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The RULES of amendments in registration dossier of a registered medicinal product for medical use

APPENDIX No. 19
to the Rules for Registration and
examination of medical drugs in EAEU

REGULATIONS
for making variations to the registration dossier
of the registered drug for medical use in EAEU

I. GENERAL PROVISIONS

1.1. Subject and scope of application

1.1.1. This annex establishes the rules for amending the registration dossiers (registration conditions) for all drugs for medical use registered in the Eurasian Economic Union (hereinafter - the EAEU).
1.1.2. This application does not apply to transfers of registration certificates from one holder of the drug registration certificate (hereinafter referred to as the holder) to another.
1.1.3. Section II applies to variations in registration conditions implemented in accordance with the Rules for registration and examination of medicinal products within the framework of the Eurasian Economic Union.
1.1.4. Section III applies exclusively to variations in the conditions of registration carried out before January 1, 2016 within the framework of national registration procedures after the procedure described in section 12 of the Rules for Registration and Examination of Drugs under the Eurasian Economic Union.
1.1.5. Section IV applies to variations in the registration conditions specified in paragraphs 1.1.3 and 1.1.4.
1.1.6. If the conditions of registration variations before January 1, 2016, within the framework of the national registration procedures, the national requirements apply to the implementation of the procedure described in section 12 of the Rules for registration and examination of medicinal products within the framework of the Eurasian Economic Union.
1.1.7. The rules for carrying out the examination when introducing variations in the registration dossier of the registered medicinal product for medical use are given in Annex No. 20 to this Regulation.

1.2. Definitions

For the purposes of this annex, the following definitions apply:
1.2.1. By "changing the conditions of registration" or "variation" is meant any correction:

a. information referred to in Annex 1 to this Regulation;
b. the conditions for deciding on the registration of a drug for medical use, including a general description of the medicinal product and any conditions, obligations or restrictions affecting the drug registration or alteration of the marking or the leaflet due to a variation in the overall characteristic of the drug;

1.2.2. "Minor variation of Type IA" is a variation that has only minimal impact on the quality, safety and efficacy of the drug in question, or does not have it at all.
1.2.3. "Major variation on Type II " is a variation which, while not being the variation referred to in paragraph 1.2.4, may have a significant impact on the quality, safety or efficacy of the drug in question.
1.2.4. "A variation requiring a new registration" or "an extension of registration" means the variations listed in Annex I and satisfying the conditions described in it.
1.2.5. "Minor variation of Type IB type" - variations that do not fall under the definition of variations of Type IA, or Type II and the extension of registration.
1.2.6. "The concerned state is a member of the EAEU"
A member state of the EAEU whose authorized body has registered the drug which is under consideration now ;
1.2.7. "The relevant body" is the authorized body of each concerned member state of the EAEU;
1.2.8. "Immediate restriction for safety" - an intermediate variation in the conditions of registration due to the appearance of new information relating to the safe use of the medicinal product;
1.2.9. "Exceptionally national registration" means any registration made by a member state of the EAEU until December 31, 2017, in accordance with its own legislation, outside the mutual recognition procedure and a decentralized procedure that has not been subjected to the registration of the registration dossier of medicines registered before the entry into force of the agreement in accordance with the requirements of the EAEU.

1.3. Classification of variations

1.3.1. For each variation that is not an extension of the registration, the classification established in Annex II applies.
1.3.2. A variation that is not an extension of the registration and whose classification can not be determined by applying the rules established by this annex to the recommendations made in accordance with Section 1.5 is recognized by default as variation of Type IB.
1.3.3. As an exception to paragraph 1.3.2, a variation that is not an extension and whose classification affiliation can not be determined by applying the rules established by this annex is recognized as a meaningful variation of type II in the following cases:

a. at the request of the holder when the variation is submitted.
b. if the authorized body of the reference state, after consulting with the authorized bodies of the states of recognition or the authorized body in solely national registration, after evaluating the validity of the notification in accordance with paragraph 2.2.1. or 3.2.1. respectively, and taking into account the recommendations made in accordance with Section 1.5, that the variation has a significant effect on the quality, safety or efficacy of the drug in question.

1.3.4. A detailed classification of the variations is given in Annex V.

1.4. Updating this application

1.4.1. The Eurasian Economic Commission is obliged to regularly update this annex in accordance with scientific and technological progress.

1.5. Recommendations for unclassified variations

1.5.1. Prior to filing an amendment, the classification of which is not contained in this annex, the holder is entitled to request a recommendation on the classification of the variation as follows:

a. the authorized body of the Member State concerned, if the variation affects exclusively the national registration of the drug;
b. at the authorized body of the reference state in other cases.

1.5.2. The recommendation referred to in paragraph 1.5.1. should not be contradict this annex. It must be compiled within 45 calendar days after receipt of the request and sent to the holder, the other member states of the EAEU and the expert committee on medicines under the Eurasian Economic Commission (hereinafter referred to as the expert committee). The 45-day period may be extended for 25 calendar days if the relevant body deems it necessary to consult an expert committee.
1.5.3. Prior to the examination of the variation, the classification of which is not available in this annex, the authorized body of the member state of the EAEU has the right to request a recommendation from the expert committee regarding the classification of such a variation.
1.5.4. The recommendation referred to in paragraph 1.5.3., should not contradict this annex. It must be submitted within 45 calendar days after receipt of the request and sent to the holder and authorized bodies of the other member states of the EAEU.
1.5.5. In order to ensure consistency of the recommendations drawn up in accordance with paragraphs 1.5.1 and 1.5.3, the Eurasian Economic Commission should publish such recommendations by first deleting all confidential information.

1.6. Variations that lead to a revision of information about the medicinal product

1.6.1. If the variation leads to a review of the general characteristics of the medicinal product, labeling or insert leaflet, as well as regulatory documentation for quality control, such a review is considered part of this variation.

1.7. Grouping variations

1.7.1. When notifying several variations or filing several applications for variations, each variation in accordance with Section II or Section 4.1.1, respectively, must be submitted a separate notification or dossier to amend the registration dossier of the registered medicinal product for medical use (hereinafter - the file to variation).
1.7.2. As an exception to paragraph 1.7.1, the following rules apply:

a. at a one-time notice of the same minor variation (s) of Type IA of the conditions for the registration of one or more medicinal products held by the same person, all such variations may be included in one notification referred to in section 2.1 or section 3.1;
b. with a simultaneous filing of several variations in the conditions for the registration of the same medicinal product, all such variations may be included in one filing if all the variations under consideration fall within one of the conditions listed in Annex III;
c. with a simultaneous filing of several variations in the conditions for the registration of the same medicinal product that do not fall under any of the conditions listed in Annex III, all such variations may be included in one submission of documents if the authorized body of the reference State, after consultation with the competent authorities of the recognition states gives consent to such a single submission.

1.7.3. Submission of documents referred to in subparagraphs "b" and "c" of paragraph 1.7.2. Shall be made simultaneously to all relevant authorities as follows:

a. a single notification in accordance with Section 2.2 if at least one of the variations is an minor variation of Type IB and all variations are insignificant;
b. a single statement in accordance with Section 2.3 if at least one of the variations is a major variation of Type II and none of the variations is an extension of the registration;
at. a single application in accordance with Section 4.1.1, if at least one of the variations is an extension of the registration.

