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Order of the Ministry of Health of Russia No. 409n from 12.07.2017 On approval of the procedure for the formation of a registration dossier for a medicinal product

On July 27, 2017, the Ministry of Health of Russia registered with the Ministry of Justice a new order on the procedure for the formation of a registration dossier of a drug for the state registration of a medicinal product. In this order, the Ministry of Health presents new requirements to the structure of the registration dossier, the way the documents for the registration dossier are formed, and the clear requirements for the submission of documents and the registration dossier to the appropriate body for state registration of drugs. Special attention is paid to the formation and submission of dossiers for orphan drugs and for pharmaceutical products, permitted for medical use in the Russian Federation for more than twenty years (with the exception of biological medicinal products).

MINISTRY OF HEALTH OF THE RUSSIAN FEDERATION

Order № 409н from 12.07.2017

On approval of the procedure for the formation of the registration dossier of  drugs and requirements to documents in its structure, requirements for the volume of information provided in the drug registration dossier, for certain types of drugs for medical use and the order of submission of documents, from which the registration dossier of a drug is formed with the purposes of its state registration


In accordance with sub-clauses 5.2.148, 5.2.1481, 5.2.1482 of the Regulation on the Ministry of Health of the Russian Federation approved by the Decree of the Government of the Russian Federation dated June 19, 2012 No. 608, I order:
1.    To approve: the procedure for the formation of a registration dossier for a medicinal product for medical use and the requirements for documents in its composition in accordance with Appendix № 1;
requirements for the amount of information provided in the registration dossier for certain types of medicinal products for medical use in accordance with Appendix № 2;
the procedure for submitting documents from which the registration dossier for a medicinal product for medical use is formed for the purposes of its state registration, in accordance with Appendix № 3.
2.    This order is applied to the registration dossiers for medicinal products for medical use submitted to the Ministry of Health of the Russian Federation with applications for the state registration of medicinal products for medical use after the entry into force of this order.
3.    To recognize as invalid the order of the Ministry of Health and Social Development of the Russian Federation of August 26, 2010, No. 759n "On approval of the procedure for submitting the necessary documents, from which the registration dossier for a medicinal product for medical use for the purposes of its state registration is formed" (registered by the Ministry of Justice Russian Federation on September 2, 2010, registration No. 18331).

 

Appendix No. 1
to the order of the Ministry of Health
of the Russian Federation
No. 409n dated July 12, 2017


The procedure for the formation of a registration dossier for a drug for medical use and the requirements for documents in its composition

