests shall not exceed 180 business days. (paragraph introduced by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
The applicant's response to this request shall not exceed 90 business days. The time required for the applicant to submit documents requested by the authorized body or expert organization during the expert examination of the medicinal product is not included in the timeframe for the expert examination of the medicinal product when bringing the registration dossier of the medicinal product into compliance with the requirements of the Union. (as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
If the applicant fails to submit the requested documents and data within the specified timeframe, the expert examination and the procedure for bringing the registration dossier of the medicinal product into compliance with the requirements of the Union shall be terminated. The authorized body (expert organization) of the reference state shall notify the applicant and the authorized bodies (expert organizations) of the states of recognition (if any) of the decision taken within 14 business days from the date of the decision in written and/or electronic form.
178. Based on the results of the expert examination of the registration dossier of a medicinal product, the authorized body (expert organization) of the reference state shall prepare and approve an expert assessment report in the form set out in Appendix No. 16 to these Rules, based on the expert examination of the documents of the registration dossier of the medicinal product submitted by the applicant in accordance with paragraphs 175 and 175(1) of these Rules, including an assessment of the clarifications received from the applicant, documents, and data submitted in response to the request of the expert organization or authorized body.
(as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
When conducting an expert examination of the registration dossier of a medicinal product as part of the procedure for bringing the registration dossier of a medicinal product into compliance with the requirements of the Union, the benefit-risk ratio shall not be reassessed, except in the cases specified in paragraph 181 of these Rules.
179. The authorized body of the reference state refuses to bring the registration dossier of a medicinal product into compliance with the requirements of the Union if, based on the results of the examination of the registration dossier of the medicinal product, it is established that its quality has not been confirmed, or, in accordance with the second part of paragraph 178 of these Rules, an unfavorable benefit-risk ratio has been identified.
180. Based on the results of the examination of the registration dossier of the medicinal product and subject to a positive decision on the compliance of the registration dossier of the medicinal product with the requirements of these Rules, the authorized bodies of the Member States in which the drug is registered and to which an application has been submitted to bring the registration dossier of the medicinal product into compliance with the requirements of the Union, within a period not exceeding 10 working days from the date of receipt of the expert assessment report, issue to the applicant a registration certificate for the medicinal product in the form in accordance with Appendix No. 17 to these Rules, the approved SmPC, instructions for medical use, a regulatory document on quality control, packaging layouts of the medicinal product (if necessary, the applicant is issued an expert assessment report, as well as SmPC, instructions for medical use and packaging layouts of the medicinal product approved in the official language of these Member States, if there are relevant requirements in the legislation of these Member States), an agreed risk management plan (if necessary) and enter information on the registration of the medicinal product into the unified register.
When harmonizing with Union requirements, a medicinal product registered in accordance with the legislation of a Member State for five years or more is issued an indefinite registration certificate if the medicinal product is intended to be marketed only in that Member State. Following the harmonizing procedure, a registration certificate for a medicinal product registered in accordance with the legislation of the Member States specified in the harmonizing application and registered in the reference state for five years or more is issued for an indefinite period as part of the harmonizing procedure in accordance with Section XIII of these Rules. If less than five years have passed since the medicinal product's registration in the reference state, the authorized body of the reference state, following the process of bringing the medicinal product into compliance with Union requirements, issues the applicant a registration certificate valid for five years. Registration (re-registration) of the medicinal product will need to be confirmed upon expiration of the registration certificate. In this case, the authorized bodies of the Member States to which the application for compliance with Union requirements has been submitted will issue the applicant a registration certificate with the validity period established by the reference state. (as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
After the registration dossier of a medicinal product has been brought into compliance with the requirements of the Union, production of the medicinal product in Member States and third countries is permitted with a registration certificate issued in accordance with the legislation of the Member State, within 180 calendar days from the date the registration dossier was brought into compliance with the requirements of the Union (the date of compliance is considered to be the date the relevant information is entered into the unified register).
(This paragraph was introduced by Decision No. 9 of the Council of the Eurasian Economic Commission dated 30.01.2020; as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
The import, simultaneous sale, and medical use of medicinal products specified in the third paragraph of this clause are permitted until the expiration of their shelf life, provided they comply with the documents and information in the registration dossier approved in accordance with the legislation of the Member States and the registration dossier brought into compliance with the requirements of the Union.
(As amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
180(1). In order to harmonize the requirements imposed on the documents of the registration dossier of a medicinal product registered in different Member States (in the event of differences in the information in the registration dossier of a medicinal product registered in accordance with the legislation of Member States), as part of the procedure for bringing it into conformity with the requirements of the Union, it is permitted to make significant changes to the registration dossier of a medicinal product in the reference state in accordance with Appendix V to Appendix No. 19 to these Rules, if the registration dossier of a medicinal product registered in accordance with the legislation of Member States contains documents and data that require changes. In this case, the authorized bodies (expert organizations) of the Member States in which the given drug is registered and to which an application for bringing it into conformity with the requirements of the Union has been submitted, make a decision on bringing the registration dossier of the medicinal product into conformity with the requirements of the Union based on the assessment of the documents specified in paragraph 69 of these Rules, in accordance with paragraph 180 of these Rules. In such a case, the applicant shall submit to the authorized body (expert organization) of the reference state the registration dossier of the medicinal product and information on any differences in the registration dossier of the medicinal product registered in accordance with the legislation of the Member States, and the justifications for these differences, in the form of a document "For the Information of Experts" provided for in paragraph 1.0 of Appendix No. 1 to these Rules. (Clause 180(1) introduced by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
181. Medicinal products may be applied for registration under the mutual recognition procedure in Member States in which the medicinal product has not been registered in accordance with the legislation of the Member States, after bringing its registration dossier into compliance with the requirements of the Union in the reference state. (as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
182. As part of the procedure for bringing the medicinal product into compliance with the Union requirements for subsequent registration under the mutual recognition procedure in a Member State in which the medicinal product has not been registered or submitted for registration in accordance with the legislation of the Member State, the applicant shall submit to the authorized body (expert organization) of the reference State:
an application on paper or as an electronic document signed with an electronic signature, in the established form in accordance with Appendix No. 2 to these Rules;
documents confirming payment of the fee (duty) for bringing the medicinal product into compliance with the Union requirements in the cases and according to the procedure established in accordance with the legislation of the recognition States, on paper or as an electronic document;
Modules 1–5 of the registration dossier in accordance with Appendices Nos. 1–5 to these Rules in the event of subsequent registration under the mutual recognition procedure in Member States in which the medicinal product has not been registered or submitted for registration in accordance with the legislation of the Member State.
In accordance with the requirements of the legislation of the Member State, the documents specified in paragraphs two through four of this clause may be submitted using electronic document management without the additional submission of relevant documents and information on paper, signed and/or certified by the applicant's electronic signature.
All available data from preclinical and clinical studies conducted in accordance with the legislation of Member States are presented in accordance with these Rules in Modules 4–5 of the registration dossier as existing reports, without the need to align them with the requirements for the formatting of reports on preclinical (non-clinical) studies and clinical studies (trials) stipulated by the rules of good laboratory practice and good clinical practice, as well as with the Rules for Conducting Bioequivalence Studies of Medicinal Products. The Member State to which the registration dossier is submitted for aligning it with Union requirements acts as the reference state in this case. (Clause 182 as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
183. If it is necessary to prepare an expert assessment report for the mutual recognition procedure in a state in which the medicinal product has not been registered or submitted for registration in accordance with the legislation of a Member State, a reassessment of the benefit-risk ratio of the medicinal product and an expert examination of the medicinal product shall be carried out in accordance with the procedures established in Section V of these Rules.
XIV. Transitional Provisions
184. Registration (expert assessments for registration), confirmation of registration (re-registration), and amendments to the registration dossier of medicinal products submitted for registration (expert assessments for registration), confirmation of registration (re-registration), and amendments to the registration dossier of medicinal products in Member States before July 1, 2021 (in the Russian Federation, before December 31, 2020) shall be carried out in accordance with the legislation of the Member States.
At the applicant's request, registration of a medicinal product submitted for registration (expert assessments for registration) before July 1, 2021 (in the Russian Federation, before December 31, 2020) may be carried out in accordance with the legislation of the Member State without regard to the requirements of these Rules.
The registration dossier of a medicinal product registered in accordance with paragraphs one and two of this clause must be brought into compliance with the requirements of the Union by December 31, 2025.
(Clause 184 as amended by Decision of the Council of the Eurasian Economic Commission dated March 5, 2021, No. 14)
185. Confirmation of registration (re-registration) and amendments to the registration dossier of a medicinal product registered in Member States in accordance with their legislation and that has not undergone the procedure for bringing it into compliance with the requirements of the Union shall be carried out in accordance with the legislation of the Member States by December 31, 2025.
(Clause 185 as amended by Decision of the Council of the Eurasian Economic Commission dated March 5, 2021, No. 14)
186. Simultaneous sale of a medicinal product in previously and newly approved packaging with previously and newly approved instructions for medical use is permitted until the expiration date (validity period) (storage) of a medicinal product.
The sale of medicinal products released into circulation in a Member State prior to the medicinal product's registration dossier being brought into compliance with the Union's requirements is permitted until the expiration of their shelf life.
XV. Special Cases
187. If the medicinal product's dosage form includes components that are medical devices, information on the registration of the medical device must be included in the registration dossier. Furthermore, if the device is complex in structure and may be a comprehensive delivery system, an expert opinion on the safety, quality, and efficacy of the medical device, in terms of its impact on the clinical characteristics of the medicinal product as a whole, must also be included in the medicinal product's registration dossier.
188. Amendments to the registration dossier of vaccines due to changes in the strain composition of influenza vaccines, as well as the registration of pandemic and pre-pandemic influenza vaccines and amendments to their registration dossier, are carried out in accordance with Appendix No. 24 to these Rules.
(Clause 188 introduced by Decision No. 55 of the Council of the Eurasian Economic Commission dated June 14, 2018)
Appendix No. 1
to the Rules for Registration
and Examination of Medicines
for Medical Use
REQUIREMENTS
FOR REGISTRATION DOSSIER DOCUMENTS (IN THE FORMAT OF A GENERAL
TECHNICAL DOCUMENT)
dated January 30, 2020 No. 9, dated March 5, 2021 No. 14, dated April 23, 2021 No. 34,
dated March 17, 2022 No. 36, dated September 23, 2022 No. 141, dated May 22, 2023 No. 60,
dated October 20, 2023 No. 114)
I. General requirements for the registration dossier modules accompanying the application for registration of a medicinal product
The registration dossier may be submitted electronically, without the need for additional paper submission of relevant documents and information.
As part of the procedure for bringing the registration dossier of a medicinal product registered under the national procedure in the member states of the Eurasian Economic Union (hereinafter referred to as the member states or the Union) into compliance with the Rules for the Registration and Examination of Medicinal Products for Medical Use, approved by Decision No. 78 of the Council of the Eurasian Economic Commission dated November 3, 2016 (hereinafter referred to as "bringing it into compliance with the requirements of the Union"), authorized bodies (expert organizations) of the member states, based on a risk analysis, may additionally request from the applicant the documents specified in subsection 11.1 of these Requirements for the registration procedure, marked "if necessary."
If the authorized body (expert organization) of a member state issues the document specified in Module 1 of the medicinal product registration dossier only in electronic form, the applicant shall indicate in the relevant section of the medicinal product registration dossier the details of the electronic document necessary for verifying its authenticity on the official website of the issuing body on the Internet.
1. Requirements for the registration dossier documents provided in Module 1: Administrative Information
1.0. Cover letter (as in the General Technical Document (hereinafter referred to as the GTD)).
A cover letter must be included in this section.
If necessary, a "For the Experts' Information" document may be submitted as an attachment to the cover letter, providing more detailed information for the purpose of improving navigation (e.g., hyperlinks, volume locations, etc.). For version (sequence) 0000 of the electronic registration dossier, when initiating the procedure for bringing it into compliance with Union requirements, the applicant, in the "For the Experts' Information" document, provides a written guarantee that the documents and data contained in the submitted updated registration dossier of the medicinal product in the general technical document format correspond in content to the data in the registration dossier of the registered medicinal product and do not contain changes that affect the safety, efficacy, quality, or benefit-risk balance of the medicinal product.
(as amended by Decision of the Council of the Eurasian Economic Commission dated October 20, 2023, No. 114)
1.1. Contents.
The complete contents of Modules 1-5 of the registration dossier must be submitted.
1.2. General Documentation:
1.2.1. The application for registration of a medicinal product (on paper or as an electronic document created in *.doc, *.docx, and *.pdf formats and signed with an electronic signature) shall be completed using the form in Appendix No. 2 to these Rules.
(Clause 1.2.1 as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
1.2.2. Documents confirming payment for expert work and/or payment of the registration fee (duty) in accordance with the legislation of the Member State registering the medicinal product (unless the legislation of the Member State prohibits the applicant from providing documents that are in the possession of or can be obtained independently by the authorized body).
1.2.3. A copy of the medicinal product certificate in the format recommended by the World Health Organization, issued by the authorized body of the manufacturing country (if any).
If such a certificate is unavailable, a document confirming registration in the manufacturing country and/or in the country holding the registration certificate for the medicinal product (if any).
If there is no registration in the manufacturing country or the country holding the registration certificate for the medicinal product, an explanatory note justifying the lack of registration data shall be submitted.
1.2.4. A translation into Russian and a copy of the expert report of the authorized body for registration of a medicinal product in the country of manufacture or in the country holding the registration certificate for the medicinal product (if any). Submission is not mandatory as part of the procedure for bringing it into compliance with Union requirements.
1.2.5. Conclusion (recommendation) of the authorized body (authorized organization) of a Member State following the preliminary scientific consultation regarding this medicinal product in Member States (if any).
1.2.6. Recommendation of the Expert Committee on Medicinal Products following the preliminary scientific consultation regarding this medicinal product, including a conclusion on the rationality of the combination of active ingredients of the combined medicinal product (if any).
(clause 1.2.6 as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
1.3. General characteristics of the medicinal product (hereinafter referred to as SmPC), instructions for medical use (package insert) (hereinafter referred to as IMU), labeling:
1.3.1. Draft summary of product characteristics (SmPC) and general characteristics of medicinal products (GCP), compiled in Russian in accordance with the requirements for the instructions for medical use of a medicinal product and the general characteristics of the medicinal product for medical use, approved by the Eurasian Economic Commission (hereinafter referred to as the Commission). (as amended by decisions of the Council of the Eurasian Economic Commission of 17.03.2022 No. 36, of 22.05.2023 No. 60)
1.3.2. Layouts (full-color copies of the flat original layout, ensuring the reproduction of both the secondary (consumer) and primary (internal) packaging and the labeling of the medicinal product in two-dimensional form, referred to as a "paper copy" or "computer version") of secondary (consumer), primary (internal), and intermediate packaging, compiled in accordance with the labeling requirements for medicinal products for medical use and veterinary medicinal products approved by the Commission. Mock-ups of intermediate packaging, labels, and stickers are submitted if available.
(as amended by Decision No. 141 of the Council of the Eurasian Economic Commission dated September 23, 2022)
1.3.3. Results of user testing of the IMP mock-up (in cases established by Appendix No. 12 to the requirements for the instructions for medical use of a medicinal product and the general characteristics of the medicinal product for medical use, approved by Decision No. 78 of the Council of the Eurasian Economic Commission dated November 3, 2016).
(as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
When presenting the results of user testing, it is necessary to briefly summarize how the testing was conducted and how all necessary changes were incorporated into the final version of the IMP. The summary must be presented in this section of the module, in the following format:
a brief description of the medicinal product;
A brief description of the testing performed or study of individual elements of the IMP (methodology used, explanations of the participant selection criteria, testing language);
Questionnaires used (questionnaires, including instructions for completing them and observation forms);
Original and revised versions of the IMP;
A brief description and discussion of the test results (subject responses, identified problems, and changes made to the relevant sections of the IMP);
Conclusion.
All other details must be provided upon request by the authorized body (expert organization).
1.3.4. Copies of the SmPC and IMP approved by the authorized body of the manufacturing country and/or the country holding the marketing authorization for the medicinal product, with the date of the last revision, certified by an authorized representative of the marketing authorization holder (if available).
1.4. Information on the regulatory status of the drug in other countries (if available).
1.4.1. A list of countries in which the medicinal product has been submitted for registration, registered, denied registration, or suspended, indicating the name of the medicinal product, the registration certificate number and date, its validity period, or the date of the decision to deny registration or suspend the registration certificate. The information provided must be certified by the registration certificate holder.
1.5. Quality Documents:
1.5.1. Certificate of Conformity with the Eurasian Economic Union Pharmacopoeia or European Pharmacopoeia article on spongiform encephalopathy, or a document issued by the authorized veterinary authorities of the country of origin of the raw materials, if pharmaceutical substances of animal origin are used (if applicable).
1.5.2. A letter or a copy of the letter from the active pharmaceutical substance master file holder, signed by the responsible person of the active pharmaceutical substance master file holder, containing an obligation to notify the manufacturer of the medicinal product and the authorized body of the Member State of any changes before any significant changes are made to the active pharmaceutical substance master file, as well as a translation of the specified letter, certified by the marketing authorization holder or notarized.
(clause 1.5.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
1.5.3. A letter confirming the consent of the pharmaceutical substance master file holder to submit documents from the closed section of the pharmaceutical substance master file upon request of the authorized body of the Member State.
(as amended by Decision of the Council of the Eurasian Economic Commission dated 23.04.2021 No. 34)
1.5.4. A copy of the certificate of conformity of the pharmaceutical substance with the requirements of the European Pharmacopoeia (if available).
1.5.5. A copy of the plasma master file certificate issued by the authorized body of the manufacturing country (if available).
1.5.6. A copy of the vaccine antigen master file certificate issued by the authorized body of the manufacturing country (if available).
1.5.7. A draft regulatory document on quality, prepared in accordance with the Guidelines for drafting regulatory documents on medicinal product quality, approved by Decision of the Board of the Eurasian Economic Commission dated September 7, 2018, No. 151.
(Clause 1.5.7 was introduced by Decision of the Council of the Eurasian Economic Commission dated April 23, 2021, No. 34)
1.6. Manufacturing documents:
1.6.1. Information on the date of issue (decision made by the authorized body) and the registration number in the relevant register of the member state, or a copy of the current document confirming the compliance of the manufacturer (production site producing the finished dosage form and performing quality control) of the medicinal product applied for registration with the Rules of Good Manufacturing Practice of the Eurasian Economic Union, approved by Decision No. 77 of the Council of the Eurasian Economic Commission dated November 3, 2016, and issued by the authorized body of the member state (if applicable in accordance with paragraph 29 of the Rules for the Registration and Examination of Medicinal Products for Medical Use).
Copies of current documents confirming the manufacturer's manufacturing site's compliance with Good Manufacturing Practice (GMP) requirements, issued by authorized bodies of the country in which the manufacturing site is located (manufacturing sites producing the finished dosage form and performing quality control) and/or another authorized body; the internet address of the website registering GMP certificates of conformity issued by the authorized body (e.g., EudraGMP) (if applicable in accordance with paragraph 29 of the Rules for the Registration and Examination of Medicinal Products for Medical Use). (Clause 1.6.1 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
1.6.2. A copy of the current permit (license) for the manufacture of medicinal products (with appendices), issued by the authorized body of the country in which the manufacturing site(s) producing the finished dosage form and performing release quality control of the medicinal product is located.
For manufacturing sites located in the territories of Member States, instead of the document specified in the first paragraph of this clause, the applicant may submit in the relevant section of the medicinal product registration dossier information contained in the relevant Member State register on the issue date and registration number of the license (permit) for the manufacture of medicinal products issued by the authorized body of the Member State.
(Clause 1.6.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.6.3. A copy of the inspection report of the manufacturing site (manufacturing sites manufacturing the finished dosage form and performing release quality control) for compliance with GMP, conducted by the authorized body of the manufacturing country or the authorized body of a Member State within the last 3 years, as well as the plan and report on the implementation of corrective and preventive actions (CAPA) after the inspection (if any), and in cases stipulated by paragraph 30 of the Rules for the Registration and Examination of Medicinal Products for Human Use, a link to the authorized body's website on the Internet containing information from the GMP inspection database (e.g., EudraGMP). When submitting the documents specified in paragraph 1.6.1 of these Requirements, as well as as part of the procedure for bringing them into compliance with Union requirements, the submission of information is optional.
(paragraph 1.6.3 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.6.4 - 1.6.5. Repealed effective December 20, 2023. - Decision of the Council of the Eurasian Economic Commission dated October 20, 2023 No. 114.
1.6.6. Information on any regulatory measures taken by the authorized body over the past three years based on the results of inspections at the declared manufacturing site (if any). When submitting the documents specified in paragraph 1.6.1 of these Requirements, as well as as part of the procedure for bringing them into compliance with Union requirements, the submission of information is optional.
(as amended by Decision of the Council of the Eurasian Economic Commission dated October 20, 2023 No. 114)
1.6.7. A letter from the authorized person for quality on the compliance of the manufacturing conditions of the medicinal product submitted for registration with the requirements of the Rules of Good Manufacturing Practice of the Union, including with respect to starting materials for each manufacturing site used in the manufacturing of the medicinal product and active pharmaceutical ingredient, including sites where quality control and in-process control are carried out. The letter must be signed by a quality representative and certified by the manufacturer's seal (stamp), if necessary, with a Russian translation.
1.6.8. Information on complaints regarding the quality of medicinal products manufactured at the manufacturing site of the medicinal product being submitted for registration over the past three years, or confirmation of the absence of complaints. When submitting the documents specified in paragraph 1.6.1 of these Requirements, as well as as part of the procedure for bringing the product into compliance with Union requirements, the submission of information is optional.
1.6.9. Consent to conduct a pharmaceutical inspection for compliance with the requirements of international treaties and acts constituting the law of the Union.
1.6.10. Repealed effective December 20, 2023. - Decision of the Council of the Eurasian Economic Commission dated October 20, 2023 No. 114.
1.6.11. A diagram of the production stages indicating all production sites involved in the production of the medicinal product and active pharmaceutical ingredient, including final quality control.
1.7. Information on specialists:
1.7.1. Information on the specialist who prepared the quality summary (if any). Submission of information is not mandatory as part of the procedure for bringing the product into compliance with Union requirements.
(clause 1.7.1 as amended by Decision of the Council of the Eurasian Economic Commission dated October 20, 2023 No. 114)
1.7.2. Information on the specialist who prepared the preclinical study summary (if any). Submission of information is optional as part of the process for aligning with Union requirements.
(Clause 1.7.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.7.3. Information on the specialist who prepared the clinical trial summary (if any). Submission of information is optional as part of the process for aligning with Union requirements.
(As amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
Information on the quality, preclinical, and clinical data specialists includes information on their education, specialization, and professional experience. It must be signed by the specialists who prepared the summary and review of quality, preclinical, and clinical data. These specialists must have the appropriate qualifications. The existence of a professional relationship between the specialist who prepared the summary and the applicant must be indicated.
1.8. Specific requirements for different types of applications:
1.8.1. A letter from the Marketing Authorization Holder regarding an additional trade name for a medicinal product is submitted if the applicant plans to register the medicinal product under different trade names in the country of manufacture, the reference state, and the state of recognition (if applicable). The letter must include guarantees that a single registration dossier is used for these purposes. The letter must be signed and dated by the Marketing Authorization Holder. Submission of information is not mandatory as part of the procedure for aligning with Union requirements.
1.8.2. Clinical trial documents and summaries substantiating the registration application (if applicable):
(clause 1.8.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 05.03.2021 No. 14)
1.8.2.1. Permission from the authorized body to conduct a clinical trial in Member States, including amendments (if any) to the clinical trial protocol. Submission of information is not mandatory as part of the procedure for bringing the clinical trial into compliance with Union requirements.
(Clause 1.8.2.1 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
1.8.2.2. A list of inspections conducted for compliance with the Good Clinical Practice Rules of the Eurasian Economic Union, approved by Decision No. 79 of the Council of the Eurasian Economic Commission dated November 3, 2016, for the medicinal product applied for registration, indicating the authorized bodies that conducted the inspections, the dates of the inspections, and the results (regardless of the availability of the documents specified in paragraph 1.8.2.1 of these Requirements). If necessary, the authorized bodies (expert organizations) of the member states independently request the results of these inspections from the relevant regulatory authorities. Submission of information is not mandatory as part of the procedure for bringing the medicinal product into compliance with Union requirements. (as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
The list of inspections includes inspections of study centers that participated in clinical trials of the medicinal product, inspections of the sponsor or contract research organization for the clinical trial of the medicinal product, or inspections of other organizations related to the trial (e.g., an analytical laboratory involved in the clinical trial of the medicinal product), and other GCP inspections.
If a clinical trial was conducted entirely at study centers in third countries, the list must include the results of GCP inspections conducted at the study centers that enrolled the maximum number of patients in the trial of the medicinal product. This list also includes indications of inspections conducted for other clinical trials at the same study center (including for another medicinal product for which the applicant and/or the declared MAH are not the MAH). In this case, the authorized bodies (expert organizations) of the Member States shall independently request reports on such inspections from the relevant authorized bodies of third countries (in the absence of the documents specified in paragraph 1.8.2.1 of these Requirements (if applicable)).
(as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
1.8.2.3 - 1.8.2.4. Repealed effective 20 December 2023. - Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114.
1.8.2.5. Summary of the application for registration of a medicinal product with well-studied medical use. Submission of information is not mandatory as part of the procedure for bringing the product into compliance with Union requirements.
(paragraph 1.8.2.5 as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
1.8.2.6. Summary of the registration application for generic, hybrid, or biosimilar medicinal products (if applicable). Submission of information is optional during the process of harmonizing with Union requirements.
(Section 1.8.2.6 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.8.2.7. Summary of the registration application if patents exist in a Member State for the medicinal product being registered.
(Section 1.8.2.7 introduced by Decision of the Council of the Eurasian Economic Commission dated 05.03.2021 No. 14)
1.8.2.8. Summary of the registration application in exceptional cases (if applicable). Submission of information is optional during the process of harmonizing with Union requirements.
(Clause 1.8.2.8 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
1.8.2.9. Summary of the application for registration with the establishment of post-registration measures or summary of the application for conditional registration (if applicable). Submission of information is not mandatory as part of the procedure for bringing the application into compliance with Union requirements.
(Clause 1.8.2.9 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
1.8.3. Table listing clinical trials (if applicable). Submission of information is not mandatory as part of the procedure for aligning with Union requirements.
(Section 1.8.3 as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
1.8.4. Repealed effective 20 December 2023. - Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114.
1.9. Applicant's documents on the assessment of potential environmental hazards (posted as Appendix No. 1 to the module) (if any).
1.9.1. Applicant's letter stating that the medicinal products contain or are derived from genetically modified organisms (if applicable).
1.10. Information regarding the applicant's pharmacovigilance in the Member State.
1.10.1. A master file of the pharmacovigilance system of a marketing authorization holder, in accordance with the requirements of the Rules of Good Pharmacovigilance Practice of the Eurasian Economic Union, approved by the Commission (hereinafter referred to as the Rules of Good Pharmacovigilance Practice of the Union), is submitted when the marketing authorization holder first applies for registration of a medicinal product in the Union market.
(as amended by Decision of the Council of the Eurasian Economic Commission dated 30.01.2020 No. 9)
For subsequent applications for registration of medicinal products on behalf of this marketing authorization holder, a brief description of the marketing authorization holder's pharmacovigilance system is submitted.
The brief description of the marketing authorization holder's pharmacovigilance system must include, among other things, the following elements:
written confirmation by the marketing authorization holder of the existence of an authorized person responsible for pharmacovigilance. If the Marketing Authorization Holder is not located in a Member State, confirmation of the presence of a pharmacovigilance contact person in the Member State is also required;
Statement of the country in which the authorized person resides and performs their functions;
Contact details of the authorized person and the pharmacovigilance contact person (if applicable);
A statement (declaration) signed by the Marketing Authorization Holder stating their commitment to fulfill the tasks and obligations listed in the Union's Good Pharmacovigilance Practice Rules;
A link to the location (address) of the pharmacovigilance system master file.
1.10.2. Written confirmation by the Marketing Authorization Holder of the presence of a authorized person responsible for pharmacovigilance in the Member State.
1.10.3. A risk management plan for the medicinal product submitted for registration, prepared in accordance with the Union's Good Pharmacovigilance Practice Rules.
1.10.4. Duly certified documents confirming the existence of interactions that ensure the proper performance of all duties of the registration certificate holder by several legal entities, if the holders of the registration certificates for the medicinal product issued by the reference state and the states of recognition are different legal entities (if applicable).
1.11. Copies of documents confirming trademark registration (if any).
2. Requirements for the registration dossier documents
provided in Module 2: Summary of the General Technical Document (GTD)
This module provides summaries of the chemical and biological documentation, preclinical and clinical studies presented in Modules 3–5 of the medicinal product registration dossier, and the opinions of the specialists who prepared the summaries on quality, preclinical, and clinical studies.
(as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated January 30, 2020)
Summarized factual data are presented, including materials in tabular form. These reports provide cross-references to tables or information contained in the primary documentation presented in Module 3 "Quality," Module 4 "Preclinical (Non-Clinical) Study Reports," and Module 5 "Clinical Study (Trial) Reports."
Summaries and summaries must comply with the core principles and requirements set forth below.
2.1. Contents of Modules 2-5.
This section of the module presents the content of the documentation on the quality, safety, and efficacy of the medicinal product included in Modules 2-5.
2.2. Introduction to the CTD.
This document should provide information on the pharmacological group, mechanism of action, and proposed clinical use of the medicinal product.
2.3. General Quality Summary.
The General Quality Summary should provide an overview of information related to chemical, pharmaceutical, and biological data.
Specific attention should be paid to key critical parameters and issues related to quality aspects, and justification should be provided in cases where relevant requirements and guidelines are not met. This document should cover the issues and describe the relevant data detailed in Module 3. (as amended by Decision of the Council of the Eurasian Economic Commission dated January 30, 2020, No. 9)
2.4. Review of Preclinical Data.
A summary and critical assessment of the in vitro animal preclinical studies of the medicinal product must be provided, along with a discussion and justification of the study strategy where deviations from relevant requirements are necessary.
An assessment of impurities and degradation products of the medicinal product must be included, along with their potential pharmacological and toxicological effects, with the exception of medicinal products of biological origin. Any differences in the chirality, chemical form, and purity of the compounds used in preclinical studies and the medicinal product to be manufactured must be considered.
For medicinal products of herbal and biological origin, the comparability of the product used in preclinical studies, clinical trials, and the medicinal product to be registered must be assessed.
Any new excipient must be subject to a separate safety assessment.
The properties of the medicinal product demonstrated in preclinical studies must be identified, and the significance of the safety results for the planned clinical use of the medicinal product must be presented.
2.5. Clinical Data Review.
The clinical data review should contain a critical analysis of the clinical data included in the executive summary and Module 5. It should provide information on the clinical development of the medicinal product, including study design, decisions made regarding the study, and the conduct of the studies.
It should provide a brief overview of the clinical trial data, including important limiting factors, as well as a benefit-risk assessment based on the clinical trial findings. It should also justify the proposed dose and indications for use based on the obtained clinical efficacy and safety data. It should also assess how the general characteristics of the medicinal product, the instructions for medical use, and other approaches can optimize benefits and limit risks.
It is necessary to explain any unanswered questions regarding efficacy and safety that arose during the development process.
2.6. Summary of preclinical studies.
Preclinical study summaries should be presented based on the actual results of pharmacological, pharmacokinetic, and toxicological studies conducted on animals in vitro, in text format and in tables in the sequence presented below, with an introductory section.
2.6.1. Pharmacological study summaries in text format.
2.6.2. Pharmacological study summaries in tables.
2.6.3. Pharmacokinetic study summaries in text format.
(as amended by Decision No. 9 of the Council of the Eurasian Economic Commission of 30.01.2020)
2.6.4. Summary of pharmacokinetic studies in tabular form.
2.6.5. Summary of toxicological studies in text format.
2.6.6. Summary of toxicological studies in tabular form.
2.7. Summary of clinical studies.
A detailed summary of clinical information on the study of the medicinal product included in Module 5, including factual data, must be provided. The summary must include the results of all biopharmaceutical studies, clinical pharmacology studies, and clinical efficacy and safety studies. A brief overview of individual studies must be provided. The clinical information in the summary form must be presented in a specific sequence of parts (with a list of referenced scientific sources).
2.7.1. Summary of biopharmaceutical studies and associated analytical methods.
2.7.2. Summary of clinical pharmacology studies.
2.7.3. Summary of clinical efficacy.
2.7.4. Summary of clinical safety.
2.7.5. Copy of references.
2.7.6. Summary of individual studies.
3. Requirements for Registration Dossier Documents
listed in Module 3: Quality
3.1. Contents of Module 3.
3.2. Key information required for submission includes:
а) Chemical, pharmaceutical, and biological data on the active pharmaceutical ingredients and the medicinal product, including information on the development, manufacturing process, characteristics and properties, quality control methods and requirements, stability, as well as a description of the composition and packaging of the medicinal product;
b) Basic information on the active pharmaceutical ingredient and the medicinal product;
c) Detailed information on the starting materials and raw materials used in the production of the active pharmaceutical ingredient and excipients included in the medicinal product;
d) All test methods and techniques used in the production and quality control of the active pharmaceutical ingredient and the medicinal product, clearly and in detail, so that they can be reproduced during control testing at the request of the authorized body of the reference state. All test methods must comply with the current scientific level and be validated. The results of the validation of the methods must be provided. When using test methods included in the Eurasian Economic Union Pharmacopoeia, the pharmacopoeias of the member states, and the primary pharmacopoeias, in accordance with the Concept for Harmonization of Pharmacopoeias of the Eurasian Economic Union Member States (hereinafter referred to as the Concept), the corresponding references to the monographs and general sections must be provided;
e) For all pharmaceutical substances specified in the monographs of the Eurasian Economic Union Pharmacopoeia, the pharmacopoeias of the member states, and the primary pharmacopoeias in accordance with the Concept, references to the listed pharmacopoeias must be provided.
However, if a pharmaceutical substance specified in the Eurasian Economic Union Pharmacopoeia, the pharmacopoeias of the member states, and the primary pharmacopoeias in accordance with the Concept is obtained by a process that may generate impurities not controlled by the monographs of the aforementioned pharmacopoeias, then these impurities and their permissible levels must be specified, and a methodology for their determination must be provided. If the specification included in the monograph of the Eurasian Economic Union Pharmacopoeia, the pharmacopoeias of the member states, and the primary pharmacopoeias in accordance with the Concept is insufficient to ensure the quality of the substance, a more detailed specification from the manufacturer or marketing authorization holder may be required.
If analytical methods and procedures are included in the Eurasian Economic Union Pharmacopoeia, there is no need to provide them in full; a relevant reference to the monographs and general sections is sufficient;
f) if the starting materials and raw materials, active pharmaceutical ingredients, or excipients are not described in the Eurasian Economic Union Pharmacopoeia, the pharmacopoeias of the member states, and the primary pharmacopoeias in accordance with the Concept, a reference to the monograph of the pharmacopoeia of another state may be applicable. In such cases, the applicant must submit a copy of the monograph along with the validation of the analytical methods described in the monograph, as well as a translation (if necessary);
g) If the active pharmaceutical substance and/or excipient and starting material are described in a monograph of the European Pharmacopoeia, the applicant may submit a certificate of conformity with the monograph of the European Pharmacopoeia in the relevant section of this module. It is recognized that certificates of conformity with the monograph of the European Pharmacopoeia replace the essential data in the relevant sections specified in this module. If the active pharmaceutical substance has a valid marketing authorization or is included in the relevant state register in accordance with the requirements of the legislation of a Member State, the applicant has the right to replace the essential data in the relevant sections specified in this module during registration and/or when bringing the registration dossier into compliance with the Union requirements for circulation only within the territory of that Member State. The manufacturer of the active pharmaceutical substance must confirm in writing to the applicant that the manufacturing process has not changed since the date of issue of the certificate of conformity with the monograph of the European Pharmacopoeia or inclusion in the relevant register of the Member State;
(subparagraph "g" as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
h) For well-studied (at least 10 years from the date of the first systematic and documented use of the active ingredients of the medicinal product, in at least three Member States, with the exception of biological ones) active pharmaceutical ingredients, the manufacturer of the active pharmaceutical ingredient or the applicant for registration of the medicinal product may prepare a separate document including the following information (active pharmaceutical ingredient dossier or master file):
a detailed description of the manufacturing process;
quality control during manufacturing;
a manufacturing process validation report.
The manufacturer of the active pharmaceutical ingredient may submit the master file for the active pharmaceutical ingredient to the authorized body of the Member State. When using an active pharmaceutical ingredient master file as part of a medicinal product registration dossier, the manufacturer of such active pharmaceutical ingredient must provide the applicant (registration certificate holder) of the relevant medicinal product with all necessary data to bear the liability stipulated by these Rules. The manufacturer of the active pharmaceutical ingredient must provide the applicant (registration certificate holder) with written confirmation guaranteeing the consistency of batch quality and that no changes will be made to the manufacturing process or specifications of such active pharmaceutical ingredient without notifying the applicant (registration certificate holder). The documents and data required to make such a change must be submitted to the authorized body; these documents and data are also submitted to the applicant for the sections pertaining to the open portion of the active pharmaceutical ingredient master file.
If the applicant does not have complete information regarding the restricted portion of the active pharmaceutical ingredient master file from which it is manufactured due to confidentiality, a written consent from the manufacturer of the active pharmaceutical ingredient must be attached to the application, provided that information about it is included in the unified register. This consent must grant the authorized body the right to use previously submitted information from the restricted portion of the master file for the specified active pharmaceutical ingredient during the expert evaluation of the medicinal product;
i) Special measures to prevent the transmission of animal spongiform encephalopathies (raw materials obtained from ruminants) must be described: at each stage of the manufacturing process, the applicant must confirm the compliance of the materials used with the requirements of the guidelines for minimizing the risk of transmission of animal spongiform encephalopathies according to the Pharmacopoeia of the Eurasian Economic Union or provide a certificate of conformity with a specific monograph of the European Pharmacopoeia or scientific data to substantiate this conformity;
j) Information on the risk assessment of potential contamination by extraneous agents (viral or non-viral) should be provided in accordance with the requirements set out in specific guidelines, as well as in the general articles (monographs) and general sections of the Pharmacopoeia of the Eurasian Economic Union, the pharmacopoeias of the Member States, and the main pharmacopoeias in accordance with the Concept;
k) Special devices and equipment used at any stage of the manufacturing process and the control stage of the medicinal product must be described in detail;
l) If necessary, documents confirming the registration of the medical device in accordance with the rules approved by the Commission must be provided.
3.2.S. Active pharmaceutical substance.
3.2.S.1. General information on starting materials and raw materials:
a) the name of the active pharmaceutical ingredient, including the recommended international nonproprietary name (INN), and, if available, the pharmacopoeial name according to the Pharmacopoeia of the Eurasian Economic Union, and the chemical name according to IUPAC nomenclature.
The structural formula, including the relative and absolute spatial structure, the molecular (empirical) formula, and the relative molecular weight, are provided. For biotechnologically derived medicinal products, if applicable, a schematic amino acid sequence and relative molecular weight must be provided.
For biological medicinal products, a list of the physicochemical and other important properties of the active pharmaceutical ingredient, including its biological activity, must be provided;
b) for the purposes of this section, starting materials are considered to be all materials from which active pharmaceutical ingredients are manufactured or isolated. For medicinal products of biological origin, starting materials are considered to be any materials of biological origin (e.g. microorganisms, organs and tissues of plant or animal origin, cells or fluids (including blood or plasma) of humans or animals, biotechnological cellular components (recombinant or non-recombinant cell substrates, including primary cells)).
A medicinal product of biological origin (for the purposes of this paragraph) is considered to be all medicinal products whose active ingredient (hereinafter referred to as the active ingredient) is a biological substance (material).
A biological substance is a substance obtained from a biological source, the description and quality confirmation of which requires the submission of a combination of physical, chemical, and biological analytical methods, along with a description of the manufacturing process and its controls.
Any other substances used for the production or isolation of an active substance or active component, but from which this active substance or active component is not directly obtained (namely, reagents, culture media, fetal or embryonic serum, additives and buffers used in preparative chromatography, etc.), are considered raw materials.
3.2.S.2. Active Pharmaceutical Ingredient Manufacturing Process:
a) The applicant is obliged to provide a description of the manufacturing process for the active pharmaceutical ingredient. To adequately describe the manufacturing process and its controls, the necessary information must be presented in accordance with the requirements established in the relevant acts within the Union law;
b) All starting materials and supplies required for the production of the active pharmaceutical ingredient must be listed, indicating the production stage at which each type of raw material and supplies is used. Information on their quality and control, as well as information confirming compliance with the requirements (standards) for the intended use, must be provided. The starting materials (raw materials) must be listed, along with quality and quality control documentation. The name and location of the production sites must be provided, and the responsibilities of each manufacturer, including contract manufacturing, must be specified, as well as information on each production site or testing laboratory used; (as amended by Decision of the Council of the Eurasian Economic Commission dated 30.01.2020 N 9)
c) The following additional requirements are established for biological medicinal products:
A description and documentary evidence of the origin and history of the source materials must be provided;
Regarding special measures to prevent the transmission of pathogens causing spongiform encephalopathy, the applicant must confirm that the active substance meets, in particular, the requirements of the relevant monograph (article) of the Eurasian Economic Union Pharmacopoeia for minimizing the risk of transmission of these pathogens with manufactured medicinal products;
When using cell banks, evidence must be provided that the cell characteristics have remained unchanged over the number of passages used for production, as well as during the subsequent period;
Seed materials, cell banks, serum or plasma pools, and other materials of biological origin, as well as, if possible, the materials from which they are obtained, are tested for the presence of adventitious agents;
If the presence of potentially pathogenic adventitious agents cannot be avoided, the materials may be used only if subsequent processing ensures the removal and/or inactivation of these adventitious agents, and this must be validated;
Vaccine production must be based (where possible) on a seed culture system and known cell banks. When producing bacterial and viral vaccines, the characteristics of the infectious agent must be demonstrated using inoculum. Furthermore, for live vaccines, the stability of attenuation characteristics (reduced virulence of pathogenic microorganisms) must be confirmed using inoculum. If this evidence is insufficient, the attenuation characteristics must also be confirmed at the production stage.
For medicinal products obtained from human blood or plasma, in accordance with the provisions set out in Part III of this Appendix, the origin, criteria and methods for selection, transport and storage of starting materials must be described and documented;
The manufacturing facilities and equipment must be described;
d) Where applicable, information on testing and acceptance criteria at each critical stage, information on the quality and control of intermediate products, as well as on process validation and/or assessment must be provided;
e) If the presence of potentially pathogenic adventitious agents cannot be avoided, the materials may be used only in cases where subsequent processing ensures their removal and/or inactivation, which is confirmed by validation and is provided in the relevant section on the viral safety assessment;
f) It is necessary to provide for the active pharmaceutical ingredient a description and analysis of significant changes made to the manufacturing process during development and/or at the manufacturing site, and (if the manufacturer of the medicinal product is not the manufacturer of the active pharmaceutical ingredient) to provide a copy of the written commitment of the manufacturer of the active pharmaceutical ingredient to inform the applicant of changes in the manufacturing process or specifications (in any form).
3.2.S.3. Description of the characteristics of the active pharmaceutical ingredient:
It is necessary to provide data on the structure and other characteristics of the active pharmaceutical ingredient;
The structure of the active pharmaceutical ingredient should be confirmed based on modern physicochemical and/or immunochemical and/or biological methods, and information on impurities should be provided.
3.2.S.4. Quality control of the active pharmaceutical ingredient:
It is necessary to provide detailed information on the specifications used for batch-by-batch control of the active pharmaceutical ingredient, the rationale for the selection of these specifications, test methods, and their validation; It is necessary to present the results of quality control of individual batches produced during the development stage.
3.2.S.5. Reference Standards or Materials:
Reference materials and reference standards must be identified and described in detail. Where possible, suitable pharmacopoeial chemical reference standards and biological reference materials must be used.
3.2.S.6. Packaging (Closure) System:
A description of the primary packaging and packaging (closure) system and specifications of its components must be provided.
3.2.S.7. Stability:
a) A summary of the studies performed, the plans (programs) used, and the results obtained during the studies must be provided;
b) Detailed stability study results, presented in an appropriate format, including information on the analytical methods used and their validation, must be provided;
c) A post-marketing stability study plan (program) and the applicant's obligations for its implementation must be provided.
3.2.P. Medicinal Product.
3.2.P.1. Description and Composition of the Medicinal Product.
A description of the medicinal product and its composition must be provided. The information must include a description of the dosage form and composition, listing all components of the finished medicinal product, their quantities per unit dose, and the functional purpose of the components:
active pharmaceutical ingredient;
excipients, regardless of their origin or quantity, including colorants, preservatives, modifiers, stabilizers, thickeners, emulsifiers, flavorings, and aromatic substances, etc.;
components of the dosage form and outer shells of medicinal products ingested by the patient or by any other route of administration (hard capsules, soft capsules, rectal capsules, film-coated tablets, film-coated tablets, etc.).
This information must be supplemented with any relevant data regarding the type of container and its closure method (if applicable), along with detailed information about the devices through which the medicinal product will be used or administered and which will be supplied with the medicinal product. The term "accepted terminology" used to describe the components of medicinal products, regardless of other provisions, means the following:
for substances with an INN recommended by the World Health Organization (WHO), the INN, or if the substance is in salt, ester, hydrate, or other form, the corresponding modified INN;
for other substances (in the absence of an INN), the generally accepted (group) name, taking into account salt, ester, hydrate, and other forms; in the absence of a generally accepted (group) name, the chemical name according to the IUPAC nomenclature; and, in the absence of the latter, information on sources and methods of production, the presence of added additives, etc. (with relevant detailed information, if necessary);
for colorants, in addition to the name, the corresponding code according to the International Food Additive Numbering System (Codex Alimentarius) (E-codes) is provided.
In the "Quantitative Composition" section of the medicinal product, for the active pharmaceutical ingredient, it is necessary to indicate, depending on the dosage form, the mass or number of biological activity units per dosage unit of the dosage form, or per unit mass, or per unit volume of each active pharmaceutical ingredient.
If the active pharmaceutical ingredients are presented as compounds or derivatives, their quantitative expression must be provided, indicating their total mass and the mass of the active moiety (if applicable).
For medicinal products containing an active pharmaceutical ingredient that is first declared in the composition of a medicinal product, the quantity of the active pharmaceutical ingredient that is a salt or hydrate must always be indicated based on the mass of the active moiety.
For medicinal products containing an active pharmaceutical ingredient that is first registered in a medicinal product in a Member State, the quantitative content of such an active pharmaceutical ingredient, if it is a salt or hydrate, must be expressed according to the systems approach based on the mass of the active moiety. The quantitative content of the same active pharmaceutical ingredient in all subsequent medicinal products registered in Member States must be indicated in the same manner.
For a substance or active substance that cannot be determined chemically, units of biological activity or, if available, international units of biological activity established by the World Health Organization (WHO) must be indicated. If international units have not been established by the WHO, units of biological activity must be expressed in a manner that provides accurate information on the activity of the substance or active substance, using, where appropriate, units of the Pharmacopoeia of the Eurasian Economic Union (EAEU). Where possible, biological activity per unit mass should be indicated.
3.2.P.2. Pharmaceutical Development:
This section contains information on development studies conducted to demonstrate that the dosage form, composition, manufacturing process, packaging (closure) system, microbiological characteristics, and instructions for preparing the final dosage form suitable for immediate use are consistent with the intended use indicated by the applicant in the medicinal product registration dossier. The studies described in this section differ from routine control testing conducted according to specifications. Critical formulation parameters and process characteristics that may impact batch reproducibility, performance, and quality of the medicinal product must be identified and described. When presenting additional supporting data, reference should be made to the relevant sections of Modules 4 and 5:
It is necessary to justify the compatibility of the active pharmaceutical substance with excipients, as well as the main physicochemical properties of the active pharmaceutical substance that may affect the characteristics of the medicinal product, or the compatibility of different active pharmaceutical substances with each other in the case of combination medicinal products;
It is necessary to justify the choice of excipients, especially with regard to their respective functional characteristics and content;
It is necessary to provide a description of the development of the medicinal product, taking into account the proposed route of administration and route of use;
The presence of any excess in the composition must be justified;
It is necessary to identify and justify any physicochemical and biological properties and any parameters affecting the characteristics of the medicinal product;
It is necessary to provide information on the selection and optimization of the manufacturing process, as well as on the differences (discrepancies) between the manufacturing process used to manufacture the batches involved in the clinical trial phases and the planned industrial process for the production of the finished medicinal product;
It is necessary to justify the suitability of the primary packaging and the closure system used for storage, transportation, and use of the medicinal product. A description of the potential interaction between the medicinal product and the primary packaging material may be required;
For both non-sterile and sterile medicinal products, the microbiological characteristics of the dosage form must be provided in accordance with the requirements of the Eurasian Economic Union Pharmacopoeia;
To provide relevant additional information on the use of solvents or a dispenser (dispensing device), the compatibility of the medicinal product with the solvents intended for dilution before use or with the dispenser must be substantiated.
3.2.P.3. Medicinal Product Manufacturing Process:
a) A description of the manufacturing method specified in the medicinal product registration application shall be presented in such a way as to provide an adequate summary of the nature of the operations performed.
To this end, the description of the manufacturing method shall include, at a minimum:
a description of the various stages of production, including in-process controls and relevant acceptance criteria to assess whether the processes used in manufacturing may result in any undesirable changes in the components of the dosage form;
a description of the measures necessary to ensure the homogeneity of the medicinal product (in the case of a continuous manufacturing process);
Results of experimental studies to validate the manufacturing process using non-standard manufacturing methods or if the process is critical to the medicinal product;
A description of existing sterilization processes and/or procedures for ensuring aseptic conditions (for sterile medicinal products);
A detailed manufacturing recipe (batch composition).
The name and location of the manufacturing sites and the responsibilities of each manufacturer, including contract manufacturing, must be provided, as well as information on each manufacturing site or testing laboratory used;
b) A description of the analytical methods for quality control of the medicinal product that can be used at intermediate stages of the manufacturing process must be provided to ensure the uniformity of the manufacturing process.
These methods are important for verifying the conformity of the medicinal product with the manufacturing formula, especially in cases where the applicant proposes an analytical method for monitoring the medicinal product that does not include the quantitative determination of all active pharmaceutical ingredients (or all excipients that must meet the same requirements as active pharmaceutical ingredients).
This also applies to cases where the quality control of the medicinal product depends on in-process testing, especially in cases where the method of manufacturing the medicinal product significantly affects its quality;
c) A description, documentation, and results of validation studies for critical production points or quantitative determination methods used in the manufacturing process must be provided.
3.2.P.4. Quality Control of Excipients:
a) A list of all starting materials used for the production of excipients must be provided, indicating at which stage of the process each of them is used. Information on the quality and quality control of these starting materials must be provided, as well as information demonstrating that the materials meet standards for their intended use.
In all cases, colorants must meet the requirements of the relevant article (monograph) of the Pharmacopoeia of the Eurasian Economic Union and the requirements of the Technical Regulation of the Customs Union "Safety Requirements for Food Additives, Flavorings, and Processing Aids" (TR CU 029/2012), adopted by Decision No. 58 of the Council of the Commission dated July 20, 2012. In addition, colorants must meet the purity criteria established by the requirements of acts constituting the Union's law;
b) Specifications and their justification must be provided for each excipient. The analytical methods used to control their quality must be described and properly validated;
c) Particular attention must be paid to excipients of human or animal origin. To comply with special measures to prevent the transmission of animal spongiform encephalopathy pathogens, the applicant must also confirm for excipients that the medicinal product meets, in particular, the requirements of the relevant monograph of the Eurasian Economic Union Pharmacopoeia for minimizing the risk of transmission of these pathogens with manufactured medicinal products.
Compliance with the above requirements can be confirmed by submitting a certificate of conformity with the European Pharmacopoeia monograph on the pathogens of animal spongiform encephalopathy or other documents (data) substantiating this conformity;
d) New excipients:
For excipients used for the first time in a medicinal product or used with a new route of administration, a full description of the manufacturing, properties, and control procedures must be provided, with reference to confirmed preclinical and clinical safety data. This information must be presented in the same manner as specified above for the active pharmaceutical ingredient.
Detailed chemical, pharmaceutical, and biological information must be provided. This information must be formatted as specified in Module 3 for the active pharmaceutical ingredient.
Information on a new excipient may be submitted as a separate document compiled according to the format described above.
If the applicant and the manufacturer of the new excipient are not the same person, such a separate document must be submitted by the manufacturer to the applicant.
Additional information on the toxicity study results for the new excipient must be provided in Module 4 of the registration dossier.
Clinical trial results for the new excipient should be described in Module 5 of the medicinal product registration dossier.
3.2.P.5. Medicinal Product Quality Control. For the purposes of drug quality control, a drug batch is defined as a product comprising the entire quantity of units of the drug manufactured from the same quantity of starting materials and supplies and subjected to the same manufacturing and/or sterilization operations, or a product comprising, in a continuous manufacturing process, all units of the drug manufactured within a specified time period and characterized by homogeneity.
The maximum permissible deviation in the active pharmaceutical ingredient content of a drug on the date of manufacture must not exceed 5%, except in duly justified cases.
Detailed specification information (at the time of release of the drug and throughout its shelf life (expiration date) based on stability testing) must be provided, along with a justification for the selection of quality indicators, test methods, and the validation of these methods.
3.2.P.6. Standard Samples and Materials.
Standard materials and reference standards used for quality control of the medicinal product must be identified and described in detail, unless information on them is already included in the section of the registration dossier containing documents and data on the active pharmaceutical ingredient.
3.2.P.7. Packaging (Closure) System.
A description of the primary (inner) packaging and closure system must be provided, including the materials from which each component of the primary packaging is made, as well as the specifications for these materials. Specifications must include a description and identification of the materials. Information on non-pharmacopeial analytical methods (including method validation) must be provided, if applicable.
For non-functional materials of secondary (consumer) and intermediate packaging, only a brief description is provided. For functional components of secondary (consumer) and intermediate packaging, additional information is provided.
3.2.P.8. Drug Product Stability:
a) A summary of the types of studies performed, the plans (programs) used, and the results obtained during the studies must be provided;
b) Detailed stability study results, recorded in an appropriate format, must be provided, including information on the analytical procedures used and the validation of the analytical procedures.
For vaccines, information on cumulative stability must be provided, if applicable.
c) A post-registration stability study plan (program) and the applicant's obligations to implement this plan must be submitted.
3.2.A. Additions.
3.2.A.1. Manufacturing facilities and equipment.
3.2.A.2. Safety assessment of medicinal products with respect to the presence of extraneous agents.
3.2.A.3. New excipients.
3.2.R.1. Excluded. - Decision of the Council of the Eurasian Economic Commission dated March 17, 2022, No. 36.
3.2.R.2. Manufacturing process validation plan.
A manufacturing process validation plan (for traditional validation) or a continuous verification plan for the manufacturing process (for an extended approach to manufacturing process validation) must be submitted. (clause 3.2.R.2 as amended by Decision of the Council of the Eurasian Economic Commission dated March 17, 2022 No. 36)
3.2.R.3 - 3.2.R.5. Excluded. - Decision of the Council of the Eurasian Economic Commission dated March 17, 2022 No. 36.
4. Requirements for the registration dossier documents provided
in Module 4: Preclinical (Non-clinical) Study Reports
4.1. Contents of Module 4.
4.2. Preclinical (Non-clinical) Study Reports.
In certain cases, in accordance with the requirements for studying individual groups of drugs in Part II of these Requirements and the Rules for Registration and Evaluation of Medicinal Products for Human Use approved by the Commission, this section may provide a review of scientific literature data instead of the results of the Commission's own preclinical studies.
Documents in the registration dossier on pharmacological and toxicological testing must define:
the potential toxicity of the medicinal product and any harmful or undesirable toxic reactions that may be observed under the proposed conditions of its use in humans, with an assessment of these reactions taking into account the relevant pathological conditions;
the pharmacological properties of the medicinal product in terms of qualitative and quantitative indicators and in accordance with the stated clinical use. All results must be reliable and generally applicable. When planning experimental studies and evaluating the obtained data, mathematical and statistical methods of data processing must be used.
Furthermore, the registration dossier must provide information for healthcare professionals on the therapeutic and toxicological potential of the medicinal product. For biological medicinal products such as immunological medicinal products and medicinal products derived from human blood and plasma, the requirements of this module of the medicinal product registration dossier may need to be adapted to the specific medicinal product. Therefore, the applicant must provide a justification for the study program used.
The medicinal product registration dossier, with respect to its study program, must stipulate that:
all studies requiring multiple administrations of the medicinal product are planned taking into account the possible stimulation of antibody formation and the effect of antibodies on the body;
the feasibility of conducting studies of reproductive function, embryonic (fetal) and perinatal toxicity, as well as the possible mutagenic and carcinogenic effects of the medicinal product, are analyzed. If the cause of toxicity is not the active substance (in the description of Module 4 and Module 5, the terms "active (active) substance," "active substance," and "active substance" are analogous), but other substances, then the studies may be omitted, provided that the validation results confirm that these components have been removed from the medicinal product. If an excipient is being used in pharmaceutical practice for the first time, toxicological and pharmacokinetic studies must be conducted.
If there is a risk of significant degradation of the drug during storage, toxicological studies of the degradation products must be considered.
4.2.1. Pharmacology.
In a medicinal product registration dossier, two different aspects of pharmacological studies must be covered:
the pharmacodynamic activity of the medicinal product proposed for therapeutic use must be adequately studied and described. Where possible, recognized and validated study methods (both in vivo and in vitro) must be used. New experimental methods must be described in sufficient detail to ensure their reproducibility. Results must be presented as quantitative indicators (e.g., dose-response and/or time-response curves, etc.). The results must be compared with data characterizing a substance or substances with a similar therapeutic effect. The absence of comparative studies must be justified;
the applicant must study the potential adverse pharmacodynamic effects of the substance in relation to changes in physiological functions in a living organism. Such studies must be conducted at exposures within and beyond the expected therapeutic dose range. If experimental methods are not standard, they must be described in sufficient detail and validated (to ensure their reproducibility and confirm their reliability). Any quantitative changes in the responses to repeated administration of the active substance must be investigated.
Registration dossier documents for studying the pharmacodynamic interactions of fixed-dose combinations of active substances must be based on the pharmacological justification or indications for use of these fixed-dose combinations. In the former case, the pharmacodynamic study must confirm the interactions that make such a combination significant for therapeutic use. In the latter case, when the scientific justification for such a combination of substances is based on experimental therapy, the study establishes the feasibility of confirming in animals the pharmacological action expected from such a combination of active substances in humans and at least the significance of any identified adverse effects. (as amended by Decision of the Council of the Eurasian Economic Commission dated January 30, 2020, No. 9)
4.2.2. Pharmacokinetics.
Pharmacokinetic study documents for a registration dossier include the results of analysis of all processes occurring with the active substance and its metabolites in vivo, and cover the absorption, distribution, biotransformation, and elimination of the active substance and its metabolites.
The study of each stage (absorption, distribution, biotransformation, and elimination) can be performed using physical, chemical, or biological methods, as well as by studying the actual pharmacodynamic activity of the active substance itself.
Information on the distribution and elimination of the active substance from the body is necessary in all cases where data on the distribution and elimination of the active substance are essential for determining the dosage of a medicinal product for humans, as well as for chemotherapeutic agents (antibiotics, etc.) and substances whose use depends on their non-pharmacodynamic effects (e.g., diagnostic drugs, etc.).
In vitro studies are more appropriately conducted using test systems derived from humans than using test systems of animal origin (e.g., studies of active substance binding to proteins, metabolism, and drug interactions).
The registration dossier of a medicinal product must include the results of pharmacokinetic studies of the pharmacologically active substances. When using new fixed-dose combinations of known active substances that have already been studied in accordance with the provisions of acts on the circulation of medicines within the Union, information on the applicant's own pharmacokinetic studies may be omitted from the registration dossier if such a decision is justified by the results of toxicity studies and experimental therapeutic trials. The pharmacokinetic study program should ensure comparison of pharmacokinetic data obtained in animals and humans and extrapolation of the pharmacokinetic results obtained in animals to humans.
4.2.3. Toxicology.
4.2.3.1. Toxicity of the active substance of the medicinal product after a single administration.
Documents in the medicinal product registration dossier for single-dose toxicity studies include a qualitative and quantitative analysis of toxic manifestations that may arise following a single administration of the active substance or substances contained in the medicinal product in the same proportions and in the same physicochemical state as in the finished medicinal product.
Single-dose toxicity studies must be conducted in accordance with Commission guidelines or, in their absence, the relevant guidelines of Member States.
4.2.3.2. Toxicity after repeated (multiple) administration.
Documentation of the registration dossier for repeated (multiple) administration toxicity studies should reflect the identification of any physiological and/or pathological changes that have arisen as a result of multiple administration of the active substance or combination of active substances, and a determination of how these changes are dose-dependent.
The registration dossier should preferably include information obtained from two studies: a short-term study (lasting 2-4 weeks) and a long-term study.
The duration of the long-term study depends on the duration of clinical use of the medicinal product.
Its objectives are to experimentally identify and characterize potential adverse events that should be considered during clinical trials.
The duration of repeated dose toxicity tests should comply with Commission guidelines, or, in their absence, with relevant Member State guidelines.
4.2.3.3. Genotoxicity.
The registration dossier for a medicinal product should include information on the mutagenic and clastogenic potential of the medicinal product. This information is intended to identify any disturbances that the active substance may cause in the genetic material of an individual organism or in cells. Mutagenic substances pose a risk to human health because their action causes mutations in germ cells and the development of hereditary disorders, as well as mutations in somatic cells, which can lead to the development of malignancies. These studies are mandatory for all new active substances.
4.2.3.4. Carcinogenicity.
The registration dossier of a medicinal product contains information on studies of its carcinogenic potential, which are typically conducted in the following cases:
the medicinal product is intended for long-term, continuous or intermittent use throughout the patient's life;
multiple-dose toxicity studies of the medicinal product revealed changes with suspected carcinogenic potential in test systems;
the active substance belongs to a chemical class or is structurally similar to known carcinogens or co-carcinogens (if the medicinal product belongs to the same pharmacological (chemical) class of compounds or has a similar structure, or if the conclusion is based on data from a repeated-dose toxicity study).
There is no need to conduct studies on the carcinogenic potential of clearly genotoxic compounds, as these compounds are carcinogens that pose a risk to humans. If such a medicinal product is intended for long-term treatment of patients, a long-term study may be necessary to detect early oncogenic effects.
4.2.3.5. Reproductive and developmental toxicity.
The drug's registration dossier includes information on studies of possible reproductive dysfunction in males and females, as well as adverse effects on offspring.
These studies are conducted using appropriate trials, which include studies of the medicinal product's effect on reproductive function in sexually mature male and female animals, studies of toxic and teratogenic effects on offspring at all stages of development from conception to sexual maturity, and studies of latent effects when the study medicinal product was administered to pregnant female animals.
The absence of such studies in the drug's registration dossier must be adequately justified.
Depending on the indications for use of the drug, additional studies (e.g., studies of the effects on the development of offspring) may be required when administration of the drug to immature animals is justified.
Preclinical study documents must contain information on embryofetal toxicity studies, which are typically conducted in two mammalian species, one of which must be non-rodents. Perinatal and postnatal toxicity studies must be conducted in at least one animal species.
If the metabolism of the active substance in a particular animal species is known to be similar to that in humans, it is advisable to use that species in the studies.
It is also desirable that one of the animal species be the same one used in the repeated-dose toxicity studies.
The state of scientific knowledge at the time of application should be taken into account when determining the study design. (as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated January 30, 2020)
4.2.3.6. Local Tolerability.
Preclinical study documents must contain information on local tolerability. This information reflects the study and determination of the local effect of the medicinal product (active ingredients and excipients) on body tissues in areas that may come into contact with the medicinal product during its administration during clinical use.
The study strategy must be aimed at distinguishing any mechanical effects of administration or effects due to the physicochemical properties of the medicinal product from toxic or pharmacodynamic effects.
The registration dossier of the medicinal product must demonstrate that the local tolerability study was conducted using a medicinal product developed for human use. As part of this study, animals in the control group are administered a vehicle (solvent) for administration of the study medicinal product and/or excipients. If necessary, information on the additional inclusion of a positive control group or comparator should be provided.
The design of the local tolerability study (choice of animal species, duration, frequency, route of administration, and dose) depends on the objectives of the study and the anticipated clinical use of the drug. Information on local injury reversibility studies should be provided, if necessary.
Information on animal studies may be replaced by data obtained using validated in vitro methods if the study results are of comparable quality and suitable for the safety analysis.
The sensitizing potential of chemicals applied topically (e.g., dermal, rectal, vaginal) should be assessed using at least one test system (guinea pig or local lymph node assay).
5. Requirements for Registration Dossier Documents
in Module 5: Clinical Trial Reports
5.1. Contents of Module 5.
5.2. List of all clinical studies (trials) in tabular form.
Particular attention must be paid to the presence of the following information in the registration dossier:
a) clinical information that must enable the formation of sufficiently substantiated and scientifically reliable conclusions regarding whether the medicinal product satisfies the conditions for registration. The results of all clinical trials (both favorable and unfavorable (negative) results) must be submitted;
b) clinical trials must always be preceded by appropriate pharmacological and toxicological studies (conducted in animals), information on which is provided in Module 4 of the registration dossier. The investigator must be familiar with the conclusions drawn from the pharmacological and toxicological studies. To this end, the applicant must provide them with at least an investigator's brochure containing all relevant information known at the start date of clinical trials (including chemical, pharmacological, and biological data, results of toxicological, pharmacokinetic, and pharmacodynamic studies in animals, as well as results of previous clinical trials providing adequate data necessary to justify the nature, scope, and duration of the planned study). Full reports of pharmacological and toxicological studies must be provided upon request. When using materials obtained from humans or animals, all measures to ensure safety against the possible transmission of infectious agents must be taken before the start of the study.
c) The marketing authorization holder must ensure that the key clinical trial documentation (including individual case report forms) is retained by the owners of the obtained results (except for the medical records of inpatients (outpatients)):
for 15 years from the date of completion or termination of the study;
for 2 years from the date of the last registration in Member States, provided that there are no pending or ongoing registration applications in the Union;
for 2 years from the date of formal termination of the clinical development of the investigational medicinal product.
Medical records of inpatients (outpatients) must be kept under appropriate conditions for the period provided for by the legislation of the Member State, in accordance with the maximum period permitted by the clinical center, institute, or private practice.
Documents may be retained for a longer period if required by relevant regulations or by agreement with the trial sponsor.
The trial sponsor is obligated to notify the clinical center, institute, or private practice if further document retention is no longer necessary.
The trial sponsor or other owner (holder) of the data must retain all other documentation related to the trial for the entire period during which the medicinal product has marketing authorization.
This documentation includes:
the protocol containing the rationale, objectives, statistical plan, and methodology of the trial, including the conditions under which it was conducted, the organization (management) of the trial, detailed information about the trial medicinal product, and the standard (comparator and/or placebo) used;
standard operating procedures;
all written feedback on the protocol and procedures, the investigator's brochure, and the individual case report form for each trial subject;
the final report;
the audit certificate (if any).
The final report must be kept by the trial sponsor or its legal successor for 5 years from the expiration date of the registration certificate for the medicinal product. The registration certificate holder must take additional measures to archive documentation in accordance with the Good Clinical Practice rules of the Eurasian Economic Union approved by the Commission and to implement detailed guidelines (recommendations).
Information about changes in the ownership of existing data must be formally documented, and data and documents must be submitted promptly upon request to the relevant authorized bodies.
d) The description of each clinical trial must contain sufficient information necessary to draw an objective conclusion:
a protocol containing the rationale, objectives, statistical plan, and methodology of the study, including the conditions of its conduct and organization, and detailed information about the medicinal product being studied;
an audit certificate (if any);
a list of investigators (each investigator must provide their name, address, position, qualifications, and responsibilities during the clinical trial);
location of the clinical trial;
Information on each individual patient, including case report forms;
a final report signed by the investigator, and in the case of a multicenter study, by all investigators or the coordinator (principal investigator);
e) The clinical trial data listed in subparagraphs "a" through "d" of this paragraph must be submitted to the authorized bodies responsible for drug registration. By agreement with the authorized bodies, the applicant has the right not to submit some of the listed information. Complete documentation must be provided promptly upon request of the authorized body.
The clinical trial report must reflect the investigator's opinion, based on experimental evidence, on the safety of the drug under normal conditions of use, the tolerability and efficacy of the drug, information regarding indications for use and contraindications, dosage regimen, duration of therapy, as well as special precautions to be taken during treatment and in the event of clinical symptoms of overdose. (as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated 30.01.2020)
In the report on the results of a multicenter study, the coordinating investigator must state the conclusion on the safety and efficacy of the study medicinal product on behalf of all centers during the multicenter study;
f) clinical observations for each type of study must be summarized and include the following data:
the number and gender of subjects who received the drugs;
the selection and age distribution of patients in the study and control groups;
the number of patients who withdrew from the study early and the reasons for this;
information on the outcomes of control group participants if controlled studies were conducted under the above conditions (received no treatment, received placebo, received another medicinal product with a known effect, received another type of treatment without the use of medicinal products);
the frequency of observed adverse reactions;
information about patients belonging to high-risk groups (for example, the elderly, children, pregnant women or women of reproductive age, or patients whose physiological or pathological condition requires special attention);
Parameters or criteria for evaluating efficacy and the results obtained;
statistical evaluation of the results, if required by the study design, and various influencing factors;
g) the registration dossier must include information on the investigator's observations regarding:
any signs of tolerance, dependence, or difficulties experienced by patients upon discontinuation of the medicinal product;
any interactions that occurred during concomitant administration with other medicinal products;
criteria determining the need to exclude certain patients from the study;
fatalities during the study or during the follow-up period;
h) information on the new combination of active substances must be identical to the data on the new medicinal product; the registration dossier must include a justification for the safety and efficacy of the combination;
i) if the registration dossier of the medicinal product is completely or partially missing the data listed in subparagraphs "a" - "h" of this paragraph, an explanation of the reason for the lack of data must be provided. If unexpected results are obtained during clinical trials, additional preclinical toxicology and pharmacology studies must be conducted and the results must be reviewed;
j) If the medicinal product is intended for long-term use, the medicinal product registration dossier must describe changes in pharmacological action resulting from repeated administration of the medicinal product, and the choice of dosage for long-term use must be justified.
5.3. Clinical Trial Reports
5.3.1. Biopharmaceutical Study Reports
The medicinal product registration dossier must include reports on bioavailability, comparative bioavailability, bioequivalence, in vitro-in vivo correlation studies, and a description of the bioanalytical and analytical methods. Where bioequivalence is required to be demonstrated, information on the comparative bioavailability assessment must be included.
In the case of a biowaiver, the medicinal product registration dossier must include a report on in vitro studies. The assessment and conduct of bioequivalence studies, or justification for not conducting bioequivalence studies, must be presented in accordance with the requirements of the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission.
5.3.2. Reports of pharmacokinetic studies using human biomaterials.
Human-derived biomaterials include proteins, cells, tissues, and related materials derived from humans that are used in in vitro or in vivo studies to evaluate the pharmacokinetic properties of active substances. The registration dossier for a medicinal product must include reports on studies of the active substance binding to plasma proteins, hepatic metabolism, and interactions with the active substance, as well as studies using other human-derived biomaterials.
5.3.3. Human Pharmacokinetic Study Reports:
The registration dossier must describe the following pharmacokinetic characteristics:
Absorption (indicating the rate and extent);
Distribution;
Metabolism;
Excretion.
A description of clinically important characteristics (including the significance of kinetic data in determining the dosage regimen for patients at risk) and differences between humans and the animal species used in the preclinical studies must be provided. In addition to information on standard pharmacokinetic studies using a significant number of samples for population pharmacokinetic analysis based on sparse sampling during clinical trials, the registration dossier for a medicinal product may include information on the influence of intrinsic and extrinsic factors on the variability of the dose-response relationship of pharmacokinetic parameters.
Reports on pharmacokinetic studies and initial tolerability studies of the medicinal product in healthy volunteers and patients, reports on pharmacokinetic studies to assess the influence of intrinsic and extrinsic factors, and population pharmacokinetic reports must be provided.
If the medicinal product is coadministered with other medicinal products, the registration dossier for the medicinal product must include a description of the study of their concomitant use, which was conducted to demonstrate a possible change in pharmacological action. Information on the study of the pharmacokinetic interaction of the active substance with other medicinal products or substances must be provided.
5.3.4. Human pharmacodynamic study reports:
a) The registration dossier must confirm the correlation between pharmacodynamic action and efficacy, including:
the dose-response relationship and its development over time;
the justification for the dosing regimen and administration conditions;
the mechanism of action, if possible.
A description of the pharmacodynamic action unrelated to efficacy must be provided. Confirmation of pharmacodynamic effects in humans is not sufficient justification for the presence of any specific therapeutic effect;
b) If the medicinal product is used in combination with other medicinal products, a description of a study of their concomitant use, conducted to demonstrate a possible change in the pharmacological action of the medicinal product, must be provided. Information on the study of the pharmacodynamic interaction of the active substance with other medicinal products or substances must be included.
5.3.5. Efficacy and Safety Study Reports.
5.3.5.1. Reports of Controlled Clinical Trials Confirming the Stated Indications for Use.
Information on clinical trials must be provided. These trials, if possible, must be randomized and controlled, and in which the investigational medicinal product is compared with a placebo and/or a medicinal product with proven therapeutic efficacy. The use of any other study design must be justified. The choice of control groups in each specific case depends on ethical considerations and the scope of application. Therefore, in some cases, it is more appropriate to compare the efficacy of a new medicinal product with that of a medicinal product with proven (established) therapeutic efficacy, rather than with a placebo.