II. VARIATIONS IN THE CASE OF REGISTRATIONS, IMPLEMENTED IN ACCORDANCE WITH THE RULES OF REGISTRATION AND EXPERTISE OF DRUGS WITHIN THE FRAMEWORK OF THE EURASIAN ECONOMIC UNION

2.1. Procedure for notification of minor variations of Type IA

2.1.1. When making a minor variation of Type IA, the holder must simultaneously submit to all relevant authorities a notice containing the elements listed in Annex IV. Such notification must be submitted within 365 calendar days (12 months) from the date of implementation of the variation.
2.1.2. However, for minor variations requiring immediate notification, in order to continuously monitor the drug in question, notification must be given immediately after the variation is implemented.
2.1.3. Within 30 calendar days from the date of receipt of the notification, it is necessary to take the measures specified in section 2.4.

2.2. The procedure for notification of major variations of Type IB

2.2.1. The holder must simultaneously submit to all the appropriate authorities a notification containing the elements listed in Annex IV.
2.2.2. If the notification satisfies the requirements specified in clause 2.2.1, the authorized body of the reference state, after consulting with the recognition states, shall acknowledge receipt of a valid notification.
2.2.3. If within 30 calendar days from the date of recognition receipt of a valid notification, the authorized body of the reference state does not send a negative opinion to the holder, the notification is recognized by all relevant authorities.
2.2.4. If the notification is accepted by the authorized body of the reference state, the measures specified in section 2.4 are taken.
2.2.5. If, according to the conclusion of the authorized body of the reference state, the notification cannot be accepted, it must notify the holder and the state of recognition about this problem, specifying the grounds for the negative conclusion.
2.2.6. Within 30 calendar days from the date of receipt of the negative conclusion, the holder shall have the right to submit a correction to all relevant authorities with a view to fully taking into account the grounds specified in the conclusion mentioned in clause 2.2.5.
2.2.7. If the holder does not correct the notification in accordance with clause 2.2.6, the notification is recognized as rejected by all relevant authorities and the measures specified in section 2.4 are taken.
2.2.8. When submitting an amended notice, the authorized body of the reference state must evaluate it within 30 calendar days from the date of its receipt, after which the measures specified in section 2.4 are taken.
2.2.9. This section does not apply if a request for a variation of Type IB is submitted as part of a group that includes variation of Type II and does not contain a registration extension. In this case, the preliminary examination procedure provided for in section 2.3 is applied.
2.2.10. This section does not apply if a request for variation of Type IB is submitted with a group that includes an extension of registration. In this case, the procedure provided in Section 4.1.1 applies.

2.3. The procedure of "preliminary examination" of major variations of Type II

2.3.1. The drug registration holder must simultaneously submit to all the relevant authorities an application containing elements, listed in Annex IV.
2.3.2. If the application meets the requirements specified in clause 2.3.1, the authorized body of the reference state, after consulting with the recognition states, must acknowledge receipt of a valid application and notify the holder and the other relevant authorities that the procedure begins on the day of such recognition.
2.3.3. Within 60 calendar days from the date of recognition of the receipt of a valid statement, the authorized body of the reference state should prepare an expert report and decision on the application, which must be communicated to the other relevant bodies.
2.3.4. The authorized body of the reference state has the right to shorten the period referred to in paragraph 2.3.3, taking into account the urgency of the matter, or extend it to 90 calendar days in respect of variations consisting in modification of approved indications for use or inclusion of new indications for use, or a group of variations in accordance with subparagraph "c" of clause 1.7.2.
2.3.5. During the period mentioned in clauses 2.3.3 and 2.3.4, the authorized body of the reference state has the right to request from the holder additional information within the terms established by such authorized body. In this case:

a. the authorized body of the reference state must notify the other interested authorized bodies of its request for additional information;
b. before the submission of such additional information, the procedure is suspended;
c. the authorized body of the reference state has the right to extend the period mentioned in paragraphs 2.3.3 and 2.3.4.

2.3.6. Without limiting the provisions of Section 2.6 and within 30 calendar days from the date of receipt of the decision and the expert report referred to in paragraphs 2.3.3 and 2.3.4, the relevant authorities shall recognize the decision and notify the authorized body of the reference state thereof.
2.3.7. If, within the period referred to in paragraph 2.3.8, the relevant authority does not express disagreement in accordance with section 2.6, the decision shall be considered as adopted by such relevant body.
2.3.8. If, in accordance with paragraphs 2.3.6 and 2.3.7, the decision referred to in paragraph 2.3.7 is accepted by all relevant authorities, the measures specified in section 2.4 shall be taken.
2.3.9. This section does not apply if a Type II variation request is filed with a group that includes an extension of registration. In this case, the procedure provided in Section 4.1.1 applies.

2.4. The measures necessary to complete the procedures provided for in Sections 2.3-2.5.

2.4.1. When referring to this section, the authorized body of the reference state should take the following measures:

a. notify the holder and the other relevant authorities of the acceptance or rejection of the variation;
b. if the variation is rejected - notify the holder and the other relevant authorities about the reasons for such a decision;
c. notify the holder and other relevant authorities about the need to correct the registration conditions specified in subparagraph "b" of paragraph 1.2.1, in connection with the introduction of the amendment.

2.4.2. When referring to this section, each relevant authority, if necessary and within the deadline set by section 4.2.1, shall correct the registration decision referred to in subparagraph (b) of paragraph 1.2.1, in accordance with the adopted amendment.

2.5. Vaccines for the prevention of human influenza

2.5.1. As an exception, from section 33 to the examination of variations affecting the variations in the pharmaceutical substance for the purpose of an annual update of the vaccine for the prevention of human influenza, the procedure provided for in 2.5.2. – 2.5.7
2.5.2. The holder must submit to all relevant bodies at a time a statement containing the elements listed in Annex IV.
2.5.3. If the application meets the requirements specified in clause 2.5.2, the authorized body of the reference state must acknowledge receipt of a valid application and notify the holder and the state of recognition that the procedure starts from the day of such recognition.
2.5.4. The authorized body of the reference state must carry out an examination of the variation dossier filed with the application. If necessary, the authorized body of the reference state has the right to request from the holder additional data necessary for the completion of the examination.
2.5.5. Within 45 calendar days from the receipt of a valid statement, the authorized body shall prepare a decision and an expert report.
2.5.6. From the date of request for additional data referred to in paragraph 2.5.4, the 45-day period referred to in paragraph 2.5.5. shall be suspended until such data are submitted.
2.5.7. Within 12 working days after receipt of the decision and expert report of the authorized body of the reference state, the authorized bodies of the state of recognition must take an appropriate decision and notify the authorized body of the recognition state and the holder thereof.

2.6. Coordination in the expert committee

2.6.1. If the recognition of a decision in accordance with clauses 2.3.6 and 2.3.7 or approval of a conclusion in accordance with paragraph 4.1.2.9 on the basis of a potential serious public health risk for a medicinal product for medical use, the relevant authority should request that the essence of the disagreement be immediately forwarded to the expert committee.
2.6.2. The dissenting party should provide a detailed description of the reasons for its position to all interested member states of the EAEU and the holder.
2.6.3. With respect to the nature of the disagreements referred to in paragraph 2.6.1, the rules contained in the Regulation on the Expert Committee on Medicines are applied.

