Attachment No. 16 CONFIRMATION BY THE AUTHORIZED PERSON OF THE CONFORMITY OF A BATCH OF PRODUCTS TO THE PURPOSE OF THEIR RELEASE

Attachment No. 16

to the Rules of Good Manufacturing Practice

CONFIRMATION BY THE AUTHORIZED PERSON OF THE CONFORMITY OF A BATCH OF PRODUCTS TO THE PURPOSE OF THEIR RELEASE

I. SCOPE OF APPLICATION (1)

1. (1.1) This Attachment determines the procedure for compliance confirmation conducted by the authorized person when batches of medicines are put into civil circulation (including registered medicines or medicines manufactured for export).

2. (1.2) This Attachment shall also cover cases when the manufacture of a batch of products or the analysis procedure is divided into several stages performed in different places or by different manufacturers, and when a batch of intermediate or bulk products is divided into two or more batches of finished products. This Attachment may apply to medicines intended for clinical studies.

3. (1.3) If regulatory legal acts of the Russian Federation set special requirements to certain blood preparations and immunobiological medicines put into civil circulation, these requirements shall be observed.

4. (1.4) The basic requirements to the release of a batch of products are indicated in the corresponding registration dossier, process description and specifications. Provisions of this Attachment shall apply to the extent that they do not contradict such basic requirements.

II. PRINCIPLE (2)

5. (2.1) Each batch of finished products shall be approved by the authorized person with regard to its conformity to the set requirement before it has been released in the internal market or for export.

6. (2.2) The release of a batch of products shall be regulated for the following purposes:

to guarantee that the batch has been manufactured and tested in accordance with the license for the manufacture of medicines, requirements of the registration dossier, requirements of these Rules and other requirements set by regulatory legal acts of the Russian Federation before its release;

to guarantee that if it is necessary to study defective items or withdraw a batch, the authorized person who has issued the permit for its release and has made corresponding records will be easily identified.

III. INTRODUCTION (3)

7. (3.1) The manufacture of a batch of medicines, including quality control, shall be divided into stages that can be performed at different production sites and by different manufacturers. Each stage shall be performed in accordance with the requirements of the process description, requirements of these Rules and other regulatory legal acts of the Russian Federation. The authorized person carrying out the procedure for confirming the compliance of a batch of finished products with the set requirements before its release shall observe the above requirements.

8. (3.2) In practice one authorized person may not know the specifics of each stage of the manufacturing process. The authorized person who confirms the compliance of a batch of finished products may rely on expert opinions of other authorized persons on individual issues. In these cases the authorized person shall be sure that these expert opinions are reliable based on personal experience or a confirmation received from other authorized persons in an established quality system.

9. (3.3) If individual stages of the manufacturing process are performed in another country, similar requirements to the conformity of the manufacture and quality control shall be set for the participant of the manufacturing process in this country. In this case medicines shall be also manufactured in accordance with the requirements of the registration dossier. The manufacturer shall have a license for its activities pursuant to the law of the country and meet the requirements of these Rules or good manufacturing practices for medicines whose requirements are not inferior to the requirements of these Rules.

IV. GENERAL REQUIREMENTS (4)

10. (4.1) Different stages (steps) of the manufacture, delivery, control and storage of one and the same batch of finished products before its release may be performed at different production sites. All these production sites shall be licensed and shall be operated under the supervision of at least one authorized person confirming before the release of the batch that this batch meets the set requirements. However the proper manufacture of a particular batch of products regardless of the number of used production sites shall remain under general supervision of the authorized person confirming before the release that this batch of finished products meets the set requirements.

11. (4.2) Different batches of products may be manufactured or imported and released in different countries having an agreement with the Russian Federation on mutual recognition of the conditions of manufacture and sale. In this case the entity in whose name the Marketing Authorization has been issued, and each production site having the right to release a batch of products shall be provided with the accurate address of the site where a particular batch of products has been released and information on the authorized person responsible for the confirmation of the compliance of its quality with the set requirements.

12. (4.3) The authorized person confirming before the issue of a release permit that the batch of finished products meets the set requirements may base the decision on the person’s own knowledge about all the premises and processes used in the manufacture, the experience of the staff taking part in the manufacture and the applied quality system in the framework of which the products are manufactured. This authorized person may rely on expert opinions of another authorize person or several other authorized persons on the compliance of intermediate stages of the manufacturing process with the set requirements.

13. Such expert opinions provided by other authorized persons shall be prepared in writing and shall clearly define the fact of compliance confirmation. The confirmation procedure shall be documented.

14. (4.4) The confirmation procedure described in Item 13 hereof shall be observed in all cases when the authorized person relies on an expert opinion of another authorized person. This document shall correspond to the provisions specified in Items 237255 of these Rules. The authorized person confirming that a batch of finished products meets the set requirements shall guarantee the implementation of measures defined in the said document. The form of the document describing the confirmation procedure shall correspond to the relations between the parties. For example, this document may represent a standard operating procedure of the manufacturer or a contract between different manufacturers, even if they are members of the same group of companies.