When presenting the assessment, measures must be taken to avoid bias, including randomization and blinding methods. The study protocol included in the medicinal product registration dossier must include a description of the statistical methods used, the number of patients and the reasons for their inclusion in the clinical trial (including power calculations), the significance level applied, and a description of the statistical unit (the statistical parameters used). Measures taken to avoid biased evaluation (especially randomization methods) must be adequately justified and documented. Information about the inclusion of a large number of patients in a clinical trial is not an equivalent substitute for a properly controlled study.
When analyzing safety data, consideration should be given to circumstances that led to dosage adjustments or the need for concomitant use of another medicinal product, serious adverse events, events that led to withdrawal from the clinical trial, and events that resulted in death. Patients or patient groups in the study with increased risk should be identified, with particular attention paid to potentially vulnerable groups in which the number of patients may be small (e.g., children, pregnant women, elderly patients with compromised health, patients with significant metabolic or excretory disorders, etc.). A final safety assessment should be described for the potential uses of the medicinal product.
5.3.5.2. Reports of uncontrolled clinical trials, reports of data analyses from multiple studies, and reports of other clinical trials.
These reports should be included in the registration dossier of the medicinal product.
5.3.6. Reports of post-marketing experience.
If a medicinal product is already registered in other countries, the medicinal product registration dossier must include information on adverse reactions to the medicinal product in question and medicinal products with the same active substance (if possible, in comparison with their clinical use).
5.3.7. Case Reports and Patient Lists.
The medicinal product registration dossier must be accompanied by case report reports and patient lists. These must be submitted in the same manner as clinical trial reports, indexed by study and maintaining the confidentiality of the personal data of the study patients.
The registration dossier must also include data from laboratory and instrumental research methods, as well as statistical analysis of the clinical trial results.
II. Special Requirements for Drug Registration Dossier Modules
6. Requirements for Registration Dossier Documents for Generic Drugs
The registration dossier for a generic medicinal product is submitted in accordance with the requirements of this section, taking into account the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission.
The selection of a reference product in bioequivalence studies is carried out in accordance with the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission.
The bioequivalence of a generic medicinal product to the original medicinal product must be demonstrated by appropriate bioavailability studies in accordance with the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission.
The general characteristics of the medicinal product and the instructions for medical use of the generic medicinal product must correspond to the general characteristics of the medicinal product and the instructions for medical use of the original medicinal product. If the indications for use differ from the original medicinal product in terms of an expanded dosage regimen, dosage regimen, or route of administration, the instructions for medical use of the generic medicinal product must include the results of relevant clinical studies.
6.1. Module 1.
In Section 1.8.2 of the registration dossier for the generic medicinal product, the applicant must provide a summary (up to 5 pages) of the justification and facts demonstrating that the medicinal product is a generic medicinal product of the corresponding original medicinal product. This summary must contain information about the product, its qualitative composition and quantitative content of the active substance, its dosage form, and the safety and/or efficacy profile of its active substance compared to the active substance of the original medicinal product, as well as, if necessary, information on the bioavailability and bioequivalence of this product.
In certain cases, a risk management plan may be required.
If some of the elements listed in this paragraph are missing from the summary, a justification for their absence must be provided in the corresponding section of the registration dossier for the medicinal product.
6.2. Module 2.
The preclinical and clinical data review should include:
a summary of the impurity profile of the active substance (and, where applicable, potential degradation products formed during storage of the medicinal product) in batches of the medicinal product to be marketed;
an assessment of bioequivalence studies or an explanation of why bioequivalence studies were not conducted;
updated literature on the active substance of the medicinal product (this requirement may be met by providing references to publications in peer-reviewed journals);
previously unknown points in the general characteristics of the medicinal product or points arising from the characteristics of the drug and/or its therapeutic group, which should be analyzed in the preclinical and clinical reviews (summaries) and supported by evidence from the scientific literature and/or evidence obtained as a result of additional studies;
additional information proving that the safety and/or efficacy profiles of the claimed drug do not differ from those of the reference drug in the event of differences in the chemical forms of the active substance (salts, esters, isomers, mixtures of isomers, complexes or derivatives of the active substance of the reference drug).
6.3. Module 3.
Module 3 of the medicinal product registration dossier must be submitted in full.
6.4. Module 4 and Module 5.
Results of bioequivalence studies conducted, where necessary, should be included in Section 5.3.1 of the medicinal product registration dossier. Results of demonstrating equivalence according to the biowaiver should be presented in Subsection 5.3.1.2. A bioanalytical method validation report must also be submitted. Data on concentration, pharmacokinetics, and statistical analysis must also be provided.
The bioequivalence study report must include information about the investigator (including their place of work), the organization where the studies were conducted, and the study duration. Audit certificates (if any) must be attached to the report.
The bioequivalence study report or a separate official letter must confirm the selection of the reference medicinal product in accordance with the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission. The following information about the reference medicinal product must also be provided:
trade name;
strength;
dosage form;
marketing certificate holder;
date of registration;
marketing certificate number;
member state in which the reference medicinal product is registered;
batch number;
manufacturer's name;
expiration date;
country of purchase.
A recommendation from the Expert Committee on Medicinal Products on the selection of the reference medicinal product (if any) must be provided.
The name and composition of the test product, batch size, manufacturing date, and, if possible, expiration date must be indicated.
The study report appendix also includes certificates of analysis for the reference and test products used in the bioequivalence study.
An official letter signed by the manufacturer's authorized quality representative confirming that the quantitative composition and manufacturing process of the test product are identical to the quantitative composition and manufacturing process of the medicinal product submitted for registration should be submitted.
Additional information (in accordance with the structure of the general technical document of the medicinal product registration dossier) should be provided demonstrating that the safety and/or efficacy profiles of the submitted medicinal product do not differ from those of the reference product in the event of differences in the chemical forms of the active substance (salts, esters, isomers, mixtures of isomers, complexes, or derivatives of the active substance of the reference product).
Results of preclinical and clinical studies of the generic medicinal product, conducted where necessary, should be included in the relevant sections of Module 4 and Module 5.
Bioavailability studies are not required if there is evidence that the generic medicinal product meets the criteria specified in the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission.
If the active substance of the generic medicinal product is a different salt, ester, or derivative of the active substance of the registered medicinal product, additional information (bibliographic reviews) or reports of relevant preclinical and/or clinical studies (comparative bioavailability studies) demonstrating the absence of changes in the pharmacokinetics, pharmacodynamics, and/or toxicity of the generic medicinal product must be provided. If such evidence is not provided, this substance is considered a new active substance.
7. Requirements for the registration dossier of a hybrid medicinal product
The registration dossier for a hybrid medicinal product must contain additional data from preclinical and clinical studies in accordance with the requirements of this section.
7.1. Module 1.
In Section 1.8.2 of the registration dossier for a generic medicinal product, the applicant must provide a summary (up to 5 pages) of the justification and facts demonstrating that the medicinal product is a hybrid medicinal product relative to the corresponding original medicinal product. The summary must include information about the product, active pharmaceutical ingredient, dosage form, dosage, indications for use, route of administration compared to the original medicinal product, and, if necessary, information on the bioavailability and bioequivalence of this product.
If certain elements are missing, a justification for their absence must be provided in the section of the registration dossier for the medicinal product corresponding to the location of the element.
7.2. Module 2.
The review of preclinical and clinical data should pay particular attention to the following elements:
a summary of the impurity profile of the active substance (and, where applicable, possible degradation products formed during storage of the medicinal product) in batches of the medicinal product to be marketed;
updated literature on the active substance of the medicinal product (this requirement may be met by providing references to articles in peer-reviewed journals);
previously unknown points in the general characteristics of the medicinal product or points arising from the characteristics of the drug and/or its therapeutic group, which should be analyzed in preclinical and clinical reviews (summaries) and supported by evidence from the scientific literature and/or evidence obtained as a result of additional studies;
additional information demonstrating that the safety and/or efficacy profiles of the proposed medicinal product do not differ from those of the reference medicinal product in the event of different chemical forms of the active substance (salts, esters, isomers, mixtures of isomers, complexes, or derivatives of the active substance of the reference medicinal product).
7.3. Module 3.
7.4. Module 4 and Module 5.
Results of preclinical and/or clinical trials of the hybrid medicinal product should be included in the relevant sections of Module 4 and Module 5.
Procedure for conducting additional studies required for
generic and hybrid medicinal products or
for registration applications with extended requirements
Characteristics of medicinal products or applications for registration
Additional data required
Various salts, esters, complexes, and their derivatives (with the same active moiety)
Evidence that there are no changes in the pharmacokinetics of the active moiety, pharmacodynamics, and/or toxicity that could significantly affect the safety and/or efficacy profile (otherwise, the active substance should be considered a new active substance)
Different route of administration or different dosage form:
New route of administration (for parenteral administration, distinctions must be made between intra-arterial, intravenous, intramuscular, subcutaneous, and other routes of administration)
Different dosage form (with the same route of administration)
Clinical data (safety and efficacy), pharmacokinetics, and relevant preclinical data (e.g., local tolerability) (if available)
Different dosage with the same route of administration (dosage form) and indications for use
Comparative bioavailability data in accordance with the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission
Super-bioavailable drugs, maintaining the same dosing interval but with a reduced dose, designed to achieve similar plasma (blood) concentrations
In certain cases, comparative bioavailability studies in accordance with the rules for conducting bioequivalence studies of medicinal products within the Eurasian Economic Union, approved by the Commission, are sufficient
8. Requirements for registration dossier documents for
medicinal products with well-studied medical use
The following special rules apply to medicinal products with confirmed efficacy and an acceptable level of safety (which include, for example, medicinal products made from raw materials of natural origin (birch tar, snake venom, bee products, medicinal leeches, bile, minerals, etc.), whose active substance has been well studied in medical use, vitamins and vitamin-mineral complexes, as well as medicinal products whose pharmacological activity is determined by a complex of biologically active substances of natural origin, antiseptic solutions (hydrogen peroxide, iodine, brilliant green, etc.), water for injection, adsorbents (activated carbon, etc.), carminative medicinal products, and medicinal products from the group of irritants and enveloping agents).
The applicant must submit Module 1, Module 2, and Module 3 of the registration dossier of the medicinal product in accordance with the requirements of Part I of these Requirements.
In Modules 4 and 5, the detailed scientific bibliography must include the preclinical and clinical characteristics of medicinal products.
To confirm well-studied medical use, the following data must be provided:
a) Factors that must be taken into account when determining the well-studied medical use of medicinal product components:
the period during which the active substance has been used in medical practice;
quantitative aspects of the use of the active substance;
frequency of scientific publications and the relevance of the use of the active substance in the 5 years prior to the date of filing the application for registration of the medicinal product (with reference to publications in scientific sources);
consistency of scientific assessments.
To determine the well-studied medical use of different active substances, assessments may be made over different time periods. The period of time required to determine the well-studied medical use of the active substance must be at least 10 years from the date of its documented use in at least three Member States. Biological medicinal products and medicinal products that require bioequivalence studies and/or clinical trials are not considered to be medicinal products with well-studied medical use;
b) The registration dossier materials submitted by the applicant must include documents and data on all aspects of the safety and efficacy assessment, containing or providing a reference to a review of the relevant literature, taking into account pre- and post-registration studies and published scientific literature regarding the results of epidemiological studies, and especially comparative epidemiological studies, all documentation (both with positive assessment results and with negative results of the medicinal product assessment). Bibliographic references to other sources of evidence of the efficacy and safety of the medicinal product (post-registration studies, epidemiological studies, etc.), with the exception of data related to control and testing methods, may be evidence of the safety and efficacy of the medicinal product, provided that the registration dossier clearly explains and justifies the use of these sources of information;
c) The documents and data of the registration dossier of the medicinal product must substantiate why an acceptable level of safety and/or efficacy can be considered proven despite the absence of some studies;
d) In the preclinical and/or clinical reviews of Module 2 of the medicinal product registration dossier, it is necessary to explain the significance of any data presented for the medicinal product proposed for registration if they differ from the data of an already registered medicinal product. It is necessary to provide a justification for whether the proposed medicinal product can be considered similar to the already registered medicinal product despite the existing differences;
e) Post-registration experience with the medicinal product may be presented in the form of information on the use of other medicinal products containing the same active substances;
f) If the medicinal product has experience in third-country markets, a periodic safety update report must be submitted for the medicinal product for 5 years prior to the date of filing the registration application.
9. Requirements for the Registration Dossier of Combination
of Medicinal Products
For new medicinal products that are a combination of two or more previously known active substances in a single dosage form (i.e., active substances included in a combination medicinal product but previously registered in single-component products), a full registration dossier (Modules 1-5) must be submitted in accordance with Part I of these Requirements. Module 3 includes information on the production, quality control, and manufacturer of each active substance included in the combination medicinal products (single-component medicinal products presented in combination packaging cannot be considered combination medicinal products). Modules 4 and 5 present the results of preclinical and clinical studies of the active substance combinations submitted for registration.
When preparing the registration dossier for a combination medicinal product, as well as when reviewing the relevant registration dossier documents, the provisions of the acts of Union bodies in the field of preclinical and clinical development of combination medicinal products are followed.
(paragraph introduced by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
10. Requirements for the Registration Dossier
of a Biosimilar (Biosimilar) Medicinal Product
To register a biosimilar (biosimilar) medicinal product, data from comparative studies of it with a reference biological medicinal product must be submitted. The quality, safety, efficacy, and immunogenicity of the biosimilar (biosimilar) medicinal product during the manufacturing, preclinical, and clinical phases of its development must be compared with the same reference biological medicinal product in accordance with the rules for the study of biological medicinal products within the Eurasian Economic Union, approved by the Commission. The registration dossier for a biosimilar medicinal product is submitted in accordance with the requirements of this section.
10.1. Module 1.
10.1.1. In Section 1.8.2 of Module 1 of the registration dossier, the applicant must provide a summary of the justifications and facts demonstrating that the medicinal product for which the application is submitted is a biosimilar medicinal product to the original medicinal product. The summary must contain information on the medicinal product, active substance, dosage form, dosage, indications for use, and route of administration, compared with similar information on the original medicinal product.
10.1.2. In Section 1.10 of Module 1 of the registration dossier, a risk management plan for the biosimilar medicinal product being submitted for registration is submitted along with brief information on the marketing authorization holder's pharmacovigilance system.
10.1.3. If certain elements of the registration dossier are missing, a justification for their absence should be provided in the relevant section of this module.
10.2. Module 2.
The quality data review, preclinical data review, and clinical data review must additionally provide comparative information on the proposed medicinal product and the reference medicinal product, as well as the criteria for selecting the reference medicinal product and their rationale.
The study report or a separate official letter must confirm the selection of the reference medicinal product in accordance with the rules for conducting trials of biological medicinal products within the Eurasian Economic Union, approved by the Commission. The following information about the reference medicinal product must also be provided:
(as amended by Decision of the Council of the Eurasian Economic Commission dated 30.01.2020 N 9)
strength and dosage form;
name of the marketing authorization holder;
date of registration and number(s) of the marketing authorization;
member states in which the reference medicinal product is registered;
batch number of the reference medicinal product used for research and pharmaceutical development;
Name of manufacturer;
Expiration date;
Country of purchase.
If available, a recommendation from the Expert Committee on Medicinal Products regarding the selection of the reference product must be provided.
The name and composition of the study product(s), batch size, manufacturing date, and, if possible, expiration date must be indicated.
A justification for the scope of comparative preclinical and/or clinical studies conducted must be provided based on the requirements of the rules for conducting biological medicinal product trials within the Eurasian Economic Union, approved by the Commission. Copies of the batch analysis certificates for the reference and study products used in the study must be attached to the study report.
10.3. Module 3.
In Module 3 of the medicinal product registration dossier, the following additional data must be provided, taking into account the requirements of the rules for conducting biological medicinal product trials within the Eurasian Economic Union, approved by the Commission:
a) confirmation of the similarity of the molecular and biological characteristics of the active substances of the biosimilar medicinal product and the reference biological medicinal product (data on the primary and higher-order structures, post-translational modifications (including, in particular, glycoforms), biological activity, purity, and impurities);
b) confirmation of the similarity of the medicinal product characteristics (dosage form, quantitative and qualitative composition, dosage, route of administration, storage conditions, shelf life, stability, and impurity profile) of the biosimilar and the reference biological medicinal product;
c) if there are differences in impurities and excipients, their potential impact on the clinical safety and efficacy profile of the biosimilar must be assessed and the acceptability of these differences must be justified (based on the results of the company's own research or data provided in the scientific literature); if there are differences whose clinical significance is unknown, especially in terms of safety, additional studies are required in the pre- and post-registration period;
d) a complete description and data on the manufacturing process (starting with the development of expression constructs (systems), the original producer strain and cell banks, cell culture (cultivation), collection, purification, additional manufacturing processes after product isolation and purification, filling of containers for bulk product and finished dosage form, and ending with storage);
e) data on studies conducted during the pharmaceutical development of a biosimilar medicinal product to determine and justify its dosage form, composition, and packaging (closure) system (including their integrity to prevent microbial contamination);
f) specification of the biosimilar medicinal product, which must contain and regulate the important quality parameters of the medicinal product established for the reference biological medicinal product (such as identity, purity, potency, molecular heterogeneity in terms of size, charge, and hydrophobicity (where these can be determined), degree of sialylation, number of individual polypeptide chains, glycosylation of the functional region, degree of aggregation, impurities such as host cell protein and DNA, etc.);
g) stability studies.
10.4. Module 4.
Module 4 should present the results of preclinical (non-clinical) studies of a biosimilar medicinal product compared to a reference biological medicinal product in accordance with the requirements of the rules for conducting studies of biological medicinal products within the Eurasian Economic Union, approved by the Commission.
10.5. Module 5.
Module 5 presents documents and data in accordance with the requirements of the rules for conducting studies of biological medicinal products within the Eurasian Economic Union, approved by the Commission, which contain:
a) the results of clinical trials of a biosimilar medicinal product in comparison with a reference medicinal product, which include:
the results of pharmacokinetic studies (single-dose pharmacokinetic studies, repeated-dose pharmacokinetic studies (if there is a dose- and time-dependent pharmacokinetic comparison of a biosimilar medicinal product and a reference medicinal product) should include a study of absorption, bioavailability, elimination characteristics, i.e., clearance and/or half-life), pharmacodynamic studies (in this case, pharmacodynamic effects should be assessed in a suitable population and using doses from the steep part of the dose-response curve obtained in preclinical studies, and pharmacodynamic markers should be selected depending on their clinical significance));
data from comparative clinical studies, including an assessment of the type, frequency, and severity of adverse events (reactions), immunogenicity studies in the target group (comparison of the frequency and type of antibodies formed, potential clinical consequences of the immune response for the biosimilar drug and the reference drug); immunogenicity should be studied in the patient population with the highest risk of an immune response and immune-related adverse reactions;
justification of the antibody determination strategy, including the selection, evaluation, and characterization of methods, establishment of sample collection time (including before drug administration), sample volumes, processing, and storage, as well as statistical methods for data analysis; analytical methods for antibody determination should be validated for the chosen research purpose; a preliminary analysis of sufficient method sensitivity should be conducted; neutralizing antibodies should be determined;
indication of the observation period during immunogenicity studies (which must correspond to the planned duration of treatment and the expected time of antibody formation and must not be less than 12 months (if the study duration is different, justification must be provided));
Clinically significant cases of antibody titer formation and titer maintenance over a certain period of time (while it is necessary to study potential changes in the nature of the immune response and clinical consequences in the pre- and post-registration periods);
The main clinical data must be obtained using the medicinal product manufactured using the final manufacturing process, i.e., the medicinal product for which the registration application is submitted. For any deviations from these requirements, the applicant must provide justification and, if necessary, data from additional comparability studies conducted in accordance with the rules for conducting studies of biological medicinal products within the Eurasian Economic Union, approved by the Commission for the medicinal product with the final and earlier formulation;
b) a risk management plan, including a safety specification (with a description of the important identified and potential negative safety aspects of the reference drug, class of drugs and (or) biosimilar) and a pharmacovigilance plan for the biosimilar drug in the post-registration period (with a description of the planned post-registration activities and measures to minimize the risk based on the safety specification, the risk management plan, including the provision of information materials for patients and (or) medical and pharmaceutical workers).
11. Registration dossier for registration applications
(as amended by Decision No. 36 of the Council of the Eurasian Economic Commission
dated March 17, 2022)
A marketing authorization for a medicinal product is granted subject to the fulfillment of specific obligations if the applicant can demonstrate (justify) that it is impossible to provide comprehensive data on the efficacy and safety of the medicinal product under normal conditions of use for one of the following reasons:
the proposed indications for the medicinal product are so rare that the applicant cannot reasonably expect to receive comprehensive confirmation of the evidence for the efficacy and safety of the medicinal product;
the current state of scientific knowledge does not permit the provision of comprehensive information on the efficacy or safety of the medicinal product;
obtaining information on the efficacy or safety of the medicinal product would be contrary to generally accepted principles of medical ethics.
These obligations include the following:
the applicant must complete, within the timeframe established by the competent authority of the reference Member State, a defined safety or efficacy study program, the results of which allow for a reassessment of the benefit-risk balance;
The medicinal product in question must be classified as a "prescription drug" and, in certain cases, only used under strict medical supervision (e.g., in a hospital setting). For radiopharmaceuticals, this means use under the supervision of an appropriately authorized person.
The general characteristics of the medicinal product, the instructions for medical use of the medicinal product (package insert), the registration certificate, and any medical information must contain information that draws the user's attention to the fact that the available data on the medicinal product are insufficient to support certain aspects of safety or efficacy.
11.1. Requirements for the composition of the registration
dossier submitted as part of the procedure for bringing it into compliance
with the Union's requirements
(introduced by Decision No. 114 of the Council of the Eurasian Economic Commission
dated October 20, 2023)
As part of the procedure for bringing an application into compliance with Union requirements, the applicant shall submit, as part of Module 1 of the registration dossier, the documents specified in Sections and Clauses 1.0, 1.1, 1.2.1, 1.2.2, 1.3, 1.3.1, 1.3.2, 1.5.3, 1.5.4, 1.5.7, 1.6.1, 1.6.2, 1.6.7, 1.6.9, 1.6.11, 1.10, 1.10.1, and 1.10.2 of these Requirements.
If necessary, the documents listed in Clauses 1.3.4, 1.5.5, 1.5.6, 1.8.2.6, 1.9.1, 1.10.3, and 1.10.4 of these Requirements shall also be submitted.
Module 2 of the registration dossier may be submitted in the form of summary sections with updated amendments (in the form of an appendix) or submitted in full at the applicant's initiative.
As part of the procedure for bringing the registration dossier into compliance with Union requirements, the submission of the documents specified in paragraphs 3.2.S.2.3–3.2.S.2.6, 3.2.S.4.3, 3.2.S.4.5, 3.2.S.7.2, 3.2.P.2.2.3, 3.2.P.2.3–3.2.P.2.6, 3.2.P.4.3, 3.2.P.4.6, 3.2.A, 3.2.A.2, 3.2.A.3, 3.2.A.3.3, and 3.2.A.3.7 of these Requirements is optional (with the exception of the registration dossier of biological medicinal products). If they are not submitted within the specified procedure, the documents must be submitted as part of the registration confirmation or when making changes to the registration dossier.
Data from preclinical and clinical studies conducted in accordance with the legislative requirements of Member States are presented in Modules 4 and 5 of the medicinal product registration dossier as reports without the mandatory procedure of aligning with Union requirements and are attached to the reports on preclinical (non-clinical) studies and clinical studies (trials) of the medicinal product.
The requirements for registration dossier documents for individual groups of drugs, as set out in Modules 4 and 5, are provided for in Sections II - IV of these Requirements.
As part of the aligning procedure with Union requirements, the authorized body (expert organization) of a Member State has the right to request information available from the applicant upon request during the examination of the medicinal product registration dossier (if necessary).
III. Special Requirements for Registration
Dossier Documents for Certain Types of Medicinal Products
12. Biological Medicinal Products
Module 3 of the registration dossier for vaccines and blood products is compiled taking into account the specific features of these medicinal products specified in this section.
12.1. Plasma-Derived Medicinal Products
For medicinal products derived from human blood or plasma, the requirements for starting materials and raw materials derived from human blood (plasma) may be replaced by a plasma master file compliant with this section, as an exception to the general requirements for Module 3 of the registration dossier presented in Part I of these Requirements.
12.1.1. General Principles for Compiling the Registration Dossier
For the purposes of these Requirements:
the plasma master file is an independent document, separate from the medicinal product registration dossier, containing all relevant detailed information on the characteristics of all human plasma used as starting material and/or raw materials in the production of subfractions or intermediate fractions, components of excipients, or active substances that are part of medicinal products or medical devices;
each center or institution fractionating (processing) human plasma must prepare and maintain an updated set of detailed relevant information specified in the plasma master file;
the plasma master file must be submitted by the applicant or marketing authorization holder to the authorized body of the Member State on paper or as an electronic document. If the applicant or marketing authorization holder is not the owner of the master file, the master file must be available to the applicant or marketing authorization holder for submission to the authorized bodies of the Member States. In any case, the applicant or marketing authorization holder is responsible for the quality, safety, and efficacy of the medicinal product;
If the registration dossier pertains to a plasma-derived component, then the plasma used as the starting material (raw material) must be referenced to the owner's master file.
12.1.2. Additional Requirements for the Contents of Registration Dossier Materials.
The owner's master file must contain the following information about the plasma used as the starting material (raw material):
Origin of the plasma:
Information on the centers or institutions where blood (plasma) is collected, including inspection data and the submission of a special permit for this type of activity, as well as epidemiological data on blood-borne infections in the region where the blood (plasma) is collected;
Information on the centers or institutions where donations and plasma pools are monitored, including the inspection and regulatory status of these centers or institutions;
Criteria for the selection (exclusion) of blood (plasma) donors;
A description of the current system that allows for tracking the path of each donation from the institution where the blood (plasma) is collected to the finished medicinal product and vice versa;
Plasma quality and safety:
quality compliance with the articles (monographs) of the Eurasian Economic Union Pharmacopoeia or, if absent, with the articles (monographs) of the state pharmacopoeias of the member states or the main pharmacopoeias in accordance with the Concept of Harmonization of Pharmacopoeia of the Eurasian Economic Union Member States;
testing of collected blood (plasma) and its pools for the presence of infectious agents, including information on the testing methods and, in the case of plasma pools, validation data for the methods used;
technical specifications of blood and plasma collection containers, including information on the anticoagulant solutions used;
plasma storage and transportation conditions;
storage procedure for any material used for production and/or quarantine period;
plasma pool characteristics;
A description of the established system of interaction between the manufacturer of a plasma-derived medicinal product and/or the center or institution fractionating and/or processing the plasma and the center or institution collecting and testing blood (plasma), as well as the plasma specifications agreed upon between them.
The plasma master file must also contain a list of the medicinal products it covers, regardless of whether these medicinal products are registered, are in the registration process, or are in clinical trials.
12.1.3. Review of the registration dossier and issuance of an opinion.
For unregistered medicinal products, the applicant must submit to the authorized body of the Member State the complete registration dossier of the medicinal product, which will be accompanied by a separate plasma master file, if one has not previously been compiled and submitted.
The plasma master file is subject to review as part of the registration and review of the medicinal product's registration dossier. If the review results are positive, a Union opinion (certificate) is issued for the master file, which must be accompanied by an expert report. The issued opinion (certificate) is valid throughout the Union.
The plasma master file is subject to annual renewal and re-evaluation.
If changes are made to the plasma master file, it is subject to review in accordance with the amendment procedure.
The issued opinion (certificate) is accepted by the authorized bodies of the Member States during registration procedures (confirmation of registration, amendments to the registration dossier) of medicinal products derived from human plasma (blood).
12.2. Vaccines
For vaccines for human use, as an exception to the general requirements for Module 3 of the "Active Pharmaceutical Substance" registration dossier, the following requirements apply based on the use of the Vaccine Antigen Master File system.
A registration dossier for a vaccine other than a human influenza vaccine must include a Vaccine Antigen Master File for each antigen that constitutes the active substance of that vaccine.
12.2.1. General Principles.
The Vaccine Antigen Master File is a separate part of the vaccine registration dossier that contains all relevant biological, pharmaceutical, and chemical information regarding each of the active substances that comprise the medicinal product. This separate part may be common to one or more monovalent and/or combination vaccines submitted by the same applicant or marketing authorization holder.
A vaccine may contain one or more different vaccine antigens. The number of active substances in a vaccine corresponds to the number of vaccine antigens. A combination (polyvalent) vaccine contains at least two different vaccine antigens intended to prevent one or more infectious diseases.
A monovalent vaccine is a vaccine that contains one vaccine antigen intended to prevent one infectious disease.
12.2.2. Additional Requirements for the Contents of Registration Dossier Materials.
The vaccine antigen master file must contain the following information, extracted from the relevant section (Active Pharmaceutical Substance) of Module 3 "Quality," as described in Part I of this Appendix.
Active Substance
1. General information, including information on compliance with the article (monograph) of the Pharmacopoeia of the Eurasian Economic Union, or, in the absence of such articles (monographs), articles (monographs) of the pharmacopoeias of the Member States or the primary pharmacopoeias in accordance with the Concept of Harmonization of Pharmacopoeias of the Member States of the Union.
2. Information about the manufacturer of the active substance: information about the production process, starting materials and raw materials, special measures regarding spongiform encephalopathies and safety assessment of foreign infectious agents, premises and equipment.
(as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
3. Characteristics of the active substance.
4. Quality control of the active substance.
5. Standard samples and materials.
6. Primary packaging and closure system of the active substance.
7. Stability of the active substance;
c) Excluded. - Decision of the Council of the Eurasian Economic Commission dated January 30, 2020, No. 9.
For new vaccines containing a new vaccine antigen, the applicant must submit to the authorized body a complete registration dossier, including all vaccine antigen master files for each vaccine antigen that is part of the new vaccine, if a vaccine antigen master file for such vaccine antigen is not available. If the examination results are positive, a Union certificate is issued for the master file, which must be accompanied by an expert report. The issued certificate is valid throughout the territory of the Union. These requirements also apply to each vaccine that consists of a new combination of vaccine antigens, regardless of whether one or more of these antigens are part of vaccines already registered in Member States.
When changes are made to the vaccine antigen master file, the master file is subject to review in accordance with the amendment procedure.
The issued conclusion (certificate, attestation) of the Union is accepted by authorized bodies during vaccine registration procedures (confirmation of registration, amendments to the registration dossier).
12.2.3. Review and issuance of conclusions.
(Clause 12.2.3 introduced by Decision No. 9 of the Council of the Eurasian Economic Commission dated 30.01.2020)
12.3. Simplified Registration Dossier for Vaccines
with Well-Studied Medical Use, Manufactured
in Member States Before 2000
The following rules apply to vaccines whose vaccine antigen has been well-studied for medical use, with confirmed efficacy and an acceptable level of safety, and manufactured in Member States before 2000.
The applicant must complete Module 3 of the registration dossier in accordance with the provisions of Part I and Section 12.2 of Part II of this Appendix.
In Modules 4 and 5 of the registration dossier, instead of preclinical and clinical study reports, a scientific review bibliography is submitted, which must include the preclinical and clinical characteristics of the vaccine.
13. Radiopharmaceuticals and Precursors
The registration dossier for radiopharmaceuticals and their precursors is submitted in accordance with the requirements of this section.
13.1. Radiopharmaceuticals
13.1.1. Module 3.
In a radiopharmaceutical kit that is radiolabeled after delivery by the manufacturer, the "active substance" means the part of the kit intended to carry or bind the radionuclide. The description of the radiopharmaceutical kit manufacturing method must include detailed data on the kit production and the recommended final processing for the production of the radiopharmaceutical. The required radionuclide specifications must be described in accordance with the general or specific monograph of the Pharmacopoeia of the Eurasian Economic Union (if such monograph exists) or, in the absence of such monographs, in accordance with the monographs of the pharmacopoeias of the Member States or the primary pharmacopoeias in accordance with the Concept of Harmonization of Pharmacopoeias of the Member States of the Union.
All compounds required for radiolabeling, as well as the structures of the radiolabeled compounds, should be described.
Nuclear reactions of the radionuclides must be analyzed.
The parent and daughter radionuclides of the generator are considered active substances.
Information on the nature of the radionuclide, isotope identity, possible impurities, carrier, application, and specific activity must be provided.
Source materials include the target materials for irradiation.
Chemical (radiochemical) purity and its relationship to biodistribution must be considered.
Radionuclide purity, radiochemical purity, and specific activity must be described.
For generators, detailed test data for the parent and daughter radionuclides are required. For generator-eluates, test results for the parent radionuclides and other components of the generator system must be provided.
The content of active substances should be expressed based on the mass of the active moiety of the molecule only for radiopharmaceutical kits. For radionuclides, radioactivity must be expressed in becquerels, with the date and, where appropriate, the time and time zone. The type of radioactivity must be specified.
Specifications for a medicinal product that is a radiopharmaceutical kit must include test results for the properties of the product after incorporation of the radioactive label. Appropriate controls for the radiochemical and radionuclide purity of the radiolabeled compound must be included. Any material required for incorporation of the radioactive label must be identified and quantified.
Stability information must be provided for isotope generators, isotope kits, and radiolabeled medicinal products. Stability must be specified when using radiopharmaceuticals in reusable containers.
13.1.2. Module 4.
Toxicity may be related to the radiation dose. In diagnostics, toxicity is an undesirable consequence of the use of radiopharmaceuticals; In therapy, this is a desirable property; therefore, when assessing the safety and efficacy of radiopharmaceuticals, it is necessary to specify drug product requirements and radiation dosimetry aspects. The effect of radiation on the human organ (tissue) must be documented. The absorbed dose of radiation must be calculated using the system of internationally recognized units of measurement used for a specific route of administration.
13.1.3. Module 5.
Clinical trial results are provided, if necessary. The absence of clinical trial results is justified in clinical reviews (Module 2 of the registration dossier).
13.2. Radiopharmaceutical precursors used for radiolabeling.
For a radiopharmaceutical precursor intended solely for radiolabeling, information must first be provided on the potential consequences of insufficient radiolabeling efficiency or in vivo dissociation of the radiolabeled conjugate—that is, issues related to the effects of the free radionuclide on patients. In addition, relevant information regarding risk factors, i.e., radiation exposure to hospital personnel and the environment, must also be provided.
Specifically, the following information must be provided:
13.2.1. Module 3.
The requirements for the content of Module 3 of the registration dossier specified in Section 3 of Part I of this Appendix shall be applied to the registration of radiopharmaceutical precursors insofar as subparagraphs "a" through "i" are applicable.
13.2.2. Module 4.
Regarding single- and multiple-dose toxicity, the results of preclinical studies conducted in accordance with the rules of good laboratory practice approved by the Commission must be provided. Mutagenicity studies of radionuclides are not considered applicable in this case.
Information on the chemical toxicity and disposition of the "cold" nuclide (containing no radioactive substances) must be provided.
13.2.3. Module 5.
Clinical information obtained during clinical trials using the precursor itself is not considered relevant in the case of a radiopharmaceutical precursor intended solely for the introduction of a radioactive label. Information confirming the clinical efficacy of the radiopharmaceutical precursor when attached to the corresponding carrier molecules must be provided.
14. Homeopathic Medicinal Products
14.1. Module 3.
Terminology.
The scientific name in Latin of the homeopathic pharmaceutical substance described in the registration dossier must correspond to the scientific name in Latin of the monograph of the Pharmacopoeia of the Eurasian Economic Union (if available), or the homeopathic pharmacopoeia of the Union member states, or the homeopathic pharmacopoeia of Germany, the French pharmacopoeia, and the European Pharmacopoeia.
Control of Source Materials.
The registration dossier must include documents confirming the quality of all components of the product, including the homeopathic pharmaceutical substance and excipients, meets the requirements of the references to monographs or regulatory documents provided in the "Composition" section. For homeopathic pharmaceutical substances, these are monographs of the Eurasian Economic Union Pharmacopoeia (if available) or the pharmacopoeias of the member states, or monographs of the German Homeopathic Pharmacopoeia, or monographs of the French Pharmacopoeia, or the European Pharmacopoeia; for excipients, these are the regulatory documentation or monographs of the aforementioned pharmacopeias.
Basic quality requirements must apply not only to all starting materials and raw materials but also to intermediate products (substance dilutions) up to the final dilution incorporated into the medicinal product. If a homeopathic pharmaceutical substance containing a potent or toxic active ingredient is used, the content of such an active ingredient must be determined by a suitable method and regulated accordingly (e.g., by bilateral standardization of the content of such an active ingredient or by testing the fourth decimal dilution). As a rule, dilutions above the D4 decimal scale and centesimal scale dilutions do not allow such an assessment. If dilutions of a homeopathic pharmaceutical substance are used to produce a homeopathic medicinal product, they are obtained in accordance with the methods and processes described in the relevant monograph of the Eurasian Economic Union Pharmacopoeia (if available), or in the monographs of the pharmacopoeias of the member states, or the monograph of the German Homeopathic Pharmacopoeia, the monograph of the French Pharmacopoeia, or the European Pharmacopoeia, and the dilution scale and degree are specified.
Control testing of the medicinal product.
Essential quality requirements must be applied to homeopathic medicinal products. If there are deviations from the essential quality requirements, the applicant must justify them.
If a homeopathic pharmaceutical substance containing a potent or toxic active ingredient is used in the production of a homeopathic medicinal product, testing must be conducted to establish the identity and quantify these substances in the homeopathic medicinal product (if necessary).
If there is justification for the impossibility of quantifying and/or identifying all toxicologically significant components (e.g., due to the degree of dilution in the medicinal product), quality must be confirmed by full validation of the manufacturing and dilution processes.
If a homeopathic pharmaceutical substance that does not contain a potent or toxic active ingredient is used in the production of a homeopathic medicinal product, testing must be conducted to establish the identity and quantify these substances in accordance with the monographs for homeopathic pharmaceutical substances of the specific name (if necessary).
Stability testing.
The stability of the medicinal product must be confirmed. Stability test data for the homeopathic source material are generally valid for dilutions and triturations prepared from this material. If quantification or identification of the active substance is not possible due to the degree of dilution, stability test data for the dosage form may be considered.
14.2. Module 4.
Preclinical Toxicity Study Data.
Any omissions must be justified, for example, by justifying how an acceptable safety profile can be confirmed in the absence of certain studies.
For new homeopathic medicinal products (matrix tinctures, triturations, and other components) not listed in pharmacopoeias and monographs: toxicology study data, justification for the selection of various dosages, and subsequent clinical trial data must be provided.
14.3. Module 5.
Clinical Trial Data, Post-Market Use (if any).
Any omissions must be justified, for example, by justifying how an acceptable efficacy and safety profile can be confirmed in the absence of certain studies. For homeopathic medicines (matrix tinctures, triturations, and other components) not listed in pharmacopoeias and monographs, clinical trial data (in accordance with the requirements of this appendix) and justification for the selection of various dosages are required.
For homeopathic medicines with many years of experience and included in pharmacopoeias, a review of scientific literature on the efficacy and safety of the homeopathic medicine in the stated area of use is required.
The general characteristics of the medicinal product and the instructions for medical use of the medicinal product include the statement: "homeopathic medicinal product."
14.4. Simplified Registration Dossier for Homeopathic Medicinal Products.
For registration of homeopathic medicinal products, a simplified registration dossier is submitted if the following conditions are met:
the medicinal product is intended for oral administration or for external, topical, or inhalation use;
the medicinal product packaging, SmPC, or UMP do not indicate a specific therapeutic indication for use;
the dilution level is sufficient to guarantee the safety of the medicinal product. Specifically, the medicinal product contains no more than 1/10,000 parts of a homeopathic substance (homeopathic mother tincture) or contains no more than 1/100 of the minimum dose used in allopathy, with respect to active ingredients whose presence in the medicinal product requires dispensing by prescription.
Evidence of therapeutic efficacy for these homeopathic medicinal products is not required. The dispensing category of such homeopathic medicinal products is established during registration.
An application for a special, simplified registration procedure may cover a series of medicinal products derived from the same homeopathic pharmaceutical substance or several homeopathic pharmaceutical substances of similar origin (e.g., animal, mineral, or plant origin).
(as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated 30.01.2020)
To confirm the pharmaceutical quality and homogeneity of the product from batch to batch, the application is accompanied by a registration dossier containing the following documents:
the scientific name in Latin of the homeopathic pharmaceutical substance, as specified in the pharmacopoeia, indicating the scale and degree of dilution, information on the routes of administration, dosage forms, and degree of dilution subject to registration;
One or more mock-ups of the consumer and primary packaging, as well as the general characteristics of the medicinal product and instructions for medical use (package insert) for homeopathic medicinal products submitted for the simplified registration procedure;
A dossier describing the method of obtaining and controlling the homeopathic pharmaceutical substance, raw material, or types of raw materials, and justifying the homeopathic use based on the relevant bibliography;
A description of the production and control for each dosage form, a description of the scale, and the dilution (potentization) method;
A license for the manufacture of medicinal products and a document confirming compliance with the rules of good manufacturing practice of the Union;
Copies of registration certificates for medicinal products under the simplified procedure obtained in other countries;
Stability data for the homeopathic medicinal product.
15. Herbal Medicinal Product
The registration dossier for herbal medicinal products shall be submitted in accordance with the requirements of this section.
15.1. Module 3.
When registering herbal medicinal products, the requirements for Module 3 specified in Section 3 of Part I of this Appendix must be applied, including the need to comply with the pharmacopoeial monographs of the Eurasian Economic Union Pharmacopoeia or the pharmacopoeias of the member states. Available scientific information as of the application submission date must be taken into account.
15.1.1. Herbal Pharmaceutical Substances.
(as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated 22.05.2023)
For the purposes of this Appendix, the term "herbal pharmaceutical substance" is general, encompassing the concepts of "medicinal plant material" and "product made from medicinal plant material."
For herbal pharmaceutical substances obtained after grinding medicinal plant material, the following must be indicated: the binomial scientific name of the producing plant: genus and species, variety and author in Latin, chemotype (if necessary), source of origin (wild or cultivated), morphological group of the producing plant, and the name (definition) of the herbal pharmaceutical substance.
For a herbal pharmaceutical substance obtained after processing medicinal plant materials by various methods (extraction, distillation, pressing, fractionation, purification, concentration, fermentation, etc.), it is necessary to indicate the binomial scientific name of the producing plant: genus and species, variety and author in Latin, chemotype (if necessary), source of origin (wild or cultivated), morphological group of the producing plant, and the name (definition) of the herbal pharmaceutical substance.
The "Structure" section for a herbal pharmaceutical substance obtained after grinding medicinal plant material includes an indication of its category (whole, ground, powder); for a herbal pharmaceutical substance obtained after processing medicinal plant material by various methods (extraction, distillation, pressing, fractionation, purification, concentration, fermentation, etc.), an indication of the aggregate (physical) state (e.g., dry, thick, liquid extract), as well as a description of components with a known therapeutic effect or markers (molecular formula, relative molecular weight, structural formula, including relative and absolute spatial structure, molecular formula and relative molecular weight) and other components.
The section on the manufacturer of medicinal herbal raw materials must contain the following information: the name, address, and responsibility of each supplier, each production site, or laboratory involved in the procurement (production) and quality control of the medicinal herbal raw materials.
The section on the manufacturer of a product made from medicinal herbal raw materials must contain the following information: the name, address, and responsibility of each supplier, each production site, or laboratory involved in the production and quality control of the product made from medicinal herbal raw materials.
The "Description of the Production Process and Its Control" section for medicinal herbal raw materials must contain information on the procurement process of wild-growing or cultivated medicinal herbal raw materials (geographical source of the medicinal plant, description of the cultivation process) and methods of further processing (collection, drying) and storage conditions. For a product made from medicinal herbal raw materials, information must be provided on the production process for obtaining the product, including a description of the processing, solvents and reagents, purification steps, and standardization (if necessary).
For the development of the production process, a summary must be provided describing the development of the herbal pharmaceutical substance. For the development of the production process for a product made from medicinal herbal raw materials, a summary must be provided describing the development of the product, taking into account the intended route of administration of the herbal medicinal product and its medical use. The results of a comparative phytochemical analysis of the medicinal herbal raw material and the product made from medicinal herbal raw materials must be considered, using bibliographic data (if necessary).
When describing the structure and other characteristics of medicinal plant materials, it is necessary to provide information on the botanical, macroscopic, microscopic, and phytochemical characteristics and biological activity (if necessary).
(as amended by Decision of the Council of the Eurasian Economic Commission dated May 22, 2023, No. 60)
When describing the composition and other characteristics of a product made from medicinal plant materials, it is necessary to provide information on the phyto- and physicochemical characteristics and biological activity of plant-based products (if necessary).
Specifications for medicinal plant materials and products made from medicinal plant materials should be provided (if necessary).
(as amended by Decision No. 60 of the Council of the Eurasian Economic Commission of May 22, 2023)
The analytical methods used for testing the herbal pharmaceutical substance must be specified, and reports on their validation (if they are not pharmacopoeial) must be provided, including experimental data for the analytical methods used for testing.
Batch analysis data must be presented as a description of the batches and the results of batch analysis for the herbal pharmaceutical substance, including such data for pharmacopoeial substances.
If necessary, a justification for the specifications of the herbal pharmaceutical substance must be provided.
(as amended by Decision No. 60 of the Council of the Eurasian Economic Commission of 22.05.2023)
Information on the reference materials and materials used for testing the herbal pharmaceutical substance must be provided.
If the monograph on the herbal pharmaceutical substance is included in the European Pharmacopoeia, the applicant may submit a certificate of conformity issued by the European Directorate for the Quality of Medicines (if available).
15.1.2. Herbal Medicinal Products.
Regarding the development of the formulation, a summary must be provided describing the development of the herbal medicinal product, taking into account the intended route of administration and use. Data on the phytochemical composition of the declared herbal medicinal product and data provided in bibliographic scientific sources must be analyzed. The "Description of the Manufacturing Process and Its Controls" section for a herbal medicinal product should contain information on the manufacturing process used to obtain the product, including a description of processing, solvents and reagents, excipients, purification steps, and standardization (if necessary).
15.1.3. Modules 4 and 5.
Results of preclinical (toxicological and pharmacological) and clinical studies.
For combination herbal medicinal products (including combinations with vitamins and/or minerals), if the individual components of the combination have not been adequately studied, data on each individual component of the combination must be provided.
(as amended by Decision of the Council of the Eurasian Economic Commission of 22.05.2023 No. 60)
15.2. Simplified Registration Dossier for Herbal Medicinal Products.
A simplified registration dossier for herbal medicinal products is submitted for herbal medicinal products in the dosage forms of tinctures, extracts, etc., as well as for crushed or powdered, cut-and-pressed parts of the plant, and other herbal medicinal products, subject to the following requirements:
the indications for use correspond to the generally known properties and composition of the medicinal plant and are intended for use without medical supervision for prophylactic or therapeutic purposes;
With the methods of administration and dosages specified by the general characteristics of the medicinal product;
intended for oral, external, topical, and/or inhalation use;
the safety of the herbal medicinal product is based on long-term experience (at least 10 years from the date of the first systematic and documented use of the herbal medicinal product in at least three Member States);
the labeling and instructions for medical use (package leaflet) of the herbal medicinal product must contain indications that:
the product is a herbal medicinal product for use for the stated purpose, based on experience of long-term use;
the consumer should consult a physician or qualified healthcare professional if symptoms persist or adverse reactions not listed in the instructions for medical use (package leaflet) are observed while using the herbal medicinal product. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
If a herbal medicinal product contains vitamins or minerals, the simplified registration procedure is carried out provided that substantiated data are provided demonstrating that the action of the vitamins or minerals is complementary to the action of the herbal active ingredients in relation to the stated indications for use.
15.2.1. Module 2.
Bibliographic data or a conclusion from the specialist who prepared Sections 2.4 and 2.5 of the module stating that the herbal medicinal product in question or the corresponding product has been used for at least 10 years from the date of the first systematic and documented use of the herbal medicinal product in all Member States.
15.2.2. List of documents for the simplified registration dossier.
To confirm the pharmaceutical quality and consistency of the drug from batch to batch, the application is accompanied by a registration dossier consisting of modules 1–3 in accordance with Appendix No. 4 to the rules for the registration and examination of medicinal products for human use, approved by the Commission. Modules 4 and 5 of the registration dossier are compiled from copies of bibliographic sources and data underlying the specialist reviews in sections 2.4 and 2.5 of module 2 of the registration dossier.
16. Orphan drugs (drugs intended for the treatment of rare diseases)
For orphan drugs, the key provisions of Part II (registration in exceptional cases) may apply. The applicant must substantiate in the preclinical and clinical summaries the reasons why it is impossible to provide complete information and provide a justification for the benefit-risk balance of the orphan drugs in question.
(as amended by decisions of the Council of the Eurasian Economic Commission of January 30, 2020, No. 9, and March 17, 2022, No. 36)
IV. High-Tech Medicinal Products
of May 22, 2023, No. 60)
17.1. Introduction.
Registration dossiers for high-tech medicinal products must comply with the format requirements (modules 1-5 of the registration dossier) described in Part I of this Appendix. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission of 22 May 2023)
The technical requirements for Modules 3–5 shall apply to high-tech biological medicinal products, as described in Part I of this Appendix. The specific requirements for high-tech medicinal products, described in Sections 17.3, 17.4, and 17.5 of this Part, explain how the requirements of Part I of this Appendix apply to high-tech medicinal products.
(as amended by Decision No. 60 of the Council of the Eurasian Economic Commission of 22 May 2023)
Due to the specific nature of high-tech medicinal products, a risk-based approach may be used to determine the scope of necessary information and requirements for quality, preclinical, and clinical studies for their inclusion in the registration dossier in accordance with applicable Union guidelines or, in their absence, in accordance with Member State guidelines.
Risk analysis may encompass the entire development process. Risk factors that may be considered include: cell origin (autologous, allogeneic, xenogeneic), proliferative and/or differentiation capacity, ability to elicit an immune response, cell manipulation, combination of cells with bioactive molecules or medical devices, the nature of the gene therapy drug, the ability of viruses to replicate or microorganisms to multiply in vivo, the degree of integration of nucleic acid sequences or genes into the genome, duration of function (lifespan), risk of oncogenicity, and the route of administration or use.
Non-clinical and clinical data or experience with other related advanced medicinal products may also be considered in the risk analysis.
Any deviation from the requirements of this Appendix must be scientifically justified in Module 2 of the registration dossier. If a risk analysis is conducted, it must be described in Module 2 of the registration dossier. In this case, it is necessary to discuss the methodology used, the nature of the identified risks, and the impact of the results of the risk-based approach on the drug development and evaluation program. Any deviations from the requirements of this Appendix resulting from the risk analysis must also be described.
17.2. Definitions
High-tech medicinal products include the following types of medicinal products for medical use:
(paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
gene therapy medicinal products;
medicines based on somatic cells;
tissue-engineered medicinal products (tissue-engineered products).
17.2.1. Gene therapy medicinal products.
A gene therapy medicinal product is a biological medicinal product:
containing an active substance containing or consisting of a recombinant nucleic acid, used or administered to humans for the purpose of regulating, repairing, replacing, adding, or removing a genetic sequence;
the therapeutic, prophylactic, or diagnostic effects of which are directly attributable to the recombinant nucleic acid sequence it contains, or to the genetic expression product of that sequence.
Gene therapy medicinal products do not include vaccines against infectious diseases.
17.2.2. Somatic Cell-Based Medicinal Products.
A somatic cell-based medicinal product (somatic cell therapy product) is a biological medicinal product containing (or consisting of) cells or tissues possessing the following characteristics:
subjected to significant manipulations that alter their biological characteristics, physiological functions, or structural properties significant for clinical use. The following are not considered such manipulations: cutting, grinding, shaping, centrifugation, treatment with antibiotic or antiseptic solutions, sterilization, irradiation, cell separation, concentration or purification, filtration, lyophilization, freezing, cryopreservation, or vitrification;
not intended for use to perform the same basic functions in the recipient and donor;
used in humans for the treatment, prevention, or diagnosis of a disease through the pharmacological, immunological, or metabolic action of the cells or tissues included in the medicinal product.
A high-tech medicinal product containing both autologous (originating from the patient) and allogeneic (coming from another person) cells or tissues should be considered a medicinal product intended for allogeneic use.
(paragraph introduced by Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 No. 36; as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
A high-tech medicinal product that may fall under the definition of a tissue-engineered product and the definition of a somatic cell-based medicinal product shall be considered as a tissue-engineered medicinal product.
A high-tech medicinal product that may fall under the definition of a somatic cell-based medicinal product or the definition of a tissue-engineered product and a gene therapy medicinal product shall be considered as a gene therapy medicinal product.
(paragraph introduced by the decision of the Council of the Eurasian Economic Commission of 17.03.2022 N 36; as amended by the decision of the Council of the Eurasian Economic Commission of 22.05.2023 N 60)
17.2.3. Tissue-engineered drug (tissue-engineered drug).
A tissue-engineered medicinal product (tissue-engineered product) is a biological medicinal product containing engineered cells or tissues of human or animal origin, or consisting of such cells or tissues, intended for use in the regeneration, repair, or replacement of human tissue.
A tissue-engineered medicinal product may contain nonviable cells in addition to viable cells. Such a product may also contain additional substances (e.g., cellular products, biomolecules, biomaterials, chemicals, scaffolds, and matrices). Products containing nonviable cells and/or tissues of human or animal origin, or consisting solely of such cells and/or tissues, whose primary action is not a consequence of pharmacological, immunological, or metabolic action, are not tissue-engineered medicinal products. Cells or tissues are considered engineered if at least one of the following conditions is met:
the cells or tissues have undergone substantial manipulation to obtain biological characteristics, physiological functions, or structural properties relevant for regeneration, repair, or replacement. The types of manipulations specified in the third paragraph of section 17.2.2 shall not be considered substantial manipulation;
the cells or tissues are not intended to perform the same essential function(s) in the recipient as in the donor.
If a tissue-engineered medicinal product contains viable cells or tissues, the pharmacological, immunological, or metabolic action of such cells or tissues is considered the primary mechanism of action of the product.
A tissue-engineered medicinal product containing both autologous (derived from the patient) and allogeneic (derived from another person) cells or tissues is considered a medicinal product intended for allogeneic use.
If a high-tech medicinal product meets the definitions of both a tissue-engineered medicinal product and a somatic cell-based medicinal product, it must be classified as a tissue-engineered medicinal product.
If a high-tech medicinal product meets the definitions of both a gene therapy medicinal product and a somatic cell-based medicinal product or a tissue-engineered medicinal product, it must be classified as a gene therapy medicinal product.
(Section 17.2.3 introduced by Decision No. 60 of the Eurasian Economic Commission Council dated May 22, 2023)
17.3. Special Requirements for Module 3 of the Registration Dossier.
17.3.1. Special Requirements for All High-Tech Medicinal Products. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
A description of the traceability system that the applicant undertakes to establish and maintain is required to trace the sources of acquisition (origin), production, packaging, storage, transportation, and delivery to the healthcare facility of an individual medicinal product and its starting materials and raw materials, including all substances that have come into contact with the cells or tissues contained therein.
The traceability system shall complement and be consistent with the requirements for Member State traceability systems for human cells and tissues.
17.3.2. Special requirements for gene therapy medicinal products.
17.3.2.1. Introduction: medicinal product, active substance, and starting materials.
17.3.2.1.1. Gene therapy medicinal products containing a recombinant nucleic acid sequence or a genetically modified microorganism or virus.
The medicinal product must consist of a nucleic acid sequence, a genetically modified microorganism, or a virus, and be packaged in primary packaging for medical use. The medicinal product may be combined with a medical device.
The active substance must consist of a nucleic acid sequence or a genetically modified microorganism or virus.
17.3.2.1.2. Gene therapy medicinal products containing genetically modified cells. The medicinal product must consist of genetically modified cells and be packaged in primary packaging for medical use. The medicinal product may be combined with a medical device.
The active substance must consist of cells genetically modified by one of the products specified in Section 17.3.2.1.1.
17.3.2.1.3. For products consisting of viruses or viral vectors, the starting materials are the components from which the viral vector is derived: the master seed bank of the viral or plasmid vector used to transfect recipient cells (packaging cells), and the master seed bank of the recipient cell line (packaging cell line).
17.3.2.1.4. For products consisting of plasmids, non-viral vectors, and genetically modified organisms other than viruses and viral vectors, the starting materials are the components used to obtain the producer cells: plasmids, bacterial host cells, and the recombinant microbial cell master bank.
17.3.2.1.5. For genetically modified cells, the starting materials are the components used to obtain the genetically modified cells, i.e., the vector starting materials, the vector, and human and animal cells. Good manufacturing practice principles should be applied from the vector banking system used for vector production to the finished product.
17.3.2.2. Special Requirements.
In addition to the requirements specified in Sections 3.2.1 and 3.2.2 of Part I of this Appendix, the following requirements should apply:
a) Information must be provided on all starting materials used for the production of the active substance, including products required for the genetic modification of human and animal cells and the subsequent cultivation and preservation of genetically modified cells (if necessary), taking into account the possible absence of purification steps;
b) For products containing microorganisms (including viruses), data must be provided on the genetic modification, sequencing, attenuation of microorganisms, tropism for specific tissue and cell types, dependence of microorganism properties on the cell cycle, pathogenicity, and characteristics of the parent strain;
c) Manufacturing and related impurities, and in particular contaminating agents in the form of replication-capable viruses, must be described in the relevant sections of the registration dossier if the vector is not replication-capable;
d) For plasmids, quantification of the various plasmid forms must be carried out throughout the shelf life of the product;
d) For genetically modified cells, testing of cell characteristics must be performed before and after genetic modification, as well as before and after any subsequent freezing (storage) procedure.
For genetically modified cells, in addition to the specific requirements for gene therapy medicinal products, the quality requirements for somatic cell-based medicinal products and tissue-engineered products in accordance with Section 17.3.3 of these Requirements should apply.
17.3.3. Special Requirements for Somatic Cell-Based Medicinal Products and Tissue-Engineered Products.
17.3.3.1. Introduction: Medicinal Product, Pharmaceutical Substance, and Starting Materials (Substances).
The medicinal product must consist of the pharmaceutical substance enclosed in the primary packaging for the proposed medical use and in its final combination, if it is a combination high-tech medicinal product.
The pharmaceutical substance must consist of engineered cells (tissues). Additional substances (e.g., scaffolds, matrices, articles, biomaterials, biomolecules, etc.) that are combined with processed cells to form a single unit are considered starting materials, even if they are not of biological origin.
Materials used in the production of the pharmaceutical substance (e.g., culture medium, growth factors) that are not intended to be included as a component of the pharmaceutical substance are considered raw materials.
17.3.3.2. Special Requirements.
In addition to the requirements specified in Sections 3.2.1 and 3.2.2 of Part I of this Appendix, the following requirements apply:
17.3.3.2.1. Starting Materials.
A summary of the acquisition, procurement, and testing of human tissues and cells used as starting materials must be provided. Justification must be provided if abnormal cells or tissues (e.g., cancer) were used as starting materials.
If allogeneic cell populations were pooled, the pooling strategy and measures to ensure traceability must be described. When validating the manufacturing process, characterizing the properties of the pharmaceutical substance and medicinal product, the analytical methods used in development, drawing up specifications and determining stability, it is necessary to take into account the potential variability due to the use of human or animal tissues and cells.
For xenogeneic cell-based medicinal products, information must be provided on the source of the animals (e.g., geographic origin, farm, age), specific acceptance criteria, measures to prevent and monitor infections in donor animals, animal testing for infectious agents, including vertically transmitted microorganisms and viruses, and confirmation of the suitability of animal welfare conditions.
For cell-based medicinal products derived from genetically modified animals, the special properties of the cells due to their genetic modification must be described. A detailed description of the method for creating and characterizing the properties of the transgenic animals must be provided.
For genetically modified cells, the requirements specified in Section 17.3.2 of this Appendix must also be taken into account.
The testing conditions of all additional substances (scaffolds, matrices, articles, biomaterials, biomolecules, etc.) combined with the engineered cells must be described and justified. For scaffolds, matrices, and articles falling within the definition of a medical device or an active implantable medical device, the information specified in Section 17.3.4 of this Appendix, as required for the evaluation of combination medicinal products for advanced therapy, must be provided.
17.3.3.2.2. Manufacturing Process
The manufacturing process must be validated to ensure batch and process homogeneity, the functional integrity of cells during production and transport (up to the point of use or administration), and the proper state of differentiation.
If cells are directly grown within or on a matrix, scaffold, or article, information must be provided on the validation of the cell culture process in terms of cell growth, function, and integrity of the combination.
17.3.3.2.3. Characterization and Quality Control Strategy.
Appropriate information must be provided to characterize the properties of the cell population or cell mixture in terms of identity, purity (e.g., presence of extraneous microbial agents or cellular contaminants), viability, potency, karyology, tumorigenicity, and suitability for the proposed medicinal use. The genetic stability of the cells must be confirmed.
Qualitative and, where possible, quantitative information must be provided on manufacturing and related impurities, as well as information on all materials that may lead to the formation of degradation products during manufacturing. The extent of impurity studies must be justified.
It must be justified that certain release quality control tests cannot be performed on the pharmaceutical substance or medicinal product, but can be performed on key intermediates and/or as part of in-process control.
If biologically active molecules (e.g., growth factors, cytokines) are components of cellular medicinal products, their effects and interactions with other components of the pharmaceutical substance must be described. If the three-dimensional structure is part of the intended function, the differentiation state, structural and functional organization of the cells, and the resulting extracellular matrix (if necessary) should be part of the description of the properties of such cellular medicinal products. Where necessary, descriptions of the physicochemical properties should be supplemented by preclinical studies.
17.3.3.2.4. Excipients.
For excipients used in somatotherapeutic medicinal products and tissue-engineered products (e.g., components of the transfer medium), the requirements for new excipients specified in Part I of this Appendix apply unless data on the interaction between cells or tissues and the excipients are available.
17.3.3.2.5. Development Studies.
When describing the development program, it is necessary to provide a rationale for the selection of materials and processes. In particular, it is necessary to analyze the integrity of the cell population in the finished medicinal product.
17.3.3.2.6. Standard Materials.
It is necessary to document and describe the properties of standard samples that are relevant and specific to the pharmaceutical substance and/or finished medicinal product.
17.3.4. Special Requirements for High-Tech Medicinal Products Containing Medical Devices. (as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
17.3.4.1. High-Tech Medicinal Products Containing Medical Devices. (as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
A description of the physical properties and action of the medicinal product, as well as a description of the methods used for its design, must be provided. It is necessary to describe the interaction and compatibility between genes and cells (tissues), on the one hand, and structural components, on the other.
17.3.4.2. Combined high-tech medicinal products. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated 22.05.2023)
A "combined high-tech medicinal product" is understood to mean a high-tech medicinal product that meets the following conditions:
it must include as a component of the product one or more medical devices, as defined by Union legislation on medical devices, or one or more active implantable medical devices, as defined by Union legislation on medical devices;
its cellular or tissue portion must contain viable cells or tissues;
its cellular or tissue portion, containing non-viable cells or tissues, must have the ability to exert an effect in the human body that can be considered primary in relation to the aforementioned devices.
The cellular or tissue portion of a high-tech combination medicinal product is subject to the special requirements for somatotherapeutic medicinal products and tissue-engineered products, as specified in Section 17.3.3 of this Appendix. If the cells have been genetically modified, the special requirements for gene therapy medicinal products, as specified in Section 17.3.2 of these Requirements, are applicable.
A medical device or active implantable medical device may be a component of a pharmaceutical substance. If a medical device or active implantable medical device is combined with cells during the manufacture, use, or administration of a medicinal product, it is considered a component of the finished medicinal product.
It is necessary to provide information concerning the medical device or active implantable medical device (which is a component of the pharmaceutical substance or medicinal product) necessary for the evaluation of high-tech combination medicinal products. Such information includes:
information on the selection and intended function of the medical device or implantable medical device and confirmation of the device's compatibility with other components of the product;
confirmation of the conformity of a medical device with the key requirements established by the Union legislation on medical devices, or the conformity of an active implantable device with the key requirements established by acts included in the Union law in the field of circulation of medical devices;
Confirmation of compliance of the medical device or implantable medical device with the requirements for spongiform encephalopathies (if necessary);
(as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 No. 60)
The results of any assessment of the medical device or active implantable medical device by an authorized body (organization) in accordance with acts included in Union law on the circulation of medical devices (if necessary).
The notified person who conducted the assessment referred to in paragraph "d" of this section must, upon request of the authorized body conducting the examination of the application, provide all information related to the assessment results in accordance with acts included in Union law on the circulation of medical devices. This may include information and documents contained in the conformity assessment of the application under consideration for the purpose of examining the combined high-tech medicinal product as a whole (if necessary).
17.4. Special Requirements for Module 4 of the Registration Dossier.
17.4.1. Special Requirements for High-Tech Medicinal Products. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
Due to the unique and diverse structural and biological properties of high-tech medicinal products, the requirements for Module 4 of the registration dossier specified in Section 4 of Part I of this Appendix are not always applicable to pharmacological and toxicological studies of medicinal products. The technical requirements of Sections 17.4.1 - 17.4.3 of this Appendix clarify how to fulfill the requirements of Part I of this Appendix for high-tech medicinal products. Where appropriate, taking into account the specific features of high-tech medicinal products, additional requirements are established for them.
The preclinical review must present the scientific rationale and analysis of the preclinical development and the criteria for selecting the relevant animal species and models (in vitro and in vivo). The selected animal models may include immunocompromised, knockout, humanized, or transgenic animals. The use of homologous models (e.g., mouse cell assays in mice) or disease-mimicking models should be considered, particularly for immunogenicity and immunotoxicity studies.
In addition to the requirements of Part I of this Appendix, data on the safety, suitability, and biocompatibility of all structural components (e.g., matrices, scaffolds, and devices) and any additional substances (e.g., cellular products, biomolecules, biomaterials, and chemicals) contained in the medicinal product should be provided. Their physical, mechanical, chemical, and biological properties should be considered.
17.4.2. Special Requirements for Gene Therapy Medicinal Products.
The design and type of gene therapy medicinal product should be considered when determining the extent and types of preclinical studies necessary to adequately characterize preclinical safety.
17.4.2.1. Pharmacology.
Results of in vitro and in vivo studies of effects relevant to the stated indication (i.e., pharmacodynamic studies of the mechanism of action) must be provided. These studies utilized appropriate animal models and species designed to confirm that the nucleic acid sequence reaches the target (organ or cells) and provides the desired function (expression level and functional activity). The duration of function of the nucleic acid sequence and the proposed dosing regimen in clinical trials must be described.
Target selectivity. If the gene therapy medicinal product is intended to exhibit selectivity or functionality limited to the target, results of studies confirming the specificity and duration of functionality and activity in target cells and tissues must be provided.
17.4.2.2. Pharmacokinetics.
Biodistribution studies must examine persistence, clearance, and mobilization. Additionally, they must address the risk of germline transfer.
If the registration dossier lacks a justification based on the type of medicinal product under consideration, results of dissemination and risk of transfer to third parties, as well as the results of an environmental risk assessment, must be provided.
17.4.2.3. Toxicology.
The toxicity of the finished gene therapy medicinal product must be studied. Additionally, depending on the type of medicinal product, separate testing of the pharmaceutical substance and excipients must be conducted, taking into account the in vivo effects of nucleic acid expression products not intended to evaluate their physiological function.
Single-dose toxicity studies may be combined with safety pharmacology and pharmacokinetic studies, for example, to study persistence. If repeated administration of the medicinal product to humans is anticipated, results of repeated-dose toxicity studies must be provided. The route and schedule of administration must be consistent with those used in clinical use. If a single administration may result in long-term functionality of the nucleic acid sequence in humans, repeated-dose toxicity studies may be necessary. Depending on the persistence of the gene therapy medicinal product and the anticipated potential risks, the duration of the studies may exceed standard toxicology studies. Justification for the duration of the studies must be provided.
Genotoxicity studies are required. However, standard genotoxicity studies are only necessary when testing a specific impurity or component of the delivery system.
Carcinogenicity studies are required. Standard lifelong carcinogenicity studies in rats are not required. However, depending on the type of medicinal product, tumorigenic potential should be studied in suitable in vivo or in vitro models.
Reproductive and developmental toxicity. If the registration dossier lacks adequate justification based on the type of medicinal product under consideration, results of fertility and general reproductive function studies must be provided. Results of embryofetal and perinatal toxicity studies, as well as germline transfer studies, must be provided.
Additional toxicology studies.
Integration studies. For all gene therapy medicinal products, results of integration studies must be provided unless the absence of such results is scientifically justified, for example, due to the lack of penetration of nucleic acid sequences into the cell nucleus. If biodistribution studies reveal a risk of germline transfer, integration studies must be conducted for gene therapy medicinal products suspected of not being capable of integration.
Immunogenicity and Immunotoxicity. Potential immunogenic and immunotoxic effects must be studied.
17.4.3. Special Requirements for Somatic Cell-Based Somatotherapeutic Medicinal Products and Tissue-Engineered Products.
17.4.3.1. Pharmacology.
To confirm the mechanism of action of a drug, appropriate primary pharmacology studies must be conducted. The interaction of cellular medicinal products with surrounding tissues must be studied.
The amount of drug required to achieve the desired effect (effective dose) and, depending on the type of drug, the dosage regimen must be determined.
To evaluate potential physiological effects unrelated to the therapeutic effect of a somatotherapeutic medicinal product, tissue engineering product, or adjuvant substances, secondary pharmacology studies must be provided, as biologically active molecules may be formed in addition to the required proteins, or the required proteins may have undesired targets.
17.4.3.2. Pharmacokinetics.
Standard pharmacokinetic studies to study absorption, distribution, metabolism, and excretion are not required. However, if the registration dossier does not adequately justify this based on the type of medicinal product under consideration, parameters such as viability, durability, distribution, growth, differentiation, and migration must be studied.
For somatotherapeutic medicinal products and tissue engineering products that continuously produce active biomolecules, the distribution, duration, and extent of expression of such molecules must be studied.
17.4.3.3. Toxicology.
The toxicity of the finished medicinal product must be studied. Separate studies of the pharmaceutical substance, excipients, additives, and all manufacturing impurities must be considered.
The duration of observations may exceed that required for standard toxicology studies; therefore, the expected life cycle of the medicinal product, as well as its pharmacodynamic and pharmacokinetic properties, must be taken into account. Justification for the duration of the studies must be provided.
Standard carcinogenicity and genotoxicity studies are not required, with the exception of the tumorigenic potential of the finished medicinal product.
The immunogenic and immunotoxic potential must be studied.
For cellular medicinal products containing animal cells, any associated safety issues, such as the risk of transmission of xenogenic pathogens to humans, must be studied.
17.5. Special Requirements for Module 5 of the Registration Dossier.
17.5.1. Special Requirements for High-Tech Medicinal Products. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated 22 May 2023)
17.5.1.1. The special requirements of this section are in addition to the requirements for Module 5 of the registration dossier of Section 5 of Part I of this Appendix.
17.5.1.2. If the clinical use of high-tech medicinal products requires special adjuvant therapy or surgical procedures, the entire range of therapeutic measures must be studied as a whole. Information on the standardization and optimization of such procedures during clinical development must be provided.
If medical devices used during surgical procedures for the application, implantation, or administration of a high-tech medicinal product may affect the efficacy and safety of that product, information on such devices must be provided.
A separate analysis must be provided to evaluate the application, implantation, administration, and subsequent monitoring. If necessary, a plan for training healthcare professionals in the procedures for use, application, implantation, and administration must be provided.
17.5.1.3. Given that the manufacturing process for advanced medicinal products may change during clinical development, additional studies may be required to confirm comparability.
17.5.1.4. During clinical development, risks associated with potential infectious agents or the use of material derived from animal sources must be examined and measures aimed at mitigating such risks must be described.
17.5.1.5. Dose-finding studies must be used to determine doses and dosing regimens.
17.5.1.6. Efficacy for the stated indications must be supported by relevant results from clinical trials that used endpoints that are clinically relevant to the intended use. Demonstration of long-term efficacy may be required for certain clinical conditions. A strategy for assessing long-term efficacy must be provided.
17.5.1.7. The risk management plan must include a strategy for long-term surveillance of safety and efficacy.
17.5.1.8. Safety and efficacy studies of combination medicinal products for advanced therapy must be planned and conducted on the entire combination product.
17.5.2. Special Requirements for Gene Therapy Medicinal Products.
17.5.2.1. Human Pharmacokinetic Studies.
Pharmacokinetic studies in humans should consider the following:
shedding studies aimed at investigating the excretion of gene therapy medicinal products;
biodistribution studies;
pharmacokinetic studies of the drug and gene expression products (e.g., expressed proteins or genomic signatures).
17.5.2.2. Human Pharmacodynamic Studies.
Pharmacodynamic studies should examine the expression and function of the nucleic acid sequence after administration of the gene therapy medicinal product.
17.5.2.3. Safety Studies.
Safety studies should consider the following:
emergence of replication-competent vectors;
emergence of new strains;
reassortment of existing genomic sequences;
tumor proliferation due to insertional mutagenesis.
17.5.3. Special Requirements for Somatic Cell-Based Medicinal Products.
17.5.3.1. Somatic Cell-Based Medicinal Products with a Mechanism of Action Based on the Production of Specific Active Biological Molecules.
If the mechanism of action of somatic therapeutic medicinal products is the production of a specific active biomolecule, the pharmacokinetic properties (in particular, the distribution, duration, and extent of expression) of such molecules must be described, if possible.
17.5.3.2. Biological Distribution, Persistence, and Long-Term Engraftment of Somatic Cell-Based Medicinal Product Components.