III. VARIATIONS IN THE CASE OF REGISTRATIONS CONDUCTED ONLY BY THE RULES OF NATIONAL REGISTRATION PROCEDURE

3.1. Procedure for notification of minor variations of Type IA

3.1.1. When making an minor variation of Type IA, the holder must file a notification to the authorized body containing the elements listed in Annex IV. Such notification must be submitted within 365 calendar days (12 months) after the implementation of the variation.
3.1.2. However, for insignificant variations requiring immediate notification, in order to continuously monitor the drug in question, notification must be given immediately after the variation is implemented.
3.1.3. Within 30 calendar days from the date of receipt of the notification, it is necessary to take the measures specified in section 3.5.

3.2. The procedure for notification of insignificant variations of type IB

3.2.1. The holder must submit to the authorized body a notice containing the elements listed in Annex IV.
3.2.2. If the notification satisfies the requirements specified in clause 3.2.1, the authorized body shall acknowledge receipt of a valid notification.
3.2.3. If within 30 calendar days from the date of recognition of receipt of a valid notification, the authorized body does not send a negative opinion to the holder, the opinion shall be recognized by the authorized body.
3.2.4. If the notification is accepted by the authorized body, the measures specified in section 3.5.
3.2.5. If, according to the conclusion of the authorized body, the notification can not be accepted, it must notify the holder thereof, indicating the grounds for the negative conclusion.
3.2.6. Within 30 calendar days from the date of receipt of the negative conclusion, the holder is entitled to submit to the authorized body a corrected notification in order to fully take into account the grounds specified in the conclusion mentioned in paragraph 3.2.5.
3.2.7. If the holder does not correct the notification in accordance with clause 3.2.6, the notice shall be deemed rejected.
3.2.8. When filing an amended notice, the authorized body must evaluate it within 30 calendar days from the date it was received, after which the measures specified in section 3.5 are taken.
3.2.9. This section does not apply if a request for variation of Type IB was submitted as part of a group that includes variation of Type II and does not contain a registration extension. In this case, the preliminary examination procedure provided for in section 3.3 applies.
3.2.10. This section does not apply if a request for variation of Type IB type was filed with a group that includes an extension of registration. In this case, the procedure provided in Section 4.1.1 applies.

3.3. The procedure of "preliminary examination" of major variations of Type II

3.3.1. The holder must submit to the authorized body an application containing the elements listed in Annex IV.
3.3.2. If the application meets the requirements set in clause 3.3.1, the authorized body must acknowledge receipt of a valid application.
3.3.3. Within 60 calendar days from the receipt of the valid application referred to in paragraph 3.3.1, the authorized body shall complete the examination.
3.3.4. The authorized body has the right to shorten the period referred to in paragraph 3.3.3, taking into account the urgency of the matter, or to extend it to 90 calendar days in respect of variations that involve modification of approved indications for use or inclusion of new indications for use or a group of variations in accordance with subparagraph in clause 3.4.2.
3.3.5. With respect to the variations listed in section 2 of Annex I, the period referred to in paragraph 3.3.3 shall be 90 calendar days.
3.3.6. During the period mentioned in clauses 3.3.3-3.3.5, the authorized body has the right to request from the holder additional information within the terms established by the authorized body. Prior to the submission of such additional information, the examination procedure is suspended. In this case, the authorized body has the right to extend the period mentioned in paragraphs 3.3.3-3.3.5.
3.3.7. Within 30 calendar days from the date of completion of the examination, the measures specified in section 3.5 are taken.
3.3.8. This section does not apply if a Type II variation request is filed with a group that includes an extension of registration. In this case, the procedure provided in Section 4.4.1 applies.

3.4. Grouping of variations to the registration dossiers of medicines registered under the national registration procedure

3.4.1. When notifying several variations or filing several variation requests, each variation in accordance with Sections 3.1, 3.2, 3.3 or 4.1.1, respectively, must be submitted a separate notice or variation file.
3.4.2. As an exception to paragraph 3.4.1, the following applies:

a. at the simultaneous notification of the same authorized body about the same minor variation (s) of Type IA of the conditions for registration of one or more medicinal products owned by the same person, all such variations may be included in one notification, mentioned in section 3.1;
b. at a one-time submission to the same authorized body of several variations in the conditions of the registration of the same drug, all such variations may be included in one filing if all the variations under consideration fall within one of the conditions listed in Annex III;
c. if the conditions for registration of the same medicinal product with the same person not subject to the conditions of subparagraphs "a" and "b" are lump-sumed to the same authorized body (s), all such variations may be included in one submission of documents, if the authorized body agrees to such a single submission.

3.4.3. The filing referred to in subparagraphs "b" and "c" of clause 3.4.2 shall be made as follows:

a. a single notification in accordance with Section 3.2 if at least one of the variations is an insignificant variation of Type IB and all variations are minor;
b. a single statement in accordance with Article 3.3 if at least one of the variations is a significant variation of Type II and none of the variations is an extension of the registration;
c. a single application in accordance with section 4.1.1, if at least one of the variations is an extension of the registration.

3.5. Measures necessary to complete the procedures in sections 3.1-3.3

3.5.1. When referring to this section, the authorized body shall take the following measures:

a. notify the holder of acceptance or rejection of the variation;
b. when rejecting the variation - to notify the holder of the grounds for such a decision;
c. if necessary, within the deadlines set by section 4.2.1, he must correct the registration decision specified in subparagraph "b" of paragraph 1.2.1, in accordance with the adopted variation.

3.6. Vaccines for the prevention of human influenza

3.6.1. As an exception, from section 3.3 to the examination of variations affecting variations in the pharmaceutical substance for the purpose of an annual update of the vaccine for the prevention of human influenza, the procedure provided for in paragraphs 3.6.2 - 3.6.6.
3.6.2. The holder must submit to the authorized body an application containing the elements listed in Annex IV.
3.6.3. If the application meets the requirements specified in paragraph 3.6.2, the authorized body must acknowledge receipt of a valid application.
3.6.4. The authorized body shall conduct an examination of the variation dossier filed together with the application. If necessary, the authorized body shall have the right to request from the holder additional data necessary for the completion of the examination.
3.6.5. Within 45 calendar days from the date of receipt of the valid application, the authorized body shall take the decision and measures specified in section 3.5.
3.6.6. From the date of request for additional data referred to in section 3.6.4, the 45-day period referred to in paragraph 3.6.5. shall be suspended until such data are submitted.

IV. OTHER ASPECTS

4.1. Special procedures

4.1.1. Extension of registration

4.1.1.1. The application for the extension of drug registration must be examined in accordance with the same procedure as the primary drug registration to which it relates.
4.1.1.2. The extension must be registered in accordance with the same procedure as the primary application for drug registration to which it relates, or be included in this drug registration dossier.