15. (4.5) The said contract between manufacturers shall include obligations on the part of the supplier of bulk or intermediate products to inform the recipient(s) of the products of all deviations, results beyond the scope of the specifications, non-compliance with the requirements of these Rules, investigations, claims or other events that shall be taken into account by the authorized person responsible for the confirmation of the compliance of a batch of finished products with all set requirements.

16. (4.6) If a computerized system is used to document the compliance confirmation and issue a permit for the release of a batch of products, it is necessary to pay special attention to the adherence to the requirements specified in Attachment No. 11 to these Rules.

17. (4.7) If there is a confirmation of compliance of a batch of finished products issued by the authorized person, this procedure shall not be repeated in countries that have an agreement with the Russian Federation on mutual recognition of results of this procedure.

18. (4.8) Regardless of certain measures aimed at confirming the compliance and releasing batches, it is necessary to perform a procedure of quick detection and withdrawal of all products that may be dangerous for consumers.

V. TESTS AND RELEASE OF A BATCH OF PRODUCTS MANUFACTURED IN THE RUSSIAN FEDERATION (5)

19. (5.1) If the manufacture is located at one licensed production site:

If all stages of manufacture and control are performed at one production site, other persons may be entrusted with separate checks and testing operations. The authorized person of this site who confirms the compliance of a batch of finished products shall generally bear personal responsibility for the accuracy of the results of the inspection in the framework of the implemented quality system. However the authorized person may also take into account expert opinions on the compliance of intermediate stages with the set requirements provided by other authorized persons of this site who are responsible for these stages.

20. (5.2) If different stages of manufacture are performed at different production sites of the same manufacturer:

If different stages of manufacture of a batch of products are performed at different production sites in one organization (regardless of whether they are covered by one and the same license for the manufacture of medicines or not), the authorized person shall be in charge of each stage of manufacture. The confirmation of compliance of a batch of finished products with the set requirements shall be issued by the authorized person of the manufacturer who is either personally responsible for all stages of manufacture, or takes into account expert opinions on the preceding stages provided by authorized persons responsible for these stages.

21. (5.3) If some intermediate stages of manufacture are performed by another organization under a contract:

One or more intermediate stages of manufacture and quality control may be performed by another organization under a contract pursuant to the provisions specified in Items 237255 of these Rules. The authorized person of the client may take into account the expert opinion of the authorized person of the contractor on the relevant stage, but this person shall be responsible for the performance of this work in accordance with the contract conditions. The confirmation of compliance of a batch of finished products with the set requirements shall be issued by the authorized person of the manufacturer responsible for the release of the batch of products.

22. (5.4) If several batches of finished products are manufactured from a batch of bulk products at different production sites and are released in the market on the basis of the same Marketing Authorization:

а) (5.4.1) The authorized person of the manufacturer having a license for the manufacture of medicines and releasing a batch of bulk products may confirm before the release the compliance of all batches of finished products. In this case the authorized person shall either take personal responsibility for all stages of manufacture, or take into account expert opinions on the stages of pre-packing and (or) packaging provided by authorized persons of sites performing these stages;

b) (5.4.2) The compliance of each batch of finished products before its release may be confirmed by the authorized person of the manufacturer who has performed the final stage of pre-packing and (or) packaging. In this case the authorized person shall either take personal responsibility for all stages of manufacture, or take into account the expert opinion on the batch quality provided by the authorized person of the place of release of the batch of bulk products;

c) (5.4.3) In all case of organization of the manufacture of finished products in different place and at different production sites under the same Marketing Authorization it is necessary to appoint one person (as a rule, the authorized person of the manufacturer of the batch of bulk products) who shall be fully responsible for the release of all batches of finished products made of one batch of bulk products. This person shall know about any problems related to the quality of any batch of finished products and coordinate the performance of all required measures taken due to any problem in terms of a batch of bulk products.

Though the numbers of the batches of bulk and finished products shall not coincide, it is necessary to document the connection between the numbers of these batches in order to ensure tracing in case of an audit.

23. (5.5) If one batch of bulk products is pre-packed and (or) packed in different places and at different production sites to get several batches of finished products which are released on the basis of different Marketing Authorizations (which happens when, for example, a multinational company has national Marketing Authorizations for the medicine in several states or the manufacturer of generic medicines acquires a bulk medicine, pre-packs and (or) packs it and releases the finished medicine under its own Marketing Authorization):

а) (5.5.1) The authorized person of the manufacturer of finished products who confirms that a batch of finished products meets the set requirements shall either take personal responsibility for all stages of manufacture or rely on the expert opinion provided by the authorized person of the manufacturer of bulk products;

b) (5.5.2) Any problem related to the quality of any batch of finished products which could have been manufactured form the initial batch of bulk products shall be referred to the authorized person responsible for the confirmation of the quality of this batch of bulk products. After this the said authorized person shall take all possible measures with regard to all batches of finished products manufactured from this batch of bulk products. The procedure for acting in this case shall be described in the agreement.

