Attachment No. 1
to the Rules of Good Manufacturing Practice
Содержание
MANUFACTURE OF STERILE MEDICINES
I. PRINCIPLE
1. Manufacture of sterile medicines shall be subject to special requirements in order to minimize the risk of contamination with microorganisms, particles and pyrogenes. Such requirements shall depend on the qualifications, training and work attitude of the process staff. In order to assure quality during the manufacture of sterile drugs it shall be required to abide by thoroughly elaborated and validated manufacturing methods and procedures. The final stage of the manufacturing process or control of finished products shall not be the only means of ensuring sterility or other product quality parameters.
2. Detailed procedures for determination of the cleanliness of air, surfaces and other monitored objects in terms of microorganisms and particles shall be stipulated by regulatory legal acts of the Russian Federation.
II. GENERAL REQUIREMENTS
3. (1) Sterile products shall be manufactured in clean areas; access of staff members and (or) delivery of equipment, starting raw materials and packing materials to such areas shall be allowed through air chambers. The level of cleanliness required to be maintained in clean rooms (areas) shall correspond to an appropriate degree of cleanliness; such rooms (areas) shall be supplied with effectively filtered air.
4. (2) Various operations related to the preparation of components, preparation of products and filling shall be carried out in separate areas (rooms) within a clean area (room). Process operations shall be divided into two categories: the first category of operations when products are subject to the terminal sterilization (in primary packaging), and the second category of operations aseptically performed at several or all stages.
5. (3) Clean areas (rooms) for the manufacture of sterile products shall be classified according to required characteristics of the process environment. Each process operation shall require a certain level of cleanliness of the process environment in operational condition for the purpose of minimizing the risk of contamination of the product or processed starting raw materials and materials with particles or microorganisms.
6. For ensuring compliance with requirements ‘operational’ clean areas (rooms) shall be designed so as to ensure a specified level of the air cleanliness in ‘at rest’ condition.
7. ‘At rest’ condition: a condition when a clean room is built and functions, and the process equipment is complete but there is no staff.
8. ‘Operational’ condition: a condition when a clean room and the process equipment function in the required mode with a set quantity of the operating staff.
9. ‘At rest’ and ‘operational’ requirements shall be set for each clean room or a complex of clean rooms.
10. Clean areas (rooms) used for the manufacture of sterile medicines shall be divided into four classes:
A Class – a local area for operations with a high risk for the product quality, particularly, filling and closure areas, areas with open ampoules and bottles, where equipment parts are joined in an aseptic environment. As a rule, such conditions shall be provided owing to the laminar air flow at work stations. Laminar air flow systems shall ensure a uniform air speed within 0.36 – 0.54 m/s (standard value) on a working surface in an open clean area. The laminarity maintenance shall be proved and validated. Unidirectional air flow at lower speeds may be used in closed isolators and boxes with gloves;
B Class – an area directly surrounding an A Class area, intended for aseptic preparation and filling;
C and D Classes – clean areas for performing less critical stages of the manufacturing of sterile products.
III. CLASSIFICATION OF CLEAN ROOMS AND CLEAN AREAS
11. (4) Clean rooms and clean areas shall be classified <*>. Confirmation of the cleanliness class shall be clearly distinguished from the in-process environment monitoring. The maximum admissible concentrations of aerosol particles for each class shall be given in Table No. 1.
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<*> For reference: GOST R ISO 14644-1 (EN ISO 14644-1).
| Area | Maximum admissible particle count in 1 cubic m of air, at the particle size equal to or above | |||
| At rest | Operational | |||
| 0.5 mum | 5.0 mum | 0.5 mum | 5.0 mum | |
| A | 3,520 | 20 | 3,520 | 20 |
| B | 3,520 | 29 | 352,000 | 2,900 |
| C | 352,000 | 2,900 | 3,520,000 | 29,000 |
| D | 3,520,000 | 29,000 | Not regulated | Not regulated |
12. (5) For classification purposes, in A Class areas the minimum taken air sample shall be 1 m3 minimum for each sampling point. A Class shall correspond to ISO 4.8 class by the critical count of air particles 5.0 mum.
By the count of aerosol particles B Class (at rest) shall correspond to ISO 5 class by the count of particles of both specified sizes.
By the count of aerosol particles C Class (at rest and operational) shall correspond to ISO 7 and ISO 8 classes, respectively.
By the count of aerosol particles D Class (at rest) shall correspond to ISO 8 class.
The cleanliness class shall be confirmed according to the method <*>, which defines the minimum number of sampling points as well as the sampling volume based on the limits applicable to the given class for the count of particles of the largest of the specified sizes, and procedures for evaluating observed data.
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<*> For reference: GOST R ISO 14644-1 (EN ISO 14644-1).
13. (6) Classes shall be confirmed by using portable particle counters with short sampling tubes due to a relatively high level of the settling of particles 5.0 mum in distant systems with long sampling tubes. Isokinetic sampling caps shall be used in case of unidirectional air flow systems.
