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Attachment No. 2 MANUFACTURE OF BIOLOGICAL (INCLUDING IMMUNOBIOLOGICAL) PHARMACEUTICAL SUBSTANCES AND MEDICINES

Attachment No. 2

to the Rules of Good Manufacturing Practice

MANUFACTURE OF BIOLOGICAL (INCLUDING IMMUNOBIOLOGICAL) PHARMACEUTICAL SUBSTANCES AND MEDICINES

I. SCOPE OF APPLICATION

1. The technology of manufacturing biological (including immunobiological) pharmaceutical substances and biological medicines (hereinafter – biological pharmaceutical substances and medicines) is a critical factor determining appropriate regulatory control. Pharmaceutical substances and medicines may be defined as biological based, to a considerable extent, on the technology of their manufacture. This Attachment shall be used as guidelines for the entire range of biological pharmaceutical substances and biological medicines.

2. The requirements set forth in this Attachment shall cover antibiotics at biological stages of their manufacture. The rules of manufacture of medicines obtained from fractioned donated blood or plasma shall be stipulated in Attachment No. 14 hereto, and of non-transgenic herbal medicines – in Attachment No. 7 hereto.

3. This Attachment shall be divided into two main parts:

a) (a) General Guidelines (Part A) – shall outline additional rules of the manufacture of biological pharmaceutical substances and medicines, starting from inoculum and cell bank control to the final operations and testing;

b) (b) Special Guidelines on Individual Types of Products (Part B) – shall outline additional guidelines for individual types of biological pharmaceutical substances and medicines.

4. The scope of the application of this Attachment shall cover two aspects:

a) (a) the manufacturing stage: before biological pharmaceutical substances become sterile, the main document applicable to them shall be Chapter IV hereof. Rules for subsequent stages of manufacture of biological medicines shall be outlined in Chapter III hereof;

b) (b) the product type: this Attachment shall be a reference document for the entire range of biological medicines.

5. These two aspects shall be presented in Table No. 1. The level of requirements shall become more stringent from earlier to later stages of the manufacture of biological pharmaceutical substances; however, the principles set out in these Rules shall be binding at all times.

6. If regulatory legal acts of the Russian Federation set special requirements:

a) (a) to tissues and cells used for the manufacture of medicines that become biological pharmaceutical substances for certain types of biological medicines;

b) (b) with respect to high-technology medicines, in which blood or blood components are used as starting raw materials regarding setting of requirements to the selection of donors, to the quality and safety during sampling, testing, processing, storage and transportation of human blood and its components;

c) (c) to the manufacture and control of genetically modified organisms subject to appropriate established and observed isolation and other protection measures at facilities, where any operations with genetically modified microorganisms are performed, for the purpose of establishing and observing an appropriate level of biological safety, such requirements shall be binding.

Table No. 1. Scope of the application of this Attachment

Type and source of material Example of product Application of these Rules to manufacturing stages (in grey background)
1. Animal-based or plant-based: non-transgenic Heparin, insulin, enzymes, proteins, allergen extracts, high-technology medicines, antisera Collection of plants, organs, tissues or liquids <1> Cutting, mixing and (or) primary treatment Isolation and purification Preparation, filling
2. Viruses or bacteria/fermentation/cell cultures Viral or bacterial vaccines, enzymes, proteins Creation and maintenance of the main <2> and working cell banks, the main and working virus seed stocks Cell culture and (or) fermentation Inactivation where necessary, isolation and purification Preparation, filling
3. Cell culture biotechnology /fermentation/ Recombinant products, monoclonal antibodies, allergens, vaccines, gene therapy medicines (viral and non-viral vectors, plasmids) Creation and maintenance of the main and working cell banks, the main and working inocula Cell culture and (or) fermentation Isolation, purification, modification Preparation, filling
4. Animal-based: transgenic Recombinant proteins, high-technology medicines Main and working transgenic bank Cutting, mixing and (or) primary treatment Isolation, purification and modification Preparation, filling
5. Plant-based: transgenic Recombinant proteins, vaccines, allergens Main and working transgenic bank Cultivation, collection of plants <3> Primary extraction, isolation, purification, modification Preparation, filling
6. Human-extracted Urinary enzymes, hormones Collection of liquids Mixing and (or) primary treatment Isolation and purification Preparation, filling
7. Human-extracted and (or) animal-based Gene therapy medicines: genetically modified cells Donation, supply and testing of initial tissues/cells <6> Production of vectors <4>, purification of cells and treatment

Purification and treatment of production vectors <5> and cells

In vitro genetic modification of cells, creation of the main and working cell banks or cell stock Preparation, filling
Somatic cell therapy medicines Donation, supply and testing of initial tissues/cells <6> Creation of the main and working cell banks or cell stock Cell isolation, culture purification, integration with non-cellular components Preparation, integration, filling
Tissue engineering medicines Donation, supply and testing of initial tissues/cells <6> Primary treatment, isolation and purification, creation of the main and working cell banks, initial cell stock Cell isolation, culture purification, integration with non-cellular components Preparation, integration, filling
Strengthening of requirements

The terms are given in this Attachment.

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<1> Items 8794 of this Attachment.

<2> Items 5462 of this Attachment.

<3> For cultivation, collection and primary treatment in the field environment, the Guidelines on Good Agricultural and Collection Practice for Starting Materials of Herbal Origin may be used.

<4> For virus vectors see Line 2 of the table.

<5> Requirements to human tissues and cells used in the manufacture of medicines are stipulated in regulatory legal acts of the Russian Federation.

II. PRINCIPLE

7. The manufacture of biological pharmaceutical substances and medicines has its specific features based on the type of products and manufacturing technologies. The nature of manufacturing processes, control and application of biological medicines shall require special precautions.

8. Unlike in case of ordinary medicines manufactured with the use of chemical and physical methods characterized by a high degree of reliability, the manufacture of biological pharmaceutical substances and medicines implies using biological processes and materials such as cell cultivation or material extraction from living organisms. Such biological processes may demonstrate inherent variability entailing a wide range of byproducts of various types. Therefore, the quality risk management principles shall be especially important for this class of materials and shall be observed when developing control methods at all manufacturing stages for minimizing variability and reducing the risk of contamination and cross contamination.

9. Materials, growth media and conditions of cultivation of target microorganisms, cell cultures and viruses favour to a large extent the possible growth of contaminating agents. Many medicines have a limited resistance to a wide range of purification methods, particularly, to the methods intended for inactivation or removal of foreign viral contaminants. In order to minimize the potential risk of such contamination, the manufacturer shall pay special attention to the planning of the manufacturing process, design of equipment, premises, support systems, conditions of preparation and addition of buffers and reagents, sampling and staff training.

10. Specifications for products (particularly, specifications in general pharmacopoeial monographs, pharmacopoeial monographs, registration dossier) shall define whether substances and materials are capable of bearing a certain level of the bioburden (and if they are capable, to what extent and until which stage) or whether they should be sterile. The manufacturing process shall comply also with other requirements outlined in the registration dossier or in the clinical trial protocol (for example, the number of generations (doublings, passages) between the inoculum or the cell bank).

11. For biological materials that cannot be sterilized (for example, by means of filtration), the manufacturing process shall be run aseptically in order to minimize the risk of introducing contaminants. Certain manufacturing methods, for example, for removal or inactivation of viruses, shall be regulated in accordance with appropriate approved procedures. Provision of appropriate control and monitoring over the condition of the process environment and, where possible, the use of a system of cleaning and sterilization ‘in place’ alongside using closed systems, may considerably reduce the risk of accidental and cross contamination.

12. Control shall comprise biological analytical methods characterized by a higher degree of variability than physical-and-chemical methods. Therefore, a secure manufacturing process shall be vitally essential in the manufacture of biological pharmaceutical substances and medicines and in-process control shall be of special importance.