During clinical development, the biodistribution, persistence, and long-term engraftment of somatic therapeutic medicinal product components must be studied.
17.5.3.3. Safety Studies.
Safety studies must consider the following:
distribution and engraftment after administration;
ectopic engraftment;
oncogenic transformation and compliance with the properties of the relevant cell line (tissues).
17.5.4. Special Requirements for Tissue-Engineered Products.
17.5.4.1. Pharmacokinetic Studies.
If standard pharmacokinetic studies for tissue-engineered products are not relevant, the biodistribution, persistence, and degradation of their components must be studied during clinical development.
17.5.4.2. Pharmacodynamic Studies.
The design of pharmacodynamic studies should be based on the characteristics of the tissue-engineered product. Evidence of proof-of-concept and the kinetics of the product required to achieve the intended regeneration, repair, or replacement must be provided. Suitable pharmacodynamic markers related to the function and structure under consideration must be considered.
17.5.4.3. Safety Studies.
The safety studies of tissue-engineered products should be guided by the requirements specified in Section 17.5.3.3 of this Appendix.
dated April 23, 2021 No. 34, dated March 17, 2022 No. 36, dated May 22, 2023 No. 60)
II. APPLICATION
for re-registration of a medicinal product
Date of receipt of application
"__" _____________ 20__ г.
N __________________
Trade names of the medicinal product
Active pharmaceutical ingredients
Dosages or concentrations
Formulation
Dosage form
Marketing authorization holder
Applicant
Applicant's representative
Registration Certificate Details
Registration Certificate Number
Registration Date
Quality Regulatory Document Number
I guarantee the accuracy of and accept responsibility for the information contained in the submitted documents and data included in the registration dossier.
I agree that if the documents and data required to complete the registration dossier are not submitted within 30 days, this application will be rejected based on comments from the authorized body (expert organization) of the reference state.
I confirm that all data in the registration dossier was obtained in accordance with the established procedure and does not violate the intellectual property rights of third parties (subparagraphs 5.3 and 5.4 of the Appendix to this application).
I also confirm that all required fees (duties) have been paid (will be paid) in accordance with legal requirements.
A power of attorney for legally significant actions on behalf of the registration certificate holder is attached (subparagraph 5.1 of the Appendix to this application).
On behalf of the applicant
_______________________________
(Signature)
(Name, Surname)
(Position)
Stamp
1. General Application Points
1.1. This application is submitted in accordance with the following:
1.1.1. The application is submitted under the mutual recognition procedure:
Reference State
Trade name in the reference state
Registration date
Registration certificate number
Copy of the registration certificate
Application identification number
Other Eurasian Economic Union member states for filing an application (if any)
Trade names in recognition states (if the trade name differs from the one registered in the reference state)
1.1.2. The application was submitted through a decentralized procedure:
Trade name in the reference State
Recognition States for filing the application
Trade names in recognition States (if trade names differ from the reference State)
Note: This section must be completed for any application, including applications referenced in this section.
2. Approved or pending amendments since the issuance of the marketing authorization
N
Submission date
Change approval date
Change type (procedure type), brief description of the change
...
If an application is submitted for the type of medicinal product listed below, the remaining sections of the application relating to other types of medicinal products do not need to be completed.
ORIGINAL MEDICINAL PRODUCT
biological drug
another drug
New active pharmaceutical ingredient (hereinafter referred to as API)
Note: There is no information on the API in the unified register of registered medicines of the Eurasian Economic Union or in the corresponding national registries of the Eurasian Economic Union member states.
Known API
Note: There is information on the API in the unified register of registered medicines of the Eurasian Economic Union or in the corresponding national registries of the Eurasian Economic Union member states.
GENERIC DRUG
one-component
multicomponent
Original medicinal product:
name of medicinal product, dosage, dosage form
marketing certificate holder (company in whose name the marketing authorization is issued), registration date, marketing authorization number, Eurasian Economic Union member states where the original medicinal product is registered
Reference medicinal product used in equivalence studies (if any):
name of medicinal product, strength, dosage form
marketing authorization holder (company in whose name the marketing authorization is issued), registration date, marketing authorization number, Eurasian Economic Union member states where the reference medicinal product is registered
provide justification for the use of the reference medicinal product if it differs from the original medicinal product
availability of recommendations from the Expert Committee on Medicines on the selection of the reference medicinal product
Note: This section must be completed for each medicinal product used in equivalence studies.
BIO-SIMILAR DRUG (BIOANALOGUE)
Original biological medicinal product:
Name of the medicinal product, dosage, formulation
Marketing Authorization Holder (company in whose name the registration certificate is issued), registration date, registration certificate number, Eurasian Economic Union member states where the original medicinal product is registered
Reference biological medicinal product:
Marketing Authorization Holder, registration date, registration certificate number, Member States of the Union where the reference medicinal product is registered
Availability of recommendations from the Expert Committee on Medicinal Products on the selection of the reference medicinal product
Differences compared to the reference biological medicinal product (if any):
Differences in source materials
Differences in the manufacturing process
Different indications for use
Differences in dosage form
Different dosages (quantitative changes in the API)
Different route of administration
Other differences:________________________
HYBRID DRUG
marketing certificate holder, registration date, marketing authorization number, EU member states where the original medicinal product is registered
Differences compared to the original medicinal product:
Changes in the active pharmaceutical ingredient
Different dosage form
Different dosages (quantitative changes in the active pharmaceutical ingredient)
Different pharmacokinetics (including different bioavailability);
Different indication for use
Other differences: ______________
COMBINATION DRUG
a well-known combination
new combination
Original medicinal product (in case of a known combination):
Name of the medicinal product, dosage, dosage form
Marketing Authorization Holder, registration date, registration certificate number, Eurasian Economic Union member states where the original medicinal product is registered
A MEDICINAL PRODUCT WITH WELL-RESEARCHED MEDICAL USE
RADIOPHARMACEUTICAL DRUG OR PRECURSOR
radiopharmaceutical kit
radionuclide precursor
radionuclide source (primary and secondary) (if available)
generator
HOMEOPATHIC MEDICINE
a new homeopathic drug not included in pharmacopoeias and monographs
homeopathic preparation included in pharmacopoeias and monographs
HERBAL MEDICINE
ORPHAN DRUG
Has the medicinal product been granted orphan drug status in the Eurasian Economic Union member states or outside of it?
no
in consideration
yes
date
registration certificate number of the orphan medicinal product
member states of the Eurasian Economic Union and/or other states that have assigned orphan medicinal product status to this medicinal product
Orphan drug designation denied:
Date
Decision number
Application for orphan drug designation withdrawn
Copy of the document confirming the assignment of orphan drug designation to the medicinal product (if any) (Subclause 5.2 of the Appendix to this application).
MEDICINAL PRODUCT SUBMITTED FOR REGISTRATION
IN ACCORDANCE WITH SECTION VII OF THE RULES
If a medicinal product is submitted for re-registration in accordance with Section VII of the Rules, it is necessary to indicate the type of procedure under which it was registered:
registration of a medicinal product in exceptional cases
conditional registration of a medicinal product
Did the regulatory authority impose any special obligations or post-registration measures as conditions of registration of the medicinal product?
Special obligations or post-registration measures as conditions of registration:
Restrictions on the use of a medicinal product established during the registration of a medicinal product
Obligations of the registration certificate holder to be fulfilled within the framework of registration
Deadlines for fulfilling obligations and imposed restrictions for the registration certificate holder established during the registration of a medicinal product
Status of fulfillment of obligations by the registration certificate holder
3. Special points of the application
3.1. Name and ATX code
3.1.1. Name of the medicinal product
3.1.2. Name of the API or composition
Note. Only one name should be given in the following order: international nonproprietary name (hereinafter referred to as INN) <*>, name according to the Pharmacopoeia of the Eurasian Economic Union, pharmacopoeias of the member states (or main pharmacopoeias in accordance with the Concept of Harmonization of Pharmacopoeia of the Member States of the Eurasian Economic Union, approved by the Eurasian Economic Commission), common or group name, scientific (chemical) name.
--------------------------------
<*> The name of the API must be indicated according to its recommended INN, with an indication of its salts or hydrate form, if necessary.
3.1.3. Pharmacotherapeutic group (use current ATC code)
ATC code
Group
If an ATC code has not been assigned, please indicate whether an application for an ATC code has been submitted.
3.2. Dosage, dosage form, and packaging, route of administration, capacity of primary packaging, number of dosage units per packaging.
3.2.1. Dosage and dosage form
(Use the list of standard terms of the nomenclature of dosage forms used in the Eurasian Economic Union.)
Dosage or concentration
3.2.2. Route of administration (use the list of standard terms for the nomenclature of dosage forms)
3.2.3. Packaging: primary and secondary packaging, intermediate packaging (if any), closure system and delivery devices, including a description of the material from which they are made (use the list of standard terms for the nomenclature of dosage forms), packaging of bulk products (if any)
For each type of packaging, please indicate:
3.2.3.1. Number of dosage units per packaging
3.2.3.2. Proposed shelf life
3.2.3.3. Proposed shelf life (after first opening of primary or intermediate packaging)
3.2.3.4. Proposed shelf life (after reconstitution (dissolution) or dilution)
3.2.3.5. Proposed storage conditions
3.2.3.6. Proposed storage conditions after first opening of packaging (primary or intermediate)
3.2.4. Information on administration devices
3.3. Dispensing category
by prescription
3.3.1. Suggested dispencing category:
without a prescription
in a hospital setting
3.4. Marketing Authorization Holder
3.4.1. Marketing Authorization Holder:
Legal entity name,
legal address
country
telephone and fax numbers (if available)
email address
3.4.2. Representative of the registration certificate holder (person acting on behalf of the registration certificate holder - applicant):
Name of the legal entity or last name, first name, and patronymic of an individual
When completing this section, please attach a power of attorney to perform legally significant actions on behalf of the marketing authorization holder (subparagraph 5.1 of the appendix to this application).
3.4.3. The applicant's representative (the person acting on behalf of the applicant) after registration of the medicinal product, if different from those specified in subparagraph 3.4.2 of this application:
Last name, first name, and patronymic of the applicant's representative or name of the legal entity
Legal address of the legal entity
State
Telephone and fax numbers (if available)
Email address
When completing this section, please attach a power of attorney (subsection 5.1 of the appendix to this application).
3.4.4. Authorized representative of the marketing authorization holder responsible for pharmacovigilance:
Last name and first name of the authorized representative of the marketing authorization holder responsible for pharmacovigilance
Name of the legal entity (marketing authorization holder)
Legal address of the legal entity (marketing authorization holder)
24-hour telephone and fax numbers
Please indicate the place of registration and actual place of residence of the authorized person of the registration certificate holder responsible for pharmacovigilance.
Pharmacovigilance Master File:
Number:
Location Address:
3.4.5. The authorized person of the registration certificate holder in a member state of the Eurasian Economic Union for the implementation of pharmacovigilance, if it differs from that specified in subparagraph 3.4.4 of this application:
Last name, first name, and patronymic of the authorized representative of the marketing authorization holder responsible for pharmacovigilance
Address of the legal entity
Country
24-hour telephone (fax)
Email
Please indicate the registered address, actual place of residence, and telephone number of the authorized person in the Eurasian Economic Union member state responsible for pharmacovigilance.
3.5. Manufacturer of the medicinal product
3.5.1. The manufacturer responsible for batch release quality control of the medicinal product (as specified in the general characteristics of the medicinal product, package insert, and, if applicable, labeling).
Name of the legal entity
Address of the place of business
3.5.2. Laboratory of the manufacturing country responsible for quality control of blood products and vaccines, responsible for batch quality control (release)
Laboratory name
Address of location
3.5.3. Organization responsible for handling complaints within the Eurasian Economic Union (for each member state, if any)
Name of legal entity
Location of legal entity
3.5.4. Manufacturer of the medicinal product and manufacturing sites:
All manufacturing sites involved in the medicinal product manufacturing process (including solvents), indicating the manufacturing stage.
Name of the manufacturing stage <*>, name of the legal entity <*>
Address of the place of business <*>
State <*>
Telephone and fax numbers (if available) <*>
Email address <*>
<*> The specified fields must be completed for each stage of the production process (please attach a diagram showing the sequence and actions for the various production sites involved in the production process, including final inspection).
Was the site inspected for compliance with the Good Manufacturing Practice Rules of the Eurasian Economic Union, approved by the Eurasian Economic Commission, by an authorized body (organization) of a Eurasian Economic Union member state?
If yes, please indicate:
date of last inspection
name of the authorized body that conducted the inspection
type of inspection
category of medicinal products and APIs inspected
conclusion
complies: no
Was the site inspected for compliance with good manufacturing practice requirements by an authorized body (organization) of another state:
3.5.5. API Manufacturer and Manufacturing Sites
All manufacturing sites involved in the production of each API, indicating the manufacturing stage. For biological medicinal products, all sites storing the master and working cell banks, as well as sites preparing the working cell bank, must be listed.
Name of the manufacturing process stage, active pharmaceutical ingredient
Name of the legal entity, last name, first name, and patronymic of the individual entrepreneur
For each API, please attach a statement from the manufacturer's authorized representative in accordance with subparagraph 5.5 of the appendix to this application (please attach a diagram showing the sequence and actions for the various production sites involved in the manufacturing process, including final inspection).
Was the site inspected for compliance with the Good Manufacturing Practice requirements of the Eurasian Economic Union by the authorized body of the Eurasian Economic Union member state?
Выдан ли сертификат соответствия монографии Европейской фармакопеи для АФС:
дyes
If Yes:
Name of the active pharmaceutical ingredient
Name of the legal entity or the last name, first name, and patronymic of the individual entrepreneur (manufacturer)
Compliance document number
Date of last revision
Date of last inspection
Name of the authorized body that conducted the inspection
Type of inspection
Conclusion
Will the API manufacturer's master file be used as part of the registration dossier?
If yes:
Name of the API manufacturer's master file holder
Name of the API manufacturer, if different from the holder of the API manufacturer's master file
Has a certificate for the vaccine antigen master file (hereinafter referred to as VAMF) used in the registration dossier been issued or has an application been submitted for its receipt?
Name of the vaccine antigen
Name of the vaccine antigen manufacturer (certificate holder for the MVFA)
Application (certificate) number
Submission date (if under review)
Approval or last revision date (if any)
3.5.6. Contract research organizations (CROs) involved in clinical trials to determine bioavailability and/or bioequivalence, or that were involved in validating blood product manufacturing processes.
For each CRO, indicate where the analytical testing was performed and clinical data were collected, as well as:
Study title
Protocol code
EudraCT number (if available)
ClinicalTrials.gov number (if available)
Name of contract research organization
Contract research organization address
Phone and fax numbers (if available)
3.6. Qualitative and quantitative composition of the medicinal product.
3.6.1. Qualitative and quantitative composition of the medicinal product (API and excipients)
The composition unit must be specified (per dosage unit, per unit volume, per unit mass, etc.).
List the API separately from the excipients:
Name of API <*>
Quantity (in units of mass, volume, activity, or concentration, etc.)
Unit of measurement
Article (monograph)
Name of excipients
Quantity (in units of mass, volume, activity, or concentration, etc.
Note. <*> Only one name for each API must be specified in the following order: INN, name according to the Eurasian Economic Union Pharmacopoeia, name according to the pharmacopoeias of the Eurasian Economic Union member states (or the main pharmacopoeias in accordance with the Concept of Harmonization of Pharmacopoeia of the Eurasian Economic Union Member States), common or generic name, and scientific (chemical) name.
<**> The name of the API must be specified according to its INN recommended by the World Health Organization, with an indication of its salts or hydrated form, if necessary.
Excess information should not be included in the composition columns; it must be presented below:
active pharmaceutical ingredients
excipient(s)
3.6.2. List of materials of animal and (or) human origin included in the composition of the medicinal product or used in the process of its production
absent
Name
Function
From animals susceptible to GE <3>
Other animals
Of human origin
Certificate of conformity with the European Pharmacopoeia regarding GE <3> (indicate the number)
АФС
ВВ <1>
Р <2>
1
2
3
....
Indicate the availability of a certificate of conformity with the European Pharmacopoeia regarding GE <3> or a document issued by the authorized veterinary supervision bodies of the country of origin of raw materials regarding the registration in the country (based on the results of clinical and laboratory monitoring) of cases of GE <3>
<1> ES - excipient (including starting materials used in the production of the API/excipient).
<2> R - reagent/culture medium (including those used to prepare the master and working cell banks).
<3> GE - spongiform encephalopathy.
3.6.3. Has a certificate for the plasma master file (hereinafter referred to as the PMF) used in this dossier been issued, or has an application for one been submitted?
Substance (material) with a reference to the IFP
API
ES<1>
R<2>
Name of the owner (applicant for the IFP)
Certificate (application) number
Application submission date (if under review)
Approval or last review date (if a certificate exists)
<1> ES - excipient (including starting materials used in the production of the API (excipient)).
<2> R - reagent (culture medium) (including those used to prepare the master and working cell banks).
3.6.4. Does the medicinal product contain or consist of genetically modified organisms (GMOs):
If yes, does the drug meet the established requirements?:
Make the necessary link.
4. Other information
4.1. Are intellectual property rights to a medicinal product protected by patents valid in the territory of a member state of the Eurasian Economic Union?
If yes, please provide the following information:
Patent number
Valid in the territory of the Member State
Issue date
Valid until
Patent owner
To register medicinal products based on or related to intellectual property rights granted under the laws of a Eurasian Economic Union member state, the applicant must submit a certified copy of a valid patent in the Eurasian Economic Union member state or a license agreement granting the right to manufacture and sell the registered medicinal product. Applicants must submit a letter stating that the intellectual property rights of third parties, protected by the patent or licensed, are not infringed by the registration of the medicinal product.
4.2. Is the trademark registered in the Eurasian Economic Union member states?
If yes, please provide such information:
Attach a certified copy of the trademark registration certificate valid in the territory of a Eurasian Economic Union member state, certified by the applicant.
If the applicant is not the copyright holder, attach a certified copy of the license agreement or confirmation of registration of the right to use the trademark.
4.3. Is the medicinal product registered in the country of manufacture?
Is the medicinal product registered in other countries?
4.4. Has a preliminary scientific consultation been conducted regarding this medicinal product in the member states of the Eurasian Economic Union?
Eurasian Economic Union member state
date of the event
notation of the presence of the conclusion in the dossier
Has a prior scientific consultation been conducted regarding this medicinal product in the Expert Committee on Medicines:
date of the conclusion
note of the presence of the conclusion in the dossier
4.5. Information on refusals, revocations, and suspensions of registration certificates for medicinal products in the country of manufacture and other countries.
Type of restriction
Reason
Period
5. Application attachments
(submitted on paper or as electronic documents
signed (certified) with an electronic signature)
5.1. A power of attorney to perform legally significant actions on behalf of the marketing authorization holder and the applicant (if applicable).
5.2. A copy of the document confirming the orphan status of the medicinal product.
5.3. Copies of valid patents in the member states of the Eurasian Economic Union in relation to the medicinal product being registered.
5.4. Written confirmation from the applicant that the registration of the medicinal product does not infringe the intellectual property rights of third parties.
5.5. A copy of the trademark registration certificate valid in the territory of the member state of the Eurasian Economic Union.
5.6. A statement from the authorized person for quality control on the compliance of production with the rules of good manufacturing practice of the Eurasian Economic Union and good practice guidelines for starting materials for each manufacturing site used in the production of the medicinal product and API, including sites where quality control is performed (in-process control).
III. APPLICATION
on amendments to the registration dossier
of a medicinal product
Appendix No. 3
INSTRUCTIONS FOR DRAWING UP A QUALITY
REGULATORY DOCUMENT ACCOMPANIING
AN APPLICATION FOR REGISTRATION OF A DRUG
The draft regulatory documentation on quality control (hereinafter referred to as RD) must include 8 sections:
1. Title page, including:
name of the medicinal product (trade name and INN, or, if none, the common (general) name; if none, the chemical name);
strength(s);
name of the marketing authorization holder and country;
field for indicating the regulatory document number (indicated as the registration certificate number issued by the reference state and the registration date in the format DD.MM.YYYY, indicated with a hyphen);
approval stamp.
2. The composition of the medicinal product is provided in accordance with Section 3.2.P.5.1 of Module 3 of the registration dossier (without specifying the functional purpose) in a separate section of the regulatory document. This section specifies the qualitative and quantitative composition of the pharmaceutical substances and excipients, with references to pharmacopoeias or regulatory documents governing their quality. 3. Specification (in accordance with Section 3.2.P.5.1 of Module 3 of the registration dossier) in the form of a 3-column table:
list of all quality parameters;
standards (acceptable limits);
references to test methods.
Quality parameters should be established in accordance with the requirements of the general pharmacopoeia monographs of the Pharmacopoeia of the Eurasian Economic Union (hereinafter referred to as the Union) for dosage forms, taking into account the specific features of the specific dosage form of the medicinal product, depending on the nature of the pharmaceutical substance, and in accordance with this document.
The names of the quality parameters in the specification are indicated in accordance with the Pharmacopoeia of the Eurasian Economic Union.
If testing of individual parameters is conducted randomly or at a specified frequency, the specification shall establish the randomness and frequency of testing. 4. A detailed description of the implementation of the methods and techniques for testing the medicinal product for all quality parameters of the specification, with references to the Pharmacopoeia of the Union (if applicable), is provided in accordance with Section 3.2.P.5.2 of Module 3 of the registration dossier.
5. The "Packaging" section of the ND describes the primary packaging (ampoules, vials, jars, bags, etc.), the number of units in the primary packaging (e.g., the number of tablets in a blister pack or cell-less package), intermediate packaging, secondary (consumer) packaging, and the number of primary packages within it (e.g., the number of blister packs in the secondary packaging), the presence of a desiccant, a package insert (instructions for medical use), completeness (needle, dropper, clamp, etc.), etc.
6. The "Labeling" section of the ND refers to Section 1.3.2 of Module 1 of the registration dossier.
7. Storage conditions.
8. Expiry date (storage period).
Appendix No. 4
FOR THE FORMAT AND LOCATION OF DOCUMENTS IN THE REGISTRATION DOSSIER
OF A DRUG IN THE FORMAT OF A GENERAL
TECHNICAL DOCUMENT (GTD)
I. List of documents in the modules of the registration dossier
NAME OF DOCUMENTS
MODULE 1. ADMINISTRATIVE INFORMATION
1.0. Covering Letter (as in the CTD)
1.1. Contents
1.2.1. Application for registration of a medicinal product
1.2.2. Documents confirming payment for expert evaluation and/or registration fee (duty) in the cases and according to the procedure established by the legislation of the Eurasian Economic Union member state conducting the registration <*>
1.2.3. A copy of the medicinal product certificate, in the format recommended by the WHO, issued by the authorized body of the manufacturing country. If such a certificate is not available, a document confirming registration in the manufacturing country and/or in the country holding the marketing authorization for the medicinal product (if any) is submitted.
1.2.4 A translation into Russian and a duly certified copy of the expert report issued by the authorized body upon registration of the medicinal product in the country of manufacture or in the country holding the registration certificate (if any).
As part of the procedure for bringing the registration dossier of a medicinal product registered under the national procedure in the member states of the Eurasian Economic Union into compliance with the Rules for Registration and Expertise of Medicinal Products for Medical Use, approved by Decision No. 78 of the Council of the Eurasian Economic Commission dated 3 November 2016 (hereinafter referred to as "bringing it into compliance with Union requirements"), the submission of information is not mandatory.
1.2.5. Conclusion (recommendation) of the authorized body (authorized organization) of a member state of the Eurasian Economic Union based on the results of a preliminary scientific consultation regarding this medicinal product in the member state of the Eurasian Economic Union (if any)
1.2.6. Recommendation of the Expert Committee on Medicines based on the results of a preliminary scientific consultation regarding this medicinal product, including a conclusion on the rationality of the combination of active ingredients of the combined medicinal product (if any)
(clause 1.2.6 as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 N 60)
1.3. General characteristics of the medicinal product, instructions for medical use (package leaflet), labeling:
1.3.1. Draft general characteristics of the medicinal product, instructions for medical use (package leaflet), compiled in accordance with the requirements of acts of the bodies of the Eurasian Economic Union in Russian
1.3.2. Mock-ups of primary (internal) and secondary (consumer) packaging, as well as intermediate packaging, prepared in accordance with the requirements of the Eurasian Economic Union's governing bodies. Mock-ups of intermediate packaging, labels, and stickers are submitted if available.
(as amended by Decision of the Council of the Eurasian Economic Commission dated September 23, 2022, No. 141)
1.3.3. Results of user testing of the IMP mock-up (in cases specified in Appendix No. 12 to the requirements for the instructions for medical use of a medicinal product and the general characteristics of the medicinal product for medical use, approved by Decision of the Council of the Eurasian Economic Commission dated November 3, 2016, No. 88)
(clause 1.3.3 as amended by Decision of the Council of the Eurasian Economic Commission dated October 20, 2023, No. 114)
1.3.4. Copies of the general characteristics of the medicinal product, certified by the marketing authorization holder, with the date of the last revision, and the instructions for medical use (package leaflet), approved by the authorized body of the manufacturing country and/or the marketing authorization holder country and/or another country with a well-regulated pharmaceutical market where the medicinal product is registered (if any)
1.4. Information on the regulatory status of the medicinal product in other countries (if any)
1.4.1. A list of countries in which the medicinal product has been submitted for registration, registered, has been denied registration, or its circulation on the market in these countries has been suspended, indicating the name of the medicinal product, the number and date of the marketing authorization, its validity period, or the date of the decision to refuse registration or suspend the marketing authorization. The information provided must be certified by the marketing authorization holder.
1.5. Quality documents:
1.5.1. a certificate of conformity with the article of the Pharmacopoeia of the Eurasian Economic Union or the European Pharmacopoeia on spongiform encephalopathy or a document issued by the authorized veterinary supervision bodies of the country of origin of the raw materials in the case of using pharmaceutical substances of animal origin (if applicable)
1.5.2. A letter from the active substance master file holder, signed by the responsible person of the active substance master file holder (or a copy of such a letter), containing an obligation to notify the manufacturer of the medicinal product and the competent authority of the Member State of any changes before any significant changes are made to the active substance master file, as well as a translation of such letter, certified by the marketing authorization holder or notarized.
(Clause 1.5.2 as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
1.5.3. A letter confirming the consent of the pharmaceutical substance master file holder to submit documents from the closed section of the pharmaceutical substance master file upon request of the authorized body of a member state of the Eurasian Economic Union.
1.5.4. A copy of the certificate of conformity of the pharmaceutical substance with the requirements of the European Pharmacopoeia (if any).
1.5.5. A copy of the plasma master file certificate issued by the authorized body of the manufacturing country (if any).
1.5.6. A copy of the vaccine antigen master file certificate issued by the authorized body of the manufacturing country (if any).
1.5.7. A draft regulatory document on quality, prepared in accordance with the Guidelines for the preparation of a regulatory document on the quality of a medicinal product, approved by Decision No. 151 of the Board of the Eurasian Economic Commission dated September 7, 2018. (clause 1.5.7 introduced by the decision of the Council of the Eurasian Economic Commission dated 30.01.2020 N 9)
1.6. Production documents:
1.6.1. information on the date of submission and the registration number in the relevant register of a member state of the Eurasian Economic Union or a copy of a valid document confirming the compliance of the manufacturer (the manufacturing site that manufactures the finished dosage form and carries out quality control) of the medicinal product applied for registration with the requirements of the Rules of Good Manufacturing Practice of the Eurasian Economic Union approved by the Decision of the Council of the Eurasian Economic Commission dated November 3, 2016 N 77 (hereinafter referred to as the Rules of Good Manufacturing Practice of the Union) and issued by the authorized body of the member state of the Eurasian Economic Union (if applicable in accordance with paragraph 29 of the Rules for Registration and Expertise of Medicines for Medical Use), as well as copies of valid documents confirming the compliance of the manufacturer's manufacturing site with the requirements of good manufacturing practice and issued by the authorized bodies of the country (countries) in which the manufacturing site (production sites) that manufactures the finished dosage form and carries out quality control is located, and (or) another authorized body, and the address of the website of the register of certificates of conformity with the requirements of good manufacturing practice issued by the authorized body Manufacturing practices (e.g., EudraGMP) on the Internet (if available) (if applicable in accordance with paragraph 29 of the Rules for the Registration and Examination of Medicinal Products for Human Use)
(paragraph 1.6.1 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
1.6.2. Copies of the current permit (license) for the manufacture of medicinal products (with appendices) issued by the authorized body of the country in which the manufacturing site(s) producing the finished dosage form and performing release quality control are located. For manufacturing sites located in the territories of member states of the Eurasian Economic Union, instead of the specified documents, information on the date of submission and the registration number of the license (permit) for the production of medicinal products issued by the authorized body of the member state of the Eurasian Economic Union in the relevant register may be submitted.
(Clause 1.6.2 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
1.6.3. a copy of the report (copies of reports) on the inspection of the manufacturing site (manufacturing sites producing the finished dosage form and final quality control) for compliance with GMP, carried out by the authorized body of the manufacturing country or another authorized body within the last 3 years, as well as a plan and report on the implementation of corrective and preventive actions (CAPA) after the inspection (if any), and in cases stipulated by paragraph 30 of the Rules for the Registration and Examination of Medicinal Products for Human Use, the address of the website of the authorized body on the Internet containing information from the GMP inspection database (e.g. EudraGMP). When submitting documents in accordance with paragraph 1.6.1 of these Requirements, as well as within the framework of the procedure for bringing them into compliance with the requirements of the Union, the submission of information is not mandatory
(Clause 1.6.3 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.6.4 - 1.6.5. Repealed effective 20 December 2023. - Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114
1.6.6. Information on any regulatory measures taken by the authorized body that carried out inspections over the past three years based on the inspection results (from the date of application) in relation to the declared production site (if any). When submitting documents in accordance with Clause 1.6.1 of these Requirements and as part of the procedure for bringing them into compliance with Union requirements, the submission of information is optional.
1.6.7. A letter from the authorized quality representative confirming that the manufacturing conditions of the medicinal product submitted for registration comply with the requirements of the Good Manufacturing Practice Rules of the Eurasian Economic Union, approved by the Eurasian Economic Commission, including with respect to starting materials for each manufacturing site used in the manufacturing of the medicinal product and active pharmaceutical ingredient, including sites where quality control and in-process control are performed. The letter must be signed by the authorized quality representative and certified by the manufacturer's seal (stamp), if necessary, with a Russian translation.
1.6.8. Information on complaints regarding the quality of medicinal products manufactured at the manufacturing site of the medicinal product submitted for registration over the past three years (if applicable). When submitting documents in accordance with paragraph 1.6.1 of these Requirements and as part of the procedure for bringing the product into compliance with Union requirements, the submission of information is optional.
1.6.9. Consent to conduct a pharmaceutical inspection for compliance with the requirements of international treaties and acts constituting Union law
(clause 1.6.9 as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated 30.01.2020)
1.6.10. Repealed effective 20 December 2023. - Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023
(clause 1.7.1 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
1.7.2. Information about the specialist who prepared the preclinical study summary (if any). Submission of this information is not mandatory for the purposes of aligning with Union requirements.
(Section 1.7.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.7.3. Information about the specialist who prepared the clinical study summary (if any). Submission of this information is not mandatory for the purposes of aligning with Union requirements.
(Section 1.7.3 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.8.1. A letter from the marketing authorization holder containing information on the additional trade name of the medicinal product (if applicable). Submission of this information is not mandatory for the purposes of aligning with Union requirements.
(Clause 1.8.1 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
1.8.2. Clinical trial documents and a summary to support the registration application (if applicable)
(as amended by Decision No. 14 of the Council of the Eurasian Economic Commission dated 05.03.2021)
1.8.2.1. Permission from the authorized body to conduct the clinical trial in the member states of the Eurasian Economic Union, including permission to amend the registration dossier (if any). Submission of information is not mandatory as part of the procedure for bringing the clinical trial into compliance with Union requirements.
(Clause 1.8.2.1 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated 20.10.2023)
1.8.2.2. List of inspections conducted for compliance with the Rules of Good Clinical Practice of the Eurasian Economic Union (submission of information is not mandatory as part of the procedure for bringing it into compliance with Union requirements)
(clause 1.8.2.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.8.2.3 - 1.8.2.4. Repealed effective 20 December 2023. - Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114
1.8.2.5. Summary of an application for registration of a medicinal product with well-studied medical use (submission of information is not mandatory as part of the procedure for bringing it into compliance with Union requirements)
(clause 1.8.2.5 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.8.2.6. A summary of the registration application for generic, hybrid, or biosimilar medicinal products (if applicable). Submission of information is not mandatory for the purposes of the harmonisation procedure with Union requirements.
(Clause 1.8.2.6 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.8.2.7. A summary of the registration application if patents exist in a Member State for the medicinal product being registered.
(As amended by Decision of the Council of the Eurasian Economic Commission dated 05.03.2021 No. 14)
1.8.2.8. A summary of the registration application in exceptional cases (if applicable) (submission of information is not mandatory for the purposes of the harmonisation procedure with Union requirements).
(Clause 1.8.2.8 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
1.8.2.9. Summary of an application for registration with the establishment of post-registration measures or Summary of an application for conditional registration (if applicable) (submission of information is not mandatory as part of the procedure for bringing the application into compliance with Union requirements)
(clause 1.8.2.9 as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
1.8.3. Table with a list of clinical trials (if applicable) (submission of information is not mandatory as part of the procedure for bringing the application into compliance with Union requirements)
(clause 1.8.3 as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
1.8.4. Repealed effective 20 December 2023. - Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114
1.9. Applicant's documents on the assessment of potential environmental hazards (if any):
1.9.1. A letter from the applicant stating that the medicinal products contain or are derived from genetically modified organisms (if applicable)
1.10. Information regarding the applicant's pharmacovigilance in a member state of the Eurasian Economic Union
1.10.1. A master file of the pharmacovigilance system of the marketing authorization holder in accordance with the good pharmacovigilance practice of the Eurasian Economic Union or a brief description of the pharmacovigilance system of the marketing authorization holder
1.10.2. Written confirmation that the marketing authorization holder has a qualified person responsible for pharmacovigilance in the territory of a member state of the Eurasian Economic Union.
1.10.3. A risk management plan for the medicinal product submitted for registration in accordance with the requirements of the Good Pharmacovigilance Practice Rules of the Eurasian Economic Union, approved by the Eurasian Economic Commission (if applicable).
1.10.4. Duly certified documents confirming the existence of interactions that ensure the proper performance of all duties of the marketing authorization holder by several legal entities (if applicable).
MODULE 2. SUMMARY OF THE COMMON TECHNICAL DOCUMENT
2.1.
2.1. Contents of Modules 2-5
2.2. Introduction to the CTD
2.3. General Quality Summary
2.4. Overview of Preclinical Data
2.5. Overview of Clinical Data
2.6. Summary of Preclinical Studies
(as amended by Decision of the Council of the Eurasian Economic Commission of 30.01.2020 No. 9)
2.6.1. Introduction
2.6.2. Summary of Pharmacological Studies in Text Format
2.6.3. Summary of Pharmacological Studies in Tabular Form
2.6.4. Summary of pharmacokinetic studies in text format
2.6.5. Summary of pharmacokinetic studies in tabular form
2.6.6. Summary of toxicology studies in text format
2.6.7. Summary of toxicology studies in tabular form
2.7. Summary of clinical studies
2.7.1. Summary of Biopharmaceutical Studies and Associated Analytical Methods
2.7.2. Summary of Clinical Pharmacology Studies
2.7.3. Summary of Clinical Efficacy
2.7.4. Summary of Clinical Safety
2.7.5. Copies of References
MODULE 3. QUALITY
3.1.
3.1. Contents of Module 3
3.2. Basic Information
3.2.S. Active Pharmaceutical Substance (APS). For medicinal products containing several active substances, information is provided in full for each of them. <**>
3.2.S.1. General Information on Starting Materials and Raw Materials <**>
3.2.S.1.1. Information on the API Name <**>
3.2.S.1.2. API Structure <**>
3.2.S.1.3. General Properties of the API <**>
3.2.S.2. API Manufacturing Process
3.2.S.2.1. Manufacturer <**>
3.2.S.2.2. Description of the Manufacturing Process and Its Control
3.2.S.2.3. Control of Starting Materials (submission of information is not mandatory as part of the procedure for bringing the drug into compliance with Union requirements (with the exception of biological medicinal products)). As part of the procedure for bringing a product into compliance with Union requirements, the specified information shall be submitted at the request of the authorized body (expert organization) of a member state of the Eurasian Economic Union during the expert work.
3.2.S.2.4. Control of critical stages and intermediate products (as part of the procedure for bringing a product into compliance with Union requirements, submission of information is optional (with the exception of biological medicinal products)). As part of the procedure for bringing a product into compliance with Union requirements, the specified information shall be submitted at the request of the authorized body (expert organization) of a member state of the Eurasian Economic Union during the expert work.
3.2.S.2.5. Validation and/or assessment of the manufacturing process (as part of the procedure for bringing a product into compliance with Union requirements, submission of information is optional (with the exception of biological medicinal products)). As part of the procedure for bringing a medicinal product into compliance with Union requirements, the specified information shall be provided at the request of the authorized body (expert organization) of a Eurasian Economic Union member state during the expert examination.
3.2.S.2.6. Development of the production process (as part of the procedure for bringing a medicinal product into compliance with Union requirements, the submission of information is not mandatory (with the exception of biological medicinal products)). As part of the procedure for bringing a medicinal product into compliance with Union requirements, the specified information shall be provided at the request of the authorized body (expert organization) of a Eurasian Economic Union member state during the expert examination.
3.2.S.3. Description of the characteristics of the API <**>
3.2.S.3.1. Confirmation of the structure and other characteristics
3.2.S.3.2. Impurities <**>
3.2.S.4. API Quality Control <**>
3.2.S.4.1. Specification <**>
3.2.S.4.2. Analytical Methods <**>
3.2.S.4.3. Validation of Analytical Methods (submission of information is not mandatory as part of the procedure for bringing the product into compliance with Union requirements (with the exception of biological medicinal products))
(clause 3.2.S.4.3 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.S.4.4. Batch Analysis (Batch Analysis Results) <**>
3.2.S.4.5. Specification Justification
3.2.S.5. Reference Standards or Materials
3.2.S.6. Packaging (Closure) System <**>
3.2.S.7. Stability <**>
3.2.S.7.1. Stability Test Summary and Stability Conclusion <**>
3.2.S.7.2. Post-marketing stability study program and stability commitments (submission of information is not mandatory under the procedure for bringing the drug into compliance with Union requirements (except for biological medicinal products)) <**>
(clause 3.2.S.7.2 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.S.7.3. Stability test data <**>
3.2.P. Medicinal product
3.2.P.1. Description and composition of the medicinal product
3.2.P.2. Pharmaceutical development
3.2.P.2.1. Components of the medicinal product
3.2.P.2.1.1. Active pharmaceutical substance
3.2.P.2.1.2. Excipients
3.2.P.2.2. Medicinal product
3.2.P.2.2.1. Development of dosage form
3.2.P.2.2.2. Production Surplus
3.2.P.2.2.3. Physicochemical and Biological Properties (submission of information is not mandatory as part of the procedure for bringing the product into compliance with Union requirements (with the exception of biological medicinal products))
(clause 3.2.P.2.2.3 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.P.2.3. Development of the Manufacturing Process. Submission may be omitted if the medicinal product, manufactured at the same production sites, is registered in all Eurasian Economic Union member states specified in the application for bringing it into compliance with Union requirements (with the exception of biological medicinal products)
(clause 3.2.P.2.3 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.P.2.4. Packaging (closure) system. Submission is not required if all Eurasian Economic Union member states specified in the application for alignment with Union requirements use the same packaging (closure) system (with the exception of biological medicinal products).
(Section 3.2.P.2.4 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.P.2.5. Microbiological characteristics (submission of information is not mandatory as part of the procedure for alignment with Union requirements (with the exception of biological medicinal products))
(Section 3.2.P.2.5 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.P.2.6. Compatibility (submission of information is not mandatory within the framework of the procedure for bringing the Union into compliance with requirements (with the exception of biological medicinal products))
(clause 3.2.P.2.6 as amended by Decision of the Council of the Eurasian Economic Commission dated 20.10.2023 No. 114)
3.2.P.3. Medicinal Product Manufacturing Process
3.2.P.3.1. Manufacturers
3.2.P.3.2. Batch Composition (Manufacturing Recipe)
3.2.P.3.3. Description of the Manufacturing Process and Its Control
3.2.P.3.4. Control of Critical Stages and Intermediate Products
3.2.P.3.5. Validation and/or Assessment of the Manufacturing Process
3.2.P.4. Quality Control of Excipients
3.2.P.4.1. Specifications
3.2.P.4.2. Analytical Methods
3.2.P.4.3. Validation of analytical methods (within the procedure for bringing into compliance with Union requirements, the submission of information is not mandatory (with the exception of biological medicinal products))
3.2.P.4.4. Justification of Specifications
3.2.P.4.5. Excipients of Human and Animal Origin
3.2.P.4.6. New Excipients (submission of information is not mandatory under the procedure for bringing them into compliance with the Union requirements (with the exception of biological medicinal products))
3.2.P.5. Quality Control of the Medicinal Product
3.2.P.5.1. Specifications
3.2.P.5.2. Analytical Methods
(clause 3.2.P.5.2 as amended by Decision of the Council of the Eurasian Economic Commission of 30.01.2020 No. 9)
3.2.P.5.3. Validation of Analytical Methods
3.2.P.5.4. Batch Analysis Results
3.2.P.5.5. Impurity Characterization
3.2.P.5.6. Specification Justifications
3.2.P.6. Reference Standards and Materials
3.2.P.7. Packaging (Closure) System
3.2.P.8. Drug Product Stability
3.2.P.8.1. Stability Test Summary and Stability Conclusion <**>
3.2.P.8.2. Post-Market Stability Testing Program and Stability Commitments
3.2.P.8.3. Stability Test Data
3.2.A. Appendices
3.2.A.1. Manufacturing Facilities and Equipment
3.2.A.2. Safety assessment of medicinal products for the presence of extraneous agents (submission of information is not mandatory as part of the procedure for bringing them into compliance with Union requirements (with the exception of biological medicinal products))
(clause 3.2.A.2 as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
3.2.A.3. New excipients
3.2.A.3.1. Information on excipients (reducing agents, solvents, diluents, carriers)
3.2.A.3.2. Description and composition of the excipient (reducing agent, solvent, diluent, carrier)
3.2.A.3.3. Pharmaceutical development of the excipient (reducing agent, solvent, diluent, carrier) (submission of information is not mandatory as part of the procedure for bringing it into compliance with Union requirements (with the exception of biological medicinal products))
(as amended by Decisions of the Council of the Eurasian Economic Commission dated 30.01.2020 No. 9 and dated 20.10.2023 No. 114)
3.2.A.3.4. Manufacturing process of the excipient (reducing agent, solvent, diluent, carrier)
3.2.A.3.5. Batch composition (manufacturing formula) of the reducing agent, solvent, diluent, and carrier
3.2.A.3.6. Quality control of the excipient (reducing agent, solvent, diluent, and carrier)
3.2.A.3.7. Microbiological characteristics of the reducing agent, solvent, diluent, and carrier (submission of information is not mandatory as part of the procedure for bringing products into compliance with Union requirements (with the exception of biological medicinal products))
(as amended by Decisions of the Council of the Eurasian Economic Commission of 30.01.2020 No. 9 and of 20.10.2023 No. 114)
3.2.A.3.8. Packaging (closure) system for an excipient (reducing agent, solvent, diluent, carrier)
3.2.A.3.9. Stability of the excipient (reducing agent, solvent, diluent, carrier)
3.2.A.3.10. Information on the compatibility of the reducing agent, solvent, diluent, carrier
3.2.R. Regional information
3.2.R.1. Excluded. - Decision of the Council of the Eurasian Economic Commission dated March 17, 2022 No. 36
3.2.R.2. Manufacturing Process Validation Plan
(clause 3.2.R.2 as amended by Decision of the Council of the Eurasian Economic Commission dated March 17, 2022 No. 36)
3.2.R.3 - 3.2.R.5. Excluded. - Decision of the Council of the Eurasian Economic Commission dated March 17, 2022 No. 36
3.3. Copies of References
MODULE 4. REPORTS ON PRE-CLINICAL (NON-CLINICAL) STUDIES
4.1. Content of Module 4
4.2. Study Reports (if applicable)
4.2.1. Pharmacology
4.2.1.1. Primary Pharmacodynamics
4.2.1.2. Secondary Pharmacodynamics
4.2.1.3. Safety Pharmacology
4.2.1.4. Pharmacodynamic Drug Interactions
4.2.2. Pharmacokinetics
4.2.2.1. Analytical Methods and Validation Reports
4.2.2.2. Absorption
4.2.2.3. Distribution
4.2.2.4. Metabolism
4.2.2.5. Excretion
4.2.2.6. Pharmacokinetic Drug Interactions
4.2.2.7. Other Pharmacokinetic Studies
4.2.3. Toxicology
4.2.3.1. Single-dose toxicity
4.2.3.2. Repeated-dose toxicity
4.2.3.3. Genotoxicity
4.2.3.4. Carcinogenicity
4.2.3.5. Reproductive and ontogenetic toxicity: fertility and early embryonic development, embryofetal development, prenatal and postnatal development; studies on immature offspring with subsequent observation
4.2.3.6. Local tolerance
4.2.3.7. Other toxicological studies: antigenicity, immunotoxicity, studies of the mechanism of action, drug dependence, metabolites, impurities, etc.
4.3. Copies of references
MODULE 5. CLINICAL TRIALS REPORTS
5.1. Contents of Module 5
5.2. List of all clinical studies (trials) in tabular form
5.3. Clinical study (trial) reports
5.3.1. Biopharmaceutical study reports
5.3.2. Pharmacokinetic study reports using human biomaterials
5.3.3. Human pharmacokinetic study reports
5.3.4. Human pharmacodynamic study reports
5.3.5. Efficacy and safety study reports
5.3.6. Post-marketing experience reports
5.3.7. Case report forms and patient lists
5.4. Copies of references
<*> Documents are submitted unless the legislation of a member state of the Eurasian Economic Union prohibits the request from the applicant for documents that are in the possession of or can be obtained independently by the authorized body.
<**> The minimum amount of information required for submission is in Section 3.2.S. If certain types of documents are not included in the dossier, a justification must be provided in the relevant section. For products of animal origin, the following additional information must be provided in Section 3.2.S: information on the species, age, and diet of the animals from which the raw materials were obtained; information on the nature (category) of the tissue from which the raw materials for the production of the medicinal product were obtained, in terms of its prion hazard; a process flow diagram for raw material processing indicating extractants and process parameters; and raw material quality control methods, including methods for detecting prions in the medicinal product (if necessary).
<***> Footnote excluded. - Decision of the Council of the Eurasian Economic Commission dated January 30, 2020, No. 9.
Note:
Unless otherwise provided by the Rules for Registration and Expertise of Medicinal Products for Medical Use approved by the Eurasian Economic Commission, documents certified by the applicant must be submitted. Registration dossier documents must be submitted in Russian or with a Russian translation in accordance with the instructions provided in Part II of this document. It is permissible to submit the document of section 1.6.3 of module 1, as well as the documents of modules 3-5 in English with the mandatory translation into Russian of the following sections of module 3: description of the production process and its control (3.2.S.2.2), control of critical stages and intermediate products (3.2.S.2.4), validation of the production process and (or) its assessment (3.2.S.2.5), impurities (3.2.S.3.2), confirmation of structure and other characteristics (3.2.S.3.1), specification (3.2.S.4.1), analytical methods (3.2.S.4.2), validation of analytical methods (3.2.S.4.3), justification of the specification (3.2.S.4.5), packaging (closure) system (3.2.S.6), summary of stability tests and conclusion on stability (3.2.S.7.1), description and composition of the medicinal product (3.2.P.1), active pharmaceutical substance (3.2.P.2.1.1), excipients (3.2.P.2.1.2), development of dosage form (3.2.P.2.2.1), production surplus (3.2.P.2.2.2), physicochemical and biological properties (3.2.P.2.2.3), development of manufacturing process (3.2.P.2.3), packaging (closure) system (3.2.P.2.4), microbiological characteristics (3.2.P.2.5), compatibility (3.2.P.2.6), description of manufacturing process and its control (3.2.P.3.3), control of critical stages and intermediate products (3.2.P.3.4), validation of manufacturing process and (or) its assessment (3.2.P.3.5), validation of analytical methods (3.2.P.4.3), justification specifications (3.2.P.4.4), excipients of human and animal origin (3.2.P.4.5), new excipients (3.2.P.4.6), specifications (3.2.P.5.1), analytical procedures (3.2.P.5.2), validation of analytical procedures (3.2.P.5.3), characterization of impurities (3.2.P.5.5), justification of specifications (3.2.P.5.6), packaging (closure) system (3.2.P.7), summary of stability studies and stability conclusion (3.2.P.8.1), post-marketing stability program and commitment to stability studies (3.2.P.8.2), safety assessment for adventitious agents (3.2.A.2), new excipients (3.2.A.3), process validation plan (3.2.R.2). Submission of a pharmacovigilance master file in English is permitted, with a mandatory Russian translation of a summary of the marketing authorization holder's pharmacovigilance system and a risk management plan in English, with a mandatory Russian translation of the summary. However, a Russian translation of documents submitted in accordance with paragraph 175.1 of these Rules is not required if Russian is not the official language of the relevant Eurasian Economic Union member state.
(as amended by decisions of the Council of the Eurasian Economic Commission of 23.04.2021 No. 34 and of 17.03.2022 No. 36)
II. Sample list of documents submitted in the registration dossier
modules for different types of medicinal products
Excluded. - Decision of the Council of the Eurasian Economic Commission dated May 22, 2023 No. 60.
Appendix No. 5
STRUCTURE OF THE COMMON TECHNICAL DOCUMENT FOR THE REGISTRATION OF MEDICINAL PRODUCTS
dated January 30, 2020, No. 9, and March 17, 2022, No. 36)
I. Purpose
This document represents a common format agreed upon by the member states of the Eurasian Economic Union (hereinafter referred to as the Member States or the Union) for the submission of a properly structured common technical document (hereinafter referred to as CTD) for registration dossiers submitted to the authorized bodies of the member states.
The common technical documentation format significantly reduces the time and resources spent on compiling registration dossiers for medicinal products for human use and facilitates the electronic submission of documents in the common technical document format (hereinafter referred to as eCTD).
By standardizing common documentation elements, regulatory review and interaction with the applicant are simplified. Furthermore, the exchange of regulatory information between the authorized bodies of the member states is facilitated.
II. Scope of application
This document primarily addresses the organization of information to be submitted in registration dossiers for new medicinal products (including biotechnological medicinal products).
This document does not specify which study results must be submitted. It merely indicates the appropriate format for presenting the obtained data. Applicants are not authorized to modify the fundamental organization of the CTD described in this document. However, in preclinical and clinical summaries, applicants are authorized to modify individual formats if this is required for optimal presentation of technical information to facilitate understanding and evaluation of the results.
III. General principles
To assist the examiner in examining the key data and to help them quickly navigate the contents of the registration dossier, the presentation of information throughout the CTD must be unambiguous and transparent. The margins of text and tables must allow the document to be printed on A4 paper. The left margin must be large enough to prevent damage to the information when stitched (e.g., left margin - 3 cm, right margin - 1.5 cm, top and bottom margins - 2 cm). The font style and size of the text and tables must be large enough to ensure legibility, even after photocopying. It is recommended to use Times New Roman, 12 pt. for narrative text. Each page must be numbered in accordance with the explanatory document (see the appendix to this document). Abbreviations and acronyms should be expanded upon their first mention in each module. References should be given in accordance with the current version of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals of the International Committee of Medical Journal Editors (hereinafter referred to as the ICMED) (The first version of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals was approved by the Vancouver Group and published in 1979).
IV. Organization of a common technical document
The CTD consists of 5 modules. Module 1 is Member State-specific. Modules 2-5 are common to all regions. Compliance with this document must ensure that these 4 modules are presented in a format acceptable to Member State competent authorities.
Module 1. Administrative and Prescribing Information.
This module should contain Member State-specific documents, such as application forms or proposed information on use in Member States. The content and format of this module are described in Appendix No. 1 to the Rules for Registration and Examination of Medicinal Products for Human Use (hereinafter referred to as the Rules).
Module 2. CTD Summary.
Module 2 should begin with a general introduction to the medicinal product, including the pharmacological class, mechanism of action, and intended clinical use. The introduction as a whole should not exceed one page.
Module 2 should contain the following 7 sections in the following order:
CTD Contents;
CTD Introduction;
Quality Summary;
Preclinical Review;
Clinical overview;
Preclinical narrative and tabular summaries;
Clinical overview.
A description of these summaries is provided in Appendix No. 1 to the Rules.
Module 3. Quality.
Quality information must be presented in a structured format in accordance with Appendix No. 1 to the Rules.
Module 4. Preclinical Study Reports.
Preclinical study reports must be submitted in the manner described in Appendix No. 1 to the Rules.
Module 5. Clinical Study Reports.
Human study reports and related information must be submitted in the manner described in Appendix No. 1 to the Rules.
The general organization of the CTD (eCTD) is presented below.
V. SCHEMATIC REPRESENTATION OF THE ORGANIZATION OF THE OTD
Drawing (not shown)
VI. Organization of the Customs Department for the Registration of Medicinal Products for Medical Use
Module 1. Administrative Information
1.2. General Documentation
Module 2. General Technical Document Summary
2.4. Preclinical Data Summary
2.5. Clinical Data Summary
2.6. Preclinical Study Summary
Pharmacology Study Summary
Pharmacokinetic Study Summary
Toxicology Study Summary
2.7. Clinical Study Summary
Biopharmaceutical Study Summary and Associated Analytical Methods
Clinical Pharmacology Study Summary
Clinical Efficacy Summary
Clinical Safety Summary
Copies of References
Individual Study Summary
Module 3. Quality
Module 4. Preclinical (Non-Clinical) Study Reports
4.1. Module 4 Contents
4.2. Study Reports
4.3. Copies of References
Module 5. Clinical Study Reports
5.1. Module 5 Contents
5.2. List of All Clinical Studies (Trials) in Tabular Form
5.3. Clinical Study Reports (Trials)
5.4. Copies of References
VII. Clarification on the location of registration dossier documents
1. Document Definition
When submitting documents on paper, a document is defined as a set of pages, sequentially numbered and separated from other documents by a separator (see the section "Numbering and Separation of Documents" in Appendix No. 4 to the Rules). A document may be considered equivalent to a file when submitted electronically. The level of detail when submitting documents on paper and/or electronically must be the same. However, when updating a paper dossier to an electronic one, certain changes in detail may be required due to ongoing lifecycle management. When submitting documents electronically, the new file must begin at the same location where the documents were separated by separators in the paper dossier.
When determining the relevance of one or more documents or files, it is necessary to keep in mind that the chosen approach must be adhered to throughout the entire lifecycle of the dossier, since any changes to the information require the entire documents (files) to be replaced. The tables below describe the DTD and/or eDTD hierarchy levels at which documents (files) should be located, as well as the need for one or more documents in each location. All DTD and/or eDTD sections are described; however, not all sections may be applicable to individual files.
2. Module 2
Module 2\\\\\\\
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Introduction
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Submission of documents at this level is not permitted..\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\\
The content is required only for the paper version of the OTD; it is not provided for in the eOTD.
At this level, one document may be submitted. #
<1> The optional detailing of the quality summary is provided to accommodate the varying complexity of drugs. The applicant has the right to choose the level of preparation of the quality summary.
<2> A separate document must be submitted for each pharmaceutical substance.
<3> If the medicinal product is supplied with solvents for reconstitution, information on the solvents must be provided in a separate section of the "P" document.
<4> A separate document must be submitted for each indication for use; however, similar indications may be presented in a single document.
3. Module 3
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One file per source <6>\\\\
(as amended by decisions of the Council of the Eurasian Economic Commission of January 30, 2020, No. 9,
March 17, 2022, No. 36)
Submission of documents at this level is not permitted. #
The content is required only for the paper version of the OTD; it is not provided for in the eOTD..
At this level, one document may be submitted.\\\\\\\\\\\\\\\\
<1> When selecting the level of detail in this module, the applicant should consider that changes to relevant information at any point during the product's life cycle require replacement of the entire CTD and eCTD documents (files).
<2> If the medicinal product contains multiple active substances, the information required for Section "S" should be provided in full for each active substance.
<3> If the medicinal product is supplied with solvent(s) for reconstitution, information on the solvent(s) should be provided in a separate Section "P," as appropriate.
<4> It is unlikely that the lower level headings included in the quality section of the CTD at this location will be presented as separate documents or files.
<6> The list of references should be included in the table of contents.
4. Module 4
Module 4 #
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<1> For each report included in Module 4, a single document is generally required. However, if the study report is large (e.g., a carcinogenicity study), the applicant may submit the report as multiple documents. In this case, the narrative portion of the report should be presented as a single document, and the appendices should be presented as one or more documents. When choosing the level of detail for these reports, the applicant should consider that changes to relevant information at any point during the life cycle of the medicinal product require replacement of the entire documents (files).
<2> The list of references should be included in the table of contents.
5. Module 5
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5.2 &
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At this level, it is permissible to submit one or more documents..\\\\\\\\\\\\\\\\
<1> Applicants should generally submit study reports in the form of several documents (a synopsis, the main body of the study report, and any necessary appendices). Appendices must be organized in accordance with Appendix No. 1 of the Rules of Good Clinical Practice of the Eurasian Economic Union, which describes the content and format of clinical study reports. When choosing the level of detail for these reports, applicants should take into account that changes to relevant information at any point during the drug's life cycle require replacement of the entire documents (files).
<2> If the registration dossier includes multiple indications for use, this section is duplicated for each indication.
<3> A list of references must be included in the table of contents.
VIII. Numbering and dividing a document
1. General requirements
Each document should be numbered (starting from the first page) with the exception of individual references, for which the actual page numbering in the journal is sufficient. Applicants are not required to provide page numbers as "1 of n," where n is the total number of pages.
In addition, all document pages must include a unique header or footer briefly outlining the document's contents. When submitting paper documents, the document divider should include the same identifier that precedes the document to facilitate its identification in the dossier. Abbreviations of the full section number and document title are permitted.
If a section contains multiple documents, a separate table of contents may be provided for each section (to indicate the chronology and titles of the documents it contains), for example:
divider with "3.2.S.4.2. Analytical Methods";
contents: name of Method A, Method B, Method C;
Separator with "3.2.S.4.2. "Methodology A";
Methodology A (i.e., document, pages 1-n);
Separator with "3.2.S.4.2. "Methodology B";
Methodology B (i.e., document, pages 1-n);
Separator with "3.2.S.4.2. "Methodology C";
Methodology C (i.e., document, pages 1-n).
If a section contains only one document (e.g., "3.2.S.1.1. Nomenclature"), the document should be preceded only by the separator "3.2.S.1.1. Nomenclature".
2. Numbering sections in a document
To avoid subheadings at levels 5, 6, etc. (e.g., 2.6.6.3.2.1), the applicant may use an abbreviated number within the document. In this case, the document number and title (e.g., 2.6.6. Narrative Summary of Toxicology) must be included in the document header or footer, followed by the section number within the document (e.g., 1, 1.1, 2, 3, 3.1, 3.2, etc.). The full number (e.g., 2.6.6.3.2.1) is also acceptable.
3. Formatting content
3.1. Module 2.
The content of section 2.1 of the CTD should be detailed to level 3 (e.g. 2.3.S) or level 4 (e.g. 2.3.S.1) depending on which document is included in the quality summary (see document definition in Module 2).
3.2. Module 3.
The table of contents for Section 3.1 of the CTD should include the top-level section numbers, their corresponding section headings, and the volume number in the order they appear in the file. This table of contents will be used to indicate the contents of Module 3 in accordance with Appendix No. 1 to the Rules. It should be detailed only to level 5 (e.g., 3.2.P.2.1). It should be noted that Appendix No. 1 to these Rules provides for additional subsections and subheadings below this level (e.g., 3.2.P.2), so this format should be used throughout the file, even if not included in Section 3.1. "Contents." The lower-level table of contents described in the "Numbering and Separation of Documents" section should not be included in Section 3.1. "Contents."
At the applicant's discretion, a table of contents may be compiled for a specific section containing multiple documents to provide chronology and numbering beyond those specified in Appendix No. 1 to the Rules. It should be provided only within the document, not as a separate document or a new subheading. In this case, a separate table of contents may be provided for such a document to indicate the chronology and titles of the subsections it contains. These documents and subsections should not be included in Section 3.1. "Table of Contents."
Additional attachments or appendices should not be included in this format; however, they are acceptable as a separate document in a section that allows for the submission of multiple documents. In this case, a reference should be made to the relevant section of the attached or enclosed document. If additional information is desired to be attached or supplemented to a section consisting of only one document, such information should be included in that document.
All table of contents entry names must correspond to the heading names and section numbers in accordance with Appendix No. 1 to the Rules or to the separator identifiers (only when submitting a dossier on paper), preferably by their full name, which should allow for easy identification of any abbreviated names that may be used in the corresponding separator. Page numbers should not be included in the table of contents.
References in the table of contents should refer only to that section.
3.3. Module 4
To identify all important components of the dossier (e.g., 4.2.3.5.1. "Fertility and Early Embryonic Development"), the table of contents for Module 4 must include all numerical elements listed in Appendix No. 1 to the Rules and must be detailed at least to the study report level. Therefore, each study report must be reflected in the table of contents. Sections of the study report may be listed in the table of contents for Module 4 of the dossier or only in the table of contents of a separate study report.
Illustration of part of the table of contents for Module 4.
4.2.3.2. Repeated-Dose Toxicity.
Study aa-aaa: 30-Day Repeated-Dose Toxicity Study of Drug C in Rats.
Study bb-bbb: 6-Month Repeated-Dose Toxicity Study of Drug C in Rats.
Study cc-ccc: 30-Day Repeated-Dose Toxicity Study of Drug C in Dogs. Study dd-ddd: 6-month repeated dose toxicity study of Preparation C in dogs.
4.2.3.3.1. In vitro.
Study ee-eee: Ames test with Preparation C.
etc.
3.4. Module 5.
To identify important components of the dossier (e.g., 5.3.5.1.1. "Placebo-Controlled Studies"), the content of Module 5 must include all numerical elements listed in Appendix No. 1 to the Rules and must be detailed at least to the clinical trial report level. Therefore, each clinical trial report must be reflected in the content. Sections of the clinical trial report (see Appendix No. 1 to the Rules of Good Clinical Practice of the Eurasian Economic Union) may be included in the content of Module 5 of the dossier or only in the content of an individual clinical trial report.
Illustration of part of the content of Module 5.
5.3.5 Indication Z - reports of efficacy and safety studies.
5.3.5.1 Indication Z - reports of controlled clinical trials related to the stated indication for use.
5.3.5.1.1 Indication Z - placebo-controlled trials.
Study xx-xxx: Double-blind, placebo-controlled study of drug A for indication Z.
Study yy-yyy: Double-blind.
5.3.5.1.2 Indication Z - studies with active control.
Study zz-zzz: Double-blind, active-controlled study of drug A versus drug C for indication Z.
5.3.5 Indication Q - Efficacy and safety study reports.
5.3.5.1 Indication Q - Reports of controlled clinical trials relevant to the stated indication.
Appendix No. 6
dated January 30, 2020, No. 9, and May 22, 2023, No. 60)
EXPERT REPORT FORM
ON ASSESSMENT OF THE RESULTS OF PRE-CLINICAL
(NON-CLINICAL) STUDIES
(template)
EXPERT REPORT
on the assessment of the results of preclinical (non-clinical) studies
______________________________________________________
(name of the drug, its dosage, formulation)
Expert:
Procedure commenced:
Date of this report:
Deadline for comments:
ADMINISTRATIVE INFORMATION
Registration Application Identification Number:
Trade Name of the Medicinal Product:
International Nonproprietary Name (INN) or Common Name of the Active Substance(s):
Applicant:
Claimed Indications for Use:
Pharmacotherapeutic Group (ATX Code):
Dosage Form and Strength(s):
Names of the Rapporteur's Experts (Internal Expert and Independent Expert):
Quality:
Full Name:
Phone (Fax):
Email:
Preclinical:
Clinical:
List of abbreviations.
EXAMINATION OF PRE-CLINICAL (NON-CLINICAL) ASPECTS
1. Introduction.
1.1. Application Type and Development Considerations.
1.2. Good Laboratory Practice Considerations.
2. Pharmacology (Modules 2.6.2 and 4.2.1).
Brief Description.
Comments of the expert
Physical and chemical properties.
Active substance structure
(insert structure)
Radiolabel position
(see structure)
Isomerism
Relative molecular weight
Solubility in water
Ionization constant (pKa)
Partition coefficient
Solubility in organic solvents
Stability
Presumed chirality and its effects
2.1. Primary Pharmacodynamics.
Expert Commentary
2.2. Secondary Pharmacodynamics.
2.3. Pharmacological Safety.
2.4. Pharmacodynamic Drug Interactions.
2.5. Overall Expert Pharmacological Conclusion.
3. Pharmacokinetics (Modules 2.6.4 and 4.2.2).
Pharmacokinetic Studies.
3.1. Research Methods.
3.2. Absorption.
Sample tables for entering absorption data:
Study Identification Number
Types
Dosage (mg/kg)
Way of administration
Method of analysis
Cmax
tmax
AUC
A
B
, el
Vd
Clt
F (%)
Notes а)
б)
3.3. Distribution.
3.4. Metabolism.
3.5. Elimination.
Виды
Dose (mg/kg)
Route
Analysis method
Urine (% dose)
Feces (% dose)
Bile (% доза)
Uchanged drug (% dose)
Time (hour)
3.6. Pharmacokinetic Drug Interactions.
3.7. Other Pharmacokinetic Studies.
3.8. Overall Expert Opinion on Pharmacokinetics.
4. Toxicology (Modules 2.6.6 and 4.3.3).
4.1. Single-Dose Toxicity.
Example of a toxicity study table for a single dose:
Study ID
Species/Sex/Number/Group
Dose/Route
Estimated Lethal Dose (Observed Maximum Non-Lethal Dose)
Main Results
Expert comments
4.2. Repeated-Dose Toxicity
Example table for repeated-dose toxicity studies:
Duration
NOEL/NOAEL (mg/kg/day)
Main results
Toxicokinetics.
Example table with data from toxicokinetic studies:
Daily dose (xx/xx)
AUC in animals (ng x h/ml)<*>
Animals: Human
XXX
Re-exposure
Note: <*> For comparison, it is advisable to use AUC values for the unbound fraction of the drug.
Interspecies comparison.
Example table comparing exposure in animal studies with exposure in clinical studies:
4.3. Genotoxicity.
Example of a genotoxicity study overview table:
Assay Type/ID/GLP Compliance
Assay System
Concentrations/Concentration Range/Metabolism System
Results Positive/Negative/Inconclusive
Gene mutations in bacteria
strains of salmonella
+/- S9
Gene mutations in mammalian
cells: Chinese hamster ovary cells (CHO cells), HGPRT locus, human lymphocytes
In vivo mouse chromosomal aberrations
bone marrow micronucleus assay
4.4. Carcinogenicity.
4.4.1. Long-term studies.
Example table describing the studies conducted
on carcinogenic activity:
Identification number/good laboratory practice compliance
Dose/route of administration
Exposure (AUC)
Species/Number of animals
Example table with tumor development data
during Study XX:
Tumor Data
Control
Low Dose
Medium Dose
High Dose
4.4.2. Short- and Medium-Term Studies.
4.4.3. Other Studies.
4.5. Reproductive and Developmental Toxicity.
Example table with data on studies conducted:
Species; number of females/group
Route of administration and dose
Period of administration and dose
NOAEL (mg/kg) и AUC
Male Fertility
Female Fertility
Embryofetal Development F0
F1
Perinatal and Postnatal
4.5.1. Fertility and Early Embryonic Development
4.5.2. Embryofetal Development
4.5.3. Prenatal and Postnatal Development, Including Maternal Function
4.5.4. Studies in Which the Product is Administered to Juveniles and/or Further Evaluated for Development
Conclusions Regarding Reproductive Toxicity
4.6. Local Tolerability
4.7. Other Toxicity Studies
4.7.1. Antigenicity
4.7.2. Immunotoxicity.
4.7.3. Dependence.
4.7.4. Metabolites.
4.7.5. Impurity Studies.
4.7.6. Other Studies.
4.8. Overall Toxicology Conclusion of the Assessing Expert.
5. References.
6. List of Comments Raised by the Expert as Part of the Conducted Evaluation.
CRITICAL COMMENTS
Pharmacology.
Pharmacokinetics.
Toxicology.
MINOR COMMENTS
RECOMMENDATIONS
7. Conditions recommended by the expert, the fulfillment of which is necessary after the applicant receives the registration certificate and approval of the general characteristics of the medicinal product, instructions for medical use (package leaflet), and the packaging design of the medicinal product.
Appendix No. 7
CLINICAL TRIAL ASSESSMENT REPORT FORM
on the evaluation of clinical trials
Administrative information
Trade name of the medicinal product:
International nonproprietary name (INN) or generic name of the active ingredient(s):
Claimed indications for use:
Pharmacotherapeutic group (ATC code):
Dosage form(s) and dosage(s):
Expert contact details:
Expert details (internal and independent):
Expert data (internal and independent):
Clinical Evaluation
1.1. Application type and development aspects:
Type of regulatory registration procedure;
Possibility of applying special grounds for the registration procedure;
Application of the biosimilar concept;
Compliance with drug development guidelines (availability of scientific advice);
Significance of pediatric studies.
1.2. Compliance with Good Clinical Practice (GCP) principles.
1.3. Data on classification as an orphan drug.
According to the conclusion of authorized healthcare authorities (conclusion dated 00/00/00), the incidence rate of the disease (indicate the name of the disease) is (XX) per 10,000 people in the territories of the member states of the Eurasian Economic Union (no data).
2. Clinical pharmacology
2.1. Pharmacokinetics.
2.1.1. Introduction.
2.1.2. Methods.
Analytical Methods and Techniques
Pharmacokinetic Data Analysis
Statistical Analysis
2.1.3. Absorption.
Bioavailability
Bioequivalence
Food Effects
2.1.4. Distribution.
2.1.5. Elimination
Elimination
Metabolism
Interconversion
Pharmacokinetics of Metabolites
Consequences of Possible Genetic Polymorphisms
2.1.6. Dose Proportionality and Time Dependence
Dose Proportionality
Time Dependence
2.1.7. Intra- and Inter-Individual Variability
2.1.8. Pharmacokinetics in the Target Population
2.1.9. Special Populations
Renal Impairment
Liver dysfunction
Expert commentary
Gender
Race
Weight
Elderly
Age 65 - 74 years (number of elderly patients (total))
Age 75 - 84 years (number of elderly patients (total))
Age 85+ years (number of elderly patients (total))
PK research
Children
General Expert Commentary on Pharmacokinetics in Special Populations
2.1.10. Interactions
In vitro
In vivo
General Expert Commentary on Interactions
2.1.11. Exposures Relevant to the Safety Assessment
2.1.12. Overall Expert Opinion on Pharmacokinetics
2.2. Pharmacodynamics
2.2.1. Introduction
2.2.2. Mechanism of Action
2.2.3. Primary Pharmacology
2.2.4. Secondary Pharmacology
2.2.5. Plasma Concentration-Effect Relationship
2.2.6. Pharmacodynamic Interactions with Other Medicinal Products or Substances.
2.2.7. Genetic Differences in Pharmacodynamic Response.
2.2.8. Overall Expert Opinion on Pharmacodynamics.
3. Clinical efficacy
3.1. Introduction.
Sample table for presenting information on study details
Study identification number
Study center numbers (locations)
Design
Study dosage
Study objective
Patients by group (included (completed the study))
Gender (m or f), median age
Diagnosis, inclusion criteria
Primary endpoints
3.2. Dose-Response Studies and Pivotal Clinical Trials
3.3. Dose-Response Study(s)
3.4. Main Study(s)
Methods
Study Participants
Treatment Types
Objectives
Outcomes (Endpoints)
Sample Size
Randomization
Blinding
Statistical Methods
Results
Participant Allocation Flow Chart (this format should be used; modifications may be made as necessary)
(───────────────────────) (───────────────────────)
│ Скринировано │ │Исключены как │
НАБОР │ на соответствие ├────>│несоответствующие │
│ требованиям │ │критериям (n=....) │
│ (n=....) │ │Отказались от участия │
(───────────┬───────────) │(n=....) │
│ │Другие причины (n=....)│
│ (───────────────────────)
\/
(───────────────────────)
│Рандомизировано │
│(n=....) │
(───────────┬───────────)
│
┌──────────────┴──────────────────┐
│ │
\/ \/
РАС- (────────────────────────────────) (──────────────────────────────)
ПРЕ- │Вошли в группу лечения (n=....) │ │Вошли в группу лечения │
ДЕЛЕ- │Получили лечение по протоколу │ │(n=....) │
НИЕ │(n=....) │ │Получили лечение по протоколу │
│Не получали лечения (n=....) │ │(n=....) │
│(указать причину) │ │Не получали лечения (n=....) │
(─────────┬──────────────────────) │(указать причину) │
│ (───────┬──────────────────────)
ПОСЛЕ- (──────────────────────────────) (──────────────────────────────)
ДУЮЩЕЕ │Не вошли в период последующего│ │Не вошли в период последующего│
НАБЛЮ- │наблюдения (n=....) │ │наблюдения (n=....) [указать │
ДЕНИЕ │[указать причины] │ │причины] │
│Лечение прекращено (n=....) │ │Лечение прекращено (n=....) │
│(указать причины) │ │(указать причины) │
(─────────┬────────────────────) (───────┬──────────────────────)
(─────────────────────────) (─────────────────────────)
│Проанализировано (n=....)│ │Проанализировано (n=....)│
АНАЛИЗ │Исключены из анализа │ │Исключены из анализа │
│(n=....) │ │(n=....) │
Study Recruitment
Study Conduct
Initial Data
Analyzed Sample
Outcomes and Their Assessment
Additional Analysis
Summary of Key Efficacy Findings
The following tables summarize the results of the key efficacy studies supporting the adequacy of this statement. This summary should be read in conjunction with the clinical efficacy notes and the risk-benefit analysis (see the following sections).
