Attachment No. 5
to the Rules of Good Manufacturing Practice
Содержимое (Table of Contents)
1. The manufacture of immunobiological medicines for veterinary application has specifics that must be taken into account when implementing and assessing the efficiency of the pharmaceutical quality system.
2. The great amount of animal species and coexisting pathogenic microorganisms may significantly enlarge the range of manufactured products though the quantity of production is small. The manufacturing process is generally organized according to the principle of separate cycles. Due to particularities of such manufacture (cultivation stages, absence of terminal sterilization, and etc.) the products need to be thoroughly protected from contamination and cross contamination. The processing environment shall be protected, especially when pathogenic and exotic microorganisms are used. If the manufacturing process includes microorganisms pathogenic to human beings, the staff shall be thoroughly protected.
3. In view of the above factors, as well as the variability of features of immunobiological medicines and relatively low effectiveness of conducted tests for obtaining sufficient information on the products (in particular, during the quality control of finished products), the pharmaceutical quality system is very important.
4. (1) All employees (including the staff cleaning and maintaining rooms and equipment) working in the processing areas for immunobiological products shall undergo training in personal hygiene and microbiology and additional training according to the specific features of manufactured products.
5. (2) Employees in charge of manufacture and quality control in accordance with their job duties shall undergo training in such fields, as: bacteriology, biology, biometry, chemistry, immunology, medicine, parasitology, pharmacy, pharmacology, virology and veterinary medicine, and shall have required knowledge of environmental protection.
6. (3) The staff shall be protected from any possible infection with microorganisms used in the manufacturing process. If microorganisms pathogenic to human beings are used, it is required to take special measures to protect the staff working with these microorganisms or experimental animals.
7. The staff shall be vaccinated, if necessary. Employees shall have medical examinations.
8. (4) It is necessary to take appropriate measures to prevent people from carrying microorganisms from the processing area. Depending on the type of microorganisms such measures may include a complete change of clothes and compulsory shower before leaving the processing area.
9. (5) The danger of the manufacture of immunobiological products is connected with the risk of contamination and cross contamination caused by the staff. To prevent contamination by the staff, employees shall take certain measures and go through procedures, including use of protective clothing at various stages of the manufacturing process.
10. To prevent cross contamination the staff shall move from one area to another observing the rules eliminating the risk of contamination. These rules shall be specified in the instructions. During working time the staff members shall not move from an area where a possibility of contamination with living microorganisms exists or animals are kept to rooms where other products or microorganisms are used. If such movements are inevitable, the staff members engaged in such manufacture shall observe the clearly set decontamination procedures, including a change of clothes, shoes and a shower, if necessary.
11. In pursuance of this Attachment it shall be deemed that staff members entering an isolated area where cultures are stored in hermetically sealed containers with decontaminated surfaces are not exposed to the risk of contamination, if no works with open microorganisms (except working with exotic microorganisms) were conducted in this area for the preceding 12 hours.
12. (6) The design of rooms shall ensure the protection of both the products and the process environment. It may be achieved by using isolated, clean, clean contained and controlled areas.
13. (7) Operations with living microorganisms shall be performed in isolated areas. The degree of isolation shall depend on the pathogenicity of microorganisms and on whether they are classified as exotic.
14. (8) Operations with inactivated microorganisms shall be performed in clean areas. Clean areas shall be also used for working with uninfected cells separated from multicellular organisms, and in some cases for working with media after filtration sterilization.
15. (9) Operations with open products or components of primary packaging not subject to further sterilization shall be performed in a unidirectional (laminar) air-flow box (system) of class A placed in an area of class B.
16. (10) If the processing area for immunobiological medicines for veterinary application is located in the same building, other operations with living microorganisms (in particular, quality control, research and diagnosis) shall be carried out in separate isolated rooms. The isolation degree shall depend on the pathogenicity of this type of microorganisms and on whether they are classified as exotic. Diagnostic operations are accompanied by the risk of introduction of highly pathogenic microorganisms. The isolation degree shall correspond to all risks indicated above. Isolation may be also required when quality control and other operations are performed in buildings located close to process buildings.