14. (7) Classes in operational condition may be confirmed during the operational process or during simulation of working operations or during filling with growth media, as may be required according to a simulated situation implying simulation of maximum admissible parameters of the manufacturing process in case of the most adverse factors and conditions (hereinafter – the worst case) <*>.
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<*> For reference: the Guidelines on Conducting Tests for Confirming the Continuous Compliance with a Set Cleanliness Class shall be outlined in GOST R ISO 14644-2 (EN ISO 14644-2).
IV. MONITORING OF CLEAN ROOMS AND CLEAN AREAS
15. (8) While in use, clean rooms and clean areas shall be subject to on-going monitoring. Sampling points for on-going monitoring shall be selected on the basis of an analysis of risks and results of the classification of clean rooms and (or) clean areas.
16. (9) In A Class areas particles shall be subject to continuous monitoring throughout the critical process, including equipment assembly, with the exception (if duly substantiated) of processes with the use of contaminating agents that may damage particle counters or compromise, inter alia, living organisms or be radiologically hazardous. In such cases monitoring shall be carried out during routine operations on equipment setup until a risk occurs. Monitoring shall be mandatory also during operation simulation. In A Class areas monitoring shall be carried out at a frequency and with a sample volume so as to fix all interferences, casual events and any damages to the system and so as to raise alarm in case of threshold warning alert. Low levels of particles 5.0 mum are not always demonstratable immediately at the place of and during filling due to formation of particles or drops from the product itself.
17. (10) It shall be recommended to use the same system for B Class areas, possibly, at lower sampling frequency rates. The criticality of the particle monitoring system shall be determined by the efficacy of the separation between adjacent A and B Class areas. In B Class areas monitoring shall be carried out at a frequency and with an appropriate sample volume so as to fix changes in the level of contamination and any deterioration of the system performance and to be able to take emergency measures in case of threshold warning alert.
18. (11) Aerosol particle monitoring systems may consist of independent particle counters, of a system of successive sampling points joined by a pipeline to one particle counter, or combine these two approaches. Monitoring systems shall be selected considering particle size requirements. When using remote sampling systems, it shall be necessary to consider the length of pipes and pipe bend radius, taking into account that particles may settle in pipes. The monitoring system shall be selected considering also any risk that may be caused by materials used in the manufacturing process, for example, presence of living microorganisms or radioactive drugs.
19. (12) In case of an automated on-going monitoring system, the sample volume shall generally depend on the sampling speed of the used system. The sample volume during on-going monitoring may differ from the sample volume during qualification of clean rooms and clean areas.
20. (13) In A and B Class areas it shall be especially important to monitor the concentration of particles 5.0 mum as it is a diagnostics tool of early detection of inconsistencies. Sometimes, the indicators of counts of particles 5.0 mum may be faulty because of electronic noise, stray light, coincidence and other factors. However, if a counter consistently and systematically registers small particle counts, it may speak of possible contamination requiring investigation. Such cases may indicate in advance malfunctioning of the ventilation and conditioning system, the filling unit or speak of the non-observance of rules during equipment setup or operation.
21. (14) The admissible particle count in at-rest condition, specified in the table, shall be reached after a short period of cleaning of 15-20 minutes (standard value) with no staff present upon completion of operations.
22. (15) C and D Class areas in operational condition shall be monitored based on the quality risk management principles. Requirements to the level of alarm and the level of action shall depend on the nature of performed operations; in any case, it shall be required to reach the recommended ‘cleaning period’ value.
23. (16) Other parameters such as temperature and relative humidity shall depend on products and the nature of performed operations. Such parameters shall not have any effect on the established cleanliness standards.
24. (17) Examples of operations to be performed in areas of difference cleanliness classes shall be given in Table No. 2 and also in Items 35 – 42 hereof.
| Class | Examples of operations for products subject to terminal sterilization (Items 35 – 37 of this Attachment) |
| A | Filling of products that may not be exposed to contamination |
| C | Preparation of solutions that may not be exposed to contamination. Filling of products |
| D | Preparation of solutions and preparation of primary packaging, materials for subsequent filling |
| Class | Examples of operations to be prepared aseptically (Items 38 – 42 of this Attachment) |
| A | Aseptic preparation and filling |
| C | Preparation of solutions subject to filtration |
| D | Operations with materials after washing |
25. (18) Aseptic processes shall be run subject to continuous microbiological monitoring with the use of sedimentation and aspiration techniques of taking air samples, taking surface samples with swabs and with the use of contact plates. Sampling procedures used in operational condition shall not cause any damage to the area protection. Monitoring results shall be taken into account when making batch dossier reviews for issuing a permit for release of finished products. Critical operations shall be followed by monitoring of surfaces and staff. It shall be necessary to conduct also additional microbiological out-of-process monitoring, particularly, after system validation, cleaning and disinfection.
