Attachment No. 14 MANUFACTURE OF MEDICINES FROM DONATED BLOOD AND PLASMA

Attachment No. 14

to the Rules of Good Manufacturing Practice

MANUFACTURE OF MEDICINES FROM DONATED BLOOD AND PLASMA

I. TERMS AND DEFINITIONS

1. For purposes of this Attachment the following basic terms shall have the following meaning:

blood component: a therapeutic blood component (erythrocytes, leucocytes, platelets and plasma) that may be prepared by different methods;

blood: whole blood taken from a donor and processed for transfusion or subsequent manufacture;

medicines manufactured from donated blood or plasma: medicines manufactured from blood components by an industrial process;

processing: any of the stages of obtaining of blood components which is carried out after blood collection and before the blood component has been obtained, e.g. separation and freezing of blood components. In this Attachment the term ‘processing’ shall also mean operations of blood collection performed in organizations that are specific to the plasma used for fractionating;

main plasma dossier: a separate document not included in the registration dossier for a medicine. This document contains all required and detailed information on the characteristics of the whole donated blood used as a starting raw material for manufacturing intermediate fractions and (or) subfractions, excipients and pharmaceutical substances that form a part of the plasma, medicines or medical products;

person in charge: a specially appointed person in the organization collecting and testing blood who is responsible for:

ensuring that the blood and its components have been collected and tested in each item regardless of their intended use, and that (if they are intended for transfusion) their processing, storage and release have been carried out pursuant to the law of the Russian Federation;

provision to authorized federal executive bodies of the required information on prescriptions, permits, accreditation or licensing;

observance in the organization collecting and testing blood of all requirements of the law of the Russian Federation.

The person in charge shall meet the following qualification conditions:

have a higher medical or biological education;

have experience of work of no less than two years in one or several organizations collecting and testing blood that collect and (or) test human blood, its components or receive, store and distribute them.

The above duties of the person in charge may be delegated to other persons with appropriate qualification and work experience.

Organizations collecting and testing blood shall submit to the authorized federal executive body the surname, name and patronymic (if any) of the person in charge, and persons to whom the duties of the person in charge have been delegated, with information on particular duties they are entrusted with.

If the person in charge or persons to whom the duties of the person in charge have been delegated are replaced on a permanent or temporary basis by another person, the organization collecting and testing blood shall immediately submit to the authorized federal executive body the surname, name and patronymic (if any) of the new person in charge and the date of appointment of this person;

fractionating plasma: the liquid part of donated blood which is left after cell components of the blood have been separated in the container with an anticoagulant, or which is left after separation with the help of continuous blood filtration or centrifugation with anticoagulants during the apheresis procedure. Fractionating plasma is intended for the manufacture of medicines from plasma that are described in the State Pharmacopoeia of the Russian Federation, namely, albumin solutions, coagulation factors and human immunoglobulins;

blood products: medicines made of donated blood or plasma;

fractionating program under a contract for third countries: fractionating under a contract at a fractioning plant or a plant manufacturing medicines from donated plasma located in the Russian Federation and using staring raw materials from other countries, in this case the manufactured products are not intended for use in the Russian Federation;

organization collecting and testing blood: a legal entity responsible for any aspect of collection and testing of blood or blood components regardless of their subsequent intended use, as well as for their processing, storage and delivery if they are intended for transfusion. This term shall not cover blood banks in hospitals, but shall apply to organizations performing plasmapheresis;

fractioning, fractioning plant: a technological process at a plant (fractioning plant) during which plasma components are separated with the help of different physical and chemical methods, for example, such as sedimentation, chromatography.

II. SCOPE OF APPLICATION (1)

2. (1.1) Provisions hereof shall apply to medicines made of donated blood or plasma and fractionated in the Russian Federation or imported into the Russian Federation. This Attachment shall also cover starting raw materials for such medicines (e.g. donated plasma). The requirements set herein shall also apply to stable fractions of donated blood or plasma (e.g. albumin) that are included in medical products.

3. (1.2) This Attachment sets special requirements to the manufacture, storage and transportation of donated plasma used for fractioning and manufacturing medicines made of donated blood or plasma.

4. (1.3) This Attachment contains special provisions for cases when starting raw materials are imported from third countries and for fractionating programs under a contract for third countries.