Summary of Key Study Findings
(Efficacy Study)
Name (as stated in the research report)
Code
List of all codes beginning with the protocol number, followed (if available) by the European Clinical Trials Database number, International Standard Randomized Clinical Trial Number, and other codes for cross-referencing publications.
Study Design
Free text
Describe the key elements of the study design (crossover, parallel, factorial, dose-escalation, fixed-dose analysis), including studies with randomization, blinding, allocation concealment, single- and multi-center studies, etc.
Duration of the main phase:
time
time not applicable
Duration of the preparatory phase:
Duration of the additional treatment phase:
Hypothesis
Advantages
Similarity
No less effective
Overview: Specify
Treatment Groups (add as many rows as needed to describe the treatment groups)
Group coded designation (indicate the abbreviation for later use in the results section table)
Treatment
Number of randomized subjects
Group coded designation
Clinical endpoints (add as many rows as necessary to describe the clinical endpoints;
as secondary clinical endpoints, include the most relevant endpoints listed in the results section)
Combined
Symbol (indicate the abbreviation for later use in the table in the results section)
free text (provide a brief description)
Primary
Clinical Trial Endpoint
Secondary
Other:
Specify the clinical trial endpoint
Symbol
Closing the database
Analyses and results (present separately for each analysis the result considered relevant for inclusion in the study report; in any case, data on the pre-specified primary analysis must be presented)
Description of the Analysis
первичный анализ
Subject Group and Description of Time Points
Sample population
initiated treatment
patients who completed the study according to the protocol
other: specify
(may require a brief description of the population)
time point
Descriptive statistics and estimated variability
Treatment group
coded group designation (according to the terminology given above)
Number of subjects
n
Clinical trial point (symbol as above)
point estimate
Statistic (e.g., mean, median, etc.)
variability
Variance statistics (e.g., standard deviation, confidence interval, etc.)
Clinical trial point (statistic)
Variance statistics Clinical trial point
Statistic
Variance statistics
Estimate of Effect in Comparison (add as many lines as necessary to describe the actual statistical analysis performed)
combined
primary
endpoint of a clinical
trial
Comparison groups
coded group designation (as per the terminology above)
Significance test (e.g., difference between groups)
Variance statistics (e.g., confidence interval, etc.)
variance
P value (specify the statistical method used, e.g., ANOVA)
P value
Indicate the clinical trial location
coded group designation
significance test
variance statistics
укажите точку клинического исследования, пользуясь терминологией, указанной выше в разделе "Точки клинического исследования и определения"
P-value
Notes
(Among other things, consider the following information:
Reasons for withdrawal from the study; Critical analysis results)
Analysis Description
Additional analysis
Combined primary analysis
Other
Specify (also indicate if the analysis was planned)
Repeat the above sections for each relevant analysis
3.5. Clinical trials in special populations.
Controlled studies
Uncontrolled studies
3.6. Analysis performed within the context of trials (pooled analysis and meta-analysis).
3.7. Additional research.
3.8. Overall Expert Opinion on Clinical Efficacy
Clinical Efficacy Conclusions
Clinical Trial Design and Conduct
Efficacy Data and Additional Analyses
4. Clinical safety
4.1. Introduction.
4.2. Drug Exposure to Patients.
Sample Table: Drug Exposure to Patients (Acceptable Levels)
Included patients
Patients who received treatment
Patients exposed to the proposed dose range
Patients with long-term <*> safety data
Placebo-controlled studies
Active-controlled studies
Open-label studies
Post-marketing studies
Compassionate use
<*> The indication applies to data from continuous or intermittent exposure over a period of 6 or 12 months.
4.3. Adverse events.
4.4. Serious adverse events and death.
4.5. Laboratory test data.
4.6. Safety of drug use in special population groups.
Dictionary terms MedDRA
age < 65 years, number (percentage)
age 65 - 74 years, number (percentage)
age 75 - 84 years, number (percentage)
ge 85+ years, number (percentage)
Total number of adverse events
Serious adverse events (total)
Fatal
Hospitalization (prolongation of existing hospitalization)
Life-threatening
Disability (incapacity)
Other (medically important)
Adverse event leading to study withdrawal
Psychiatric disorders
Nervous system disorders
Accidents and injuries
Cardiac disorders
Vascular disorders
Cerebral circulatory disorders
Infectious and parasitic diseases
Anticholinergic syndrome
Decreased quality of life
In summary: orthostatic hypotension, falls, blurred vision, syncope, dizziness, ataxia, fractures
Other adverse events more common in elderly patients
4.7. Immunological phenomena.
4.8. Safety in drug and other interactions.
4.9. Withdrawal from the study due to adverse events.
4.10. Post-market studies.
4.11. Overall conclusion of the clinical safety assessor.
Clinical efficacy conclusions
Clinical safety conclusions
5. Pharmacovigilance
5.1. Pharmacovigilance system.
The applicant submitted documents detailing the pharmacovigilance system. The pharmacovigilance application is signed by the applicant and the authorized representative, stating that the applicant is provided with the services of an authorized representative responsible for pharmacovigilance and has the necessary means to report any adverse reaction occurring in the Eurasian Economic Union or a third country.
The expert considers that the pharmacovigilance system described by the applicant satisfies the requirements and provides adequate evidence that the applicant is provided with the services of an authorized representative responsible for pharmacovigilance and has the necessary means to report any suspected adverse reaction occurring in the Eurasian Economic Union or a third country.
The expert considers that the pharmacovigilance system described by the applicant has the following deficiencies: <list of deficiencies>.
Given that deficiencies are corrected before the applicant launches the medicinal product, the authorized expert organization can deem the pharmacovigilance system compliant. Before a medicinal product is marketed, the applicant must provide convincing evidence that the pharmacovigilance system is in place and functioning.
5.2. Risk Management Plan.
Questions and/or comments for consideration by the pharmacovigilance expert when assessing the risk management plan: _______________________________________________________________________
______________________________________________________________________
6. Bibliography:
_______________________________________________________________________
7. List of questions raised by the expert
Clinical aspects:
a) Critical comments:
pharmacokinetics;
pharmacodynamics;
efficacy;
safety;
pharmacovigilance system;
risk management plan;
b) Minor comments:
c) Recommendations:
8. Conditions recommended by the expert, compliance with which is required after the applicant receives a registration certificate and approval of the general characteristics of the medicinal product
Applicant consultation:
Appendix No. 8
dated May 22, 2023, No. 60)
ON CRITICAL ASSESSMENT OF QUALITY ASPECTS
OF A MEDICINAL PRODUCT
Instructions for filling out: when using ready-made text templates, they are highlighted in this form with < > signs and in italics; fragments of text templates, which are filled out by entering specific text options for a specified property (parameter), are given in curly brackets { } with an indication of the property (parameter) that must be entered in italics.
on the critical assessment of quality aspects
(name of the drug, its formulation, dosage)
LIST OF ABBREVIATIONS
I. CRITICAL ASSESSMENT AND QUALITY EXPERTISE
1. Request for an inspection of a pharmaceutical
production facility prior to issuing a registration certificate
2. Introduction
Name:
Dosage form and strength (concentration):
Registration procedure:
Therapeutic class or indication:
Suggested dose range:
3. Active pharmaceutical substance (API, module 3.2.S)
Notes: 1. It should be noted whether the submitted document is a Certificate of Conformity of the European Pharmacopoeia Monograph (hereinafter referred to as the CEC), a Dossier on the Active Pharmaceutical Substance (hereinafter referred to as the DAPI), or full information on the active pharmaceutical substance.
2. If an Active Pharmaceutical Substance Master File (hereinafter referred to as the MFAPI) is used, it should be noted that its assessment is presented in a separate AMPFS Critical Assessment Report with a confidential appendix for the closed section of the document.
3. If the dossier contains information on several AMPFS, a separate report is submitted for each AMPFS.
4. For the medicinal product in question, information on permission to access confidential information must be provided. 5. When using CEPs and MFAPI, only sections 3.4 "Active Pharmaceutical Ingredient Quality Control" and 3.5 "Reference Standards or Materials" related to the manufacturing of the medicinal product need to be completed, unless the applicant has provided additional data, namely, stability data to support a longer follow-up period in accordance with section 3.2.S.7.
6. Questions regarding the closed section of the MFAPI reports should be addressed not to the applicant, but exclusively to the relevant manufacturer of the active pharmaceutical ingredient (MFAPI holder).
7. When using CEPs and MFAPS, the source (applicant, MFAPI owner, or CEP holder) and the level of detail of the information for compiling the critical assessment report should be specified.
8. The quality assessment of the active pharmaceutical ingredient in this report should also reflect additional information provided by the applicant that is not included in the open section of the document submitted by the MFAPI holder. If the applicant provides complete information on the active pharmaceutical substance, the report must include an assessment of this information.
3.1. General information on starting materials and raw materials
(Module 3.2.S.1).
Information on the name of the API (module S.1.1)
International Nonproprietary Name (INN):
Chemical Name:
Alternative Name (if applicable):
IUPAC Name:
CAS Number:
Laboratory Code:
Molecular Formula:
Relative Molecular Mass:
Structure of the AFS (module S.1.2)
_________________________________________________________________________
___________________________________________________________________________
General properties of API (module S.1.3)
Physical properties:
Solubility:
pKa value (if available):
Solution pH value (if available)
Melting point (for solids)
Partition coefficient:
Hygroscopicity:
Stereochemistry:
Polymorphism:
Degree of crystallinity (for solids)
Expert commentary _______________________________________________
__________________________________________________________________
3.2. API production process (module 3.2.S.2)
3.2.1. Manufacturers (Section S.2.1).
3.2.2. Compliance with the Good Manufacturing Practices of the Eurasian Economic Union, approved by the Eurasian Economic Commission (hereinafter referred to as the Commission) (GMP).
3.2.3. Description of the manufacturing process and its controls (Section S.2.2).
3.2.4. Quality control of starting materials (Section S.2.3).
3.2.5. Control of critical stages and intermediate products (Section S.2.4).
3.2.6. Validation and/or assessment of the manufacturing process (Section S.2.5).
3.2.7. Development of the manufacturing process (Section S.2.6).
3.3. Description of API Characteristics (Module 3.2.S.3)
3.3.1. Confirmation of Structure and Other Characteristics (Section S.3.1).
3.3.2. Impurities (Section S.3.2).
3.4. Active Pharmaceutical Ingredient Quality Control
(Module 3.2.S.4)
3.4.1. Specification (Section S.4.1).
Table S.4-1
Specification
Quality indicators
Test method
Acceptable standards
3.4.2. Analytical methods (Section S.4.2).
3.4.3. Validation of analytical methods (Section S.4.3).
Table S.4-2
Краткий обзор параметров валидации аналитических методик
Analytical methodology
Accuracy
Reproducibility:
Repeatability (precision)
Interlaboratory reproducibility (if available)
Specificity
Detection limit
Lower limit of quantification
Linearity
Range of detectable contents
Robustness
Solution stability
Note: A "+" sign indicates that the parameter has been determined in accordance with the requirements; a "-" sign indicates that the parameter has not been determined; and a "?" sign indicates that questions remain before the parameter's acceptability is assessed.
3.4.4. Batch Analysis (Batch Analysis Results) (Section S.4.4).
3.4.5. Specification justification (Section S.4.5).
3.5. Standard samples or materials (module 3.2.S.5)
3.6. Packaging (closure) system (module 3.2.S.6)
3.7. Stability (Module 3.2.S.7)
3.7.1. Stability Test Summary and Stability Conclusion (Section: S.7.1).
Table S.7-1
Stability tests
Temperature, °C; relative humidity (RH), %
n batches
x months
Batch size
Packaging
25 °C/ОВ 60%
industrial scale or pilot industrial scale
is intended for implementation or not
40 °C/ОВ 75%
3.7.2. Post-marketing stability testing program and stability commitments (Section S.7.2).
3.7.3. Stability test data (Section S.7.3).
The stability test data on which the summary and conclusion in Section S.7.1 are based are included in the dossier.
4. Medicinal Product (Module 3.2.P)
4.1. Description and Composition of the Medicinal Product
(Module 3.2.P.1)
The composition of <name of medicinal product> is presented in Table P.1-1.
Table P.1-1
Full composition of <name of drug>
Component
Reference to ND
<Name> Quantity (<name>)
Note: When registering a dosage line, the number of columns "<Name> Quantity (<name>)" corresponds to the number of dosages submitted for registration.
4.2. Pharmaceutical Development (Module 3.2.P.2)
4.2.1. Medicinal Product Components (Section P.2.1).
4.2.2. Active Pharmaceutical Substance (Section P.2.1.1).
4.2.3. Excipients (Section P.2.1.2).
4.2.4. Medicinal Product (Section P.2.2).
4.2.5. Dosage Form Development (Section P.2.2.1).
Bioequivalence Study and Reference Product or Clinical Development of Dosage Form
4.2.6. Manufacturing Excess (Section P.2.2.2).
4.2.7. Physicochemical and Biological Properties (Section P.2.2.3).
4.2.8. Manufacturing Process Development (Section P.2.3).
4.2.9. Packaging (closure) system (Section P.2.4).
4.2.10. Microbiological characteristics (Section P.2.5).
4.2.11. Compatibility (Section P.2.6).
4.3. Medicinal Product Manufacturing Process
(Module 3.2.P.3)
4.3.1. Manufacturers (Section P.3.1).
4.3.2. Batch Composition (Manufacturing Formulation) (Section P.3.2).
4.3.3. Description of the Manufacturing Process and Its Control (Section P.3.3).
4.3.4. Control of Critical Steps and Intermediate Products (Section P.3.4).
4.3.5. Validation and/or Assessment of the Manufacturing Process (Section P.3.5).
4.4. Quality Control of Excipients
(Module 3.2.P.4)
4.4.1. Specification (Section P.4.1).
4.4.2. Analytical Procedures (Section P.4.2).
4.4.3. Validation of Analytical Procedures (Section P.4.3).
4.4.4. Justification of Specifications (Section P.4.4).
4.4.5. Excipients of Human and Animal Origin (Section P.4.5).
4.4.6. New Excipients (Section P.4.6).
4.5. Quality Control of the Medicinal Product (Module 3.2.P.5)
4.5.1. Specifications (Section P.5.1).
Table P.5-1
Release and Expiry Date Specifications
Quality Indicator
Test Method
Acceptable Limits
4.5.2. Analytical methods (Section P.5.2).
4.5.3. Validation of analytical methods (Section P.5.3).
Table P.5-2
Brief overview of validation parameters for analytical methods
Interlaboratory reproducibility
Стабильность раствора
Note: The "+" sign indicates that the parameter has been determined in accordance with the requirements, the "-" sign indicates that the parameter has not been determined, and the "?" sign indicates that there are questions to be answered before assessing the acceptability of the parameter.
4.5.4. Batch Analysis Results (Section P.5.4).
4.5.5. Impurity Characterization (Section P.5.5).
4.5.6. Specification Justification (Section P.5.6).
4.6. Standard samples and materials (module 3.2.P.6)
4.7. Packaging (closure) system (module 3.2.P.7)
4.8. Stability (Module 3.2.P.8)
4.8.1. Stability Test Summary and Stability Conclusion (Section P.8.1).
Table P.8-1
Basic stability tests
4.8.2. Post-marketing stability testing program and commitments regarding stability studies (Section P.8.2).
4.8.3. Stability test data (Section P.8.3).
The stability test data on which the summary and conclusion in P.8.1 are based are included in the dossier.
4.8.4. Summary of confirmation of the declared shelf life and storage conditions of the medicinal product.
5. Addenda (Module 3.2.A)
5.1. Manufacturing Facilities and Equipment
5.2. Safety Assessment with Respect to Adverse Agents
5.3. New Excipients
6. Regional Information
6.1. Process Validation Framework
6.2. Issues Affecting Medical Devices
6.3. Issues Related to the Risk of Transmission of BSE
7. Expert Comments on the General Characteristics of the Medicinal Product, Instructions for Medical Use (package leaflet), and Packaging Design
8. General Conclusions of the Expert on Quality
9. List of Comments Provided by the Expert as Part of the Conducted Expertise
9.1. Quality Aspects
9.2. Critical Comments
9.2.1. Active pharmaceutical ingredient (applies to additional data provided by the applicant only).
9.2.2. Active pharmaceutical ingredient (part of the application submitted by the holder of the ASMF).
Note. When using the ASMF, in the case of a potential serious risk to public health reflected in its closed section, the following should be indicated: <for the potential serious risk to public health in the closed section of the ASMF, please refer to the separate expert report on the critical assessment of the ASMF>. #
9.2.3. Medicinal product.
9.3. Minor comments
9.3.1. Active pharmaceutical ingredient (applies to additional data provided by the applicant only).
Note. If applicable, the following should be indicated: <for other comments on the closed section of the ASMF, please refer to the separate expert report on the critical assessment of the ASMF>. #
9.3.2. Medicinal product.
9.4. Recommendations
10. Appendix 1 (if necessary)
on the critical assessment of the Active Pharmaceutical Ingredient Master File
{Active Pharmaceutical Ingredient} #
{Active Pharmaceutical Ingredient Manufacturer} #
{Registration Number} # (if any)
{(Applicant's Part Version Number, Date, Service Part Version Number) Date} #
10.1. Administrative Information
ID number:
International nonproprietary name (INN) (common name) of the active pharmaceutical substance(s):
Internal code of the active pharmaceutical ingredient manufacturer (if applicable):
Names and addresses of the active pharmaceutical ingredient manufacturer's manufacturing sites
Address:
Contact person:
Phone number:
Fax number:
Email address:
Date of the active pharmaceutical ingredient master file assessment report
registration procedure (registration, variation):
Maximum daily dose
(e.g., < 1 g, < 10 g, etc.)
Routes of administration
Target groups
<newborns, infants, children, adults> #
Notes: 1. The report structure should reflect the relevant parts of Module 3.2.S.
2. A separate expert report is prepared for each active pharmaceutical substance master file (ASMF).
3. This report is not sent to the marketing authorization holder, but only to the relevant API manufacturer/ASMF holder.
4. Access authorizations for specific medicinal products are described in the expert report on the critical assessment of the quality aspects of the medicinal product in question.
10.2. Expert Report and Questions on the Part of the ASMF Open
to the Applicant
This report concerns only the ASMF. However, it should always be considered in conjunction with the expert report(s) on the critical assessment of the registration dossier of the medicinal product to which it (they) relates.
The ASMF in the format of a common technical document was submitted (by the ASMF holder) to (the ASMF):________________________________________________________________________
{Applicant's Section Version Number} #
{Closed Section Version Number} #
S.1 General Information.
S.2 Manufacturing.
S.2.1 Manufacturer (Name and Address of API Manufacturer).
S.2.2 Description of Manufacturing Process and Its Controls (Brief Overview).
S.3 Description of Characteristics.
S.3.1 Confirmation of Structure and Other Characteristics.
S.3.2 Impurities.
S.4 Quality Control.
S.4.1 Specification.
S.4.2 Analytical Procedures.
S.4.3 Validation of Analytical Procedures.
S.4.4 Batch Analysis.
S.4.5 Specification Justification.
S.5 Reference Standards or Materials.
S.6 Packaging (Closure) System.
S.7 Stability. S.7.1. Stability Test Summary and Stability Conclusion.
S.7.2. Post-Market Stability Testing Program and Stability Commitments.
S.7.3. Stability Test Data.
OVERALL CONCLUSION
on the applicant's FSMF
LIST OF COMMENTS
Critical Comments:
Minor Comments:
ASSESSMENT OF RESPONSES
to the list of comments on the applicant's FSMF
Question ________________________________________________________________
Summary of Applicant's Response________________________
Evaluation of Applicant's Response
_______________________________________________
Overall Summary and Conclusion_____________________________________________
Minor comments:
GENERAL CONCLUSION
on the applicant's portion of the ASMF
10.3. Expert report and questions on the portion of the ASMF closed
to the applicant
CONFIDENTIAL
THIS SECTION OF THE OPINION MAY NOT BE TRANSFERRED TO THE APPLICANT
{Registration number} # (if any)
{(Applicant's portion version number, date,
service portion version number) date} #
10.4. Administrative Information
Note. The report structure should reflect the relevant sections of Module 3.2.S.
S.2. Manufacturing
S.2.1. API Manufacturer (name, address, and responsibility of each party, including contractors, involved in the manufacturing chain).
S.2.2. Description of the Manufacturing Process and Its Controls (detailed information).
S.2.3. Quality Control of Starting Materials.
S.2.4. Control of Critical Steps and Intermediate Products.
S.2.5. Validation and/or Assessment of the Manufacturing Process.
S.2.6. Manufacturing Process Development.
S.3. Description of Characteristics
S.3.2. Impurities (in accordance with Appendix No. 10 to the Rules for Registration and Examination of Medicinal Products within the Eurasian Economic Union, approved by the Eurasian Economic Commission (if applicable)).
S.4. API Control
S.4.5. Specification justification (in accordance with Appendix No. 10 to the Rules for Registration and Examination of Medicinal Products within the Eurasian Economic Union, approved by the Eurasian Economic Commission (if applicable)).
GENERAL CONCLUSION on the closed section of the IFAS___________________________________________________________________________
to the closed section of the ASMF
Critical comments:
to the list of comments to the closed section of the ASMF
On the closed part of ASMF
11. Appendix 2.
Design Scope and Change Management Protocols
(if applicable)
This section of the report should briefly summarize all aspects of the development and design of the dosage form of the medicinal product, its quality, safety, and efficacy, as agreed in the registration dossier and necessary to ensure flexible management during the post-registration phase. This appendix can subsequently be used by experts and pharmaceutical inspectors as a basis for assessing post-registration change applications.
1. Active Pharmaceutical Substance
1.1. Design Scope for API.
The design scope (characteristics and corresponding change ranges) should be presented in tabular format.
1.2. Change Management Protocols for API.
The changes included in the agreed protocol should be described, as well as the categories of agreed deviation limits for reporting the implementation of changes.
2. Medicinal Product
2.1. Design Scope for the Medicinal Product.
Presentation of the design scope (characteristics and their corresponding change ranges) in tabular format.
2.2. Change management protocols for the medicinal product.
Description of the changes included in the agreed protocol, as well as the categories of agreed variations for reporting on change implementation.
Appendix No. 9
ON ASSIGNING THE STATUS OF A NEW ACTIVE
PHARMACEUTICAL SUBSTANCE
Instructions for completion: When using pre-made text templates, they are highlighted in this form with < > signs and in italics. Text template fragments that are completed by entering specific text variations for a specified property (parameter) are provided in curly brackets { }, with the property (parameter) to be entered in italics. If the form offers a choice of several pre-made text fragments, the selection criteria are provided in square brackets [ ] in normal font.
on assigning the status of a new active pharmaceutical ingredient (API) to _______________________________________,
(name of active pharmaceutical ingredient)
included in _________________________________________________
(name of medicinal product)
Registration Application Identification Number
Trade Name of the Medicinal Product
Active Pharmaceutical Substance
International Nonproprietary Name (INN) or Common Name of the Active Pharmaceutical Substance
Claimed Indications for Use
Pharmacotherapeutic Group (ATC Code)
Dosage Form and Dosage
Expert Details
Module 3 Expert:
Phone (Fax) Number:
Email Address:
Module 4 Expert:
Module 5 Expert:
1. Recommendation
Based on the review of the data, the expert believes that the active pharmaceutical substance (active ingredient) <name of the active pharmaceutical substance> contained in the medicinal product <name of the medicinal product>
<may qualify as a new <independent> active pharmaceutical substance <in comparison with the known <registered isomer (mixture of isomers, complex, derivative, salt {INN (salt)} previously registered in the Union <active pharmaceutical substance>, since it differs significantly in properties from the previously registered substance in terms of safety and efficacy.>
<may qualify as a new <independent> active pharmaceutical substance <in comparison with the <known> <registered isomer (mixture of isomers, complex, derivative, salt {INN (salt)}) previously registered in the Union>> as {name of the registered medicinal product}, <if provided that satisfactory responses are provided to the comments, which are detailed in the List of Comments.
does not qualify as a new <independent> active pharmaceutical ingredient <in comparison with a known <registered isomer (mixture of isomers, complex, derivative, salt {INN (salt)} previously registered in the Union as {name of the registered medicinal product}, since it does not significantly differ in properties from the previously registered substance in terms of safety and efficacy.> Comments preventing the qualification of the active pharmaceutical ingredient as new are detailed in the List of Comments.
2. Executive Summary
2.1. Statement of the Problem
The registration application was accepted for review in accordance with the Rules for Registration and Examination of Medicinal Products within the Eurasian Economic Union, and includes a justification and analysis of the reasons for classifying the active pharmaceutical ingredient <name of the active pharmaceutical ingredient> as a new active pharmaceutical ingredient.
The applicant made a request for classification active pharmaceutical substance <name of the active pharmaceutical substance> contained in the above-mentioned medicinal product to an <independent> new active pharmaceutical substance <in comparison with a known <registered isomer (mixture of isomers, complex, derivative, salt {INN (salt)} previously registered in the Union as {name of the registered medicinal product}, and stated that <the active pharmaceutical substance> differs significantly in properties from the previously registered substance in terms of safety and efficacy.>
3. Expert Scientific Assessment
3.1. Quality Aspects
Quality Aspect Analysis
Quality Aspect Conclusions
Preclinical Aspects
Preclinical Aspect Analysis
Preclinical Aspect Conclusions
3.2. Clinical Aspects
Clinical Aspect Analysis
Clinical Aspect Conclusions
4. Overall Conclusions
[If it is concluded that the applicant should provide additional information, please provide the following]
<Based on the review of the data on the quality, preclinical and clinical properties of the active pharmaceutical substance, the examiner believes that the applicant should provide additional evidence that <name of active pharmaceutical substance> should qualify as a new active pharmaceutical substance. Satisfactory responses to the comments set out in the List of Comments must be provided.
[If the conclusion made does not require the applicant to submit additional information, and the applicant asserts that the compound is an independent new active pharmaceutical substance, indicate the following]
<Based on the review of the data on the quality, preclinical, and clinical properties of the active pharmaceutical substance, the expert believes that <name of the active pharmaceutical substance> <does not> qualify as a new active pharmaceutical substance.>
[If the conclusion made does not require the applicant to submit additional information, and the applicant asserts that the compound is a new active pharmaceutical substance in comparison with a known isomer (mixture of isomers, complex, derivative, salt) of a chemical substance previously registered in the Eurasian Economic Union of a medicinal product, indicate the following]
<Based on the review of the data on the quality, preclinical, and clinical properties of the active pharmaceutical substance, the expert believes that <isomer (mixture of isomers, complex, derivative, salt) {INN (salt) of the applicant} in Compared to a known <isomer (mixture of isomers, complex, derivative, salt) {approved INN (salt)} <does not> qualify as a new active pharmaceutical ingredient, <differs>, <does not differ> significantly in properties from the previously registered substance in terms of safety and efficacy.>
5. List of Comments
Appendix No. 10
PROCEDURE FOR WORKING WITH A MASTER FILE FOR
AN ACTIVE PHARMACEUTICAL SUBSTANCE
I. Introduction
The primary objective of the Active Pharmaceutical Ingredient Master File (ASMF) procedure is to protect valuable confidential intellectual property or know-how of the active pharmaceutical ingredient (API) manufacturer, while simultaneously allowing the applicant or marketing authorization holder (MAH) to assume full responsibility for the medicinal product, as well as the quality and quality control of the active pharmaceutical ingredient. This procedure allows authorized bodies of the Eurasian Economic Union member states (hereinafter, respectively, Member States and the Union) to have full access to the information necessary for assessing the suitability of the active pharmaceutical ingredient for use in medicinal products.
II. Scope
This Appendix is intended to assist applicants (registration registration holders) in compiling the active pharmaceutical ingredient section of a medicinal product registration dossier or a dossier for amendments to the registration dossier of a registered medicinal product (amendment dossier) (Section 3.2.S). It is also intended to assist holders of the ASMF in compiling the ASMF.
III. Contents of the Active Pharmaceutical Substance Master File
The ASMF must contain detailed scientific information, identified under the various headings of Module 3 of the registration dossier in the format of a common technical document (Table 1).
The scientific information in the ASMF must be physically separated into two parts: the applicant's part (hereinafter referred to as AP) and the confidential part (hereinafter referred to as CP). The AP contains information that the ASMF holder does not consider confidential to the applicant (MA holder), while the CP contains information that the ASMF holder considers confidential (Appendix No. 1 to this Appendix). It should be noted that the CP is still a confidential document and cannot be disclosed to third parties without the written consent of the FSMA holder. In all cases, the CP must contain sufficient information to enable the applicant (MA holder) to assume full responsibility for assessing the suitability of the active pharmaceutical ingredient specification and to control the quality of such active pharmaceutical ingredient for its use in the manufacture of a specific medicinal product. The AP may contain additional information, such as details of individual manufacturing stages (reaction conditions, temperature, validation and evaluation of critical manufacturing steps) and quality control data during the manufacture of the active pharmaceutical ingredient. Member State competent authorities have the right to disagree with the failure to provide certain information in the DMF to the applicant (MA holder). In such cases, the Member State competent authorities have the right to request correction of the DMF.
In addition to the AP and CP of DMF, the ASMF must have a table of contents and separate overall quality summaries for the AP and CP. Each version of the AP and CP must have unique and independent version control numbers.
IV. Use of the Active Substance Master File Procedure
ASMF may only be submitted to support the registration of a medicinal product in the Union or amendments to the registration dossier of a medicinal product registered in the Union. The relationship between the quality of the active pharmaceutical ingredient and its use in a medicinal product must be substantiated in the registration dossier or amendment dossier.
Although the ASMF procedure was developed to protect the intellectual property of the MAPS, it may also be used in the absence of confidentiality between the applicant (MA holder) and the MAPS (for example, when the applicant (MA holder) independently synthesizes the active pharmaceutical ingredient). The MAPS must be the MFAFS holder.
The ASMF procedure is used for the following active pharmaceutical ingredients, including herbal medicinal raw materials (herbal pharmaceutical substances):
new active pharmaceutical ingredients;
known active pharmaceutical ingredients not included in the Pharmacopoeia of the Union or the pharmacopoeia of a Member State;
pharmacopeial active pharmaceutical ingredients included in the Pharmacopoeia of the Union or the pharmacopoeia of a Member State. The ASMF procedure is not permitted for biological active pharmaceutical ingredients (Appendix No. 5 to this Annex).
An ASMF holder may hold an ASMF as well as a CEP issued for a separate active pharmaceutical ingredient. However, in general, it is unacceptable for an applicant (MA holder) to refer to both the ASMF and the CEP for the same active pharmaceutical ingredient in a single registration dossier (variation dossier). If the CEP contains insufficient information (e.g., regarding stability), competent authorities of Member States have the right to require additional information to be included in the dossier. In this case, both the ASMF and the CEP may be referenced.
The ASMF Holder must authorize the competent authorities of Member States to review the ASMF data in relation to a specific registration dossier (change dossier) in the form of an "Access Authorization" (Appendix No. 2 to this Annex).
The ASMF Holder must provide the applicant (MA Holder) with the following documents:
a copy of the latest version of the FS (and, if applicable, a notification to the competent authority of the Member State regarding insufficient data in the CP, if they have not yet been included in the FS);
a copy of the overall quality summary for the latest version of the CP;
a copy of the Access Authorization, if such authorization has not been previously granted for the medicinal product in question. In addition, the ASMF holder is required to submit to all Member State competent authorities involved in the registration procedure (amendments to the registration dossier):
ASMF (and, if applicable, responses to notifications from the Member State competent authority regarding insufficient data, if they have not yet been included in the ASMF) along with the referral letter and administrative data (Appendix No. 3 to this Annex). This requirement also applies to the ASMF holder's responses to notifications from the Member State competent authority regarding insufficient data;
Authorization of access, if such authorization has not previously been submitted for the medicinal product in question.
The ASMF holder must submit the ASMF to the Member State competent authority only once. The ASMF holder must synchronize the submission of relevant documentation to the Member State's competent authority with the submission of the registration dossier (or change dossier): the documents must arrive no earlier and no later than one month after the submission of the corresponding registration dossier (or change dossier).
When using the ASMF procedure, the applicant (MA holder) must submit the registration dossier or change dossier to the competent authority of the reference state along with the Access Permit, unless one has previously been submitted for the medicinal product in question by the MA holder (applicant) or the ASMF holder.
If the same active pharmaceutical substance is used in multiple dossiers for different medicinal products in one or more Member States, the ASMF holder must submit identical documentation to each competent authority in that Member State. Subsequently, the competent authorities of Member States have the right to require that any updates to the ASMF made for one registration dossier be applied to the others. It is the responsibility of the holder of the ASMF to notify the interested MAHs and the competent authorities of the Member States of any changes in the CP and/or AP so that the MAHs can update all affected registration dossiers of medicinal products accordingly.
V. Contents of the registration dossier when using the
active pharmaceutical substance master file procedure
The applicant (MA holder) is responsible for ensuring access to all necessary information regarding the actual production of the active pharmaceutical ingredient.
The registration dossier must clearly state the specification used by the applicant (MA holder) for quality control of the active pharmaceutical ingredient (section 3.2.S.4.1 or 3.2.S.4.2 of the CTD format). The applicant (MA holder) must include a copy of the QR in the registration dossier (section 3.2.S of the CTD format). The version of the QR in the registration dossier must be the most recent and identical to the QR submitted by the ASMF holder to the authorized body of the Member State as part of the ASMF. The applicant (MA holder) must transfer all necessary information from the QR to the overall quality summary (module 2.3) of the registration dossier. The overall quality summary of the registration dossier should highlight the sections of the ASMF that are specific to the medicinal product under consideration.
In the case of a single supplier and the use of the DMF or CEP procedure, the specification for the active pharmaceutical ingredient included by the applicant (MA holder) in the registration dossier should, in principle, be identical to that of the ASMF or CEP holder. However, the applicant (MA holder) is not required to agree to redundant specification tests, unreasonably stringent specification limits, or outdated analytical methods.
If the applicant (MA holder) uses an analytical method different from that described in the ASMF, both methods must be validated. Technical specification tests that are relevant to the medicinal product but that are not typically part of the DMF specification (e.g., particle size) must be part of the applicant's (MA holder's) specification.
If there are multiple suppliers, the applicant (MA holder) must have a single, consolidated specification that is identical for each supplier. A specification may specify more than one acceptance criterion and/or analytical method for the same quality indicator, with the indication "if verified" (e.g., for residual solvents).
VI. Modification and Updating of the Active
Pharmaceutical Substance Master File
For medicinal products, holders of the ASMF must ensure that their ASMFs are continually updated regarding the actual synthesis (manufacturing process). Quality control methods must comply with current regulatory and scientific requirements.
Holders of the ASMF may not change the content of their ASMFs (e.g., manufacturing process or specifications) without notifying each applicant (MA holder) and each Member State authorized body. This obligation remains in effect until the Access Permission is revoked by the ASMF holder (Appendix No. 4 to this Annex). Holders of the ASMF must provide the updated ASMF to all interested parties, indicating the amended version number. The MA holder must notify the relevant Member State authorized body of any change to the ASMF through the relevant amendment procedure. A Direction Letter (Appendix No. 3 to this Annex) must be submitted.
If the contents of the ASMF cannot be amended within a specified period due to procedural reasons (i.e., primarily due to ongoing mutual recognition procedures), the MA holder must nevertheless submit the aforementioned data to the MA holder and the Member State authorized bodies, indicating this and requesting a later implementation deadline.
When confirming the registration of a medicinal product, MAHs must declare that the quality of the medicinal product, in terms of production and control methods, has been regularly updated through the amendment procedure to account for technical and scientific progress, and that the medicinal product complies with current Union documents regulating the quality of medicinal products. They must also declare that no information about the medicinal product has been changed, except for those authorized by the Member State's authorized body.
In this regard, MAHs must verify with their MFAFS holders the accuracy of the above declaration regarding the active pharmaceutical ingredient information. If the MAH and the Member State's authorized body are not notified of the changes, the appropriate procedure for amending the registration dossier of the registered medicinal product must be initiated without delay.
Amendment N 1
OVERVIEW OF THE CONTENTS OF THE ASMF
dated January 30, 2020, No. 9, dated May 22, 2023, No. 60, dated October 20, 2023, No. 114)
Table 1
Part of the dossier module
OTD format
3.2.S.1
General Information
x
3.2.S.1.1
Nomenclature
3.2.S.1.2
Structure
3.2.S.1.3
General Properties
3.2.S.2
Production
3.2.S.2.1
Manufacturers (including all companies involved in the production of the active pharmaceutical ingredient, including quality control (in-process testing) facilities, intermediate product manufacturers, and milling and sterilization facilities)
3.2.S.2.2
Description of the production process and process controls
3.2.S.2.3
Control of starting materials
(clause 3.2.S.2.3 as amended by the Eurasian Economic Commission Council Decision No. 114 of 20.10.2023)
3.2.S.2.4
Control of critical stages and intermediate products
4
(clause 3.2.S.2.4 as amended by the Eurasian Economic Commission Council Decision No. 114 of 20.10.2023)
3.2.S.2.5
Validation and/or assessment of the production process
clause 3.2.S.2.4 as amended by the Eurasian Economic Commission Council Decision No. 114 of 20.10.2023)
3.2.S.2.6
Development of the production process
3.2.S.3
Description of Properties
3.2.S.3.1
Determination of Structure and Other Characteristics
3.2.S.3.2
Impurities
5
3.2.S.4
Quality Control of the Pharmaceutical Substance
3.2.S.4.1
3.2.S.4.2
Analytical Methods
3.2.S.4.3
Validation of Analytical Methods
3.2.S.4.4
Batch Analysis
3.2.S.4.5
Specification Justification
6
3.2.S.5
Standard Samples and Materials
3.2.S.6
Packaging and Closure System
3.2.S.7
3.2.S.7.1
Summary and Conclusion on Stability
3.2.S.7.2
Post-Marketing Stability Program and Commitments Regarding Stability
3.2.S.7.3
Stability data
1. If detailed information is contained in a closed section, a flow chart and a brief description are considered sufficient. However, the applicant's section may require full validation data on the sterilization process (if there is no subsequent sterilization of the medicinal product).
2. Detailed information.
3. To the extent that this information is also required by the applicant (MA holder).
4. To the extent that this information is relevant to the detailed description of the manufacturing process, and to the extent that this information is not required by the applicant (MA holder).
5. To the extent that this information is relevant to the detailed description of the manufacturing process, and to the extent that the MFAS holder sufficiently justifies that there is no need to control these impurities in the active pharmaceutical ingredient.
6. To the extent that this information is relevant to the detailed description of the manufacturing process, quality control of materials, and validation of the manufacturing process.
Table 2
CTD format: herbal raw materials (herbal pharmaceutical substances)
Applicant's part
Closed part
General information
A) Herbal pharmaceutical substance obtained by grinding medicinal plant material: binomial scientific name of the plant (genus, species, subspecies, and author) and chemotype (if any)
morphological group
Latin name of the medicinal plant material
other names (synonyms described in other pharmacopoeias)
source of origin (wild or cultivated)
B) Herbal pharmaceutical substance obtained after processing medicinal plant material by various methods (extraction, etc.):
binominal scientific name of the plant (genus, species, subspecies, and author) and chemotype (if any)
plant parts
name of the herbal pharmaceutical substance
proportion of medicinal plant material in the herbal pharmaceutical substance
extraction solvents
(as amended by decisions of the Council of the Eurasian Economic Commission of 30.01.2020 No. 9, of 22.05.2023 No. 60)
Physical State
Description of components with known therapeutic activity or markers (molecular formula, relative molecular weight, structural formula including relative and absolute stereochemistry, molecular formula and relative molecular weight)
Other components
General properties
Manufacturers:
Medicinal herbal raw materials (the name, address, and responsibility of each manufacturer, including subcontractors, as well as each proposed manufacturing site involved in the production (collection) and control of medicinal herbal raw materials must be provided)
Herbal pharmaceutical substances (the name, address, and responsibility of each manufacturer, including subcontractors, as well as each proposed manufacturing site involved in the production and control of herbal pharmaceutical substances must be provided)
(as amended by Decisions No. 9 of the Council of the Eurasian Economic Commission of 30.01.2020 and No. 60 of 22.05.2023)
Description of the production process and process control:
block diagram
details
Medicinal herbal raw materials (information must be provided that adequately describes the production and collection of plants), including: geographical source of the medicinal plant
growing, harvesting, drying, and storage conditions; batch size
Herbal pharmaceutical substances (information must be provided that adequately describes the production process of the herbal pharmaceutical substance), including:
description of processing (including a flow chart)
solvents, reagents
purification steps
standardization; batch size
(as amended by decisions of the Council of the Eurasian Economic Commission of January 30, 2020, No. 9, and May 22, 2023, No. 60)
(clause 3.2.S.2.3 as amended by the decision of the Council of the Eurasian Economic Commission dated 20.10.2023 N 114)
если также значимо для держателя РУ (заявителя)
(clause 3.2.S.2.4 as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
Validation and/or assessment of the manufacturing process
(clause 3.2.S.2.5 as amended by Decision of the Council of the Eurasian Economic Commission of 20.10.2023 No. 114)
Development of the manufacturing process:
A brief summary of the development of the medicinal plant materials and herbal pharmaceutical substances (if applicable) must be provided, taking into account the proposed route of administration and use.
The results of a comparison of the phytochemical composition of the medicinal plant materials and herbal pharmaceutical substances used must be analyzed, taking into account the bibliographic data and descriptions of the medicinal plant materials and herbal pharmaceutical substances presented in Section C.1
(as amended by Decisions of the Council of the Eurasian Economic Commission of 30.01.2020 No. 9, No. 60 of May 22, 2023, No. 114 of October 20, 2023)
(as amended by Decision of the Council of the Eurasian Economic Commission of January 30, 2020 No. 9)
Description of structure and other properties
Medicinal plant materials (information on botanical, macroscopic, microscopic, phytochemical properties, and biological properties (if required) must be provided)
Plant-based pharmaceutical substances (information on phyto- and physicochemical properties and biological activity (if required) must be provided)
(as amended by decision of the Council of the Eurasian Economic Commission of 30.01.2020 No. 9)
Quality control of pharmaceutical substance
Reference Materials and Standards
(as amended by Decision No. 9 of the Council of the Eurasian Economic Commission of January 30, 2020)
Post-registration Stability Studies Program and Stability Commitments
(Clause 3.2.S.7.2 as amended by Decision No. 114 of the Council of the Eurasian Economic Commission dated October 20, 2023)
Stability Data
Amendment N 2
PERMISSION FORM
FOR ACCESS TO THE CLOSED PART OF THE ACTIVE
PHARMACEUTICAL SUBSTANCE MASTER FILE
(form)
LETTENHOOD
of the active pharmaceutical substance master file holder
{Address of the authorized body of the Member State}
{Date}
Active pharmaceutical substance master file number:
{ASMF code number}
It is indicated in the following format: EAEU/MFAFS/XXXXX or YY/MFAFS/XXXXX, where XXXXX is the digital designation, YY is the Latin 2-digit letter code of the member state.
Name of the active pharmaceutical substance:
Internal code of the active pharmaceutical substance (if applicable):
Active pharmaceutical substance master file holder: {name and address}
The above-mentioned active pharmaceutical substance master file holder hereby grants permission to {name of the authorized body of the Member State} to refer to the above-mentioned active pharmaceutical substance master file and conduct its examination in support of the following registration dossiers or dossiers for amendments to the registration dossier of a medicinal product registered in the Union (include the new IMFAS from the new PAFS), submitted by {name of the marketing authorization holder (applicant)} {planned date of submission}:
{name of the medicinal product (if the trade name of the medicinal product has not been agreed upon at the time of submission, "INN + name of the marketing authorization holder" should be indicated) and the number of the marketing authorization (if known)}
{name of the applicant or marketing authorization holder Certificates}
The above-mentioned holder of the active substance master file undertakes to ensure consistency of batch quality and notify {name of the marketing authorization holder (applicant)} and the competent authority of the Member State of any changes to the active substance master file.
The above-mentioned holder of the active substance master file is hereby notified and accepts that the competent authorities of the Member States may exchange expert reports on the above-mentioned active substance master file with each other.
Signature of the holder of the active substance master file
{Name and position}
{Signature}
Amendment N 3
LETTER FORM
ON SUBMITTING ADMINISTRATIVE DATA TO DOCUMENTS
ACCORDING TO THE ACTIVE PHARMACEUTICAL SUBSTANCE MASTER FILE (APMS)
Subject to simultaneous submission, along with the APMS, of each registration dossier (amendment dossier) as a single document.
LETTERHEAD
of the Active Pharmaceutical Ingredient Master File Holder
From: {name of the AFMF holder}
{address of the AFMF holder}
{country of the AFMF holder}
To: {name and address of the authorized
body of the Member State}
{date}
{reference number}
Subject: Submission of documents under the ASMF
for {name of active pharmaceutical ingredient}
- {ASMF code number}
Indicated in the following format: EAEU/ IFAPS/XXXXX or YY/ ASMF/XXXXX,
where: XXXXX is the digital designation, YY is the Latin 2-digit letter code
of the Member State.
Dear ...:
This Active Pharmaceutical Substance Master File is submitted for the following medicinal product:
Medicinal product
{name of the medicinal product}
(If the trade name of the medicinal product has not been approved at the time of submission, please indicate "INN + name of the marketing authorization holder")
Assigned procedure number (if applicable)
(Expected) date of submission of registration dossier or change dossier (if known)
{procedure code}
Administrative Data for Active Pharmaceutical Substance Master File (APMS)
This guidance letter should be used for active pharmaceutical substance master files (APMS) subject to review in conjunction with the registration dossier or amendment dossier for the medicinal product. All information fields must be completed.
These documents will also be sent to:
to all Member States participating in the procedure
exclusively to the {reference State}
MFAS Code Number
{MFAFS code number}
In the following format: EAEU/MFAFS/XXXXX or YY/MFAFS/XXXXX, where XXXXX is the numeric designation and YY is the Latin 2-character code of the Member State
MFAS Holder Version (included in this submission)
Applicant part:
Version [version number]/date (dd-mm-yyyy) Closed part:
Version [version number]/date (dd-mm-yyyy)
Name of the Pharmaceutical Substance
{INN, common name} (+ salt (water content), if applicable)
Internal API Code of the Active Pharmaceutical Substance Manufacturer (if applicable):
{Internal API code}
Additional Information (if applicable, e.g., different synthetic routes, class)
(Applicable if the MFAS Holder holds multiple MFAS for the same active pharmaceutical substance)
ASMF Holder
{name of the MFAS holder}
{full legal address of the MFAS holder}
{country}
Full name of contact person:
Active Pharmaceutical Ingredient Manufacturer Production Sites
(All companies involved in the production of the active pharmaceutical ingredient, including quality control (in-process testing) sites, intermediate product manufacturers, milling and sterilization sites, must be listed in separate columns.)
{production site addresses}
{USND number}
All sites must submit a universal data numbering system (USND) if registered. The USND was developed by Dun & Bradstreet (D&B) and assigns a unique digital identifier to a single economic entity. It is used to expedite the identification of production sites outside the Union.
{GPS (WGS 84) site coordinates} Latitude (S or N) and longitude (E or W) are expressed in degrees, minutes, and seconds to 1 decimal place (alternatively, degrees with at least 5 decimal places or degrees and minutes with at least 3 decimal places may be specified). If not the main entrance, the location should be indicated.
Contact person's name:
Type of document submission
New submission of documents
Updating the MFAS
Response to a notification of insufficient data (both the applicant's portion and the closed portion, if applicable)
Administrative changes only (in all cases, the manufacturing site remains unchanged)
Change of the MFAS holder
Change of the name (address) of the MFAS holder
Change of the name (address) of the manufacturer of the pharmaceutical substance
Paper submission of documents
Electronic format (paper versions are not accepted if submitted electronically)
Number of volumes of the paper version
{Number}
Submitted documents
Access Permission (as per Appendix No. 2 to this Appendix)
A copy of the expert's CV
A general summary of quality
A table of changes (when submitting an update to the Union's Unified Register of the MFAS)
A copy of the MFAS holder's proposed specification for the active pharmaceutical ingredient
A copy of the notification of insufficient data in the MFAS, sent by the authorized body of the Member State (only when submitting response documents)
Table of Changes between Different Versions of the AFMF
This section is only completed when updating a previously submitted AFMF.
The table of changes should be included as a separate document in the main submission letter. The AFMF holder should use the following sample table templates. If the changes were previously approved by another authorized body of a member state, the AFMF holder must annotate the table with the procedure number.
(as amended by Decision No. 9 of the Eurasian Economic Commission Council dated January 30, 2020)
Sample format of the change table
TABLE OF CHANGES
CURRENTLY
OFFERED
Version number of AP and/or CP of the ASMF holder [version number]/date (dd-mm-yyyy)
Section OTD
Current situation
Description of the change
Administrative information on other registration dossiers
Other registration dossiers (regardless of their status)
referring to the same MFAS
The MFAFS was previously submitted to the competent authority of the Member State
Yes
No
If so, a list of medicinal products for medical use containing an active pharmaceutical ingredient manufactured in accordance with the data included in the MFAS should be provided. Additional sheets should be used if necessary. The five most recently submitted medicinal products or all submitted medicinal products over the past two years, whichever is greater, should be included.
Registration procedure code
ASMF number
ASMF holder version number (AP and CP)/Date
The holder of the MFAS may provide additional information. Competent authorities of Member States may request information on other medicinal products covered by this MFAS.
{Signature of the authorized contact person}
{Name, address, and position within the company}
Addition N 4
REVOCATION FORM
PERMISSION TO ACCESS THE CLOSED PART
OF THE ACTIVE PHARMACEUTICAL SUBSTANCE MASTER FILE
of the Active Pharmaceutical Substance Master File Holder
Active Pharmaceutical Substance Master File Number:
{MFAS Code Number}
Indicated in the following format: EAEU/MFAS/XXXXX or YY/MFAS/XXXXX, where XXXXX is the numeric designation and YY is the two-character Latin alphabetic code of the Member State.
Active Pharmaceutical Substance Name:
Active Pharmaceutical Substance Internal Code (if applicable):
Active Pharmaceutical Substance Master File Holder: {name and address}.
The above-mentioned holder of the active substance master file hereby notifies the {name of the competent authority of the Member State} that it no longer wishes the above-mentioned active substance master file to be used to support the following marketing authorisation dossier held by {name of the marketing authorisation holder (applicant)} (however, separate revocations of authorisation must be submitted for the different marketing authorisation holders (applicants)):
If the medicinal product is not registered at the time of submission or the trade name of the medicinal product has not been approved, please indicate "INN + name of the marketing authorization holder"
{registration certificate number or registration procedure code}
The above-mentioned Active Substance Master File Holder hereby confirms that, in accordance with the terms of their supply agreement, they have previously notified [name of the Marketing Authorization Holder (Applicant)] of their decision.
The active substance manufactured in accordance with the above-mentioned Active Substance Master File will no longer be supplied after [date of termination of the supply agreement].
The Active Substance Master File has been replaced by a Certificate of Conformity, [N CEP]. A copy of the Certificate of Conformity is attached to this letter.
Signature of the Active Substance Master File Holder
{Name and Title}
Addition N 5
INAPPLICABILITY OF THE ACTIVE
PHARMACEUTICAL SUBSTANCE MASTER FILE (APMS) CONCEPT
1. Inapplicability of the Active Pharmaceutical Ingredient Master File (ASMF) concept to biological active pharmaceutical ingredients.
MAHs and applicants are advised not to apply the active pharmaceutical ingredient master file concept to biological medicinal products.
Characterization and quality confirmation of biological pharmaceutical ingredients requires not only a combination of physicochemical and biological tests, but also in-depth knowledge of the manufacturing process and its controls.
Therefore, the MAH (applicant) for a biological medicinal product may not be able to satisfy the requirement to "assume responsibility for the medicinal product" without full and transparent access to this active pharmaceutical ingredient quality data. The use of the APMI will interfere with such access and is therefore not permitted for biological active pharmaceutical ingredients. Furthermore, active pharmaceutical ingredients included in certain medicinal products, such as vaccines or cell therapy medicinal products, do not fit the concept of a "well-studied" active pharmaceutical ingredient.
2. Inapplicability of the VAMF concept to the open and closed sections of the Active Vaccine Antigen Master File (AVMA) and Plasma Master File (PMF)
The legislation does not specify the use of open (closed) sections in the Vaccine Antigen Master File (VAMA) and Plasma Master File (PMF). The concept of open (non-confidential) and closed (confidential) sections is specific to the Active Pharmaceutical Substance Master File.
With respect to the VMA, the legislation specifies that the VMA holder cannot differ from the RM holder (applicant) of the medicinal product in question; therefore, there are no grounds for using the "open (closed)" sections of the system.
With regard to the MFP, the legislation states that if the RU holder (applicant) differs from the MFP holder, the MFP must be transferred to the RU holder (applicant) for submission to the authorized body of the member state.
Addition N 6
DEFINITIONS
For the purposes of this annex, the following concepts and definitions apply:
"active pharmaceutical ingredient manufacturer" means a party within the active pharmaceutical ingredient production chain, including distributors, repackagers, and relabelers;
"active pharmaceutical ingredient master file holder" means the company solely responsible for the active pharmaceutical ingredient master file;
"production chain" means the sequence of production stages, presented in the form of a flowchart or narrative text, explaining the production and distribution pathway of an active pharmaceutical ingredient, from the first starting materials to the finished active pharmaceutical ingredient;
"new pharmaceutical ingredient" means an active substance that has not previously been authorised in a Member State (also known as a new molecular entity or new chemical entity), which may be a complex, ester, or salt of a previously authorised active pharmaceutical ingredient that differs from the latter in terms of safety and efficacy.
Appendix No. 11
dated January 30, 2020, No. 9, dated March 17, 2022, No. 36, dated May 22, 2023, No. 60)
PRELIMINARY SUMMARY REPORT FORM
Instructions for completion: When using ready-made text templates, they are highlighted in this form with < > and italics. Text template fragments that are completed by entering specific text variations for a specified property (parameter) are provided in curly brackets { }, with the property (parameter) indicated in italics.
PRELIMINARY SUMMARY REPORT
on the critical evaluation of a medicinal product
<Trade name> #
<(Active ingredient(s))> #
Commencement of the procedure:
Date of preparation of this report:
I. Administrative information
Pharmacotherapeutic Group (ATC Code):
Email Address
<In accordance with the Rules for Registration and Expertise of Medicines of the Union, I, the expert, hereby declare that I have completed my expert report in less than 80 days> #
дата
подпись
Recommendation
Based on expert reviews of the quality, safety, and efficacy modules of the registration dossier, the experts believe that the registration application for <name of medicinal product>, for the treatment of <indication> #, <may be approved, provided that satisfactory responses are provided to the preliminary list of minor concerns (Section V)> # <does not merit approval, as critical concerns have been identified that currently preclude a recommendation for registration. Detailed information on these key concerns is provided in the preliminary list of questions (Section V). #
<The critical concerns that preclude a recommendation for registration concern the following key deficiencies: <list briefly the deficiencies from Section VI of the conclusion>>. #
Questions for review by additional experts
Provide a list of questions # __________________________________________
Inspection Requests
Inspection(s) for compliance with the Good Manufacturing Practices (GMP) of the Eurasian Economic Union, approved by the Eurasian Economic Commission.
[for scheduled GMP inspections] #
<A GMP inspection request has been made for the following manufacturing sites to confirm their GMP compliance status due to the expiration of the site's current certificate of compliance. The results of these inspections are required to complete the application review and will be required by Day 181.> #
[for initiated GMP inspections] #
<A GMP inspection request has been made for the following manufacturing sites to confirm their GMP compliance status in accordance with the inspection assignment criteria set out in the Rules for Registration and Expertise of Medicinal Products for Medical Use, approved by the Eurasian Economic Commission. The results of these inspections are required to complete the application review and will be required by Day 181.> #
Inspection(s) for compliance with the Good Clinical Practice (GCP) Rules of the Eurasian Economic Union, approved by the Eurasian Economic Commission.
<A GCP inspection request was made for the following clinical trials <indicate study numbers> in accordance with the inspection assignment criteria set out in the Rules for Registration and Examination of Medicinal Products for Medical Use, approved by the Eurasian Economic Commission. The result of this inspection and satisfactory responses to the data obtained form part of the responses to the list of comments and will be submitted by Day 121.> #
<Status of new active substance> #
Based on the review of the data, the experts consider that the active substance <indicate the name of the active substance> # contained in the medicinal product <indicate the name of the medicinal product> #
<is subject to verification of compliance with the requirements as a new active substance <in itself> <in comparison with the known substance <indicate the name of the approved isomer (mixture of isomers, complex, derivative, salt)> previously registered in the Union as a medicinal product, since it differs significantly in properties from the previously registered substance with respect to safety and efficacy.> #
<may qualify as a new active substance <in itself> <in comparison with the known substance <indicate the name of the approved isomer (mixture of isomers, complex, derivative, salt> previously registered in the Union as a medicinal product, provided that satisfactory responses to the comments are provided, which are listed in the List of Comments> #
<does not qualify as a new active substance <in itself> <in comparison with a known substance <indicate the name of the approved isomer (mixture of isomers, complex, derivative, salt)> previously registered in the Union as a medicinal product, since it does not differ significantly in properties from the previously registered substance with respect to safety and efficacy.> Critical comments that do not allow for a recommendation to register this substance as a new API are set out in detail in the List of Comments>. #
II. Executive Summary
2. Brief Description of the Medicinal Product.
3. Assessment of the Medicinal Product Development Program, Compliance with Medicinal Product Development Guidelines, Availability of Scientific Consultation.
4. General Comments on Compliance with GMP, GLP, and GCP Principles.
5. Application Type and Other Comments on the Submitted Dossier:
Type of Regulatory Procedure for Registration;
Possibility of Applying Special Reasons for the Registration Procedure;
Application of the Biosimilar Concept;
Relevance of Pediatric Studies.
III. Scientific Review and Discussion
1.1. Introduction.
1.2. Quality Aspects.
1.3. General Quality Issues.
1.4. Active Pharmaceutical Substance (API).
1.4.1. General Information.
1.4.2. Manufacturing, Description of Properties, and Process Control.
1.4.3. Specification.
1.4.4. Stability.
1.4.5. Comparability Studies for API.
1.5. Medicinal Product.
1.5.1. Description of the Medicinal Product and Pharmaceutical Development.
1.5.2. Manufacturing of the Medicinal Product and Process Control.
1.5.3. Medicinal Product Specification.
1.5.4. Confirmation of the Expiry Date and Storage Conditions of the Medicinal Product with Stability Study Data.
1.5.5. Comparability Studies for the Medicinal Product.
1.5.6. Contributing Agents.
1.5.7. GMOs.
1.6. Discussion of Chemical, Pharmaceutical, and Biological Aspects.
1.7. Conclusion on Chemical, Pharmaceutical, and Biological Aspects.
1.8. Preclinical Aspects.
1.9. Pharmacology.
1.10. Pharmacokinetics.
1.11. Toxicology.
1.12. Discussion of Preclinical Aspects.
1.13. Conclusion of Preclinical Aspects.
1.14. Clinical Aspects.
Tabular Summary of Clinical Studies.
1.15. Pharmacokinetics.
1.16. Pharmacodynamics.
1.17. Discussion of Clinical Pharmacology.
1.18. Conclusions on Clinical Pharmacology.
1.19. Clinical Efficacy:
Dose-Response Studies and Pivotal Clinical Trials.
Summary of Key Efficacy Findings.
The following tables summarize the efficacy results from the pivotal studies supporting the submitted application. These summarized results should be analyzed in conjunction with the discussion of clinical efficacy and the benefit-risk assessment (see the final sections).
Table {number}
Summary of the main results of the study
<study> on the effectiveness of the drug
Title {as stated in the research report}
<code>
{list of all codes starting with the protocol number, followed, if available, by the European Clinical Trials Database number, International Standard Randomized Clinical Trial Number, and other codes for cross-referencing publications} #
<free text>
{describe key elements of the study design (crossover, parallel, factorial, dose-escalation, fixed-dose analysis), including studies with randomization, blinding, allocation concealment, single-center (multi-center), etc.} #
of the main phase:
<time> #
<time> <not applicable> #
<Availability of advantages> <Similarity> <Not less effective> <Overview: specify> #
Treatment Groups {add as many rows as needed to describe the treatment groups #}
<coded designation
of the group> {indicate the abbreviation for later use in the results section table} #
<treatment>, <duration>, <number of randomized subjects> #
<treatment>, <duration>, #
of the group> #
<number of randomized subjects> #
<treatment>, <duration>,
<number of randomized
subjects> #
Clinical Endpoints {add as many rows as needed to describe the clinical endpoints; for secondary clinical endpoints, include the most relevant endpoints listed in the results section #}
<Combined> #
Primary clinical trial endpoint
<symbol> {indicate the abbreviation for later use in the results section table} #
<free text> {provide a brief description} #
<Secondary>
<other: please specify> #
clinical trial endpoint
<symbol> #
Закрытие базы данных
<дата>
Analyses and Results
{present separately for each analysis the result considered relevant for inclusion in the study report; in any case, data on the pre-specified primary analysis must be presented}
Primary Analysis
Subject Population and Time Point Description
<Intent to Treat Population> <patients who completed the study according to the protocol>
<other: specify>
{may require a brief description of the population}
<time point>
Descriptive Statistics and Estimated Variability
Treatment Group
<coded group designation> {as per terminology above} #
Number of Subjects
<n>
<clinical trial endpoint>
{label as above}
(<statistic>) {e.g., mean, median, etc.} #
<point estimate> #
<variance statistic>
{e.g., standard deviation, confidence interval, etc.} #
<variability> #
(<statistic>) #
<variance statistic> #
<clinical trial endpoint> #
(<statistic>)
Оценка эффекта при сравнении {добавьте строки в количестве, необходимом для описания фактически выполненного статистического анализа #}
<Combined> # Primary Clinical Endpoint
Comparison Groups
<group coded designation> {as per terminology above} #
<Significance Test> {e.g., difference between groups} #
<Variance Statistic> {e.g., confidence interval, etc.} #
P Value {specify statistical method used, e.g., ANOVA} #
<P value> #
<<Combined>
Primary> <Secondary>
<other: specify> #
<group coded designation> #
<Significance Test> #
<Variance Statistic> #
{specify the clinical endpoint using the terminology defined above in the "Clinical Trial Endpoints and Definitions" section} #
<P Value> #
Primary>
endpoint clinical trial
{Please also consider the following information:
Reasons for withdrawal, critical analysis results} #
<additional analysis>
<combined primary analysis>, <other, specify:>
{Also specify if analysis was planned} #
{repeat the above sections for each relevant analysis} #
Clinical Trials in Special Populations.
Analysis performed across all studies (pooled analyses and meta-analysis).
Maintenance Study.
1.20. Clinical Efficacy Analysis.
Clinical Trial Design and Conduct.
Efficacy Data and Additional Analyses.
1.21. Clinical Efficacy Conclusion.
1.22. Clinical Safety.
Patient Impact.
Adverse Events.
Serious Adverse Events and Deaths.
Laboratory Data.
Safety in Special Populations.
Immunological Events.
Safety Related to Drug-Drug Interactions and Other Interactions.
Study Discontinuation Due to Serious Adverse Events.
1.23. Clinical Safety Discussion.
1.24. Clinical Safety Conclusions.
IV. Pharmacovigilance System
<The expert considers that the pharmacovigilance system described by the applicant meets the requirements and provides adequate evidence that the applicant is provided with the services of a designated person responsible for pharmacovigilance and has the necessary means to report any suspected adverse reactions occurring within the Eurasian Economic Union or in a third country.> #
<The expert considers that the pharmacovigilance system described by the applicant has the following deficiencies: <list of deficiencies.> #
<Considering that the deficiencies are corrected before the applicant markets the medicinal product, the designated expert organization may consider the pharmacovigilance system to be compliant. Before marketing the medicinal product, the applicant must provide convincing evidence that the pharmacovigilance system is in place and functioning.> #
1. Risk Management Plan
Questions and/or issues for consideration by specialists from organizational structures and the authorized expert organization responsible for pharmacovigilance (hereinafter referred to as "AEOVR") during the assessment of the PUR.
2. Medicinal products capable of producing significant effects in rare, life-threatening, or disabling diseases.
<According to the conclusion of the authorized body (Conclusion dated <date>), the incidence rate of <indicate condition> is <give prevalence> per 10,000 people in <indicate name of Union state>> #<нет данных (Н/Д)>.
3. Benefit-Risk Assessment.
Benefit.
Positive effects.
Uncertainty in knowledge regarding beneficial effects.
Risk.
Harmful effects.
Uncertainty in knowledge regarding harmful effects.
Benefit-Risk Balance.
Importance of beneficial effects and harmful effects.
Discussion of the Benefit-Risk Assessment.
4. Conclusions.
The overall benefit-risk balance for <indicate the name of the medicinal product #> is <positive>, <positive, provided <indicate the condition for maintaining a positive balance>>; <negative>. #
V. List of Expert Comments
1. Module 3 (Quality Aspects).
Active Pharmaceutical Ingredient;
Medicine.
Recommendations.
2. Module 4 (Preclinical Aspects).
Pharmacology;
Pharmacokinetics;
3. Module 5 (Clinical Aspects).
Pharmacodynamics;
Efficacy;
Safety;
Pharmacovigilance System.
Pharmacovigilance System;
4. Status of a New Active Substance.
VI. Proposed Additional Conditions for Issuing a Registration Certificate and Approving the SmPC, IMP (LP)
1. Additional conditions for issuing a registration certificate.
2. Possibility of approving a revision of the general characteristics of the medicinal product (SmPC).
3. Labeling.
4. Instructions for medical use (package leaflet) of the medicinal product (IPM (LP)).
5. User testing assessment (see Section VII of this report).
VII. Document quality checklist for reviewing the user testing results
Product information
Name of the medicinal product
Name and address of the applicant
Name of the company that conducted the user testing
Type of application for registration certificate
INN
Pharmacotherapeutic group (ATC code)
Therapeutic indications
Orphan drug
Expert
Full user testing report provided yes no
Summary report provided yes no
Reasons for bridging testing based on justification:
additions for the same route of administration
reference to a test for a drug of the same class
reference to a test with the same safety questions
other ________________________________________________
Is the justification for bridging testing acceptable?
(If a full user testing report or summary report is not provided, a justification is required.)
Is the justification for not providing a report acceptable?
(e.g., administration only in a hospital setting, administration only by a healthcare professional, compliance with quality assurance document templates, studied drug use over a long period of time)
Reasons [expert opinions regarding the acceptability or unacceptability of the rationale (consolidated) report - assessment of the rationale (consolidated) report #]
_____________________________________________________________________
1. Technical Assessment
1.1. Recruitment
Is the population surveyed acceptable? Yes No
Comments (additional) information______________________
1.2. Questionnaire
Is the number of questions __________ sufficient? Yes No
Do the questions cover important aspects (safety) of the drug? Yes No
1.3. Time Aspects
Is the time provided for answering questions acceptable? Yes No
Is the length of the interview acceptable? Yes No
1.4. Procedural Aspects
Testing rounds, including the pilot round__________________
1.5. Interview Aspects
Was the interview conducted in a structured (organized) manner? Yes No
Comments (additional) information ______________________
2. Evaluation of Responses
2.1. Scoring System
Is the qualitative assessment of responses acceptable? Yes No
Does the assessment methodology meet the minimum requirements? Yes No
2.2. Question Rating System
Is the quantitative assessment of responses acceptable? Yes No
3. Data Processing
Is the data properly recorded and documented? Yes No
4. Quality Aspects
4.1. Assessment of Diagnostic Questions
Does the methodology comply with the Appendix to the Requirements for the Instructions for Medical Use of the Medicinal Product and the General Characteristics of the Medicinal Product for Human Use? Yes No
Overall, does each question meet the criterion of 81% correct answers? Yes No
Comments (additional information) ______________________
4.2. Assessment of Layout and Design
Are the general design principles of the Appendix to the Requirements for the Instructions for Medical Use of the Medicinal Product and the General Characteristics of the Medicinal Product for Human Use followed? Yes No
Is the text written in a language understandable to patients? Yes No
Is the layout easy to navigate? Yes No
Is the use of flowcharts acceptable? Yes No
5. Quality of Diagnostics (Assessment)
Were any weaknesses identified in the LP? Yes No
Have the weaknesses been adequately addressed? Yes No
6. Conclusion
Were the main objectives of user testing achieved? Yes No
Is the applicant's conclusion correct? Yes No
Overall impression of the methodology: Positive
Negative
Overall impression of the package insert's structure: Positive
Conclusion (summary)_____________________________________________________
________________________________________________________________________
Appendix No. 12
LIST OF INFORMATION TO BE INCLUDED IN THE PROTOCOL OF LABORATORY TESTS CONDUCTED IN ACCREDITED LABORATORIES OF THE MEMBER STATES OF THE EURASIAN ECONOMIC UNION
(as amended by Decision No. 60 of the Council of the
Eurasian Economic Commission dated May 22, 2023)
1. Name of the authorized body of the Eurasian Economic Union member state.
2. Name of the expert organization or testing laboratory.
3. Number and validity period of the accreditation certificate of the testing laboratory.
4. Address and telephone number of the expert organization (testing laboratory).
5. Details of the test protocol (heading "TEST PROTOCOL No. _______ dated _______________" (indicating the date in the format dd.mm.yyyy (day, month, calendar year)).
6. Name of the medicinal product sample.
7. Name of the manufacturer and country of manufacture of the medicinal product sample.
8. Name of the applicant.
9. Batch number of the medicinal product sample.
10. Expiry date (shelf life) of the medicinal product sample.
11. Date of receipt of the medicinal product sample by the testing laboratory.
12. Purpose of the test.
13. Name of the parameters (indicating the test method).
14. Acceptance criteria according to regulatory documentation.
15. Test results.
16. Evaluation of conformity (non-conformity) of the medicinal product sample with the acceptance criteria according to regulatory documentation.
17. Signatures of the experts (indicating their full name and position).
18. Footnote (instruction) with the following content:
"The protocol applies only to the submitted The applicant for the medicinal product sample tested.
Reproduction of the protocol, in whole or in part, without the permission of the testing laboratory is prohibited.
Appendix No. 13
INSTRUCTIONS FOR PREPARING AN EXPERT REPORT TO ASSESS THE RESULTS OF
PRECLINICAL (NON-CLINICAL) STUDIES\
The expert report on the evaluation of preclinical (non-clinical) study results (hereinafter referred to as the report) must be sufficiently detailed to permit re-evaluation by other experts from authorized bodies and organizations of the Eurasian Economic Union member states.
The report must describe the most significant study results, particularly those related to deficiencies, and provide substantiated comments that are presented to the applicant. These comments must also be listed in the summary expert report "Assessment of Safety, Quality, and Efficacy."
To accurately present the sources of information cited in the report (including specific sections of the dossier: general description, summary information, study reports), cross-references to dossier documents, references to referenced literature, and other sources must be used.
Critical assessments (e.g., comments on the reliability and interpretation of data, conclusions) must be included in the "Expert Commentary" subsection at the end of each section of the report. If necessary, the following wording may be used: "Critical comment - see the proposed list of comments." The report must indicate whether the obtained results affect the safety of the medicinal product for human use and whether additional evaluation is necessary to assess such consequences (e.g., there is evidence of carcinogenicity, but receptors in the studied animal species and humans differ).
The report must also identify any data that must be included in the general characteristics of the medicinal product (hereinafter referred to as the SmPC).
References to information that is confidential and not intended for the applicant (e.g., references to an evaluation report for another medicinal product) must be marked as "Confidential Information" and highlighted with a yellow background. These sections must be removed from the report before it is sent to the applicant.
Whenever possible, information should be presented in the form of tables, graphs, and figures. Examples of these are provided in Appendix No. 6 to the Rules for Registration and Evaluation of Medicinal Products for Human Use (hereinafter referred to as the Registration Rules) and should be used when necessary. Pharmacokinetic and toxicokinetic data tables must indicate the number of animals and the standard deviation for each parameter. For repeated-dose studies, the day of sample collection for toxicokinetic analysis must be specified. Tables from the drug dossier may be included in the evaluation report. The relevant references must be provided.
The report template provided in Appendix No. 6 to the Registration Rules has been expanded to include several pages for a list of abbreviations and a bibliography, which should be completed if necessary.
The main text of the report is recommended to be printed in Times New Roman font size 11. If the report exceeds 7 pages, a table of contents should be included.При подготовке отчета эксперт также может использовать акты органов Союза по составлению регистрационного досье в формате общего технического документа.
These guidelines address only those sections of the report that require clarification and commentary.
II. Preclinical (Non-Clinical) Review
1.1. Application Type and Development Considerations. (as amended by the decision of the Council of the Eurasian Economic Commission of 30.01.2020 N 9)
Application type.
The type of application for registration certificate (reference to the legal basis for the application) is indicated (e.g., an application for an original medicinal product, an application based on a compilation of proprietary and third-party data, an application based on generally accepted use, an application for a biological product, etc.), as well as the availability of acceptable justifications for refusing certain studies or replacing original studies with data from literary sources. If any studies exist only in published form, it is important to clarify whether they are of sufficient quality to allow for a comprehensive analysis of the most critical data.
