欧盟GMP附录1.pdf

1、 EUROPEAN COMMISSION ENTERPRISE AND INDUSTRY DIRECTORATE-GENERAL Consumer goods Pharmaceuticals Brussels, 25 November 2008 (rev.) EudraLex The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Us

2、e Annex 1 Manufacture of Sterile Medicinal Products (corrected version) Document History Previous version dated 30 May 2003, in operation since September 2003 Revision to align classification table of clean rooms, to include guidance on media simultations, bioburden monitoring and capping of vials N

3、ovember 2005 to December 2007 Date for coming into operation and superseding 01 March 20091Please note correction on the implementation of provisions for capping of vials! 1Note: Provisions on capping of vials should be implemented by 01 March 2010. Commission Europenne, B-1049 Bruxelles / Europese

4、Commissie, B-1049 Brussel Belgium. Telephone: (32-2) 299 11 11 2 ANNEX 1 MANUFACTURE OF STERILE MEDICINAL PRODUCTS Principle The manufacture of sterile products is subject to special requirements in order to minimize risks of microbiological contamination, and of particulate and pyrogen contaminatio

5、n. Much depends on the skill, training and attitudes of the personnel involved. Quality Assurance is particularly important, and this type of manufacture must strictly follow carefully established and validated methods of preparation and procedure. Sole reliance for sterility or other quality aspect

6、s must not be placed on any terminal process or finished product test. Note: This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces etc. Reference should be made to other documents such as the EN/ISO Standards. General 1. The

7、 manufacture of sterile products should be carried out in clean areas entry to which should be through airlocks for personnel and/or for equipment and materials. Clean areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appro

8、priate efficiency. 2. The various operations of component preparation, product preparation and filling should be carried out in separate areas within the clean area. Manufacturing operations are divided into two categories; firstly those where the product is terminally sterilised, and secondly those

9、 which are conducted aseptically at some or all stages. 3. Clean areas for the manufacture of sterile products are classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in

10、 order to minimise the risks of particulate or microbial contamination of the product or materials being handled. In order to meet “in operation” 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 c

11、ondition where the installation is installed and operating, complete with production equipment but with no operating personnel present. The “in operation” state is the condition where the installation is functioning in the defined operating mode with the specified number of personnel working. The “i

12、n operation” and “at rest” states should be defined for each clean room or suite of clean rooms. For the manufacture of sterile medicinal 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 asepti

13、c connections. Normally such conditions are provided by a laminar air flow work station. Laminar air flow systems should provide a homogeneous 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 demon

14、strated and validated. 3 A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes. Grade B: For aseptic 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 man

15、ufacture of sterile products. Clean room and clean air device classification 4. Clean rooms and clean air devices should be classified in accordance with EN ISO 14644-1. Classification should be clearly differentiated from operational process environmental monitoring. The maximum permitted airborne

16、particle concentration for each grade is given in the following table. Maximum permitted number of particles per m3equal to or greater than the tabulated size At rest In operation Grade 0.5 m 5.0m 0.5 m 5.0m 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

17、 000 Not defined Not defined 5. For classification purposes in Grade A zones, a minimum sample volume of 1m3 should be taken per sample location. For Grade A the airborne particle classification is ISO 4.8 dictated by the limit for particles 5.0 m. For Grade B (at rest) the airborne particle classif

18、ication is ISO 5 for both considered particle sizes. . For Grade C (at rest a network of sequentially accessed sampling points connected by manifold to a single particle counter; or a combination of the two. The system selected must be appropriate for the particle size considered. Where remote sampl

19、ing systems are used, the length of tubing and the radii of any bends in the tubing must be considered in the context of particle losses in the tubing. The selection of the monitoring system should take account of any risk presented by the materials used in the manufacturing operation, for example t

20、hose involving live organisms or radiopharmaceuticals. 12. The sample sizes taken for monitoring purposes using automated systems will usually be a function of the sampling rate of the system used. It is not necessary for the sample volume to be the same as that used for formal classification of cle