13. Biological medicines comprising donated tissues or cells, for example, certain high-technology medicines, shall comply with the requirements of the legislation of the Russian Federation regarding traceability, notification of the authorized federal executive authority of adverse reactions and clinical events during therapy, as well as regarding technical requirements to the identification, treatment, preservation, storage and transportation of donated tissues and cells. Materials sampling and testing shall be conducted in accordance with a quality system with defined standards and technical requirements.

14. Biological pharmaceutical substances and medicines shall comply with the requirements of regulatory legal acts of the Russian Federation in terms of reducing the risk of transmitting animal spongiform encephalopathy agents and latent viruses via human and veterinary medicinal products.

III. GENERAL GUIDELINES (PART A)

Staff

15. (1) The staff working in the areas of manufacture and control of biological pharmaceutical substances and medicines (including the staff involved in cleaning, service and quality control) shall undergo training and regular re-training according to their job duties and specifics of the manufactured products, including all special precautions for the safety of products, staff and environmental protection.

16. (2) To ensure the safety of products, it shall be necessary to protect the health of staff members. Staff members involved in the manufacturing process, technical maintenance, testing and animal care (including those in charge of control) shall be, if and where necessary, vaccinated with appropriate specific vaccines and shall undergo regular medical examinations.

17. (3) Staff members with any diseases that may affect the product quality shall be suspended from working in the processing area; appropriate records shall be made and kept. BCG vaccines and tuberculin medicines shall be manufactured with the involvement of only those staff members who regularly undergo examinations of their immune status or breast X-ray examinations. Staff members shall undergo medical examinations considering the risks they are exposed to. Medical examinations shall be required for the staff handling hazardous organisms.

18. (4) For the purpose of minimizing potential cross contamination it shall be required to control restrictions of the movements of the staff (including staff members working in the quality control services, maintenance and cleaning specialists) on the basis of the quality risk management principles. Staff members shall be generally prohibited to move from areas where they may come into contact with living microorganisms, genetically modified organisms, toxins or animals to areas where other products, inactivated products or other organisms are handled. If such movements cannot be avoided, it shall be necessary to take measures to control contamination according to the quality risk management principles.

Premises and equipment

19. (5) The degree of control of the process environment with respect to contamination with particles and microorganisms in processing premises shall correspond to the type of a pharmaceutical substance, intermediate or finished product and the stage of the manufacturing process. It shall be necessary to take into account the level of contamination of starting materials and the extent of risk for finished products. The process environment monitoring programme shall additionally include methods for identifying the presence of specific microorganisms (in particular, host organism, yeast fungi, mould fungi, anaerobic microorganisms), if indicated by the quality risk management process.

20. (6) Manufacturing and warehouse facilities shall be designed based on the cleanliness class requirements; processes shall be planned so as to prevent contamination of products with foreign substances. Prevention of contamination shall be more effective than its detection and elimination, though contamination may become apparent during manufacturing processes such as fermentation and cultivation of cell cultures. Control measurements, including control of support systems and control of the process environment, shall be made according to the quality risk management principles at sites where open processes are run and products may be directly exposed to the effect of the process environment (for example, during addition of excipients, media, buffers, gases, operations during the manufacture of high-technology medicines). For the selection of consecutive classes of cleanliness in manufacturing facilities and appropriate control methods, the quality risk management principles shall consider the principles outlined in corresponding items of Attachment No. 1 hereto.

21. (7) Operations with living cells resistant to the environment of manufacturing facilities shall be conducted in specially dedicated manufacturing premises. If the manufacturing process implies using pathogenic microorganisms (for example, risk groups 1 and 2), also only specially dedicated manufacturing premises shall be used for these purposes.

22. (8) It may be allowed to use one room for the manufacture of several medicines if the below or equivalent factors and activities (according to the product types in question) make part of an effective control strategy aimed at preventing cross contamination:

a) (a) awareness of the basic characteristics of all cells, organisms and any foreign agents (for example, pathogenicity, detectability, stability, sensitivity to inactivation), handled in the same room;

b) (b) in case of manufacture of products from numerous small batches obtained from different starting raw materials (for example, medicines on the basis of cell technologies), the control strategy shall be developed considering factors such as the health conditions of donors for the purpose of reducing the risk of full loss of products;

c) (c) prevention of the transfer of living microorganisms and spores to adjacent premises or on equipment by identifying all potential routes of cross contamination and using single-use components and appropriate engineering measures (for example, closed systems);

d) (d) control measures aimed at removing microorganisms and spores before the subsequent manufacturing of other products. Procedures for cleaning and decontamination from microorganisms and spores shall be validated (including for heating, ventilation and air conditioning systems);

e) (e) if microorganisms are resistant to conditions of the process environment and there are established appropriate methods, control of the process environment specific for the obtained microorganism shall be provided in adjacent areas during the manufacturing process and after completion of cleaning and decontamination. It shall be also necessary to take into account risks associated with the use of certain control and measuring equipment (for example, for measuring particles in the air) in areas where living and (or) spore-forming microorganisms are handled;

f) (f) products, equipment, auxiliary equipment (for example, for calibration and validation) and single-use materials shall be relocated within the designated areas and shall be removed from such areas in a way so as to prevent contamination of other areas, other products at various manufacturing stages (particularly, it shall be required to prevent contamination of inactivated products or anatoxins with non-inactivated products);

g) (g) manufacture on the basis of the principle of one-type manufacturing cycles (sessions).

23. (9) Whether or not it is necessary to have special-purpose premises for the finishing treatment (particularly, for preparation, filling, packaging) shall depend on the foregoing factors and also on additional factors with regard to the specifics of a biological medicine and characteristics of other products, including any non-biological products manufactured in the same premises. Final stages may require other control measures of a certain sequence over addition of substances, mixing speed, time and temperature control, critical time of exposure to light and sealing (isolation) and also during cleaning procedures in case of spillage (dispersal).

24. (10) Activities and procedures necessary for ensuring safety of the process environment and staff shall not come into conflict with activities and procedures necessary for ensuring the product quality.

25. (11) Air handling systems shall be designed, constructed and serviced in a way so as to exclude the risk of cross contamination between different processing areas. Certain areas may require separate air handling systems. When deciding to use ventilation systems without re-circulation it shall be recommended to be guided by the quality risk management principles.

26. (12) Operations with sterile products shall be carried out in areas with excessive pressure; points of location of pathogenic microorganisms in special areas shall be provided with a negative pressure difference for the purpose of preventing dissemination of contaminants outside such areas. If reduced-pressure areas or safe boxes are used for aseptic handling of materials posing special risks (for example, pathogenic microorganisms), such areas or boxes shall be surrounded with areas of a corresponding cleanliness class with excessive pressure. Such pressure differences shall be clearly determined and shall be constantly monitored by using alarm systems appropriately set up.

27. (13) Equipment used for handling living microorganisms and cells, including sampling equipment, shall be designed so as to exclude potential contamination during operations.

28. (14) The construction ensuring primary isolation shall exclude the risk of leakage of biological agents to the immediate working area, which shall be confirmed by the results of tests at certain time intervals.

29. (15) If and where possible, it shall be recommended to use ‘cleaning in place’ and ‘steam treatment in place’ (‘sterilization in place’) systems. Fermenter valves shall be designed so as to allow their steam sterilization.

30. (16) Air filters shall be hydrophobic; their service life shall be determined during validation by means of integrity checks at certain time intervals according to appropriate quality risk management principles.

31. (17) Drainage systems shall be designed so as to allow effective effluent neutralization and decontamination for excluding the risk of cross contamination. It shall be required to ensure compliance with the requirements of the legislation of the Russian Federation for the purpose of minimizing the risk of environmental contamination according to the risks associated with the biological hazards of processing waste.

32. (18) Due to variability of properties of biological medicines or processes of their manufacture, it shall be necessary to measure or weigh any appropriate and (or) critical starting raw materials (for example, growth media and buffers) during the manufacturing process. In such cases small stocks of such starting raw materials may be kept in the processing area during a period of time established on the basis of appropriate criteria (for example, duration of the batch manufacturing or duration of a session).

