《EU-GMP-Part-II-Annexes-1.pdf》由会员分享,可在线阅读,更多相关《EU-GMP-Part-II-Annexes-1.pdf(12页珍藏版)》请在三一文库上搜索。
1、EUROPEAN COMMISSION ENTERPRISE DIRECTORATE-GENERAL Single market : management firstly those where the product is terminally sterilised, and secondly those which are conducted aseptically at some or all stages. 3. Clean areas for the manufacture of sterile products are classified according to the req
2、uired charac- teristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimise the risks of particulate or microbial con- tamination of the product or materials being handled. In order to meet “in operati
3、on” conditions these areas should be designed to reach certain specified air-cleanliness levels in the “at rest” occupancy state. The “at-rest” state is the condition where the installation is installed and operating, complete with production equipment but with no operating per- sonnel present. The
4、“in operation” state is the condition where the installation is functioning in the de- fined operating mode with the specified number of personnel working. The “in operation” and “at rest” states should be defined for each clean room or suite of clean rooms. For the manufacture of sterile medicinal
5、products 4 grades can be distinguished. Grade A : The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homoge
6、neous air speed in a range of 0.36 0.54 m/s (guidance value) at the working position in open clean room applications. The maintenance of laminarity should be demonstrated and validated. A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes. Grade B : For ase
7、ptic preparation and filling, this is the background environment for the grade A zone. Grade C and D: Clean areas for carrying out less critical stages in the manufacture of sterile products. The airborne particulate classification for these grades is given in the following table. at rest (b)in oper
8、ation (b) Grademaximum permitted number of particles/m3 equal to or above (a) 0.5 m (d)5 m0.5 m (d)5 m A3 5001 (e)3 5001 (e) B (c)3 5001 (e)350 0002 000 C (c)350 0002 0003 500 00020 000 D (c)3 500 00020 000not defined (f)not defined (f) Notes: (a) Particle measurement based on the use of a discrete
9、airborne particle counter to measure the concentration of particles at designated sizes equal to or greater than the threshold stated. A continuous measurement system should be used for monitoring the concentration of particles in the grade A zone, and is recommended for the surrounding grade B area
10、s. For routine testing the total sample volume should not be less than 1 m3 for grade A and B areas and preferably also in grade C areas. (b) The particulate conditions given in the table for the “at rest” state should be achieved after a short “clean up” period of 15-20 minutes (guidance value) in
11、an unmanned state after completion of op- erations. The particulate conditions for grade A “in operation” given in the table should be main- tained in the zone immediately surrounding the product whenever the product or open container is exposed to the environment. It is accepted that it may not alw
12、ays be possible to demonstrate conformity with particulate standards at the point of fill when filling is in progress, due to the gen- eration of particles or droplets from the product itself. (c) In order to reach the B, C and D air grades, the number of air changes should be related to the size of
13、 the room and the equipment and personnel present in the room. The air system should be provided with appropriate terminal filters such as HEPA for grades A, B and C. (d) The guidance given for the maximum permitted number of particles in the “at rest“ and “in opera- tion” conditions correspond appr
14、oximately to the cleanliness classes in the EN/ISO 14644-1 at a particle size of 0.5 m. (e) These areas are expected to be completely free from particles of size greater than or equal to 5 m. As it is impossible to demonstrate the absence of particles with any statistical significance the limits are
15、 set to 1 particle / m3. During the clean room qualification it should be shown that the ar- eas can be maintained within the defined limits. (f) The requirements and limits will depend on the nature of the operations carried out. Other characteristics such as temperature and relative humidity depen
16、d on the product and nature of the operations carried out. These parameters should not interfere with the defined cleanliness stan- dard. Examples of operations to be carried out in the various grades are given in the table below. (see also par. 11 and 12) GradeExamples of operations for terminally
17、sterilised products. (see par. 11) AFilling of products, when unusually at risk CPreparation of solutions, when unusually at risk. Filling of products DPreparation of solutions and components for subsequent filling GradeExamples of operations for aseptic preparations. (see par. 12) AAseptic preparat
18、ion and filling. CPreparation of solutions to be filtered. DHandling of components after washing. 4. The areas should be monitored during operation, in order to control the particulate cleanliness of the various grades. 5. Where aseptic operations are performed monitoring should be frequent using me
19、thods such as settle plates, volumetric air and surface sampling (e.g. swabs and contact plates). Sampling methods used in operation should not interfere with zone protection. Results from monitoring should be considered when reviewing batch documentation for finished product release. Surfaces and p
20、ersonnel should be monitored after critical operations. Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitisation. Recommended limits for microbiological monitoring of clean areas during operation. Recommended li
21、mits for microbial contamination (a) Gradeair sample cfu/m 3 settle plates (diam. 9 0 mm), cfu/4 hours (b) contact plates (diam. 55 mm), cfu/plate glove print 5 fingers cfu/glove A 1 1 1 1 B10555 C1005025- D20010050- Notes (a) These are average values. (b) Individual settle plates may be exposed for
22、 less than 4 hours. 6. Appropriate alert and action limits should be set for the results of particulate and microbiological monitoring. If these limits are exceeded operating procedures should prescribe corrective action. Isolator technology 7. The utilisation of isolator technology to minimise huma
23、n interventions in processing areas may result in a significant decrease in the risk of microbiological contamination of aseptically manufactured products from the environment. There are many possible designs of isolators and transfer devices. The isolator and the background environment should be de
24、signed so that the required air quality for the respective zones can be realised. Isolators are constructed of various materials more or less prone to puncture and leakage. Transfer devices may vary from a single door to double door designs to fully sealed systems incorporating sterilisation mechani
25、sms. The transfer of materials into and out of the unit is one of the greatest potential sources of contamination. In general the area inside the isolator is the local zone for high risk manipulations, although it is recognised that laminar air flow may not exist in the working zone of all such devi