4.1.2. Procedure for assigning responsibilities

4.1.2.1. As an exception to paragraph 1.7.1 and sections 2.2 and 2.3, if an minor variation of Type IB, a major variation of Type II or a group of variations in the cases provided for by subparagraph (b) of paragraph 1.7.2, not containing an extension of drug registration, affects several registration dossiers, owned by one holder, the holder of such registration certificates is entitled to adhere to the procedure established in clauses 4.1.2.3-4.1.2.10.
4.1.2.2. For the purposes of paragraphs 4.1.2.3-4.1.2.10, the "reference body" means the authorized body of the Member State concerned, appointed by the expert committee, taking into account the recommendation of the holder.
4.1.2.3. The holder must simultaneously submit to all relevant authorities a statement containing the elements listed in Annex IV, indicating the recommended reference body.
4.1.2.4. If the application meets the requirements specified in clause 4.1.2.3, the expert committee appoints the reference body, and such authority must acknowledge receipt of a valid application.
4.1.2.5. If the selected reference body is an authorized body of the reference state that has not registered all medicinal products affected by the application, the expert committee has the right to require another relevant body to assist the referent body in examining this application.
4.1.2.6. The reference body shall draw up an opinion on the valid statement referred to in paragraph 4.1.2.3 within 60 calendar days from the date of recognition of the receipt of a valid statement with insignificant variations of Type IB type and major variations of Type II.
4.1.2.7. The reference body has the right to shorten the period referred to in paragraph 4.1.2.6, taking into account the urgency of the matter, or to extend it to 90 calendar days in respect of variations in the modification of approved indications for use or inclusion of new indications for use.
4.1.2.8. During the period referred to in paragraph 4.1.2.6, the referent body is entitled to require additional information from the holder of the submission within the time limits established by such a reference body. In this case:

a. the referent body shall notify the remaining relevant authorities of its request for additional information;
b. before the submission of such additional information, the procedure is suspended;
c. The reference body may extend the period referred to in paragraph 4.1.2.6.

4.1.2.9. The reference body should forward its opinion on the valid application to the holder and the other relevant authorities; without limiting the provision to clause 2.6 and within 30 calendar days from the date of receipt of the conclusion, the relevant authorities must approve such an opinion, notify the referring body and correct the registration dossiers in question accordingly.
4.1.2.10. In order to verify the validity of the application and draw up an opinion on the valid application at the request of the reference body, the Member States concerned must provide information relevant to the registration dossier affected.

4.1.3. Pandemic Influenza Situation

4.1.3.1. As an exception to Chapters I, II and III, with proper recognition by the World Health Organization or the EAEU of Pandemic Influenza Situations, relevant authorities are entitled, on an exceptional basis, to temporarily accept variations in the conditions for the registration of a vaccine for the prevention of human influenza in the absence of certain preclinical or clinical data.
4.1.3.2. When accepting a variation in accordance with Part 1, the holder must file the missing preclinical and clinical data within the deadline set by the relevant authority.

4.1.4. Urgent safety restrictions

4.1.4.1. If, at the risk of public health from drugs for medical use, the holder initiates immediate security restrictions on his own initiative, he must immediately notify all relevant authorities of this.
4.1.4.2. If, within 24 hours after the receipt of the information referred to in paragraph 4.1.4.1., the relevant authority does not raise an objection, urgent safety restrictions are deemed to be accepted.
4.1.4.3. If a public health risk arises from the use of medicinal products for medical use, the relevant authorities may impose immediate security restrictions on the holder.
4.1.4.4. If the holder imposes an emergency security restriction or imposes an imposition on it by the relevant body, the holder must submit a relevant variation application within 15 working days from the date of commencement of such restriction.

4.2. Correction of the decision on registration and its implementation

4.2.1. Correction of the decision to register

4.2.1.1. Corrections of the decision on registration based on the results of the procedures stipulated in Sections II and III should be implemented:

a. with major variations of Type II within 60 calendar days after receiving the information mentioned in subparagraph "c" of clause 2.4.1 and subparagraph "a" of clause 3.5.1, subject to the transfer of documents necessary for correcting the registration dossier to the interested member states of the EAEU ;
b. in other cases - within 180 calendar days after receiving the information referred to in subparagraph "c" of clause 2.4.1 and clause "a" of clause 3.5.1, subject to the transfer of documents required for correcting the registration dossier to the interested member states of the EAEU.

4.2.1.2. When correcting the registration decision due to one of the procedures provided for in Sections II, III and IV, the relevant authority must immediately notify the holder of the correction of the decision.

4.2.2. Implementation of variations

4.2.2.1. Realization of minor variations of Type IA is allowed at any time before the completion of the procedure provided for in clauses 2.1 and 3.1.
4.2.2.2. If a notice affecting one or more minor variations of Type IA type is rejected, the holder immediately after receiving the information referred to in subparagraph "a" of paragraph 2.4.1 and subparagraph "a" of paragraph 3.5.1, shall cease the implementation of the considered variation (s).
4.2.2.3. Realization of minor variations of Type IB is allowed only in the following cases:

a. with respect to variations filed in accordance with the procedures provided in Section II, after the notified body of the reference State has notified the holder that it has accepted the notification pursuant to Section 2.2 or if the notice is deemed to have been accepted pursuant to paragraph 2.2.3;
b. with respect to variations filed in accordance with the procedures provided in Section III, after the notified body of the holder has notified that it has accepted the notification pursuant to Section 3.2 or if the notice is deemed to have been accepted pursuant to paragraph 3.2.3;
c. in respect of variations filed in accordance with the procedure provided for in Section 4.2.1, after the notice by the reference body to the holder that the conclusion is positive.

4.2.2.4. Realization of significant variations of type II is allowed only in the following cases:

a. with respect to variations brought in line with the procedures provided in Section II within 30 calendar days from the date of notification by the authorized body of the reference state that the holder has accepted the amendment in accordance with Section 2.3 provided that the documents necessary for correcting the registration dossier are submitted to the interested Member States of the EAEU. If, in accordance with Section 2.6, the approval procedure is initiated, the holder shall not implement the variations until the end of the approval procedure for the variation in question;
b. with respect to variations brought in line with the procedures provided in Section III, after notification by the relevant authority of the holder that it has accepted the amendment under paragraph 3.3;
c. with respect to variations filed in accordance with the procedure provided in clause 4.1.2, within 30 calendar days from the date of notification by the reference body of the holder that the conclusion is positive, provided that the documents necessary for correcting the registration dossier are submitted to the interested Member States of the EAEU if, in accordance with section 2.6 the approval procedure has not been initiated. If, in accordance with section 2.6, the approval procedure is initiated, the holder shall not implement the variation until the approval procedure for acceptance of the variation is completed.

4.2.2.5. The expansion can be implemented only after the relevant body has corrected it or, in case of centralized registration by the Commission, the decision on registration and the corresponding notice to the holder.
4.2.2.6. The implementation of urgent security restrictions and variations affecting security issues may be carried out within the timeframes agreed between the holder and the relevant authority.
4.2.2.7. As an exception to paragraph 4.2.2.6, the implementation of urgent security restrictions and variations affecting safety related to medicinal products registered in accordance with the Rules for Registration and Examination of Medicinal Products within the Eurasian Economic EAEU may be exercised within the time frames agreed between the holder and the authorized body of the reference State, after consultation with the other relevant bodies.

V. FINAL PROVISIONS

5.1. Continuous monitoring

5.1.1. At the request of the relevant body, the holder must promptly provide all information affecting the implementation of a particular variation.