Animals

33. (19) Various types of animals are used for the manufacture of biological medicines. Two large groups of sources may be singled out:

a) (a) live animals grouped in groups, herds and/or flocks, for example, monkeys (polio vaccine), horses, sheep and goats (antisera for snake venom and tetanus), cats (allergens), rabbits, mice and hamsters (antirabic vaccine), goats, cattle (transgenic products);

b) (b) animal tissues and cells extracted from killed animals (sheep and pigs), used for the manufacture of high-technology medicines or as raw materials for enzymes, anticoagulants and hormones.

34. Animals shall be also used for quality control according to specifications (pyrogenicity, toxicity, safety, specific activity).

35. (20) In addition to compliance with the regulatory requirements with respect to animal spongiform encephalopathy, other hazardous agents (zoonotic, animal anthropozoonotic agents) shall be controlled and registered according to a continuous monitoring programme. Such programs shall be arranged upon consultations with appropriate specialists. In case of diseases of donor animals or animals used as raw materials, it shall be necessary to conduct and register appropriate studies on the usability of such animals and on the usability of animals that contacted an infected animal in the manufacturing process (as starting materials or starting raw materials), during product control and during safety tests. It shall be necessary to develop a retrospective analysis procedure for making decisions on the suitability of a biological pharmaceutical substance or a medicine, in which or in the manufacture of which such animal material was used as a starting material or a starting raw material. For the purposes of identifying the last donation that gave a negative response to disease, where applicable, samples retained at the time of the previous sampling of materials from the same animal donor (if any) shall be re-tested, which may influence the result of the decision-making. The period of withdrawing animals from the programme shall be determined considering the period of withdrawing medicines administered into animal donors or animals used as raw materials, which shall be documented.

36. (21) Special attention shall be paid to preventing and monitoring infectious diseases in animals used as raw materials and in animal donors. Measures undertaken shall include control of sources, facilities, pasture grounds, control of biological safety, testing modes, control of auxiliary materials and animal feed. It shall be especially important to control animals free from specific pathogens. It shall be necessary to define requirements to the management and monitoring of health conditions of other animals (for example, those living in flocks or herds).

37. (22) With respect to medicines manufactured with the use of transgenic animals it shall be necessary to ensure traceability of source animals used for creating transgenic animals.

38. (23) Special attention shall be paid to the compliance with requirements of regulatory legal acts of the Russian Federation concerning protection of animals used for experimental purposes, animal facilities wherein animals are kept, animal care and quarantine. Animal facilities housing animals used for the manufacture and quality control of biological pharmaceutical substances and medicines shall be separated from processing and quality control areas.

39. (24) For different types of animals it shall be necessary to define basic parameters, which shall be afterwards controlled and registered. Such parameters may include age, sex, weight and health conditions.

40. (25) For the purpose of preventing the risk of confusing animals, biological agents and results of conducted tests and for the purpose of avoiding potential hazards, it shall be necessary to have a system of their identification.

Documents

41. (26) Starting raw materials and starting materials for the manufacture of biological medicines may require additional information about the source, origin, supply chain, manufacturing method and applied quality control methods for ensuring an appropriate scope of control, including microbiological control.

42. (27) Certain types of products may require specific descriptions of materials making part of a batch, particularly, of somatic cells used in the manufacture of high-technology medicines. In case of autologous medicines and medicines from specially selected donors products shall be regarded as one batch.

43. (28) For medicines manufactured with the use of human cells or donated tissues it shall be necessary to ensure full traceability, from starting raw materials and materials, including information about all substances that contacted cells or tissues, to the confirmation of receipt of the medicine at the place of its application. Alongside with this, it shall be required to ensure confidentiality of patients and information about their health conditions. Appropriate records ensuring traceability of a medicine shall be kept during thirty years from the expiration date of the medicine. Special attention shall be paid to ensuring traceability of specific medicines to be used in special cases, for example, cells from specially selected donors. The manufacture of medicines with the use of blood components as starting raw materials or materials shall comply with the legislative requirements. The manufacture of high-technology medicines shall imply ensuring traceability of human cells, including hematopoietic stem cells. Activities ensuring traceability and safe-keeping of documents during an appropriate period of time shall be incorporated in the technical agreements between the parties involved in such activities.

Manufacture

44. (29) Considering potential high variability of properties of biological substances and products, at various stages of the product life cycle (for example, at the stage of the process development) it shall be necessary to increase the process reliability and stability, reducing in this way its variability and increasing repeatability. Re-evaluation shall be made in the process of product quality reviews.

45. (30) As in the cultivation conditions media and reagents provide for growth of cells or microorganisms that are generally monocultures, special attention shall be paid to the quality control strategy to guarantee prevention and minimization of the bioburden and associated contamination with metabolites and endotoxins. In case of high-technology cell-based medicines, normally produced in small batches, the risk of cross contamination between cell-based medicines from different donors with different health conditions shall be controlled according to established requirements and procedures.

Starting raw materials and starting materials

46. (31) It shall be necessary to clearly identify the source, the origin and suitability of biological starting raw materials and starting materials for their further use (for example, cryoprotectors, nutritional cells, reagents, growth media, buffers, sera, enzymes, cytokines, growth factors). If the necessary tests take much time, processing of starting materials may be commenced before obtaining results of such tests; however, such starting materials may be used considering their effect on other batches in case of detection of inconsistencies and assessing risks according to the quality risk management principles. In such cases a permit for release of a batch of finished products shall be conditioned on the satisfactory results of tests of starting raw materials. Requirements to corresponding manufacturing stages shall form the basis for identification of all starting materials. Additional requirements for biological medicines shall be outlined in Chapter III hereof and Attachment No. 8 hereto and for biological pharmaceutical substances — in Chapter IV hereof.

47. (32) Risks of contamination of starting raw materials and starting materials during their delivery along the supply chain shall be assessed by paying special attention to the risk associated with animal spongiform encephalopathy and latent viruses. It shall be also necessary to consider starting materials directly contacting the process equipment or products (such as growth media used for simulating the aseptic fill, and lubricants that may come into contact with products).

48. (33) The risks of transmitting contamination and corresponding consequences for a finished medicine do not depend on the manufacturing stage; therefore, establishment of a control strategy for the protection of products, preparation of solutions, buffers and added components shall be based on the principles and guidelines outlined in corresponding items of Attachment No. 1 hereto. Control activities necessary for checking the quality of starting materials and also for the process of the aseptic manufacture of cell-based products where terminal sterilization is impossible and possibilities of removing microbial byproducts are limited shall be of special importance. When the registration dossier or the clinical trial protocol sets an admissible bioburden type and level, for example, at the stage of production of a pharmaceutical substance, the control strategy shall offer methods to maintain the set bioburden level.

49. (34) If starting raw materials and materials need to be sterilized, such sterilization shall be made, where possible, with the use of the thermal method. If and where necessary, it shall be possible to use also other appropriate methods used for inactivation of biological materials (particularly, irradiation and filtration).

50. (35) It may appear to be necessary to carry out other activities, specifically, to use antibiotics at early manufacturing stages for the purpose of reducing the bioburden, which may occur upon delivery of living tissues and cells. It shall be recommended to avoid such activities where possible; if such activities are necessary, their use shall be substantiated and, when used in the manufacturing process, such activities shall be discontinued at a stage specified in the registration dossier or the clinical trial protocol.