26. (19) Recommended limits for microbiological monitoring of operational clean areas shall be given in Table No. 3.
| Class | Recommended microbial contamination limits (a) | |||
| In air, CFU/cubic m | Sedimentation on a plate with a diameter of 90 mm, CFU during 4 h (b) | Contact plates with a diameter of 55 mm, CFU/plate | Glove print (5 fingers), CFU/glove | |
| A | < 1 | < 1 | < 1 | < 1 |
| B | 10 | 5 | 5 | 5 |
| C | 100 | 50 | 25 | – |
| D | 200 | 100 | 50 | – |
| Note:
(a) Mean values (b) Individual sediment plates may be exposed less than 4 hours. |
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27. (20) Based on the results of monitoring of particles and microorganisms, it shall be necessary to set appropriate limits: the level of alarm and the level of action. Operational procedures shall describe corrective actions to be taken it such limits are exceeded.
28. (21) The isolation technology allows minimizing the human interference in processing areas, which significantly mitigates the risk of microbial contamination of aseptically manufactured products from the process environment. There are many types of isolators and transfer devices. An isolator and its components shall be designed so as to ensure the required air quality in a corresponding area. Isolators made of different materials shall be subject, to a greater or lesser extent, to isolation damage and depressurization. Transfer devices may vary: from designs with one-fold or double-fold doors to fully sealed systems supplied with sterilization devices.
29. (22) Transfer of materials inside and outside the isolator is one of the most serious potential sources of contamination. Generally, the space inside the isolator is a limited area for performing operations posing high risks for the product quality. At the same time, the working area of all such devices may be arranged without any laminar air flow units.
30. (23) Requirements to the cleanliness of the air in the environment surrounding the isolator shall depend on the isolator design and intended purpose. The cleanliness of such environment shall be controlled; for aseptic manufacturing it shall correspond, as minimum, to D cleanliness class.
31. (24) Isolators may be brought into operation only after appropriate validation is performed. Validation shall consider all critical factors of the isolation technology, particularly, the quality of the air inside and outside the isolator, the isolator disinfection procedures, transfer methods and the isolator integrity.
32. (25) It shall be necessary to conduct continuous monitoring comprising frequent tests of the sealing of the isolator and ‘glove – sleeve’ units.
VI. ‘BLOW – FILL – SEAL’ TECHNOLOGY
33. (26) The ‘blow – fill – seal’ device shall be a special-design device where within one automatic complex during one continuous manufacturing cycle packages are generated from thermoplastic granulate, are filled with products and are sealed. A ‘blow – fill – seal’ device used in the aseptic manufacturing and classified as an A Class area with an effective air flow may be installed, as minimum, in a C Class area given usage of clothing used in A and (or) B Class areas. The process environment at rest shall correspond to the set standards for particles and microorganisms, and in operational condition – only for microorganisms. A ‘blow – fill – seal’ device used in the manufacture of products subject to terminal sterilization shall be installed, as minimum, in D Class areas.
34. (27) Considering specifics of this technology, special attention shall be paid to:
equipment design and qualification;
validation and repeatability of ‘cleaning-in-place’ and ‘sterilization-in-place’ processes;
clean room space, which is the process environment for the equipment installed there;
training and clothes of operators;
actions in the critical equipment area, including connections and assemblies in aseptic conditions before filling.
VII. PRODUCTS SUBJECT TO TERMINAL STERILIZATION
35. (28) Primary packaging components and other materials shall be prepared and most types of products shall be manufactured in a process environment of D Class, as minimum, in order to ensure an adequately low level of risks of contamination with particles and microorganisms, suitable for filtration and sterilization. If microbial contamination poses high or special risks for products (particularly, when products form a good medium for the growth of microorganisms or their sterilization is preceded by a long period of time or the manufacturing process is run for the most part in open receptacles), preparations shall be made in a process environment of C Class.
36. (29) Filling with products subject to terminal sterilization shall be made in a process environment of C Class, as minimum.
37. (30) In case of an increased risk of contamination of products from the process environment, specifically, when filling operations are run slowly or when packages have wide necks, or when they have to be kept open longer than a few seconds before sealing, filling operations shall be performed in an A Class area with a process environment of C Class, as minimum. Ointments, creams, suspensions and emulsions shall be normally prepared and pre-packed before terminal sterilization in a C Class process environment.
VIII. ASEPTIC MANUFACTURING
38. (31) Operations with primary packaging components and other materials after washing shall be performed in a processing environment of D Class, as minimum. If no future sterilization or sterilization filtration is planned afterwards, sterile starting raw materials and components shall be processed in an A Class working area with a B Class process environment.
39. (32) Solutions subject to sterilization filtration in the course of the manufacturing process shall be prepared in a C Class process environment. If no sterilization filtration is made, materials shall be prepared and products shall be manufactured in an A Class working area with a B Class process environment.