17. (11) Isolated rooms shall ensure easy disinfection and meet the following requirements:
а) (a) no direct outlet of ventilated air;
b) (b) ventilation with negative pressure difference (reduced pressure). Air shall be removed through a High Efficiency Particulate Air Filtration System (hereinafter HEPA filters). Air recirculation is unacceptable, except recirculation in the same area subject to additional air purification by HEPA filters (as a rule, this condition is fulfilled when recirculating air is forced through HEPA inlet filters used in this area). It is allowed to let air come from one area to another only if the exhaust air goes through two HEPA filters installed in series. In this case the manufacturer shall ensure continuous failure monitoring of the first filter and provide means for safe removal of the exhaust air if the filter is damaged;
c) (c) the air from processing areas where exotic microorganisms are used shall be forced through two HEPA filters installed in series. In this case air recirculation between processing areas is unacceptable;
d) (d) use of a collection and disinfection system for liquid waste, including contaminated condensation from sterilizers, bioreactors. Solid waste, including dead bodies of animals, shall be disinfected, sterilized and burnt. Contaminated filters shall be removed in a safe manner;
e) (e) changing rooms shall be designed and used as air chambers and shall be equipped, if necessary, with washbasins and shower cabins. The model of air pressure difference shall stop circulation of the air between the processing area and the environment, and eliminate the risk of contamination of the clothing used outside the processing area;
f) (f) moving of the equipment requires a system of air chambers whose design shall prevent any circulation of the contaminated air from the operating area to the external environment, and eliminate the risk of contamination of the equipment inside the chamber. The size of the chamber shall be enough for efficient decontamination of the surfaces of moved materials. It is recommended to install a timer on the chamber doors to control the time sufficient for efficient decontamination;
g) (g) in many cases it is necessary to use a pass-through autoclave with two doors to remove waste and supply sterile objects.
18. (12) Pass boxes and changing rooms shall be equipped with blocking and other appropriate devices interfering with simultaneous opening of more than one door. Changing rooms shall be filled with filtered air of the same degree of filtration as for processing areas. They shall be equipped with air extraction systems that ensure an air exchange independent from processing areas. Pass boxes shall be generally ventilated in the same way, however it is acceptable to use boxes without ventilation or with inlet systems only.
19. (13) Process stages that may lead to contamination of the products (e.g. storage of cells, preparation of media, cultivation of viruses) shall be performed in individual areas. Special precautions shall be taken in case of work with animals and products of animal origin.
20. (14) Operations with microorganisms showing high resistance to disinfection (e.g. spore-forming bacteria) – before these microorganisms have been inactivated – shall be performed in isolated areas intended specially for such operations.
21. (15) It is permitted to work with microorganisms of only one type at a time, except processes of mixing and subsequent pre-packing.
22. (16) The manufacturer shall design processing areas so as to ensure the possibility of disinfection of the processing areas between manufacturing cycles with the help of validated methods.
23. (17) It is permitted to manufacture microorganisms in controlled areas provided that it is carried out in completely sealed and thermally sterilized equipment, and after the work has been completed or before dismantling the equipment, all joints are also thermally sterilized. It is acceptable to join parts under a laminar air flow, if their number is limited, appropriate aseptic methods are used and there is no risk of leakage. Parameters of the sterilization process used before dismantling the joints shall be validated for all used microorganisms. Within one area different products may be loaded in different bioreactors only if there is no risk of accidental cross contamination. However operations with microorganisms falling under special isolation requirements shall be performed only in areas specially provided for such products.
24. (18) It is necessary to maintain a regime of an isolated and (or) clean area in rooms intended for animals to be used (or used) in the manufacturing process. These rooms shall be separated from rooms used for other animals. Rooms for animals used to control the quality of products (including, with the use of pathogenic microorganisms) shall be appropriately isolated.
25. (19) Access to processing areas shall be provided only to authorized staff members. It is necessary to have clear and short guidelines on the access to processing areas which shall be displayed on the wall.
26. (20) Documents containing data on manufacturing areas shall be available as part of the main dossier of the production site.