Each main section of the report (Modules 4 and 5) must contain data presented in accordance with the requirements of Appendix No. 1 to the Registration Rules. The types of studies described in each section must be specified with references to paragraph (item, section) numbers, as specified in Appendix No. 1 to the Registration Rules. For each type of study, after identifying the primary and supporting data, it is necessary to assess whether the primary data are presented by original reports on preclinical (non-clinical) and clinical studies (original data), bibliographic references, a combination of both, or whether such data are absent.
The presented data must be assessed taking into account the application type, other regulatory requirements, current guidelines, and scientific criteria.
If the nature of data presentation deviates from existing requirements, the acceptability of each justification for such deviation must be assessed. In particular, the lack of information on preclinical (clinical) trials or studies, and the use of bibliographic references that fully or partially replace data on the primary studies, must be justified. If the applicant uses data from scientific publications or such data is used in the context of the expert report, references must be provided that clearly identify each publication.
A bibliography should be considered if the report uses a large number of references. If necessary, the expert's opinion on the publication should be clearly stated (for example, if the article is used not only as a reference but also in the context of the discussion).
The table provides examples of justifications and their expert assessments.
Justification
Evaluation
Appendix No. 1 to the Registration Rules provides for special exceptions for non-performance of research.
Please indicate these exceptions and confirm the reasons why the application satisfies the conditions set out in these exceptions.
If specific research features are provided for in Union recommendations or Member State guidelines
please indicate the relevant methodological documents and the proposed features and confirm the reasons why the application satisfies the conditions set out in these features.
iven the state of scientific knowledge, certain clinical trials are considered unethical (in accordance with the Good Clinical Practice rules of the Eurasian Economic Union, approved by the Eurasian Economic Commission, and the legislation of member states regarding the humane treatment of animals), or certain types of animal testing are considered unnecessary due to the possibility of using alternative assessments (for example, some toxicology tests are not considered necessary given extensive clinical experience).
Consider the data that underpins scientific knowledge, the significance and reliability of such data, and assess the validity of any extrapolations.
Based on these data, assess whether repeating certain trials (tests) (conducting additional tests) would lead to an increase in the scientific base that would be significant for assessing the benefit-risk balance and providing adequate information for patients and physicians.
Consider all deviations from standard drug development plans, in particular with respect to the timing of animal testing and clinical studies described in regulatory legal acts and guidelines, and analyze the impact of such deviations on the final assessment of the benefit-risk profile.
The applicant cannot provide complete data on the efficacy and safety of the drug when used under normal conditions (exceptional circumstances or conditional registration)
To reach a conclusion on possible approval under exceptional circumstances, the expert should evaluate the validity of the reasons in accordance with the section "Special Conditions for Making a Decision on Registration of a Medicinal Product" of the Registration Rules.
To approve an application under conditional registration, the expert must evaluate the validity of the reasons in accordance with the section "Special Conditions for Making a Decision on Registration of a Medicinal Product" of the Registration Rules and note the need for annual approval of the application. Conditional registration generally does not require the inclusion of preclinical information in the application, except in cases of registration necessitated by emergency situations.
Development Issues.
Describe the preclinical development program in terms of the proposed indications for use and dosage regimen (indicate whether there are indications for use in children). If registration is carried out taking into account the provisions of paragraph 3 of clause 6 of these Rules, state the conclusion regarding the possibility of classifying the registered medicinal product as an orphan drug. Specify whether the scope of the conducted studies complies with the recommendations of the Union and the methodological guidelines and requirements established by the legislation of the Member State.
Specify whether the applicant requests an expedited assessment and fulfillment of the necessary examination criteria.
For biosimilarity studies, it is necessary to describe, justify, and evaluate the development strategy chosen by the company, taking into account the relevant methodological guidelines. For biosimilar medicinal products, the relevant acts constituting Union law should be used. A thorough comparative analysis must be conducted to demonstrate that the biosimilar and reference products already registered in the Union have similar quality, safety, and efficacy profiles. The quality assessment section of the report must provide detailed information on the reference product (name, strength, dosage form, marketing authorization holder, date of registration in the Union) in tabular form, as well as complete information on the product batches (batch numbers, country of manufacture) used to compare quality indicators, preclinical, and clinical data.
It must also indicate whether the pediatric study plan (with or without a deferment) was approved by authorized bodies and organizations conducting drug evaluations, or whether such a plan was waived for a specific product (or whether this waiver applies to the entire class of drugs). A brief description of the terms and key requirements for the pediatric study plan regarding preclinical aspects (if possible) is provided, along with relevant information on the current status of preclinical studies (completed studies, ongoing studies, etc.). Indicate whether the applicant received scientific advice or assistance in drafting the protocol (if so, when), describe the problematic issues, and whether the applicant followed the recommendations received.
Indicate whether the medicinal product was granted orphan drug status (if so, when). If necessary, this decision is provided for products with a similar mechanism of action.
If the studies partially utilized batches of the product not intended for sale on the market, an assessment of the qualifications of new impurities (if any) must be conducted.
1.2. Aspects of good laboratory practice.
This section, as well as the consolidated expert report "Assessment of Safety, Quality, and Efficacy," must indicate the presence of a declaration of compliance with the Union's Good Laboratory Practice (GLP) requirements approved by the Eurasian Economic Commission (hereinafter referred to as GLP).
This section, in particular, describes:
any issues related to compliance with GLP requirements identified during the assessment of the submitted reports (data accuracy or compliance with protocol requirements);
consideration of the need for an inspection to monitor compliance with GLP standards.
To request an inspection for compliance with GLP requirements, it is necessary to:
contact the pharmaceutical inspectorate of the Member State;
determine with the inspectorate the studies, objects, and specific issues or problems relevant to the inspection;
Prepare a formal request for an inspection, which is submitted for review by inspectors and subsequent approval by authorized expert organizations of member states. The request is then approved by the authorized bodies of these states and included in the inspection plan (60 or 80 working days of the overall registration procedure).
2. Pharmacology (modules 2.6.2 and 4.2.1).
Brief Description
This section should describe the active substance, mechanism of action, and a brief rationale for developing the medicinal product in accordance with the proposed indication.
For biosimilar medicinal products, this section should reflect the comparative nature of the studies and the rationale for the preclinical development program. At the end of the section, in the "Discussion" section, you can analyze the study results.
Physical and Chemical Properties
The proposed table should be completed in accordance with Appendix No. 8 to the Registration Rules. If certain fields in the table cannot be completed, please note this and assess the criticality of the missing information.
2.1. Primary pharmacodynamics.
This section describes pharmacodynamic studies evaluating the active substance for the primary (target) disease based on the proposed indications, including the following:
Proof of concept (in vitro and in vivo) and mechanism of action;
Availability of animal models relevant to the proposed indications and suitable for cross-species analysis;
Activity (e.g., ED50), including animal species used in toxicology studies;
Preliminary pharmacokinetic parameters (plasma concentrations) in animals (if data are available);
Duration (reversibility) of effects, resistance profiles (anti-infective agents);
Pharmacologically active metabolites (relative contribution to pharmacodynamics);
Immunological properties, including antigen specificity for monoclonal antibodies. For antimicrobial agents, a description of the mechanism of action, the spectrum of in vitro activity, including the distribution of wild-type strains by minimum inhibitory concentrations (if available), post-antibiotic effects, and the mechanism of resistance should be provided. As an example, in vivo efficacy data in animals against different bacterial species should be provided.
This section (as well as the pharmacokinetics section) can describe the relationship between pharmacokinetic and pharmacodynamic parameters determined in animals. The clinical data section should cross-reference this information.
For biosimilar drugs:
A battery of receptor binding assays or cell-based assays (which may be available from previous quality assurance studies of the drug in biological systems) is the core element of a comparative analysis conducted to assess differences in reactivity and identify their likely causal factors. Animal studies should be designed to provide the maximum amount of information for comparison between the reference product and the biosimilar product subsequently used in clinical trials. Such studies should be conducted in relevant animal species using the most modern technologies.
This section describes pharmacological effects unrelated to the primary therapeutic activity. Information on receptor interaction screening is included, where appropriate.
For monoclonal antibodies, detailed information on immunological properties that differ from those expected is provided, including complement-binding properties and any unexpected reactivity and/or cytotoxicity with human tissues other than the target tissues for the drug. Similar cross-reactivity studies may be conducted using various human tissues. Information on such studies should be included in this section.
2.3. Pharmacological safety.
This section addresses the following issues:
a) a battery of core tests (in accordance with good laboratory practice):
cardiovascular system (including QT prolongation in vitro or in vivo studies);
central nervous system;
respiratory system;
b) other tests (e.g., kidneys, gastrointestinal tract, etc.).
Biosimilar drugs generally do not require other routine toxicology studies, such as safety pharmacology studies, unless such tests are justified by the results of repeated dose toxicity studies.
Potential pharmacodynamic drug interactions may include:
interaction at the receptor level;
possible concomitant use of drugs in clinical practice;
Adverse reaction reports obtained during safety pharmacology, pharmacokinetic (metabolism), or toxicology studies.
2.5. Overall Pharmacology Expert Opinion.
The content of this section may be moved to the "Safety, Quality, and Efficacy Assessment" section of the summary expert report.
To ensure that those reviewing the report are able to fully evaluate all relevant results, this section should be as detailed as possible.
It should briefly describe the main findings of the pharmacology studies and analyze the suitability of the models used for the proposed therapeutic indications.
It should also briefly describe the results of the safety pharmacology studies, noting data that may indicate potential adverse reactions in humans.
Alternatively, this section may contain only the main findings, in which case a separate "Summary" section should be developed. The expert should highlight the sections of the "preclinical review" of the submitted drug dossier with which he or she agrees or disagrees, and provide comments regarding the suitability of the wording and information used in it for the SmPC. The consistency of the text in the dossier and the SmPC should be checked (in particular, in section 5.3 of the report "Preclinical Safety Data," as well as in sections 4.3 "Contraindications," 4.5 "Drug Interactions," 4.6 "Pregnancy and Lactation," and 5.1 "Pharmacodynamic Properties"), and it should be ensured that all information contained in the SmPC is fully supported by the results of the scientific review.
Pharmacokinetic Studies
This section provides a brief overview of the studies. A description of the toxicokinetic studies is provided in the section on repeated-dose toxicity.
3.1. Research Methods. The report should include a brief review of the bioanalytical methods and their validation. For toxicokinetic studies, the methods must comply with Good Laboratory Practice (GLP).
Concentrations must be clearly stated in units of measurement (e.g., mol/L or mg/mL) and, if possible, the data must be presented in the same units.
The evaluator should comment on the availability of this information and any inconsistencies between studies.
3.2. Absorbance.
The list of topics addressed in this section may include, but is not limited to:
if applicable, a description of the site of absorption for oral dosage forms (the specific gastrointestinal tract sites of absorption are generally unknown);
single- and multiple-dose kinetics;
dose proportionality;
gender differences (if any);
interspecies comparison (data on the animal species used in toxicology studies and information on human use should be included);
absolute bioavailability;
neutralizing antibody formation (for biotechnological products).
It is recommended that data be presented in tabular form, including information on the animal species, dose, route of administration, Cmax, tmax, AUC, t1/2, Vd, Clt, and f% (as indicated in the example table in this section of Appendix No. 6 to the Registration Rules). If the pharmacokinetics is linear, describing the data for one of the groups (dose groups) will be sufficient.
This section should address the following issues:
the method used in tissue distribution studies (e.g., autoradiographic analysis);
protein binding (albumin, etc.) in various animal species with an estimate of the unbound fraction of the substance, including in humans;
blood cell distribution (not a routinely required study), if applicable;
placental penetration studies;
melanin binding (a special study in pigmented rats);
data on drug excretion in breast milk (should be assessed separately).
Data on the extent of distribution in potential target organs should be provided in the context of toxicity and drug accumulation in tissues (if possible) (particularly in the presence of tissue-specific adverse reactions in tissues where accumulation is observed).
Plasma protein binding should be considered in detail. Data on the use of the drug in humans should be provided, and a cross-species comparison should be made. The need to compare unbound fraction concentrations across different species should be assessed.
If there are signs indicating binding to melanin, consideration should be given to assessing phototoxicity (e.g., taking into account the degree of light absorption) and the possibility of DNA binding.
If necessary, this section should describe the distribution pattern of the parent drug compared to the distribution of its metabolites.
This section covers the following information:
chemical structure and metabolite content in biological fluids (in tabular form);
possible metabolic pathways (if present in the dossier, a diagram should be provided);
presystemic metabolism (first-pass effects through the gastrointestinal tract (liver));
in vitro metabolism, primarily cytochrome P450 (microsomal) studies: affinity, substrate specificity for isoforms, inhibitory activity studies (if positive, the type of inhibition: reversible, suicidal); drug interactions (clinically significant interactions). If necessary, non-microsomal oxidation, reduction, and hydrolysis reactions are described;
enzyme induction;
second-stage (conjugation) metabolism (primarily in vivo studies).
Metabolism patterns in humans and animals should be compared.
Species-specific metabolites should be indicated, especially if the animals used in safety studies do not produce metabolites found in humans.
This information is an important part of assessing the suitability of the animal models used.
3.5. Elimination
This section should use tabular presentation of data whenever possible. It describes the drug elimination pathways that are relevant for assessing organ-specific toxicity.
If there are significant differences in elimination pathways (including metabolites) between animals and humans, the elimination pathways in animals may be less relevant for assessing toxicity associated with the corresponding excretory organ in humans.
This section should also include data and comments on material balance.
Focus should be placed on interactions with drugs that could potentially be used in combination therapy with the study drug in clinical practice.
The following subheadings should be used in this section, as appropriate:
Studies conducted in young animals;
Studies conducted in pregnant animals;
Studies conducted using animal models of a specific disease.
The content of this section can be transferred to the "Safety, Quality, and Efficacy Assessment" module of the consolidated expert report.
To ensure that those reviewing the report are able to fully assess the benefit-risk profile, this section must be carefully prepared.
This section should include a general overview of the most important pharmacokinetic characteristics and a comment on the suitability of the animal models used in toxicity studies for assessing the safety of the medicinal product in humans, particularly with regard to potential differences in metabolic pathways. Other important aspects include significant differences in absorption (bioavailability), interindividual (interspecies) variability, elimination rates (different t½ values), etc.
Further, other issues important for the safety assessment should be described, such as the distribution pattern in target organs, elimination routes, and pharmacologically active metabolites. Describe the identified interspecies differences and compare them with a possible clinical situation.
This section may also contain only the main conclusions; in such cases, the text of the "Safety, Quality, and Efficacy Assessment" section of the summary expert report should be reviewed separately.
The consistency of the text in the dossier and the SmPC should be verified (specifically, in section 5.3 "Preclinical Safety Data," as well as in sections 5.2 "Pharmacokinetic Properties," 4.3 "Contraindications," 4.5 "Drug Interactions," and 4.6 "Pregnancy and Lactation"). It should also be ensured that all information contained in the SmPC is fully supported by the results of the scientific assessment.
This section should include information covering an observation period of at least 14 calendar days for a standard study conducted in accordance with good laboratory practice requirements, and a brief conclusion regarding whether the studies revealed significant or mild acute toxicity.
It is recommended to provide data on the approximate lethal dose or observed maximum non-lethal dose.
The clinical signs of acute toxicity should be described (briefly), as well as the nature and timing of death (before the end of the observation period (same day) or with a delay).
If necessary, provide information on target organs and pathological examination results.
4.2. Repeated Dose Toxicity
Information on the primary studies should be broken down by animal species and route of administration. The overall compliance of the study program with Good Laboratory Practice (GLP) and any deviations from GLP (e.g., contamination of control animals) should be discussed.
A brief description of the study plan should be provided (animal strain, route of administration, dosing regimens, number (sex, groups) of animals, recovery groups (if any), and toxicokinetic studies, if conducted).
The main study findings should be described in detail, including mortality, body weight changes, relevant laboratory data, pathological changes in target organs, dose-response relationships, time to onset of reactions, severity of reactions, and differences in toxic effects and their duration depending on animal species and sex.
The no-observation-adverse-effect-level (NOAEL) value for different animal species, if established, should be provided, and the relationship between the exposure at a given dose in animals and the exposure at the maximum recommended dose in humans (the exposure limit). This section should also include information on whether reversibility of reactions was observed in the recovery group.
Information on toxicokinetic parameters (linearity, gender dependence, and accumulation) should be commented on.
To facilitate understanding of the significant amount of information presented in these tests, it is recommended to use tables or figures.
The main results of the studies should be highlighted, the mechanism of action of the drug should be briefly described, and the exposure limit for clinical use of the drug should be described.
For biosimilar drugs, as a rule, only one repeated-dose toxicity study is conducted, including toxicokinetic parameters. Toxicokinetic data include determination of antibody titers, cross-reactivity, and neutralizing capacity. These studies allow for the identification of significant differences in toxic and/or immune responses between the biosimilar and reference drug. As a general rule, biosimilar products do not require other standard toxicology studies, including reproductive toxicity, mutagenicity, and carcinogenicity studies, unless required by repeated-dose toxicity studies.
Toxicokinetics
This section should also include kinetic data obtained from analysis of plasma samples from control animals.
All studies performed should be briefly described.
The tests performed should be grouped according to the level of genotoxicity, i.e., mutagenic effect (induction of gene mutations), chromosomal aberrations (clastogenicity) in vitro, chromosomal aberrations (clastogenicity) in vivo, primary DNA damage, and other genotoxic effects. It is recommended to present the research results in tabular form (as indicated in the example table of this section of Appendix No. 6 to the Registration Rules) with the addition of comments in text form (if necessary).
If in vitro testing has not yielded significant results, tabular data alone will suffice.
This section should address the suitability of the animal species used in in vivo testing and the system used to study metabolism (e.g., S9 fraction) for in vitro testing, comparing them with human metabolic pathways.
For in vivo testing, exposure information should always be provided.
Issues that should be addressed when evaluating genotoxicity tests include:
a) for in vitro testing:
strains (cells) and endpoints used;
choice of concentrations used;
stability in the medium (control of concentrations (degradation products));
metabolizing system;
positive and negative controls;
duration of therapy (sampling time);
criteria for a positive response;
concentration-response relationship;
reproducibility;
cytotoxicity (cell survival);
b) For in vivo testing:
strains (animal species, models) used;
number and sex of animals;
doses and exposure;
exposure established based on toxicity or kinetic parameters;
differences in metabolism between animals and humans;
duration of therapy (sample collection time);
criteria proposed by the applicant for evaluation as a positive response;
dose-time-response relationship.
Example of wording that can be used to briefly describe a battery of genotoxicity tests:
"A genotoxicity study of drug <X> was conducted by studying gene mutations in bacteria and mammalian cells, as well as chromosomal aberrations in vitro and in vivo. Additionally, tests for primary DNA damage in vitro and tumor cell formation were performed."
Aspects that should be analyzed in this section of the expert review:
positive in vitro or in vivo test results;
description of the mechanism of action: mutagenic or clastogenic;
Is it possible to use a threshold-based approach, and if so, what are the safe exposure limits based on plasma drug concentrations (human exposure);
conclusion on genotoxic potential.
4.4. Carcinogenic effect.
A brief description of the studies performed should be provided, preferably in table form under the appropriate subheading (e.g., long-term studies, short-term studies, etc. - as indicated in the example table of this section of Appendix No. 6 to the Registration Rules).
If studies of the carcinogenic effect of the drug have not been conducted, an analysis of the applicant's justification for not conducting such studies is required.
The study results should be briefly presented, including data on neoplastic changes and, if necessary, significant changes not related to neoplastic changes. The description of non-neoplastic changes should be accompanied by references to observations made during the repeated-dose toxicity studies. It is recommended to present the results in table form (as indicated in the example table of this section of Appendix No. 6 to the Registration Rules).
Aspects requiring detail in this section:
strain and sex of animals;
number of groups (control groups);
number of animals in each group;
route of drug administration;
duration of administration (exposure);
general development (weight gain, food consumption);
Survival rate at the end of the study;
toxicokinetic parameters (in tabular form: day of sample collection, AUC). Collection of control samples;
organs in which tumor cells were detected, type (benign or malignant), extent of dissemination;
precancerous conditions;
description of tumor types;
statistical methods used;
toxic reactions not observed in shorter-term studies.
4.4.2. Short- and medium-term studies.
New (non-classical) models should be described:
model type and rationale for its use;
whether genotoxicity is the subject of the study;
number of animals and duration of administration (exposure);
use of positive controls and assessment of response to them;
use of control substances for comparison (if applicable);
statistical analysis of the most significant tumor types.
4.4.3. Other studies.
Description of other types of studies (if any), such as mechanism-of-action studies aimed at elucidating the oncogenic effect of the drug or its metabolites.
4.5. Reproductive and developmental toxicity.
A brief description of the studies conducted should be provided, preferably in table form (as indicated in the example table in this section of Appendix No. 6 to the Rules for Registration and Expertise of Medicinal Products for Human Use), including dose-finding studies.
A commentary on the compliance with good laboratory practice for each primary study in this group should be provided. If the information in the table is insufficient to describe a specific study in detail, it should be presented below under the appropriate heading as factual data.
Information relevant to reproductive toxicity reactions mentioned in other sections of the medicinal product dossier should be considered in the form of cross-references or factual data. Examples include analysis of reproductive tract pathology following repeated dose toxicity, endocrine effects, and pharmacokinetic and pharmacodynamic parameters.
4.5.4. Studies in which the drug is administered to juveniles and/or their development is further assessed.
Conclusions regarding reproductive toxicity.
The relevance of the test systems used (e.g., animal species/strains) should be analyzed using a comparison of metabolic parameters, pharmacokinetic and pharmacodynamic parameters, or another approach. An assessment of drug exposure and the distribution pattern in pregnant and/or lactating animals, as well as in the offspring (including excretion in breast milk), should be provided.
Each specific aspect of the studies should be critically assessed, and summary conclusions regarding significant findings should be provided.
Exposure thresholds should be reviewed, and the clinical significance of these data should be assessed.
A rationale for including this information in the SmPC should be provided.
4.6. Local Tolerability.
Briefly describe whether the drug caused irritation at the injection site. If appropriate (for subcutaneous administration), information on sensitization studies should be included in this section (duplicating it in section 4.7.1 of the report).
4.7. Other Toxicity Studies.
The presence of all other studies performed should be noted, and the results obtained should be discussed.
4.7.1. Antigenicity.
Cases of antibody formation and sensitization reactions (guinea pig tests, if applicable) should be described. In the specific case of biosimilar drugs, special attention must be paid to assessing differences in immunogenicity between the biosimilar and reference drugs. All potential implications for clinical efficacy and safety should be considered, taking into account the opinions of the quality assessment experts (Module 3) and the clinical section (Module 5) of the registration dossier.
This section discusses specific immunotoxicity studies performed (in conjunction with the results of repeated-dose toxicity studies), particularly in cases where there is evidence of potential clinical manifestations.
Such studies may include tests using cell surface markers (immunohistochemistry or flow cytometry), functional tests (primary antibody response to sheep red blood cells, natural killer cell activity, macrophage function, delayed-type hypersensitivity, host resistance tests, complement activation, etc.).
To conduct the assessment, the assessor may refer to appropriate guidelines for repeated dose toxicity studies.
This section should also include data on immune suppression, autoimmune potential, and hypersensitivity reactions observed in humans.
This section describes the various types of drug dependence observed in pharmacodynamic studies (models) (not typically performed in routine toxicology studies).
Specific studies of major metabolites (or isomers) in humans that are present at low levels in animals should be described.
Studies on the qualification of impurities should be described: single- and multiple-dose studies, genotoxicity, and reproductive toxicity. Appropriate guidelines may be used by the expert when preparing this section.
The following studies should also be included in the report (if necessary):
phototoxicity. Including information on skin (ocular) phototoxicity, photosensitivity, photogenotoxicity, and photocarcinogenicity. The potential need for such studies depends on photoabsorption (degradation), exposure (route of administration) (subcutaneous administration, ocular instillation) (The expert may use relevant guidelines when compiling this section);
molecular toxicology:
reactive metabolites (in vitro covalent binding to proteins, lipids, nucleic acids). Possible consequences in the form of idiosyncratic reactions or autoimmune diseases;
other studies of the mechanism of action (mitochondrial toxicity, chemical activity against hemoglobin, etc.);
data from studies in the fields of proteomics, genomics, and other areas of molecular biology.
4.8. Overall toxicology conclusion of the assessor.
The content of this section may be transferred to the "Safety, Quality, and Efficacy Assessment" module of the consolidated expert report.
To fully assess the benefit-risk profile, a thorough analysis of the information is required and this section must be compiled in as much detail as possible.
All deviations from the toxicology testing program specified in relevant guidelines or good laboratory practice requirements, or the absence of required studies, must be analyzed.
If the application is based on bibliographic data used as supporting information, it is important to reflect this.
(as amended by Decision of the Council of the Eurasian Economic Commission of January 30, 2020, No. 9)
The validity of the choice of animal species (test systems), duration, and doses (concentrations) used in the studies should be assessed.
The observed effects must be summarized, as well as the language proposed by the applicant regarding the potential significance of these effects for humans. If possible, a conclusion must be drawn on this matter. Data should be provided on the potential consequences of differences in chirality, active substance molecule modification (salt, ester, hydrate, etc.), and impurity profile between the substance used in preclinical studies and the drug that will be marketed.
Cross-species comparative studies of metabolism and systemic exposure in humans and animals (AUC, Cmax, and other parameters) should be considered, and the limitations and applicability of these studies for predicting potential adverse reactions in humans should be discussed.
The suitability of the animal species used in toxicology studies should be considered in the context of potential interspecies differences in pharmacology.
Particular attention should be paid to the results of studies on genotoxicity, carcinogenicity, reproductive toxicity, and developmental toxicity. If positive genotoxic effects are observed, data on tumor formation and/or the drug's effect on reproductive function (ontogenesis) should be analyzed, along with the potential significance of this information for humans, and, if possible, an appropriate conclusion should be drawn.
With regard to carcinogenic potential, attention should be paid to the following: the biological significance of tumor growth, historical data, relationship with pharmacological effect, dose-dependent effects, species-specific differences, studies of the mechanism of action, relationship with genotoxicity, comparison of exposure in humans and animals, etc.
Alternatively, the expert may present only the main conclusions in this section; in such cases, the text of the "Assessment of Safety, Quality, and Efficacy" module of the consolidated expert report should be reviewed separately. Special emphasis should be placed on cases where additional expert assessment is required to evaluate the potential consequences of drug use in humans. This includes the need to obtain expert opinions from pediatric specialists based on the obtained data from studies involving immature individuals.
Comments should be provided on the suitability of the wording in the SmPC. Verify consistency between the text in the dossier and the SmPC (in particular, in section 5.3 "Preclinical Safety Study Data," as well as sections 4.3 "Contraindications," 4.5 "Drug Interactions," and 4.6 "Pregnancy and Lactation"), and ensure that all information contained in the SmPC is fully supported by the results of the scientific evaluation.
For biosimilar drugs, it is necessary to analyze the similarity (or difference) in the therapeutic response between the biosimilar and reference drug, and not just the response per se.
6. List of comments made by the expert as part of the conducted assessment.
The presence of critical comments makes it impossible to recommend approval of a medicinal product registration application. Theoretically, one critical comment can include more than one issue, so paragraphs and subheadings should be used. It is important that the critical comment be clear and logical. This may require detailed comments with references to relevant regulations and recommendations (guidelines).
Ideally, the comment should include an explanation regarding the response (measures) expected from the applicant.
"Minor comments" may impact the proposed conditions for obtaining a registration certificate and the content of information about the medicinal product. These problematic issues must be resolved before approving the application; otherwise, the application may be rejected.
This list of comments must be copied to the "Safety, Quality, and Efficacy Assessment" module of the consolidated expert report.
"Recommendations" contain the expert's comments (conditions) that do not preclude the registration of the medicinal product and that can be taken into account after the drug's registration and included (amended) as part of the amendment procedure.
7. Conditions recommended by the expert.
The issues discussed in this section should be analyzed in the corresponding section of the "Safety, Quality, and Efficacy Assessment" module of the consolidated expert report (e.g., comments regarding the medicinal product information).
More general comments can also be provided in this section.
Appendix No. 14
and Expertise of Medicines
INSTRUCTIONS
ON PREPARING AN EXPERT REPORT ON THE CRITICAL ASSESSMENT
OF QUALITY ASPECTS OF A MEDICINAL PRODUCT
of January 30, 2020, No. 9, of March 17, 2022, No. 36, of May 22, 2023, No. 60)
I. General instructions
These Guidelines address only those sections of the report that require clarification and commentary.
When preparing the report, the following aspects must be considered:
The report must be sufficiently detailed to allow for re-evaluation by other experts from authorized bodies and organizations of the Eurasian Economic Union member states (hereinafter referred to as "Member States" or "Union").
The report must describe the most significant quality aspects, particularly those related to deficiencies, and include substantiated comments that are presented to the applicant. These comments must also be listed in the "Safety, Quality, and Efficacy Assessment" module of the consolidated expert report.
To accurately present the sources of information cited in the report (including specific sections of the dossier—general description, summary information, study reports), cross-references to dossier documents, references to literature, and other sources must be used.
The report must also specifically highlight those data that must be included in the summary characteristics of the medicinal product (hereinafter referred to as the SmPC). Whenever possible, information should be presented in the form of tables, graphs, and figures. Examples of these are provided in Appendix No. 8 to the Rules for Registration and Expertise of Medicinal Products for Medical Use, approved by the Eurasian Economic Commission, and should be used when necessary. Tables from the drug dossier may be included in the report. Relevant references should be provided. To simplify the presentation, limited applicant data, such as flowcharts, specifications, etc., may be included.
The report template in Appendix No. 8 to the Rules for Registration and Expertise of Medicinal Products for Medical Use, approved by the Eurasian Economic Commission, includes several separate pages for a list of abbreviations and a list of references. These pages should be completed as necessary.
It is recommended to use Times New Roman for the main text, with a font size of at least 11 pt. If the report exceeds 7 pages, a table of contents should be provided to facilitate navigation within the expert report.
II. Critical Assessment and Quality Review
The structure of the critical assessment report below generally follows the structure of the registration dossier, with the exception of some preliminary sections, such as the "Introduction" section, for providing introductory information about the product.
Although this guidance is applicable to both new and established active substances and biotechnological/biological products, in some cases specific additional guidance is provided for either new active substances or biotechnological/biological products.
The applicant's registration dossier recommendations should also be consulted—not so much for the application of these instructions in this document, but rather to draw the examiners' attention to certain additional aspects not specifically described in the registration dossier. Please note that for simplicity, the report structure below includes only the "main" headings of the registration dossier. Examiners may add additional headings depending on the specifics of the product.
References to confidential information not intended for the applicant's knowledge (e.g., references to an evaluation report for another medicinal product) must be clearly marked as "Confidential Information" and highlighted with a yellow background. These sections must be removed from the report before it is sent to the applicant.
This critical quality assessment report should be a stand-alone document, which can be achieved in the following ways:
by presenting or copying data taken from the applicant's dossier, followed by the reviewer's own critical assessment of this data, in particular with respect to safety (efficacy) issues, and focusing on compliance with the requirements of specific guidance documents. In such cases, to avoid confusion, comments are entered under the appropriate heading "Reviewer's Comments."
The report primarily presents the reviewer's own views, with references to the applicant's data and/or the Quality Summary. In this case, the reviewer's conclusion should be read in conjunction with the attached Quality Summary. There is no need for additional headings for reviewer comments.
The expert may also use relevant guidelines and recommendations when preparing their opinion.
The expert should generally balance quality issues with the efficacy and safety of the medicinal product under consideration. Issues arising from the scientific assessment (described below) and related to the product information (comments regarding the SmPC, labeling, and package insert) should also be addressed.
When submitting an application for registration of a biosimilar medicinal product, it is necessary to provide a comprehensive comparative assessment to confirm that the biosimilar medicinal product and reference products already registered in the Union have similar characteristics in terms of quality, safety, and efficacy. (as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated 30.01.2020)
Detailed information on the dosage, dosage form of the comparator drug (name), registration certificate holder, and date of issue of the registration certificate must be verified during the validation (completeness assessment) of the registration dossier. In addition to this information, the expert confirms the batch numbers and country of origin of the medicinal product batches used in the comparative assessment (quality characteristics, preclinical and clinical trial data) and subsequently presents them in tabular form in the section on the quality of the drug (Standard Samples and Materials, Appendix No. 4 to the Rules for Registration and Expertise of Medicinal Products for Human Use, approved by the Eurasian Economic Commission, OTD module 3.2.P.6).
When evaluating registration dossiers for biosimilar medicinal products, the requirements set forth in the Union guidelines and relevant national guidelines of Member States should be followed. In addition to those specified, other relevant guidelines for biotechnological medicinal products may be applicable if deemed acceptable.
The results of the comparative assessment of the characteristics of a biosimilar medicinal product are an additional element to the registration dossier in the CTD format. If deemed acceptable, this assessment is performed based on individual sections containing comparative data submitted by the applicant. The conclusion in the "Safety, Quality, and Efficacy Assessment" module of the consolidated expert report must determine whether comparability has been confirmed for both the active pharmaceutical ingredient and the medicinal product.
1. Request for an Inspection of a Pharmaceutical
Manufacturing Facility Prior to Issuing a Registration Certificate
If, during the review process, facts are identified that cast doubt on the accuracy of the information provided in the registration dossier regarding the manufacturing of a medicinal product and require an inspection of the facility, the relevant authorized body must be notified as soon as possible during the assessment of the registration dossier. Since organizing an inspection requires time, such action must be taken before issuing a registration certificate. The relevant authorized body should be notified, if possible, before the preparation of the critical assessment report of the registration dossier, and this request should subsequently be indicated in the relevant section of the report. It should be noted that requests may be made based on the results of the review of any sections of the registration dossier modules that relate to quality aspects. The basis for the request should be briefly described, both in relation to verification of general compliance with GMP rules and/or inspections to assess the manufacturing process, and in relation to the quality of a specific product, in the relevant section and in more detail in the relevant section of the report below, e.g., S.2, P.3.
Active Pharmaceutical Ingredient Production
The production of active pharmaceutical ingredients used in the manufacture of medicinal products must comply with the requirements of the Good Manufacturing Practice Rules of the Eurasian Economic Union, approved by the Eurasian Economic Commission. Ensuring compliance with GMP rules by manufacturers of active pharmaceutical ingredients is the responsibility of pharmaceutical manufacturing license holders using active pharmaceutical ingredients as starting materials. If the expert has questions related to reasonable doubts regarding the quality of an active pharmaceutical ingredient, a request for an inspection of the manufacturing site of that active pharmaceutical ingredient may be made. Inspections are initiated automatically for biological substances or if there is a sterilization step in the production of a sterile active pharmaceutical ingredient, when there is no evidence that the site has undergone scheduled inspections by an authorized body.
Manufacturing of a medicinal product
A manufacturing site is a geographically separate complex of a medicinal product manufacturer, designed to carry out the entire medicinal product manufacturing process or a specific stage thereof, including intermediate stages and quality control. If an expert has questions related to the quality of a medicinal product, a request for an inspection of the manufacturing site of that product may be made.
Testing
When conducting laboratory tests in accordance with the Rules for the Registration and Examination of Medicinal Products for Medical Use, approved by the Eurasian Economic Commission, the expert determines the type of samples to be tested (active pharmaceutical ingredient, bulk medicinal product, medicinal product), lists the tests required, the number of samples, the number of batches, and selects the laboratory(ies) to conduct the specified tests.
General information about the medicinal product.
General information about the medicinal product includes the following:
a brief description of the type of medicinal product (active pharmaceutical ingredient (e.g., a new chemical compound, a known chemical compound, a biotechnological (biological) substance), radiopharmaceutical, herbal medicinal product), dosage form, packaging). Particular attention should be paid if the medicinal product is intended for use in children;
an indication of the orphan medicinal product (ODP) status, if applicable or if there are grounds for registering the medicinal product as an orphan product, taking into account the provisions of paragraph three of clause 6 of these Rules;
indications, target population, dosage regimen (taking into account the ability of the medicinal product to provide the required dosage regimen, e.g., divisible tablets), route of administration (if the route of administration is specific, the administration device);
information on the relationship between this medicinal product and other substances of the same therapeutic class;
Preparation of the medicinal product prior to use (e.g., radiopharmaceutical, lyophilisate);
Other features of the medicinal product, such as delivery or administration systems, devices for administration, etc.;
Related or interdependent claims (e.g., an application for registration of a medicinal product whose active substance is a metabolite of a prodrug previously registered by the applicant, a medicinal product intended to expand the product line).
The information provided below is intended to summarize the key critical features of the medicinal product. The extent of the information provided depends on the properties of the specific product. A summary of clinical experience should also be provided.
Dosage form and strength (concentration)
Registration procedure
Therapeutic class or indication
Suggested dose range
3. Active pharmaceutical ingredient (API, module 3.2.S)
It should be noted that information on the active pharmaceutical ingredient is contained in the closed section of the Active Pharmaceutical Ingredient Master File (DMF). The results of the review of the closed section must be reflected in a separate review report, along with a separate list of comments, as an addendum to this review report (see Appendix No. 8 to the Rules for the Registration and Review of Medicinal Products for Human Use, approved by the Eurasian Economic Commission). The requirements for the DMF do not apply to biological medicinal products.
3.1. General Information on Starting Materials and Raw Materials (Module 3.2.S.1).
This heading contains the information specified in the sections below.
S.1.1. Information on the API Name.
Indicate the chemical name (if applicable). Confirm whether the drug has a recommended international nonproprietary name, proposed international nonproprietary name, common name, etc.
S.1.2. API Structure.
Provide information on the structure of the active substance and compounds with similar characteristics or structure.
S.1.3. General Properties of the API.
Indicate (if applicable) properties relevant to clinical practice, expressing them through characteristics such as pKa, solubility, polymorphism, isomerism, particle size distribution, etc.
For biotechnological (biological) substances, section S.1 should include a description of the active substance. The name and description of the molecule must be provided. The description should include properties such as glycosylation/post-translational modifications, structural modifications (amino acid substitution, PEGylation), and molecular size. If appropriate, information on the secondary and tertiary structure should be provided. Structural elements important for the mechanism of action should be highlighted and discussed.
Identify issues not adequately addressed in the dossier and should be addressed in the List of Comments (referring to the question number, if necessary). Identify critical comments.
Notes. 1. It should be noted whether a Certificate of Conformity of the European Pharmacopoeia Monograph (CEP), or a DMF, or a full information sheet on the active pharmaceutical substance is provided.
2. When using an DMF, it should be indicated that the results of its assessment are presented in a separate expert report on the critical assessment of the DMF with a confidential appendix for the closed part of the document.
3. If the dossier contains information on several DMFs, a separate report is submitted for each IFAP.
4. For the medicinal product under consideration, information on permission to access confidential information must be provided.
5. When using a CEP and DMS, only sections 3.4 "Quality Control of the Active Pharmaceutical Substance" and 3.5 "Reference Standards or Materials" related to the manufacture of the medicinal product need to be completed, unless the applicant has provided additional data, namely, stability data to support a longer retest period in accordance with section 3.2.S.7.
6. Questions regarding the closed section of the DMF reports should be addressed only to the relevant manufacturer of the active pharmaceutical ingredient/DMF holder, not to the applicant.
7. When using CEPs and DMF, the source (applicant, DMF holder, or DMF holder) and the level of detail of the information for compiling the critical assessment report should be specified.
8. The assessment of the quality of the active pharmaceutical ingredient in this report should also reflect additional information provided by the applicant that is not included in the open section of the document submitted by the DMF holder. If the applicant provides complete information on the active pharmaceutical ingredient, the report should include an assessment of this information.
International Nonproprietary Name (INN)
Chemical Name
Alternative Name (if applicable)
IUPAC Name
CAS Number
Laboratory Code
Molecular Formula
Relative Molecular Weight
API Structure (Module S.1.2):
General Properties of API (Module S.1.3)
Physical properties
Solubility
pKa value (if available)
Hygroscopicity
Stereochemistry
Polymorphism
This heading reflects the information specified in the following sections:
S.2.1. Manufacturer(s).
S.2.2. Description of the Manufacturing Process and Its Controls.
S.2.3. Control of Starting Materials.
S.2.4. Control of Critical Steps and Intermediates.
S.2.5. Validation and/or Evaluation of the Manufacturing Process.
S.2.6. Development of the Manufacturing Process.
New or Known Chemical Entities
S.2.1. Manufacturers.
The name and country of the manufacturer (and the name of the plant, if applicable) should be indicated.
A chemical synthesis scheme and a process flow diagram (if possible, including this diagram in the body of the report rather than in an appendix) indicating the critical steps should be provided.
The declared size of the industrial batch should also be indicated.
Alternative Processes - include comments if these processes are available. Processing - Include comments if such a process exists (e.g., at what stage this process may take place).
Catalysts and solvents - If the relevant information is not provided in the registration dossier, include comments if this information is contained in the closed section of the MFAS.
S.2.3. Control of starting materials.
Include comments on the degree of compliance with the established requirements of the proposed specifications, paying particular attention to the control of all impurities (including solvents) that may affect the quality of the active substance, especially if impurities in it are not controlled. Provide comments regarding substances of biological origin.
S.2.4. Control of critical steps and intermediates.
Discuss the degree to which the proposed process controls meet the established requirements.
S.2.5. Validation and/or assessment of the manufacturing process.
Summarize the data and results.
S.2.6. Development of the manufacturing process.
Briefly present the data and results with reference to the substances used in preclinical (clinical) studies, if applicable.
Indicate whether a design scope (design space) is proposed (i.e., a justification for the acceptable set of quality indicators and the limits of change in their indicators under the influence of the drug composition, technological processes, and the impact of physical factors during storage, based on statistical methods of risk assessment and analysis. Using a design scope (design space) allows one to determine the quality of a drug, set it during the development of such a drug, and make justified adjustments when its composition and manufacturing processes change during development and lifecycle management). A multifactorial relationship has been established between the process input data (material properties and process parameters) and the critical quality indicators of the active substance. If a design scope is proposed (Appendix No. 3 to this document).
In general, the expert is required to provide critical comments regarding the adequacy of the description of the synthesis, quality control of materials and intermediates, and the reproducibility of the manufacturing process, identifying issues insufficiently addressed in the registration dossier and to be addressed in the List of Comments (with reference to the number, if necessary). Critical comments must be highlighted.
Biotechnological Products
Provide a list of manufacturers. From this list, identify those manufacturers with issues with comparability of quality parameters or other quality issues. Potential issues related to compliance with the Good Manufacturing Practices of the Eurasian Economic Union, as approved by the Eurasian Economic Commission (e.g., transportation between production sites, etc.), should be highlighted.
Provide a brief description of the manufacturing process and in-process controls (especially with regard to product safety, such as testing for foreign agents and RT activity), and highlight product processing processes.
Provide brief information on the service life and regeneration procedure of chromatographic columns used in the product purification process, and assess any impact on product safety.
Conduct a critical assessment of the degree of conformity of the design, consistency, and control with established requirements. For a biosimilar medicinal product, attention should be paid to significant differences from the manufacturing process of the reference product that could impact quality indicators.
Provide information on the genetic development, including the gene origin, description of the gene structure, rationale for the gene structure, and information on genetic stability (indicate the state of the recombinant gene and the copy number).
Provide a description of the producer strains (genetically homogeneous cell lines) (type, origin), the history of their creation, including identification data. Attention should be paid to any issues related to components used in the development process that could impact product safety (e.g., reagents of biological origin).
Cell banks: indicate the formation of the master (working) cell bank, the adequacy of the tests performed, the stability of the cell banks, a description of the phenotypic and genotypic properties, and the protocol for the formation of the future working cell bank. For biological materials (e.g., monoclonal antibody purification columns, blood/plasma derivatives) used in the production of the active substance, the source of the materials, production, characterization, and control shall be assessed. For biological materials (e.g., blood/plasma derivatives such as human albumin) used in the production of the active substance, the source, production, characterization, and control shall be assessed. For plasma-derived products, such as human albumin, their compliance with applicable Union guidelines and recommendations, including donor information, as well as quality and specification requirements, shall be noted.
A reference shall be made to section A2 of the registration dossier regarding adventitious agents (viral safety) related to the materials; any issues related to the risk assessment with respect to spongiform encephalopathy (SE) pathogens shall be highlighted.
(as amended by Decision of the Council of the Eurasian Economic Commission dated 22.05.2023 N 60)
S.2.4. Control of critical stages and intermediate products.
Describe the final manufacturing process (cultivation criteria, batch definition) presented in the dossier.
Proposed intervals for specifications at control points and acceptable limits for in-process control parameters in relation to the process validation results.
A description of the storage conditions (shelf life) of intermediate products should be provided.
All manufacturing steps aimed at (validated) for the elimination (inactivation) of viruses (e.g., processing in a low pH environment) should be highlighted.
S.2.5. Manufacturing process validation and/or evaluation.
The adequacy of the manufacturing process validation should be assessed, the parameters tested and their significance for the product being submitted for registration should be specified.
It should be noted that reprocessing should be included only in a special manner or excluded entirely.
A reference should be made to Section A2 of the registration dossier regarding adventitious agents/viral safety related to materials.
The adequacy of procedures for the removal of process and related impurities should be assessed.
The manufacturing process development history should be analyzed and comments should be made on its impact on the comparability of product quality (e.g., product batches used for clinical trials versus industrial batches, etc.) with reference to section S.4.4 of the registration dossier.
Changes and their reasons (justification) should be described in relation to the impact on quality.
The significance of the changes should be critically assessed.
S.3.1. Confirmation of Structure and Other Characteristics.
S.3.2. Impurities.
This section should provide a brief description of the methods used to determine the structure and properties of the active substance, such as chirality, polymorphism, etc.
For radiopharmaceuticals, it should be clearly defined whether the active substance is to be considered an unlabeled ligand, a radioactive substance, or a radioactive label for another carrier molecule. (In the latter case, information is typically included in the dossier for such a carrier substance.)
As a general rule, a critical assessment of the adequacy of the methods used to establish the structure is necessary.
The "Quality Summary" text of the medicinal product registration dossier should be used to provide a brief overview of relevant impurity data, including process impurities, degradation products, solvents and reagents, etc., with reference to the stability data and information contained in Section S.4 of the registration dossier.
For radiopharmaceuticals, the radiochemical and radionuclide purity should also be specified.
When possible, distinctions should be made between process impurities and degradation products of the active pharmaceutical ingredient.
A conclusion should be reached on the applicability of the manufacturer's approach to impurity control and qualification, particularly taking into account the results of preclinical (toxicology) and clinical studies.
For a biosimilar medicinal product, a fundamental part of the comparative quality assessment is the comparison of characteristics. The structural identity and impurity profile must be considered (analyzed) relative to the corresponding parameters of the reference product.
Section S.3.1 includes the following information:
physicochemical properties;
determination of the composition, physical properties, and primary structure, information on higher-order structures;
heterogeneity profile (relative to related compounds); and confirmation of the homogeneity of its biological activity.
The validity of the method for quantitative determination of biological activity must be confirmed.
A correlation between the results of quantitative determination of biological activity and the clinical response must be established.
When characterizing activity (expressed in units), the results of quantitative determination of biological activity must be expressed in units of activity calibrated using an international, national, or in-house standard material. When using only physicochemical methods to quantify biological activity (based on appropriate correlation), the results should be expressed as immunochemical activity per unit mass.
If the product is an antibody, its immunological properties must be fully characterized.
The immunochemical properties of proteins can serve as indicators of their identity, homogeneity, or purity, or be used for protein quantification.
Quantitative Content. When quantifying a protein by a physicochemical method, its content is expressed in units of mass.
Purity (including related compounds). An API may be represented by several molecular compounds or variants that are considered related compounds: in this case, it is necessary to define individual or combined acceptance criteria for the related compounds included in the product.
In section S.3.2 (Impurities), the analysis of the registration dossier is conducted based on the following assumptions.
Impurities must be characterized to the greatest possible extent, and, if possible, their biological activity must be assessed. Acceptance criteria for impurities (individual and/or total) should be based on data from batches used in preclinical and clinical studies and batches used under homogeneous manufacturing process conditions.
Process-Related Impurities. Process-related impurities include impurities formed during the manufacturing process, i.e., cellular substrates (e.g., host cell proteins, host cell DNA), cell culture factors (e.g., growth factors, antibiotics, or media components), or during further processing.
Related Impurities. Related impurities (e.g., precursors, certain degradation products) are molecular variations formed during manufacturing and/or storage that do not exhibit properties comparable to the target product in terms of activity, efficacy, and safety. Note: Contaminants are unintentionally introduced substances not intended for use in manufacturing and subject to review in Appendix A.2 of the registration dossier modules.
Comparability assessment.
3.4. Active pharmaceutical ingredient quality control (Module 3.2.S.4)
This heading reflects the results of the review of the information specified in the following sections:
S.4.1. Specification.
S.4.2. Analytical Procedures.
S.4.3. Validation of Analytical Procedures.
S.4.4. Batch Analyses (Batch Analysis Results).
S.4.5. Specification Justification.
A table with specification data should be inserted. Provide a summary specification if the active substance is obtained from different sources and has different specifications.
If they are presented in the table above, a reference to the procedure is sufficient.
Confirm compliance with the requirements of Union guidelines or other relevant guidelines, indicating deviations.
Assess the adequacy of the procedures for routine quality control of the API.
S.4.4. Batch analyses (batch analysis results) <specify number of batches>.
The consistency and homogeneity of the product from batch to batch should be assessed. Do the presented results demonstrate that the process is under control?
The adequacy of the specification justification proposed by the applicant should be assessed, taking into account the intended use of the API in the finished product.
If the manufacturer proposes real-time release testing, it should be noted to what extent this is supported by a thorough understanding of the product and manufacturing process. Also, in this case, it should be stated whether the applicant has implemented adequate control of critical process parameters and critical material properties that justify the release testing regime. It should be stated whether the influence of environmental factors on the results of batch release testing performed in a routine and real-time manner has been assessed. It should be stated whether a design is used that provides for comparison of batch release test results from a sufficient number of batches, both in a routine and real-time manner. When using multivariable models to predict API quality indicators or for online process monitoring, please refer to Appendix No. 3 of the expert report on quality aspects assessment.
Biotechnological products
Section S.4.1 includes the following information:
Appearance and Description. A qualitative assessment should be provided, describing the physical (aggregate) state (e.g., solid, liquid) and color of the API.
Identity. Identity tests should be highly specific for the API and be based on unique characteristics of the molecular structure and/or other specific properties. Determining identity may require more than one test method (physicochemical, biological, and/or immunochemical).
Purity and Impurities. Since the absolute purity of biotechnological and biological products is difficult to determine, results often depend on the method selected. Therefore, the purity of the API is typically assessed using several different methods. When evaluating the selection and optimization of analytical methods, the expert should focus on achieving the result of separating the desired product from related compounds and impurities. Impurities contained in these products are divided into related and technological ones.
Activity. It should be ensured that the specification includes a suitable, validated method for quantitative determination of the activity of the biotechnological or biological API and/or medicinal product. If the applicant uses a suitable method for quantitative determination of the activity of the medicinal product, the use of an alternative method (physicochemical and/or biological) at the API quantification stage may be sufficient. In some cases, measurement of specific activity can provide additional valuable information.
Quantitative Content. The quantitative content of the API, based on protein content (mass), should be determined using an appropriate quantitative determination method. Quantitative determination may not require standard samples or materials.
If the manufactured product is measured in units of activity, quantitative determination by an alternative method may not be necessary.
The API specification should be included in the expert report or be an appendix to it.
Section S.4.3 includes the following information.
Expert assessment of the adequacy of validation of analytical methods.
Section S.4.4 includes the following information.
Information on the API's batch-to-batch homogeneity.
It is necessary to evaluate how the consistency of the heterogeneity profile (e.g., glycoforms, isoforms) was demonstrated.
Differences, if any, in impurity levels between API batches for preclinical and clinical studies and between production batches should be analyzed.
Section S.4.5 includes the following information:
A description of the presented rationale underlying the determination of the acceptable range of acceptance criteria, taking into account the entire manufacturing and purification process, as well as the analytical methods used. Acceptance criteria should be established and justified based on data from batches used in preclinical and/or clinical studies, data from batches used to demonstrate the consistency of the manufacturing process, as well as stability test data and relevant development data.
In some cases, it is more appropriate and feasible to conduct testing at the manufacturing stages rather than on the finished API or drug product. In such cases, test results should be considered as acceptance criteria for the in-house manufacturing process and included in the API or medicinal product specification in accordance with the requirements of the Union or regional authorized bodies.
The examiner should determine whether the applicant has selected an appropriate set of test methods to be used for routine monitoring of the API specification parameters from the entire range of methods used during the product development and characterization phase.
3.5. Reference Standards or Materials (Module 3.2.S.5)
New or Known Chemical Compounds
Indicate whether reference standards for the main pharmacopoeias are available in accordance with the Concept for Harmonization of Pharmacopoeial Standards of the Eurasian Economic Union Member States, approved by the Eurasian Economic Commission.
For applications for registration of new molecular substances, the availability of an applicable international or national reference standard is unlikely.
By the time of application, the manufacturer must have approved appropriately characterized internal reference materials based on the batch(es) representing a representative production sample and used in clinical trials. In-house working reference materials used in testing batches of the starting product are subject to standardization (certification) using this reference material.
If an international or national standard exists and is appropriate for use, the standardization (certification) of reference materials should be performed using these standards. Although it is preferable to use the same reference material for biological assays and physicochemical testing, in some cases the use of different reference materials may be necessary. In addition, various reference materials may be required to identify related compounds, related impurities, and process impurities.
Where applicable, a description of the manufacturing and/or purification process for the reference materials may be required to be included in the registration dossier. Documentation regarding the characterization, storage conditions, and composition that ensure the stability of the reference materials must also be provided.
For a biosimilar medicinal product, the results of a comparability study of the active pharmaceutical ingredient (API) properties must be provided. Where appropriate, the use of the API of the reference medicinal product specified in Section 3.2.P.6 must be confirmed.
3.6. Packaging (Closure) System (Module 3.2.S.6)
The choice of container and closure method should be assessed for their appropriateness, taking into account the physical/chemical properties of the API.
It should be assessed whether this choice provides adequate protection against microbial contamination, if this parameter is important. It is necessary to confirm that the containers proposed for routine storage are the same as those used in the stability studies used to justify the proposed retest period (Section S.7).
This section should reflect the review of the information provided in the following sections of the registration dossier:
S.7.1. Stability Study Summary and Stability Conclusions;
S.7.2. Post-Market Stability Program and Stability Commitments;
It should be stated whether the studies were conducted in accordance with current Union guidelines or applicable International Conference on Harmonization (ICH) guidelines. Any deviations and their justification should be noted.
Stability Summary and Conclusions: References to any manufacturing differences should be provided, along with a description of the processes used, with comments on whether they have a significant impact on the stability profile.
The adequacy of the post-market stability program, in particular with respect to the parameters measured, should be commented on.
It should be ensured that the results of the analytical procedures provide a reliable indicator of stability (see S.4). Analytical procedures should be selected that provide reliable evidence of stability and are capable of detecting significant changes in the quality parameters of the API. In particular, for new or known chemical active substances, it should be ensured that the containers used in the stability study are consistent with those proposed for routine storage (see Section S.6) and this should be reflected in the expert report.
Final conclusion on the reasonableness of the proposed retest period.
The dosage form of the medicinal product, including diluents (solvents), medical devices, etc., must be clearly stated in the expert report.
If the dosage form of the medicinal product includes a medical device, a reference to the availability of information on this device should be provided in Section 3.2.R of the expert report. It is necessary to note the registration of medical devices on the Union market and/or the presence of a special mark on the medical devices indicating circulation of medical devices on the Union market in accordance with the requirements for a special mark for circulation of medical devices on the Union market. It is also necessary to verify that the special mark for circulation of medical devices within the Union corresponds to the intended use of the device.
Particular attention should be paid to the characteristics of the packaging and closure system, especially for labile (unstable) or sterile products.
For a biosimilar medicinal product, attention should be paid to significant differences from the composition of the reference product.
This section reflects the results of the review of the information specified in the following sections of the registration dossier:
P.2.1. Medicinal Product Components
P.2.1.1. Active Pharmaceutical Substance
P.2.1.2. Excipients
P.2.2. Medicinal Product
P.2.2.1. Dosage Form Development
P.2.2.2. Manufacturing Surplus
P.2.2.3. Physicochemical and Biological Properties
P.2.3. Manufacturing Process Development
P.2.4. Packaging (Closure) System
P.2.5. Microbiological Characteristics
P.2.6. Compatibility
Medicinal Product Components
For the API, indicate whether the applicant has determined the physicochemical properties that are clinically significant for the patient. Are these properties adequately reflected in the specification and are they adequately controlled?
Indicate the basis on which the applicant determined the acceptable limits.
Indicate the quality parameters of the API that may affect the critical quality parameters of the medicinal product. These parameters may be determined through empirical or systematic assessment using risk assessment methods and statistically designed experiments. If systematic assessment is used, see Appendix No. 3 to this document.
Determine the acceptability of the justification for excluding potentially critical parameters from control.
Is the use of materials of animal or human origin justified?
Excipients
Are there any important, new, or non-standard excipients with respect to their impact on the properties of the drug product?
The applicant's selection of key excipients and their functions, such as those affecting the release, site of release, or pharmacokinetics of the API, should be noted. In some cases (e.g., gas dispersions for ultrasound imaging), where the entire dosage form or system determines the clinical efficacy of the drug product, these cases require detailed consideration.
Is the amount of excipients (preservatives, buffers, etc.) used justified?
Specify the API quality attributes that may impact the critical quality attributes of the drug product. These attributes may be determined through empirical or systematic assessment using risk assessment methods and statistically designed experiments. If systematic assessment is used (Appendix No. 3 to this document), The information contained in Section 4 of this report (Appendix No. 4 to the Rules for Registration and Expertise of Medicinal Products for Human Use, approved by the Eurasian Economic Commission, Module 3.2.A.3, New Excipients) should also be considered. This section provides a more detailed assessment of the excipient itself. It should be noted that new excipients not contained in medicinal products registered within the Union or in the territory of Member States may be considered new APIs, which entails the application of requirements for the full submission of relevant data, i.e., with respect to a description of manufacturing and control, provision of references to toxicology studies, etc.
Medicinal Product
Development of a Dosage Form: Assess the target profile of the product submitted by the applicant, i.e., the list of quality characteristics that the product must have to ensure the stated quality, taking into account safety and efficacy. Indicate whether the development of the dosage form has been supported by clinical trials. If the compositions of the medicinal product submitted for registration and the medicinal product used in clinical trials differ, their bioequivalence must be assessed. Potential differences in the qualitative characteristics of the medicinal product (e.g., impurity and dissolution profiles) should be commented on in the case of differences in dosages or when expanding the range of dosages or dosage forms. Comment on the development of the dissolution test method, a description of the changes, and confirmation of the method's ability to detect differences between a high-quality and a low-quality medicinal product (the discriminatory properties of the method) should be provided. If applicable, the results of studies establishing in vitro-in vivo correlations should be provided. Where appropriate, special attention should be paid to previously developed formulations of the medicinal product for preclinical and clinical studies, and the results obtained from these studies should be commented on. If applicable, additional information on the development of the pediatric dosage form should be provided, including the target age group, if any.
Manufacturing surpluses. The justification for these surpluses should be assessed.
Physicochemical and biological properties. The accuracy of the establishment and control of critical quality parameters should be assessed. It is necessary to assess whether Module 3 of the registration dossier provides an appropriate list of parameters affecting the properties of the drug (if applicable). For example, for tablets, it may be necessary to evaluate the particle size (dispersity) and polymorphism of an API with low aqueous solubility for their impact on dissolution and bioavailability. In this example, the pH-dependent solubility profile would also be important background information influencing the choice of dissolution testing methodology.
Manufacturing Process Development:
If the physicochemical properties of the API change during drug manufacturing (e.g., polymorphism), the validity of the results of studies conducted with the API should be ensured.
The justification for the choice of manufacturing process must be reflected. It must be reflected whether critical process parameters significant for subsequent validation have been established. It must be reflected whether differences in the manufacturing processes of the medicinal product being registered and used in clinical trials that are significant for subsequent validation have been identified. It must be assessed whether the manufacturing process compensates for variability in material quality indicators.
Critical process parameters should be identified based on empirical or systematic assessment, using risk assessment and statistical modeling methodology. In the latter case, relevant textbooks on mathematical statistics should be consulted.
Packaging and closure system.
It is necessary to evaluate whether the choice of packaging and closure materials ensures stability and suitability for use in the target patient population (e.g., in the elderly, child-resistant features).
It is necessary to evaluate the technical properties of packaging and closures that ensure ease of use by patients, such as nasal sprays, inhalers, and pre-filled syringes.
Microbiological and other characteristics: It is necessary to reflect whether the use of special excipients, such as preservatives and antioxidants, is justified, taking into account their concentration (content) and properties.
Compatibility.
It is necessary to evaluate whether the data presented in the package insert and the summary of product characteristics regarding pharmaceutical compatibility and incompatibility correspond to the actual studies conducted.
P.3.1. Manufacturer(s).
P.3.2. Batch Composition (Manufacturing Formulation).
P.3.3. Description of the Manufacturing Process and Its Controls.
P.3.4. Control of Critical Stages and Intermediate Products.
P.3.5. Validation and/or Assessment of the Manufacturing Process.
The names, addresses, and responsibilities of each manufacturer, including contractors (contract manufacturing), each proposed manufacturing site, or facility involved in manufacturing and testing must be provided.
Description of the Manufacturing Process and Its Controls: a flow chart (preferably included in the main body of the report rather than as an appendix) indicating the critical stages.
It is necessary to indicate whether the applicant has provided for real-time monitoring of critical material quality indicators and critical process parameters. It is necessary to evaluate whether control measures mitigate risks identified during the development of the dosage form and the manufacturing process. It is necessary to indicate whether feedback mechanisms are provided to allow for adjustment of manufacturing process conditions to compensate for identified variability.
It is necessary to indicate whether a design space (design scope) is proposed. It is necessary to indicate whether the dependence of critical quality indicators on input process parameters (material quality indicators and manufacturing process parameters) has been established within the framework of a multivariate model. If a design space is proposed, refer to Appendix No. 3 to this document.
If the medicinal product consists of an API without excipients, information about its manufacturers and their licensing should also be provided in this section.
If multiple industrial batches of different sizes, or the mixing of batches or the use of subbatches are proposed, their acceptability must be assessed. The size of the batches for which data is provided must be assessed. It is necessary to identify any specialized processes that may require inspection (see the preamble to this report).
It is necessary to ensure that process transition times, storage, and/or transportation conditions are justified and validated.
In this section, the need for process validation information in the dossier should be assessed (i.e., whether it is necessary to submit this information before registration). Such information is typically required when using non-standard methods (processes). For standard processes, the process validation scheme included in section 3.2.R of the registration dossier should be assessed.
If continuous process verification is proposed, it is necessary to assess the availability of sufficient development data and a sufficient control strategy to enable real-time monitoring of critical process parameters and critical material quality indicators.
In this section, all parametric release requests should be fully assessed and commented on, incorporating comments from GMP inspectors (if applicable), taking into account the relevant Union guidance. Where applicable, a safety assessment of the drug from the perspective of adventitious agent transfer may be required and should be included in Appendix A.2. This assessment is more applicable to biotechnological/biological products.
P.4.1. Specification.
P.4.2. Analytical Methods.
P.4.3. Validation of Analytical Methods.
P.4.4. Justification of Specifications.
P.4.5. Excipients of Human or Animal Origin.
P.4.6. New Excipients.
In most cases, if a Union Pharmacopoeia monograph is available, a brief characterization is sufficient.
If a Union Pharmacopoeia monograph is not available, the validity of the proposed specification must be assessed.
It is necessary to evaluate whether the specifications and testing adequately reflect the pharmacopeial properties of the product. This is particularly applicable to new delivery systems, some components of which have a specialized function and require more detailed description and control, particularly with regard to pharmacopeial testing.
For biological materials (e.g., blood or plasma derivatives such as human albumin) used in the manufacture of a medicinal product, the source, production, characterization, and control must be assessed. Whenever plasma-derived products, such as human albumin, are used in the manufacture of medicinal products, they must comply with the Union guidelines for plasma-derived medicinal products and be documented, including the origin of the donations, quality, and specifications, as for albumin-derived medicinal products. A reference to Section A2 of the registration dossier regarding adventitious agents (viral safety) of excipients must be provided. All issues related to the assessment of the risk of transmission of spongiform encephalopathy (SE) must be addressed.
It should be indicated whether the drug contains excipients that can be considered fundamentally new or non-standard for the pharmaceutical market as a whole (with respect to their impact on the properties of the drug). The results of a detailed assessment of such new excipients, including their manufacturing and toxicological evaluation, must be reflected separately.
4.5. Quality Control of the Medicinal Product
(Module 3.2.P.5)
This section reflects the results of the examination of the information specified in the following sections of the registration dossier:
P.5.1. Specifications.
P.5.2. Analytical Methods.
P.5.3. Validation of Analytical Methods.
P.5.4. Batch Analysis Results.
P.5.5. Impurity Characterization.
P.5.6. Specification Justifications.
Specification: Specifications for release and up to the expiration date (shelf life) must be presented in tabular form, compared with each other, with a brief reference to the method used.
If parametric release with real-time control is proposed, indicate whether the applicant has demonstrated a thorough understanding of the product characteristics and its manufacturing process. It should be stated whether the applicant has adequately controlled critical process parameters and critical material quality attributes that would justify parametric release with real-time control. It should be assessed whether the applicant has taken into account production environmental factors when comparing the results of batches obtained from testing the final product with those obtained from real-time testing. It should be stated whether a scheme is included for comparing the parametric release results of the finished product with the parametric release results of a sufficient number of batches within one year. If multivariate models are used to predict the quality attributes of the drug product or to monitor the on-line manufacturing process, reference should be made to Appendix No. 3 to this document. A summary of the specification, including important tests, particularly those related to bioavailability or efficacy (e.g., dissolution, particle size, polymorphism, if applicable) and safety (impurities, sterility, pyrogens or bacterial endotoxins, etc. for sterile products). The overall significance of the release specification should be assessed, taking into account the manufacturing method and clinical use, route of administration, etc.
Validation of analytical methods: Compliance with the requirements of the relevant Union Guideline should be assessed, with deviations noted if any. In this section (P.5), all analytical methods should be assessed, both those described in the release specification and those for shelf life.
It is necessary to ensure that impurity tests in the medicinal product specification are focused on degradation products (degradation) formed during manufacturing and storage, and not on process impurities originating from the pharmaceutical substance, if they are subject to control at the pharmaceutical substance level and their profile does not change during storage of the medicinal product. Batch analysis protocols (n = <specify quantity>): It is necessary to evaluate whether the obtained results confirm the consistency and homogeneity of the medicinal product. It is necessary to evaluate whether the manufacturing processes are controlled.
For radiopharmaceuticals, the radiochemical purity of "cold" reconstituted kits, if applicable, must be assessed.
For biotechnological medicinal products, the critical elements described in the API specification are in many cases also applicable to the medicinal product.
4.6. Reference Standards and Materials (Module 3.2.P.6)
This section is completed, if applicable, taking into account the information in Module S.5 of the registration dossier.
Indicate whether reference standards of the main pharmacopoeias are available in accordance with the Concept for Harmonization of Pharmacopoeial Standards of the Eurasian Economic Union Member States, approved by the Eurasian Economic Commission.
For a biosimilar medicinal product, the following information about the reference medicinal product must be provided in tabular form: name, strength, dosage form, marketing authorization holder, batch numbers, and country of origin of the batches used in the comparability studies (the reference medicinal product must be manufactured in countries with a well-regulated pharmaceutical market).
4.7. Packaging (Closure) System (Module 3.2.P.7)
The appropriateness of the choice of container and closure must be assessed, taking into account the physical and chemical properties of the medicinal product.
The ability of the packaging and closure to provide adequate protection against microbial contamination, if required, must be assessed.
It must be ensured that the containers proposed for routine storage match those used in the stability studies conducted to justify the shelf life (Section 3.2.P.8 of the registration dossier).
This section reflects the results of the review of the information provided in the following sections of the registration dossier:
P.8.1. Stability Study Summary and Stability Conclusion.
P.8.2. Post-Market Stability Study Program and Commitments Regarding Stability Studies.
P.8.3. Stability Study Data.
It should be stated whether the studies were conducted in accordance with current Union guidelines. Any deviations and their justification should be noted.
The adequacy of the post-market stability study program, particularly with respect to the parameters being determined, should be commented on. The appropriateness of the bracketing and matrixing methods (grouping or matrixing methods) should be assessed.
It should be stated whether the methods used are consistent with those described in P.5. It should be ensured that they are validated and allow for the assessment of the stability of the medicinal product.
It should be ensured that the containers used in the stability studies are consistent with those proposed for routine storage. It should be noted that impurities classified in the API do not always include degradation products formed in the medicinal product or during its manufacturing process. Furthermore, other characteristics of the product may change during storage, requiring an assessment of the justification, taking into account the results of preclinical and clinical studies.
It is necessary to ensure that the proposed shelf life is sufficiently justified and that the storage conditions are acceptable.
Stability of the ready-to-use medicinal product:
Stability after opening and during use must also be assessed. For example, for concentrates for dilution, stability must be assessed after dilution and during administration, compatibility with available medical devices for administration, etc. The need to determine the shelf life and storage conditions of the ready-to-use medicinal product should be assessed. The compliance of the developer's proposals with current Union guidelines must be assessed. If they do not comply, the justification for the deviations must be assessed.
For radiopharmaceuticals, this section may include an assessment of the methods for reconstitution of "cold" kits by users, as well as an assessment of their stability after reconstitution.
General Information:
It is necessary to assess whether all of the above is adequately reflected in the SmPC and package insert. A conclusion must be reached on the validity of all expiration dates and storage conditions specified in the SmPC.
A.1. Manufacturing Facilities and Equipment
A.2. Safety Assessment for Adventitious Agents
A.2.1. Non-Viral Adventitious Substances.
A.2.1.1. Mycoplasma, Bacteria, and Fungal Control.
A.2.1.2. Risk of Contamination with Animal Spongiform Encephalopathy.
1.1. Mycoplasma, Bacteria, and Fungal Control.
Cross-references to other parts of the expert report (manufacturing process, etc.) must be provided. When using non-pharmacopeial methods for testing for mycoplasma, bacteria, and fungi, they must be evaluated.
If sterility issues have been encountered with certain reagents or substances, a detailed assessment must be conducted.
1.2. Risk of transmission of animal spongiform encephalopathy.
(as amended by Decision of the Council of the Eurasian Economic Commission of May 22, 2023, No. 60)
The materials mentioned in the Guidelines for Minimizing the Risk of Transmission of Animal Spongiform Encephalopathy Agents in accordance with the Pharmacopoeia of the Union (see Table A) must be listed, and the applicant's compliance with the requirements for the control of GE agents (CEP certificate or scientific documentation) must be assessed. It is advisable to present a summary of the most important information in tabular form. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
Documentation confirming compliance with the requirements of the Guidelines for Minimizing the Risk of Transmission of Animal Spongiform Encephalopathies in accordance with the Pharmacopoeia of the Union, if applicable, must be assessed.
A.2.2. Adventitious Viruses.
2.1. When establishing the presence of materials of biological origin, the following aspects should be analyzed.
The expert report should contain a brief description or list of materials of biological origin used in the manufacturing process of the medicinal product or that came into contact with it, along with a summary of the characteristics of the materials with respect to the potential for viral contamination. Cell substrates, reagents directly or indirectly used (e.g., materials for affinity chromatography) in manufacturing, and excipients must be taken into account. Some information may be contained in sections 3.2.S.2.3 "Quality Control of Materials" and 3.2.P.4.5 "Excipients of Human or Animal Origin" of the registration dossier.
2.2. Testing of Starting Materials and Raw Materials.
Characterization of Cell Lines. The results of the tests performed must be tabulated. The table should reflect which tests were performed and on which cells (master cell bank, working cell bank, post-production cells). Cell lines used for in vitro testing for adventitious viruses must be indicated; tests for mouse and hamster antibody production do not require detailed description. When describing the results of in vivo tests, the animal species and, if relevant, the route of administration must be specified. It must be stated whether three batches of the unprocessed bulk product were tested for the presence of adventitious viruses.
For plasma derivatives, a reference to the plasma master file or the results of the data analysis contained therein must be provided. The expert report must address control measures for donors, donor tissues, and cell banks (for products derived from human tissue).
For vaccines, it must be indicated whether all tests and control measures required by the Union Pharmacopoeia and WHO recommendations to prevent contamination with specific and non-specific adventitious agents have been carried out.
Based on the information provided in section 2.1, it must be assessed whether the applicant has conducted adequate testing for viral contamination.
2.3. Routine testing of unprocessed bulk product (if applicable):
For cell-derived products, it must be indicated whether routine testing of the unprocessed bulk product is required. The appropriateness and adequacy of the testing regime must be assessed.
Based on the information provided in section 2.2, it is necessary to evaluate whether the applicant has developed an appropriate routine testing strategy.
2.4. Testing of purified bulk product (if applicable).
It is necessary to indicate whether the applicant has provided a sufficiently justified regimen for routine and non-routine testing of the purified bulk product.
2.5. Viral clearance studies:
General information on the study design is necessary.
The need for viral clearance of the product should be assessed.
The appropriateness and sufficiency of the manufacturing process steps for viral clearance should be assessed.
The appropriateness of the choice of viruses should be assessed.
The compliance of the studies with the recommendations of the relevant Union guidelines should be assessed.
2.5.1. Evaluation of validation studies according to the various manufacturing stages studied.
1) The degree of reproducibility of the industrial manufacturing process under laboratory conditions should be assessed. It is necessary to evaluate whether important process parameters have been compared and adequately reproduced during downscaling (reducing the production scale to laboratory scale).