5. (1.4) This Attachment shall not apply to blood components intended for transfusion.

III. PRINCIPLES (2)

6. (2.1) Medicines made of donated blood or plasma (and their pharmaceutical substances used as starting raw materials) shall meet the requirements of these Rules, and the registration dossier for the medicine. They shall be considered biological medicines and starting raw materials comprising biological substances, such as human cells or liquids (including blood or plasma). Due to the biological origin of the sources of raw materials, these sources have certain specific features. For example, starting raw materials may be contaminated by infecting agents, in particular, viruses. For this reason the quality and safety of such medicines shall depend on the control of the starting raw materials and the source of their origin, as well as subsequent technological procedures, including testing for infectious markers, removal and inactivation of viruses.

7. (2.2) All pharmaceutical substances used as starting raw materials for medicines shall meet the requirements of these Rules (Item 6 hereof). It is necessary to observe the below requirements with regard to collection and testing of starting raw materials made of donated blood or plasma. Collection and testing shall be performed in accordance with the appropriate quality system, requirements of corresponding regulatory legal acts of the Russian Federation and specifications. It is necessary to observe the requirements set in regulatory legal acts of the Russian Federation to tracing from the donor to the recipient and informing about adverse effects and adverse reactions. It is required to be guided by the State Pharmacopoeia of the Russian Federation.

8. (2.3) Starting raw materials imported from third countries for the manufacture of medicines made of donated blood or plasma, if these medicines are intended for use or sale in the Russian Federation, shall meet the norms that are not inferior to the applicable norms of the Russian Federation with regard to quality systems of organizations collecting and testing blood. It is also necessary to observe the requirements set by regulatory legal acts of the Russian Federation in terms of tracing from the donor to the recipient and informing about adverse effects and adverse reactions and to ensure adherence to the requirements set by regulatory legal acts of the Russian Federation to blood and its components.

9. (2.4) In case of fractionating programs conducted under a contract with third countries starting raw materials imported from other countries shall meet the requirements set by regulatory legal acts of the Russian Federation. Works performed in the Russian Federation shall comply with these Rules in full. It is necessary to meet the requirements applicable in the Russian Federation with regard to quality systems of organizations collecting and testing blood. It is also necessary to observe the requirements set by regulatory legal acts of the Russian Federation in terms of tracing from the donor to the recipient and informing about adverse effects and adverse reactions and to ensure adherence to the effective requirements to blood and its components.

10. (2.5) These Rules shall cover all stages after collection and testing of blood (e.g. processing, including separation, freezing, storage and transportation to the manufacturer). Specified activities are generally included in the area of responsibility of the authorized person of the manufacturer. If specific stages of processing intended for plasma fractioning are carried out in an organization collecting and testing blood, this organization may specially appoint an authorized person, however the presence and responsibility of this person may differ from the presence and responsibility of the person in charge. To resolve this situation and ensure that the duties of the authorized person indicated in regulatory legal acts of the Russian Federation are dully fulfilled, the fractioning plant (the manufacturer of the medicines) shall sign a contract with the organization collecting and testing blood pursuant to Items 237255 of these Rules. The said contract shall specify corresponding obligations and detailed requirements for quality control. The person in charge in the organization collecting and testing blood and the authorized person of the fractioning plant (the manufacturer of the medicines) shall take part in the preparation of this contract. To confirm that the organization collecting and testing blood meets the conditions of this contract, the authorized person shall ensure corresponding audits.

11. (2.6) Special requirements to documents and other measures concerning starting raw materials aimed at manufacturing medicines from plasma shall be indicated in the main plasma dossier.

IV. QUALITY MANAGEMENT (3)

12. (3.1) Quality management shall cover all stages from the selection of donors to the delivery of finished products. It is necessary to observe the requirements set by regulatory legal acts of the Russian Federation in terms of tracing both at the stage before the delivery of plasma to the fractioning plant, and the stage of delivery, as well as at all stages related to the collection and testing of donated blood and plasma intended for the manufacture of medicines.