26、ces. The air classification required for the background environment depends on the design of the isolator and its application. It should be controlled and for aseptic processing it should be at least grade D. 8. Isolators should be introduced only after appropriate validation. Validation should take
27、 into account all critical factors of isolator technology, for example the quality of the air inside and outside (background) the isolator, sanitisation of the isolator, the transfer process and isolator integrity. 9. Monitoring should be carried out routinely and should include frequent leak testin
28、g of the isolator and glove/sleeve system. Blow/fill/seal technology 10. Blow/fill/seal units are purpose built machines in which, in one continuous operation, containers are formed from a thermoplastic granulate, filled and then sealed, all by the one automatic machine. Blow/fill/seal equipment use
29、d for aseptic production which is fitted with an effective grade A air shower may be installed in at least a grade C environment, provided that grade A/B clothing is used. The environment should comply with the viable and non viable limits at rest and the viable limit only when in operation. Blow/fi
30、ll/seal equipment used for the production of products which are terminally sterilised should be installed in at least a grade D environment. Because of this special technology particular attention should be paid to, at least the following: equipment design and qualification, validation and reproduci
31、bility of cleaning-in-place and sterilisation-in-place, background cleanroom environment in which the equipment is located, operator training and clothing, and interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling. Terminally sterilis
32、ed products 11. Preparation of components and most products should be done in at least a grade D environment in order to give low risk of microbial and particulate contamination, suitable for filtration and sterilisation. Where the product is at a high or unusual risk of microbial contamination, (fo
33、r example, because the product actively supports microbial growth or must be held for a long period before sterilisation or is necessarily processed not mainly in closed vessels), then preparation should be carried out in a grade C environment. Filling of products for terminal sterilisation should b
34、e carried out in at least a grade C environment. Where the product is at unusual risk of contamination from the environment, for example because the filling operation is slow or the containers are wide-necked or are necessarily exposed for more than a few seconds before sealing, the filling should b
35、e done in a grade A zone with at least a grade C background. Preparation and filling of ointments, creams, suspensions and emulsions should generally be carried out in a grade C environment before terminal sterilisation. Aseptic preparation 12. Components after washing should be handled in at least
36、a grade D environment. Handling of sterile starting materials and components, unless subjected to sterilisation or filtration through a micro-organism-retaining filter later in the process, should be done in a grade A environment with grade B background. Preparation of solutions which are to be ster
37、ile filtered during the process should be done in a grade C environment; if not filtered, the preparation of materials and products should be done in a grade A environment with a grade B background. Handling and filling of aseptically prepared products should be done in a grade A environment with a
38、grade B background. Prior to the completion of stoppering, transfer of partially closed containers, as used in freeze drying should be done either in a grade A environment with grade B background or in sealed transfer trays in a grade B environment. Preparation and filling of sterile ointments, crea
39、ms, suspensions and emulsions should be done in a grade A environment, with a grade B background, when the product is exposed and is not subsequently filtered. Personnel 13. Only the minimum number of personnel required should be present in clean areas; this is particularly important during aseptic
40、processing. Inspections and controls should be conducted outside the clean areas as far as possible. 14. All personnel (including those concerned with cleaning and maintenance) employed in such areas should receive regular training in disciplines relevant to the correct manufacture of sterile produc
41、ts. This training should include reference to hygiene and to the basic elements of microbiology. When outside staff who have not received such training (e.g. building or maintenance contractors) need to be brought in, particular care should be taken over their instruction and supervision. 15. Staff
42、who have been engaged in the processing of animal tissue materials or of cultures of micro-organisms other than those used in the current manufacturing process should not enter sterile-product areas unless rigorous and clearly defined entry procedures have been followed. 16. High standards of person
43、al hygiene and cleanliness are essential. Personnel involved in the manufacture of sterile preparations should be instructed to report any condition which may cause the shedding of abnormal numbers or types of contaminants; periodic health checks for such conditions are desirable. Actions to be take
44、n about personnel who could be introducing undue microbiological hazard should be decided by a designated competent person. 17. Changing and washing should follow a written procedure designed to minimise contamination of clean area clothing or carry-through of contaminants to the clean areas. 18. Wr
45、istwatches, make-up and jewellery should not be worn in clean areas. 19. The clothing and its quality should be appropriate for the process and the grade of the working area. It should be worn in such a way as to protect the product from contamination. The description of clothing required for each g
46、rade is given below: Grade D: Hair and, where relevant, beard should be covered. A general protective suit and appropriate shoes or overshoes should be worn. Appropriate measures should be taken to avoid any contamination coming from outside the clean area. Grade C: Hair and where relevant beard and
47、 moustache should be covered. A single or two-piece trouser suit, gathered at the wrists and with high neck and appropriate shoes or overshoes should be worn. They should shed virtually no fibres or particulate matter. Grade A/B: Headgear should totally enclose hair and, where relevant, beard and mo
48、ustache; it should be tucked into the neck of the suit; a face mask should be worn to prevent the shedding of droplets. Appropriate sterilised, non-powdered rubber or plastic gloves and sterilised or disinfected footwear should be worn. Trouser-legs should be tucked inside the footwear and garment s
49、leeves into the gloves. The protective clothing should shed virtually no fibres or particulate matter and retain particles shed by the body. 20. Outdoor clothing should not be brought into changing rooms leading to grade B and C rooms. For every worker in a grade A/B area, clean sterile (sterilised or adequately sanitised) protective garments should be provided at each work session. Gloves should be regularly disinfected during operations. Masks and gloves should be changed at least for every working session. 21. Clean area clothing should be cleaned and handled in such a way that it d
链接地址:https://www.31doc.com/p-3756098.html