40. (33) Aseptically prepared products shall be processed and filled in an A Class working area with a B Class process environment.
41. (34) Not finally closed primary packages with products, for example, lyophilized ones, shall be transferred (transported) before completion of the closure process either in an A Class area in a B Class process environment or in hermetically sealed transfer containers in a B Class process environment.
42. (35) Sterile ointments, creams, suspensions and emulsions shall be prepared and filled in an A Class area in a B Class process environment if products are in open receptacles and are not subject to further sterilization filtration.
IX. STAFF
43. (36) Only minimum required staff members shall be admitted to clean areas, this condition being especially critical for aseptic manufacturing. If and where possible, inspections and control operations shall be conducted outside clean areas.
44. (37) All staff members (including staff involved in cleaning and maintenance) who work in such areas shall be regularly trained for proper manufacture of sterile products, including hygiene requirements and microbiology principles. If unauthorized persons who have not undergone such training (for example, builders or setup crews working on a contractual basis) need to stay in a clean room, such persons shall undergo detailed briefing and shall be subject to close supervision.
45. (38) Staff members working with raw materials from animal tissues or microorganisms cultures that are not used in the current manufacturing process shall be admitted to the sterile manufacturing areas only if such staff members abide by the established procedures for such admittance.
46. (39) It shall be required to abide by the personal hygiene and cleanliness requirements. Staff members involved in the manufacture of sterile medicines shall be instructed to report any circumstances that may cause dissemination of inadmissible quantities or types of contaminants; should such circumstances occur, staff members shall be subject to periodic medical examinations. Actions to be taken with respect to staff members who may become a source of microbial contamination shall be determined by a specially designated person granted appropriate powers.
47. (40) In clean areas it shall be prohibited to wear watches, jewellery and use make-up.
48. (41) Staff members shall change clothes and wash according to instructions approved by the manufacturer; such instructions shall be developed so as to minimize the risk of contamination of clothes for work in clean areas or introduction of contaminants in clean areas.
49. (42) Clothes and their quality shall correspond to the manufacturing process and the class of the working area. Clothes shall be worn so as to protect products from contamination.
50. (43) Clothes required to be used for each room cleanliness class:
D Class: hair, beards and moustache (if any) shall be covered. Staff members shall wear ordinary protective suits and appropriate footwear or shoe covers. Appropriate measures shall be taken to prevent any contamination of the clean area from outside;
C Class: hair, beards and moustache (if any) shall be covered. It shall be required to wear high-collar overalls or trouser suits tightly fitting wrists, appropriate footwear or shoe covers. Clothes and footwear shall not produce falling threads or parts;
A/B Class: headgear shall fully cover hair, beards and moustache (if any) and shall be embedded in the suit collar; faces shall be covered with masks for preventing drop dispersal. It shall be also required to wear duly sterilized powder-free rubber or plastic gloves and sterilized or disinfected footwear. Trouser edges shall be tucked into boots, sleeves – into gloves. Protective clothes shall not produce any threads or parts and shall hold up any body fragments.
51. (44) It shall be prohibited to bring street wear to changing rooms leading to B and C Class rooms. Each staff members in A/B Class rooms shall be provided with clean sterile (sterilized or sanitary treated) protective clothes for each work shift. During work gloves shall be regularly disinfected. Masks and gloves shall be changed, at least, each shift.
52. (45) Clothes for clean rooms shall be cleaned and treated so that they do not cause contamination afterwards. Such operations shall be carried out according to approved instructions. It shall be recommended to have separate laundry rooms for handling such clothes. Improper handling of clothes shall damage fabric, thus, increasing the risk of separation of parts of clothes.
X. PREMISES
53. (46) All open surfaces in clean areas shall be smooth, impermeable and intact in order to minimize formation and accumulation of particles or microorganisms and to allow multiple use of detergents and, if and where necessary, disinfectants.
54. (47) For the purpose of reducing accumulation of dust and facilitating cleaning of premises, premises shall not contain any uncleanable cavities and as few jutting edges, shelves, cabinets and equipment items as possible. Doors shall be without uncleanable cavities; it shall not be recommended to use folding doors.
55. (48) Suspended ceilings shall be hermetically sealed to prevent penetration of contaminants from the space above them.
56. (49) Pipelines, air ducts and other equipment shall be assembled so as to exclude any hollows and uncovered openings and uncleanable surfaces.
57. (50) It shall be prohibited to install sinks and drains in A and B Class areas used for aseptic manufacture. In other areas it shall be required to ensure an air gap between equipment and the drain pipe (funnel). Floor drains in clean rooms of a lower cleanliness class shall be supplied with traps or water seals to prevent backflow.
58. (51) Changing rooms shall be constructed as air chambers and used for physical separation of different stages of clothes changing and to minimize contamination of protective clothes with microorganisms and particles. They shall be effectively flowed with filtered air. The area in front of the exit from a changing room (area) at rest shall be of the same cleanliness class as the area to which it leads. In some cases it shall be recommended to have separate changing rooms (areas) for entering and exiting clean areas. Hand washing facilities shall be normally installed only close to the entrance in changing rooms.