1.    This procedure establishes the rules for the formation of a registration dossier of a drug submitted to the Ministry of Health of the Russian Federation by a legal entity acting in its own interests or authorized to represent the interests of another legal entity and submitting the pharmaceutical product for state registration and the requirements for documents in such dossier.
2.    The registration dossier of a medicinal product for medical use in the form of a general technical document is a set of documents and materials consisting of several sections - administrative documentation, chemical, pharmaceutical and biological documentation, pharmacological, toxicological documentation, clinical documentation.
3.    The administrative documentation section is formed from:
1)    application for state registration of a drug, which shall specify:
а)    name and address of the applicant and the manufacturer of the drug and the address of the place of its production (in the case several participants are involved in the production process, it is necessary to indicate each participant in accordance with its respective production stage);
b) the name of the medicinal product for medical use (international non-proprietary, or grouping, or chemical and trade names);
c) a list of active pharmaceutical ingredients and excipients included in the drug for medical use, indicating the amount of each of them;
d) dosage form, dosage, methods of administration and use, the expiration date of the pharmaceutical product;
e) Pharmacotherapeutic group, code of anatomical-therapeutic-chemical classification recommended by The World Health Organization, the claimed indications for the use of the drug;
f) the absence of the need to provide a report on the results of a clinical trial, a study of the bioequivalence of a drug permitted for medical use in the Russian Federation for more than twenty years, indicating the normative legal acts that confirm this period of application;
g) the need to obtain a permit for import into the Russian Federation a specific batch of registered and (or) unregistered pharmaceutical products intended for pharmaceutical examination of drugs with the purposes of state registration;
h) the need to carry out an examination of the documents submitted for determining the possibility of considering a drug for medical use to be an orphan drug while performing state registration;
i) the need to apply the accelerated procedure for the examination of drugs for the purposes of state registration of the drug;
j) copies of documents confirming payment of the relevant state fee:
for the examination of documents submitted for the determination of the possibility to consider a pharmaceutical to be an orphan drug while performing state registration;
for conducting the examination of the quality of the drug and examining the rate of the expected benefit to the possible risk of a medicinal product permitted for medical use in the Russian Federation for more than twenty years in the process of the state registration of the drug;
for performing the examination of the quality of the pharmaceutical product and examination of the rate of the expected benefit to the possible risk of using the drug for medical use when it is registered with the state;
for conducting the examination of the quality of the medicinal product and the examination of the expected benefit to the possible risk ratio of the use of a drug in respect of which international multicenter clinical studies were conducted, some of which were carried out in the Russian Federation, in the process of the state registration of the drug;
k) the consent of the manufacturer of the pharmaceutical product, the production of which is performed outside the Russian Federation, to inspect the manufacturer for compliance with the requirements of Good Manufacturing Practice;
l) the consent of the developer of the reference drug or the person authorized by him to use for commercial purposes information on the results of preclinical studies and clinical studies of referent drug for medical use, when submitting an application for state registration of a generic pharmacuetical product before the expiration of six years from the date of state registration of the reference drug in the Russian Federation;
m) indication of the type of a drug submitted for registration (reference drug, reproduced pharmaceutical product, biological medicinal product, biosimilar (bio-like) drug (bioanalog), homeopathic medicinal product, medicinal plant preparation);
2)    a copy of the document in Russian, certified in accordance with the established procedure and confirming the eligibility of the applicant to file an application for drug registration in Russia (Power of Attorney);
3)    copies of the manufacturing license of a drug producer or a copy of the conclusion on the compliance of the manufacturer of drugs with the requirements of Good Manufacturing Practice issued by the authorized federal executive body if production of the pharmaceutical product is performed in the Russian Federation;
4)    copies of a manufacturing license issued by the authorized body of the country of production for manufacturing of a drug and its translation into Russian, certified in accordance with the established procedure, and a copy of the conclusion on the compliance of the manufacturer of pharmaceutical products with GMP requirements issued by the authorized federal executive body, if production of a drug is carried out outside the Russian Federation;
5)    the draft of instruction for medical use of a drug containing the information specified in clause 5 of part 4 of Article 18 of Federal Law No. 61-FZ;
6)    instructions for medical use or a brief description of the medicinal product approved in the country of the manufacturer;
7)    projects of mock-ups of primary packaging and secondary packaging of a drug;
8)     the draft of normative document for a pharmaceutical product, containing a list of quality indicators for a drug, determined by the results of relevant expert examinations, quality validation methods established by its manufacturer, or the reference to a relevant pharmacopoeia article;
9)    a document containing information on the presence or absence of registration of a pharmaceutical product outside the Russian Federation;
10)    copies of documents certified in accordance with the established procedure and confirming the fact of drug registration in foreign countries as an orphan drug;
11)    a risk management plan for biological drugs for medical use that contains a detailed description of pharmacovigilance activities aimed at identifying, assessing and preventing or minimizing the risks associated with drugs, including evaluating the effectiveness of these activities;
12)    a document on the pharmacovigilance system of the Marketing Authorization holder or holder of the drug registration certificate containing information on the system organized by the holder or owner of the drug registration certificate intended for the control of drug safety, the timely detection of all changes in the assessment of the ratio of the expected benefit to the possible risk of drug use for medical application, development and implementation of measures to ensure the use of the drug maintains a positive ratio of the expected benefit to the possible risk;
13)    a document confirming the quality of the medicinal product of three pilot industrial and (or) industrial batches (analysis protocol or Certificate of Analysis), one series of which must coincide with a series of a sample of a drug submitted for state registration.
4.    The section of chemical, pharmaceutical and biological documentation is formed from documents containing information on pharmaceutical substance and drug, its production process and quality control methods, including:
1)    a copy of the document containing the following information about the pharmaceutical substance or pharmaceutical substances that make up the pharmaceutical product:
a) the name of the pharmaceutical substance, its structure, general properties;
b) the name and address of the producer;
c) technology of production with a description of the stages of production and methods of control at all stages of production;
d) brief description of the development of the production process;
e) description of control of critical stages of production and intermediate products, including data that can be presented in a block diagram, with a list of information on production stages, types and (or) methods of quality control of intermediate products;
e) documentary confirmation (validation) of the processes, including information confirmation of the applicability of the selected scheme for the production of the drug, and (or) their evaluation;
g) properties and structure of active pharmaceutical substances, including information on their physical and chemical properties;
h) characteristics of impurities, including information on their origin and properties;
i) the specification for the pharmaceutical substance and its rationale;
j) analytical methods used in quality control of a pharmaceutical substance;
k) documentary confirmation (validation) of analytical techniques used in the quality control of a pharmaceutical substance, including information confirming the applicability and sufficiency of methods for quality control of an API;
m) Protocols (Certificates or passports) of analysis of API series, including analytical data confirming the numerical quality indicators for quality of the pharmaceutical substance;
n) a list of standard samples or substances used in quality control, including the indication of their manufacturers and their designation;
o) description of characteristics and properties of packaging materials and closures;
n) data on the stability of the pharmaceutical substance;
p) shelf life;
2) a document containing the following information about a pharmaceutical product:
a) description and composition of the durg;
b)    description of pharmaceutical development (justification of the choice of composition, primary packaging, etc.);
c)    production technology with a description of the production stages and control methods at all stages of production, including an indication of the scheme of the manufacturing process of the pharmaceutical substance and its description, which may also include information on the control of feedstock, critical stages of production and intermediates, methods of controlling the excipients used in production of the drug;
d)    a description of the control of the critical stages of the production process and intermediate products, which may include a sequential presentation of all stages of the manufacturing process;
e) the name and address of the production site of the durg for medical use (if there are several participants in the production process, it is necessary to indicate each of them)
e) pharmaceutical compatibility, including data confirming the compatibility of the active ingredients and excipients that comprise the pharmaceutical product;
g) microbiological characteristics;
h) material balance for the production of a series of finished products, which can be represented in a block diagram that shows the sequence of execution of all stages and stages (operations) of the technological process, indicating the main material flows (raw materials, materials, intermediate products, output of finished medicinal preparation);
i) a description of the characteristics and properties of packaging materials and closures;
j) documentary confirmation (validation) of production processes, including information on the validation of the production process and selection of control parameters and tests in the production process, and (or) their evaluation;
k) requirements for the quality of excipients (certificate, specification for excipients and their justification), including as evidence supporting the evidence of the use of excipients for the manufacture of pharmaceutical products in order to ensure the stability of the finished dosage form;
m) the list of brief description of analytical methods used in quality control of excipients;
l) documentary confirmation (validation) of analytical methods used in the quality control of excipients, presented in the form of evidence confirming the applicability and sufficiency of quality control methods for excipients;
m) information on the use of excipients of human and animal origin;
n) information on the use of new excipients;
o) requirements for the quality of the drug (certificate, specification for the medicinal product and their rationale);
p) Analytical methodologies used in the quality control of a drugs for medical use, which may also be referred to as pharmacopoeia articles or a detailed list of the quality control methods used;
q) documentary confirmation (validation) of analytical methods used in the quality control of the pharmaceutical product, including information confirming the applicability and sufficiency of methods for quality control of the drug;
r) results of analyzes of batches of the medicine;
s) characteristic of impurities;
t) a list of reference standards used in the quality control of a drug;
u) stability data for the drug.