13. (3.2) Collection of blood and plasma used as starting raw materials for manufacturing medicines shall be performed in organizations collecting and testing blood, and the tests shall be conducted in laboratories which apply quality systems that meet the requirements set by regulatory legal acts of the Russian Federation, have appropriate permits issued by the authorized federal executive body and are subject to regular audits in accordance with the law of the Russian Federation. If the manufacturer has fractionating programs under a contract for third countries, the manufacturer shall inform the authorized federal executive body thereof.

14. (3.3) If plasma is imported from third parties, it shall be supplied only by approved suppliers (e.g. organizations collecting and testing blood, including external warehouses). Such suppliers shall be indicated in specifications for starting raw materials set by the fractioning plant or the manufacturer and approved by the authorized federal executive body in accordance with the conditions and procedure described in regulatory legal acts of the Russian Federation and specified by the authorized person of the fractioning plant located in the Russian Federation. Assessment and issue of a permit for use of plasma (fractionating plasma) as starting raw materials shall be performed pursuant to Item 39 hereof.

15. (3.4) The fractioning plant or the manufacturer of finished medicines shall carry out qualification of suppliers, including assessment of suppliers in accordance with the approved procedures. It is necessary to regularly re-qualify suppliers subject to an approach based on the risk assessment.

16. (3.5) The fractioning plant or the manufacturer of finished medicines shall sign contracts with organizations collecting and testing blood that act as suppliers.

17. It is recommended to include in these contracts the following conditions, without limitation:

the definition of obligations and liabilities;

requirements to the quality system and documents;

donor selection criteria and testing;

requirements to blood separation into blood components and plasma;

plasma freezing;

plasma storage and transportation;

tracing and informing processes after blood donation and collection (including about adverse effects).

18. The fractioning plant of the manufacturer of the medicines shall have results of tests of all items of starting raw materials supplied by the organization collecting and testing blood. If any stage is conducted under a subcontract, this subcontract shall be made in writing.

19. (3.6) An appropriate change management system shall be put in place to plan, assess and document all changes which may influence the quality and safety of the products or traceability. It is necessary to assess the potential influence of suggested changes. It shall be determined whether additional tests or validation are required, especially at the stages of inactivation and removal of viruses.

20. (3.7) To minimize risks connected with infecting agents and new infecting agents, it is necessary to implement a system of safety measures. This system shall include risk assessment for the following purposes:

to determine the retention time of production supplies (the period of internal quarantine) before plasma processing for withdrawing doses that raise doubts (doses taken within the period indicated by regulatory legal acts of the Russian Federation before it has been stated that doses collected from high-risk donors must be excluded from processing, e.g. due to positive test results);

to take into account all aspects related to the decrease in the number of viruses an (or) tests for infecting agents or their analogues;

to define the possibilities of decrease in the number of viruses, to determine the batch size of starting raw materials and other significant aspects of the manufacturing process.

V. TRACEABILITY AND MEASURES TAKEN AFTER BLOOD COLLECTION

(4)

21. (4.1) It is necessary to organize a system enabling to trace each donated dose of blood or plasma from the donor and the procedure of its collection through the organization collecting and testing blood to the batch of the medicine, and vice versa.

22. (4.2) It is required to determine responsibility for tracing the products (no stage may be omitted):

from the donor and the dose collected by the organization collecting and testing blood to the fractioning plant, which is the responsibility of the person in charge of the organization collecting and testing blood;

from the fractioning plant to the manufacturer of the medicine and any subcontractor regardless of whether it manufactures the medicine or a medical product, which is the responsibility of the authorized person.

23. (4.3) The data ensuring complete traceability shall be stored for at least 30 years, unless otherwise stated by the law of the Russian Federation.

24. (4.4) Contracts specified in Item 16 hereof between organizations collecting and testing blood (including control laboratories) and the fractioning plant or the manufacturer shall contain conditions indicating that the traceability and measures taken after blood collection shall cover the entire chain from plasma collection to all manufacturers responsible for the issue of a permit for the release of finished products.

25. (4.5) The organization collecting and testing blood shall inform the fractioning plant or the manufacturer of any incident that may affect the quality or safety of the products, and provide other important information obtained after the donor’s visit or the issue of a permit for plasma release, for example, feedback information (information obtained after blood collection). If the fractioning plant or the manufacturer are located in the territory of another country, the information shall be provided to the manufacturer locate in the Russian Federation and responsible for the issue of a permit for the release of medicines. In both cases such information, if it is related to the quality and safety of finished products, shall be submitted to the authorized federal executive body whose jurisdiction covers the fractioning plant or the manufacturer.