51. (36) With respect to human tissues and cells used as starting materials for biological medicines, it shall be necessary to take into account the following requirements:

a) (a) such human tissues and cells shall be purchased, donated and tested in accordance with the regulatory legal acts of the Russian Federation. Suppliers of starting raw materials shall have permits issued by the authorized federal executive body in accordance with the legislation of the Russian Federation. Availability of necessary permits shall be verified within the framework of the supply management system;

b) (b) in case of import of such human tissues and cells from other countries, it shall be required to observe the quality control and safety standards conforming to requirements of the regulatory legal acts of the Russian Federation;

c) (c) in certain cases cells and tissues used as starting materials for biological medicines shall be handled by organizations specializing in tissue drawing and (or) testing, including for creation of initial cell banks or cell lines, preceding the creation of the main cell bank. In such cases it shall be required to appoint, in accordance with the legislation of the Russian Federation, a person to be in charge of the specified operational stages;

d) (d) a responsible person of the organization specializing in tissue drawing and (or) testing shall issue a permit for use of tissues and cells before they are delivered to the medicine manufacturer, with the standard procedures for the control of starting materials applied afterwards. Results of tests of all tissues and cells supplied by the organization specializing in tissue drawing and (or) testing shall be provided to the medicine manufacturer. Such information shall be used for the appropriate separation of materials and for determination of storage methods. If and where necessary, tissues and cells may be delivered to the medicine manufacturer before receiving test results from the organization specializing in tissue drawing and (or) testing provided that there are appropriate control measures for preventing cross contamination with tissues and cells. Such delivery shall be authorized by the responsible person of the organization specializing in tissue drawing and (or) testing;

e) (e) human tissues and cells shall be transported to the manufacturing site in accordance with an agreement between responsible parties. Manufacturing sites shall be supplied with documentary evidence of the observance of the appropriate specific storage and transportation conditions;

f) (f) it shall be necessary to comply with the requirements to traceability, from the organization specializing in tissue drawing and (or) testing to delivery to the receiver, including materials that contacted cells or tissues;

g) (g) responsible parties (for example, manufacturers, organizations specializing in tissue drawing and (or) testing, sponsors, parties in whose names Marketing Authorizations have been issued) shall conclude an agreement defining areas of responsibilities of each of the parties (and specifying responsible and authorized persons).

52. (37) Requirements to be observed with respect to the gene therapy:

a) (a) for products manufactured with the use of virus vectors, starting materials shall be components from which the virus vector is obtained, i.e. the master virus seed stock or plasmids used to transfect packaging cells and the main cell bank used for the packaging cell line;

b) (b) for products manufactured with the use of plasmids, non-virus vectors and genetically modified microorganisms, excluding viruses and virus vectors, starting materials shall be components used for creation of the producer cells, i.e. plasmids, host bacterium and the main bank of recombinant microorganisms;

c) (c) starting materials for genetically modified cells shall be components used for obtaining genetically modified cells, i.e. starting materials for production of vectors and also human or animal cells;

d) (d) the principles of these Rules shall apply starting from the system of the cell bank used for production of the vector or plasmid used for transgenation.

53. (38) Manufacturing processes, in which human and animal cells are used as nutritional cells, shall be subject to appropriate control of sources, tests, transportation and storage of these materials, including control in accordance with the requirements of the legislation of the Russian Federation.

Inoculum and cell bank system

54. (39) For the purpose of preventing unwanted changes in properties that may result from multiple reinoculations or numerous generations, the manufacture of biological pharmaceutical substances and medicines obtained from microorganism cultures, cell cultures or by means of multiplication in embryos, tissues and organs of animals shall be based on the system of the main and working virus inocula and (or) cell banks. Such system shall not be applicable to all types of high-technology medicines.

55. (40) The number of generations (doublings, passages) between the inoculum or the cell bank and a biological pharmaceutical substance or a medicine shall conform to the requirements of the specifications in the registration dossier or the clinical trial protocol.

56. (41) Creation of the systems of inocula and cell banks, including main and working inocula, shall be part of the product life cycle management and shall be made in proper conditions. The process environment shall be under appropriate control for ensuring safety of the systems of inocula and cell banks and staff members working with them. When creating inocula and cell banks, it shall be prohibited to use the same areas or the same staff members for simultaneous handling of other living or infecting materials (for example, viruses, cell lines or strains). It shall be required to make available documents that allow ensuring the traceability of stages preceding generation of the main inoculum or the main cell bank, subject to the principles of these Rules only. Such documents shall include information concerning components, which were used during the development and which potentially may affect the product quality (for example, biological reagents), from the initial source to the main cell or the main seed bank, if applicable.

57. (42) After the main and the working cell banks and inocula are generated, it shall be necessary to observe the procedures for quarantine and authorization of the banks for use. Contaminants shall be subject to appropriate qualification and testing. Their further usability shall be supported by stability of characteristics and the quality of subsequent batches of products. Proofs of the stability and reproducibility of inocula or cell banks shall be documented. Contents of records shall allow evaluating tendencies.

58. (43) Inocula and cell banks shall be created, stored and used so as to minimize the risk of their contamination or change (for example, by keeping them in hermetically sealed containers in liquid nitrogen). If different inocula and cell banks are kept in the same areas or with the use of the same equipment, it shall be necessary to take measures aimed at preventing confusion and cross contamination, based on the infectious nature of materials.

59. (44) Cell-based medicines shall be normally produced from the cell stock obtained from a limited number of passages. Unlike in case of the two-level system of main and working cell banks, the number of manufacturing cycles on the basis of the cell stock shall be limited by the number of aliquots obtained after growth and shall not be applicable to the entire product life cycle. The validation protocol shall consider changes in the cell stock.

60. (45) Storage containers shall be hermetically sealed and clearly labelled, and shall be kept at an appropriate temperature. It shall be necessary keep records of stored containers. The storage temperature shall be continuously registered; the level of liquid nitrogen in liquid nitrogen units shall be controlled. Deviations of storage parameters from the set limits and any undertaken corrective and preventive measures shall be documented.

61. (46) It shall be recommended to divide stocks in parts and keep them separately for avoiding full loss. Location control shall ensure fulfilment of the above requirements.

62. (47) Conditions of storage and handling of stocks shall be determined according to the same procedures and parameters. Once containers are taken from the inoculum or cell bank storage, such containers may not be returned to the storage.

Operation principles

63. (48) During the change management process it shall be required to analyse at set time intervals effects of changes, including cumulative effects of changes (for example, in manufacturing processes) influencing the quality, safety and efficacy of a finished medicine.

64. (49) Critical operational (process) or other initial parameters influencing the medicine quality shall be determined, validated, documented and maintained according to established requirements.

65. (50) The strategy of monitoring the receipt of starting raw materials and starting materials in processing areas shall be based on the quality risk management principles. For aseptic processes thermal-resistant starting raw materials and starting materials that come to a clean or a clean and isolated area shall be delivered to such areas, where possible, through a pass-through autoclave or a dry-air sterilizer. Temperature-sensitive starting raw materials and starting materials shall be delivered through air chambers with door interlocking, being subject to effective sanitary treatment of surfaces. Objects and materials may be sterilized in another place provided that the quantity of their wraps corresponds to the number of stages necessary for their pass-through to the clean area and that they are delivered to such area through an air chamber subject to appropriate precautions by means of sanitary treatment of surfaces.

66. (51) Growth properties of growth media shall be confirmed to prove their usability for intended purposes. If and where possible, growth media shall be sterilized in place. For scheduled supply of gases, growth media, acids or alkalis, anti-foaming agents to fermenters, it shall be recommended to use, where possible, sterilizing filters embedded in supply lines.

67. (52) Substances or cultures shall be added to and/or sampled from fermenters and other vessels in thoroughly controlled conditions for preventing contamination. When introducing additives or taking samples, it shall be necessary to control the accuracy of the vessel connections.

68. (53) If and where necessary, it shall be required to provide continuous control of certain manufacturing processes (for example, fermentation), by fixing the control results in the batch manufacturing records. The manufacture with the use of the continuous cultivation method shall be subject to special requirements to the quality control to be abided by if such manufacturing method is selected.

69. (54) Centrifugation and product mixing processes may produce aerosols and, therefore, shall be run in isolated areas for the purpose of avoiding cross contamination.

70. (55) Emergency safety measures shall be taken in case of accidental leakage, especially of living microorganisms. Special decontamination actions shall be established for each type or group of microorganisms. In case of use of different strains of bacteria of one type or very similar viruses, such procedure shall be validated with respect to only one of them provided that there are no significant differences in their stability to a corresponding agent(s) for decontamination.