59. (52) Both doors of the air chamber may not be simultaneously opened. Simultaneous opening of more than one door shall be prevented by a block system or a visual and (or) audit warning system.
60. (53) Filtered air delivery shall maintain a positive pressure drop in relation to process areas of a lower class under all process conditions; the air flow shall effectively flow the area. Adjacent premises of different cleanliness classes shall have a pressure difference within 10 – 15 Pa (standard value). Special attention shall be paid to protecting areas posing the highest risks for the product quality, i.e. the process environment directly influencing products or cleaned product-contacting components. It shall be allowed to use different variants for the air delivery and pressure drop that may appear to be necessary due to presence of certain materials, specifically, pathogenic, highly toxic, radioactive or living viruses or bacterial materials, or drugs made of them. Certain operations may require decontamination of premises and equipment and treatment of the air removed from clean areas.
61. (54) It shall be necessary to confirm that the direction of air flows poses no risks of product contamination; particularly, it shall be necessary to make sure that no particles produced by the service staff, a performed operation or equipment are brought with the air flow to an area posing the highest risks for the product quality.
62. (55) It shall be necessary to provide an emergency alert system to signal failure of the ventilation system. If the difference of pressure between two premises is critical, differential pressure sensors shall be installed between them. Pressure drop values shall be regularly recorded or otherwise documented.
XI. EQUIPMENT
63. (56) The partition separating an A or B Class area from the processing area with lower air cleanliness may not be crossed by a conveyor belt unless such belt is subject to continuous sterilization (for example, in a sterilization tunnel).
64. (57) Equipment, fittings (joints) and service areas shall be recommended to be designed and arranged so that operations with equipment, its technical maintenance and repair could be performed outside the clean area. If sterilization is needed, it shall be made after the maximum complete equipment assembly.
65. (58) If technical maintenance of equipment has been performed inside the clean area and the appropriate cleanliness and (or) aseptics standards have been violated during such maintenance, the area shall be cleaned, disinfected and (or) sterilized (as may be appropriate) before the process is resumed.
66. (59) Water preparation installations and water distribution systems shall be designed, constructed and operated so as to ensure reliable supply of water of an appropriate quality. They may not be operated in excess of the design capacity. Water for injections shall be manufactured, stored and distributed so as to prevent growth of microorganisms, for example, due to its constant circulation at a temperature above 70 °C.
67. (60) All equipment such as sterilizers, air treatment and filtration systems, air and gas filters, water treatment, production, storage and distribution systems shall be subject to validation and scheduled maintenance; their re-entry into service shall be authorized by a person granted appropriate powers.
XII. SANITARY TREATMENT
68. (61) Sanitary treatment of clean areas shall be especially important. Areas shall be thoroughly cleaned according to instructions approved by the manufacturer. In case of disinfection several types of disinfectants shall be used. Regular control shall be provided to detect development of resistant strains of microorganisms.
69. (62) Detergents and disinfectants shall be monitored for microbiological purity. Their solutions shall be kept in preliminarily cleaned containers and only during the set periods of time, except for sterilized solutions. Detergents and disinfectants used in A and B Class areas shall be sterile before use.
70. (63) Fumigation of clean areas shall be recommended for the purpose of decreasing microbial contamination in inaccessible places.
XIII. MANUFACTURING PROCESS
71. (64) At all manufacturing stages, including at the stages preceding sterilization, it shall be necessary to take measures minimizing contamination.
72. (65) It shall not be allowed to manufacture microbial medicines or perform filling with such products in areas used for manufacture of other medicines. After inactivation, vaccines containing dead microorganisms or bacterial extracts may be pre-packed in the same areas as are used for other sterile medicines.
73. (66) Validation of aseptically run processes shall include process simulation with the use of a growth medium (growth media fill). The growth medium shall be selected based on the pharmaceutical form of the medicine, selectivity, transparency, concentration and suitability of the growth medium for sterilization.
74. (67) Process simulation shall imitate as accurately as possible the serial process of the aseptic manufacturing and include its consecutive critical stages. It shall be also necessary to consider various interferences that may arise during the ordinary manufacturing process and also ‘worst case’ situations.
75. (68) At the initial validation the process simulation shall comprise three consecutive satisfactory tests for each shift of operators. Afterwards, such tests shall be repeated at set time intervals and also after any material change in the ventilation and air conditioning system, equipment, process or number of shifts. Tests simulating the process shall be repeated twice a year for each shift of operators and each process.