26. (4.6) If as a result of an inspection of the organization collecting and testing blood by the authorized federal executive body the license of this organization has been revoked, a notice shall be sent pursuant to Item 25 hereof.

27. (4.7) The standard operating procedures shall describe the process of managing the information obtained after blood collection, subject to license requirements and the procedure for informing the authorized federal executive body. Measures taken after blood collection shall be performed in accordance with the requirements set by regulatory legal acts of the Russian Federation.

VI. PREMISES AND EQUIPMENT (5)

28. (5.1) To minimize the possibility of microbial contamination of or introduction of a foreign material into a batch of plasma, items of plasma shall be defrosted and combined in areas that meet the requirements set by Attachment No.1 to these Rules in terms of the contamination class no less than class D. It is necessary to use appropriate clothing, including face masks and gloves. All other operations with open products in the course of the manufacturing process shall be performed in conditions that meet corresponding requirements stipulated in Attachment No. 1 to these Rules.

29. (5.2) Pursuant to the requirements set in Attachment No. 1 to these Rules, regular monitoring of the process environment shall be required, especially when containers with plasma are opened and during processes of defrosting and combining. Acceptance criteria shall be set.

30. (5.3) During manufacture of medicines made of donated plasma appropriate methods of inactivation and removal of viruses shall be applied and measures taken to prevent contamination of processed products by products that have not been processed yet. It is required to use specially intended separate rooms and equipment for stages of the manufacturing process that are performed after viral inactivation.

31. (5.4) To eliminated risks of contamination of the current output by viruses used for validation tests, the validation of methods decreasing the number of viruses shall not be carried out with the help of the manufacturing equipment. In this case validation shall be conducted in accordance with the requirements stipulated in corresponding regulatory legal acts of the Russian Federation.

VII. MANUFACTURING PROCESS (6)

Starting raw materials

32. (6.1) Starting raw materials shall meet the requirements of the State Pharmacopoeia of the Russian Federation and the conditions specified in the corresponding registration dossier, including the main plasma dossier. The said conditions shall be included in the contract (Item 16 hereof) between the organization collecting and testing blood and the fractioning plant or the manufacturer. The observance of these requirements shall be controlled by the quality system.

33. (6.2) Starting raw materials for fractionating programs under a contract for third countries shall comply with the requirements described in Item 9 hereof.

34. (6.3) Depending on the type of the collection procedure (e.g. whole blood collection or automated apheresis) different processing stages may be required. All processing stages (e.g. separation, including centrifugation, sampling, marking, freezing) shall be indicated in the instructions.

35. (6.4) It is necessary to prevent any confusion of the items and samples, especially during marking, and any contamination, for example, when cutting segments of tubes or sealing containers.

36. (6.5) Freezing is a critical stage of isolation of proteins which are labile in plasma, for example, coagulation factors. For this reason freezing shall be performed with the help of validated methods as soon as possible after blood collection. In this case it is required to follow the requirements of the State Pharmacopoeia of the Russian Federation.

37. (6.6) The conditions of storage and transportation of blood and plasma to the fractioning plant shall be defined and documented at all stages of the delivery chain. The fractioning plant shall be informed of any deviations from the set temperature. It is necessary to use qualified equipment and validated procedures.

Assessment and issue of a permit for the release of fractioning plasma used as starting raw materials

38. (6.7) The permit for the release of fractioning plasma (from quarantine) may be provided only subject to systems and procedures that ensure the quality required for the manufacture of finished products. Plasma shall be delivered to the fractioning plant or the manufacturer only after the person in charge (or if blood or plasma are collected in third countries – a person with a similar qualification and duties) has confirmed in writing that the fractioning plasma meets the requirements and complies with specifications indicated in corresponding contracts, and that all stages have been carried out in accordance with these Rules.

39. (6.8) After delivery to the fractioning plant the use of all containers with fractioning plasma shall be permitted by the authorized person. The authorized person shall confirm that the plasma meets the requirements of pharmaceutical norms of the State Pharmacopoeia of the Russian Federation and the conditions of the corresponding registration dossier, including the main plasma dossier, or, in case of using plasma for fractionating programs under a contract for third countries, all requirements specified in Item 9 hereof.