27. It is necessary to include corresponding details in the description of processing areas and buildings (by attaching plans of the areas and their explanation), intended use and conditions of use of all rooms, as well as types of biological agents applied for the work. The direction of movement of the staff and relocation of products shall be also clearly shown. It is necessary to indicate animal species kept in vivaria and other rooms of the production site, and the types of works performed close to the processing area.
28. Plans of isolated and (or) clean rooms and areas shall contain the description of the ventilation system indicating the places of air intake and air exhaust, applied filters and their specifications, air change and pressure drop rates. It is required to indicate between which rooms manometers are used to control pressure drops.
29. (21) Applied equipment shall be designed and installed so as to meet the requirements for each type of products.
30. Before commissioning the equipment shall undergo qualification and validation, subsequently followed by routine maintenance and re-validation.
31. (22) The equipment shall guarantee satisfactory primary isolation of biological agents. If necessary, the design and installation of the equipment shall ensure its easy and effective decontamination and (or) sterilization.
32. (23) The design and installation of sealed equipment used for the primary isolation of biological agents shall guarantee protection against leakage, drop formation and spraying.
33. Gas inputs and outputs shall be protected so as to ensure the required degree of isolation, e.g. by means of sterilizing hydrophobic filters.
34. A sterilized closed system or appropriate conditions of a laminar air flow shall be used to supply and remove materials.
35. (24) If necessary, the equipment shall be sterilized before use preferably by dry steam under pressure. Other methods shall be used if the properties of the equipment exclude its sterilization by steam. It is important also to treat such types of equipment as centrifuges and water baths.
36. The equipment used for cleaning, separation and concentration shall be at least sterilized or disinfected when it is intended for manufacturing a product after the production of another product. It is necessary to study the effect of sterilization methods on the efficiency and validation status of the equipment in order to determine its service life.
38. (25) The equipment design shall exclude any possibility of confusion between different organisms or products. Pipelines, valves and filters shall be marked according to their intended use.
39. Individual incubators shall be used for containers with infected and uninfected materials, as well as, generally, different organisms or cells. It is permitted to keep more than one type of organisms or cells in one incubator only subject to appropriate measures ensuring hermetic sealing, surface decontamination and separation of containers. Vessels with cultures and other contents shall be individually marked. It may be difficult to clean and disinfect these vessels, so these operations may require special attention.
40. The design and operating procedure of the equipment used to store biological agents or products shall exclude any possibility of confusion.
41. All stored samples shall be clearly and definitely marked and kept in containers protected from leakage. The stock of inocula and organisms shall be kept in specially designated equipment.
42. (26) Some types of equipment (e.g. equipment that requires temperature monitoring) shall have recording devices and (or) alarm systems. To prevent failures of such equipment the manufacturer shall analyse the trends in the recorded data and organize a system of preventive maintenance.
43. (27) The lyophilic dryer shall be filled in a clean and (or) isolated area. When the lyophilic dryer is unloaded, these operations result in the pollution of the environment. For this reason when lyophilic dryers opening at one side are used, the clean room shall be decontaminated before another batch of products is brought to this room, except batches with the same organisms. Two-sided lyophilic dryers shall be sterilized after each production cycle, unless they open into a clean area.
44. Lyophilic dryers shall be sterilized pursuant to Items 35 – 37 hereof. If the process is organized according to the principle of separate cycles, they shall be sterilized at least after each cycle.
45. (28) General requirements to animal care, rooms where animals are kept, treatment and quarantine are stipulated in relevant regulatory legal acts of the Russian Federation.
46. (29) Vivaria shall be isolated from other processing premises. They shall be designed in accordance with corresponding requirements.
47. (30) The sanitary condition of animals used in the manufacturing process shall be evaluated, controlled and registered. If regulatory legal acts of the Russian Federation contain rules of care with regard to certain animal species (e.g. a line of animals free from pathogens), these rules shall be observed.
48. (31) Animals, biological agents and conducted tests shall be distinctly identified according to the set system to prevent any risk of confusion and to control all possible types of hazards.
49. (32) Disinfection and (or) disposal of solid and liquid waste may be of prime importance for the manufacture of immunobiological products. For this reason, it is required to thoroughly select methods and equipment applied to prevent the pollution of the environments, as well as their validation.