71. (56) If materials used for manufacturing and control purposes, including paper documents, are clearly contaminated, for example, with spilled liquids, aerosols or potentially hazardous microorganisms, such materials shall be duly disinfected or information shall be communicated by other means.

72. (57) During inactivation or removal or viruses in the course of the manufacturing process it shall be necessary to take measures against re-contamination of treated products by untreated ones.

73. (58) For products inactivated by adding reagents (for example, microorganisms in the manufacturing of vaccines), the process shall ensure full inactivation of living microorganisms. After the accurate mixing of the culture and the inactivator, all product-contacting surfaces that came into contact with the culture shall be controlled.

74. (59) Chromatographic methods shall imply using different types of equipment. The quality risk management principles shall be observed when developing the strategy of control of sorbents, column bodies and other equipment when such are used for manufacturing by sessions or in a process environment intended for the manufacture of several product types. It shall not be recommended to use the same sorbents at different manufacturing stages. It shall be necessary to establish acceptance criteria, working conditions, recovery methods, service life and methods of sterilization or disinfection of columns.

75. (60) Additional instructions on using irradiated equipment and materials shall be outlined in Attachment No. 12 hereto.

76. (61) It shall be necessary to establish a system ensuring integrity and hermiticity of containers after their fill and to set procedure for any leakage or spillage if a product or an intermediate product poses a special risk. Fill and packaging operations shall be supported with procedures for the observance of conditions ensuring the product maintenance within the set limits (for example, time and (or) temperature).

77. (62) Operations with containers (for example, ampoules, bottles) containing biological agents shall be carried out in a way so as to avoid contamination of other medicines or penetration of living agents to the process or external environment. Such risks shall be decided to be managed considering viability of such organisms and their biological classification (risk group).

78. (63) Due attention shall be paid to preparation, printing, storage and application of labels onto packages, including application onto primary and secondary packages of specific information for patient-specific products or about use of genetic engineering methods. If high-technology medicines are intended for autologous application, the label shall bear the unique patient identifier and the indication ‘for autologous use only’. In the absence of the outer package, such information shall be indicated on the primary package.

79. (64) If extra-low storage temperatures are used, resistance of the labels to the temperatures in use shall be confirmed.

80. (65) Cases where information about health conditions of the donor (human or animal), which is relevant for the product quality, becomes available after purchase shall be taken into consideration for withdrawal procedures.

Quality control

81. (66) For biological pharmaceutical substances and medicines the in-process control shall be more critical for ensuring their quality stability than for other medicines. The in-process control shall be provided at corresponding manufacturing stages for the purpose of controlling conditions critical for the quality of finished products.

82. (67) In cases where intermediate products may be stored for long-term periods (days, weeks or more), it shall be considered applying the on-going stability testing programme also to such batches of finished products that have been manufactured out of intermediate products with maximum in-process storage periods.

83. (68) If consistent with the registration dossier, for certain types of cells (for example, autologous cells used in the manufacture of high-technology medicines) that may be available in limited quantities, procedures for testing and storage of control samples may be changed, which shall be documented.

84. (69) Sterility tests for cell-based high-technology medicines shall be conducted by using antibiotic-free cell cultures or cell banks for the purpose of obtaining evidence of absence of contamination with bacteria and fungi as well as for detecting organisms requiring special cultivation conditions (if applicable).

85. (70) An appropriate control strategy shall be implemented for the manufacture of biological medicines with a short shelf life defined in this Attachment as a period of up to 14 days, for which the batch release is required to take place before completion of the quality tests for the whole batch of finished products (for example, sterility studies). Such control shall imply fundamental understanding of the properties of the medicine and the manufacturing process and shall consider control and characteristic properties of starting raw materials and starting materials. The entire release procedure shall be clearly and fully described, including duties of certain staff members involved in the evaluation of the process and analytical data. The effectiveness of the quality assurance system, including keeping of records allowing evaluating tendencies, shall be subject to continuous evaluation. It shall be necessary to provide for alternative methods (for example, rapid microbiological methods) of obtaining appropriate results for the preliminary confirmation of the batch compliance in cases where the finished medicine cannot be tested due to its short shelf life. The procedure for the confirmation of the batch compliance and release may be carried out in two or more stages:

a) (a) evaluation by the responsible person(s) of the records related to the batch manufacturing process and results of the monitoring of the process environment (if applicable), which shall cover manufacturing conditions, all deviations from standard procedures and the existing analytical results for the authorized person’s initial authorization of the product batch for release;

b) (b) evaluation by the authorized person of the results of final analytical tests and other available information for the final confirmation of the compliance of the batch with the established requirements.

86. It shall be necessary to establish a procedure describing the activities to be conducted (including interaction with medical officers) if received test results are outside the limits of specifications. Such cases shall be fully investigated; appropriate corrective and preventive actions aimed at excluding re-occurrence of such cases shall be registered in documentary form.

IV. SPECIAL GUIDELINES FOR INDIVIDUAL PRODUCT TYPES (PART B)

Animal-based medicines (B1)

87. These guidelines shall apply to animal-extracted materials, specifically, to materials produced at facilities such as slaughter houses. As supply chains may be extensive and complex, it shall be necessary to apply control means based on the quality risk management principles. For these purposes it shall be required to take into account the requirements of the State Pharmacopoeia of the Russian Federation, including appropriate tests at certain stages. It shall be necessary to maintain corresponding documents ensuring the supply chain traceability with a clear description of the role of each participant of the supply chain, including, as a rule, a sufficiently detailed description of the supply chain scheme.

88. (1) It shall be necessary to develop programs for monitoring animal diseases dangerous for humans (veterinary certification). Risk factors shall be assessed by taking into account notifications disseminated by credible sources regarding domestic disease prevalence, including information about animal health examinations and state and local control programme(s), specifically, actions aimed at monitoring sources (for example, farms and farmyards) supplying animals and control during transportation of animals to slaughter houses. One of the organizations monitoring the global animal disease situation is the World Organization for Animal Health.

89. (2) When acting as suppliers of animal tissues, slaughter houses shall comply with the requirements stipulated by the regulatory legal acts of the Russian Federation. It shall be necessary to take into account information provided by the authorized federal executive authority to confirm the compliance with the safety and feed quality requirements stipulated by the regulatory legal acts of the Russian Federation and (or) other countries, from which raw materials are imported to the Russian Federation.

90. (3) Activities on the control of starting raw materials and starting materials, conducted at facilities such as slaughter houses, shall comprise certain elements of the quality management system for ensuring a satisfactory level of the professional training of the staff, traceability of materials, control and stability.

91. (4) It shall be necessary to have established activities on the control of starting materials or starting raw materials aimed at preventing interferences influencing the quality of such materials or raw materials or, as minimum, at providing information about the implementation of such activities during the advancement of starting raw materials or starting materials along the manufacturing or supply chain. Such activities shall be carried out with respect to relocation of the said materials or raw materials from the sites of initial collection, partial or full purification to the sites of storage, accumulation, arrangement and storage with intermediaries. Implemented activities shall be subject to detailed registration within the framework of the system ensuring traceability of products, including registration of any violations, associated investigations and undertaken measures.

92. (5) It shall be necessary to regularly evaluate suppliers of starting raw materials and starting materials; such evaluations shall confirm compliance with requirements to control of starting raw materials and starting materials at various manufacturing stages. The manufacturer shall have complete documents regarding event investigations conducted with due diligence corresponding to the event significance. It shall be necessary to have systems ensuring implementation of effective corrective and preventive actions.

93. (6) Cells, tissues and organs used for the manufacture of xenogeneic cell-based medicines shall be obtained exclusively from animals in captivity, which do not contact other animals and are bred specially for this purpose. It shall be strictly prohibited to use cells, tissues and organs of wild animals or animals from slaughter houses. It shall be also prohibited to use tissues of founder animals (animals bearing foreign genes). Health conditions of animals shall be observed and documented.