Plasma processing for fractioning

40. (6.9) Fractioning stages differ depending on the product and the manufacturer. As a rule, they include various fractioning operations, and some of them may contribute to inactivation or removal of possible contamination.

41. (6.10) It is necessary to set requirements to the processes of combining, taking samples from combined plasma, fractioning and inactivating or removing viruses which shall be observed.

42. (6.11) Methods used in the process of viral inactivation shall be applied subject to strict adherence to validated procedures. Such methods shall correspond to the methods that have been used to validate viral inactivation procedures. All unsuccessful viral inactivation procedures shall be thoroughly investigated into. The observance of the validated manufacturing process is greatly important for the procedures aimed at decreasing the number of viruses, as any deviation may result in a risk for the safety of finished products. It is necessary to put in place procedures that take account of the said risks.

43. (6.12) Any reprocessing or recycling may be performed only after risk management measures have been taken in terms of the quality and only on certain stages of the manufacturing process as defined in the corresponding process description.

44. (6.13) It is required to organize a system for clear separation and (or) differentiation of medicines or intermediate products which have undergone and which have not undergone the viral reduction procedure.

45. (6.14) Depending on the results of a thoroughly conducted risk management process (subject to possible differences in epidemiological data) it may be permitted to manufacture according to the principle of production cycles, if plasma or intermediate products of a different origin are processed at one production site, including required procedures of clear separation and use of set and validated cleaning procedures. Requirements to such measures shall be based on relevant regulatory legal acts of the Russian Federation. The risk management process shall help to solve the issue concerning the necessity to use special equipment in case of implementation of fractionating programs conducted under a contract with third countries.

46. (6.15) The storage period for intermediate products intended for storage shall be set based on the stability data.

47. (6.16) It is necessary to set and document requirements to the storage and transportation of intermediate products and finished medicines at all stages of the delivery chain. It is necessary to use qualified equipment and validated procedures.

VIII. QUALITY CONTROL (7)

48. (7.1) Requirements to tests for viruses or other infecting agents shall be set subject to new knowledge about infecting agents and availability of validated testing methods.

49. (7.2) The first homogeneous plasma pool (e.g. after separation of cryoprecipitate from plasma) shall be controlled by validated methods with appropriate sensitivity and specificity pursuant to relevant pharmaceutical norms of the State Pharmacopoeia of the Russian Federation.

IX. ISSUE OF A PERMIT FOR THE RELEASE OF INTERMEDIATE AND FINISHED PRODUCTS

(8)

50. (8.1) It shall be permitted to release only batches which have been manufactured from plasma pools found negative with regard to markers of blood borne viral infections according to the test results, as well as pursuant to the relevant requirements of pharmaceutical norms of the State Pharmacopoeia of the Russian Federation (including any special thresholds limiting the content of viruses) and approved specifications (in particular, the main plasma dossier).

51. (8.2) A permit for the release of intermediate products intended for subsequent treatment of the in-process site or delivery to any other production site, and a permit for the release of finished medicines shall be issued by the authorized person subject to the set requirements.

52. (8.3) The authorized person shall issue the permit for the release of intermediate or finished products used for fractionating programs under a contract for third countries based on norms approved by the client and in accordance with the requirements of these Rules. If such medicines are not intended for use in the Russian Federation, the requirements of pharmaceutical norms of the State Pharmacopoeia of the Russian Federation may not apply thereto.

X. STORAGE OF SAMPLES OF PLASMA POOLS (9)

53. (9.1) One plasma pool may be used to manufacture several batches and (or) medicines. Control samples of each plasma pool, as well as corresponding records shall be stored for at least one year after the expiry of the storage period of the medicine made of this pool with the longest storage period among all medicines manufactured from this plasma pool.

XI. WASTE DISPOSAL (10)

54. (10.1) It is necessary to approve procedures for safe storage and disposal of waste, disposable and rejected materials (e.g. contaminated items, items from infected donors, as well as blood, plasma, intermediate products or finished medicines with an expired period of shelf life) and this approval shall be made in writing.