5.    The section of pharmacological, toxicological documentation is formed from the reports on the results of preclinical studies of the вкгп for medical use, including:
1)    a report on pharmacodynamic studies, including a brief summary of the pharmacodynamic studies performed if several such studies have been carried out;
2)    a report on pharmacokinetic studies, including a brief summary of the pharmacokinetic studies performed if several such studies have been conducted;
3)    a report on toxicological studies, including a brief summary of the toxicological investigations that have been carried out, if several such studies have been performed.
6.    The section of clinical documentation is formed from the reports on the results of clinical trials of the drug for medical use, including:
1)    reports on bioavailability and bioequivalence studies, studies correlating the results obtained under in vitro and in vivo conditions;
2)    reports on pharmacokinetic studies;
3)    reports on pharmacodynamic studies;
4)    reports on clinical trials of efficacy and safety, including reports on the results of clinical trials of drugs not attributed to orphan medicinal products conducted in the Russian Federation, or international multicenter clinical trials of medicinal products not assigned to orphan drugs, some of which were performed in the Russian Federation;
5)    report on post-registration experience of application (if available).
7.    Requirements for the volume of information provided in the drug registration dossier for certain types of medicinal products for medical use are specified in Appendix No. 2 to Order No. 409n of the Ministry of Health of the Russian Federation of July 12, 2017.