94. (7) In case of the xenogeneic cell therapy and handling of xenogeneic medicines it shall be necessary to abide by the requirements of the regulatory legal acts of the Russian Federation regarding animal cell supplies and tests.

Allergen medicines (B2)

95. Starting materials may be produced by means of extraction from natural sources or with the use of the recombinant DNA technology.

96. (1) To ensure the conformity of supply of starting materials, they shall be supplied with a description, including necessary details, in particular, nonproprietary and scientific names, origin, nature, contaminant content limits, drawing methods. Animal-extracted materials shall be obtained from healthy animals. For colonies (for example, ticks, animals), used for extraction of allergens, it shall be necessary to introduce an appropriate control system ensuring biological safety. Allergen medicines shall be stored in appropriate conditions ensuring their quality.

97. (2) Stages of the manufacturing process, including preliminary treatment, extraction, filtration, dialysis, concentration or lyophilization, shall be described in detail and validated.

98. (3) Modification processes used for the manufacture of modified allergen extracts (for example, allergoids, conjugates) shall be described in corresponding documents. Intermediate products in the manufacturing process shall be identified and controlled.

99. (4) Allergen extract mixtures shall be prepared from separate extracts of starting materials obtained from one source. Each separate extract shall be defined as a separate pharmaceutical substance.

Animal antiserum medicines (B3)

100. (1) The manufacturer shall pay special attention to the control of biological agents in order to ensure their quality, constancy and absence of accessory agents. Procedures such as preparation of materials used for animal immunization (for example, use and (or) administration of antigens, hapten-carriers, adjuvants, stabilizing agents) and storage of such materials directly before immunization shall be performed according to documented procedures.

101. (2) Immunization, blood analysis and blood withdrawal procedures shall be performed according to the registration dossier.

102. (3) Conditions of the manufacture of medicines from sub-fragments of antibodies (for example, Fab and antigen-binding sites) and any further modifications shall conform to validated and approved parameters. If the enzymes used in the manufacturing process consist of several components, it shall be necessary to ensure their stability.

Vaccines (B4)

103. (1) In case of use of bird embryos, it shall be necessary to see to it that all flocks used for their production (for flocks free from specific pathogens and for healthy flocks) are healthy.

104. (2) The integrity of containers used for storing intermediate products and the period of their storage shall be subject to validation.

105. (3) In areas containing living biological agents it shall be prohibited to open and take samples from receptacles containing inactivated medicines.

106. (4) The sequence of adding active components, adjuvants and excipients during the manufacturing of intermediate or finished products shall correspond to the process instructions.

107. (5) If the manufacturing process or testing implies using microorganisms classified as having the highest level of the biological hazard (for example, pandemic strains), appropriate isolation measures shall be taken. It shall be necessary to obtain a documentary proof that the specified activities have been authorized to be conducted by corresponding authorized federal executive authorities. Such documents shall be available and accessible for inspection.

Recombinant products (B5)

108. (1) In order to ensure the constancy of properties of a medicine containing admissible impurities within a set range, it shall be necessary to observe validated conditions of manufacturing processes during cell growth, protein expression and purification. Additional measures may be required for excluding viral contamination in certain cell types used in the manufacturing process. For medicines whose manufacture implies multiple cell harvesting during cultivation, its duration shall be within the approved limits.

109. (2) Processes of purification from undesired products originating from host cells, specifically, from proteins, nucleic acids, carbohydrates, viruses and other impurities, shall be run within established validated limits.

Monoclonal antibody medicines (B6)

110. (1) Monoclonal antibodies may be produced from mouse or human hybridomas or with the use of the recombinant DNA technology. For the purpose of ensuring the safety and the quality of medicines, it shall be necessary to conduct appropriate control activities with respect to initial cells (including, nutritional cells if such are used) and starting materials used for the generation of a hybridoma and (or) a cell line. It shall be necessary to see to it that such activities are conducted within the approved limits. Special attention shall be paid to proving absence of viruses in medicines. The usability of medicines manufactured on the same processing basis may be proved by using data obtained during tests of one of them.

111. (2) It shall be necessary to check that the criteria at the intermediate and final stages of the manufacturing process are controlled and maintained within the approved limits.

112. (3) Processing conditions for the preparation of sub-fragments of antibodies (for example, Fab, , scF v) and any other modifications (for example, introduction of radioactive labels, conjugation, chemical binding) shall conform to validated parameters.

Transgenic animal-based medicines (B7)

113. Ensuring the constancy of a starting material obtained from a transgenic source is more problematic than when using standard non-transgenic biotechnological sources. Therefore, more stringent requirements shall be applied to prove the constancy of all properties of a medicine from batch to batch.

114. (1) Biological medicines may be manufactured by using various types of animals, including by drawing and purifying biological liquids (for example, milk). Animals shall be subject to clear unique labelling; backup measures shall be provided to be used in case of loss of the initial identifying marker.

115. (2) Conditions of the animal maintenance and care shall provide for the minimum possible contact of animals with pathogenic agents and zoonoses. It shall be necessary to develop appropriate environmental protection measures. It shall be required to develop an animal health surveillance programme with corresponding records to be entered in documents. It shall be also required to investigate into any incidents and to determine their effect on the further usability of the animal and previously manufactured product batches. It shall be necessary to make sure that none of the medicines used for treating animals may lead to contamination of the medicine being manufactured.

116. (3) It shall be necessary to have documents with pedigrees, for all animals from the founder animal to animals used for the manufacturing purposes. It shall be prohibited to mix materials obtained from different transgenic animal lines because they originate from different founder animals.

117. (4) The materials sampling conditions shall conform to the standards of the registration dossier and the clinical trial protocol. The materials sampling schedule and conditions under which animals may be excluded from the medicine manufacturing process shall correspond to the approved procedures and acceptance criteria.

Transgenic plant-based medicines (B8)

118. Ensuring the constancy of a starting materials obtained from a transgenic source is more problematic than when using standard non-transgenic biotechnological sources. Therefore, more stringent requirements shall be applied to prove the constancy of all properties of a medicine from batch to batch.

119. (1) For the purpose of preventing contamination of the main and working transgenic banks with foreign plant-based materials and corresponding foreign agents it may appear to be necessary to take additional measures before or after the activities specified in the General Guidelines (Items 1586 of this Attachment). The gene stability control shall be provided during a certain number of generations.

120. (2) For the purpose of ensuring the constancy of harvesting from different plant cultures, plants shall be clearly marked with unique labels indicating, inter alia, their main characteristics. In particular, the state of health of plants making part of a culture shall be monitored at certain intervals throughout the growing period.

121. (3) It shall be necessary to establish precautions for protecting cultures. If and where necessary, it shall be required to minimize their contamination with microbiological agents and cross contamination with plants of another type. It shall be necessary to take measures to prevent contamination of medicines with materials such as pesticides and fertilizers. It shall be required to develop a monitoring programme with corresponding records to be entered in documents. It shall be also required to investigate into any incidents and to determine their effect on the further usability of the culture in the manufacturing process.

122. (4) Conditions determining cases when plants may be excluded from the manufacturing process shall be clearly described. It shall be necessary to set acceptability limits for materials (for example, basic proteins) that may intervene with the product purification procedure. Results shall be proved to be within the limits of the approved standards.

123. (5) It shall be necessary to fix environmental conditions (temperature, rain) that may influence the qualitative characteristics of a medicine and the production output of the recombinant protein, from the moment of inoculation, throughout the cultivation process and until collection and intermediate storage of collected materials. Such documents shall be executed in accordance with the requirements of the regulatory legal acts of the Russian Federation concerning plant cultivation and collection.

Gene therapy medicines (B9)

124. There are several types of gene therapy medicines (gene therapy medicines containing sequence(s) of recombinant nucleic acids or genetically modified microorganism(s) or virus(es) and gene therapy medicines containing genetically modified cells) covered in Items 124136 of this Attachment. Cell-based gene therapy medicines may be subject to certain provisions set out in Items 137144 of this Attachment.