5.2. Revision

5.2.1. Not later than five years from the date of entry into force of the Rules for registration and examination of medicinal products within the framework of the Eurasian Economic Union, the expert committee should evaluate the application of this annex to the classification of variations in order to propose necessary variations aimed at adapting Additions I and II to take into account scientific and technological progress.

ANNEX I
Extensions of registrations

1. Variations in the active pharmaceutical (s) substance (s):

a. replacement of the active pharmaceutical substance obtained by chemical synthesis, another salt / ester / complex / derivative with the same active part of the molecule of the active substance, in the absence of significant differences in efficacy / safety;
b. substitution by another isomer, another mixture of isomers, a mixture of individual isomers (for example, a racemate with a single enantiomer), with no significant differences in efficacy / safety;
c. replacement of a biologically active pharmaceutical substance with another with a slightly altered molecular structure in the absence of significant differences in efficacy and / or safety, with the exception of variations in the active pharmaceutical substance of a seasonal, pre-pandemic or pandemic vaccine for the prevention of human influenza.
d. a modification of the vector used to produce the antigen or starting material, including a new main cell bank from another source, with no significant differences in efficacy / safety.
e. a new ligand or binding mechanism of a radiopharmaceutical drug in the absence of significant differences in efficacy / safety.
f. a variation in the extractant or the ratio of plant material and plant pharmaceutical substance in the absence of significant differences in efficacy / safety.

2. Variations in dosage, dosage form or route of administration:

a. variation in bioavailability;
b. variation in pharmacokinetics, for example, release rate;
c. variation or addition of a new dosage / activity;
d. variation or addition of a new dosage form;
e. variation or addition of a new route of administration.

 

ANNEX II
Classification of variations

1. The following variations should be classified as minor variations of Type IA:

a. variations of an exclusively administrative nature relating to the name and contact information:

- the MA holder;
- the manufacturer or supplier of any source material, reagent, intermediate, active pharmaceutical substance used in the manufacturing process or in a medicinal product;

b. variations in the exclusion of any production site of an active pharmaceutical substance, an intermediate product or a medicinal product, a packer, a producer responsible for producing a series, a site that produces quality control;
c. variations in minor changes in approved physico-chemical analytical methods, if it is confirmed that the updated methodology is at least equivalent to what was previously used, proper validation has been performed and its results indicate that the updated analytical technique is at least equivalent to the previous one (replaced);
d. variations in the specifications (regulatory documentation) of an active pharmaceutical substance or excipient substance carried out in order to comply with the updated relevant article of the EAEU Pharmacopeia or the national pharmacopoeia of a Member State of the EAEU, if the variation is made solely for the purpose of meeting the requirements of the pharmacopeia, and the specification parameters (normative documentation) on product-specific properties do not change;
e. variations in packaging material that does not come into contact with the medicinal product, do not affect the delivery, use, safety or stability of the medicinal product;
f. variations involving stricter criteria for the acceptability of the specification (normative documentation), if such variations are not a consequence of any obligation taken on the basis of the results of previous examinations with the purpose of analyzing the criteria for the acceptability of the specification (normative documentation), or unexpected situations that occurred during the production process.

2. The following variations should be classified as major variations of Type II:

a. variations in the addition of a new indication to the application or modification of the existing one;
b. Variations in significant modifications of general characteristics of the medicinal product, especially due to new quality data, preclinical or clinical results, pharmacovigilance data;
c. Changes that involve variations exceeding range, limits or eligibility criteria for approved specifications (normative documentation);
d. variations that involve significant changes in the process of production, composition, specifications (normative documentation) or impurity profile of an active pharmaceutical substance or medicinal product that may significantly affect the quality, safety or efficacy of the drug;
e. variations in the modifications of the process of production or production sites of active a pharmaceutical substance of a biological medicinal product;
f. variations that involve the introduction of a new project field or the expansion of a previously approved one if the project field is developed on the basis of relevant EAEU manuals or international scientific guidelines;
g. changes in the active pharmaceutical substance of a seasonal, pre-pandemic or pandemic vaccine for the prevention of human influenza.

ANNEX III
The cases of grouping the variations described in subparagraph "b" clause 1.7.2 and subparagraph "b" of clause 3.4.2

1. One of the variations in the group is the expansion of registration.
2. One of the variations in the group is a significant variation of Type II, the remaining variations in the group are a consequence of such a significant variation in Type II.
3. One of the variations in the group is an insignificant variation of Type IB type, the remaining variations in the group are the consequence of this minor variation in the Type IB.
4. All variations in the group are solely variations in the administrative nature of the general characteristic of the medicinal product, labeling or leaflet.
5. All variations in the group are variations in the master file of the active pharmaceutical substance, the vaccine antigen master file or the master plasma file.
6. All variations in the group are part of a program aimed at improving the production process and the quality of the drug in question or its active pharmaceutical (s) substance (s).
7. All variations in the group are variations that affect the quality of the vaccine for the prevention of pandemic human influenza.
8. All variations in the group are variations in the pharmacovigilance system.
9. All variations in the group are the result of a certain urgent safety restriction and are filed in accordance with clause 4.1.4 of this annex.
10. All variations in the group relate to correcting the information of a particular class in the general characteristic of the medicinal product, labeling or leaflet (for example, adding a class-specific warning).
11. All variations in the group are the result of the examination of a particular periodic security report.
12. All variations in the group are the result of a post-marketing study conducted under the supervision of the holder.
13. All variations in the group are the result of a special obligation imposed upon registration.
14. All variations in the group are the result of a special procedure or registration condition.

 

ANNEX IV
Submitted elements (dossier for variation)

1. A list of all registration dossiers affected by the notification or application.
2. Description of all variations filed, including:

a. with minor variations of Type IA - the date of implementation of each described variation;
b. for minor variations of Type IA that do not require immediate notification, a description of all minor variations of Type IA type implemented in the last 365 calendar days (12 months) previously not reported.

3. All necessary documents listed in Annex V with respect to the relevant amendment.
4. If a change leads to a variation or is a consequence of other variations in the conditions of the same registration, a description of the relationship between such variations.
5. Confirmation of payment of payments provided by the national legislation.
6. List of Member States of the EAEU with reference to the reference State, if applicable.

ANNEX V
Detailed classification of variations

This Addendum consists of four chapters that classify variations due to:

A) administrative variation;
B) quality variations;
B) variations in safety, efficacy and pharmacovigilance;
D) certain variations in the Plasma Master Files (PMFs) and Vaccine Antigen Master Files (VAMFs).

When mentioning individual variations to this Addendum, the variation in question should be cited using the following structure: X.N.x.n ("variation code").

- X refers to the capital letter of the chapter in the Annex to this Guideline where the variation is included (e.g. A, B, C or D)
- N refers to the roman number of the section inside a chapter where the variation is included (e.g. I, II, III…)
- x refers to the letter of the subsection inside a chapter where the variation is included (e.g. a, b, c…)
- n refers to the number given in the Annex to this Guideline to a specific variation (e.g. 1, 2, 3…)

Each chapter of this Supplement contains:

- a list of the variations classified as minor variations of Type IA and major variations of Type II in accordance with the definitions of Section 1.2 and Annex II to this annex. It also indicates which of variations of Type IA require immediate notification under paragraphs 2.1.2 and 3.1.2 of this annex;
- a list of examples that should be considered as minor variations of Type IB. According to Section 1.3 of this annex, this category is assigned by default. This Addendum, in this connection, is not intended to establish an exhaustive list of such a category of variations.