 

Appendix No. 2
to the order of the Ministry of Health
of the Russian Federation
No. 409n dated July 12, 2017

Requirements for the volume of information provided in the drug registration dossier for certain types of drugs for medical use

1.    For medicinal products permitted for medical use in the Russian Federation for more than twenty years (with the exception of biological medicinal products), it is allowed to include the review of scientific works on the results of preclinical drug studies and clinical trials of these drugs, including but not limited to post-marketing experience of drug application, instead of the inclusion of a developer's report on the results of their own preclinical studies of drugs and clinical research of medicines into section of pharmacological, toxicological documentation and a section of clinical documentation.
2.    At the process of state registration of reproduced drugs it is allowed to include in the section of pharmacological, toxicological documentation and section of clinical documentation a review of scientific works on the results of preclinical studies of the reference medication instead of the developer's report on the results of own preclinical studies of drugs, and presentation of a report on the results of bioequivalent studies of a reproduced drug or a report on the results of therapeutic equivalence studies instead of clinical studies in full  in the section of clinical documentation.
It is not required to present a report on the results of bioequivalence studies of a reproduced drug or a report on the results of studies of the therapeutic equivalence of a pharmaceutical product if registered medicinal products:
          1) are intended for parenteral administration (subcutaneous, intramuscular, intravenous, intraocular, intracavitary, intraarticular, intracoronary) and are aqueous solutions;
          2) are solutions for oral administration;
          3) are produced in the form of powders or lyophilizates for the preparation of solutions; are gases;
           4) are ear or eye medications, produced in the form of aqueous solutions;
           5) are intended for topical application and are prepared in the form of aqueous solutions;
           6) are aqueous solutions for use in the form of nebulizer inhalations or as nasal sprays used with similar devices.
           3. For the cases specified in subparagraphs 1-3, 5-7 of point 2 of these requirements, the reproduced drug should contain the same excipients in the same quantities as the reference medicinal product. If the formulation of the excipients are different, the applicant must provide evidence that the excipients used in these concentrations do not affect the safety and / or efficacy of the drug. If the applicant can not provide such evidence and / or does not have access to the relevant data, he must conduct appropriate studies in the manner established by the authorized federal executive authority to prove that there is no influence of various auxiliary substances or auxiliary devices on the safety and (or) effectiveness of the drug.
4.    In the process of state registration of combinations of previously registered drugs for medical use, it is allowed to include in the section of the pharmacological, toxicological documentation and section of the clinical documentation a review of scientific papers on the results of preclinical studies of reference medications included in the composition combination of drugs and the lack of their interaction in one finished dosage form instead of the developer's report on the results of own preclinical studies of drugs.
5.    In order to examine the documents submitted for determining the possibility of considering a medicinal product in the process of state registration to be an orthopedic medicinal product, the applicant shall submit in electronic form and on hard copies the documents specified in subparagraphs 1, 2, 5, 6, 10 of paragraph 3 and paragraph 6 of the procedure for the formation of a drug registration dossier and the requirements for documents in its composition approved by the order of the Ministry of Health of the Russian Federation the Federation № 409n from 07.12.2017.
6.    At the state registration of an orphan drug, the applicant shall provide the information necessary for the formation of a section of clinical documentation in the amount established by the Ministry of Health of the Russian Federation.
7.    When registering a biological drug obtained from blood, human blood plasma, additional data should be presented in the drug registration dossier:
1) in the section of the administrative documentation, a document containing information on the subjects of circulation of the donor blood and (or) its components, on where the donation (blood and/or blood plasma) took place, as well as data on infectious diseases transmitted parenterally, information on the subjects of circulation of donor blood and (or) its components in respect of which the control of donor blood and (or) its components is monitored;
2) in the section of chemical, pharmaceutical and biological documentation:
a) criteria and methods for selecting, transporting and storing donor blood and (or) its components;
b) results of studies of selected donor blood and/or blood plasma and pools for the presence of infectious agents, including information on the research methods used and in the case of pooled blood plasma pooling the results of documentary confirmation (validation) of the methods used;
c) technical characteristics of the packaging for the selection of donor blood and/or blood plasma, including information on anticoagulant solutions used.