76. (69) The number of containers (primary packages) intended for pre-packing of growth media shall be sufficient to ensure reliable assessment. In case of small batches, the number of containers for pre-packing of growth media shall correspond, as minimum, to the size of the product batch. It shall be necessary to aim at excluding growth of microorganisms, subject to the following standards:
a) if less than 5,000 product units were filled, not a single unit should be contaminated;
b) if from 5,000 to 10,000 product units were filled, then:
one (1) contaminated unit shall entail an investigation into reasons and repeated pre-packing of growth media;
two (2) contaminated units shall entail an investigation into reasons and re-validation;
c) if more than 10,000 units were filled, then:
one (1) contaminated unit shall entail an investigation into reasons;
two (2) contaminated units shall entail an investigation into reasons and re-validation.
77. (70) With any number of primary packages with growth media, periodic detections of microbial contamination may speak of small levels of contaminants, which shall be subject to investigation. In case of detection of significant microbial contamination, it shall be necessary to consider potential effects on the sterility of batches released after the last successful tests with the medium fill.
78. (71) It shall be necessary to create conditions ensuring that no validation creates risks for manufacturing processes.
79. (72) Water supply sources, water treatment equipment and treated water shall be subject to regular monitoring for chemical and biological contaminants and, if and where necessary, for endotoxins. Results of such monitoring and any undertaken actions shall be documented.
80. (73) In clean areas, especially during the aseptic manufacturing process, interferences of the staff shall be minimum and movements of staff members shall be regulated and controlled for the purpose of avoiding excessive production of particles and microorganisms caused by intensive physical activities. The temperature and the humidity of the environment shall not be too high so as not to cause discomfort considering characteristics of the clothes used.
81. (74) Microbial contamination of starting raw materials and materials shall be minimum. Specifications for such materials shall incorporate microbiological purity requirements.
82. (75) In clean areas quantities of containers and materials that can produce falling fragments shall be minimized.
83. (76) It shall be necessary to take measures aimed at preventing contamination of finished products with particles.
84. (77) After being cleaned, components, containers and equipment shall be handled in a way so as to exclude their repeated contamination.
85. (78) Time intervals between washing, drying and sterilization of components, containers and equipment, and also between their sterilization and subsequent use shall be minimum and subject to time constraints according to the storage conditions.
86. (79) The time between the start of the preparation of a solution and its sterilization or sterilization filtration shall be minimum. The maximum admissible time shall be set for each product type based on its composition and established storage procedures.
87. (80) Before sterilization it shall be necessary to control the level of microbial contamination. It shall be necessary to set operational limits of contamination immediately before sterilization, such limits correlating to the efficiency of the method used. The level of microbial contamination shall be measured for each batch of products filled aseptically as well as of products subject to terminal sterilization. If more stringent sterilization parameters re set for medicines subject to terminal sterilization, the level of microbial contamination may be controlled only at appropriate time intervals according to a schedule. If parameter-based release systems are used, microbial contamination shall be measured for each batch and shall be regarded as in-process testing. If and where necessary, the level of endotoxins shall be controlled. All solutions, especially high volumes of infusion liquids, shall be subject to sterilization filtration, where possible, immediately before filling.
88. (81) Components, containers, equipment and any other items necessary in a clean area, especially during operations in aseptic conditions, shall be sterilized and delivered to the clean area through a pass-through two-way wall sterilizer or in another manner preventing contamination. Incombustible gases shall pass through filters entrapping microorganisms.
89. (82) Efficiency of any new process shall be confirmed during validation to be regularly re-run according to a plan based on the operational schedule as well as in case of any material change in the process or equipment.
XIV. STERILIZATION
90. (83) All sterilization processes shall be subject to validation. Special attention shall be paid if an applied sterilization method is not described in the State Pharmacopoeia of the Russian Federation or is used for a product other than an ordinary water or oil solution. The preferred method shall be the thermal sterilization method. In any case the sterilization method shall be consistent with the manufacturing license and the registration dossier.
91. (84) Before selecting any sterilization process, it shall be necessary to demonstrate, by means of physical measurements and, where possible, biological indicators, that the process is suitable for the given product and effective for creating necessary sterilization conditions in all parts of each feed type. The process validation shall be re-run at time intervals established by the schedule, but no less often than once a year, and also in case of material modifications in equipment. Records with results shall be subject to safe-keeping.
92. (85) For effective sterilization the whole material shall be subject to appropriate treatment and the process shall be arranged so as to ensure attaining the required effectiveness.
93. (86) Feed methods shall be developed and validated for all sterilization processes.
94. (87) Biological indicators shall be regarded only as an additional sterilization control method. Biological indicators shall be kept and used according to the manufacturer’s instructions; their quality shall be monitored by means of positive control methods. If biological indicators are used, it shall be necessary to take stringent measures preventing microbial contamination from such indicators.
95. (88) It shall be necessary to clearly define measures for products to be divided into sterilized and non-sterilized ones. Each basket, tray or other container for products or components shall bear a clear label with the material name and batch number, specifying if the product has been sterilized or not. Where necessary, indicators such as autoclave tapes may be used to indicate whether a batch (or part of a batch) has been sterilized or not; however, such indicators do not provide any reliable proof that the batch is really sterile.