The Annex does not address the extension of registrations, as they are exhaustively described in Annex I to this guideline. All variations described in Annex I to this guideline should be considered as extensions of registrations; all other variations should not be interpreted as such.

If one or more of the conditions specified in this Addendum for insignificant variations of Type IA are not met, this variation may be submitted as a variation of Type IB type ("variation of Type IB by default") if such variation in this Addendum or recommendation made in according to Section 1.5 of this annex, is not treated as a variation of Type II, or if the applicant does not consider that the variations can have a significant impact on the quality, safety and efficacy of the drug.

If the authorized body considers that a variation submitted as a default variation of Type IB may have a significant impact on the quality, safety or efficacy of the medicinal product, it may request the applicant to update the variation and classify it as Type II.

For the purposes of this Addendum, the term "test procedure" has the same meaning as the "analytical procedure", the term "limits" - "acceptance criteria". The "specification parameter" refers to the quality indicator for which an analytical methodology and eligibility criteria are established, for example, quantification, authenticity and water content. Thus, the addition or deletion of a specification parameter includes the appropriate analytical methodology and eligibility criteria.

If several insignificant variations occur (for example, the same method, process or material) at the same time or with a significant update of the quality of the active pharmaceutical substance or medicinal product, the applicant, in selecting the appropriate classification category, should take into account the combined effect of such variations in the quality, safety and efficacy of the medicinal product and submit them accordingly.

Documents justifying the introduction of variations of Type IB and Type II, depend on the nature of such variations.

In addition, if a variation requires a review of the general characteristics of the drug, labeling or leaflet (combined with the term "drug information"), this circumstance is considered as part of such a variation. In this case, the updated information on the medicinal product should be submitted as part of the dossier with the necessary translations. Layouts and packaging samples should be provided to the reference state or the national authorized body, respectively.

Notification the authorized bodies about the updated article of the EAEU Pharmacopeia or the national pharmacopoeia of a Member State of the EAEU is not required if a reference to the "current version" is indicated in the dossier of the registered medicinal product. Applicants should remember that compliance with the updated article must be implemented within 180 calendar days from the date of its publication.

Chapter D of this Addendum provides a list of variations that are specific to the PMF and the VAMF. After examination of such variations, any affected registration dossier is subject to updating in accordance with chapter B of this Addendum. If the documentation of the human plasma used as a starting material of a drug derived from plasma is not supplied as a PMF, variations to such source material described in the registration dossier should also be processed in accordance with this Annex.

In the absence of specific instructions, references in this Annex to variations to the registration dossier are intended to add, replace or exclude. If amendments to the registration dossier are editorial variations, such variations, as a whole, should not be submitted in the form of a separate amendment, they may be included in other amendments to the relevant part of the registration dossier. In such cases, in the form of an application, it is necessary to clearly identify such variations as editorial variations and provide a guarantee that the content of the relevant part of the file as a result of editorial variations has not exceeded the limits provided for by the type of variation filed.

It should be noted that editorial edits allow the elimination of outdated or redundant text, but not the exclusion of specification parameters and descriptions of production.

А. Administrative changes

А.1 Change in the name and/or address of the marketing authorisation holder Conditions to be fulfilled Documentation to be supplied Procedure type
  1 1,2 1Ain
Conditions
1. The marketing authorisation holder shall remain the same legal entity.
Documentation
1. A formal document from a relevant official body (e.g. Chamber of Commerce) in which the new name or new address is mentioned.
2. Revised product information.
А.2 Change in the (trade) name of the medicinal product Conditions to be fulfilled Documentation to be supplied Procedure type
а) Medicinal products registered in accordance with the Rules for registration and examination of medicinal products within the framework of the Eurasian Economic Union 1 1,2 1Ain
б) Medicinal products registered under the national procedure   2 IB
Conditions
1. Confirmation by the reference state of the acceptability of the new name.
Documentation
1. A copy of the letter of the reference state on the acceptability of a new (trade) name.
2. Revised information on the medicinal product.
А.3 Change in the name of an active pharmaceutical substance or excipient Conditions to be fulfilled Documentation to be supplied Procedure type
  1,2 1,2 1Ain
Conditions
1. The active substance shall remain the same.
Documentation
1. WHO certificate of approval or copy of the INN list. If applicable, confirmation that the change corresponds to the Pharmacopoeia of the Eurasian Economic Union. Declaration that the name of herbal medicinal products of plant origin corresponds to the documents of the Eurasian Economic Union.
2. Revised information on the medicinal product.
A.4 Change of name and / or address of manufacturer (including, if applicable, quality control sites), or holder of DMF, or supplier of an active pharmaceutical substance, starting materials, reagents or intermediates used in the manufacture of an active pharmaceutical substance (if indicated in the technical dossier), if the registration dossier does not contain Ph. Eur., Or the manufacturer of a new excipient (if specified in the technical dossier) Conditions to be fulfilled Documentation to be supplied Procedure type
  1 1,2,3 IA
Conditions
1. The manufacturing site and all manufacturing operations shall remain the same.
Documentation
1. A formal document from a relevant official body (e.g. Chamber of Commerce) in which the new name and/or address is mentioned.
2. Amendment to the relevant section (s) of the dossier.
3. In case of change in the name of the holder of the Active Substance Master File holder, updated “letter of access”.
А.5 Change in the name and/or address of a manufacturer of the finished product, including quality control sites Conditions to be fulfilled Documentation to be supplied Procedure type
a) Manufacturer responsible for batch release 1 1,2 1Ану
b) The actions for which the producer / importer is responsible do not include the batch release 1 1,2 IA
Conditions
The manufacturing site and all manufacturing operations shall remain the same.
Documentation
1. A copy of the revised production permit (if any) or an official document from the relevant authorized body (for example, the tax authority), in which the new name and / or address is mentioned.
2. If applicable, an amendment to the relevant section (s) of the dossier, including revised information on the medicinal product.
А.6 Change of ATX code Conditions to be fulfilled Documentation to be supplied Procedure type
  1 1,2 IA
Conditions
1. Change following granting of or amendment to ATC Code by WHO.
Documentation
1. Proof of acceptance (by WHO) or copy of the ATC (Vet) Code list.
2. Revised product information
A7. Deletion of manufacturing sites (including for an active substance, intermediate or finished product, packaging site, manufacturer responsible for batch release, site where batch control takes place, or supplier of a starting material, reagent or excipient (when mentioned in the dossier)). Conditions to be fulfilled Documentation to be supplied Procedure type
  1,2 1,2 IA
Conditions
1. There must remain at least one previously approved production site / manufacturer, performing the same functions as those to be excluded. If applicable, within the Eurasian Economic Union there shall be at least one manufacturer in charge of the production of series, capable of certifying a product test for the purpose of issuing series to the EAEU.
2. The deletion should not be due to critical deficiencies concerning manufacturing.
Documentation
1. In the form of a declaration of change, it is necessary to clearly identify the "current" and "proposed" producers listed in section 2.5 of the application form for registration.
2. Amendment to the relevant section (s) of the dossier, including revised information on the medicinal product.
A.8 Changes in the audit date for verification of compliance of the manufacturer of an active pharmaceutical substance with good manufacturing practices Conditions to be fulfilled Documentation to be supplied Procedure type
  1 1,2 IA
Documentation
Written confirmation of the manufacturer of the medicinal product, containing an indication of verification of compliance of the manufacturer of an active pharmaceutical substance with the Rules of Good Manufacturing Practice of the EAEU.