125. (1) As cells used for the manufacture of gene therapy medicines are obtained either from humans (autologous or allogenic) or from animals (xenogeneic), there is an increased risk of their contamination with accessory agents. Special activities shall be developed for isolating autologous materials obtained from infected donors. Reliability of control and testing activities for such starting materials and also for cryoprotectors, growth media, cells and vectors shall be based on the quality risk management principles and shall be consistent with the registration dossier. The generated cell lines for producing virus vectors and implementing control and testing activities shall be also based on the quality risk management principles. If and where necessary, virus inocula and cell bank systems shall be used.

126. (2) Potential contents of impurities, foreign agents and cross contamination shall be influenced by such factors as the nature of the genetic material, the type of the vector (virus or non-virus) and the type of cells, which shall be taken into account for the development of the general risk minimization strategy. Such strategy shall be the basis for developing the manufacturing process, designing manufacturing and warehouse facilities and equipment, establishing cleaning, decontamination, packaging, labelling and marketing procedures.

127. (3) The manufacture and testing of gene therapy medicines shall require dealing with specific aspects of the safety and the quality of the finished medicine and the problems of the patient and staff safety. It shall be necessary to use a risk management-based approach to ensure the staff and patient safety and environmental security and to take control measures according to the established class of biological hazard. Safety measures shall comply with the requirements of the regulatory legal acts of the Russian Federation.

128. (4) Movements of staff members (including staff members involved in quality control and service staff) and flows of materials, including those that are stored and tested (for example, starting materials, samples for the in-process control, samples of the finished medicine and samples of the process environment) shall be arranged and regulated on the basis of the quality risk management principles. Unidirectional flows shall be used, where possible. Attention shall be paid to movements between areas containing various genetically modified organisms and areas containing non-genetically modified organisms.

129. (5) Premises and equipment shall be designed considering all possible special procedures required for decontamination or purification from organisms used in the medicine manufacturing. If and where possible, the process environment status monitoring programme shall be supplemented with methods for detecting presence of specific microorganisms that have been cultivated.

130. (6) If virus vectors with limited replicability are used, it shall be necessary to take measures aimed at preventing transmission of wild-type viruses, which may produce replicable recombinant vectors.

131. (7) It shall be necessary to develop an emergency response plan for unexpected release of living microorganisms. The plan shall include a description of methods and procedures for isolation of microorganisms, protection of operators, cleaning, decontamination and safe recommencement of operations. It shall be necessary to evaluate the effect of the release on the medicines in close vicinity as well as on any other medicines in the areas exposed to such release.

132. (8) It shall be necessary to establish measures for separating premises for the production of virus vectors from other areas. The efficiency of the measures used for such separation shall be proved. Closed systems shall be used wherever applicable. It shall be required to prevent release of the virus material during sampling, introduction of additives and transfer of materials.

133. (9) Concurrent production of different gene therapy viruses within the same area shall be prohibited. Concurrent production of non-virus vectors within one area shall be monitored according to the quality risk management principles. The efficiency of procedures for the transition from session to session shall be demonstrated.

134. (10) In order to ensure traceability of a medicine from the initial stages (plasmids, target genes and regulatory sequences, cell banks and stocks of virus or non-virus vectors) to the finished medicine, it shall be necessary to have a detailed description of the production of vectors and genetically modified cells.

135. (11) Medicines containing or composed of genetically modified organisms shall be transported in accordance with the legislative requirements.

136. (12) Requirements to the in-vitro transfer of genes to recipient cells:

a) (a) such process shall be run in premises that are designated for such operations and have an appropriate level of isolation;

b) (b) it shall be necessary to take measures (including the requirements set out in Item 24 of this Attachment) for reducing potential cross contamination and confusion of cells obtained from different patients. The process shall also imply using validated purification procedures. Simultaneous use of different virus vectors shall be controlled according to the quality risk management principles. It shall not be allowed to use certain virus vectors (for example, retro- and lentiviruses) for the production of genetically modified cells before they are proved to be free from any foreign replicable vector;

c) (c) traceability requirements shall be fulfilled. It shall be necessary to clearly identify a product batch, from cellular raw materials to containers with finished medicines;

d) (d) physical-and-chemical properties of medicines manufactured with the use of non-biological gene delivery agents shall be analysed and documented.

Somatic cell therapy medicines and tissue engineering medicines (B10)

137. Genetically modified cell medicines not classified as gene therapy medicines may be governed by Items 124136 of this Attachment.

138. (1) Such medicines shall be manufactured, where practical, by using authorized sources (for example, medicines or medical products authorized for use) of supplementary materials (particularly, cell products, biomolecules, biomaterials, support systems, matrixes).

139. (2) If products, including custom-made ones, make part of finished products, the following requirements shall be fulfilled:

a) (a) the manufacturer of the medicine and the manufacturer of the medical product shall conclude an agreement containing sufficient data on the medical product for the purpose of preventing changes in its properties during the manufacture of a high-technology medicine. Such agreement shall stipulate requirements to control of changes proposed for the medical product;

b) (b) the agreement between the manufacturer of the medicine and the manufacturer of the medical product shall also envisage exchange of information about deviations during the manufacture of the medical product.

140. (3) As somatic cells are obtained either from humans (autologous or allogenic) or from animals (xenogeneic), there is an increased risk of their contamination with accessory agents. Special activities shall be developed for isolating autologous materials obtained from infected donors. It shall be necessary to ensure reliability of control and testing activities for such starting materials.

141. (4) If the finished medicine cannot be sterilized with the use of standard methods, for example, filtration, stages of the manufacturing process shall be run aseptically.

142. (5) Due attention shall be paid to specific requirements for all cryoconservation stages, for example, the rate of change of temperature during freezing and unfreezing. The type of the storage room, methods of arrangement of materials and processes of extraction shall minimize the risk of cross contamination, ensure the quality of medicines and facilitate their due extraction. Documented procedures shall be used for ensuring safety of operations with and storage of medicines comprising positive serological markers.

143. (6) It shall be necessary to conduct sterility tests for the absence of bacterial or fungal contamination in antibiotic-free cell cultures or cell banks free. It shall be also taken into account that it is necessary to identify specific microorganisms requiring special cultivation conditions.

144. (7) If and where necessary, it shall be required to implement a stability monitoring programme providing for control and retention samples in quantities sufficient for further tests.

V. TERMS AND DEFINITIONS

145. In addition to the terms and definitions stipulated in Chapter II hereof, the following basic terms shall be used for purposes of this Attachment:

adjuvant: a chemical or biological substance, which enhances the immune response to an antigen;

allergens: antigenic or haptenic substances capable of sensitizing the organism and provoking allergy;

allergoids: chemically modified allergens with a decreased response of the immunoglobulin E (IgE);

antigens: substances (for example, toxins, foreign proteins, bacteria, tissue cells) capable of provoking specific immune reactions;

monoclonal antibodies: a homogenous population of antibodies capable of binding to the only epitope (the antigenic determinant), produced from the only lymphocyte clone or with the use of the recombinant DNA technology;

polyclonal antibodies: antibodies obtained from several lymphocyte clones and (or) produced by a human or animal organism in response to the administration of an antigen;

antibody: proteins produced by B lymphocytes, which specifically bind to certain antigens. The basic differences in the methods of their production allow singling out two main antibody types: monoclonal antibodies and polyclonal antibodies;

cell bank: a set of appropriate containers stored in specific conditions and bearing contents of a homogenous composition. The contents of each container form a multiple single cell pool;

biological pharmaceutical substance: a pharmaceutical substance produced with the use of a biological source or extracted from a biological source, which should be characterized by means of physical, chemical and biological tests and the quality of which is determined by such tests in combination with control of processes of its manufacture;

biological medicine: a medicine, whose pharmaceutical substance is a biological pharmaceutical substance;

bioburden: the level and the type of microorganisms (for example, admissible or non-admissible microorganisms) that may be present in starting raw materials, starting raw materials for manufacture of a pharmaceutical substance, intermediate products or in a pharmaceutical substance. The bioburden shall not be regarded as contamination provided that its levels are within the set limits and there are no detected microorganisms defined as non-admissible;

vector: a transmission agent transmitting genetic information from one cell or organism to another one, for example, plasmids, liposomes, viruses;

virus vector: a vector produced by means of virus modification with the use of molecular biology methods for retaining some, but not all, maternal virus genes. In case of removal of genes responsible for the virus replicability, the produced vector is not replicable;

in vitro: a process during which procedures are performed on tissues or cells outside a living organism with tissues or cells returned afterwards to a living organism;

in vivo: procedures performed inside living organisms;

excipients: organic or non-organic substances used in the production, manufacture of medicines for generating necessary physical-and-chemical properties <*>, excluding pharmaceutical substances and packing material;