96. (89) For each sterilization cycle it shall be necessary to make records to be approved as part of the procedure for the issue of a permit for release of a batch.
XV. THERMAL STERILIZATION
97. (90) Each thermal sterilization cycle shall be recorded as a sufficiently large-scale time-temperature chart or registered with the use of other appropriate equipment providing necessary accuracy and precision. Locations of temperature sensors used for control and (or) recording shall be determined at the time of validation and, if and where necessary, also checked by using another independent temperature sensor located in the same place.
98. (91) It shall be allowed to use chemical and biological indicators, but not instead of physical measurements.
99. (92) Sufficient time shall be provided for the entire feed volume to reach the necessary temperature before the start of the sterilization countdown. Such period of time shall be determined for each type of sterilized feed.
100. (93) Upon completion of the high-temperature phase of the thermal sterilization cycle, it shall be necessary to take precautions preventing contamination of the sterilized feed during cooling. Any product-contacting cooling liquid or gas shall be sterilized except in cases where possible use of unsealed packages is excluded and appropriate proofs are presented.
101. (94) Steam sterilization shall require temperature and pressure control. Command facilities shall be recommended to be independent from control means and recorders. If automatic management and control systems are used for this purpose, they shall be validated in order to ensure their compliance with the critical process requirements. Violations in the course of the process shall be registered by the system and supervised by the operator. Readings of the independent temperature sensor during the sterilization process shall be constantly compared with the values in the recorder diagram. For sterilizers with drains in chamber pans it may appear to be necessary to register the temperature at this point throughout the sterilization cycle. If the sterilization cycle includes a vacuuming stage, the chamber shall be regularly checked for hermiticity.
102. (95) If not in sealed packages, items being sterilized shall be wrapped in an air- and steam-permeable material preventing repeated contamination of such items after sterilization. All feed portions shall contact the sterilant at the set temperature and time.
103. (96) It shall be necessary to make sure that steam of a required quality is used for sterilization, free of impurities in quantities that might cause contamination of products or equipment.
XVII. DRY-HEAT STERILIZATION
104. (97) Dry-heat sterilization shall require air circulation inside the chamber and maintenance of an excessive pressure for preventing penetrations of non-sterile air in the chamber. Any air coming inside shall pass through high-efficiency filters (HEPA filters). If sterilization implies removing pyrogenes, tests with the purposeful use of endotoxins shall be conducted as part of validation.
XVIII. IRRADIATION STERILIZATION
105. (98) Irradiation sterilization shall be used mainly for sterilization of temperature-sensitive materials and products. Many medicines and certain packaging materials are sensitive to ionizing radiation, hence, this method may be applied only when it has been experimentally confirmed that there is no adverse effect on products. As a rule, ultraviolet irradiation may not be accepted as a sterilization method.
106. (99) The sterilization process shall require measuring the absorbed ionizing radiation dose. This shall be done by using dosimeters, whose readings do not depend on the used power of the radiation dose and which ensure quantitative registration of the radiation dose absorbed by products themselves. Dosimeters shall be arranged among the feed in a sufficient quantity and within a short range from one another so that all points subject to radiation are supplied with dosimeters. Plastic dosimeters shall be used only within the period of validity of their calibration. Dosimeter readings shall be taken within a short time interval after radiation.
107. (100) Biological indicators may be used as an additional control means.
108. (101) Validation procedures shall ensure that the effect of the different density of packing of products being sterilized has been taken into account.
109. (102) Materials handling procedures shall prevent confusion of irradiated and unirradiated materials. Each package shall be supplied with radiation-sensitive colour indicators to differentiate between irradiated and unirradiated packages.
110. (103) The total absorbed radiation dose shall be taken within the time intended for the sterilization process.
XIX. ETHYLENE OXIDE (EtO) STERILIZATION
111. (104) This method may be used only when no other method may be applied. During the validation process it shall be proved that there is no damaging effect on products and that the conditions and the time provided for degassing ensure that the quantity of the residual gas and reaction products shall remain within the permissible limits set for the given type of products or materials.
112. (105) Direct contact between gas and microorganisms shall be essentially important. It shall be necessary to take precautions preventing incorporation of microorganisms in the material (for example, in crystals or dried protein). The type and the quantity of packing materials may significantly influence the process.
113. (106) Before gas treatment it shall be necessary to make sure that the humidity and the temperature of materials correspond to the process requirements. The time needed for this purpose shall be, where possible, minimum.
114. (107) Each sterilization cycle shall be controlled with the use of appropriate biological indicators that shall be evenly distributed in sufficient quantities throughout the whole feed. The data obtained during this process shall make part of the finished product batch dossier.
115. (108) Each sterilization cycle shall be accompanied by records specifying the time of the full cycle completion, pressure, temperature and humidity in the chamber during the process, concentrations and the total quantity of the gas used. Pressure and temperature shall be registered in the chart throughout the cycle. Such records shall make part of the finished product batch dossier.