50. (33) Due to the broad range of products, a great amount of stages of the manufacturing process of immunobiological medicines for veterinary application and the character of biological processes, special attention shall be paid to strict observance of validated technological processes, continuous monitoring of all technological stages of the manufacture and supervision in the manufacturing process. It is necessary to pay special attention to starting raw materials, culture media and use of inoculum systems.
51. (34) Requirements to starting raw materials shall be indicated in specifications. Specifications shall contain data on the supplier, the production method, location and animal species these starting raw materials are made of, as well as their control procedures. Special role is played by microbiological control methods.
52. (35) The test results of starting raw materials shall conform to specifications. If tests take a lot of time (e.g. specific pathogen free (SPF) eggs (embryos) of birds), it may be necessary to process starting raw materials before obtaining results of analytical tests. In these cases a permit for the release of finished products shall depend on positive results of tests of starting raw materials.
53. (36) Special attention shall be paid to the data on the supplier’s quality assurance system used for assessing the conformity of sources of raw materials and materials and on the scope of testing required for acceptance quality control.
54. (37) If possible, it is necessary to sterilize starting raw materials by the thermal method. It is acceptable to use other validated methods, for example, ionising radiation.
55. (38) Growth properties of media shall be confirmed by appropriate methods in advance.
56. (39) It is preferable to sterilize media on site or at the line. The method of thermal sterilization shall be preferable. Gases, media, acids, bases, defoaming agents and other substances introduced into a sterile bioreactor shall be sterile.
57. (40) To prevent any unwanted change of properties that may result from repeated reinoculations or numerous generations, the manufacturing process of immunobiological medicines for veterinary application made of cultures of microorganisms, cell cultures, tissues or by means of multiplication in embryos and animals, shall be based on a system of inocula or cell banks.
58. (41) The number of generations (duplications, passages) between the inoculum or the cell bank and finished products shall meet the requirements of the registration dossier.
59. (42) Inocula and cell banks shall be differentiated and checked for the absence of contaminants. Acceptance criteria shall be set for new inocula. Inocula and cell banks shall be created, kept and used so as to minimize the risk of their contamination or any change. When inocula or cell banks are created, it is prohibited to simultaneously work in the same area or engage the same staff for working with other animals or infectious materials (e.g. viruses or cell lines).
60. (43) It is necessary to create the inoculum or cell bank pursuant to the set requirements to the process environment in order to protect inocula and the cell bank, as well as the staff working with them and the external environment.
61. (44) The origin, form and storage conditions of inocula shall be described in detail in the relevant documents. It is necessary to have evidence of the stability and reproducibility of inocula and cells. Storage tanks shall be hermetically sealed, clearly marked and kept at the required temperature. The manufacturer shall control the storage conditions for inocula and cells. It is required to keep accurate records of each stored tank.
62. (45) Only specially appointed employees shall work with materials. The work shall be supervised by a person in charge. Different inocula and cell banks shall be stored so as to prevent any confusion or cross contamination. It is recommended to divide inocula and cell banks and store different parts separately to avoid their total loss.
63. (46) During manufacturing processes it is necessary to avoid or minimize any formation of drops or foam. Processes of centrifugation or mixing that may lead to drop formation shall be performed in isolated containers or clean and (or) isolated areas to prevent any transfer of living organisms.
64. (47) Accidental spillage of liquids, especially those containing living organisms, shall be quickly removed by a safe method. Validated decontamination procedures shall be used for each type of microorganisms. When different strains of bacteria of one type or of very similar viruses are used, the decontamination procedure may be validated only for one of them provided that there are no significant differences in the resistance to the decontamination effect.
65. (48) Operations that include relocation of such materials as sterile media, cultures or products shall be carried out in previously sterilized closed systems. If it is impossible, operations of relocation of materials shall be performed under a laminar air flow.
66. (49) Media or cultures shall be added into bioreactors and other vessels in thoroughly controlled conditions that ensure that no contaminants will be introduced. When cultures are added, the correctness of connection of the vessels shall be carefully checked.
67. (50) If necessary, (e.g. if two or several fermenters are placed in the same area), sampling holes and holes for putting additives and connection elements shall be sterilized by steam (after connection, before introduction of the product and before disconnection). In other cases it is acceptable to use chemical disinfection of inlet holes and protect connections by means of a laminar air flow.