It is necessary to evaluate whether the downscaling is supported by the results of analysis of the intermediates or fractions used.
If chromatographic steps are used, the comparability of parameters (bed height, loading, flow rate at all processing stages, loading, elution profiles) must be assessed.
It is necessary to evaluate whether the post-elution fraction (wash), as well as the high-salt fraction, if applicable, are tested for viruses. It is necessary to indicate whether the parameters for each chromatographic run are provided.
If column reuse is proposed, it is necessary to indicate whether the conditions for column regeneration and reuse are described and validated.
If filtration steps are included, it is necessary to indicate whether the parameters (volume to filter area ratio, flow rate or pressure, and/or transmembrane pressure) are identical to those of the industrial manufacturing process. It is necessary to evaluate whether the clearance studies adequately reflect the various stages of the filtration process during manufacturing (filtration and/or ultrafiltration or product wash) and the adequacy of the study of these stages.
It is necessary to list the deficiencies.
2) The validity of the results of the viral clearance experiments must be assessed.
It is necessary to determine whether the potential for cytotoxicity of the material being studied and its confounding effect on the viral test results has been assessed.
If filtration processes have been evaluated by the applicant, it is necessary to determine whether the applicant has tested for viral aggregates and whether suitable methods for their determination have been used.
It is necessary to indicate whether the raw data have been presented and whether they have been taken into account when calculating the viral load reduction factors.
3) Evaluation of the claimed viral load reduction factors (Rf).
It is necessary to evaluate the validity of the claimed Rf values and whether they are supported by the test results.
A table containing the viral load reduction factors (adjusted values, if required) must be provided. It is necessary to indicate whether the stability (the influence of important manufacturing process parameters) of the manufacturing step has been studied.
It is necessary to evaluate whether the validated viral clearance steps have been demonstrated to eliminate significantly more viruses than the potential amount of the crude bulk product, equivalent to a single dose of the medicinal product.
Summary of Section A.2.2.5.
A table of viral load reduction factors for the overall process (adjusted values, if required) must be provided.
A summary of the assessment results must be provided.
A.2.3. Conclusion on Section 5.2.
A summary and conclusion must be provided regarding:
sterility (mycoplasma, bacterial, fungal);
safety with respect to GE;
viral safety.
A.3. New Excipients
It should be noted that new excipients not contained in medicinal products registered within the Union or in the territory of the Union Member States may be considered new APIs, which entails the application of requirements for the full submission of relevant data, i.e., with respect to a description of manufacturing and control, provision of references to toxicology studies, etc. This section should assess the results of a detailed study of such new excipients.
Medicine Manufacturing Process Validation Scheme.
Issues Affecting Medical Devices.
If the medicinal product is packaged in a medical device (e.g., needles, catheters, etc.), information on the registration of the medical device must be included. Otherwise, in order to complete the assessment of the medicinal product as a whole, the authorized body for medicinal products must contact the authorized body for medical devices to verify the compliance of such medical device with the requirements of Union legislation, if necessary. Furthermore, in cases where the device is complex in structure and may comprise a comprehensive delivery system (e.g., a transdermal iontophoretic delivery system incorporated into the dosage form), an expert report on the medical device is also required, covering the clinical characteristics of the medicinal product as a whole.
Risk of Transmission of Hematogenous Epidemiological Surveillance
7. Expert Comments on the General Characteristics
of the Medicinal Product, Instructions for Medical Use (package leaflet), and Labeling
of the Medicinal Product
8. Overall Expert Conclusion on Quality
The contents of this section may be repeated in the "Overview Module" of the expert report.
Therefore, an independent and targeted review may be required to enable the user of the report to comprehensively evaluate the expert review results for the purpose of a full benefit-risk assessment.
Regarding quality aspects affecting the benefit-risk balance, all quality aspects (of both the API and the medicinal product) that could affect the benefit-risk balance must be identified.
If applicable, additional information on the development of the pediatric dosage form must be provided, including the target age group, if any. Alternatively, this section may only include the main conclusions; in this case, the text of the "Overview Module" should be reviewed separately.
All sections of the Quality Summary (Module 2.3) of the registration dossier with which the expert agrees or disagrees must be highlighted. For pediatric dosage forms, it must be indicated whether a separate expert opinion from national authorized bodies or organizations conducting expert evaluation of medicinal products for pediatric use is required.
9. List of expert comments
Classification of comments:
"Critical comments" - such comments make it impossible to register a medicinal product. Theoretically, a single critical comment may include several issues; in this case, unnumbered lists and subheadings should be used. Critical comments must be clear and understandable. This may require detailed comments with references to relevant regulatory legal acts and recommendations (guidelines) of the Union.
If possible, the comment should include an explanation regarding the response and/or measures expected from the applicant;
"Minor (other) comments" - such comments may affect the applicant's proposed registration conditions and medicinal product information (e.g., SmPC, package insert, labeling). Minor (other) comments must be addressed before receiving a registration certificate; otherwise, registration may be denied.
To compile objections and recommendations when compiling the list of comments, use the subheadings and headings of the expert report. This list of comments must be repeated in the "Overview Module" of the expert report.
Quality Aspects
Critical Comments.
API (regarding additional data provided only by the applicant).
API (part of the master file submitted by the DMF holder)
Notes:
1. When using the DMF and identifying potential serious risks to public health as a result of the review of the closed section of the DMF, the following note must be included: "Information on the potential serious risks to public health identified in the closed section of the MFAS is provided in a separate expert report on the DMF."
2. Additional critical comments regarding the closed section of the MFAS, if any, must be provided. These will be discussed in detail in an appendix to the main part of the expert report on the critical assessment of quality aspects (see Appendix 8 to the Rules for Registration and Expertise of Medicinal Products within the Eurasian Economic Union).
Other Comments
Additional critical comments regarding the closed section of the DMF, if any, should be provided. They will be discussed in detail in an appendix to the main part of the expert report on the critical assessment of quality aspects.
Note (if applicable). Indicate the following: "Information on other comments regarding the closed section of the FAMS is provided in a separate expert report on the critical assessment of the DMF."
Recommendations
This section contains expert comments (conditions) that do not preclude registration of the medicinal product, can be taken into account after registration, and are included (amended) as part of the amendment procedure.
10. Supplement No. 1 (if applicable)
DMF
Critical assessment expert report - in a separate document.
11. Appendix No. 2. Design Scope
and Change Management Protocols (if applicable)
The purpose of this Appendix is to highlight issues that should be reflected in the assessment report regarding the analysis of risk assessment methods and statistical tools used in the context of relevant Union guidance. Assessors are encouraged to read this appendix, taking into account all of these Union guidance documents.
1. Risk assessment methodology
Risk assessment tools can be used in many situations. For example, they can be used to evaluate and select material quality attributes and/or process parameters that must be within acceptable limits to ensure the desired quality of the drug product. Such tools can also be used to select process parameters that could potentially impact drug product quality, based on prior experience and experimental data.
It is necessary to evaluate whether summary data are provided for all critical quality attributes and process parameters that, based on prior experience and/or experimental data, could impact drug product quality.
With regard to failure mode and effects analysis, it is necessary to evaluate:
whether all relevant risk factors have been included. For example, known risk factors for the drug product (e.g., degradation, solubility, etc.);
whether the effects of individual operations and material properties have been taken into account;
has the applicant explained how risks are classified and considered;
has the applicant justified the procedure for setting cutoff values for selecting which parameters will be subject to further analysis;
do you agree with the proposed risk classification scheme;
Does the failure mode and effects analysis result correspond to current scientific knowledge? If not, is the acceptability of this result justified?
Are the identified risks managed by the design space or the proposed control strategy?
2. Design Experiments.
Design experiments are a strategy for implementing experimental activities in which all factors under study are simultaneously varied according to carefully designed mathematical protocols. The goal is to design representative and informative experiments that maximize information with a minimum number of trials. The factors to be studied during experimental activities are based on risk assessment. A full statistical evaluation of experimental activities performed early in the development process (e.g., for screening) is not necessary. A verbal description of the factors and levels studied, as well as the conclusions, is considered sufficient. However, for design experiments aimed at establishing critical quality attributes, critical process parameters, and/or the design space (design scope), the following information should be considered:
the type of design experiment used and the rationale for its suitability (e.g., some screening designs are not suitable because they do not allow for the detection of interactions). The validity of the design experiment should be stated. (Experimental error versus response differences should be reported);
the factors studied and their ranges (in tabular format, if possible);
a list of planned experiments, clearly indicating the lot or study number and the lot size of the product in each experiment. The number of replicate experiments should be indicated;
a reference to the analytical methods used to evaluate the data and demonstrate their suitability for the intended use;
statistical results (e.g., Pareto charts or a simple list of effect sizes and interactions) should be presented, reflecting the relative importance of the factors under study, as well as interactions between them (if applicable). Ensure that predictions based on the experimental study are consistent with the ranges being investigated and differences in scale (equipment) ratios.
3. Multivariable data analysis (MVDA) for multivariable statistical process control (MSPC).
Multivariable data analysis (MVDA), including principal component analysis (PCA) and partial least squares (PLS), can be used to model pharmaceutical processes. PVDA is often used to provide an overview of data, such as identifying patterns and trends in a set of observations and assessing relationships between variables and between observations and variables. PLS, on the other hand, is used to establish relationships between input and output variables to predict one or more components. Questions to consider when using a MVDA model for multivariable statistical process control include:
Is the sample preparation method for spectral analysis and the reference analytical method used to analyze the samples fit for purpose? For online or in-line control where no sampling is performed, what is the repeatability and reproducibility of the sample in combination with the analytical method?
Do the validation (preparation) and calibration (test) datasets provide evidence of the predicted process variability? Has the model's applicability been demonstrated over the full range of variation permitted by the design parameter space? In cases where this is difficult to capture, risk assessment results may be used. The impact of all important risk factors should be verified and included in the calibration, validation, and testing programs;
Does the variability of the calibration (testing) program reliably reflect the majority of the variability in the validation (training) parameters?
Have outliers been identified in the original dataset, and if so, is there a valid justification for not using these data? Note that if the dataset used for model development is generated from experimental data, not using these datasets may have a greater impact on the predictive ability of the model than using historical data;
Is information regarding data preprocessing (if any) adequately described and consistently applied across all datasets used to create, optimize, and validate the model?
Are the multivariable data analysis modeling methods adequately described, including a brief justification for the choice of the chosen algorithm;
Do you agree with the choice of variables included in the models? Compare this with the risk assessment results. Are there relevant sources of variation not included in the model, and if so, is this justified?
For PLS models, is the PLS model fit for purpose? Is the model complexity optimal? Note: The complexity of a PLS model typically corresponds to the number of PLS (latent) factors that contribute to the lowest-level cross-validation standard deviation. Model complexity (the number of PLS factors used to build the model) should be demonstrated by a plot displaying the regression coefficients for each variable.
Can the proportions (high/low) of variables in the model be explained by existing scientific knowledge or rationale regarding such variables and/or the production process?
Has the MVDA model been statistically evaluated for suitability and predictive ability? The standard error of prediction should be considered in comparison to the accuracy of the reference analytical method.
Has a model validation framework been proposed for the entire product lifecycle? Have the criteria that will trigger the need for a model update been determined, and are these criteria adequate?
4. Design Parameter Space (DS).
Aspects to be considered when proposing a design space include the following:
has the applicant provided sufficient data to support the applicability of the proposed design space (risk assessment, experimental data, models that have been statistically evaluated and validated at full scale);
in developing the design space in the laboratory or on an experimental basis, has the applicant demonstrated its applicability for use at industrial scale by applying scaling factors or independent experiments, or has the scale independence of the parameters been demonstrated in some other way? Scaling factors may be used based on data from various sources or past experience. Has the applicant considered potential risks associated with scale-up, and is an appropriate control strategy in place to manage such risks?
has the applicant taken into account all critical quality aspects in developing the design space (see risk assessment and experimental results);
does the control strategy provide additional support for the proposed design space;
have all critical parameters been identified during the implementation of the design space. If not, is there adequate justification for this.
12. Appendix 3. Design Scope and Change Management Protocols (if applicable)
This appendix is an extract from the main section of the report, the purpose of which is to briefly summarize all aspects agreed upon in the dossier that are necessary to ensure post-marketing regulatory flexibility. This appendix can be used by inspectors as a basis for assessing post-marketing change applications.
1.1. Design Scope for the API.
Presentation of the design scope (characteristics and corresponding ranges of their variations) in tabular format.
1.2. Change Management Protocols for the API.
Description of the variations included in the agreed protocol, as well as the categories of agreed variations for reporting on the implementation of changes.
2.2. Change management protocols for medicinal products.
Description of changes included in the agreed protocol, as well as categories of agreed variations for reporting on change implementation.
Appendix No. 15
GUIDELINES FOR PREPARING AN EXPERT REPORT ON THE ASSESSMENT OF
CLINICAL TRIALS
dated January 30, 2020 No. 9, March 17, 2022 No. 36, May 22, 2023 No. 60)
When preparing an expert's clinical trial assessment report (hereinafter referred to as the report), the following aspects must be considered:
the report must be sufficiently detailed to allow for re-assessment by other experts from authorized bodies and organizations of the Eurasian Economic Union member states (hereinafter referred to as the Member States or the Union, respectively);
the use of tables (graphs, images) is recommended. Examples of these, if applicable, are provided in the format specified in Appendix No. 7 to the Rules for the Registration and Expertise of Medicinal Products for Human Use, approved by the Eurasian Economic Commission (hereinafter referred to as the Rules). The report may also include tables taken from the dossier. Appropriate footnotes should be included in this regard;
cross-references must be used throughout the report to clearly indicate the source of any information provided in the report, such as specific parts of the dossier (e.g., overview, summary, study protocols), references to referenced literature, or other sources;
A separate page has been added to the report template for a list of abbreviations and references, which is filled in as needed.
The recommended font for the main text is Times New Roman, font size 11.
When compiling the report, other applicable documents on the evaluation of the efficacy and safety of medicinal products should be consulted.
II. Critical Assessment of Clinical Aspects
Each section of the report must summarize the data presented in Module 5 of the registration dossier, taking into account the interrelated questions in Module 4 of the registration dossier.
Each main section of the report must contain the data presented in accordance with Appendix No. 1 to the Rules. The types of studies described in each section must be listed with all paragraph (item, section) numbers, as specified in Appendix No. 1 to the Rules. For each type of study, after identifying the primary and secondary results, it is necessary to assess whether the primary results are presented by the applicant's own clinical trial reports ("original data"), bibliographic references, a combination of both, or whether such data is absent.
If the applicant uses data from scientific publications or such data is used in the context of the report, references must be provided that allow for the clear identification of each publication. Consideration should be given to compiling a reference list if the report uses a large number of references. If necessary, the expert's opinion regarding the publication should be clearly formulated (for example, if the article is used not only as a data reference but also in the context of the discussion).
The acceptability of justifications for non-compliance with any requirements should be assessed. In particular, the absence of any preclinical (clinical) study data or the use of bibliographic references that partially or completely replace the original data from the primary studies must be justified. See the "Safety, Quality, and Efficacy Assessment" guidance document (template) for further guidance.
1.1. Application Type and Development Aspects.
1.1.1. Application Type.
Indicate the type of registration application (reference to the legal basis for the application), e.g., an application for an original medicinal product, an application based on a compilation of proprietary and third-party data, an application based on generally accepted use, an application for a biological product, etc., and specify whether there are acceptable justifications for excluding certain studies or replacing original studies with data from literature sources. If any studies exist only in published form, it is important to clarify whether they are of sufficient quality to allow a comprehensive analysis of the most critical data.
(as amended by Decision of the Council of the Eurasian Economic Commission dated January 30, 2020, No. 9)
It should also be indicated that the applicant requested registration subject to special conditions when issuing the registration application or registration subject to the application of the exceptional case criterion (or indicate that such registration options are proposed by the expert). The conclusion on the compliance of the application and registration dossier with the applicable criteria is an integral part of this report.
With regard to conditional registration, the expert must assess the validity of the grounds proposed by the applicant in accordance with the Rules. The following should be noted: the use of the medicinal product for the treatment of a serious (life-threatening) disease, its use in cases of life-threatening diseases requiring emergency care, the medicinal product has a pronounced effect in rare life-threatening (disabling) diseases and has a positive benefit-to-risk ratio. In this case, the medical necessity and the fact that the widespread use of this medicinal product outweighs the existing risks should be taken into account. Conditional registration is permitted subject to a positive benefit-to-risk ratio assessment pending the results of subsequent further studies. The advisability of conducting such studies after registration of the medicinal product should be commented on. When considering registration in exceptional cases, the expert must assess the validity of the applicant's presented grounds. Granting registration approval in exceptional cases does not require the applicant to submit comprehensive efficacy and safety data at the registration stage. Therefore, it is necessary to comment on the important aspects of this application (rarity of the disease, ethical aspects, stage of scientific study of the drug) and the types of specific obligations (procedures) that the marketing authorization holder may be required to fulfill during the post-registration period.
1.1.2. Biosimilar medicinal products.
In certain cases of "biocomparability studies," the expert may be required to describe the company's chosen development strategy, including its analysis and assessment of its validity, taking into account the Rules for the Study of Biological Medicinal Products within the Eurasian Economic Union, approved by the Eurasian Economic Commission. Regarding the review of registration dossiers for biosimilar medicinal products, Appendix No. 1 to the Rules and the Rules for the Study of Biological Medicinal Products within the Eurasian Economic Union, approved by the Eurasian Economic Commission, should be followed.
Quality aspects of the medicinal product and active pharmaceutical ingredient (Module 3 of the registration dossier) must be taken into account. A comprehensive comparative assessment must be provided to confirm that biosimilar and reference products already approved for use have similar quality, safety, and efficacy characteristics. Detailed tabular information on the concentration (content) of the API in the registered reference product (indicating its trade name, dosage form, registration certificate holder, and date of issue of the registration certificate in the Union), as well as detailed information (e.g., batch number and country of manufacture) on the batch of the medicinal product used in the comparative assessment (key quality specification parameters, preclinical and clinical trial data) can be analyzed by an expert based on information from the expert report on quality aspects (assessment of Module 3 of the registration dossier).
1.1.3. Development Aspects.
Describe the clinical trial development program in terms of the proposed indications for use and dosage regimen (indicate whether there are indications for use in children). Indicate whether the scope of the studies conducted complies with Union recommendations and the requirements of Member State legislation.
Indicate whether the pediatric study plan (with or without a deferral) was approved by national authorized bodies and organizations conducting drug evaluations, or whether such a plan was waived for a specific drug (or whether this waiver applies to an entire class of drugs). Briefly describe the terms and key requirements of the pediatric study plan regarding preclinical aspects (where possible) and provide relevant information on the current status of the clinical trials (completed studies, ongoing studies, etc.).
Indicate whether clinical development has been conducted for other special population groups, for example, taking into account age grading, gender, and ethnicity. If applicable, indicate the number and characteristics of healthy volunteers (patients) (male and female) included in the studies (if necessary, see Section 3.1 for details on including a more detailed table in the report, which should correspond to Table 2.7.3.1 of the registration dossier).
Indicate whether the applicant received scientific advice or assistance in drafting the protocol (if so, when), describe the problematic issues, and indicate whether the applicant followed the advice received.
Indicate whether the medicinal product has been assigned orphan drug status (if so, when) or may be assigned, taking into account the provisions of paragraph three of clause 6 of these Rules. If applicable, provide information on this decision in relation to medicinal products with a similar mechanism of action.
The submitted data on the development of a medicinal product may be limited by criteria applicable to conditional registration or registration in exceptional cases. An assessment of compliance with such criteria must be a mandatory part of the report.
1.2. Compliance with the Good Clinical Practice Rules of the Eurasian Economic Union approved by the Eurasian Economic Commission.
This section and Section 3.1, as well as the "General Description" module, must address compliance with the Good Clinical Practice Rules of the Eurasian Economic Union approved by the Eurasian Economic Commission.
This section must address:
all concerns that arose during the review regarding compliance with the Good Clinical Practice Rules of the Eurasian Economic Union approved by the Eurasian Economic Commission and related regulatory and ethical requirements (data accuracy, protocol compliance, and ethical considerations);
a declaration of compliance with the ethical standards of clinical trials stipulated by the Good Clinical Practice Rules of the Eurasian Economic Union approved by the Eurasian Economic Commission, or their equivalent;
The feasibility of conducting an inspection for compliance with the Rules of Good Clinical Practice of the Eurasian Economic Union, approved by the Eurasian Economic Commission, based on the instructions provided in the Rules.
The decision on the need for an inspection is made based on a combination of critical factors set out in the Rules, taking into account the assessment of the entire registration dossier. This list of critical factors is not exhaustive; the significance of each factor in determining the need for an unscheduled inspection for compliance with the requirements of the Rules of Good Clinical Practice of the Eurasian Economic Union, approved by the Eurasian Economic Commission, may vary significantly depending on many factors.
To request an inspection for compliance with the Good Clinical Practice Rules of the Eurasian Economic Union, approved by the Eurasian Economic Commission, it is necessary to:
contact the national pharmaceutical inspectorate;
together with the inspectorate, identify the studies, objects, and specific questions or issues relevant to the inspection;
prepare a formal inspection request, which is submitted for review by inspectors and subsequent coordination with authorized expert organizations of member states, after which the request is approved by authorized bodies and included in the inspection plan (90 or 120 days).
Detailed information on the factors determining the need for an inspection is provided in the Rules and Rules for Conducting Pharmaceutical Inspections of the Eurasian Economic Union.
1.3. Information on the class of orphan medicinal products.
It should be indicated whether the medicinal product can be assigned orphan drug status based on its indications. The indications for its use in this capacity and the prevalence of the disease to be treated with this drug should be stated (according to official statistics of Member States or official lists of orphan diseases approved in Member States).
Where applicable, the following wording should be provided: "According to data from (indicate source), the prevalence of disease (indicate disease) in Member State (indicate country) is (number) per 10,000 population."
The examiner should pay particular attention to the analysis of the orphan drug application, taking into account the rarity of the disease and the indications for use proposed by the applicant.
2. Clinical Pharmacology.
2.1.1. Introduction. Provide brief background information regarding the study design (e.g., crossover clinical trial (pharmacokinetic study) in a specific population), the number and characteristics of patients (healthy volunteers) included in the various studies, and a brief description of the validated bioanalytical methods used. Typically, pharmacokinetic data from healthy volunteers as well as from patients are used in the assessment.
Comment on the requirements for this specific drug (e.g., for a new chemical entity, a complete pharmacokinetic documentation package) and the quality of the clinical review (expert opinion in Module 2 and compliance with the requirements of the Good Clinical Practice Rules of the Eurasian Economic Union, approved by the Eurasian Economic Commission, for pharmacokinetic studies of the medicinal product).
In particular, the availability of pharmacokinetic study results in children (as well as special populations) should be indicated.
Each section and subsection of the report must contain two items:
a) experimental study results (data in the relevant subsections of RD modules 5.3.1, 5.3.2, 5.3.3, as well as PK/PD study data contained in module 5.3.4), preferably in tabular form (with a reference to the clinical study summary (module 2.7), individual reports, or the table in module 2);
b) expert comments, if necessary.
The various studied pharmacokinetic parameters of the drug may be included in one general summary table in this section. Comments regarding the various pharmacokinetic parameters of the drug may contain cross-references to this table.
Depending on the type of appendix, the subheadings of the "Pharmacokinetics" section may be removed or changed as appropriate.
Regarding the review of registration dossiers for biosimilar medicinal products, Appendix No. 1 to the Rules and the Rules for the Study of Biological Medicinal Products approved by the Eurasian Economic Commission should be followed.
Clinical comparability assessment is a step-by-step procedure that should begin with comparative pharmacokinetics (PK) and pharmacodynamics (PD) studies and culminate in comparative clinical efficacy studies using a selected reference medicinal product registered in the Union.
In certain cases (e.g., when registering an additional dosage form of an original medicinal product), submitting PK/PD study data for the drugs will be sufficient to confirm their therapeutic equivalence.
2.1.2.1. Analytical Methods and Techniques.
A brief description of the analytical methods used, with an emphasis on the performance characteristics of the assay validation and quality control.
2.1.2.2. Pharmacokinetic Data Analysis.
Brief description of pharmacokinetic analysis methods.
2.1.2.3. Statistical analysis.
Brief description of statistical analysis methods.
Data from registration dossier modules 5.3.1 - 5.3.3 (if necessary, where applicable) should tabulate study data (e.g., rate and extent of absorption, involvement of active transport proteins in the absorption process).
2.1.3.1. Bioavailability.
Data from registration dossier module 5.3.1.1 reflect data from biopharmaceutical study reports. Absolute and relative bioavailability.
Expert commentary.
2.1.3.2. Bioequivalence.
Data from bioequivalence studies of dosage forms used in clinical trials and the final dosage form to be marketed. Reference should be made to bioequivalence studies conducted to analyze equivalence with respect to manufacturing changes during the development phase and to justify changes between clinical trial dosage forms and the final marketed product.
For biological or biotechnological products, this section should also contain cross-references to preclinical and functional assay data.
Comparative PK studies, which demonstrate the degree of equivalence of key PK parameters between a biologically similar medicinal product and a reference product, are an integral part of the overall comparative assessment. The name of the drug (used in clinical trials) must be provided, along with an explanation of the drug's approval for sale in the Union.
Volume of distribution, protein binding data from in vitro and in vivo analyses, tissue distribution data, and red blood cell count data.
2.1.5. Elimination.
Excretion route (metabolism, renal or biliary elimination), clearance, half-life.
2.1.5.1. Excretion.
Excretion routes. Proportion of product excreted unchanged. Involvement of active transport proteins in renal excretion.
2.1.5.2. Metabolism.
Identification of metabolites, extent of metabolism, metabolic pathways, and enzymes involved in metabolism. Involvement of metabolites in drug action. Data from in vitro and in vivo studies.
2.1.5.3. Interconversions.
Relevant to chiral products.
2.1.5.4. Pharmacokinetics of metabolites.
Information regarding the pharmacokinetics of active metabolites and, if present, inactive metabolites.
2.1.5.5. Consequences of potential genetic polymorphism.
Assessment of consequences if polymorphic forms of enzymes (e.g., CYP2D6, CYP2C19, N-acetyl) are involved in metabolism.
2.1.6. Dose proportionality and time dependence.
2.1.6.1. Dose proportionality.
Dose proportionality after a single dose and at steady state.
2.1.6.2. Time dependence.
Systemic exposure after single and multiple therapeutic doses and assessment of time dependence.
2.1.7. Intra- and interindividual variability.
Intra- and interindividual variability data for pharmacokinetic parameters (preferably in the target population). Intra- and interindividual variability data may be taken from pooled results of population pharmacokinetic analyses.
2.1.8. Pharmacokinetics in the target population.
Available PK data for the parent compound and active metabolites in the target population, with particular emphasis on differences in healthy volunteers, including variability in patients. PK data for the drug in the target population, if available.
Depending on the scope of the information, several subheadings may be included in the table of contents. If the PK data were primarily obtained from studies in the target population rather than in healthy volunteers, this section should be deleted, and the pharmacokinetic data for the target population should be presented above.
2.1.9. Special Populations.
Available PK data for the parent drug and active metabolites in special populations should be analyzed.
Data from the registration dossier module 5.3.3.3, Intrinsic Factor PK Study Report, and the registration dossier module 5.3.3.5, Population PK Study Report (data should be presented similarly to the previous sections and can be included in a single summary table).
This section may include the results of an overview analysis of data from various studies that may contribute to understanding differences in pharmacokinetic performance, with statements of potential consequences. These variations may be due to extrinsic or intrinsic factors, such as age, gender, race, smoking, metabolic polymorphisms, renal function, and hepatic impairment. Variants associated with metabolic polymorphisms should be described and commented on in the "Excretion" section above. Depending on the circumstances, modeling and simulation data may be included for the pediatric population.
2.1.9.1. Elderly population.
If the specified data cannot be obtained from the application materials or given the different age limits provided by the applicant, it is recommended that the table be added as a question to the list of questions in the report submitted on day 120.
If the disease (condition) is prevalent in the elderly, specific data from PK studies and randomized controlled clinical trials in the elderly should be provided, or the fact that such studies have not been conducted should be confirmed.
If there is a possibility of PK changes in the elderly, for example, due to impaired renal function, the need for dose adjustment should be discussed.
2.1.9.2. Children.
General comments from the expert on pharmacokinetics in specific population groups are provided.
It should be noted whether the pharmacokinetics of the parent drug and active metabolites in specific population groups has been adequately characterized. Does the summary of product characteristics (SPC) for the medicinal product for human use include sufficient information on the pharmacokinetics of specific populations, and is any missing information (restrictions, precautions, dose adjustments) addressed?
It is important to consider the PK/PD relationship when assessing the need for restrictions, precautions, and dose adjustments for specific populations. Concentration-effect and concentration-adverse effect relationships must be considered.
2.1.10. Interactions.
Critical presentation of study results.
If data are available, comments on drug-drug interactions should be provided (data should be presented similarly to the previous sections and can be included in 1 general summary table).
2.1.10.1. In vitro.
Data from Marketing Authorization Module 5.3.2: In vitro studies using human biomaterials.
2.1.10.2. In vivo.
Data from Marketing Authorization Module 5.3.3.4: Intrinsic Factor PK Study Report.
2.1.10.3. General comments from the expert on the interaction aspects assessment.
Comments regarding the interaction studies performed.
Have appropriate conclusions been drawn from the studies?
Comments regarding the interaction information included in the summary of product characteristics (limitations, precautions, dose adjustments). It is important to consider the PK/PD relationship when assessing the need for limitations, precautions, and dose adjustments when co-administering with other medicinal products. Concentration-effect and concentration-adverse effect relationships should be considered.
Identification of potential interactions, such as inhibition or induction of enzymes (transporters), that have not been studied in vitro or in vivo interaction studies.
Identification of potential interactions not studied at the absorption level.
2.1.11. Exposures relevant to the safety assessment.
Summarize the planned safety margin data in the target population at steady-state concentrations, as well as in specific population groups with an elevated safety margin, for subsequent use in the preclinical safety assessment.
2.1.12. Overall Pharmacokinetic Expert Opinion.
The content of this section may be transferred to the "Safety, Quality, and Efficacy Assessment" expert module.
Therefore, a separate, in-depth analysis may be required to ensure the expert has comprehensive access to the relevant data for a more adequate assessment of the drug's benefit-risk balance.
In this section, the evaluator should highlight the key issues described in the various sections of the report (absorption, distribution, elimination) and provide an opinion on the quality of the pharmacokinetic documentation, with a particular emphasis on any identified deficiencies.
In addition, this section should assess the presentation of pharmacokinetic information in the summary of product characteristics (SPC) and, in particular, should include appropriate justification for the statements made in the relevant sections of the SPC. The assessor should comment on the presence or absence of sufficient information and/or information on precautions (restrictions) in the general characteristics of the medicinal product in the absence of information for certain patient groups (renal (hepatic) impairment, children, the elderly, etc.).
Alternatively, this section can simply formulate the main conclusions, in which case the text in the "Overview Module" will need to be reviewed separately.
Highlight any areas of consistency (inconsistency) with the content of the "Clinical Overview" section of the submitted dossier.
2.2. Pharmacodynamics.
2.2.1. Introduction.
Summary of the studies conducted, characteristics of healthy volunteers (patients), study design, and information on clinical endpoints.
For biosimilars, a comparative assessment of the pharmacodynamic effect of the test and reference medicinal product should be performed in populations whose characteristics best allow for the identification of differences. The design and duration of the studies must be justified. Combined PK/PD studies can provide essential information on the relationship between the amount of drug administered and the effect. The selected dose should be reflected in the steep portion of the dose-response curve. Data from studies using more than one dose may be helpful. If PK/PD studies are used to demonstrate the similarity of biological medicinal products, it is imperative to study the acceptable dose range to demonstrate the sensitivity of the assay. The limits defining the equivalence of PK and PD parameters must be defined and justified in advance.
2.2.2. Mechanism of Action.
The mode of pharmacodynamic action can be described in relation to the clinically desired primary physiological (therapeutic) effects (primary pharmacodynamic action). This section or sections below may also include comments on the relevance of the selected pharmacodynamic biomarkers.
Additionally, given the nature of the test substance, the potential secondary pharmacodynamic effects of the drug should be discussed.
2.2.3. Primary Pharmacology.
A critical assessment of the relevance of the biomarkers used should be conducted.
A description of the mechanism of action, the dose-response relationship, including the duration of action of the drug, and the rationale for the dosing regimen should also be provided.
It is especially important to include a description of the initial dose-finding studies.
The purpose of presenting the above information is to describe the dose selection for confirmatory dose-response studies based on efficacy and tolerability parameters with increasing dose. The goals are to preliminary explore the therapeutic range and determine the dose response of the drug.
Describe any genetic differences in pharmacodynamic responses to the drug, as well as potential differences in children (e.g., due to maturation).
Results of specialized studies (e.g., immunogenicity studies and microbiological studies) may be described in this section.
2.2.4. Secondary Pharmacology.
Review secondary pharmacology parameters (relating to the indication for use). General tolerability characteristics in healthy volunteers regarding secondary pharmacology in the context of relevant studies with dynamic clinical efficacy endpoints, such as 24-hour blood pressure, biochemical parameters, viral load, ECG, EEG, etc.
2.2.5. Plasma Concentration-Response Relationship.
Data from the PK/PD module 5.3.4 in healthy volunteers and patients.
Plasma concentration-response relationship, divided into dose-response relationship and concentration-response relationship, with particular emphasis on onset and offset of action.
If available, PK data relevant to PD may also be described here to convey information about sources of PK/PD variation. Dose (concentration, effect) relationships following, for example, population pharmacokinetic screening may also be described in the "Clinical Efficacy, Dose-Response Studies" section if the results support claims of efficacy and safety.
In principle, this section and the "Pharmacokinetics" section may reflect the results of a review analysis of data from various studies, which may facilitate understanding of differences in the PK/PD of the drug.
A critical assessment of the choice of biomarkers used is necessary.
The content of this section may be moved to the "Overview Module" of the report.
Therefore, a separate and in-depth analysis may be required to ensure comprehensive access to relevant data for a more adequate assessment of the benefit-risk ratio of the drug.
In this section, the evaluator should highlight the most important issues described in the various sections of the report (absorption, distribution, elimination from the body), and also provide an opinion on the quality of the pharmacodynamic documentation, with a particular emphasis on on the identified shortcomings.
Alternatively, this section may simply formulate the main conclusions, in which case the text in the "Assessment of Safety, Quality, and Efficacy" module will need to be reviewed separately.
Highlight any areas of consistency (or inconsistency) with the content of the "Clinical Overview" section of the submitted dossier and comment on the applicability of the general characteristics of the medicinal product for human use.
3. Clinical Efficacy.
3.1. General Guidance.
The report should contain sufficient detail to permit re-evaluation by other experts of the authorized expert organization of the reference state and the state of acceptance.
While this report should include the necessary information to understand the content of the registration dossier, it is recommended to focus on the significant findings and deficiencies that serve as the basis for developing questions for the applicant, with a discussion (interpretation) of the results for further benefit-risk review and development of recommendations by the Medicinal Products Expert Committee. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
Indiscriminate copying from the applicant's dossier (the "Overview" and "Summary Information" sections) into the registration dossier is unacceptable.
Therefore, it is necessary to adhere to a brief description of individual studies (to ensure a balanced presentation of positive and negative findings).
A distinction must be made (also in the comments) between pivotal clinical studies and additional trials, based on the conclusion regarding the significance of each individual study (all studies should be listed, with reference to summary data tables, if possible).
The use of tables (graphs, images) is preferred (rather than lengthy text descriptions).
A clear distinction must be made between the presented data and the evaluator's comments.
A critical assessment (e.g., comments regarding the applicability of the results and interpretation of the data, conclusions) should be provided at the end of each subsection of the "Evaluator's Comments" section.
The report should indicate the need for additional review (e.g., a meeting with a group of scientific advisors to resolve some unresolved clinical issues or the need for further assessment of pharmacovigilance issues).
The report should highlight findings to be reflected in the summary of product characteristics.
3.2. Introduction.
Use a brief introduction outlining the general features of the presented data and the stated indication for use.
The introduction should include a tabular overview of the relevant clinical studies, study number, study design, and number of patients in treatment groups, baseline characteristics of the treatment groups (e.g., age, gender, and disease severity), efficacy parameters, and efficacy outcomes. This table should be compiled in accordance with Table 2.7.3.1 of the registration dossier, where applicable.
With respect to the indications for use, experience from studies in special populations should be described in addition to that specified in Section 3.3. (as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated January 30, 2020)
If applicable, information on scientific recommendations for clinical efficacy must be provided (a section detailing the declared and submitted recommendations).
The introduction must include a final assessment of compliance with the Union's Good Clinical Practice rules (to be moved to Section 1.2 "Aspects of Good Clinical Practice" and "Overview Module").
3.3. Dose-Response Studies and Pivotal Clinical Trials.
An assessment of the basis for selecting the drug dose for the pivotal trials must be provided. This section may include detailed information or a reference to the "Clinical Pharmacology" section.
A brief description (if not provided elsewhere) including (if appropriate) the administration regimen, dose level, dose range studied, rationale for the selection of surrogate clinical efficacy endpoints, and results reflecting the impact on:
preliminary efficacy data.
dosing recommendations.
A description of the most appropriate PK/PD assays and their results should be provided, as well as population PK data, with references to relevant sections for detailed information.
3.4. Primary Studies.
For each study identified in the text (e.g., by protocol number), the relevant methods and results should be presented and commented on. Inclusion of tables is recommended.
A detailed questionnaire for description of test methods, results, and commentary is provided in the template. This questionnaire is optional; it serves as a source for an ordered list of suggested questions to be included in the report. The relevance of each question and (if necessary) the required level of detail should be considered on a case-by-case basis. Critical comments should be included in the table of contents where appropriate.
Study Identification and Description.
The study number and title should be provided. The allocation of participants to treatment groups (e.g., random assignment, randomization, or randomized assignment) should also be specified.
Methods and results may be presented together or separately for each trial (depending on the type of study and similarities).
3.4.1. Methods.
The most important points (see bullet points) should be addressed for each specific case.
3.4.1.1. Study Participants.
Inclusion/exclusion criteria, sites (e.g., regions where recruitment sites were located), and settings (type of recruitment sites, e.g., hospital type (department)) where data were collected.
3.4.1.2. Treatment.
This section should provide detailed information on the treatment (or other interventions) for each group, as well as the order and timing of drug administration.
3.4.1.3. Objectives.
Specific objectives and hypotheses. State the statistical hypothesis (e.g., superiority, equivalence, or non-inferiority) for the primary clinical efficacy endpoint(s) and any justification for the probability of the expected effect size or the choice of margin of error.
3.4.1.4. Clinical Effectiveness Outcomes.
This section should clearly define the primary and secondary outcome measures and, where applicable, any methods used to improve the quality of measurements (e.g., multiple observations, assessor training, centralized (independent) reviews).
Where applicable, focus on the most important secondary clinical efficacy endpoints. Where applicable, outline the applicant's justification for the selection of any surrogate clinical efficacy endpoints.
Comment on the validity of any surrogate clinical efficacy endpoints.
Brief comments on the clinical significance of the aforementioned clinical efficacy endpoints should be provided.
3.4.1.5. Sample Size.
The sample size determination procedure and, where applicable, a description of any interim analyses and stopping rules should be provided.
3.4.1.6. Randomization.
The methods used to ensure the consistency of randomized allocation and the stratification criteria for its implementation.
3.4.1.7. Ensuring data anonymity ("blinding").
Regardless of study participation, those delivering the intervention and those assessing the outcome were aware of the group allocation. If not, how was the success of blinding assessed?
3.4.1.8. Statistical Methods.
Statistical methods used to compare groups for the primary clinical efficacy endpoints (including definition of the primary analysis population, error rates, adjustment for multiplicity, a brief description of the statistical methods used, and interim analyses); methods for additional analyses (e.g., subgroup analyses and adjusted analyses).
Appropriateness of the statistical analysis plan.
Any deviations from the predefined statistical analysis plan should be commented on.
3.4.2. Results.
The most important points (see bulleted list) should be followed for each specific case.
3.4.2.1. Study Allocation Flow
The order in which participants completed all stages of the study should be described (if possible, use the flow chart below (or alternatively, use a table)).
Specifically, for each group, the number of participants randomized to the groups, who received the assigned treatment, complied with the study protocol, and completed the primary outcome analyses should be reported, such as:
study inclusion (number of subjects screened, number of subjects randomized, number of subjects excluded from the study with the reason, dates and periods of recruitment for participation in the study);
Allocation (by treatment group, number of randomized subjects, number of subjects who started the assigned treatment, number of subjects who did not start the assigned treatment with reasons);
Post-treatment follow-up (by treatment group, number of subjects who did not complete post-treatment follow-up with reasons, number of protocol-based treatment discontinuations, observation period);
Analysis (number of subjects included in the analysis group for determining the primary clinical efficacy endpoints, number of subjects withdrawn with reasons).
Protocol deviations from the planned studies must be reported, with reasons.
Criteria for treatment withdrawal and early withdrawal from the study must be described if such information will facilitate understanding the interpretation of the results.
3.4.2.2. Recruitment.
Dates of recruitment and post-treatment follow-up.
3.4.2.3. Study Conduct.
Indicate whether significant protocol changes were made (unless described in the statistical analysis section). Where applicable, information regarding the results of the protocol compliance check and the Union's Good Clinical Practice Rules should be provided.
3.4.2.4. Baseline Data.
Baseline demographic and clinical characteristics of each group.
In particular, information demonstrating asymmetry in characteristics across all treatment groups should be provided.
Comment on how the characteristics of the study population reflect the intended indication for use of the drug should be provided (or comments should be deferred until they are included in the overall conclusions).
Comment on similarities and differences between treatment groups (if applicable).
Comment on participant adherence to treatment should be provided, if appropriate.
3.4.2.5. Sample Analyzed.
Indicate the number of participants (denominator) in each group included in each analysis, as well as whether participation in the analysis was conditional on "adherence to treatment." When possible, results should be presented in absolute numbers (e.g., 10/20, not 50%).
3.4.2.6. Outcomes and assessment.
A brief summary of the results for each primary and secondary outcome in subjects in each group with estimated precision (e.g., 95% CI) is required.
The clinical significance of the observed effect should be described, as this may be particularly important for assessing the benefit-to-risk ratio.
3.4.2.7. Additional Analyses.
A commentary on the presented information on a number of analyses performed, including subgroup and adjusted analyses, as well as planned and summary analyses (subgroup analyses and other analyses based on the results obtained), should be provided.
A justification for the choice of analysis may be required.
3.4.2.8. Summary of Main Efficacy Results.
The most relevant information reflecting the results of the main efficacy study should be summarized (in tabular form). This summary should be adapted to the dataset used by the authorized expert organizations of Member States to form the conclusion on efficacy. Therefore, it is important to present the results of the analysis considered most relevant (preferably, an analysis of the overall population and the per-protocol group, but a clinically defined subgroup analysis (pre-specified analysis or analysis by results, etc.) is also possible). Data from the pre-specified primary analysis should be presented in any case.
The following standardized table should be used to present data from specific studies. The level of detail should allow the data to be used for further commentary and conclusions about the benefit of the drug, as well as for an overview of the benefit-risk balance. Treatment group data, as well as information on the population of different subjects to be analyzed, should be presented in separate cells (e.g., overall population and per-protocol group). Reasons for attrition should be summarized.
Data from the different main trials should be presented in separate tables. No additional text other than these tables is expected to be included in this section. A detailed description of the trial data, with specific information on the design structure and calculation of the ratios, is provided elsewhere. sections. Safety data should be reported in the "Clinical Safety" section.
3.5. Clinical Studies in Special Populations.
This section should describe special studies (e.g., in children, the elderly, and subjects with renal or hepatic impairment). These studies should be described in accordance with the recommendations for the main studies, including considerations for dose adjustments.
3.6. Intra-Trial Analysis (Pooled Analysis and Meta-Analysis).
This section should specify the criteria for these analyses, including an overview analysis of the entire database, taking into account various effect modifiers (gender, age, the effect of the drug on comorbidities, smoking, etc.).
A review of the dose-response relationship in special populations (weight, creatinine clearance, etc.) may also be required.
3.7. Additional Studies.
Additional studies should be briefly reviewed using a cumulative approach. For biopharmaceuticals, antibody formation and the corresponding impact on efficacy should be noted (e.g., information on (neutralizing antibodies).
3.8. Overall Expert Opinion on Clinical Efficacy.
3.8.1. Clinical Efficacy Conclusions.
The discussion of the results is often the most important part of the critical appraisal report. In terms of structure, the discussion of the conclusions should generally follow the outline for presenting the results described above.
It is important to ensure that the discussion is as precise and concise as possible (often, the discussion of the results is characterized by verbosity and redundancy, but the true meaning of the data is not conveyed to the reader).
When discussing the results for each section, the following issues should be considered:
the most important conclusions and limitations described above (repetition of results is not permitted), an overview of the consistency of the results, a summary of the available arguments for each conclusion;
compliance (non-compliance) of the presented data with the required requirements (legal basis, guidelines, scientific recommendations);
the main issues that arose and the extent to which they should be resolved;
important issues to be considered by the Expert Committee on Medicinal Products.
(as amended by the decision) (Resolution of the Council of the Eurasian Economic Commission dated May 22, 2023, No. 60)
Both the design and results of the study are subject to critical review. A clear conclusion must be provided on key elements (e.g., the choice of comparators, clinical efficacy endpoints, and data limitations). A selection of potential aspects to be considered in this discussion of the results is provided below.
3.8.2. Design and Conduct of Clinical Trials
Does the study design meet the established requirements (randomized, active-drug-controlled trials and placebo-controlled trials)? If not, what is the rationale, and is it acceptable?
Is the study population appropriately selected (comments on inclusion/exclusion criteria)?
Is the comparator drug applicable? If an active comparator drug is used, its relevance to treatment options approved in the Union should be discussed.
What is the critical assessment of the appropriateness of the selection of clinical efficacy endpoints, as well as the duration of the study, taking into account regulatory guidance (scientific recommendations)? Are surrogate markers sufficiently informative to replace fixed clinical efficacy endpoints? What is the appropriateness of the composite endpoint and its application?
As appropriate, the applicability of the methods, their application, analysis, and presentation of the results of the main studies should be addressed. Any special concerns regarding the study design should be discussed.
Does the design comply with legal requirements, current guidelines, and scientific recommendations? What are the implications of any inspection for compliance with the Union's Good Clinical Practice Rules?
3.8.3. Efficacy data and additional analyses.
Magnitude and clinical significance of the effect. The clinical significance of the observed effect should be described, as this may be particularly important for the benefit-risk balance review.
What are the key findings (or uncertainties)? Which key findings (or uncertainties) should be included in the benefit-risk balance review?
Generalizability of trial results (degree of appropriateness). Do the results support the stated indication for use?
Are any additional analyses required, and what are the reasons for requesting them?
If subgroup analysis data are particularly relevant to the overall efficacy assessment, this should be explained.
What are the main issues raised during the assessment (serious objections and other problematic issues).
Any justification for omitting certain studies or replacing original studies with data from scientific sources should be commented on. Insufficient information on certain patient groups (children, the elderly, women of childbearing potential, etc.) must be indicated to support the statement in section 4.4 of the general characteristics of the medicinal product for human use. This information must also be noted in the general conclusion if the authorized expert organization proposes conducting a subsequent study.
What data support the possibility of use in children?
For biosimilars, the comparative nature of the obtained study results with the selected reference medicinal product must be indicated.
What conclusions (or information about the lack of information) are reflected in the general characteristics of the medicinal product for human use? It is necessary to ensure that the data corresponds to the information provided in the general characteristics of the medicinal product for human use (especially the data in section 5.1) and that all information in the general characteristics of the medicinal product for human use has undergone appropriate expert review and scientific analysis.
The presence of any unconfirmed data that require confirmation after the issuance of a marketing authorization must be specified, and whether this is reflected in the summary of product characteristics for human use.
3.8.4. Clinical Efficacy Conclusions.
This section should present a summary of the conclusions that can be drawn from the review of the clinical efficacy study documentation.
4. Clinical Safety.
The safety data should include a data set for all patients participating in the study, and these data should be presented as the results of a single analysis. Specific features associated with the clinical safety study should also be described and explained.
Issues identified in preclinical studies that may adversely affect human use of the drug (e.g., toxicity, metabolites not formed by animals but produced by humans), as well as similar issues in pharmacodynamic studies, should be identified.
4.1.1. A brief introduction to the general features of the data presented.
For biosimilars, the clinical safety assessment results should highlight any potentially significant clinical differences between the safety profiles of the reference and biosimilar products.
Particular attention should be paid to aspects of immunogenicity (e.g., antibody production and characteristics). In addition, any results from post-marketing surveillance after marketing authorization or pharmacovigilance monitoring should be considered (see the Rules for the Study of Biological Medicinal Products within the Eurasian Economic Union, approved by the Eurasian Economic Commission).
4.2. Effect of the medicinal substance on the patient.
Clinical studies demonstrating the safety of the medicinal product should be listed (the use of summary tables is recommended).
The date of completion of data collection should be indicated.
The number and characteristics of patients included in the study (age, stage of the study (disease severity)) and healthy subjects (data may be included in a summary table). The size of the safety database at months 6 and 12, if long-term treatment is involved.
Specifically, the safety database for use in pediatric patients should be reported by age group, as appropriate and as appropriate.
This generally applies to data obtained at months 6 and 12 in a study with a continuous treatment program, or to data from a study with an intermittent treatment program.
Any information on treatment for a period exceeding 12 months should be provided.
A review of any limitations in the safety database should be provided for the proposed target population.
4.3. Adverse Events.
Results should be presented according to System Organ Classification (SOC) (preferred terms), including severity data for all adverse events. Data should be presented in a summary table similar to the table included in the registration dossier (2.7.4.3), with statistical analysis.
In all cases, a review of the relationship between adverse events and reactions (with an indication of causality) and other variables must be provided.
Such variables may include the following:
treatment duration;
dosing regimen and periods;
cumulative toxicity and dose-related toxicity;
concomitant medications, if applicable.
Comments on the reversibility of the event and on the confirmation of preclinical data are provided, if necessary.
Possible connections to relevant manufacturing (quality) aspects (e.g., with respect to antigenic compounds) must be indicated.
In the case of a biosimilar registration dossier review, even if there is evidence of comparable efficacy data, the biosimilar may have a different safety profile (in terms of the nature, severity, or frequency of adverse reactions). Pre-marketing safety data in a subset of patients, as well as data from a long-term study, should be available to review the comparability of the adverse event profiles between the study and reference medicinal products. Particular attention should be paid to comparing the types, severity, and incidence of common adverse reactions observed with the biosimilar and reference medicinal product.
4.4. Serious Adverse Events and Fatalities.
Following the review of the overall safety profile, a separate analysis of serious adverse events should be performed.
Results should be presented according to System Organ Classification (SOC) (preferred terms), including data on the severity of serious adverse events. Data should be presented in a summary table similar to the table included in the registration dossier (2.7.4.3 and 2.7.4.6). In all cases, a review of the relationship between serious adverse events (fatalities) and other variables is necessary.
general toxicity and dose-related toxicity;
concomitant medications, if appropriate;
reversibility (outcome) of the event (excluding fatalities);
4.5. Laboratory data.
If the disease (condition) is common in the elderly, safety information specific to the elderly should be provided, or the absence of such information should be noted.
When evaluating data in the elderly, not only the number of patients included in the study should be considered, but also the results of a benefit-risk analysis, as specific potential risks (e.g., effects on cognitive function, cardiovascular system, kidneys, and liver function) should be taken into account. When reviewing the benefit-risk balance, the prevalence and severity of comorbidities in the elderly should be taken into account. A review of available information on concomitant medications should also be conducted, particularly when there is a potential for potentiation of adverse events with concomitant administration of other medicinal products.
It is recommended that a summary table of adverse event information be completed, as specified in the relevant section of Appendix No. 7 to these Guidelines. If it is not possible to compile such a table, it is recommended that the table be added as a question to the Checklist compiled on Day 120 of the critical appraisal.
Any statements made in this section should be reflected in the product information.
Clinically significant deviations (e.g., a decrease in hemoglobin levels by 2 g/dL in 10% of patients over a 20-week exposure) should be included (compared to placebo-controlled data).
The return to normal levels should be indicated. This information may be included in the table.
Information on patients with deviations greater than 3 times the standard deviation should be reported separately.
4.6. Safety of the drug in special populations.
A brief summary of all available information obtained from preclinical and clinical studies to support specific statements in the summary of product characteristics (SPC) for human use (e.g., gender differences, risk of use in pregnant women, expected or observed effects in children (in appropriate age groups), the elderly, etc.).
The wording should be concise, and details beyond the basic information should be included only if relevant for critical evaluation.
In the context of the safety review, antibody formation (e.g., neutralizing antibodies, autoantibodies, species-specific antibodies (e.g., HAMA (human anti-mouse antibodies), HAHA (human immunoglobulin to humanized antibody)) should be noted in the case of monoclonal antibody production. The relevance (utility) of the analysis should be commented on.
4.8. Safety in Drug-Drug and Other Interactions.
This section should include pharmacokinetic and pharmacodynamic interaction data that are directly relevant to safety. Data from relevant clinical safety studies with concomitant administration of other drugs should also be considered.
4.9. Withdrawals from the Study Due to Adverse Events.
Summary data, possibly cross-referencing the registration dossier table (2.7.4.5).
4.10. Post-Marketing Studies.
New information regarding post-marketing studies should be highlighted.
4.11. Overall Expert Opinion on the Clinical Evaluation Safety.
4.11.1. Clinical Efficacy Conclusions.
It is important to ensure maximum precision and conciseness (often, the discussion of the results is characterized by verbose expressions and wordiness, but the true meaning of the data is not conveyed to the reader).
When discussing the results for each section, the following questions should be addressed:
the most important conclusions and shortcomings presented above (repetition of results is not permitted). An overview of the consistency of the results should be provided and a summary of the existing conclusions of each report;
the compliance (non-compliance) of the presented data with the existing requirements;
the main issues that arose, and to what extent they should be resolved;
important issues to be considered by the extended panel of experts of the authorized expert organization of the Member State for discussion;
what information should be reflected in the summary of product characteristics and in the conclusion;
what are the key conclusions? (or uncertainties) should be included in the benefit-risk review.
4.11.1.1. Specific questions for discussion.
The effect of the medicinal product on the patient: a description of any limitations in the safety database for the proposed target population.
What conclusions (or missing information) are reflected in the summary of product characteristics (SPC) of the medicinal product for human use. It is necessary to ensure that the data correspond to the information provided in the summary of product characteristics (SPC) of the medicinal product for human use (e.g., depending on the circumstances, sections 4.3 "Contraindications," 4.4 "Special instructions," 4.7 "Influence on the ability to drive and use machines," 4.8 "Adverse effects," 4.9 "Overdose"), including that all information in the SPC has been subjected to appropriate peer review and scientific analysis.
Description of the safety profile of the medicinal product and the degree of safety studied.
Conformity of the safety profile to the predicted safety profile from preclinical studies and known classes of effects.
Where applicable, the relevant safety aspects specific to the use of the medicinal product in children must be described by age group, indicating the relationship of these data with the recommendations provided in the summary of product characteristics. Are there any specific (serious) adverse reactions and/or monitoring requirements?
Are the long-term study data sufficient? Are there any unconfirmed data that require confirmation after the issuance of the marketing authorization, and is this reflected in the summary of product characteristics for human use? Is there a need for additional studies (control measures) after the issuance of the marketing authorization?
For biosimilars, the comparative nature of the obtained study results with the selected reference medicinal product must be clearly stated.
4.11.2. Clinical Safety Conclusions
This section should present a summary of the conclusions that can be drawn from the review of the clinical safety study documentation (e.g., the most common adverse reactions to the medicinal product and other significant safety issues).
5. Pharmacovigilance.
5.1. Pharmacovigilance System.
The prospective marketing authorization holder must ensure that a pharmacovigilance system is in place and properly functioning before the product is placed on the market and throughout its marketing period.
The applicant shall submit documents detailing the pharmacovigilance system and a statement signed by the applicant and a qualified pharmacovigilance specialist indicating that the applicant uses a qualified specialist responsible for pharmacovigilance and has the necessary means to report any adverse reactions that may be detected either in Member States or in third countries.
5.1.1. Key Issues to Consider by the Assessor.
Are the various system elements specified in the Union's Good Pharmacovigilance Practice Rules present, and if not, how justified is their omission? Have missing system elements or elements identified as planned for implementation (to be implemented before the product is placed on the market) been adequately addressed, and are they subject to subsequent control measures (how realistic are these obligations?) Is this the first product the company plans to place on the market, and what is its level of maturity? If this is not the first product, are there any information regarding compliance issues in individual safety reports or periodic safety reports for other drugs (in other words, are there any indications that the company's system is not functioning properly?).
Are there data from previous pharmacovigilance system inspections, specifically those indicating problems, or are such data missing (this is typically applicable for the near future, but becomes less relevant over time).
Is the described pharmacovigilance system capable of processing the projected volume of safety reports for this drug, or does it appear "too small-scale" to support such processing? Does the drug have a higher benefit-to-risk ratio than the marketing authorization holder's previous drugs?
Does the company's organization involve a complex network of subcontractors and licensing partners, etc., i.e., a system with multiple divisions (often the weakest points of the organizational process).
Has the company recently undergone a merger?
Is the licensing activity highly specific to the drug (implying a lack of audits, even for well-organized companies (subcontractors)).
Does this information describe an existing system or a system planned for implementation upon marketing authorization of the drug (this will most likely apply to first-time products, completely new products, or different licensing agreements?)?
Does this description represent significant changes to the existing system?
Do subcontractors employ a qualified specialist? If so, are there any indications that this subcontractor is influencing the pharmacovigilance system?
Is there other information that casts doubt on the compliance of the described system with existing requirements (e.g., information received from other authorities, known issues with a specific contractor, software, etc.?)?
Is an inspection of the pharmacovigilance system recommended soon after marketing authorization of the drug to address some of the identified nonconformities?
Other emerging issues.
The following statements may be included in the report:
The applicant has submitted documents that provide a detailed description of the pharmacovigilance system. A pharmacovigilance application, signed by the applicant and the authorized representative, stating that the applicant has access to a designated authorized person responsible for pharmacovigilance and the necessary means to report any adverse reactions occurring in Member States or a third country.
The expert considers the pharmacovigilance system described by the applicant to be adequate and provides adequate evidence that the applicant has access to a designated authorized person responsible for pharmacovigilance and the necessary means to report any suspected adverse reactions occurring in Member States or a third country. If the pharmacovigilance system description contains any outstanding issues that must be resolved and addressed before marketing authorization of the medicinal product, these must be listed as questions in the checklist and/or as targets for subsequent monitoring activities in the "Safety, Quality, and Efficacy Assessment" module of the consolidated expert report. If deficiencies are found in the description of the pharmacovigilance system, or if a qualified specialist and means for reporting adverse reactions are missing, depending on the severity of the deficiencies, one of the following points should be included in the report:
The expert considers that the pharmacovigilance system described by the applicant has the following deficiencies: then a list of deficiencies;
Provided that deficiencies are addressed before the applicant markets the medicinal product, the authorized expert organization may deem the pharmacovigilance system compliant. Before marketing the medicinal product, the applicant must provide convincing evidence that the pharmacovigilance system is in place and functioning.
By day 80, the assessor must perform an initial overall assessment of the application to identify any significant risk management concerns. A pharmacovigilance specialist may be assigned to assist the assessor and provide recommendations (specific issues and concerns identified during the critical assessment of the dossier that could impact the risk management plan). This includes specific preclinical safety findings, insufficiencies in the clinical pharmacology dossier, potential safety risks identified from clinical trial data, etc. At this stage, it is particularly important to identify safety concerns (significant identified risks, significant potential risks, significant missing information). This is especially important if these issues were not described by the applicant in the application and, therefore, are unlikely to be reflected in the risk management plan.
The recommendations received are included in the draft list of questions to be submitted after the registration application is submitted. It is important to note that these recommendations may contain suggested questions for the risk management plan, which should be added to the list of questions.
It is necessary to list the questions and issues identified during the overall assessment of the application and to be considered during the assessment of the risk management plan.
6. List of references.
7. List of questions proposed by the expert.
7.1. Classification of comments:
"Critical comments" - comments that make it impossible to register the medicinal product. Theoretically, one critical comment may include several questions; in this case, unnumbered lists and subheadings should be used. The critical comment must be clear and understandable. This may require detailed comments with references to relevant regulatory legal acts and recommendations (guidelines). If possible, the comment should include an explanation of the response (measures) expected from the applicant.
"Minor comments" are comments that may impact the applicant's proposed registration conditions and information about the medicinal product (general characteristics of the medicinal product for human use, package insert, labeling). Minor comments must be addressed during the pre-registration stage; otherwise, registration may be denied.
To compile objections and recommendations from stakeholder groups, subheadings should generally be used when compiling the list.
The list of comments should be duplicated in the "Overview Module" of the expert report.
"Recommendations" - recommendations that contain expert comments (conditions) that do not preclude the registration of a medicinal product and can be taken into account after the drug's registration, included (amended) as part of the amendment procedure.
8. Conditions recommended by the expert, the fulfillment of which is required after the applicant receives a registration certificate and approval of the general characteristics of the medicinal product for human use:
The information contained in this section must also be specifically addressed in the corresponding section of the "Assessment of Safety, Quality, and Efficacy" module of the consolidated expert report (e.g., specific comments on product information).
"Consultations with users" regarding the readability of the instructions for medical use of the medicinal product:
The applicant must submit the results of a readability assessment of the instructions for medical use of the medicinal product, conducted with the participation of target patient groups (see "Consultations with users"), or justify refusing to conduct such consultations (for additional information regarding the requirements, presentation, and evaluation of the results of "consultations with users," see the relevant acts of the Union bodies).
In all cases, it is necessary to determine and indicate (see "Overview") whether user consultations regarding the readability of the medicinal product's instructions for medical use were actually conducted or planned, or to determine and indicate the justification for refusing to conduct such consultations.
If user consultations regarding the readability of the medicinal product's instructions for medical use are conducted and the results are included in the application, the experts must include an assessment of the user consultation results in their assessment reports, as well as in their conclusion on the overall readability of the instructions for medical use.
Any potential discrepancies or comments (questions) must be included in the list of questions.
Appendix No. 16
List of Amending Documents
ON THE ASSESSMENT OF SAFETY, EFFECTIVENESS, AND QUALITY
Expert Report
on the Assessment of Safety, Efficacy, and Quality
SUMMARY
[Trade name]
__________________________
(Active Substance)
Application No_______ Date __________
Applicant ______________________
Report Date ____________________
TITLE PAGE
Name of the drug in the reference state
INN (or common name) of the active substance
Dosage form(s) and strength(s)
Registration number
Reference state
Recognition states
Name of the registration certificate holder and address in the recognition states
Name and address of the manufacturer(s) of the dosage form
Name and address of the manufacturer(s) responsible for releasing the batch into circulation in the Eurasian Economic Union
Date of the first registration certificate
Registration certificate number(s) in the recognition state
Contact person in the recognition state
Full name
Tel.:
Full names of the experts who conducted the assessment
I. Recommendation
Based on an analysis of quality, safety, and efficacy data, the recognizing state has deemed it appropriate to approve the application for <name of drug> for the treatment of <indication>. The marketing authorization for this drug in the country was issued on <date>.
II. Explanatory Note
II.1. Statement of the Problem
Rationale for the drug: epidemiology, main features of the disease course, and current therapy.
Note: This section does not apply to generic drug applications.
II.2. About the drug
Mechanism of Action.
Pharmacological Classification.
Claimed Indications and Recommendations for Use (including risk management strategy) and Dosage.
Special pharmacological aspects (if any) (e.g., new route of administration, etc.)
II.3. General Comments on the Submitted Dossier
Indicate the type of application for a marketing authorization, including a reference to the legal basis for the application. If appropriate, elaborate on key aspects of the dossier.
Indicate whether the active substance is considered new or not.
For applications submitted based on Sections 14.4 and 15.2 of Appendix No. 1 to the Rules for Registration and Examination in the Eurasian Economic Union (simplified dossier): in this section, you must submit a document from Module 1.5.1 briefly summarizing the reasons and facts used to demonstrate that the use of the substances included in the medicinal product has been well studied, has an acceptable level of safety, and has recognized efficacy. You must provide a clear scientific justification for the permissibility of waiving certain studies typically conducted in the home country.
For applications submitted for generic medicinal products: in this section, you must submit a document from Module 1.5.2 briefly summarizing the reasons and facts used to demonstrate that the medicinal product is substantially equivalent to the registered original medicinal product.
Indicate whether the applicant has submitted a risk management plan (if applicable).
Present the clinical development program for the drug and provide relevant comments regarding the proposed indications for use and dosage (if applicable).
Indicate whether scientific consultation was conducted (if so, when), and whether the applicant has followed the recommendations provided.
Indicate whether the applicant has complied with the requirements of the Eurasian Economic Union (hereinafter referred to as the EAEU).
II.4. General Notes on Compliance with Good Manufacturing Practice (GMP), Good Laboratory Practice (GLP), Good Clinical Practice (GCP), and Harmonized Ethical Principles
<The Recognizing State has confirmed compliance with accepted standards of Good Manufacturing Practice (GMP) for this product at all sites responsible for its production and packaging, <except... This site must be inspected because...
<For manufacturing sites in the territory of... Recognizing States, copies of current manufacturing permits issued by competent inspection authorities have been accepted as confirmation of compliance with accepted GMP standards at these sites.>
<For manufacturing sites..., copies of current GMP certificates of conformity based on satisfactory inspection reports, letters of correction, or information exchange sent by competent inspection authorities (or by those countries with which the Union has concluded a Mutual Recognition Agreement in their territories) have been accepted as confirmation of compliance with accepted GMP standards at such sites.>
Indicate what is appropriate in accordance with the provisions of the pre-assessment modules.
Specifically, indicate whether any inspections are required (if so, for which Good Manufacturing Practices, Good Laboratory Practices, and/or Good Clinical Practices).
If one or more inspections are required, provide a reference to the detailed information in the Good Manufacturing Practices, Good Laboratory Practices, or Good Clinical Practices sections of the relevant quality, preclinical, or clinical trial reports.
The need for an inspection should be indicated in the relevant part of Sections III and V of this document.
This section may utilize information from the "General Conclusions of the Assessors..." paragraphs provided in Appendices Nos. 6 through 8. The relevant paragraphs are provided at the end of the relevant parts of Appendices Nos. 6 through 8. The assessor may, at their discretion, copy and paste or insert these paragraphs under the relevant headings below. In any case, it is necessary to clearly highlight all important findings for each part of the preliminary assessment, consider the basis for the benefit-risk assessment, the recommendations of the Member State, and the questions posed to the applicant.
This chapter should be presented in sufficient detail for subsequent use in preparing a public report on the medicinal product assessment.
For applications for generic medicinal products:
If a reference product is used, the reference State must clearly indicate whether the rationale for using this product is based on its own data or data provided upon request by another Member State of the Union (hereinafter referred to as the "Member State").
III.1. Quality Aspects
Drug Substance
<The pharmaceutical documentation and overall quality summary for <name of product> are of acceptable quality in terms of current regulatory requirements.>
<Control tests and specifications for the drug substance of the product have been properly performed.>
<Stability testing has been performed for the drug substance. No significant changes in any parameters have been identified. The proposed retesting period <...> is justified.>
Drug Product
<The development of the product is described, the selection of excipients is justified, and their functions are explained.>
<The product specifications cover the appropriate parameters for this dosage form. Validation of analytical methods is provided. Batch analysis has been performed on batch <number>. Based on the results of the batch analysis, the finished product meets the requirements of the proposed specifications.>
<Stability testing conditions comply with the stability testing guidelines of the International Conference on Harmonization (ICH). Control tests and specifications for the drug substance of the drug product have been properly completed.
The proposed shelf life of <number> months under <specify storage conditions> for the drug product is considered acceptable.
Please indicate what is appropriate in accordance with the provisions of the pre-assessment modules.
The following information may be added:
- General information on the dissolution test results;
- A statement that the active ingredients and excipients used are well known and of appropriate pharmacopoeial quality;
- A statement of the active substance stability certificate issued by the European Directorate for the Quality of Medicines and Healthcare (EDQM).
III.2. Preclinical Aspects
Applications for generic medicinal products typically refer to existing substances. When conducting a preclinical assessment, it is necessary to focus on new information. Preclinical assessment may be omitted only in cases where the medicinal product can be classified as well-studied in both the reference and acceptance states, or in the absence of new data from preclinical studies. However, if new preclinical study data (e.g., regarding pregnancy and lactation, QT interval, etc.) emerge that could impact the SmPC, a new preclinical assessment should be conducted.
"Bibliographic" statements are "partial dossier" statements. These statements should address preclinical study data. The assessment report should indicate whether the presented studies (literature publications) are relevant to the medicinal product. If some studies were not conducted, a clear scientific justification for excluding such studies must be provided, based on the "well-studied medical use" criteria specified in Appendix No. 1.
Pharmacology
Pharmacokinetics
Toxicology
III.3. Clinical Aspects
Generic Product Statement:
For systemic medicinal products, this section should highlight the need for bioequivalence studies or provide appropriate justification for the lack of relevance or necessity of such studies. The conclusions from the assessment of these studies should be summarized here; A confidential annex (not to be disclosed to the applicant) must provide the full composition and specifications of the reference product used in the bioequivalence studies so that interested Member States can compare it with data on products authorized for marketing in their territory.
This annex must justify the use of the reference product.
If the SmPC differs from the original product used for comparison, the assessment report must contain data justifying the relevant changes.
"Bibliographic" statements are "partial dossier" statements. This annex must consider clinical trial data.
Pharmacodynamics
Clinical efficacy
Clinical safety
Pharmacovigilance system
<The applicant (prospective future Marketing Authorization Holder) has submitted a signed explanatory note on the applicant's (prospective future Marketing Authorization Holder's) pharmacovigilance system (Type IA/<X> amendment). The Reference State considers the explanatory note acceptable, provided that the pharmacovigilance system dossier fully complies with the requirements set out in the Good Pharmacovigilance Practice module.
Risk Management Plan
Insert summary table(s) of proposed pharmacovigilance and risk mitigation activities for hazards.
<Risk Management Plan Approved>
If the risk management plan is submitted in the previously used format, it must be submitted in the new format along with adverse drug reaction data on day 60 of the procedure.
Periodic Safety Update Report for the Medicinal Product
<The Marketing Authorization Holder must submit the first Periodic Safety Update Report for this medicinal product within {xx} months of its authorization.
Thereafter, the Marketing Authorization Holder must submit periodic safety update reports for this medicinal product.>
IV. Benefit-Risk Assessment
Summarize the key findings and assessment questions (detailed information should be provided in the main sections on quality, efficacy, and safety, respectively). Integrate these aspects when considering the benefit-risk balance for specific populations.
Include preclinical and clinical safety data, post-marketing obligations, and any risk management aspects that may impact the benefit-risk assessment.
The benefit-risk assessment should also include the following aspects, if applicable (taken from the registration dossier in the common technical document format):
1. Compliance with the requirements of the Eurasian Economic Commission and the Expert Committee on Medicinal Products guidelines.
2. Optimal dosage range and dosing regimen.
3. Efficacy and safety in subpopulations (e.g., for patients of specific age, gender, race, organ function, disease severity, and genetic polymorphisms).
4. Known and potential mechanisms of drug-drug interactions.
5. Safety signals related to, for example, carcinogenicity, teratogenicity, QT prolongation, or suspected hepatotoxicity.
6. Use of surrogate endpoints for effective action when toxicity is serious.
7. Check that all safety issues are addressed in the pharmacovigilance plan (if present).
8. Safe and/or effective use of the product implies potential difficulties in selecting management approaches that require specific medical expertise or patient education.
9. Check that risks and uncertainties are addressed in the marketing authorization conditions, product information, follow-up monitoring activities, or risk management plan.
10. Check that sufficient information is available to characterize the benefit-risk balance of the product compared to an appropriate, recognized treatment regimen (if available). This should be reviewed as appropriate.
In addition, data in children or any development plans for pediatric use should be considered. If appropriate, this section should include information and data from bioequivalence assessments for generic drug claims. The selection of the reference product should be discussed.
V. Recommended Conditions for Issuing a Marketing Authorization and Product Information
V.1. Conditions for Issuing a Marketing Authorization
Legal Status
An opinion from the reference state on the proposed marketing authorization for the medicinal product is required.
Follow-up Measures
Special Obligations
This section should specify the conditions for issuing a marketing authorization (if applicable):
V.2. General Characteristics of the Medicinal Product
V.3. Package Leaflet and User Testing
V.3.1. Package Leaflet
V.3.2. User Testing Evaluation
The reference state should include an evaluation of user testing (if any) using the relevant appendix to the Requirements for the Instructions for Medical Use of Medicinal Products and the General Characteristics of Medicinal Products for Human Use to analyze the results of user testing. Otherwise, it should be stated whether user testing is provided or justified its absence.
<The evaluation of user testing is provided in the attached documentation quality assessment guide for the analysis of user testing results.> or <The applicant's obligation to conduct a readability test of the package insert during the period of suspension of the marketing authorization may be approved.
V.4. Labeling
VI. Appendix. Documentation Quality Assessment Guide for the Analysis of User Testing Results.
This guide has been developed to provide practical information on the procedure for evaluating user testing reports based on the readability testing method. It does not preclude the submission and assessment of user testing reports based on methods other than those described above.
DRUG INFORMATION
Name and address of the applicant:
Type of application for registration certificate:
Full user testing report submitted yes no
Summary report submitted yes no
In the case of a summary report, multiple ancillary studies are generally unacceptable.