21、an rooms and clean air devices. 13. In Grade A and B zones, the monitoring of the 5.0 m particle concentration count takes on a particular significance as it is an important diagnostic tool for early detection of failure. The occasional indication of 5.0 m particle counts may be false counts due to

22、electronic noise, stray light, coincidence, etc. However consecutive or regular counting of low levels is an indicator of a possible contamination event and should be investigated. Such events may indicate early failure of the HVAC system, filling equipment failure or may also be diagnostic of poor

23、practices during machine set-up and routine operation. 14. The particle limits 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 an unmanned state after completion of operations. 15. The monitoring of Grade C and D area

24、s in operation should be performed in accordance with the principles of quality risk management. The requirements and alert/action limits will depend on the nature of the operations carried out, but the recommended “clean up period” should be attained. 16. Other characteristics such as temperature a

25、nd relative humidity depend on the product and nature of the operations carried out. These parameters should not interfere with the defined cleanliness standard. 17. Examples of operations to be carried out in the various grades are given in the table below (see also paragraphs 28 to 35): 5 Grade Ex

26、amples of operations for terminally sterilised products. (see paragraphs 28-30) A Filling of products, when unusually at risk C Preparation of solutions, when unusually at risk. Filling of products D Preparation of solutions and components for subsequent filling Grade Examples of operations for asep

27、tic preparations. (see paragraphs. 31-35) A Aseptic preparation and filling. C Preparation of solutions to be filtered. D Handling of components after washing. 18. Where aseptic operations are performed monitoring should be frequent using methods such as settle plates, volumetric air and surface sam

28、pling (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 personnel should be monitored after critical operations. Add

29、itional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitisation. 19. Recommended limits for microbiological monitoring of clean areas during operation: Recommended limits for microbial contamination (a) Grade air sample c

30、fu/m3settle plates (diameter 90 mm) cfu/4 hours (b) contact plates (diameter 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 - Notes (a) These are average values. (b) Individual settle plates may be exposed for less than 4 hours. 20. Appropriate alert

31、 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 21. The utilisation of isolator technology to minimize human interventions in processing areas may

32、 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 designed so that the required air quality

33、 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 mechanisms. 6 22. The transfer of materials in

34、to 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 devices. 23. The air classification r

35、equired 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. 24. Isolators should be introduced only after appropriate validation. Validation should take into account all critical f

36、actors 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. 25. Monitoring should be carried out routinely and should include frequent leak testing of the isolator and glove

37、/sleeve system. Blow/fill/seal technology 26. 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 used for aseptic production wh

38、ich 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/fill/seal equipment used for

39、the production of products which are terminally sterilised should be installed in at least a grade D environment. 27. Because of this special technology particular attention should be paid to, at least the following: equipment design and qualification validation and reproducibility of cleaning-in-pl

40、ace and sterilisation-in-place background clean room environment in which the equipment is located operator training and clothing interventions in the critical zone of the equipment including any aseptic assembly prior to the commencement of filling. Terminally sterilised products 28. Preparation of

41、 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, (for example, because the product

42、 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. 29. Filling of products for terminal sterilisation should be carried out in at least

43、a grade C environment. 30. 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 be done in a grade A zo

44、ne with at least a grade C background. Preparation and filling of ointments, creams, 7 suspensions and emulsions should generally be carried out in a grade C environment before terminal sterilisation. Aseptic preparation 31. Components after washing should be handled in at least a grade D environmen

45、t. 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. 32. Preparation of solutions which are to be sterile filtered dur

46、ing 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. 33. Handling and filling of aseptically prepared products should be done in a grade A environment with a grade B back

47、ground. 34. 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. 35. Preparation and filling of sterile ointments, creams,

48、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 36. Only the minimum number of personnel required should be present in clean areas; this is particularly important during aseptic proc

49、essing. Inspections and controls should be conducted outside the clean areas as far as possible. 37. 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 products. 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 su