68. (51) Equipment, laboratory glassware, external surfaces of containers with products and other similar materials shall be disinfected by a validated method before relocated from an isolated area. Certain problems may arise in connection with documents for a batch of products. Only the absolute minimum of documents necessary to meet the requirements of these Rules shall be brought into and taken out of the operating area. In case of obvious contamination (e.g. by drops or sprays) or in case of use of exotic microorganisms, paper document shall be disinfected in the chamber for equipment relocation or provided in the form of photocopies or by fax.
69. (52) Liquid and solid waste, such as eggshells left after materials were taken from eggs, disposable bottles for cultures, unwanted cultures or biological agents, shall be sterilized or disinfected before being taken from an isolated area. In some cases it is acceptable to use other methods, e.g. use of hermetically sealed containers or pipelines.
70. (53) The manufacturer shall ensure strict control so that only objects, materials, and documents related to the manufacture of products are delivered to the processing area. A recording system shall be implemented to control the correspondence between the number of brought and taken objects and materials and to prevent their accumulation in the processing area.
71. (54) Heat-resistant objects and materials shall be delivered to a clean or clean contained area through pass-through autoclaves or dry-heat furnaces. Objects and materials sensitive to heating shall be delivered through an air chamber with blocked doors, where such objects and materials are disinfected. Objects and materials may be disinfected in another place, if they enter the chamber in a double cover subject to the required precautions.
72. (55) The manufacturer shall take appropriate precautionary measures to prevent contamination or confusion of cultures of cells or microorganisms for the period of incubation. It is necessary to approve the cleaning and disinfection procedure for incubators. Containers placed in incubators shall be clearly and accurately marked.
73. (56) It is permitted to perform operation in one room with only one living biological agent at a time, except processes of mixing and subsequent pre-packing or in case of completely closed systems. Production rooms shall be disinfected between operations with different living biological agents.
74. (57) Products shall be inactivated by means of adding an activating agent with subsequent thorough agitation. After this operation the mixture shall be placed into the second sterile vessel, except if the form and size of the vessel facilitate its turning and shaking so as to dampen all internal surfaces with the final mixture of the culture and the activating agent.
75. (58) It is prohibited to open vessels containing the inactivated product. It is also prohibited to take samples from these vessels in areas where living biological agents are stored. All subsequent treatment of inactivated products shall be performed in clean areas of class A and B or in closed equipment specially intended for inactivated products.
76. (59) Special attention shall be paid to validation of methods of sterilization, disinfection, removal of viruses and their inactivation.
77. (60) Filling shall be carried out within the shortest possible period of time after manufacturing operations have been completed. Before filling containers with bulk products shall be hermetically sealed, properly marked and stored at the required temperature.
78. (61) The manufacturer shall develop a system ensuring control over the integrity and leak resistance of packages after filling.
79. (62) Bottles containing living biological agents shall be closed with lids so as to prevent any possible contamination of other products or penetration of living agents into other areas or the external environment.
80. (63) For various reasons a certain period of time may take place between filling of primary packages, their marking and packaging. The manufacturer shall approve processes that describe the storage procedure for unmarked containers preventing their possible confusion and ensuring appropriate storage conditions. Special attention shall be paid to the storage of thermolabile and light-sensitive products. The manufacturer shall set requirements to the storage temperature.
81. (64) At each processing stage the actual output shall be compared to the expected output of products. All significant deviations shall be investigated.
82. (65) Control plays an important role in the manufacturing process for the stable quality of immunobiological medicines. Types of inspection that are critical to quality evaluation (e.g. virus monitoring) but cannot be performed for finished products shall be carried out at one of the preceding manufacturing stages.
83. (66) For repeated quality control of a batch of products or confirmation of results of such control it may be necessary to store a sufficient amount of samples of intermediate products in appropriate conditions.
84. (67) It may be required to ensure continuous control of the parameters in the manufacturing process (e.g. continuous control of physical parameters in the process of fermentation).
85. (68) In case of continuous cultivation of biological products special requirements to the organization of the quality control of products shall be observed.