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<*> Paragraph 3 Article 4 of Federal Law No. 61-FZ dated 12 April 2010 “On Circulation of Medicines” (Collection of Legislative Acts of the Russian Federation, 2010, No. 16, Art. 1815).

hapten: a molecule with a low molecular weight, which is not an antigen by its nature until conjugation with the ‘carrier molecule’;

gene: a sequence of DNA coding one or several proteins;

genetically modified organism (GMO): any organism, excluding human organism, in which the genetic material has been modified so that such modification is impossible as a result of natural crossing and (or) natural recombination;

hybridoma: an immortalized (‘immortal’) cell line producing desired (monoclonal) antibodies and normally obtained by means of artificial fusion of B lymphocytes with tumour cells;

main cell bank: an aliquote of one cell pool produced from a certain cell clone in certain conditions, distributed in a variety of containers and stored in certain conditions;

main virus inoculum: an aliquote of one virus pool produced from a certain virus clone in certain conditions, distributed in a variety of containers and stored in certain conditions;

main transgenic bank: an aliquote of one pool of cells of transgenic plants or animals, produced from a certain cell clone in certain conditions, distributed in a variety of containers and stored in certain conditions;

closed system: a system in which a pharmaceutical substance or a medicine has no direct contact with the process environment;

area: a certain number of premises/rooms within one building, in which one or several medicines are manufactured and which are supplied with a separate air handling system;

zoonosis: infectious and invasive animal diseases, which can be transmitted to humans;

use in isolation/isolated conditions: any activity, during which genetically modified organisms are produced, cultivated, stored, transported, broken, destroyed or used otherwise and which requires using special isolation measures to restrict dissemination of such organisms and to ensure safety of the population and environmental security;

starting materials: all materials, from which a medicine or a pharmaceutical substance is produced or extracted, excluding packing materials. Starting materials for biological medicines are any biological substances such as plant- or animal-based microorganisms, organs and tissues, human or animal cells or liquids (including blood and plasma), and biotechnological cell substrates (recombinant and natural), including initial cells;

cell stock: initial cells, which have grown to a set quantity of cells, divided into aliquotes and used as starting materials for the manufacture of a limited quantity of batches of cell-based medicines;

responsible person: a specially designated person in an organization manufacturing biological (including immunobiological) pharmaceutical substances and medicines, in charge of:

ensuring that a biological material (including human cells and (or) tissues) is obtained, controlled, used in the manufacturing of a medicine, including control of the finished product quality, is stored and released in accordance with the legislation of the Russian Federation;

submitting to authorized federal executive authorities appropriate information concerning instructions, authorizations, accreditation or licensing;

compliance by the organization manufacturing biological (including immunobiological) pharmaceutical substances and medicines with all requirements of the legislation of the Russian Federation.

The responsible person’s qualifications shall meet the following criteria:

higher medical, pharmaceutical or biological education;

at least two years of experience of working in one or several organizations of the appropriate specialization.

The foregoing duties of the responsible person may be delegated to other persons possessing appropriate qualifications and work experience for performing such duties.

Manufacturers of biological (including immunobiological) pharmaceutical substances and medicines shall notify the authorized federal executive authority of the full name of the responsible person and also other persons, to whom the responsible person’s duties have been delegated, including information about specific assigned duties.

If the responsible person or persons, to whom the responsible person’s duties have been delegated, are substituted, on a permanent or temporary basis, with another person, the manufacturer of biological (including immunobiological) pharmaceutical substances and medicines shall immediately notify the authorized federal executive authority of the full name of the newly appointed responsible person and the date of his/her appointment;

gene transfer: the process of the transfer of a gene to cells, including the expression system incorporated in the delivery system, which is referred to as a vector. Vectors can be virus and non-virus. After gene transfer, genetically modified cells may be also referred to as ‘transformed cells’;

nutritional cells: cells used in a combination culture for maintaining pluripotency (the ability to be differentiated into a variety of specialized cell types) of stem cells. For a culture of human embryonic stem cells, typical nutritional layers consist of mouse embryonic fibroblasts (MEF) or human embryonic fibroblasts (HEF), in which division is prevented by means of special methods;

plasmid: a DNA part normally existing in a bacterial cell as a circular structure separated from the cell chromosome. A plasmid may be modified by using molecular biology methods, extracted from a bacterial cell and used for transferring and inserting its DNA into the genome of another cell;

support system (scaffold): a method of support, a means of delivery or a matrix, which support the structure or facilitate migration, binding or transport of cells and (or) biologically active molecules;

facilities/premises/rooms for the manufacture of several medicines: facilities/premises/rooms for consecutive manufacture or session-based manufacture of various groups of biological pharmaceutical substances and medicines, in which the set of used equipment may be specialized or not specialized for each individual group of substances or medicines;

deliberate release: a deliberate environmental release of genetically modified organisms, not subject to special isolation measures for restricting their dissemination and ensuring safety of the population and environmental security;

manufacturing by sessions: consecutive manufacture of a number of batches of the same medicine during a certain period of time, to be followed by stringent control activities before starting the manufacturing of another medicine. Medicines are not manufactured simultaneously; however, one and the same equipment may be used for their manufacture;

retrospective analysis procedure: a documented procedure ensuring traceability of biological pharmaceutical substances or medicines of improper quality due to the use of animal or human materials that have been found defective because they contain contaminating agent(s) or because negative factors have been detected with the animals or humans that are the source of such materials;

working cell bank: a homogeneous pool of microorganisms or cells obtained from the main cell bank and uniformly distributed in a certain number of containers. The working cell bank shall be stored in conditions ensuring its stability and usability for manufacturing purposes;

working virus inoculum: a homogeneous pool of viruses obtained from the main virus inoculum and uniformly distributed in a certain number of containers. The working virus inoculum shall be stored in conditions ensuring its stability and usability for manufacturing purposes;

working transgenic bank: a homogeneous pool of cells of transgenic plants or animals, obtained from the main transgenic bank and uniformly distributed in a certain number of containers. The working transgenic bank shall be stored in conditions ensuring its stability and usability for manufacturing purposes;

free from specific pathogens: animal materials (for example, chicken, embryos or cell cultures) used for the manufacture or quality control of biological medicines, obtained from a group of animals (for example, herds or flocks) free from specific pathogens. Such herds or flocks are defined as groups of animals living in a common environment, with staff taking care of them and not contacting animals not free from specific pathogens;

somatic cells: all cells of a human body or an animal, excluding reproductive cells. Such cells may be autologous (from the same patient), allogenic (from another human) or xenogeneic (from an animal) somatic living cells, which were manipulated or modified in vitro and were afterwards administered in a human organism for attaining a therapeutic, diagnostic or preventive effect;

transgenic: an organism whose regular genetic structure contains a foreign gene for expression of biological pharmaceutical materials;

biological safety level: isolation conditions required for the safety of operations with microorganisms of various risk groups, starting from Risk Group 4 (the lowest risk, unlikely to provoke human diseases) to Risk Group 1 (the highest risk provoking serious, easily transmitted diseases);

pure culture (axenic culture): a culture containing identical microorganisms, not contaminated with any other organisms.

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