1、ANNEX 1 附件1MANUFACTURE OF STERILE MEDICINAL PRODUCTS无菌医药产品的生产Principle 原则The manufacture of sterile products is subject to special requirements in order to minimise risks of microbiological contamination, and of particulate and pyrogen contamination. Much depends on the skill, training and attitudes
2、 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 aspects must not be placed on any terminal process or fini
3、shed product test.无菌药品的生产，必须符合一些特殊的要求，以防止微生物、微粒和热源的污染。这很大程度上要依赖工作人员的技术水平、培训和工作态度。在这方面质量保证显得特别重要，这种类型的生产，必须严格按照完善的和经过验证的生产方法和工作程序。仅靠产品的最终灭菌和某一方面的质量控制是不允许的。Note:This guidance does not lay down detailed methods for determining the microbiological and particulate cleanliness of air, surfaces etc. Refere
4、nce should be made to other documents such as the EN/ISO Standards.注：本规范没有详述测定空气、表面等微生物和微粒洁净度的详细方法，请参阅EN/ISO中相关标准。General 一般要求1. The 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
5、areas should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency.无菌产品的生产要在洁净区域内进行，进入这些区域内的人员、设备或原料，必须通过气闸室。洁净区必须保持一定的洁净级别，空气必须通过规定的过滤器。2. The various operations of component preparation, product preparation and fill
6、ing 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 which are conducted aseptically at some or all stages.各种原料的准备、产品的准备和灌装，必须在洁净区的不同区域进行，生产操作分为两类，一是最终
7、灭菌型，二是部分过程或全过程的无菌操作。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 order to minimise the risks of part
8、iculate 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 condition where the installation is in
9、stalled 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 “in operation” and “at rest” states shou
10、ld be defined for each clean room or suite of clean rooms. For the manufacture of sterile medicinal products 4 grades can be distinguished.无菌生产的洁净区，按照产品对环境的要求分级，每一步生产操作，在操作状态，对环境有相应的洁净级别的要求，以防止对所处理的材料或产品造成粉尘或微生物的污染。为达到“动态 ”的条件，这些区域在设计上要达到 “静态”的洁净标准。“ 静态”指设备已经安装并运行，生产设备就位但是没有操作人员在场。“动态” 是指在设备正常运转状态下和
11、有规定的工作人员在场的情况下。每个或每套房间都要分别进行“ 静态” 和“动态”的确定。无菌产品的生产有4个环境级别：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 shoul
12、d 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 demonstrated and validated.A uni-directional air flow and lower velocities may be used in closed isolators and glove boxes.A级
13、：用于高风险的生产操作，如灌装区、加盖区、容器开口区、和进行无菌连接的地方。通常这种情况是带有层流罩的工作点。在开放的洁净区内的工作点上，层流罩应该能产生风速为0.36 0.54米/秒的均匀气流。层流罩的维护，必须有充分的证明和经过验证。密封隔离箱和手套箱内，可采用单向低速气流。Grade B : For aseptic preparation and filling, this is the background environment for the grade A zone.B级：对于无菌制备和灌装，B级区域是A级区域的背景环境。Grade C and D: Clean areas fo
14、r carrying out less critical stages in the manufacture of sterile products.C级和 D级：无菌产品非关键生产步骤的洁净区。The airborne particulate classification for these grades is given in the following table:上述级别的环境的空气中尘埃粒子标准如下：at rest (b) 静态 （b） in operation (b) 动态 (b)Grade空气级别 maximum permitted number of particles/m3
15、equal to or above (a)允许最大尘埃粒子数/m 3 等于或大于 (a)0.5m(d) 5m 0.5m(d) 5mA 3500 1（e） 3500 1（e）B(C) 3500 1（e） 350000 2000C(C) 350000 2000 3500000 20000D(C) 3500000 20000 未规定 (f) 未规定 (f)Notes注 : a) Particle measurement based on the use of a discrete airborne particle counter to measure the concentration of pa
16、rticles 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 areas. For routine testing the total sample volume should not be
17、 less than 1 m3 for grade A and B areas and preferably also in grade C areas.尘埃粒子检查是用不连续尘埃粒子记数器测量一定量空气中等于或大于一定粒子大小的尘埃粒子的浓度。在A区必须有持续监控的装置，来检测该区域内尘埃粒子的浓度，建议在A区周围的B区也安装这样的装置。在 A级和B级区常规的检查取样量，应不少于1 m 3，在C级区的取样量最好也达到该要求。b) The particulate conditions given in the table for the “at rest” state should be ac