However, for one drug, up to three ancillary study procedures are permitted (e.g., the first for scientific content, the second for device design, and the last for package insert layout).
Reasons for bridging testing, based on justification:
other ______________________________________________
(If a full user testing report or summary report is not submitted, a justification must be provided.) yes no
Is the justification for not submitting the report acceptable?
(Examples of reasons not considered acceptable justification for the omission of user testing are as follows:
administration only in a hospital setting;
administration only by a healthcare professional;
compliance with quality assurance document templates:
studied long-term use of the drug yes no
Reasons [expert opinions regarding the acceptability or inadmissibility of the rationale for the summary report - assessment of the rationale/summary report]
_____________________________________________________________
1. TECHNICAL ASSESSMENT
Is the survey population acceptable? Yes No
Comments (additional information) _____________________
Recruitment Guidelines
When evaluating recruitment methods, the following points should be considered:
Is the recruitment method well defined? Is it clear that careful consideration was given to the selection of the test group (e.g., in terms of parameters such as gender, age, education, experience with the drug, existing complaint information, etc.)?
How was the test group recruited? Were they naive users or patients, patients or caregivers?
Is it clear how many people participated in the test(s)?
Is the number of people sufficient (the package insert (PLE) (hereinafter referred to as the PLE) must be tested in at least two rounds with 10 participants in each).
Is the number of questions _______ sufficient? Yes No
Do the questions cover the important aspects (safety) of the medicinal substance? Yes No
Comments (Additional Information) _____________________
Questionnaire Guidelines
When evaluating the questionnaire, the following points should be considered:
Has the applicant provided basic information on safe use?
Do the questions cover the basic information and the following aspects:
overall impression of the package leaflet;
The "diagnostic" part of the IMP (PL) (i.e., questions aimed at testing participants' ability to quickly and easily find specific information in each section of the IMP (PL) and their ability to correctly understand this information; the questionnaire should focus primarily on the safety and correct use of the medicinal product, as well as participants' understanding of the information on ensuring safe use; i.e., key safety issues should be addressed);
- Design and layout of the IMP (PL);
Is the number of questions sufficient? (Too few or too many, e.g., 12-15);
Do the questions address aspects of "presentation"; can respondents easily understand the content of the text they are reading?
Do the questions require an expanded or predetermined answer? When interviewing respondents, avoid closed questions with obvious answers, as this increases the likelihood of positive results. Use open-ended, non-leading questions, randomly ordered, to demonstrate patients' use of the IMP (DI). Avoid questions that require self-assessment (e.g., "In your opinion," "Is paragraph X clear?"). Use questions that require detailed responses (e.g., "What are the adverse reactions associated with this medication?").
Is the time allocated to answer questions acceptable? Yes No
Comments (additional) information _____________________
Guidelines for Time Aspects
When evaluating time aspects, consider the following:
Is the duration of the test clear?
Is the time allocated to respondents to answer questions adequate? How long did the interview last? [To avoid participant fatigue, the test should be designed so that its duration does not exceed 45 minutes.]
Testing rounds, including the pilot round _________________
Guidelines for Procedural Aspects
When evaluating procedural aspects, consider the following:
Is the test structured in different rounds? (At least two rounds of 10 participants each are required. Because this is an interactive process, more rounds may be required to meet success criteria. A pilot test (with 3-6 participants) can be conducted to ensure the questions are understandable and key inconsistencies are addressed before testing. After making changes to the IMP (LV), a pilot test with 10 participants is required. However, in some cases, a single round of testing may also be considered sufficient and acceptable.)
A satisfactory test result for the method described above is when 90% of literate adults can find the requested information in the IMP (LV), and 90% of them can demonstrate understanding of this information, i.e., at least 81% of participants answer each question correctly.
Are revision stages used between testing rounds to ensure maximum readability?
Do interviewers use scripts or live demonstrations (e.g., to enhance testing efficiency, if appropriate)?
Guidelines for Interview Aspects
When evaluating interview aspects, consider the following:
Were the test instructor(s) given clear instructions (e.g., regarding how to obtain more information from consumer testing, whether or not it is acceptable to assist them, etc.)?
Do the interviewers allow respondents to show them where the necessary information about the medication can be found in the package insert?
Do they ask respondents to provide answers in their own words, rather than relying on memory?
2. Scoring Responses
Rules for the scoring system
When evaluating the scoring system, it is important to consider whether respondents were able to:
-> find information (e.g., the respondent can easily find information about dosage);
-> understand the information (e.g., the respondent can explain in their own words what the correct dosage should be and how to take the medication);
-> apply the information (e.g., "imagine you were in situation X and Y happened, what should you do?").
Rules for the question rating system
When evaluating the question rating system, it is important to consider the following:
How responses are scored. For example: 1 = no answer, 2 = incorrect answer, 3 = incomplete answer, 4 = ambiguous answer, 5 = complete and correct answer.
Are the data properly recorded and documented? Yes No
Data Processing Rules
When assessing data processing, the following points should be considered:
is the data recorded clearly;
is the data recording method satisfactory;
is the data processed satisfactorily (e.g., is it clear how verbal assessments are transformed into different response categories?)
has the evaluator been provided with the package inserts used during the patient testing (various rounds of testing);
changes in the IMP (PL) are explained (justified). Is it clear which of the test participants' comments were ignored and why.
Does each question generally meet the criterion of 81% correct answers? Yes No
4.2. Layout and design assessment
Are the general design principles specified in the appendix to the Requirements for the Instructions for Medical Use of the Medicinal Product and the General Characteristics of the Medicinal Product for Medical Use met? Yes No
Is the use of diagrams acceptable? Yes No
Quality Aspect Guidelines
When assessing quality aspects, the following points should be considered:
is the report complete?
does the report clearly distinguish between quantitative and qualitative results?
are the names of the medicinal product and the corresponding company clearly stated?
based on Union rules, were the "diagnostic" questions (see section 1.2) rated satisfactorily?
do respondents consider the layout and design of the package insert satisfactory?
Particular attention should be paid to the following points:
writing style (simplicity of language, conciseness of sentences, use of subparagraphs);
font style (font size, use of italics, underlining, lowercase and uppercase letters);
layout (spacing, white space, contrast, left-aligned text, columns);
headings (uniform placement, emphasis);
use of color (current, adequate contrast).
User testing of pictograms is necessary, as patients are known to have difficulty navigating them. Do respondents experience difficulty finding and correctly applying (if applicable) the information provided in the IMP (LP)?
5. Quality of Assessment/Evaluation
Were any weaknesses identified in the IMP (LP)? Yes No
Have weaknesses been adequately addressed? Yes No
Comments (Additional) Information _____________________
Guidelines for Quality of Assessment (Evaluation)
When assessing aspects of the quality of assessment (evaluation), consider the following:
Are the results (as far as possible) related to the actual parts of the text?
Was an attempt made to explain that readers' problems arose from certain features inherent in these parts (e.g., something was difficult to find due to an unfortunate title; or a passage was unclear due to the use of double negatives; or specific information was difficult to apply correctly due to unclear meanings of some terms);
Was a revision performed after the second round? Were weaknesses from the first round clearly identified and adequately addressed (e.g., questions with low scores led to a change in the IMP (LP) and stylistic changes to improve readability or to eliminate redundant and confusing information);
- Is it clear which passages were revised, how this was done, and based on which observations from the first round?
Is it clear which observations were ignored during the revision process and why?
Did the tested changes actually improve readability?
CONCLUSION (SUMMARY) __________________________________________
______________________________________________________________
Testing Results Report Guidelines
This section should provide an overall opinion regarding the user testing conducted and the readability (quality) of the IMP (LP) [the full text of the user testing report may be attached for reference purposes for use in the final report].
When preparing the report, the following points should be considered:
Objectives:
to reflect the results of patient testing in the final IMP (LP) and address their needs to ensure safe and effective use of the medicinal product;
to assess the readability of the IMP (LP);
to identify problems related to the presentation and content of the information;
to describe possible changes to the package leaflet to improve its readability.
The report should clearly indicate the test results on which the conclusions are based.
It is necessary to analyze whether the test conclusions are consistent with the results or, given the actual results, paint an overly favorable picture.
It should be analyzed whether the conclusions are clearly, concisely, well, and structuredly presented. It should be noted whether the recommendations and opinions of patients were taken into account when revising the text of the package leaflet.
Appendix No. 17
(as amended by decisions of the Council of the Eurasian Economic Commission of January 30, 2020, No. 9, April 23, 2021, No. 34, and March 17, 2022, No. 36)
FORM OF REGISTRATION CERTIFICATE
FOR A MEDICINAL PRODUCT FOR MEDICINAL USE
EURASIAN ECONOMIC UNION
____________________________________________
Name of the authorized body
REGISTRATION CERTIFICATE
of a medicinal product for medical use
LP-N (XXXXXX)-(YY-ZZ)
-------------------------------------
(Registration certificate number)
In accordance with the Rules for Registration and Expertise of Medicinal
Products for Medical Use, this registration
certificate is issued by:
1 Name of the registration certificate holder:
2 Address of the registration certificate holder:
3 Date of registration:
4 Expiry date of the registration certificate:
5 Date of confirmation of registration (re-registration):
6 Date of amendments (re-issuance) to the registration certificate:
7 Date of registration in the reference state:
and confirms that the medicinal product is registered and approved for medical use in the territory of
(state - Member of the Eurasian Economic Union)
Information about the registered medicinal product
8 Trade name of the medicinal product:
9 International nonproprietary name (INN), or common (generic) name, or chemical name of the active pharmaceutical ingredient (if no INN):
10 Dosage form:
11 Dosage(s):
12 Release form(s):
12.1 Bulk product release form
13 Composition of the medicinal product:
14 Expiry date
Information about the manufacturer of the medicinal product (names and addresses of production sites involved in the medicinal product manufacturing process)
Production stage (all participants in the production process)
Name of the organization
Address of the production site
Production of the finished dosage form
Primary packaging
Secondary packaging
Release quality control
Appendix: on ____ p.
Head of the authorized body Signature MP
(or authorized person)
(Appendix form
to the registration certificate
for medical use)
Appendix No. ______
for medical use
No. ______________
Special conditions for registration of a medicinal product
Obligations of the holder of a registration certificate to be fulfilled within the framework of "registration under conditions"
Deadlines for fulfilling obligations and restrictions imposed on the holder of a registration certificate established during the registration of a medicinal product
Head of the authorized body Signature M.P.
RULES
for completing a registration certificate for a medicinal product for medical use
1. A registration certificate is a document confirming the registration of a medicinal product for medical use within the Eurasian Economic Union (hereinafter, respectively, the registration certificate or the Union). It is completed by the authorized body of the Union member state that registered the medicinal product for medical use within the Union, in accordance with these Rules (hereinafter, respectively, the authorized body or the Member State), using a uniform form.
2. The registration certificate is completed in Russian using electronic printing devices and, if required by the legislation of the Member States, in the official language of the Member State in which the authorized body issuing the document is located. If the said documents are prepared in Russian and the official language of one of the Member States, such documents are completed on double-sided forms, with each side corresponding to one of the languages.
The registration certificate is a strictly accountable document; the form must be printed and have security features in accordance with the legislation of the relevant Member State.
If necessary, the name of the manufacturer, its location (legal address), and the name and legal address of the registration certificate holder may be indicated (duplicated) using Latin letters.
3. The registration certificate number is formed in the following order:
LP-N (XXXXXX)-(YY-ZZ) where:
position "LP" - medicinal product;
position "N (XXXXXX)" - the unified six-digit serial number of the registration certificate assigned by the reference Member State (assigned automatically from the unified register of medicines registered within the Union);
position "YY" - the status of the Member State in the process of examination and registration of the medicinal product ("RG" - reference state; "RG" - recognition state);
Position "ZZ" is the two-letter code of the Member State (in accordance with the international standard ISO 3166-1-2013 "Codes for the representation of names of countries and their subdivisions. Part 1: Country codes": Republic of Armenia - AM; Republic of Belarus - BY; Republic of Kazakhstan - KZ; Kyrgyz Republic - KG; Russian Federation - RU).
4. Field 1 indicates the full name of the registration certificate holder.
5. Field 2 indicates the legal address of the registration certificate holder, including the country.
6. Field 3 indicates the registration date in the format DD.MM.YYYY, which is the date the authorized body makes the decision to register the medicinal product.
7. Field 4 indicates the expiration date of the registration certificate in the format DD.MM.YYYY, calculated from the date of registration of the medicinal product by the reference state. 8. Field 5 indicates the registration confirmation (re-registration) date in the DD.MM.YYYY format, calculated from the date of registration of the medicinal product by the reference state.
9. Field 6 indicates the date of amendments (renewal) to the registration certificate in the DD.MM.YYYY format.
10. Field 7 indicates the date of registration of the medicinal product in the reference state.
11. The subtable rows are completed with the name of the Member State in which the medicinal product is approved for medical use.
12. Field 8 indicates the trade name of the medicinal product in accordance with the requirements for the instructions for medical use of the medicinal product and the general characteristics of the medicinal product for medical use, approved by the Eurasian Economic Commission.
13. Field 9 indicates the international nonproprietary name of the active pharmaceutical ingredient (hereinafter referred to as INN). If the INN is unavailable, the generally accepted (grouping) names are used, and if these are unavailable, the names according to the IUPAC chemical nomenclature are used. For combination medicinal products, the corresponding generally accepted (grouping) name is used, which will be a listing of the INN and/or grouping names separated by the "+" sign in alphabetical order. If the pharmacological activity of one or more active components does not directly determine the pharmacological effect of the medicinal product, but is auxiliary, then the name of such component(s) is indicated in square brackets at the end of the generally accepted (grouping) name, regardless of alphabetical order. 14. Field 10 indicates the name of the dosage form, based on the Union Nomenclature of Dosage Forms. For kits (sets), indicate the name of the dosage form for each component of the kit (set).
15. Field 11 indicates the dosage of each unit of the dosage form. For combination drugs, the dosage of each component of the dosage form is indicated by a "+" sign in the order corresponding to the generally accepted (group) name. The dosage(s) indicated must match the information provided in the regulatory document on the quality of the drug.
16. Field 12 indicates the dosage form of the drug, indicating the type of primary and secondary packaging, the quantity of the dosage form (number of doses) in them, and the complete set. The instructions must match the information provided in the regulatory document on the quality of the drug.
16.1. Field 12.1, if necessary, indicates the form of release of the bulk product, indicating the type and volume (volume range) of the bulk product packaging.
(Clause 16.1 introduced by Decision of the Council of the Eurasian Economic Commission dated April 23, 2021, No. 34)
17. Field 13 indicates the composition of the medicinal product, indicating the quantitative content of active pharmaceutical ingredients and listing the qualitative composition of excipients. This information must match the information provided in the regulatory document on the quality of the medicinal product.
18. Field 14 indicates the expiration date of the medicinal product as a corresponding time interval, expressed verbally and numerically (1 year, 2 years, 3 years, etc.). The expiration date must match the information provided in the regulatory document on the quality of the medicinal product. 19. The table "Information on the manufacturer of the medicinal product (names and addresses of production sites involved in the medicinal product manufacturing process)" is completed with the actual addresses of each production site, in accordance with the information specified in Section 3.2.P.3 "Medicine Manufacturing Process" of the registration dossier.
The table must contain information on production sites throughout the medicinal product manufacturing cycle, including production sites involved in the production of solvents, diluents, and other participants in the manufacturing process that ensure the production of the finished medicinal product. Information on such production sites is entered in the appropriate fields under each stage of the manufacturing cycle.
Each field of the table indicates all process participants related to a given stage of the manufacturing cycle. If multiple production sites are involved in the manufacturing of a medicinal product at any stage of the manufacturing process, a number of rows corresponding to the number of participants in the manufacturing process are added to the table in the registration certificate form. 20. If there are special conditions for registration of a medicinal product, the appendix to the registration certificate includes a table titled "Special Conditions for Registration of a Medicinal Product" (completed in a separate appendix to the registration certificate). The left field of the table indicates restrictions on the use of the medicinal product, the center field indicates additional obligations that the registration certificate holder must fulfill, and the right field indicates the deadline for fulfilling the obligations and imposed restrictions in the format DD.MM.YYYY.
The appendix is an integral part of the registration certificate. Each page of the appendix must be numbered and contain the registration certificate number, position, signature, last name, first name, and patronymic of the head (authorized person) of the authorized body that issued the registration certificate. Each page must be certified by the authorized body's seal.
21. The "Head of Authorized Body, Signature, Seal" field must be completed in person; a facsimile signature is not permitted.
Appendix No. 18
dated January 30, 2020 No. 9, dated May 22, 2023 No. 60)
FORM OF COMMENTS FROM THE RECOGNITION STATE
Comments from the recognition state
Procedure type Mutual recognition procedure
decentralized procedure
1. Day
2. Comments from
Application No.
Name of medicinal product
Active pharmaceutical ingredient(s)
Dosage(s) or concentration(s)
Applicant (applicant's representative)
<Member State of the Union>
-------------------------- in accordance with the general conclusion of the reference
<applicant to
States and is prepared to issue a registration certificate for the -------------
registration of the medicinal product>.
or:
------------------------- believes that the use of this drug
is associated with a serious potential risk to public health (see
below), and is not currently prepared to issue a registration certificate.
2. Serious potential risk to public health
2.1. General characteristics of the medicinal product, instructions for medical use (package insert), and labeling
Detailed objections with justifications and cross-references to pages of the registration dossier, regulatory documents, scientific guidelines, publications, and expert opinions attached to the form
2.2. Module 3. "Quality"
2.3. Module 4. "Preclinical Studies"
2.4. Module 5. "Clinical Trials"
Detailed objections with justifications and cross-references to pages of the registration dossier, regulatory documents, scientific guidelines, publications, and expert opinions attached to the form.
3. Comments for the response.
3.1. Module 1. "Comments related to the application, general characteristics of the medicinal product, instructions for medical use (package leaflet), and labeling (including the name of the drug)"
<1>
List the comments for the response, dividing them into groups: critical comments and minor comments.
3.2. Module 3. "Quality"
3.3. Module 4. "Preclinical Studies"
3.4. Module 5. "Clinical Trials"
Please provide a list of comments for your response, dividing them into groups: critical comments and minor comments.
4. Information for the Applicant
Attention! Any responses sent by email must be sent to our general email address @, not to any personal
addresses. The maximum email size is 2 MB.
You must also send a hard copy to the following address:
<address> <2>.
Name of Project Manager Contact Person in Member State Figure (not provided)
Figure (not provided)
Name of Assessors (if applicable):
Quality (Module 3):
Figure (not provided) Clinical Trials (Module 5): Pharmacokinetics
Preclinical Studies
(Module 4): Efficacy and Safety
Figure (not shown)
<1> Please note that for applications submitted for generic and biosimilar medicinal products, where the reference product is a product authorized for marketing in the Union, it is important to submit comments regarding the product name at the earliest possible stage.
<2> Will be entered in accordance with the requirements of each Union Member State.
Appendix No. 19
RULES FOR AMENDING THE REGISTRATION DOSSIER
OF A REGISTERED MEDICINAL PRODUCT
FOR MEDICINAL USE
of January 30, 2020, No. 9, March 17, 2022, No. 36, May 22, 2023, No. 60)
1.1. Subject and Scope
1.1.1. This Appendix establishes the procedure for amending the registration dossier (hereinafter referred to as amendments) of medicinal products for medical use registered in the Eurasian Economic Union (hereinafter referred to as the Union), in accordance with the Rules for Registration and Expertise of Medicinal Products for Medical Use (hereinafter referred to as the Rules for Registration of Medicinal Products) or undergoing the procedure of bringing them into conformity with the requirements of acts included in the law of the Union.
1.1.2. No longer in effect. - Decision of the Council of the Eurasian Economic Commission dated 17.03.2022 N 36.
1.1.3. Section II of this Appendix shall apply to changes in the conditions of registration of medicinal products (hereinafter referred to as registration conditions), carried out in accordance with Sections V.II and VI of the Rules for Registration of Medicinal Products within the framework of the mutual recognition procedure and the decentralized registration procedure, as well as to changes in the conditions of registration of medicinal products registered in several Member States of the Union (hereinafter referred to as Member States) and that have undergone (are undergoing) the procedure of bringing them into conformity in accordance with Section XIII of the Rules for Registration of Medicinal Products.
1.1.4. Section III of this Appendix applies exclusively to changes in the registration conditions of medicinal products registered in one Member State (reference state) in accordance with Section V.I of the Rules for Registration of Medicinal Products, as well as to changes in the registration conditions of medicinal products registered in one Member State and that have undergone (are undergoing) the procedure for bringing them into compliance in accordance with Section XIII of the Rules for Registration of Medicinal Products.
1.1.5. Section IV of this Appendix applies to changes in the registration conditions specified in subparagraphs 1.1.3 and 1.1.4 of this Appendix.
1.1.6. The rules for conducting expert examination of a medicinal product when making changes to the registration dossier of a registered medicinal product for human use are provided in Appendix No. 20 to the Rules for Registration of Medicinal Products.
1.2. Definitions
For the purposes of this Appendix, the following terms are used:
"interested Member State" - the Member State whose authorized body has registered the medicinal product in question;
"significant change type II" - a change that, while not being a change requiring new registration, may have a significant impact on the quality, safety or efficacy of the registered medicinal product;
"Amendment requiring new registration" or "registration extension" - changes listed in Appendix I and satisfying the conditions described therein;
"Change in the registration conditions" of a medicinal product or "amendment to the registration dossier" means any change:
to the documents and data specified in Appendix No. 1 to the Rules for Registration and Expertise of Medicines;
to the conditions for making a decision on registration of a medicinal product for human use, including the general characteristics of the medicinal product and any conditions, obligations, or restrictions affecting the registration of the medicinal product or changes to the labeling or package leaflet due to a change in the general characteristics of the medicinal product;
"Minor Type IA Change" - a change that has minimal or no impact on the quality, safety, and efficacy of the registered medicinal product;
"Minor Type IB Change" - a change that does not fall under the definitions of Type IA, Type II changes, or registration extension;
"Urgent restriction for safety reasons" - an interim change to the registration conditions due to the emergence of new information related to the safe use of a medicinal product;
"relevant authority" - the authorized body (expert organization) of each interested Member State.
1.3. Classification of changes
1.3.1. The classification established in Appendix II applies to each amendment that is not an extension of the medicinal product's registration.
1.3.2. An amendment that is not an extension of the medicinal product's registration and whose classification cannot be determined using the provisions of this Appendix, taking into account the recommendations prepared in accordance with paragraph 1.5, is by default a Type IB amendment.
1.3.3. As an exception to subparagraph 1.3.2, an amendment that is not an extension of the medicinal product's registration and whose classification cannot be determined using the rules established by this Appendix is a Type II significant amendment in the following cases:
at the applicant's request when submitting an application for an amendment;
If the authorized body (expert organization) of the reference state, after consultation with the authorized bodies (expert organizations) of the recognition states, or the authorized body (expert organization) of the reference state in the case of registration of a medicinal product only in that Member State, after assessing the notification in accordance with subparagraphs 2.2.2 or 3.2.2, respectively, and taking into account the provisions of paragraph 1.5 of this Annex, decides that the change has a significant impact on the quality, safety, or efficacy of the registered medicinal product.
1.3.4. A detailed classification of changes is provided in Appendix V. Appendix VI provides a classification of changes to the registration dossier that may be made simultaneously with the submission of an application to bring the registration dossier into compliance with the requirements of the Union, as provided for in paragraph 172 of the Rules for Registration of Medicines.
1.4. Amendments
1.4.1. The Eurasian Economic Commission (hereinafter referred to as the Commission) is obliged to regularly update this Appendix in accordance with current scientific data.
1.5. Recommendations for Unclassified Variations
1.5.1. Before submitting an application for a variation not classified in this Appendix, the applicant has the right to request a recommendation on the classification of the variation from the authorized body (expert organization) of the reference state.
1.5.2. The recommendation referred to in subparagraph 1.5.1 must not contradict this Appendix. The authorized body (expert organization) of the reference state must, within 30 working days of receiving the request from the applicant, send the recommendation to the applicant, other Member States, and the Expert Committee on Medicinal Products (hereinafter referred to as the Expert Committee) in electronic and/or paper form. This period may be extended for an additional 30 working days if the authorized body (expert organization) of the reference state deems it necessary to consult with the Expert Committee.
(as amended by decisions of the Council of the Eurasian Economic Commission of 17.03.2022 No. 36, of 22.05.2023 No. 60)
1.5.3. Prior to the examination of a change not classified in this Appendix, the authorized body (expert organization) of the interested Member State has the right to request a recommendation from the Expert Committee regarding the classification of such change.
1.5.4. The recommendation referred to in subparagraph 1.5.3 must not contradict this Appendix. The Expert Committee must submit it within 30 working days of receiving the request from the interested authorized body (expert organization) and send it to the applicant and the relevant authorized bodies of the Member States. (as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
1.5.5. In order to ensure the consistency of recommendations prepared by authorized bodies (expert organizations) and the Expert Committee in accordance with subparagraphs 1.5.1 and 1.5.3, the Commission shall publish such recommendations on the official website on the Internet, after first removing all information of a confidential nature.
1.6. Changes Resulting in a Revision of Information
on the Medicinal Product
1.6.1. If a change results in a revision of the general characteristics of the medicinal product, the labeling or package leaflet, or a regulatory document on quality, or a change in information in the registration certificate of the medicinal product, such revision is considered part of that change.
1.7. Grouping of Changes
1.7.1. When notifying multiple changes or submitting multiple applications for changes in relation to each change in accordance with Section II of this Appendix or subparagraph 4.1.1, respectively, a separate notification or dossier for changes to the registration dossier of the registered medicinal product for human use (hereinafter, the change dossier) must be submitted.
1.7.2. As an exception to subparagraph 1.7.1 of this Appendix, the following rules shall apply:
in the case of a single notification of identical minor Type IA changes to the registration conditions of one or more medicinal products held by the same organization, all such changes may be included in a single notification (application) for amendments specified in paragraph 2.1 or paragraph 3.1 of this Appendix;
in the case of a single notification of several changes to the registration conditions of the same medicinal product, all such changes may be included in a single notification for amendments (with the relevant documents attached), if all the changes in question fall under one of the conditions listed in Appendix III;
In the case of a single notification of several changes to the registration conditions of the same medicinal product that do not fall under any of the conditions listed in Appendix III, all such changes may be included in a single notification (with the relevant documents attached) if the authorized body (expert organization) of the reference state, after consultation with the authorized bodies (expert organizations) of the interested recognition states (if necessary), gives consent to such notification.
1.7.3. The notification (with the relevant documents attached) specified in paragraphs three and four of subparagraph 1.7.2 of this Appendix shall be made as follows:
a single notification of changes in accordance with paragraph 2.2 of this Appendix, if at least one of the changes is a minor change of type IB and all the changes are minor;
a single application for changes in accordance with paragraph 2.3 of this Appendix, if at least one of the changes is a major change of type II and none of the changes is an extension of registration;
a single application for amendments in accordance with subparagraph 4.1.1 of this Appendix, if at least one of the amendments is an extension of the registration.
II. Amendments to the Registration Dossier
of Medicinal Products Registered in More Than One Member State
2.1. Notification Procedure for Type IA Minor Amendments
2.1.1. When making a minor Type IA change, the applicant shall simultaneously submit to all relevant authorized bodies (expert organizations) an application for the change on paper or as an electronic document signed with an electronic digital signature (electronic signature) in accordance with the legislation of the Member State in which such application is submitted (hereinafter referred to as the electronic signature), in accordance with Appendix No. 2 to the Rules for Registration of Medicines, as well as documents (or electronic documents) confirming payment of the fee (duty) for making the change in the cases and according to the procedure established in accordance with the legislation of the Member States.
The applicant shall submit to the authorized body (expert organization) of the reference state a change dossier (notification) containing the elements listed in Appendix IV. Such notification must be submitted within 365 calendar days (12 months) from the date of implementation of the change, with the exception of changes resulting in revisions to the medicinal product information in accordance with paragraph 1.6 of this Appendix, for which the corresponding application for amendment must be submitted before the change is implemented.
2.1.2. For minor changes requiring immediate notification, for the purposes of ongoing surveillance of the medicinal product in question, notification must be submitted immediately after the change is implemented.
2.1.3. The authorized body (expert organization) of the reference state, no later than 5 working days from the date of submission of the application for amendment, after assessing the completeness, completeness, and correctness of the submitted documents, provides the relevant authorities of the recognition states with access to the change dossier (notification) through the integrated system.
Within 20 working days from the date of receipt of the notification, the relevant authorities must take the measures specified in paragraph 2.4 of this Appendix.
If the changes lead to a revision of the information on the medicinal product in accordance with paragraph 1.6 of this Appendix, the relevant authorized bodies, within no more than 10 business days from the period specified in subparagraph 2.1.3, shall post information on the changes in the unified register of registered medicinal products of the Union (hereinafter referred to as the unified register) with the attached amended approved general characteristics of the medicinal product, instructions for medical use, packaging layouts, and regulatory document on quality, in accordance with the procedure for the formation and maintenance of the unified register, and shall also issue the amended general characteristics of the medicinal product, instructions for medical use, packaging layouts, regulatory document on quality, and registration certificate (if necessary) to the applicant.
The relevant authorized bodies (expert organizations) may extend the period specified in paragraphs one, two, and three of this clause to a total of 60 working days if the applicant submits multiple group amendments in accordance with subparagraphs 1.7.2 and 1.7.3 of this Appendix.
2.2. Notification Procedure for Minor Amendments of Type IB
2.2.1. The applicant shall simultaneously submit to all relevant authorized bodies (expert organizations) an application for amendments on paper or as an electronic document signed with an electronic signature, in accordance with Appendix No. 2 to the Rules for Registration of Medicines, as well as documents (or electronic documents) confirming payment of the fee (duty) for amendments in the cases and according to the procedure established in accordance with the legislation of the Member States. (as amended by the decision of the Council of the Eurasian Economic Commission of 17.03.2022 N 36)
The applicant shall submit to the authorized body (expert organization) of the reference state an amendment dossier (notification) containing the elements listed in Appendix IV.
2.2.2. The authorized body (expert organization) of the reference state, no later than 5 working days from the date of filing the application for amendments, after assessing the completeness, completeness, and correctness of the submitted documents, shall provide the relevant authorities of the recognition states with access to the amendment dossier (notification) using the tools of the Integrated Information System for Foreign and Mutual Trade of the Union (hereinafter referred to as the Integrated System).
If the notification meets the requirements set forth in subparagraph 2.2.1 of this Appendix, the authorized body (expert organization) of the reference state shall acknowledge receipt of a valid notification within 20 working days, having consulted with the relevant authorities of the recognition states, if necessary.
2.2.3. If, within 20 business days of receipt of the notification, the authorized body (expert organization) of the reference state does not send the applicant, in electronic or paper form, a conclusion on the impossibility of accepting the notification and making this change to the registration dossier, the notification is deemed accepted (approved) by all relevant authorities.
2.2.4. If the authorized body (expert organization) of the reference state makes a positive decision to approve (accept) the notification, then the authorized body (expert organization) of the reference state shall take the measures specified in paragraph 2.4 of this Appendix.
If changes lead to a revision of information on the medicinal product in accordance with paragraph 1.6 of this Appendix, the relevant authorized bodies (expert organizations), within no more than 10 business days from the period specified in subparagraph 2.2.3, shall post information on the changes in the unified register, along with the amended approved general characteristics of the medicinal product, instructions for medical use, packaging layouts, and quality regulatory document, in accordance with the procedure for forming and maintaining the unified register, and shall also issue the amended general characteristics of the medicinal product, instructions for medical use, packaging layouts, quality regulatory document, and registration certificate (if necessary) to the applicant.
The relevant authorized bodies (expert organizations) shall have the right to extend the period specified in subparagraphs 2.2.3 - 2.2.4 to a total of 60 business days if the applicant has submitted multiple group changes in accordance with subparagraphs 1.7.2 and 1.7.3 of this Appendix.
2.2.5. If, according to the conclusion of the authorized body (expert organization) of the reference state, the applicant's notification of amendments cannot be accepted (approved), the authorized body (expert organization) of the reference state must notify the applicant and the relevant authorities of the recognition states thereof in electronic or paper form within the timeframe specified in subparagraph 2.2.3 of this Appendix, indicating the grounds for the negative conclusion.
2.2.6. Within 20 business days from the date of receipt of the negative conclusion, the applicant has the right to resubmit to the authorized body (expert organization) of the reference state an amended change dossier (notification) in accordance with the conclusion specified in subparagraph 2.2.5 of this Appendix.
The authorized body (expert organization) of the reference state, no later than 5 business days from the date of submission of the supplemented notification to the reference state, after assessing the completeness and adequacy of the submitted materials, submits the supplemented dossier for amendments (notification) to the relevant authorities of the recognition states using the integrated system.
2.2.7. If the applicant fails to submit an amended notification in accordance with subparagraph 2.2.6 of this Appendix, the notification is deemed rejected by all authorized bodies (expert organizations), and the measures specified in paragraph 2.4 of this Appendix will be taken.
2.2.8. When submitting an amended notification, the authorized body (expert organization) of the reference state must review the newly submitted documents and data within no more than 20 business days from the date of receipt, after which the measures specified in subparagraph 2.2.4 of this Appendix will be taken.
If the changes lead to a revision of the information on the medicinal product in accordance with paragraph 1.6 of this Appendix, the relevant authorized bodies (expert organizations), within no more than 10 business days from the period specified in subparagraph 2.2.8, shall post information on the changes in the unified register, along with the amended approved general characteristics of the medicinal product, instructions for medical use, packaging layouts, and regulatory document on quality, in accordance with the procedure for the formation and maintenance of the unified register, and shall also issue the amended general characteristics of the medicinal product, instructions for medical use, packaging layouts, regulatory document on quality, and registration certificate (if necessary) to the applicant.
The relevant authorized bodies (expert organizations) have the right to extend the period specified in paragraphs one and two of this clause to a total of 60 business days if the applicant submits multiple group amendments in accordance with subparagraphs 1.7.2 and 1.7.3 of this Appendix.
2.2.9. The provisions of subparagraphs 2.2.1–2.2.8 of this Appendix shall not apply if the request for a Type IB amendment is submitted as part of a group of amendments that includes a Type II amendment and does not contain a registration extension. In this case, the amendment examination procedure provided for in paragraph 2.3 of this Appendix shall apply.
2.2.10. The provisions of subparagraphs 2.2.1–2.2.8 of this Appendix shall not apply if the request for a Type IB amendment is submitted as part of a group of amendments that includes a registration extension. In this case, the procedure provided for in subparagraph 4.1.1 of this Appendix applies.
2.3. Procedure for Examination of Type II Significant Changes
2.3.1. The applicant shall simultaneously submit to all relevant authorized bodies (expert organizations) an application for amendments on paper or as an electronic document signed with an electronic signature, in accordance with Appendix No. 2 to the Rules for Registration of Medicines, as well as documents (or electronic documents) confirming payment of the fee (duty) for amendments in the cases and according to the procedure established by the legislation of the Member States.
The applicant shall submit to the authorized body (expert organization) of the reference state a dossier for the amendment (notification) containing the elements listed in Appendix IV.
If necessary and in agreement with the expert organization, the applicant shall submit to the authorized body (expert organization) of the reference state samples of medicinal products, standard samples of active pharmaceutical ingredients and related impurities, specific reagents, and other materials necessary for laboratory testing.
Samples, specific reagents, and other materials are not required if testing cannot be conducted by the expert organization due to:
the inaccessibility of medicinal product samples, standard samples, specific reagents, and other materials (including when they are classified as orphan, high-tech, radiopharmaceutical, narcotic, psychotropic, or intended for the treatment of high-cost nosologies due to their high cost);
the impossibility of complying with the conditions for transporting the said samples to the territory of a Member State and/or storing them;
the lack of specialized equipment and consumables in the expert organization;
and other reasons, as decided by the authorized body (expert organization), in the event of force majeure or circumstances beyond the control of the parties, including those related to the specifics of the production and quality control of the medicinal product.
In the cases specified above, laboratory tests are conducted in the quality control laboratory of the medicinal product manufacturer in the presence of representatives of the expert organization or in a contract laboratory used by the manufacturer in the presence of representatives of the expert organization.
In cases where it is impossible to conduct laboratory tests in the manufacturer's laboratories or contract laboratories used by the manufacturer (under conditions of the threat of occurrence, occurrence and elimination of an emergency situation and (or) in the event of a threat of the spread of a disease posing a danger to others, diseases and injuries resulting from exposure to unfavorable natural, chemical, biological, radiation factors), in which the presence of a representative of an expert organization is not possible, or in other circumstances (for example, related to the specifics of the production and quality control of a specific medicinal product of the categories specified above), in agreement with the authorized body (expert organization), a quality examination is carried out on the basis of the manufacturer's documentation (manufacturer's analysis protocols), including using remote interaction tools, including audio or video communication.
2.3.2. The applicant is given no more than 90 working days, not included in the period of examination of the medicinal product and the procedure Amendments, to submit missing dossier materials based on comments from the authorized body (expert organization) of the reference state.
The authorized body (expert organization) of the reference state shall reject an application to amend the registration dossier of a medicinal product if materials are not submitted based on comments from the authorized body (expert organization) of the reference state and/or if payment of the fee (duty) for amending the registration dossier is not confirmed in the cases and according to the procedure established by the legislation of the reference state.
The authorized body (expert organization) of the reference state, no later than 14 business days from the date of submission of the application to amend the registration dossier to the reference state, after assessing the completeness, completeness, and correctness of the submitted documents in accordance with subparagraph 2.3.1 of this Appendix, shall provide the relevant authorities of the recognition states with access to the amendment dossier using the integrated system.
When If necessary, written consultations between the authorized bodies (expert organizations) of the reference state and the states of recognition shall be carried out electronically using the integrated system.
2.3.3. Within 40 working days from the date of receipt of the application for amendments, the authorized body (expert organization) of the reference state must prepare a draft expert assessment report and a draft decision on the application for amendments, which must be sent to the relevant bodies of the states of recognition within the specified time frame in paper and/or electronic form.
(as amended by Decision of the Council of the Eurasian Economic Commission of 17.03.2022 N 36)
2.3.4. The authorized body (expert organization) of the reference state has the right to shorten the period specified in subparagraph 2.3.3 of this Appendix, taking into account the urgency of the matter, or extend it to 60 working days for amendments consisting of modifications of approved indications for use or the inclusion of new indications for use, or a group of amendments
2.3.5. Within the period specified in subparagraphs 2.3.3 and 2.3.4, the authorized body (expert organization) of the reference state has the right to send the applicant a written and/or electronic request for missing additional information, necessary clarifications, or refinements to the submitted documents and data in the registration dossier (including proposals for amendments to the general characteristics of the medicinal product, instructions for medical use, medicinal product packaging layouts, quality regulatory documentation, or other documents in the registration dossier).
The authorized body (expert organization) of the reference state sends a copy of the applicant's requests to the relevant authorities of the recognition states, using the form set out in Appendices Nos. 6–8 to the Rules for Registration and Examination of Medicines.
The applicant's response to this request must not exceed 90 business days.
The time required for the applicant to submit documents requested by the authorized body or expert organization is not included in the timeframe for the examination and amendment procedure.
If the applicant fails to submit the requested documents and data within the specified timeframe, the examination and amendment procedure are terminated. The authorized body (expert organization) of the reference state notifies the applicant and the relevant authorities of the recognition states of the decision made within 10 business days of the decision being made, in written and electronic form.
2.3.6. Without limiting the provisions of paragraph 2.6 of this Appendix, and within 20 business days of receiving the draft expert assessment report and the draft decision specified in subparagraphs 2.3.3 and 2.3.4 of this Appendix, the authorized bodies (expert organizations) of the recognizing states shall make a decision on the recognition or non-recognition of the expert assessment report prepared by the expert organization of the reference state and shall notify the authorized body (expert organization) of the reference state accordingly.
No later than 15 business days after receiving access to the draft assessment report, the authorized body (expert organization) of the recognizing state shall, if necessary, send a request to the applicant and to the authorized body (expert organization) of the reference state in the form set out in Appendix No. 18 to the Rules for the Registration and Examination of Medicines.
The applicant shall submit a response to the request to the authorized body (expert organization) of the recognition and reference states within a period not exceeding 90 business days. The applicant's response time is not included in the overall timeframe for the examination and amendment procedure for the medicinal product's registration dossier.
If the applicant fails to submit the documents and data requested by the authorized body (expert organization) of the recognition state within the specified timeframe, the examination and amendment procedure in that recognition state shall be terminated.
The applicant shall be notified of the authorized body's (expert organization's) decision within 10 business days of the decision's adoption, in both electronic and paper form.
2.3.7. If, within the period specified in the first paragraph of subparagraph 2.3.6, the authorized body (expert organization) of the recognizing states does not submit a conclusion on the impossibility of recognizing the expert assessment report prepared by the expert organization of the reference state, then the decision shall be considered as adopted by such authorized body (expert organization).
2.3.8. If, in accordance with subparagraphs 2.3.6 and 2.3.7 of this Appendix, the decision referred to in subparagraph 2.3.7 of this Appendix is recognized by all authorized bodies, the measures specified in paragraph 2.4 of this Appendix shall be taken.
In the event that the changes lead to a revision of information on the medicinal product in accordance with paragraph 1.6 of this Appendix, the authorized bodies, within 10 working days from the adoption of the decision to approve the change, post information on the changes in the unified register with the attachment of the amended approved general characteristics of the medicinal product, instructions for medical use, packaging layouts, and regulatory document on quality, in accordance with the procedure for the formation and maintenance of the unified register, and also issue the amended general characteristics of the medicinal product, instructions for medical use, packaging layouts, regulatory document on quality, and registration certificate (if necessary) to the applicant.
Authorized bodies may extend the period specified in the first paragraph of this clause to 20 business days if the applicant submits group amendments in accordance with clauses 1.7.2 and 1.7.3 of this Appendix.
2.3.9. This section does not apply if a request for a Type II amendment is submitted as part of a group of amendments that includes an extension of the registration of a medicinal product. In this case, the procedure provided for in subclause 4.1.1 applies.
2.4. Measures Required to Complete the Procedures
Provided for in Clauses 2.3 - 2.5 of this Appendix
2.4.1. When referring to this clause, the authorized body (expert organization) of the reference state must take the following measures:
notify the applicant and the relevant authorities of the recognition states of approval or rejection of the amendment;
If a change is rejected, notify the applicant and the relevant authorities of the States of recognition of the grounds for such decision;
notify the applicant and the relevant authorities of the States of recognition of the need to amend the conditions for the decision to register the medicinal product, including the general characteristics of the medicinal product and any conditions, obligations, or restrictions affecting the registration of the medicinal product or changes to the labeling or package leaflet resulting from the change in the general characteristics of the medicinal product, in connection with the amendment.
2.4.2. When referring to this paragraph, each authorized body, if necessary and within the deadline established by subparagraph 4.2.1 of this Appendix (except for amendments resulting in a revision of the information on the medicinal product in accordance with paragraph 1.6 of this Appendix), shall amend the registration decision in accordance with the adopted amendment.
2.5. Review by the Expert Committee
2.5.1. If the authorized bodies of one or more recognition states submit a conclusion regarding the impossibility of recognizing an expert assessment report prepared by an expert organization of the reference state, in accordance with subparagraph 4.1.2.9 and subparagraphs 2.3.6 - 2.3.7 of this Appendix, the Expert Committee shall, within a period not exceeding 60 calendar days from the date of submission of such conclusion by the authorized bodies of the recognition states, carry out a dispute resolution procedure in accordance with the procedure established by the Commission's decision.
2.5.2. The authorized body of the reference state and the relevant recognition states shall refuse to amend the registration dossier if, based on the results of the expert examination of the medicinal product and following the dispute resolution procedure in the Expert Committee, the Expert Committee has adopted a recommendation to refuse to amend the registration dossier of the medicinal product.
III. Amendments to the Registration Dossier of Medicinal Products Registered
under the National Procedure (only in the Reference State)
3.1. Procedure for Notifying Minor Changes
Type IA
3.1.1. The applicant shall simultaneously submit to all relevant authorities (expert organizations) an application for amendments on paper or as an electronic document signed with an electronic signature, in accordance with Appendix No. 2 to the Rules for Registration of Medicines, as well as documents (or electronic documents) confirming payment of the fee (duty) for amendments in the cases and according to the procedure established by the legislation of the Member States. Such notification must be submitted within 365 calendar days (12 months) after the amendment is implemented, with the exception of changes resulting in a revision of information on the medicinal product, in accordance with paragraph 1.6 of this Appendix, for which the corresponding application for amendments must be submitted before the amendment is implemented.
3.1.2. For minor changes requiring immediate notification, notification must be submitted immediately after the change is implemented for the purposes of ongoing surveillance of the medicinal product in question.
3.1.3. Within 20 working days from the date of receipt of the notification, the authorized body (expert organization) of the reference state shall take the measures specified in Section 3.5 of this Appendix.
If the changes lead to a revision of the information on the medicinal product in accordance with Section 1.6 of this Appendix, the authorized body of the reference state, within 10 working days from the deadline specified in subparagraph 3.1.3, shall post information on the changes in the unified register, along with the amended approved general characteristics of the medicinal product, instructions for medical use, packaging layouts, and regulatory document on quality in accordance with the procedure for the formation and maintenance of the unified register, and shall also issue the amended general characteristics of the medicinal product, instructions for medical use, packaging layouts, regulatory document on quality, and registration certificate (if necessary) to the applicant.
The authorized body (expert organization) of the reference state may extend the period specified in paragraphs one and two of this subparagraph to a total of 60 working days if the applicant submits multiple group amendments in accordance with paragraphs 1.7.2 and 1.7.3 of this Appendix.
3.2. Notification Procedure for Minor Amendments of Type IB
3.2.1. The applicant shall simultaneously submit to all relevant bodies (expert organizations) an application for amendments on paper or as an electronic document signed with an electronic signature, in accordance with Appendix No. 2 to the Rules for Registration of Medicines, as well as documents (or electronic documents) confirming payment of the fee (duty) for amendments in the cases and according to the procedure established in accordance with the legislation of the Member States.
(Clause 3.2.1 as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
3.2.2. The authorized body (expert organization) of the reference state shall, no later than 5 business days from the date of filing the application for amendments, assess the completeness, completeness, and correctness of the submitted documents in accordance with Subclause 3.2.1 of this Appendix.
If the notification meets the requirements set forth in Clause 3.2.1 of this Appendix, the authorized body (expert organization) of the reference state shall confirm receipt of a valid notification within the following 20 business days.
3.2.3. If, within 20 business days of receiving the notification, the authorized body (expert organization) does not send the applicant, in electronic or paper form, a conclusion regarding the impossibility of accepting the notification and making this change to the registration dossier, the conclusion shall be deemed accepted (approved) by the authorized body.
3.2.4. If the authorized body (expert organization) of the reference state makes a positive decision to approve the notification, then the authorized body (expert organization) of the reference state shall take the measures specified in paragraph 3.5 of this Appendix.
If the changes lead to a revision of the information on the medicinal product in accordance with paragraph 1.6 of this Appendix, the authorized body of the reference state, within 10 working days from the period specified in subparagraph 3.2.3 of this Appendix, shall post information on the changes in the unified register with the attached amended general characteristics of the medicinal product, instructions for medical use, packaging layouts, and regulatory document on quality in accordance with the procedure for the formation and maintenance of the unified register, and shall also issue the amended general characteristics of the medicinal product, instructions for medical use, packaging layouts, regulatory document on quality, and registration certificate (if necessary) to the applicant.
The authorized body (expert organization) of the reference state has the right to extend the period specified in subparagraphs 3.2.3 and 3.2.4 of this Appendix for up to 60 business days in total if the applicant submits multiple group amendments in accordance with subparagraphs 1.7.2 and 1.7.3 of this Appendix.
3.2.5. If, according to the conclusion of the authorized body (expert organization) of the reference state, the applicant's notification of amendments cannot be approved, the authorized body (expert organization) of the reference state shall notify the applicant thereof electronically or in paper form within the timeframe specified in subparagraph 3.2.3 of this Appendix, indicating the grounds for the negative conclusion.
3.2.6. Within 20 business days from the date of receipt of the negative conclusion, the applicant has the right to resubmit to the authorized body (expert organization) of the reference state an amended dossier on the amendment in accordance with the conclusion specified in subparagraph 3.2.5 of this Appendix.
3.2.7. If the applicant fails to submit an amended notification in accordance with paragraph 3.2.6 of this Appendix, the notification shall be deemed rejected.
3.2.8. When submitting an amended notification, the authorized body (expert organization) of the reference state shall review the newly submitted documents and data within no more than 20 business days from the date of its receipt, after which the measures specified in paragraph 3.5 of this Appendix shall be taken.
3.2.9. This paragraph shall not apply if the request for a Type IB change is submitted as part of a group of changes that includes a Type II change and does not contain a registration extension. In this case, the amendment review procedure provided for in paragraph 3.3 of this Appendix shall apply.
3.2.10. This paragraph shall not apply if the request for a Type IB change is submitted as part of a group of changes that includes a registration extension. In this case, the procedure provided for in subparagraph 4.1.1 of this Appendix shall apply.
3.3. Procedure for Review of Significant Type II Changes
3.3.1. The applicant shall submit to the authorized body (expert organization) of the reference state an application for amendments on paper or as an electronic document signed with an electronic signature, in accordance with Appendix No. 2 to the Rules for Registration of Medicines, documents (or electronic documents) confirming payment of the fee (duty) for amendments in the cases and according to the procedure established in accordance with the legislation of the member state, and a dossier on the amendment containing the elements specified in Appendix IV of Appendix No. 19 to the Rules for Registration of Medicines, in the form of electronic documents.
Samples, specific reagents, and other materials need not be provided if testing cannot be conducted at an expert organization due to:
the difficulty of accessing samples of medicinal products, standard samples, specific reagents, and other materials (including when they are classified as orphan, high-tech, radiopharmaceutical, narcotic, psychotropic, or intended for the treatment of high-cost nosologies due to their high cost);
(paragraph introduced by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022; as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated 22.05.2023)
the impossibility of complying with the conditions for transporting the specified samples to the territory of a Member State and/or storing them;
and other reasons determined by the authorized body (expert organization) in the event of force majeure or circumstances beyond the control of the parties, including those related to the specifics of the production and quality control of the medicinal product.
In the cases specified above, laboratory testing is conducted in the quality control laboratory of the medicinal product manufacturer in the presence of representatives of the expert organization or in a contract laboratory used by the manufacturer in the presence of representatives of the expert organization.
In cases where it is impossible to conduct laboratory tests in the manufacturer's laboratories or contract laboratories used by the manufacturer (due to the threat of an emergency, the occurrence and elimination of an emergency, and/or the threat of the spread of a disease posing a danger to others, diseases and injuries resulting from exposure to unfavorable natural, chemical, biological, or radiation factors), in which the presence of a representative of an expert organization is not possible, or in other circumstances (e.g., related to the specifics of the production and quality control of a specific medicinal product of the categories specified above, in agreement with the authorized body (expert organization)) the quality assessment is conducted based on the manufacturer's documentation (manufacturer's analysis protocols), including through the use of remote interaction tools, including audio or video communication.
3.3.2. The authorized body (expert organization) of the reference state shall, no later than 14 business days from the date of submission of the application for amendments to the reference state, assess the completeness, completeness, and correctness of the submitted documents in accordance with subparagraph 3.3.1 of this Appendix.
If the application meets the requirements set forth in subparagraph 3.3.1 of this Appendix, the authorized body (expert organization) shall acknowledge receipt of a valid application.
The applicant shall be given no more than 90 business days, outside the timeframe for the medicinal product review and amendment procedure, to submit missing dossier materials based on the comments of the authorized body (expert organization) of the reference state. (as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
The authorized body (expert organization) of the reference state shall reject an application for amendments to the registration dossier of a medicinal product in the event of failure to submit materials responding to the comments of the authorized body (expert organization) of the reference state and/or failure to confirm payment of the fee (duty) for amendments in the cases and according to the procedure established by the legislation of the reference state.
3.3.3. Within no more than 40 business days from the date of receipt of a valid application for amendments specified in subparagraph 3.3.1 of this Appendix, the authorized body (expert organization) must complete the examination of the medicinal product and prepare an expert assessment report.
3.3.4. The authorized body (expert organization) has the right to shorten the period specified in subparagraph 3.3.3 of this Appendix, taking into account the urgency of the matter, or extend it to 60 business days for changes consisting of modifications to the approved indications for use or the inclusion of new indications for use, or a group of changes in accordance with the third paragraph of subparagraph 3.4.2 of this Appendix.
3.3.5. For changes listed in Section 2 of Appendix I, the examination period specified in subparagraph 3.3.3 of this Appendix shall not exceed 60 business days.
3.3.6. Within the period specified in subparagraphs 3.3.3 - 3.3.5 of this Appendix, the authorized body (expert organization) has the right to send the applicant a written and/or electronic request for missing additional information, necessary clarifications, or amendments to the submitted documents and data in the registration dossier (including proposals for amendments to the general characteristics of the medicinal product, instructions for medical use, medicinal product packaging layouts, quality regulatory documents, or other documents in the registration dossier).
The applicant's response to this request must be submitted within 90 business days.
The time required for the applicant to submit documents at the request of the authorized body or expert organization is not included in the timeframe for the examination and amendment procedure.
If the applicant fails to submit the requested documents and data within the specified timeframe, the review and amendment process will be terminated. The authorized body (expert organization) of the reference state will notify the applicant of the decision made within 10 business days of the decision, in writing and electronically.
3.3.7. Within 10 business days of the completion of the review, the measures specified in paragraph 3.5 of this Appendix will be taken.
If the changes lead to a revision of the information on the medicinal product in accordance with paragraph 1.6 of this Appendix, the authorized body of the reference state, within 10 business days from the date of completion of the examination, shall post information on the changes in the unified register, along with the amended approved general characteristics of the medicinal product, instructions for medical use, packaging mock-ups, and quality regulatory document, in accordance with the procedure for forming and maintaining the unified register, and shall also issue the amended general characteristics of the medicinal product, instructions for medical use, packaging mock-ups, quality regulatory document, and registration certificate (if necessary) to the applicant.
The authorized body shall have the right to extend the period specified in the second paragraph of this subparagraph to 20 business days if the applicant submits group changes in accordance with subparagraphs 1.7.2 and 1.7.3 of this Appendix.
3.3.8. This section does not apply if a Type II change request is submitted as part of a group of changes that includes an extension of the registration of a medicinal product. In this case, the procedure provided in subparagraph 4.1.1 applies.
3.4. Grouping of changes made to registration dossiers of medicinal products registered exclusively in the reference state.
3.4.1. When notifying of multiple changes or submitting multiple applications for changes, a separate notification or change dossier must be submitted for each change in accordance with paragraphs 3.1, 3.2, and 3.3 of this Appendix or subparagraph 4.1.1 of this Appendix.
3.4.2. As an exception to paragraph 3.4.1 of this Appendix, the following applies:
in the case of a single notification to the same authorized body (expert organization) of identical minor changes to the Type IA conditions of registration of one or more medicinal products held by a single organization, all such changes may be included in a single application for amendments and notification specified in paragraph 3.1 of this Appendix;
In the event of a single notification to the same authorized body (expert organization) of several changes to the registration conditions of the same medicinal product, all such changes may be included in a single change dossier, if all the changes in question meet one of the conditions listed in Appendix III;
In the event of a single notification to the same authorized body (expert organization) of changes to the registration conditions of the same medicinal product, held by a single organization, that do not meet the conditions listed in this subparagraph, all such changes may be included in a single change dossier, with the consent of the authorized body (expert organization).
3.4.3. Submission of documents in accordance with paragraphs two and three of subparagraph 3.4.2 of this Appendix shall be carried out as follows:
a single notification (change dossier) in accordance with paragraph 3.2 of this Appendix, if at least one of the changes is a Type IB minor change and all changes are minor;
A single application for amendments in accordance with paragraph 3.3 of this Appendix, if at least one of the amendments is a Type II Major Amendment and none of the amendments is a registration extension;
A single application for amendments in accordance with subparagraph 4.1.1 of this Appendix, if at least one of the amendments is a registration extension.
3.5. Measures Required to Complete the Procedures
Provided for in Paragraphs 3.1 - 3.3 of this Appendix
3.5.1. When referring to this section, the authorized body (expert organization) of the reference state must take the following measures:
notify the applicant of acceptance (approval) or refusal to approve the amendment;
if approval of the amendment is refused, notify the applicant of the reasons for such decision;
if necessary, within the time limits established by subparagraph 4.2.1 of this Appendix, the authorized body of the reference state must amend the registration decision specified in paragraph "b" of subparagraph 1.2.1 in accordance with the adopted amendment.
IV. Other Aspects
4.1. Special Procedures
4.1.1. Expansion of Registration
An application for an extension of registration must be reviewed in accordance with the same registration and review procedure for the medicinal product as the initial registration to which it relates, in accordance with Sections V and VI of the Rules for Registration of Medicines.
An extension of registration must be carried out in accordance with the same registration procedure as the initial application for registration of the medicinal product to which it relates, or must be included in the same registration dossier.
4.1.2. Procedure for Allocation of Responsibilities.
As an exception to subparagraph 1.7.1 and paragraphs 2.2 and 2.3 of this Appendix, if a Type IB minor change, a Type II major change, or a group of changes in the cases specified in the third paragraph of subparagraph 1.7.2 of this Appendix that do not provide for an extension of registration affects multiple registration dossiers of medicinal products belonging to the same holder, the holder of such registration certificates has the right to adhere to the procedure established by this subparagraph. For the purposes of this subparagraph, "reference authority" means the competent authority of the Member State concerned, appointed by the Expert Committee, taking into account the recommendation of the holder.
The applicant shall simultaneously submit to all relevant authorities an application for amendment containing the elements listed in Appendix IV, indicating the recommended reference authority.
If the application for amendment meets these requirements, the Expert Committee shall appoint a reference authority, and such authority shall acknowledge receipt of a valid application for amendment.
If the selected reference authority is a competent authority of the reference state that has not registered all the medicinal products covered by the application, the Expert Committee may request assistance from another relevant authority in the assessment of the application for amendment.
The reference authority shall issue an opinion on the validity of the application for amendment within 40 working days from the date of acknowledgement of receipt of the valid application for amendment for minor amendments of Type IB and major amendments of Type II. (as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated 17.03.2022)
The reference body has the right to shorten the specified period, taking into account the urgency of the matter, or extend it to 60 business days for amendments to the approved indications for use or the inclusion of new indications for use.
During the specified period, the reference body has the right to request that the applicant submit additional information within the timeframes established by such reference body. In this case:
the reference body must notify the other relevant authorities of its request for additional information;
until such additional information is submitted, the procedure is suspended;
the reference body has the right to extend the established period.
The reference body must send its conclusion on the validity of the application to the applicant and other authorized bodies; Within 20 business days of receiving the conclusion, the relevant authorities must approve such conclusion, notify the reference body, and amend the registration dossiers under consideration accordingly.
In order to verify the validity of an application for amendment and to draw up an opinion on the validity of the application for amendment, interested states must, upon request of the reference authority, provide information related to the registration dossiers affected by the amendment.
4.1.3. Influenza pandemic situation.
As an exception to Sections I, II, and III, if the World Health Organization or the Union recognizes an influenza pandemic situation, authorized bodies may, on an exceptional basis, temporarily accept an amendment to the conditions for registration of a vaccine for the prevention of human influenza in the absence of certain preclinical or clinical data.
When accepting an amendment in accordance with Part 1 of this Appendix, the applicant must provide the missing preclinical and clinical data within the deadline set by the relevant authority.
4.1.4. Urgent safety restrictions.
If, due to the emergence of a public health risk from medicinal products for human use, the holder, on its own initiative, introduces urgent safety restrictions, it must immediately notify all relevant authorities of the Member States thereof. If the authorized body does not file an objection within 24 hours of receiving the specified information, the urgent safety restrictions are considered accepted.
If a public health risk arises due to the use of medicinal products for medical use, the relevant authorities have the right to impose urgent safety restrictions on the holder.
If the holder introduces an urgent safety restriction or if the relevant authority imposes one, the holder must submit a corresponding application for an amendment to the registration dossier to the authorized body (expert organization) within 14 business days from the date of commencement of such restriction.
4.2. Changes to the Registration of a Medicinal Product
and its Marketing Authorization
4.2.1. Changes to the Registration of a Medicinal Product
Changes to the registration of a medicinal product based on the procedures provided for in Sections II and III of this Appendix shall be made:
in the case of significant changes of Type II, within 40 working days of receiving the information specified in paragraph 4 of subparagraph 2.4.1 and paragraph 2 of subparagraph 3.5.1 of this Appendix, provided that a full set of documents required to amend the registration dossier of the medicinal product is provided to the authorized bodies (expert organizations) of the interested Member States;
in other cases, within 120 working days of receiving the information specified in paragraph 4 of paragraph 2.4.1 and paragraph 2 of paragraph 3.5.1, provided that the documents required to amend the registration dossier are provided to the authorized bodies (expert organizations) of the interested Member States.
If a decision on the registration of a medicinal product is changed as a result of one of the procedures provided for in Sections II, III, and IV of this Annex, the relevant authority of the Member State must immediately notify the applicant of the change in registration.
4.2.2. Implementation of Changes.
Minor Type IA changes may be implemented at any time prior to completion of the procedure provided for in Sections 2.1 and 3.1 of this Annex.
If a notification affecting one or more minor Type IA changes is rejected, the applicant must immediately cease implementing the changes in question upon receipt of the information referred to in paragraph 2 of Section 2.4.1 and paragraph 2 of Section 3.5.1 of this Annex. Minor Type IB amendments may only be implemented in the following cases:
for amendments submitted by the applicant in accordance with the procedures provided for in Section II, not earlier than after the authorized body (expert organization) of the applicant's reference state has notified the applicant that the authorized body (expert organization) has accepted the notification in accordance with paragraph 2.2 or, if the notification is deemed to have been accepted in accordance with subparagraph 2.2.3;
for amendments submitted by the applicant in accordance with the procedures provided for in Section III, not earlier than after the relevant body of the applicant has notified the applicant that the authorized body (expert organization) has accepted the notification in accordance with paragraph 3.2 or, if the notification is deemed to have been accepted in accordance with subparagraph 3.2.3;
for amendments submitted by the applicant in accordance with the procedure provided for in subparagraph 4.2.1, not earlier than after the reference body of the applicant has notified the applicant that the conclusion is positive.
Any changes resulting in a revision of the medicinal product information in accordance with paragraph 1.6 of this Appendix may be implemented after amendments have been made to the registration dossier.
Significant Type II changes may only be implemented in the following cases:
for changes submitted by the applicant in accordance with the procedures provided for in Section II, within 20 working days from the date of notification by the authorized body (expert organization) of the applicant's reference state that the change has been accepted in accordance with paragraph 2.3, provided that the documents required for amending the medicinal product's registration dossier have been submitted to the relevant authorities of the interested Member States. If the approval procedure has been initiated in accordance with paragraph 2.6, the applicant must not implement the changes until the approval procedure for the change in question has been completed;
with respect to amendments submitted by the applicant in accordance with the procedures provided for in Section III, after the relevant body notifies the applicant that the amendment has been accepted in accordance with Section 3.3;
with respect to amendments submitted by the applicant in accordance with the procedure provided for in Subsection 4.1.2, within 20 working days from the date of notification by the applicant's reference body that the conclusion is positive, provided that the documents required for amending the registration dossier of the medicinal product have been submitted to the interested Member States, unless the approval procedure has been initiated in accordance with Section 2.6. If the approval procedure has been initiated in accordance with Section 2.6, the applicant must not implement the amendment until the approval procedure for acceptance of the amendment has been completed.
Any changes leading to revision of information on the medicinal product, as specified in paragraph 1.6 of this document, may be implemented after amendments have been made to the registration dossier.
Expanded registration of medicinal products may only be implemented after the relevant authorized body has amended its registration decision and notified the applicant accordingly.
Urgent safety restrictions and changes affecting safety issues may be implemented within the timeframes agreed upon between the applicant and the relevant authority.
As an exception, urgent safety restrictions and changes affecting safety issues may be implemented within the timeframes agreed upon between the holder (applicant) and the authorized body of the reference state after consultation with the other relevant authorities.
V. Final Provisions
5.1. Continuous Monitoring
Upon request of the relevant authority, the applicant must promptly provide all information relevant to the implementation of the change.
5.2. Revision of this document
No later than 5 years from the date of entry into force of the Rules for Registration and Evaluation of Medicinal Products for Human Use, the Expert Committee on Medicinal Products shall evaluate the application of this document in terms of classification of amendments in order to propose necessary amendments aimed at adapting Appendixes I and II to keep it current in light of current scientific data.
Appendix I
Extension of Registration
1. Changes in Active Pharmaceutical Ingredients:
a) replacement of an active pharmaceutical ingredient obtained by chemical synthesis with another salt (ester, complex, derivative) of the same active moiety of the active substance molecule, provided there are no significant differences in efficacy and/or safety;
b) replacement of an active pharmaceutical ingredient with another isomer, another mixture of isomers, or a mixture of individual isomers (e.g., a racemate with a single enantiomer), provided there are no significant differences in efficacy and/or safety;
c) replacement of a biological active pharmaceutical ingredient with another with a slightly modified molecular structure, provided there are no significant differences in efficacy and/or safety, with the exception of changes to the active pharmaceutical ingredient of a seasonal, pre-pandemic, or pandemic vaccine for the prevention of human influenza;
d) modification of the vector used to produce the antigen or starting material, including a new master cell bank from another source, provided there are no significant differences in efficacy and/or safety;
d) a new ligand or binding mechanism for a radiopharmaceutical drug in the absence of significant differences in efficacy and/or safety;
e) a change in the extractant or the ratio of herbal raw material to herbal pharmaceutical substance in the absence of significant differences in efficacy and/or safety.
2. Changes in dosage, dosage form, or route of administration:
a) a change in bioavailability;
b) a change in pharmacokinetics, such as release rate;
c) a change or addition of a new dosage (potency);
d) a change or addition of a new dosage form;
d) a change or addition of a new route of administration (for parenteral administration, a distinction should be made between intra-arterial, intravenous, intramuscular, subcutaneous, and other routes of administration).
Appendix II
Classification of Changes
1. The following changes should be classified as Type IA minor changes:
a) administrative changes related to the name and contact information of:
the marketing authorization holder, applicant, representative of the marketing authorization holder, etc.;
the manufacturer or supplier of any starting material, reagent, intermediate, or active pharmaceutical ingredient used in the manufacturing process of the medicinal product or contained in the medicinal product;
the transfer of a marketing authorization from one marketing authorization holder to another legal entity (change of marketing authorization holder);
(subparagraph "a" as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
b) changes involving the exclusion of any manufacturing site, including the active pharmaceutical ingredient, intermediate, or medicinal product, the packer, the manufacturer responsible for batch release, or the manufacturing site performing final quality control;
c) changes involving minor changes to approved physicochemical analytical procedures, if it has been confirmed that the updated procedure is at least equivalent to the previously used one, appropriate validation has been carried out, and its results indicate that the updated analytical procedure is at least equivalent to the previous (replaced) one;
d) changes involving changes to the specifications of the active pharmaceutical ingredient or excipient, or to the regulatory document on the quality of the medicinal product, implemented in order to ensure compliance with the updated relevant article of the Pharmacopoeia of the Union or the pharmacopoeia of a Member State, if the change is implemented solely for the purpose of ensuring compliance with the requirements of the pharmacopoeia, and the parameters of the specification (regulatory document on quality) for the product (specific properties) do not change;
d) changes consisting of a change in packaging material that does not come into contact with the medicinal product, which do not affect the delivery, use, safety, or stability of the medicinal product;
e) changes consisting of a tightening of the acceptance criteria of a specification or quality normative document, unless such changes are a consequence of any commitment made based on the results of previously conducted assessments to analyze the acceptance criteria of the specification (quality normative document), or unexpected situations that arose during manufacturing.
2. The following changes should be classified as Type II significant changes:
a) changes consisting of the addition of a new indication for use or the modification of an existing one;
b) changes consisting of significant modifications to the general characteristics of the medicinal product, especially due to new quality data, results of preclinical or clinical studies, or pharmacovigilance data;
c) changes consisting of changes that exceed the range, limits, or acceptance criteria of the approved specifications (quality normative document);
d) changes involving significant changes to the manufacturing process, composition, specifications (quality normative document), or impurity profile of the active pharmaceutical ingredient or medicinal product that may significantly affect the quality, safety, or efficacy of the medicinal product;
d) changes involving modifications to the manufacturing process or manufacturing sites of the active pharmaceutical ingredient of a biological medicinal product;
e) changes involving the introduction of a new design area or the expansion of a previously approved one, if the design area has been developed based on relevant Union guidelines or international scientific guidelines;
g) changes involving changes to the active pharmaceutical ingredient of a seasonal, pre-pandemic, or pandemic vaccine for the prevention of human influenza.
Appendix III
Cases of grouping changes described in paragraph 3 of clause 1.7.2 and paragraph 3 of clause 3.4.2 of this document
1. One of the changes in the group is a registration extension.
2. One of the changes in the group is a Type II major change; the remaining changes in the group are a consequence of this Type II major change.
3. One of the changes in the group is a Type IB minor change; the remaining changes in the group are a consequence of this Type IB minor change.
4. All changes in the group are solely administrative changes to the general characteristics of the medicinal product, labeling, or package insert.
5. All changes in the group are changes to the active pharmaceutical substance master file, vaccine antigen master file, or plasma master file.
6. All changes in the group are part of a program aimed at improving the manufacturing process and quality of the medicinal product in question or its active pharmaceutical ingredients.
7. All changes in the group are changes affecting the quality of the vaccine for the prevention of human pandemic influenza.
8. All changes in the group are changes to the pharmacovigilance system. 9. All group changes are a consequence of a specific urgent safety restriction and are submitted in accordance with section 4.1.4 of this document.
10. All group changes relate to a correction of information about a specific class in the summary of product characteristics, labeling, or package insert (e.g., the addition of a class-specific warning).
11. All group changes are a consequence of an assessment of a specific periodic safety report.
12. All group changes are a consequence of a post-marketing study conducted under the supervision of the holder.
13. All group changes are a consequence of an obligation imposed by the competent authority of the Member State upon registration.
14. All group changes are a consequence of conditional registration.
Appendix IV
Documents submitted by the applicant for amendments to the registration dossier of a medicinal product
(amendment dossier)
1. A list of all registration dossiers affected by the notification or application for amendment. 2. A description of all submitted changes, including:
for minor Type IA changes, the implementation date of each described change;
for minor Type IA changes that do not require immediate notification, a description of all minor Type IA changes implemented in the last 365 calendar days (12 months) for which no notifications have been previously submitted.
3. All required documents specified in Appendix V to this document regarding the relevant change. If these documents are submitted in a language other than Russian, an authentic Russian translation must be provided.
4. A description of the relationship between the changes, if the change leads to a change in, or is a consequence of, other changes to the terms and conditions of the same medicinal product registration.
5. Documents confirming payment of the fee (duty) for amending the medicinal product registration dossier in accordance with the legislation of the Member State.
6. A list of interested Member States, indicating the reference state, if applicable.
Appendix V
Classification of Changes to the Registration Dossier
Changes to the registration dossier of medicinal products are classified in accordance with this supplement as changes due to:
administrative changes;
quality changes;
changes in safety, efficacy, and pharmacovigilance;
certain changes to plasma master files (PMFs) and vaccine antigen master files (VAMFs).
When classifying individual amendments to this supplement, the amendment in question shall be coded using the following structure:
X.N.x.n ("amendment code"),
where:
X indicates the capital letter of the section of the supplement containing the amendment (e.g., "A," "B," "C," or "D")
N indicates the Roman numeral of the subsection of the section containing the amendment (e.g., I, II, III, etc.)
x indicates the letter of the clause of the subsection containing the amendment (e.g., "a," "b," "c," etc.)
n indicates the subclause number assigned to the individual amendment in the supplement (e.g., 1, 2, 3, etc.).
Each section of this supplement shall contain:
a list of amendments classified as minor amendments of Type IA and major amendments of Type II in accordance with the definitions in paragraph 1.2 of this document and Appendix II to this document. It also specifies which Type IA changes require immediate notification under subparagraphs 2.1.2 and 3.1.2 of this Appendix;
a list of examples that should be considered as Type IB minor changes. According to paragraph 1.3 of this document, this category is assigned by default. Therefore, this appendix is not intended to provide an exhaustive list of this category of changes.
Appendix V does not address registration extensions, as they are adequately described in Appendix I of this document. All changes described in Appendix I of this document should be considered registration extensions. All other changes should not be construed as such. If one or more of the conditions set forth in this supplement for minor Type IA changes are not met, such a change may be submitted as a Type IB change ("default Type IB change"), unless such a change is treated as a Type II change in this supplement or in a recommendation prepared in accordance with paragraph 1.5 of this document, or unless the applicant considers that the changes may have a significant impact on the quality, safety, or efficacy of the medicinal product.
If, when reviewing an application for changes, the authorized body considers that a change submitted as a default Type IB change may have a significant impact on the quality, safety, or efficacy of the medicinal product, it has the right to require the applicant to amend the application for changes and submit documents confirming this change and its classification as a Type II change.
For the purposes of this supplement, the term "test procedure" has the same meaning as "analytical procedure," and the term "limits" has the same meaning as "acceptance criteria." A "specification parameter" is a quality attribute for which an analytical procedure and acceptance criteria are established, such as quantification, identity, and water content. Therefore, the addition or deletion of a specification parameter includes the corresponding analytical procedure and acceptance criteria.