8.    For drugs which were recognized as orphan drugs (as a result of examination of the documents submitted for the determination of the possibility to consider a drug to be an orphan drug), and for which clinical studies were performed outside the Russian Federation in accordance with the requirements of Good Laboratory Practice and the requirements of Good Clinical Practice, it is allowed to include in the section of clinical documents a report on the results of clinical trials performed outside the Russian Federation instead of a report on the results of clinical trials of drugs for medical use conducted in the Russian Federation.

Appendix No. 3
to the order of the Ministry of Health
of the Russian Federation
No. 409n dated July 12, 2017

The procedure for submitting documents to compile a drug registration dossier for the state registration of pharmaceutical products

1.    This procedure establishes the rules for the submission of applications for state registration of a drug for medical use (hereinafter referred to as "the applicant") by a legal entity acting in its own interests or authorized to represent the interests of another legal entity and submitting the pharmaceutical product for state registration (hereinafter - application) and the necessary documents, from which the drug registration dossier is formed (hereinafter - the documents of the registration dossier).
2.    The application and documents of the drug registration dossier shall be submitted in electronic form and in hard copy in Russian or with translation into Russian, certified in accordance with the established procedure.
3.    In case the document of the drug registration dossier has several sheets, they are stitched, numbered and on the back of the last sheet of the document at the bonding place are certified by the signature of the authorized person with the total number of sheets of the document. If the applicant submits documents of the drug registration dossier that have several sheets and is certified in accordance with the established procedure, this requirement for such documents is not presented.
4.    For the state registration of various dosage forms of the same drug, the applicant shall submit separate applications and documents to the registration dossier for each dosage form. In case of simultaneous submission of a single dosage form with different dosage, concentration, volume, to the state registration, the applicant shall submit one application for state registration of the drug for medical use and documents.
5.    The application for drug state registration, the documents of the drug registration dossier and other documents related to the procedure of the state registration of the drug shall be processed by the Department for State Regulation of Medicinal Products of the Ministry of Health of the Russian Federation in a separate file that is kept in the federal state budgetary institution “Scientific Center for Expertise of Medical Applications” of the Ministry of Health of the Russian Federation.

 

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