 

B. Quality changes

1. Active pharmaceutical substance

a) Production

B.I.a.1 Change in the manufacturer of a starting material/reagent/intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control sites) of the active substance, where no Ph. Eur. Certificate of Suitability is part of the approved dossier Conditions to be fulfilled Documentation to be supplied Procedure type
a) The proposed manufacturer is part of the same pharmaceutical group as the currently approved manufacturer. 1,2,3 1,2,3,4,5,6,7 IA,in
b) Introduction of a new manufacturer of the active substance that is supported by an ASMF     II
c) The proposed manufacturer uses a substantially different route of synthesis or manufacturing conditions, which may have a potential to change important quality characteristics of the active substance, such as qualitative and/or quantitative impurity profile requiring qualification, or physico-chemical properties impacting on bioavailability.     II
d) New manufacturer of material for which an assessment is required of viral safety and/or TSE risk     II
e) The change relates to a biological active substance or a starting material/reagent/intermediate used in the manufacture of a biological/immunological product.     II
f) Changes to quality control testing arrangements for the active substance-replacement or addition of a site where batch control/testing takes place 2,4 1,5 IA
g) Introduction of a new manufacturer of an active pharmaceutical substance that does not have ASMF and requires a substantial update of the relevant section on the active pharmaceutical substance dossier     II
h) The inclusion of an alternative site for the sterilization of an active pharmaceutical substance using the Pharmacopoeia Method of the EAEU   1,2,4,5,8 IB
i) Introduction of a new site for micronization 2,5 1,4,5,6 IA
j) Changes to the agreements on tests for the quality control of a biological active pharmaceutical substance: replacement or inclusion of the site on which the series control / testing is carried out, including the biological / immunological / immuno-chemical method     II
k) A new site for storing the main cell bank and (or) working cell banks   1,5 IA
Conditions

1. For starting materials and reagents the specifications (including in process controls, methods of analysis of all materials), are identical to those already approved. For intermediates and active substances the specifications (including in process controls, methods of analysis of all materials), method of preparation (including batch size) and detailed route of synthesis are identical to those already approved.
2. The active substance is not a biological/immunological substance or sterile.
3. If materials of human or animal origin are used in the production process, the manufacturer does not use a new supplier for which an evaluation of the viral safety and conformity of the EAEU Pharmacopoeia is necessary to minimize the risk of transmitting spongiform encephalopathy agents of animals through medications for medical and veterinary use.
4. The transfer method from the old to the new site is made successfully.
5. The specification for the particle size of the active pharmaceutical substance and the corresponding analytical method do not change.

Documentation

1. If applicable, an amendment to the relevant section (s) of the dossier.
2. A declaration from the marketing authorisation holder or the ASMF holder, where applicable, that the synthetic route (or in case of herbal medicinal products, where appropriate the method of preparation, geographical source, production of herbal drug and manufacturing route) quality control procedures and specifications of the active substance and of the starting material/reagent/intermediate in the manufacturing process of the active substance (if applicable) are the same as those already approved.
3. Either a TSE Ph. Eur. Certificate of Suitability for any new source of material or, where applicable, documentary evidence that the specific source of the TSE risk material has previously been assessed by the competent authority and shown to comply with the current Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products. The information should include the following: Name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, its use and previous acceptance. For the Centralised Procedure, this information should be included in an updated TSE table A (and B, if relevant).
4. Batch analysis data (in a comparative tabular format) for at least two batches (minimum pilot scale) of the active substance from the current and proposed manufacturers/sites.
5. In the form of a declaration of change, it is necessary to clearly identify "current" and "proposed" producers, as indicated in section 2.5 of the application form.
6. A declaration by the Qualified Person (QP) of each of the manufacturing authorisation holders listed in the application where the active substance is used as a starting material and a declaration by the Qualified Person (QP) of each of the manufacturing authorisation holders listed in the application as responsible for batch release. These declarations should state that the active substance manufacturer(s) referred to in the application operate in compliance with the detailed guidelines on good manufacturing practice for starting materials. A single declaration may be acceptable under certain circumstances - see the note under variation no. B.II.b.1
7. Where relevant, a commitment of the manufacturer of the active substance to inform the MA holder of any changes to the manufacturing process, specifications and test procedures of the active substance
8. Confirmation that the proposed site is properly licensed with respect to the dosage form, drug or manufacturing operation in question.

B.Ia.2 Changes in the manufacturing process of the active substance Conditions to be fulfilled Documentation to be supplied Procedure type
a) Minor change in the manufacturing process of the active substance. 1,2,3,4,5,6,7 1,2,3 IA
b) Substantial change to the manufacturing process of the active substance which may have a significant impact on the quality, safety or efficacy of the medicinal product. II
c) The change refers to a biological / immunological substance or use of a different chemically derived substance in the manufacture of a biological/immunological medicinal product and is not related to a protocol. II
d) The change relates to a herbal medicinal product and there is a change to any of the following: geographical source, manufacturing route or production. II
e) Minor change to the restricted part of an Active Substance Master File. 1,2,3,4 IB
Conditions
1. No adverse change in qualitative and quantitative impurity profile or in physico-chemical properties.
2. The synthetic route remains the same, i.e. intermediates remain the same and there are no new reagents, catalysts or solvents used in the process. In the case of herbal medicinal products, the geographical source, production of the herbal substance and the manufacturing route remain the same.
3. The specifications of the active substance and intermediates do not change.
4. The change is fully described in the open part (part of the "applicant") of the ASMF (if applicable).
5. Active pharmaceutical substance is not a biological / immunological substance.
6. The change does not affect the geographical source, the method of production or preparation of the medicinal herbal preparation.
7. The change does not affect the closed part of the ASMF.
Documentation
1. Amendment to the relevant section (s) of the dossier, including a direct comparison of the current and new processes.
2. Analysis data of series (in the format of the comparative table), at least two series (at least pilot-industrial), produced by the approved and proposed processes.
3. Copies of approved specifications of the active pharmaceutical substance.
4. A declaration from the marketing authorisation holder or the ASMF Holder, where applicable, that there is no change in qualitative and quantitative impurity profile or in physico-chemical properties, that the synthetic route remains the same and that the specifications of the active substance or intermediates are unchanged.