116. (109) The feed after sterilization shall be kept under control in ventilation conditions to reduce the content of the residual gas and reaction products to a set level. This process shall be subject to validation.
XX. FILTRATION OF MEDICINES THAT CANNOT BE STERILIZED IN FINAL PACKAGING
117. (110) Sterilization filtration shall not be deemed as a sufficient sterilization criterion in cases where sterilization can be run for products in final packaging. Steam sterilization shall be the preferred method. If products cannot be sterilized in final packaging, solutions or liquids may be filtered through a sterile filter with a nominal pore size of 0.22 µm (or less) or through a filter with a similar capability of retaining microorganisms in preliminarily sterilized containers (packages). Such filters may remove most bacteria and moulds but not all viruses or micoplasma. Therefore, it shall be necessary to consider supplementing the filtration process with thermal treatment of a certain extent.
118. (111) Since, as opposed to the other sterilization processes, sterilization filtration implies an extra potential risk, the pre-packing process is recommended to be preceded with repeated filtration through an additional sterilizing filter entrapping microorganisms. The subsequent sterilization filtration shall be made as close to the place of pre-packing as possible.
119. (112) It shall be necessary to use filters with minimum fiber separation.
120. (113) Before and immediately after the sterilizing filter is used, the filter shall be checked for its integrity by using methods such as ‘bubble point’, diffusion flow or pressure testing. During validation it shall be necessary to determine the time needed for filtration of a solution of a set volume and the pressure difference on the filter. Any material deviations from the specified parameters during the on-going manufacturing process shall be registered and studied. Results of such studies shall be incorporated in the product batch dossier. Immediately after use, it shall be necessary to confirm the integrity of critical gas and air filters. Integrity of other filters shall be also confirmed at appropriate time intervals.
121. (114) It shall be prohibited to use one and the same filter during more than one working day except in cases where its usability for a longer period of time is confirmed by validation.
122. (115) Filters shall not influence the products, by retaining their ingredients or producing any substances into products.
XXI. END OF THE STERILE PRODUCT MANUFACTURING PROCESS
123. (116) After cool dehumidification, partially closed bottles shall be stored in an A Class area until they are finally capped.
124. (117) Containers (primary packages) shall be closed by using appropriate validated methods. If the method of sealing is used, for example, for glass or plastic ampoules, all products shall be subject to 100% integrity control. In other cases the product integrity shall be controlled by using established methods.
125. (118) The system of closure of aseptically filled bottles shall not be fully integral until an aluminium seal (cap) is fastened (clamped) onto a capped bottle. Therefore, after capping, caps shall be fastened as soon as possible.
126. (119) As the cap fastening may produce large quantities of mechanical particles, fastening equipment shall be separately located and supplied with an air exhaust system.
127. (120) Caps may be fastened onto bottles as part of the aseptic process with the use of sterilized caps or in a clean room outside the aseptic area. In the latter case bottles shall be protected by an A Class area until they are carried out of the aseptic area; afterwards, capped bottles shall be protected by supplying A Class clean air until the caps are fastened.
128. (121) Bottles without caps or with displaced caps shall be removed before cap fastening. If the cap fastening process requires human interference, appropriate technologies shall be used to exclude direct contact with bottles and minimize microbial contamination.
129. (122) An effective means of protection may be barriers or isolators restricting access to the working area, ensuring the required conditions and minimizing direct human access to the fastening operation.
130. (123) Vacuum sealed primary packages (vacuum packages) shall be checked for the preservation of vacuum after a pre-set period of time.
131. (124) Primary packages with products for parenteral administration shall be individually checked (by piece) for the presence of foreign matters or other quality inconsistencies. Visual control shall be provided at the set levels of illumination and the work field background. Operators in charge of visual control shall be subject to regular eyesight tests (if operators use glasses, the eyesight in glasses shall be tested). It shall be recommended to make frequent breaks in the work of operators during visual control. In case of use of other control methods the control process shall be validated and the condition of equipment shall be regularly checked. Results of visual control shall be documented.
XXII. QUALITY CONTROL
132. (125) Testing of finished products for sterility shall be regarded only as the final stage of a series of control activities ensuring sterility. The sterility testing procedure shall be validated for each product.
133. (126) In cases where the permit for release of sterile products by parameters is obtained (Attachment No. 17 hereto), special attention shall be paid to validation and control of the entire manufacturing process.
134. (127) Samples of products selected for stability testing shall be representative for the whole batch and shall include samples taken from those parts of the batch that are assumed to pose the highest risk of contamination, particularly:
a) (a) for aseptically filled products samples shall include containers (primary packages), which were filled at the beginning and the end of the batch manufacturing and also after any significant interference;
b) (b) with respect to products that were subject to thermal sterilization in final packaging, special attention shall be paid to taking samples from the potentially coldest feed portions.