If multiple minor changes (e.g., to the same method, process, or material) occur at the same time, or if there is a significant update to the quality information of the active pharmaceutical ingredient or medicinal product, the applicant must consider the cumulative impact of such changes on the quality, safety, and efficacy of the medicinal product when selecting the appropriate classification category and submit them accordingly.
The documents substantiating Type IB and Type II amendments depend on the nature of such amendments.
If the amendment requires a revision of the general characteristics of the medicinal product, the labeling, and/or the package insert, the medicinal product packaging mock-ups (collectively, "medicinal product information"), and/or the quality regulatory document, this circumstance is considered part of the amendment. In this case, the updated medicinal product information should be submitted as part of the dossier, translated into the official languages of the Member States, if required by the legislation of the Member States. Packaging mock-ups should be provided to the authorized body (expert organization) of the reference state or the state of recognition, respectively.
Notifying the authorized bodies of the Member States of an updated article of the Pharmacopoeia of the Union or the pharmacopoeia of a Member State is not required if the dossier of the registered medicinal product contains a reference to the current version. Applicants should remember that compliance with the updated article must be achieved within 180 calendar days from the date of its publication.
Section D of this supplement provides a list of changes specific to the PMF and the VAMF. Following review of such changes, any affected registration dossier must be updated in accordance with Subsection B.V of this supplement. If documentation on human plasma used as the starting material for a plasma-derived medicinal product is not submitted as a PMF, changes to such starting material described in the registration dossier must also be processed in accordance with this supplement.
Unless otherwise specified, references in this supplement to changes to the registration dossier of a medicinal product imply addition, substitution, or deletion. If amendments to the registration dossier are editorial changes, such changes should not be submitted as a separate amendment; they may be included in other amendments to the relevant part of the registration dossier. In such cases, the application form must clearly identify such changes as editorial revisions and provide a letter of guarantee confirming that the submitted editorial revisions do not affect the classification type of the submitted amendment. The editorial revisions submitted by the applicant may exclude obsolete or redundant text, but not specification parameters or production descriptions.
A. Administrative Changes
A.1. Change of Marketing Authorization Holder
Prerequisites
Documents and data
Procedure
a) Change of name and/or address of the Marketing Authorization Holder
1, 3
IAНУ
b) Transfer of the Marketing Authorization from one Marketing Authorization Holder to another legal entity
1, 2, 3, 4
Conditions
1. The Marketing Authorization Holder must remain the same legal entity.
2. The Marketing Authorization Holder is a different legal entity.
Documentation
2. Documents justifying the transfer of the registration certificate(s) and confirming the ability of the new registration certificate holder to ensure the proper performance of all obligations of the registration certificate holder;
A copy of the document confirming the transfer of the registration certificate from one legal entity to another;
A revised summary of the pharmacovigilance system or a revised pharmacovigilance system master file, if included in the registration dossier;
Information on the organization responsible for handling complaints in the Eurasian Economic Union.
3. Revised information on the medicinal product in the relevant sections, and a regulatory document on quality.
4. A document(s) submitted by the legal entity to which the powers of the registration certificate holder are being transferred, confirming the absence of changes in the information on the medicinal product that are not related to the transfer of the registration certificate.
(Clause A.1 as amended by Decision No. 36 of the Council of the Eurasian Economic Commission dated March 17, 2022)
A.2. Change of the (trade) name of a medicinal product
a) Medicinal products registered in accordance with the Rules for Registration and Examination of Medicinal Products within the Eurasian Economic Union
1, 2
b) Medicinal products registered under the national procedure (registration only in the reference state)
-
IB
1. Confirmation from the reference state of acceptability of the new name.
1. Copy of the reference state's letter of acceptance of the new (trade) name.
2. Revised product information.
A.3. Change of name of active pharmaceutical substance or excipient
1. The pharmaceutical substance (excipient) remains unchanged.
Documentation 1. WHO approval certificate or a copy of the INN list. If applicable, confirmation that the change complies with the Union Pharmacopoeia. Declaration that the name of the herbal medicinal product complies with Union documents. 2. Revised product information. (as amended by Decision No. 60 of the Council of the Eurasian Economic Commission dated May 22, 2023)
A.4. Change of name and/or address: of the manufacturer (including, if applicable, quality control sites), or the holder of the DMF, or the supplier of the active pharmaceutical substance, starting materials, reagents or intermediates used in the production of the active pharmaceutical substance (if specified in the technical dossier), if there are no Ph. Eur. certificates of conformity in the registration dossier, or the manufacturer of a new excipient (if specified in the technical dossier)
1, 2, 3
IA
1. The production site and none of the production operations are changed.
1. An official document from an authorized body (e.g., a tax authority) indicating the new name and/or address.
2. An amendment to the relevant section of the dossier.
3. If the name of the Active Pharmaceutical Substance Master File Holder (APMSH) has changed, an updated "permit to access."
A.5. Change of name and/or address of the manufacturer of the medicinal product, including production sites and quality control sites
a) actions for which the manufacturer (importer) is responsible include the release of batches
b) actions for which the manufacturer (importer) is responsible do not include the release of batches
1. The manufacturing site whose name and/or address are being changed, and none of the manufacturing processes are being changed.
1. A copy of the amended manufacturing permit (if available) or an official document from the relevant authorized body (e.g., tax authority) mentioning the new name and/or address.
2. If applicable, an amendment to the relevant section of the dossier, including the revised product information.
A.6. Changing the ATX code
1. Change due to approval or WHO change to the ATC code.
1. Certificate (WHO) of approval or a copy of the ATC code list.
A.7. Exclusion of a manufacturing site (including for the active pharmaceutical ingredient, intermediates, medicinal product, packager, manufacturer responsible for batch release, batch quality control, or supplier of starting material, reagent, or excipient (if specified in the dossier))
1. At least one previously approved manufacturing site (manufacturer) must remain, performing the same functions as those subject to exemption. If applicable, at least one manufacturer responsible for batch release must remain within the Union and capable of certifying product testing for batch release within the Union.
2. The exemption must not be a result of critical manufacturing deficiencies.
1. The section on amendments to the application for bringing the registration dossier into compliance with Union requirements (in the cover letter or the application form for amendments attached to the cover letter) must clearly identify the previously approved and proposed manufacturers, as specified in Section 2.5 of the application form.
2. An amendment to the relevant section(s) of the dossier, including revised product information.
A.8. Changes in the audit date for verification of compliance of the manufacturer of the active pharmaceutical substance with the rules of good manufacturing practice
Written confirmation from the manufacturer of the medicinal product, containing an indication of verification of the manufacturer's compliance with Good Manufacturing Practices (GMP).
B. Quality Changes
B.I. Active Pharmaceutical Substance
B.I.a) Manufacturing
B.I.a.1. Change of manufacturer of a starting material (reagent, intermediate) used in the manufacturing process of an active pharmaceutical ingredient or change of manufacturer of an active pharmaceutical ingredient (including, if applicable, quality control sites) of an active pharmaceutical ingredient, if the registration dossier does not contain a certificate of conformity with the European Pharmacopoeia.
a) the proposed manufacturer belongs to the same pharmaceutical group as the approved manufacturer
1, 2, 3, 4, 5, 6, 7
b) addition of a new manufacturer of an active pharmaceutical ingredient justified by the DMF
II
c) the proposed manufacturer uses a significantly different synthetic route or manufacturing conditions that may alter important quality parameters of the active pharmaceutical ingredient, such as a qualitative and/or quantitative impurity profile requiring qualification, or physicochemical properties affecting bioavailability
d) a new manufacturer of material requiring an assessment of viral safety and/or GE risk -
d) the change affects a biological active pharmaceutical ingredient or a starting material (reagent, intermediate) used in the production of a biological (immunological) medicinal product
e) change in the procedure for quality control of the active pharmaceutical ingredient: change or addition of a site where batch control (testing) is performed
2, 4
1, 5
g) inclusion of a new manufacturer of an active pharmaceutical ingredient that does not have an DMF and requires a significant update of the relevant section of the active pharmaceutical ingredient dossier
h) inclusion of an alternative site for sterilization of the active pharmaceutical ingredient using the method of the Pharmacopoeia of the Union
1, 2, 4, 5, 8
i) inclusion of a new site for micronization
2, 5
1, 4, 5, 6
k) changes in agreements for quality control testing of biologically active pharmaceutical substances: replacement or inclusion of a site where batch control (testing) is carried out, including a biological (immunological, immunochemical) method
l) a new site for storing the main cell bank and (or) working cell banks
1. The specifications of starting materials and reagents (including in-process controls and analytical methods for all materials) are identical to those previously approved. The specifications (including in-process controls and analytical methods for all materials), preparation methods (including batch sizes), and detailed method for synthesizing intermediates and active pharmaceutical ingredients are identical to those previously approved.
2. The active pharmaceutical ingredient is not biological (immunological) or sterile.
3. If materials of human or animal origin are used in the manufacturing process, the manufacturer does not use a new supplier for which a viral safety assessment and compliance with the Pharmacopoeia of the Union for minimizing the risk of transmission of animal spongiform encephalopathy agents through medicinal products for human and veterinary use is required.
4. The method transfer from the old to the new site has been completed successfully.
5. The particle size specification of the active pharmaceutical ingredient and the corresponding analytical method remain unchanged.
1. If applicable, an amendment to the relevant section(s) of the dossier.
2. Declaration by the Marketing Authorisation Holder or the DMF Holder, respectively, that the quality control procedures for the route of synthesis (or for herbal medicinal products (respectively): method of preparation, geographical source, production of the herbal pharmaceutical substance, and manufacturing process) and the specifications of the active pharmaceutical substance and starting material (reagent, intermediate) during the manufacturing process of the active pharmaceutical substance (if applicable) do not differ from those previously approved.
3. Either a certificate of conformity with the European Pharmacopoeia for GE for any new source material, or (if applicable) documentary evidence that the source material exposed to GE risk has previously been investigated by a competent authority and confirmed to comply with the Union Pharmacopoeia for minimizing the risk of transmission of animal spongiform encephalopathy agents through medicinal products for human and veterinary use. The following information must be provided: name of the manufacturer; animal species and tissue from which the material was obtained; Country of origin of the animals, their use and past acceptability.
4. Batch analysis data (in comparative table format) for at least two batches (at least pilot-scale) of the active pharmaceutical ingredient from current and proposed manufacturers (sites).
5. In the section on amendments to the application for aligning the registration dossier with Union requirements (in the cover letter, the amendment application form attached to the cover letter), it is necessary to clearly identify previously approved and proposed manufacturers, as specified in Section 2.5 of the application form.
6. If the active pharmaceutical ingredient is used as a starting material, a declaration from the Qualified Person (QP) of each manufacturing authorization holder specified in the application and the authorized person of each manufacturing authorization holder specified in the application as responsible for batch release. Declarations must indicate that the manufacturer(s) of the active pharmaceutical ingredient specified in the application operate in accordance with the Union's Good Manufacturing Practice (GMP) for starting materials. Under certain circumstances, one declaration may be required (see note to Amendment B.II.b.1).
7. An obligation (if necessary) for the manufacturer of the active pharmaceutical ingredient to notify the MAH of any changes to the manufacturing process, specifications, and analytical methods for the active pharmaceutical ingredient.
8. Confirmation that the proposed site is duly licensed for the dosage form, medicinal product, or manufacturing operation in question.
(as amended by decisions of the Council of the Eurasian Economic Commission of 30.01.2020 No. 9 and of 22.05.2023 No. 60)
B.I.a.2. Changes in the manufacturing process of the active pharmaceutical ingredient
a) a minor change in the manufacturing process of the active pharmaceutical ingredient
b) a significant change in the manufacturing process of the active pharmaceutical ingredient that may have a significant impact on the quality, safety, or efficacy of the medicinal product
c) the change affects a biological (immunological) substance or the use of another substance obtained by chemical synthesis in the manufacture of a biological (immunological) medicinal product that may have a significant impact on the quality, safety, or efficacy of the medicinal product and is not related to the protocol
d) the change affects a herbal medicinal product, namely the geographical source, production method, or preparation method
d) an insignificant change to the closed part of the DMF
1. There is no undesirable change in the qualitative or quantitative impurity profile or physicochemical properties.
2. The synthesis route remains the same, i.e., intermediates are unchanged and no new reagents, catalysts, or solvents are introduced into the process. The geographical source, preparation of plant materials, and manufacturing method of herbal medicinal products remain unchanged.
3. The specifications of the active pharmaceutical ingredient and intermediates remain unchanged.
4. The change is fully described in the open section (the "applicant" section) of the DMF (if applicable).
5. The active pharmaceutical ingredient is not a biological (immunological) substance.
6. The change does not affect the geographical source, manufacturing method, or preparation of the herbal medicinal product.
7. The change does not affect the closed section of the DMF.
1. Amendment to the relevant section(s) of the dossier, including a direct comparison of the current and new processes.
2. Batch analysis data (in comparative table format) for at least two batches (at least pilot-scale) produced using the approved and proposed processes.
3. Copies of the approved specifications of the active pharmaceutical ingredient.
4. Declaration by the Marketing Authorization Holder or the MFAFS Holder, respectively, that there is no change in the qualitative and quantitative impurity profile or physicochemical properties, and that the synthesis method, specifications of the active pharmaceutical ingredient, and intermediates remain unchanged.
Note
Significant changes in active pharmaceutical ingredients obtained by chemical synthesis are changes in the synthesis method or manufacturing conditions that are capable of altering important quality parameters of the active pharmaceutical ingredient, such as the qualitative and/or quantitative impurity profile requiring qualification, or physicochemical properties affecting bioavailability.
B.I.a.3. Change in the batch size (including batch size ranges) of an active pharmaceutical ingredient or intermediate used in the manufacturing process of the active pharmaceutical ingredient
a) increase in the batch size by up to 10 times the registered size
1, 2, 3, 4, 5, 6, 7, 8
1, 2, 5
b) 10-fold downsizing
1, 2, 3, 4, 5
c) change requires an analysis of the comparability of the biological (immunological) active pharmaceutical ingredient
d) increase in the batch size by more than 10 times the registered size
d) increase (decrease) in the scale of production of the biological (immunological) active pharmaceutical ingredient without changing the manufacturing process (e.g., duplication of the line)
1. All changes in manufacturing methods are limited to those necessary for upscaling or downscaling, such as using equipment of a different size.
2. Test results must be submitted for at least two batches of the proposed batch size, according to specifications.
3. The medicinal product in question is not a biological (immunological) medicinal product.
4. The change does not adversely affect the reproducibility of the process.
5. The change must not be a consequence of unforeseen situations arising during manufacturing or a stability issue.
6. The specifications of the active pharmaceutical ingredient (intermediates) are not changed.
7. The active pharmaceutical ingredient is not sterile.
8. The batch size is within 10 times the batch size range stipulated at registration or after a subsequent change that is not a Type IA change.
1. Amendment to the relevant section(s) of the dossier.
2. Batch numbers of the tested batches correspond to the proposed batch size.
3. Batch analysis data (in comparative table format) for at least one production batch of the active pharmaceutical ingredient or intermediate, respectively, manufactured in the approved and proposed sizes. Data for a further two full production batches must be provided upon request; the holder is obliged to advise if the analysis results are not within specification and propose an action plan.
4. Copies of the approved specifications of the active pharmaceutical ingredient (and intermediates, if applicable).
5. Declaration by the Marketing Authorisation Holder or the ASMF holder, respectively, that any changes to manufacturing methods only affect those necessary for upscaling or downscaling, such as the use of equipment of a different size; the change does not adversely affect the reproducibility of the process; the change is not a consequence of unforeseen situations arising during manufacturing or a loss of stability; the specifications of the active pharmaceutical ingredient (intermediates) are not changed.
B.Ia.4. Changes to in-process tests or acceptance criteria used in the manufacture of the active pharmaceutical ingredient
a) Tightening of in-process acceptance criteria
b) Addition of new in-process tests or acceptance criteria
1, 2, 5, 6
1, 2, 3, 4, 6
c) Elimination of a non-significant in-process test
1, 2, 7
d) Expansion of approved in-process acceptance criteria that may significantly affect the overall quality of the active pharmaceutical ingredient
d) Elimination of an in-process test that may significantly affect the overall quality of the active pharmaceutical ingredient
e) addition or replacement of in-process testing for safety or quality reasons
1. The change is not a consequence of any commitment made based on the results of previously conducted assessments to analyze the specification acceptance criteria (e.g., during registration or Type II amendments).
2. The change is not a consequence of unforeseen situations that arose during manufacturing, such as a new unqualified impurity or a change in the impurity limits.
3. Any change must be within the range of the currently approved acceptance criteria.
4. The analytical procedure is unchanged or changes only slightly.
5. No new test method is based on a new, non-standard methodology or a standard methodology used in a new way.
6. The new test method is not a biological (immunological, immunochemical) method or a method that uses a biological reagent for a biologically active pharmaceutical ingredient (with the exception of standard pharmacopoeial microbiological methods).
7. The specification parameter does not address a critical parameter, such as any of the following: assay, impurities (unless a specific solvent is explicitly used in the manufacture of the active pharmaceutical ingredient), any critical physical characteristic such as particle size, bulk density before and after compaction, identity testing, water, or any request to change the testing frequency.
2. Comparison table of current and proposed in-process testing.
3. Detailed description of the new non-pharmacopeial analytical method and validation data (where applicable).
4. Analysis data from two production batches (for biological active pharmaceutical ingredients, in the absence of adequate justification - three production batches) of the active pharmaceutical ingredient for all specification parameters. 5. Justification (risk assessment) from the Marketing Authorization Holder or the DMF Holder, respectively, confirming that the in-process parameters are insignificant or obsolete.
6. Justification from the Marketing Authorization Holder or the DMF Holder, respectively, for new in-process tests and limits.
B.I.a.5. Change in the active pharmaceutical ingredient of a seasonal, pre-pandemic, or pandemic influenza vaccine
a) Replacement of the strain(s) of a seasonal, pre-pandemic, or pandemic influenza vaccine
B.I.b) Quality control of the active pharmaceutical substance
B.I.b.1. Change in specification parameters and/or acceptance criteria of the active pharmaceutical ingredient, starting material (intermediate, reagent) used in the manufacturing process of the active pharmaceutical ingredient
a) tightening the specification acceptance criteria for medicinal products subject to batch release by the official control body
b) tightening the specification acceptance criteria
c) adding a new parameter and its corresponding test method to the specification
1, 2, 5, 6, 7
1, 2, 3, 4, 7
d) excluding an insignificant specification parameter (e.g., excluding an obsolete parameter)
1, 2, 8
1, 2, 6
d) excluding a specification parameter that may significantly affect the overall quality of the active pharmaceutical ingredient and/or medicinal product
e) a change outside the approved range of the specification acceptance criteria of the active pharmaceutical ingredient
g) expanding the approved specification acceptance criteria for starting materials (intermediates) that may significantly affect the overall quality of the active pharmaceutical ingredient and/or medicinal product
h) adding or replacing (excluding biological and immunological substances) a specification parameter and its corresponding test method for safety or quality reasons
1, 2, 3, 4, 5, 7
i) if the active pharmaceutical ingredient the substance does not have an article in the Pharmacopoeia of the Union or the pharmacopoeia of a Member State, or the change of its own specification data to data from an unofficial pharmacopoeia or a pharmacopoeia of a third country
1. The change is not a consequence of any commitment made based on the results of previously conducted assessments to revise the specification acceptance criteria (e.g., during drug registration or Type II amendments).
6. The new test method is not a biological (immunological, immunochemical) method or a method that uses a biological reagent for a biologically active pharmaceutical ingredient (except for standard pharmacopoeial microbiological methods).
7. The change in any material does not affect a genotoxic impurity. If the active pharmaceutical substance is involved, with the exception of residual solvents, which must comply with the limits of the relevant chapter of the Union Pharmacopoeia, the control of any new impurity must comply with the Union Pharmacopoeia or the pharmacopoeia of a Member State.
8. The specification parameter does not affect a critical parameter, such as any of the following: assay, impurities (unless a specific solvent is clearly used in the production of the active pharmaceutical substance), any critical physical characteristic, such as particle size, bulk density before and after compaction, identity testing, water, or any request for omission testing.
2. Comparison table of current and proposed specifications.
3. Detailed description of any new analytical procedure and validation data (if applicable). 4. Analysis data from two industrial batches (or, in the absence of justification to the contrary, three batches for biological active pharmaceutical ingredients) of the corresponding active pharmaceutical ingredient for all specification parameters.
5. Where applicable, data from a comparative dissolution kinetics test of a medicinal product containing the active pharmaceutical ingredient from at least a pilot industrial batch that complies with the current and proposed specifications. For herbal medicinal products, comparative disintegration data may be sufficient.
6. Justification (risk assessment) by the Marketing Authorization Holder or the DMF Holder, respectively, confirming that the in-process parameter is insignificant or obsolete.
7. Justification by the Marketing Authorization Holder or the DMF Holder, respectively, for the new specification parameter and acceptance criteria.
B.I.b.2 Change in the analytical procedure of the active pharmaceutical ingredient or starting material (intermediate, reagent) used in the process of manufacturing the active pharmaceutical ingredient
a) minor changes to the approved analytical procedure
b) exclusion of the analytical procedure of the active pharmaceutical ingredient or starting material (intermediate, reagent), if an alternative analytical procedure has already been approved
7
c) other changes to the analytical procedure (including replacement or addition) of a reagent that does not have a significant effect on the overall quality of the active pharmaceutical ingredient
1, 2, 3, 5, 6
d) significant change or replacement of a biological (immunological, immunochemical) test method or a method that uses a biological reagent for a biological active pharmaceutical ingredient
d) other changes to the analytical procedure (including addition or replacement) of the active pharmaceutical ingredient Substance or starting material (intermediate)
1. In accordance with the relevant Union guidelines, the required validation has been conducted, confirming that the updated analytical method is at least equivalent to the previous one.
2. The limits for the content of total impurities have not changed, and no new unqualified impurities have been detected.
3. The analytical method has not changed (e.g., a change in column length or temperature, but not a different column type or method).
4. The test method is not biological (immunological, immunochemical) or a method that uses a biological reagent for a biological active pharmaceutical substance (with the exception of standard pharmacopoeial microbiological methods).
5. No new test method is based on new non-standard methods or standard methods used in a new way.
6. The active pharmaceutical substance is not biological (immunological).
7. An alternative analytical procedure for a specification parameter has already been approved, but such procedure was not included through an IA notification.
1. Amendment to the relevant section(s) of the dossier, including a description of the analytical methodology, a summary of validation data, and revised impurity specifications (if applicable).
2. Comparative validation results or, if justified, comparative analytical results confirming that the current and proposed tests are equivalent. This requirement does not apply if a new analytical procedure is added.
B.I.c) Packaging and capping system
B.I.c.1. Change in the primary packaging of an active pharmaceutical ingredient
a) Qualitative and/or quantitative composition
b) Qualitative and/or quantitative composition for sterile or non-frozen biological (immunological) active pharmaceutical ingredients
c) Liquid active pharmaceutical ingredients (non-sterile)
1. The proposed packaging material must be at least equivalent to the approved one in terms of the relevant properties.
2. Relevant stability studies have been initiated in accordance with Union documents, and at the time of introducing the changes, the applicant has analyzed the relevant stability parameters in at least two pilot-scale or industrial batches, and has satisfactory results from at least a three-month stability study. However, if the proposed packaging is more stable than the registered one, three-month stability data are not required. Upon completion of such studies, if the results are not within specification or have the potential to be outside specification at the end of the shelf life (retest period), they must be immediately submitted to the competent authority along with a proposed action plan.
3. Excluding sterile, liquid, and biological (immunological) active pharmaceutical ingredients.
2. Required data on the new packaging (e.g., comparative data on permeability, e.g., for O2, CO2, moisture, etc.), including confirmation that the material complies with the relevant pharmacopoeial requirements or Union legislation on plastic materials and food contact items. 3. Where applicable, evidence must be provided that there is no interaction between the contents and the packaging material (e.g. no migration of components of the proposed material into the contents, no migration of components of the medicinal product into the packaging), including evidence that the material complies with the relevant pharmacopoeial requirements or Union legislation on plastic materials and objects in contact with food.
4. A declaration by the Marketing Authorisation Holder or the Holder of the DMF that the required stability studies have been initiated in accordance with Union documents (indicating the batch numbers); and that (where applicable) the required minimum satisfactory stability data were available at the time of introduction of the change; and that the available data did not indicate any problem. Confirmation must also be provided that the studies will be completed and that if the results are, or have the potential to be, out of specification at the end of the shelf life (retest period), they will be submitted promptly to the competent authority, along with a proposed action plan. 5. Results of stability studies conducted in accordance with the requirements of Union law for significant stability parameters on at least two pilot-scale or industrial batches covering at least three months, and confirmation that these studies will be completed and, if the results are not within specifications or have the potential to be outside specifications at the end of the shelf life (retest period), will be immediately submitted to the authorized body along with a proposed action plan.
6. Comparison of current and proposed primary packaging specifications (if applicable).
B.I.c.2. Change in specification parameters and/or acceptance criteria of primary packaging of an active pharmaceutical ingredient Prerequisites Documents and data Procedure
a) tightening the specification acceptance criteria
b) adding a new parameter and corresponding test method to the specification
c) exclusion of a nonessential specification parameter (e.g. exclusion of an obsolete parameter)
d) addition or replacement of a specification parameter for safety or quality reasons
1. The change is not a consequence of any commitment made as a result of previously conducted assessments to review the specification acceptance criteria (e.g., during drug registration or the introduction of Type II variations), unless it has previously been reviewed and approved as a follow-up measure. 2. The change is not a consequence of unforeseen situations that arose during the manufacture of the packaging material or during storage of the active pharmaceutical ingredient.
3. Any change must be within the range of currently approved acceptance criteria.
5. No new test method is based on a new non-standard methodology or a standard methodology used in a new way.
3. Detailed description of any new analytical procedure and validation data (if applicable).
4. Analysis data from 2 batches of the packaging material for all specification parameters.
5. Justification (risk assessment) by the Marketing Authorization Holder or the Holder of the DMF, confirming that the in-process parameter is insignificant or obsolete.
6. Justification by the RU holder or the DMF holder of the new specification parameter and acceptance criteria.
B.I.c.3. Change in the analytical method for testing the primary packaging of an active pharmaceutical ingredient.
a) Minor changes to the approved analytical method
b) Other changes to the analytical method (including addition or replacement)
1, 3, 4
c) Exclusion of an analytical method if an alternative method has already been approved
1. In accordance with the relevant Union documents, the necessary validation has been carried out, confirming that the updated analytical method is at least equivalent to the previous one.
2. The analytical method has not changed (e.g., a change in column length or temperature, but not a different column type or method).
3. No new test method is based on new non-standard methods or standard methods used in a new way.
4. The active pharmaceutical substance (medicinal product) is not biological (immunological).
5. The analytical procedure for the specification parameter is retained, provided that such procedure was not added via an IA notification.
1. Amendment to the relevant section(s) of the dossier, including a description of the analytical methodology and a summary of the validation data.
B.I.d) Stability
B.I.d.1. Changing the retest period (storage period) or storage conditions of the active pharmaceutical ingredient if the registration dossier does not contain a certificate of conformity with the European Pharmacopoeia covering the retest period
a) Retest period (storage period)
1. Reduction
2. Increasing the retest period by extrapolating stability data that does not comply with the Union documents <*>
3. Increasing the shelf life of a biological (immunological) active pharmaceutical ingredient that does not comply with the approved stability study program
4. Increasing or introducing the retest period (storage period) confirmed by natural storage data
b) Storage conditions
1. Changing the storage conditions of the active pharmaceutical ingredient to more stringent ones
2. Changing the storage conditions of biological (immunological) active pharmaceutical ingredients if stability studies were not conducted in accordance with the current Approved Stability Protocol
3. Change in Storage Conditions of the Active Pharmaceutical Substance
c) Change in the Approved Stability Study Program
1, 4
1. The change must not be a consequence of unforeseen situations arising during manufacturing or a change in stability.
2. The changes do not result in expansion of the acceptance criteria for the parameters tested, exclusion of a stability parameter, or reduction in the frequency of testing.
1. Amendment to the relevant section(s) of the dossier. The results of relevant real-time stability studies conducted in accordance with the relevant stability guidelines on at least two (for biological medicinal products - three) pilot-scale or production batches of the active pharmaceutical substance, packaged using the registered packaging material, and covering the entire proposed retest period or proposed storage conditions must be submitted.
2. Confirmation that the stability studies were conducted in accordance with the currently approved program. The study results must confirm that the relevant approved specifications continue to be met.
3. Copies of the approved specifications for the active pharmaceutical ingredient.
4. Justification for the proposed changes.
<*> Note
The retest period does not apply to biological (immunological) active pharmaceutical substances.
B.I.e) Project field and protocol of post-registration changes
B.I.e.1. Introduction of a new design space or expansion of an approved design space for an active pharmaceutical ingredient, affecting
a) one operational unit of the active pharmaceutical ingredient manufacturing process, including the relevant in-process control (or) analytical methods
b) analytical methods for starting materials (intermediates) and/or the active pharmaceutical ingredient
1. The design space has been developed based on relevant Union documents and international scientific guidelines. Results of product development, process, and analytical methodology studies (e.g., the interaction of various parameters forming the design space to be studied, including risk assessment and multivariate studies, respectively), where appropriate, confirming that a holistic mechanistic understanding of the impact of material quality attributes and process parameters on the critical quality attributes of the active pharmaceutical ingredient has been achieved. 2. Description of the design field in tabular form, including variables (material properties and manufacturing process parameters) and their proposed ranges.
3. Amendment to the relevant sections of the dossier.
B.I.e.2. Introduction of a post-registration change management protocol affecting the active pharmaceutical ingredient
1. Detailed description of the proposed change.
2. Change management protocol affecting the active pharmaceutical ingredient.
B.I.e.3. Exception to the Post-Market Change Management Protocol Affecting the Active Pharmaceutical Substance
An exception to the post-market change management protocol affecting the active pharmaceutical substance is not a consequence of unforeseen situations or non-compliance with the specification during the implementation of changes described in the protocol and does not affect the approved information included in the registration dossier
1. Justification for the proposed exception.
2. Amendment to the relevant sections of the dossier.
B.I.e.4. Changes to the Approved Change Management Protocol
a) significant changes to the change management protocol
b) minor changes to the change management protocol that do not alter the strategy described in the protocol
Declaration that any change must be within the range of currently approved acceptance criteria. In addition, a declaration that no comparability assessment is required for biological (immunological) medicinal products.
B.I.f.5. Implementation of Changes Provided by the Approved Change Management Protocol
a) Implementation of the change does not require additional supporting data
1, 2, 4
b) Implementation of the change requires additional supporting data
c) Implementation of a change to a biological (immunological) medicinal product
The proposed change has been implemented in full compliance with the approved change management protocol.
1. Reference to the approved change management protocol.
2. Declaration that the change complies with the approved change management protocol and that the study results meet the acceptance criteria specified in the protocol. In addition, a declaration that no comparability assessment is required for biological (immunological) medicinal products.
3. Results of studies conducted in accordance with the approved change management protocol.
4. Amendment to the relevant section of the dossier.
5. A copy of the approved specifications for the active pharmaceutical ingredient.
B.II. Medicinal product
B.II.a) Appearance and composition
B.II.a.1. Alteration or addition of imprints, engravings, or other markings, including replacement or addition of ink used in the manufacture of the medicinal product.
a) Alteration of imprints, engravings, or other markings
b) Alteration of score lines (break lines) intended to divide the product into equal doses
1. The medicinal product specifications at release and at the end of the expiration date remain unchanged (except for appearance).
2. All ink must comply with current pharmaceutical legislation.
3. Scores (break lines) are not intended to divide the product into equal doses.
4. The medicinal product markings used to differentiate dosages are not completely removed.
1. Amendment to the relevant section(s) of the dossier, including a detailed graphical or narrative description of the current and new appearance, as well as the corresponding revision of the medicinal product information.
2. Where applicable, samples of the medicinal product.
3. Results of relevant tests in accordance with the Pharmacopoeia of the Union, confirming the equivalence of properties (correct dosage).
B.II.a.2. Change in Dosage Form or Size.
a) Immediate-release tablets, capsules, suppositories, and pessaries.
b) Delayed-, modified-, or extended-release dosage forms, and scored tablets intended for division into equal doses
c) Addition of a new radiopharmaceutical kit with a different fill volume
1. The dissolution profile of the modified drug product is comparable to the old one, if applicable. If dissolution testing is not possible, the disintegration time of the new drug product is compared to that of the unchanged drug product.
2. The drug product specifications at release and at the end of the expiration date have not changed (except for the dosage form dimensions).
3. The qualitative and quantitative composition and average weight have not changed.
4. The change does not affect tablets with a score line intended to divide the dosage form into equal doses.
1. Amendment to the relevant section(s) of the dossier, including a detailed graphical representation of the current and proposed position, as well as a revision of the medicinal product information, respectively.
2. Comparative dissolution data for at least one pilot batch with the current and proposed sizes (no significant differences in terms of comparability - see the Rules for Conducting Bioequivalence Studies of Medicinal Products in the Eurasian Economic Union (hereinafter referred to as the Rules for Conducting Bioequivalence Studies)). For herbal medicinal products, comparative disintegration data may be acceptable.
3. Justification for not submitting the results of a new bioequivalence study in accordance with the Rules for Conducting Bioequivalence Studies.
4. Where applicable, samples of the medicinal product.
5. Results of relevant tests in accordance with the Pharmacopoeia of the Union, confirming the equivalence of properties (correct dosage).
For B.II.a.2.b, any change in the dosage of a medicinal product requires the submission of an application for extension of registration.
B.II.a.3. Change in the composition (excipients) of a medicinal product
a) Change in the composition of flavorings or colorings
1. Addition, exclusion, or replacement
1, 2, 3, 4, 5, 6, 7, 9, 10
1, 2, 4, 5, 6
2. Increase or decrease in content
1, 2, 3, 4, 10
b) Other excipients
1. Any minor adjustment to the quantitative composition of the excipients of a medicinal product
1, 2, 4, 8, 9, 10
2. Qualitative or quantitative changes in one or more excipients that may significantly affect the quality, safety, or efficacy of the medicinal product
3. A change affecting a biological (immunological) product
4. Any new excipient that involves the use of materials of human or animal origin requiring an assessment of viral safety data and/or the risk of GE
5. Change justified by the results of a bioequivalence study
6. Replacement of one excipient with a similar excipient with the same functional characteristics in a similar quantity
1, 3, 4, 5, 6, 7, 8, 9, 10
1. There are no changes in the functional characteristics of the dosage form, such as disintegration time or dissolution profile.
2. Any minor adjustments to the composition to maintain the overall weight must be made using the excipient that currently constitutes the main part of the medicinal product.
3. The medicinal product specification has been updated with regard to appearance (odor, taste) and, where necessary, identity testing has been excluded.
4. Relevant stability studies have been initiated in accordance with Union documents (indicating batch numbers); the relevant stability parameters have been analyzed on at least two pilot-scale or industrial batches; the applicant has satisfactory results from at least a three-month stability study (at the time of introduction of Type IA amendments and notification of Type IB amendments); the stability profile is similar to the currently approved profile. Confirmation that the studies will be completed and that if the results at the end of the shelf life are not within specification or have the potential to be outside specification, they will be submitted promptly to the competent authority along with a proposed action plan. In addition, where appropriate, photostability testing must be performed.
5. All new components must meet the requirements of the relevant Union documents concerning colours and flavourings for use in food.
6. No new component involves the use of materials of human or animal origin requiring the assessment of viral safety data or compliance with the current requirements of the Union Pharmacopoeia for minimizing the risk of transmission of animal spongiform encephalopathy agents through medicinal products for human and veterinary use.
7. Where appropriate, the changes do not affect the differences between dosages and do not adversely affect the taste of medicinal products intended for children.
8. The dissolution profile of at least two pilot batches of the new medicinal product is comparable to that of the unchanged drug (no significant differences in terms of comparability – see the Union's Rules for Conducting Bioequivalence Studies). If dissolution testing with herbal medicinal products is not possible, the disintegration time of the new medicinal product is comparable to that of the unchanged drug.
9. The change is not a consequence of instability and/or should not affect safety, i.e., differences between dosages.
10. The medicinal product in question is not a biological (immunological) medicinal product.
1. Amendment to the relevant section(s) of the dossier, including identity testing methods for all new colorants (if applicable), and revision of the product information accordingly.
2. Declaration that the required stability studies in accordance with the Union documents (indicating batch numbers) have been initiated; and that (where applicable) the required minimum satisfactory stability data were available at the time of introduction of the amendment; and that the available data did not indicate any problem. Confirmation must also be provided that the studies will be completed and that if the results are not within specification or have the potential to be out of specification at the end of the expiration date, they will be immediately submitted to the competent authority, along with a proposed action plan. 3. Results of stability studies conducted in accordance with Union documents on the relevant stability parameters on at least two pilot-scale or industrial batches covering at least 3 months, and confirmation that these studies will be completed and, if the results are not within specification or have the potential to be out of specification at the end of the shelf life, will be provided promptly to the competent authority, along with a proposed action plan.
4. Where applicable, samples of the new medicinal product.
5. Either a certificate of conformity with the European Pharmacopoeia on GE for any new source material, or (if applicable) documentary evidence that the source material at risk of GE has previously been assessed by the competent authority and has been confirmed to comply with the current Union Pharmacopoeia monograph on minimizing the risk of transmission of animal spongiform encephalopathy agents through medicinal products for human and veterinary use. For each such material, the following information must be provided: name of the manufacturer; animal species and tissue from which the material is obtained; country of origin of the animals; and its use. 6. Where applicable, data confirming that the new excipient does not interact with the analytical methods used to specify the medicinal product.
7. Justification for the change (selection) of excipients, etc., must be provided through appropriate pharmaceutical development (including stability and antimicrobial preservation, if applicable).
8. Comparative dissolution profile data for solid dosage forms on at least two pilot batches of the medicinal product with the new and old formulations. For herbal medicinal products, comparative disintegration data may be sufficient.
9. Justification for failure to submit the results of a new bioequivalence study in accordance with the Rules for Conducting Bioequivalence Studies of the Union.
B.II.a.4. Change in the shell weight of oral dosage forms or change in the shell weight of capsules
a) Solid oral dosage forms
b) Delayed-, modified-, or extended-release dosage forms in which the shell is a key release factor
1. The dissolution profile of at least two pilot-scale batches of the new medicinal product is comparable to the old one. If dissolution testing with herbal medicinal products is not possible, the disintegration time of the new medicinal product is comparable to that of the old one.
2. The shell is not a key factor in the release mechanism.
3. The medicinal product specification has been updated only in terms of weight and dimensions (if applicable).
4. Relevant stability studies have been initiated in accordance with Union documents on at least two pilot-scale or industrial batches; The applicant has at least 3 months of satisfactory stability data at the time of introducing the change; confirmation that the studies will be completed. If the results are not within specification or have the potential to be out of specification at the end of the shelf life, they will be submitted promptly to the competent authority, along with a proposed action plan.
2. Declaration that the required stability studies in accordance with Union documents have been initiated (indicating the batch numbers); and that (where applicable) the required minimum satisfactory stability data were available at the time of introducing the change; and that the available data did not indicate any problem. Confirmation must also be provided that the studies will be completed and that if the results are not within specification or have the potential to be out of specification at the end of the shelf life, they will be submitted promptly to the competent authority, along with a proposed action plan. In addition, where applicable, photostability testing must be performed.
B.II.a.5. Changing the concentration of a single-dose, fully administered parenteral medicinal product while maintaining the active pharmaceutical ingredient content per unit dose (i.e., dosage)
B.II.a.6. Removing the solvent (diluent) container from the packaging
1. Justification for the exclusion, including reference to alternative methods of obtaining the solvent (diluent) to ensure safe and effective use of the medicinal product.
B.II.b) Production
B.II.b.1. Replacement or addition of a new manufacturing site for part or all of the drug product manufacturing processes
a) Secondary packaging site
1, 3, 8
b) Primary packaging site
1, 2, 3, 4, 8, 9
c) A site where manufacturing operations are carried out for biological (immunological) medicinal products or dosage forms produced using complex manufacturing processes, with the exception of batch release, batch quality control, and secondary packaging
d) A site requiring primary or product-specific inspection
e) A site where any manufacturing operations are carried out for non-sterile medicinal products, with the exception of batch release, batch control, primary and secondary packaging
1, 2, 3, 4, 5, 6, 7, 8, 9
f) A site where any manufacturing operations are carried out with sterile medicinal products manufactured using aseptic methods (excluding biological (immunological) medicinal products), with the exception of batch release, batch quality control, and secondary packaging
1, 2, 3, 4, 5, 7, 8
1. Satisfactory inspection within the last three years by inspection bodies of Member States, or by a country with which a valid agreement on mutual recognition of good manufacturing practice has been concluded.
2. The site is duly licensed (for the production of the dosage form or medicinal product in question).
3. The medicinal product in question is not sterile.
4. Where applicable, e.g., for suspensions or emulsions, a validation scheme is in place, or a new site has been successfully validated with at least three production batches in accordance with the current protocol.
5. The medicinal product in question is not a biological (immunological) product.
1. Confirmation that the proposed site is duly licensed for the manufacture of the dosage form or medicinal product under consideration.
2. Where applicable, the batch numbers, corresponding batch size, and batch production date (3) used in the validation study must be indicated, and the validation data or validation protocol (scheme) to be submitted must be provided.
3. In the section on amendments to the application for aligning the registration dossier with Union requirements (in the cover letter or the amendment application form attached to the cover letter), the previously approved and proposed manufacturers must be clearly identified, as specified in Section 2.5 of the application form.
4. Copies of the approved release specifications and expiration dates (if applicable).
5. Analysis data for one industrial batch and two pilot batches simulating the production process (or two industrial batches), and comparative data with three batches produced at the previous manufacturing site. Upon request, data for the next two complete production batches must be provided; if the analytical results are not within specification, a statement must be provided, and an action plan must be proposed.
6. Relevant validation data, including microscopic results of particle size distribution and particle morphology for soft and liquid dosage forms in which the pharmaceutical substance is undissolved.
7. If the active pharmaceutical substance is used as a starting material at the new manufacturing site, a declaration by the authorized person at the site responsible for batch release that the active pharmaceutical substance has been produced in accordance with the Union Good Manufacturing Practice for starting materials.
8. Amendment to the relevant section(s) of the dossier.
9. If the manufacturing site and the site where primary packaging takes place differ, the transport and storage conditions for the bulk product must be described and validated. (as amended by the decision of the Council of the Eurasian Economic Commission of 30.01.2020 N 9)
When changing or establishing a new manufacturing site in a country outside the Union with which there is no mutual recognition agreement for good manufacturing practice, holders are advised to consult with authorized bodies before submitting notification and provide information on all previous Union inspections over the past 2-3 years and/or all planned Union inspections, including inspection dates, product categories inspected, the supervisory authority, and other information. All this, if necessary, will facilitate preparations for the inspection for compliance with the Good Manufacturing Practice Rules of the Eurasian Economic Union by the Member State inspectorate.
Authorized Person Declarations Concerning Active Pharmaceutical Substances
Manufacturing license holders are required to use only active pharmaceutical ingredients manufactured in accordance with GMP as starting materials. Therefore, each manufacturing license holder is required to declare that it uses active pharmaceutical ingredients manufactured in accordance with GMP as starting materials. Furthermore, since the authorized person responsible for batch certification assumes overall responsibility for each batch, if the site producing the batch differs from the one specified above, the authorized person responsible for batch certification must submit an additional declaration.
In many cases, only one manufacturing license holder is involved, so only one declaration is required. However, if multiple manufacturing license holders are involved, a single declaration signed by a single authorized person may be submitted instead of submitting multiple declarations. This is permissible provided that:
the declaration clearly indicates that it is signed on behalf of all authorized persons involved;
the arrangements are secured by a technical agreement described in Chapter 7 of the Union's Good Manufacturing Practices, and the authorized person submitting the declaration is specified in such an agreement as undertaking compliance of the manufacturer(s) of the active pharmaceutical ingredient with the Union's Good Manufacturing Practices. Note: These agreements are subject to inspection by authorized bodies.
B.II.b.2. Change of importer, agreements on batch release, and quality control testing of a medicinal product
a) replacement or addition of a site where batch quality control (testing) is performed
2, 3, 4, 5
b) replacement or addition of a manufacturer responsible for batch release of a biological (immunological) medicinal product and any test methods performed at the site that are biological (immunological) methods
c) replacement or addition of a manufacturer responsible for batch release
1. Excluding batch quality control (testing)
2. Including batch quality control (testing)
3. Including batch quality control (testing) of a biological (immunological) medicinal product and one of the test methods performed at the site is biological (immunological, immunochemical)
1. The manufacturer responsible for batch release must be located within the Union. At least one batch release site capable of certifying drug testing for batch release within the Union is maintained within the Union.
2. The site is licensed in accordance with the established procedure.
3. The medicinal product is not a biological (immunological) medicinal product.
4. The technology transfer from the old to the new site or new testing laboratory has been successfully completed.
5. At least one batch control (testing) site capable of testing the drug for batch release within the Union is maintained within the Union or in a country with which a valid and corresponding agreement on mutual recognition of good manufacturing practice has been concluded between that country and the Union.
1. A copy of the manufacturing licenses or, in their absence, a certificate of good manufacturing practice issued within the last three years by the relevant authorized body.
2. In the section on amendments to the application for bringing the dossier into compliance with Union requirements (in the cover letter or the amendment application form attached to the cover letter), the previously approved and proposed manufacturers must be clearly identified, as specified in Section 2.5 of the application form.
(Clause 2 as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated 30.01.2020)
3. A declaration from the authorized person responsible for batch certification stating that the manufacturer(s) of the active pharmaceutical substance specified in the registration dossier comply with the Union's Good Manufacturing Practice for starting materials. Under certain circumstances, one declaration may be submitted (see note to Amendment B.II.b.1).
4. An amendment to the relevant section(s) of the dossier, including the information on the medicinal product.
B.II.b.3 Change in the manufacturing process of a medicinal product, including an intermediate used in the manufacture of the medicinal product
a) Minor changes in the manufacturing process
1, 3, 4, 5, 6, 7, 8
b) Significant changes in the manufacturing process that may have a significant impact on the quality, safety, and efficacy of the medicinal product
c) The medicinal product is a biological (immunological) product, and the change requires a comparability assessment
d) Introduction of a non-standard terminal sterilization method
e) Introduction or increase in an excess used for the active pharmaceutical ingredient
f) Minor change in the manufacturing process of an aqueous oral suspension
1, 2, 4, 6, 7, 8
1. There are no changes in the qualitative or quantitative impurity profile or physicochemical properties.
2. The change concerns a solid oral dosage form (oral solution) with immediate release, and the medicinal product in question is not biological (immunological) or herbal.
3. The manufacturing principle, including its individual stages, remains unchanged, for example, the processing of intermediates, and there are no changes to any solvents used in the manufacturing process.
4. The currently registered manufacturing process is monitored by in-process controls, and a change to such controls (expansion or exclusion of acceptance criteria) is not required.
5. The specifications of the medicinal product or intermediates remain unchanged.
6. The new process must result in a medicinal product that is identical in all aspects of quality, safety, and efficacy.
7. In accordance with the relevant Union documents, appropriate stability studies have been initiated on at least one pilot or industrial batch; The applicant has satisfactory results from at least a 3-month stability study. Confirmation that the studies will be completed and that if the results are not within specification or have the potential to be outside specification at the end of the shelf life, they will be promptly submitted to the competent authority along with a proposed action plan.
2. For soft and liquid dosage forms in which the active pharmaceutical ingredient is undissolved: appropriate validation of the amendment, including particle microscopy to check for visible changes in morphology; comparative data on particle size distribution (dispersity), obtained by an appropriate method.
3. For solid dosage forms: dissolution profile data for one representative production batch and comparative data for the last three batches produced using the previous process. Upon request, data for a further two complete production batches must be provided or a statement must be provided if the results are not within specification and a proposed action plan must be proposed. For herbal medicinal products, comparative disintegration data may be sufficient.
4. Justification for failure to submit the results of a new bioequivalence study in accordance with the Union Bioequivalence Study Rules.
5. When changing process parameter(s) that are considered not to affect the quality of the medicinal product, a declaration that this was achieved in a previously approved risk assessment.
6. Copies of release and expiration date specifications.
7. Batch analysis data (in comparative table format) for at least one batch produced using the approved and proposed process. Upon request, data for two further complete production batches must be provided; if the analysis results are not within specification, an action plan must be proposed. 8. Declaration that the relevant stability studies in accordance with the Union documents (indicating the batch numbers) have been initiated and the required stability parameters have been studied on at least one pilot-scale or industrial batch, and that at the time of notification the applicant had satisfactory results of at least a 3-month stability study; and the stability profile is similar to the currently reported situation. Confirmation is provided that the studies will be completed and that if the results are not within specifications or may potentially be outside specifications at the end of the shelf life, they will be immediately submitted to the competent authority along with a proposed action plan.
B.II.b.4. Change in the batch size (including batch size ranges) of a medicinal product
a) increase by up to 10 times compared to the approved batch size
b) decrease by up to 10 times
1, 2, 3, 4, 5, 6
c) the change requires a comparability analysis of the biological (immunological) medicinal product or the change in batch size requires a new bioequivalence study
d) the change affects all other dosage forms produced using integrated manufacturing processes
e) increase by more than 10 times compared to the approved batch size of immediate-release dosage forms (for oral administration)
f) the scale of production of the biological (immunological) medicinal product has increased (decreased) without changing the production process (e.g., duplicating a line)
1. The change does not affect the reproducibility and/or consistency of quality of the medicinal product.
2. The change affects standard immediate-release oral dosage forms or non-sterile liquid dosage forms.
3. Any changes in manufacturing methods and/or in-process controls are necessary only for a change in batch size, such as the use of equipment of a different size.
4. A validation scheme is in place, or, in accordance with the current protocol, manufacturing validation has been successfully completed on at least three production batches with the new size in accordance with the applicable requirements.
6. The change must not be a consequence of unforeseen situations arising during manufacturing or a change in stability.
7. The batch size is within 10 times the range specified at registration or after a subsequent change that was not a Type IA change.
2. Batch analysis data (in comparative table format) for at least one industrial batch produced in the registered and proposed sizes. Upon request, data for the following two full industrial batches must be provided; the MAH is obliged to inform if the analysis results are not within specification and propose an action plan.
3. Copies of the approved release and expiration date specifications.
4. Where applicable, the batch numbers corresponding to the batch size and their production date (3) used in the validation study must be indicated, or a validation protocol (flowsheet) must be provided.
5. Validation results must be provided.
6. Results of stability studies conducted in accordance with Union documents for significant stability parameters on at least one pilot or industrial batch covering at least 3 months; Confirmation that such studies will be completed and that if the results are not within specifications or may potentially be outside specifications at the end of the shelf life, they will be promptly submitted to the competent authority along with a proposed action plan. For biological (immunological) products: a declaration that a comparability assessment is not required.
B.II.b.5. Changes to in-process tests or acceptance criteria used in the manufacture of a medicinal product
b) Addition of new tests or acceptance criteria
c) Elimination of a nonessential in-process test
d) Elimination of an in-process test that may significantly affect the overall quality of the medicinal product
d) Expansion of approved in-process acceptance criteria that may significantly affect the overall quality of the medicinal product
e) Addition or replacement of an in-process test for safety or quality reasons
1. The change is not a consequence of any commitment made as a result of previously conducted assessments to review the specification acceptance criteria (e.g., during registration or Type II amendments).
6. The new test method is not a biological (immunological, immunochemical) test or a method that uses a biological reagent for a biologically active pharmaceutical ingredient (except for standard pharmacopoeial microbiological methods).
7. In-process testing does not affect the control of a critical parameter, such as:
quantitation;
Impurities (unless a specific solvent is clearly used in production);
Any critical physical characteristic (particle size, bulk density before and after compaction, etc.);
Identity testing (in the absence of a suitable alternative control);
Microbiological testing (unless required for a specific dosage form).
2. Comparison table of current and proposed in-process tests and acceptance criteria.
3. Detailed description of the new analytical method and validation data (where applicable).
4. Analysis data for two industrial batches (three batches in the absence of adequate justification for biologically active pharmaceutical ingredients) of the medicinal product for all specification parameters.
5. Where applicable, comparative dissolution profile data for the medicinal product for at least one pilot batch produced using the current and new in-process tests.
6. For herbal medicinal products, comparative disintegration data may be sufficient.
7. Justification (risk assessment) confirming that the in-process test is irrelevant or outdated.
8. Justification for the new in-process test and acceptance criteria.
B.II.c) Quality control of excipients
B.II.c.1. Change in specification parameters and/or excipient acceptance criteria
a) Tightening of specification acceptance criteria
b) Addition of a new specification parameter and its corresponding test method to the specification
1, 2, 3, 4, 6, 8
c) Deletion of a nonessential specification parameter (e.g., deletion of an obsolete parameter)
d) Change that goes beyond the approved specification acceptance criteria
e) Deletion of a specification parameter that may significantly affect the overall quality of the medicinal product
f) Addition or replacement (excluding biological and immunological products) of a specification parameter and its corresponding test method for safety or quality reasons
1, 2, 3, 4, 5, 6, 8
g) If there is no monograph of the Pharmacopoeia of the Union or the pharmacopoeia of a Member State for the excipient, change the specification data to an unofficial pharmacopoeia or a third-country pharmacopoeia
1. The change is not a consequence of any commitment made based on the results of previously conducted assessments to analyze the specification acceptance criteria (e.g., during drug registration or Type II amendments).
7. The change does not concern a genotoxic impurity.
8. A specification parameter does not affect the control of a critical parameter, such as:
impurities (unless a specific solvent is explicitly used in production)
any critical physical characteristic (particle size, bulk density before and after compaction, etc.)
identity testing (in the absence of a suitable alternative control) microbiological control (unless required for a specific dosage form)
3. Detailed description of any new analytical method and validation data (if applicable).
4. Analysis data for two industrial batches (or three batches, if not adequately substantiated for biologically active pharmaceutical ingredients) of the excipient for all specification parameters.
5. Where applicable, comparative dissolution kinetics test data for at least one pilot batch containing the excipient meeting the current and proposed specifications. For herbal medicinal products, comparative disintegration data may be sufficient.
6. Justification for failure to submit the results of a new bioequivalence study in accordance with the Union Bioequivalence Study Rules.
7. Rationale (risk assessment) confirming that the parameter is irrelevant or outdated.
8. Justification of the new specification parameter and acceptance criteria.
B.II.c.2. Changes to the analytical procedure for an excipient
a) Minor changes to an approved analytical procedure
b) Exclusion of an analytical procedure if an alternative procedure has already been approved
c) Replacement of a biological (immunological, immunochemical) test method or a method that uses a biological reagent
d) Other changes to the analytical procedure (including addition or substitution)
1. In accordance with the relevant documents, the necessary validation studies have been conducted to confirm that the updated analytical procedure is at least equivalent to the previous one.
2. The limits for the total impurity content have not changed, and no new unqualified impurities have been detected.
4. The new test method is not a biological method (immunological, immunochemical) or a method that uses a biological reagent (with the exception of standard pharmacopoeial microbiological methods).
5. An alternative analytical procedure for the specification parameter has already been approved, and such procedure was not included through an IA notification.
Amendment to the relevant section(s) of the dossier, including a description of the analytical methodology, a summary of validation data, and revised impurity specifications (if applicable).
Comparative validation results or, if justified, comparative analytical results confirming that the current and proposed assays are equivalent. This requirement does not apply if a new analytical procedure is added.
B.II.c.3. Change in the source of an excipient or reagent with a GE risk
a) from a material with a GE risk to a material of plant or synthetic origin
1. For excipients or reagents not used in the production of a biological (immunological) active pharmaceutical ingredient or biological (immunological) medicinal product
2. For excipients or reagents used in the production of a biological (immunological) active pharmaceutical ingredient or biological (immunological) medicinal product
b) modification or introduction of a material with a GE risk or replacement of a material with a GE risk with another material with a GE risk that does not have a GE certificate of conformity
The release and expiration date specifications for the excipient and medicinal product remain unchanged.
Declaration by the manufacturer or marketing authorization holder of the material that it is of purely plant-based or synthetic origin.
A study of the equivalence of the materials and their impact on the production of the finished material and the impact on the characteristics (e.g., dissolution characteristics) of the medicinal product.
B.II.c.4. Change in the synthesis or production of a non-pharmacopeial excipient (if described in the registration dossier) or a new excipient
a) An insignificant change in the synthesis or production of a non-pharmacopeial excipient or a new excipient
b) The specifications change or there is a change in the physicochemical properties of the excipient that may affect the quality of the medicinal product
c) The excipient is a biological (immunological) substance
The synthesis method and specifications are identical, and there are no qualitative or quantitative changes in the impurity profile (excluding residual solvents, provided that they are controlled in accordance with the maximum content specified in the Union documents) or physicochemical properties.
Excluding adjuvants.
2. Batch analysis data (in comparative table format) for at least two batches (at least pilot-scale) of the excipient, manufactured using the old and new processes.
3. Where applicable, comparative dissolution kinetics test data for at least two batches (at least pilot-scale). For herbal medicinal products, comparative disintegration data may be sufficient.
4. A copy of the approved and new (if applicable) excipient specifications.
B.II.d) Quality control of the medicinal product
B.II.d.1. Change in specification parameters and/or acceptance criteria of a medicinal product
Documents
b) tightening the specification acceptance criteria for medicinal products subject to batch release by an official control body
c) adding a new parameter and corresponding test method to the specification
d) excluding a nonessential specification parameter (e.g., excluding an obsolete parameter)
e) a change that goes beyond the approved specification acceptance criteria
f) excluding a specification parameter that may significantly affect the overall quality of the medicinal product
g) adding or replacing (excluding biological and immunological products) a specification parameter and corresponding test method for safety or quality reasons
h) updating the dossier to comply with the provisions of the updated general monograph of the Pharmacopoeia of the Union for the medicinal product <*>
1, 2, 3, 4, 7, 8
i) the Union Pharmacopoeia article "Uniformity of Dosage Units" is introduced to replace the previously approved registered method, or the article "Uniformity of Unit Mass of a Dosage Form (Medicinal Product)" is introduced.
(subparagraph "i" as amended by Decision No. 9 of the Council of the Eurasian Economic Commission dated January 30, 2020)
1, 2, 10
1. The change does not result from any commitment made following previously conducted reviews to revise the specification acceptance criteria (e.g., during drug product registration or Type II changes), unless the supporting documentation has previously been reviewed and approved under another procedure.
2. The change does not result from unforeseen situations that arose during manufacturing, such as a new unqualified impurity or a change in the impurity limits.
7. The change does not affect any impurities (including genotoxic ones) or dissolution.
8. The amendment concerns updating the acceptance criteria for microbiological controls to comply with the current Pharmacopoeia of the Union, and the currently registered acceptance criteria for microbiological controls do not include any additional controls included in the specification, other than the pharmacopoeial requirements for a particular dosage form.
9. The specification parameter does not affect a critical parameter, such as:
quantitation
of an impurity (unless a specific solvent is clearly used in the production of the medicinal product)
any critical physical characteristic (hardness or friability of uncoated tablets, size, etc.)
any request to skip a test
10. The proposed control fully complies with the table of the Pharmacopoeia of the Union article "Uniformity of unit mass of a dosage form (dosed medicinal product)" and does not include proposals for alternative dosage uniformity tests using variation mass or content homogeneity, if these alternative tests are specified in the table of the article of the Pharmacopoeia of the Union "Uniformity of Mass of a Unit of Dosage Form (Medicinal Product)".
(Clause 10 as amended by Decision of the Council of the Eurasian Economic Commission dated 30.01.2020 N 9)
4. Analysis data from two industrial batches (in the absence of adequate justification for biologically active pharmaceutical ingredients - 3 batches) of the medicinal product for all specification parameters.
5. Where applicable, data from a comparative dissolution kinetics test of the medicinal product for at least one pilot batch corresponding to the current and proposed specifications. For herbal medicinal products, comparative disintegration data may be sufficient.
6. Justification (risk assessment) confirming that the parameter is insignificant.
7. Justification of the new specification parameter and acceptance criteria.
If the registered medicinal product dossier mentions the "current edition," it is necessary to notify authorized bodies of the updated article of the Union Pharmacopoeia or the pharmacopoeia of a Member State. Therefore, such an amendment applies when there is no reference to the updated pharmacopoeial article in the technical dossier, and the amendment is made to include a reference to the updated version.
B.II.d.2. Changes to the analytical procedure of a medicinal product
c) Change (replacement) of a biological (immunological, immunochemical) test or method that uses a biological reagent, or replacement of a biological reference product not covered by the approved protocol
d) Other changes to the analytical procedure (including addition or replacement)
e) Updating the analytical procedure to comply with the updated general article of the Pharmacopoeia of the Union
f) To reflect compliance with the Pharmacopoeia of the Union and to exclude reference to an outdated proprietary analytical procedure and its number <*>
1. In accordance with the relevant documents, the necessary validation studies have been conducted to confirm that the updated analytical method is at least equivalent to the previous one.
5. The registered analytical method already references the general monograph of the Pharmacopoeia of the Union, and any changes are minor and require an update of the technical dossier.
1. Amendment to the relevant section(s) of the dossier, including a description of the analytical methodology, a summary of the validation data, and revised impurity specifications (if applicable).
<*> Примечание
If the dossier of a registered medicinal product mentions the "current edition", there is no need to notify the authorized bodies about the updated article of the Pharmacopoeia of the Union.
B.II.g.3. Change affecting the introduction of real-time release or parameter release in the manufacture of a medicinal product
B.II.e) Packaging and capping system
B.II.e.1. Change in the primary packaging of a medicinal product
a) Qualitative and quantitative composition
1. Solid dosage forms
2. Soft and non-sterile liquid dosage forms
3. Sterile medicinal products and biological (immunological) medicinal products
4. The change affects packaging with less protective properties while simultaneously changing storage conditions and/or shortening the shelf life
b) Change in container type or addition of a new container
1. Solid, soft, and non-sterile liquid dosage forms
1, 2, 3, 5, 6, 7
2. Sterile medicinal products and biological (immunological) medicinal products
3. Elimination of a primary packaging container that does not lead to complete elimination of the dosage or dosage form
1, 8
1. The change affects only one type of packaging (container) (e.g., blister pack to blister pack).
2. The proposed packaging material must be at least equivalent to the approved one in terms of its significant properties.
3. Relevant stability studies have been initiated in accordance with Union documents, and the applicant has analyzed the relevant stability parameters in at least two pilot-scale or industrial batches at the time of the change, and has satisfactory results from at least a three-month stability study. However, if the proposed packaging is more stable than the approved one, three-month stability data are not required. The studies must be completed; if their results do not meet specifications or have the potential to exceed specifications at the end of the expiration date, they must be immediately submitted to the authorized body along with a proposed action plan. 4. The remaining dosage form(s) of the medicinal product must be sufficient to comply with the dosage and duration of treatment recommendations specified in the general characteristics of the medicinal product.
2. Required data on the new packaging (e.g., comparative permeability data, e.g., for O2, CO2, moisture, etc.).
3. Where applicable, evidence must be provided that no interaction between the contents and the packaging material occurs (e.g., no migration of components of the proposed material into the contents, no migration of components of the medicinal product into the packaging), including evidence that the material complies with the relevant pharmacopoeial requirements or Union legislation on plastic materials and objects in contact with food.
4. Declaration that the required stability studies have been initiated in accordance with Union documents (indicating the batch numbers); and that (where applicable) the applicant had the required minimum satisfactory stability data at the time of introduction of the amendments; and that the available data did not indicate any problem. Confirmation must also be provided that the studies will be completed and that if the results are not within specification or have the potential to be out of specification at the end of the shelf life, they will be immediately submitted to the competent authority along with a proposed action plan.
5. Results of stability studies conducted in accordance with Union documents on the relevant stability parameters on at least two pilot-scale or industrial batches covering at least three months, and confirmation that these studies will be completed and that if the results are not within specification or have the potential to be out of specification at the end of the shelf life, they will be immediately submitted to the competent authority along with a proposed action plan.
7. Where applicable, samples of the new container (closure).
8. Declaration that the remaining package size(s) correspond(s) to the dosage regimen and duration of treatment and are sufficient to comply with the dosage recommendations given in the general characteristics of the medicinal product.
For B.II.D.1.b) - if the change leads to the “creation of a new dosage form”, then such a change requires the filing of an application for expansion of registration.
B.II.e.2. Changes in specification parameters and/or acceptance criteria of primary packaging of a medicinal product
b) adding a new parameter and corresponding analytical method to the specification
c) eliminating a nonessential specification parameter (e.g., eliminating an obsolete parameter)
d) adding or replacing a specification parameter for safety or quality reasons
The change does not result from any commitment made based on the results of previously conducted assessments to review specification acceptance criteria (e.g., during drug product registration or Type II changes).
The change does not result from unforeseen situations that arose during manufacturing.
Any change must be within the range of currently approved acceptance criteria.
The analytical procedure is unchanged or changes only slightly.
No new test method is based on a new, non-standard methodology or a standard methodology used in a new way.
4. Analysis data from two batches of packaging material for all specification parameters (indicators).
5. Rationale (risk assessment) confirming that the parameter is insignificant.
6. Justification for the new specification parameter and acceptance criteria.
B.II.e.3. Changes to the analytical procedure for the primary packaging of a medicinal product
b) other changes to the analytical procedure (including replacement or addition)
c) exclusion of an analytical procedure if an alternative procedure has already been approved
1. According to the relevant documents, the required validation has been conducted, confirming that the updated analytical procedure is at least equivalent to the previous one.
2. The analytical method has not changed (e.g., a change in column length or temperature, but not a different column or method).
3. No new test method is based on a new, non-standard methodology or a standard methodology used in a new way.
4. The active pharmaceutical ingredient (drug product) is not a biological (immunological).
2. Comparative validation results or, if justified, comparative analytical results confirming that the current and proposed assays are equivalent. This requirement does not apply if a new analytical procedure is added.
B.II.e.4. Change in shape or size of primary packaging or closure (primary packaging)
a) non-sterile medicinal products
b) change in shape or size affects key performance indicators of the packaging material that may significantly impact the delivery, use, safety, or stability of the medicinal product
c) sterile medicinal products
1. The qualitative and quantitative composition of the primary packaging has not changed.
2. The change does not affect key quality indicators of the packaging material that may impact the delivery, use, safety, or stability of the medicinal product.
3. If the headspace or surface-to-volume ratio is changed, appropriate stability studies have been initiated in accordance with the relevant Union stability documents; the relevant stability parameters have been analyzed in at least two pilot-scale (for biological (immunological) medicinal products - three batches) or industrial batches; the applicant has satisfactory results from at least a three-month stability study (for biological (immunological) medicinal products - a six-month study). Confirmation that the studies will be completed and that if the results are not within specifications or may potentially be outside specifications at the end of the expiration date, they will be promptly submitted to the authorized body along with a proposed action plan.
1. Amendment to the relevant section(s) of the dossier, including a description, detailed drawing, and material composition of the container or closure, as well as a revision of the medicinal product information.
2. Where applicable, samples of the new container (closure).
3. Repeat validation studies of sterile products subject to terminal sterilization have been conducted. Where applicable, the batch numbers used in the validation studies must be indicated.
4. If the headspace or surface-to-volume ratio has been changed, a declaration that the required stability studies have been initiated in accordance with Union documents (indicating the batch numbers); and that (where applicable) satisfactory stability study results are available at the time of implementation of the Type IA change notification and submission of the Type IB change notification; and that the available data do not indicate any problems. Confirmation must also be provided that the studies will be completed and that if the results are not within specification or may potentially be outside specification at the end of shelf life, they will be presented promptly to the competent authority along with a proposed action plan.
B.II.e.5. Change in the size of a medicinal product packaging
a) Change in the number of units of a dosage form (e.g., tablets, ampoules, etc.) in a packaging
1. The change is within the approved range of packaging sizes
2. The change is not within the approved range of packaging sizes
b) Change in the size(s) of the packaging(s)
c) Change in the nominal weight (nominal volume) of sterile multi-dose (or single-dose with partial extraction) parenteral medicinal products and biological (immunological) multi-dose parenteral medicinal products
d) Change in the nominal weight (nominal volume) of non-parenteral multi-dose (or single-dose with partial extraction) medicinal products
1. The new package size must comply with the dosage regimen and treatment duration specified in the summary of product characteristics.
2. The primary packaging material remains unchanged.
3. The remaining dosage forms comply with the dosage and treatment duration recommendations specified in the summary of product characteristics.
1. Amendment to the relevant section(s) of the dossier, including revision of the product information.
2. Justification that the new (remaining) package sizes comply with the dosage regimen and treatment duration specified in the summary of product characteristics.
3. Declaration that if an impact on stability is expected, stability studies will be initiated in accordance with the relevant Union documents. Data must be submitted (with a proposed action plan) only if they are outside the specifications.
For B.II.e.5.v and B.II.e.5.g - if the change results in a change in the "dosage" of the medicinal product, then such a change requires the filing of an application for expansion.
B.II.e.6. Changes to any component of the packaging (packaging material) that does not directly come into contact with the medicinal product (e.g., the color of removable caps, color code rings on ampoules, changes to the needle cap (use of a different plastic), changes to the design, color of the markings, application of a barcode (2D, 3D), application of Braille)
a) change affecting information about the medicinal product
b) change not affecting information about the medicinal product
1. The change does not affect any portion of the packaging material that could affect the delivery, use, safety, or stability of the medicinal product.
1. Amendment to the relevant section(s) of the dossier, including revision of the medicinal product information.
B.II.e.7 Change in supplier of packaging components or device (if specified in the dossier)
a) Deletion of supplier
b) Substitution or addition of supplier
c) Any change in suppliers of metered-dose inhaler spacers
1. No packaging or product component is excluded.
2. The qualitative and quantitative composition of the packaging (product) components and the design specifications remain unchanged.
3. The specifications and quality control methods are at least equivalent.
4. The sterilization method and conditions remain unchanged (if applicable).
2. Confirmation of registration of the medical device in the Union for medical devices supplied with the medicinal product.
3. Comparison table of current and proposed specifications (if applicable).
B.II.f) Stability
B.II.f.1. Changing the shelf life or storage conditions of a medicinal product
a) Reducing the shelf life of a medicinal product
1. Packaged in commercial packaging
2. After first opening
3. After dilution or reconstitution
b) Increasing the shelf life of a medicinal product
1. Packaged in commercial packaging (confirmed by real-time data)
2. After first opening (confirmed by real-time data)
3. After dilution or reconstitution (confirmed by real-time data)
4. Increasing the shelf life by extrapolating stability data that does not comply with Union documents <*>
5. Increasing the shelf life of a biological (immunological) medicinal product in accordance with an approved stability study program
c) Changing the storage conditions of biological (immunological) medicinal products if stability studies were not conducted in accordance with the currently approved stability study program
d) Changing the storage conditions of the medicinal product or the medicinal product after dilution (reconstitution)
d) Changing the approved stability protocol
1. The change must not be a consequence of unexpected situations arising during manufacturing or a change in stability.
2. The changes do not lead to expansion of the acceptance criteria for the parameters tested, exclusion of a stability parameter, or reduction in the frequency of testing.
1. Amendment to the relevant section(s) of the dossier. It must contain the results of relevant real-time stability studies (covering the entire shelf life) conducted in accordance with the relevant Union documents on at least two pilot-scale batches <1> of the medicinal product packaged using the registered packaging material and/or, respectively, after first opening or dilution; where applicable, the results of microbiological tests must be provided.
3. Copies of the approved specifications at the end of the shelf life and, if applicable, the specifications after dilution (reconstitution) or after first opening.
Extrapolation is not applicable to biological (immunological) medicinal products.
If there is an obligation to verify the expiration date on industrial batches, pilot batches are permitted.
B.II.g) Project field and protocol of post-registration changes
B.II.g.1 Introduction of a new design area or expansion of an approved design area of a medicinal product (except for a biological product), affecting:
a) One or more individual operations of the medicinal product manufacturing process, including the corresponding in-process control and/or analytical methods
b) Analytical methods for excipients (intermediates) and/or the medicinal product
1. Results of drug and process development studies (including risk assessment and multivariate studies, respectively) confirming that a comprehensive mechanistic understanding of the impact of material quality attributes and process parameters on the critical quality parameters of the drug product has been achieved.
2. A description of the design space in tabular form, including variables (material properties and manufacturing process parameters) and their proposed ranges.
3. Amendment to the relevant section(s) of the dossier.
B.II.2 Introduction of a post-registration protocol for managing changes affecting the medicinal product
2. Protocol for managing changes affecting the medicinal product.
B.II.g.3 Exclusion of the approved protocol for managing changes affecting the medicinal product
1. An exemption from the post-marketing change management protocol affecting the medicinal product is not a consequence of unforeseen circumstances or non-compliance with the specification during the implementation of changes described in the protocol and does not in any way affect the approved information included in the dossier.
1. Justification for the proposed exemption.
2. Amendment to the relevant section(s) of the dossier.
B.II.g.4 Changes to the approved change management protocol
b) minor changes to the change management protocol that do not change the strategy described in the protocol
1. Declaration that any change must be within the range of currently approved acceptance criteria. Additionally, a declaration that no comparability assessment is required for biological (immunological) medicinal products.
B.II.g.5 Implementation of changes provided for in the approved change management protocol
a) implementation of the change does not require additional supporting data
b) implementation of the change requires additional supporting data
c) implementation of a change to a biological (immunological) medicinal product
1. The proposed change is implemented in full compliance with the approved change management protocol, requiring immediate notification upon implementation.
2. Declaration that the change complies with the approved change management protocol and that the study results meet the acceptance criteria specified in the protocol. Additionally, a declaration that comparability assessment is not required for biological (immunological) medicinal products.
4. Amendment to the relevant section(s) of the dossier.
5. Copy of the approved specifications for the medicinal product.
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