24. (5.6) If a batch of finished products is purchased and sold by a manufacturer having a license for the manufacture of medicines in accordance with its own Marketing Authorization (which happens, for example, when the manufacturer supplying a generic medicine is the entity in whose name the Marketing Authorization for the medicine manufactured by another manufacturer has been issued) and the former manufacturer purchases finished products whose compliance has not been yet confirmed by its manufacturer and releases these products on the basis of its own license for the manufacture of medicines and its own Marketing Authorization:

the authorized person of the manufacture purchasing the products and having no documented results of the confirmation of their compliance shall confirm for the release that this batch of finished products meets the set requirements. In this case the authorized person of the purchasing manufacturer shall take the responsibility for all stages of manufacture or shall rely on the expert opinion on the quality of the batch of products of the authorized person of the supplying manufacturer.

25. (5.7) If the medicine quality control laboratory and the manufacturer are different organizations:

The authorized person confirming compliance of a batch of finished products with the set requirements shall take the responsibility for laboratory tests conducted by such a laboratory or take into account the confirmation of the tests issued by another authorized person. If there is no such confirmation, the authorized person shall be familiar with the activities of this laboratory and methods used there to confirm the compliance of the quality of these finished products.

VI. DUTIES OF THE AUTHORIZED PERSON (6)

26. (6.1) Before performing the procedure for confirming the compliance of a batch of finished products before their release the authorized person shall make sure that the following requirements, without limitation, are observed:

а) (a) the batch of finished products and their manufacturing process comply with the provisions of normative documents;

b) (b) the batch of finished products is manufactured pursuant to the requirements of these Rules, and in case of a batch of products imported from other countries – pursuant to good manufacturing practices for medicines whose requirements, at least, are not inferior to the requirements of these Rules;

c) (c) the main manufacturing processes and control methods are validated, the actual manufacturing environment and the dossier for the batch of products are taken into account;

d) (d) any deviations or planned changes in the technological process or the quality control are approved by persons having appropriate powers, the corresponding authorized federal executive body is informed of any changes requiring any amendments to the registration dossier or the license for the manufacture of medicines, and a permit to introduce such changes has been obtained from the authorized federal executive body;

e) (e) all required examinations and tests (including additional sampling, inspections, examinations and tests connected with deviations in the manufacturing process or planned changes) have been conducted;

f) (f) documents on the manufacturing process and quality control are prepared and approved by the staff having appropriate powers;

g) (g) all audits are conducted in accordance with the requirements of the quality management system;

h) (h) all factors that in the opinion of the authorized person are significant for the quality of this batch of products are taken into account.

27. The authorized person may have additional duties pursuant to the law of the Russian Federation or the job description approved by the manufacturer.

28. (6.2) The authorized person confirming the compliance of the intermediate stage of manufacture pursuant to Items 1213 hereof shall fulfil duties similar to the duties specified above with regard to this stage.

29. (6.3) The authorized person shall maintain their qualification at the appropriate level in view of achievements of the scientific and technical progress and shall take into account the changes in the quality management system that are connected with the products the compliance of which with the set requirements is confirmed by the authorized person.

30. (6.4) If the authorized person is engaged in the confirmation of compliance of a batch of products about which this person does not have enough information (e.g. in case of mastering of a new type of products or a transfer to another enterprise), the authorized person shall gain required knowledge and experience necessary to fulfil these duties.

31. Pursuant to regulatory legal acts of the Russian Federation the authorized person may be entrusted with a duty to inform the authorized federal executive body of any change that requires re-qualification.

VII. TERMS AND DEFINITIONS (7)

32. For purposes hereof, in addition to the terms and definitions stipulated in Chapter II of these Rules, the following basic terms are used:

compliance assessment of a batch of finished products: a documented confirmation of the compliance of a batch of finished products with the set requirements before the release of these products;

confirmation: a signed certificate indicating that the process or tests have been performed in accordance with the requirements of the Rules of the organization of manufacture and quality control of medicines and requirements set during the state registration that is approved in writing by the authorized person responsible for the compliance assessment of a batch of finished products before its release;

a batch of finished products: a batch of products in the final packaging that is ready for release;

a batch of bulk products: a batch of products of a size specified during the registration of the medicine that is ready for pre-packing, final packaging or is placed in individual packages and ready for the preparation of final packages. A batch of bulk products may comprise, for example, a liquid bulk product, solid medicines (pills or capsules) or filled ampoules;

mutual recognition agreement: an agreement on mutual recognition of inspections with the country where (from which they are imported) imported medicines are manufactured.