Note to B.Ia.a.2.b) For chemical active substances, this refers to substantial changes to the synthetic route or manufacturing conditions which may have a potential to change important quality characteristics of the active substance, such as qualitative and/or quantitative impurity profile requiring qualification, or physico-chemical properties impacting on bioavailability.
B.I.a.3 Change in batch size (including batch size ranges) of active substance or intermediate used in the production of an active substance Conditions to be fulfilled Documentation to be supplied Procedure type
a) Up to 10-fold increase compared to the currently approved batch size 1,2,3,4,5,6,7,8 1,2,5 IA
b) 10-fold Downscaling 1,2,3,4,5 1,2,5 IA
c) The change requires assessment of the comparability of a biological/immunological active substance. II
d) More than 10-fold increase compared to the currently approved batch size 1,2,3,4 IB
e) The scale for a biological/immunological active substance is increased / decreased without process change (e.g. duplication of line). 1,2,3,4 IB
Conditions
1. Any changes to the manufacturing methods are only those necessitated by scale-up or downscaling, e.g. use of different-sized equipment.
2. Test results of at least two batches according to the specifications should be available for the proposed batch size.
3. The product concerned is not a biological/immunological medicinal product.
4. The change does not adversely affect the reproducibility of the process.
5. The change should not be a consequence of unforeseen situations that have arisen in the course of production, or a breach of stability.
6. The specifications of the active pharmaceutical substance / intermediates remain the same.
7. Active pharmaceutical substance is not sterile.
8. The series size is in the 10-fold range limit of the series size provided during registration or after a subsequent change, which is not a variation of the IA type.
Documentation
1. Amendment to the relevant section (s) of the dossier.
2. The series numbers of the tested series have the proposed size of the series.
3. Batch analysis data (in a comparative tabulated format) on a minimum of one production batch of the active substance or intermediate as appropriate, manufactured to both the currently approved and the proposed sizes. Batch data on the next two full production batches should be made available upon request and reported by the marketing authorisation holder if outside specification (with proposed action).
4. Copies of approved specifications for the active pharmaceutical substance (and intermediates, if applicable).
5. A declaration from the marketing authorisation holder or the ASMF holder as appropriate that the changes to the manufacturing methods are only those necessitated by scale-up or downscaling, e.g. use of different-sized equipment, that the change does not adversely affect the reproducibility of the process, that it is not the result of unexpected events arising during manufacture or because of stability concerns and that the specifications of the active substance/intermediates remain the same.

B.Ia.4 Change to in-process tests or limits applied during the manufacture of the active substance Conditions to be fulfilled Documentation to be supplied Procedure type
a) Tightening of in-process limits 1,2,3,4 1,2 IA
b) Addition of a new in-process test and limits 1,2,5,6 1,2,3,4,6 IA
c) Deletion of a non-significant in-process test 1,2,7 1,2,5 IA
d) Widening of the approved in-process test limits, which may have a significant effect on the overall quality of the active substance II
e) Deletion of an in-process test which may have a significant effect on the overall quality of the active substance II
f) Addition or replacement of an in-process test as a result of a safety or quality issue 1,2,3,4,6 IB
Conditions
1. The change is not a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a type II variation procedure).
2. The change does not result from unexpected events arising during manufacture e.g. new unqualified impurity; change in total impurity limits
3. Any change should be within the range of currently approved limits.
4. The test procedure remains the same, or changes in the test procedure are minor.
5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way
6. The new test method is not a biological/immunological/immunochemical method or a method using a biological reagent for a biological active substance (does not include standard pharmacopoeial microbiological methods)
7. The parameter of the specification does not affect the critical parameter, for example, any of the following: quantification, impurities (unless a certain solvent is uniquely used in the production of an active pharmaceutical substance), any critical physical characteristic, for example, particle size, bulk density before and after compaction , a test for authenticity, water, any request for a change in test frequency.
Documentation
1. Amendment to the relevant section (s) of the dossier.
2. Comparative table of current and proposed in-process tests
3. Details of any new non-pharmacopoeial analytical method and validation data, where relevant.
4. Batch analysis data on two production batches (3 production batches for biologicals, unless otherwise justified) of the active substance for all specification parameters
5. Justification/risk-assessment from the marketing authorisation holder or the ASMF Holder as appropriate showing that the parameter is non-significant.
6. Justification from the MAH or ASMF Holder as appropriate for the new in-process test and limits

B.I.a.5 Changes to the active substance of a seasonal, prepandemic or pandemic vaccine against human influenza Conditions to be fulfilled Documentation to be supplied Procedure type
a) Replacement of the strain(s) in a seasonal, prepandemic II

B.I.b) Quality control of active substance

B.I.b.1 Change in the specification parameters and/or limits of an active substance, starting material / intermediate / reagent used in the manufacturing process Conditions to be fulfilled Documentation to be supplied Procedure type
a) Tightening of specification limits for medicinal products subject to Official Batch Release 1,2,3,4 1,2 IAну
b) Tightening of specification limits 1,2,3,4 1,2 IA
c) Addition of a new specification parameter to the specification with its corresponding test method 1,2,5,6,7 1,2,3,4,7 IA
d) Deletion of a non-significant specification parameter (e.g. deletion of an obsolete parameter) 1,2,8 1,2,6 IA
e) Deletion of a specification parameter which may have a significant effect on the overall quality of the active substance and/or the finished product II
f) Change outside the approved specifications limits range for the active substance II
g) Widening of the approved specifications limits for starting materials/intermediates, which may have a significant effect on the overall quality of the active substance and/or the finished product II
h) Addition or replacement (excluding biological or immunological substance) of a specification parameter as a result of a safety or quality issue 1,2,3,4,5,7 IB
i) If an active pharmaceutical substance does not contain an article of the Pharmacopoeia of the Eurasian Economic Union or a national pharmacopoeia of a Member State of the EAEU, a change in its own specification data to data of an unofficial pharmacopoeia or pharmacopoeia of a third country 1,2,3,4,5,7 IB
Conditions
1. The change is not a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a type II variation procedure).
2. The change does not result from unexpected events arising during manufacture e.g. new unqualified impurity; change in total impurity limits
3. Any change should be within the range of currently approved limits.
4. The test procedure remains the same, or changes in the test procedure are minor.
5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way
6. The test method is not a biological/immunological/immunochemical method or a method using a biological reagent for a biological active substance (does not include standard pharmacopoeia microbiological methods)
7. The change in any material does not affect the genotoxic impurity. If an active pharmaceutical substance is involved, with the exception of residual solvents that must comply with the limits of the relevant Article of the Pharmacopeia of the EAEU, the control of any new impurity must conform to the Pharmacopoeia of the Eurasian Economic Union or the national pharmacopoeia of a Member State of the EAEU.
8. The specification parameter does not affect the critical parameter, for example, any of the following: quantification, impurities (unless a certain solvent is uniquely used in the production of an active pharmaceutical substance), any critical physical characteristic, for example, particle size, bulk density before and after compaction , a test for authenticity, water, any request for a test pass.
Documentation
1. Amendment to the relevant section (s) of the dossier.
2. Comparative table of current and proposed specifications.
3. Details of any new analytical method and validation data, where relevant.
4. Batch analysis data on two production batches (3 production batches for biologicals, unless otherwise justified) of the relevant substance for all specification parameters.
5. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch containing the active substance complying with the current and proposed specification. For herbal medicinal products, comparative disintegration data may be acceptable.
6. Justification/ risk-assessment from the MAH or ASMF holder as appropriate showing that the parameter is non-significant.
7. Justification from the MAH or ASMF Holder as appropriate of the new specification parameter and the limits

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