18、hieved after a short “clean up” period of 15-20 minutes (guidance value) in an unmanned state after completion of operations. The particulate conditions for grade A “in operation” given in the table should be maintained in the zone immediately surrounding the product whenever the product or open con
19、tainer is exposed to the environment. It is accepted that it may not always be possible to demonstrate conformity with particulate standards at the point of fill when filling is in progress, due to the generation of particles or droplets from the product itself.上表中的“静态 ”下的微粒情况，必须在操作完成后，“自净”运行15-20分钟
20、后达到。当产品和开口容器接触环境时，在紧接产品的的周围区域，尘埃情况必须保持在A级“ 动态” 标准。灌装时，在灌装点由于产品本身产生的微粒和液滴，有时达不到微粒标准是可以接受的。c) In order to reach the B, C and D air grades, the number of air changes should be related to the size of the room and the equipment and personnel present in the room. The air system should be provided with app
21、ropriate terminal filters such as HEPA for grades A, B and C.为达到B 、C、D级洁净，要结合房间的大小、设备和相关人员的情况确定换气次数。在A、B、C 级洁净区，必须在空气系统中使用合适的终端过滤器，如HEPA。d) The guidance given for the maximum permitted number of particles in the “at rest“ and “in operation” conditions correspond approximately to the cleanliness clas
22、ses in the EN/ISO 14644-1 at a particle size of 0.5 m.对粒径为0.5m的粒子，规范规定的“ 静态”和“动态”下允许的最多尘埃粒子数，与EN/ISO14644-1中洁净区的规定相当。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
23、 significance the limits are set to 1 particle / m3. During the clean room qualification it should be shown that the areas can be maintained within the defined limits.这些区域不允许有大于或等于5m的粒子，由于不可能用任何统计学意义证明没有尘埃粒子，这里将限度定为1个/m 3。在洁净房间的验证中，必须表明在规定的限度内。f) The requirements and limits will depend on the nature
24、 of the operations carried out.要求和限度，将根据操作的性质而定。Other characteristics such as temperature and relative humidity depend on the product and nature of the operations carried out. These parameters should not interfere with the defined cleanliness standard.其他特征参数，如温度和相对湿度，必须根据操作的性质和相应的产品而定。这些参数必须不影响规定的洁净
25、度。Examples of operations to be carried out in the various grades are given in the table below. (see also par. 11 and 12)下表列出各种洁净级别所适应的生产操作：Grade级别Examples of operations for terminally sterilised products. (see par. 11)最终灭菌产品的操作举例（见11节）A Filling of products, when unusually at risk产品灌装、高风险的情况C Filling
26、 of products, when unusually at risk高风险情况下的配液、产品灌装D Preparation of solutions and components for subsequent filling灌装前溶液及各组分准备级别 Examples of operations for aseptic preparations. (see par. 12)无菌制备型操作举例（见12节）A Aseptic preparation and filling.无菌制备和灌装C Preparation of solutions to be filtered.过滤前溶液配制D Han
27、dling of components after washing.清洗后材料处理4. The areas should be monitored during operation, in order to control the particulate cleanliness of the various grades.这些区域内必须有运行过程中的监控，以控制各个级别下的尘埃粒子洁净度。5. Where aseptic operations are performed monitoring should be frequent using methods such as settle pla
28、tes, 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 personnel should be monit
29、ored after critical operations.对无菌操作区，必须经常使用沉降皿、空气定量法和表面取样（棉签或接触皿）等方法进行监控。生产过程中所用的取样方法，必须不影响洁净区的保护，当审核最终产品放行的批记录时，也要考虑环境监控的结果。在关键操作后，要对人员和设施的表面进行监控。Additional microbiological monitoring is also required outside production operations, e.g. after validation of systems, cleaning and sanitisation.在非生产状态
30、下，要进行微生物的监控，包括在系统的验证、清洁或消毒后。Recommended limits for microbiological monitoring of clean areas during operation.生产过程中微生物的监控标准推荐如下：Recommended limits for microbial contamination (a)建议的微生物污染限度Grade级别air sample空气取样CFU/m3settle plates沉降皿diam. 90mmcfu/4 hours(b)contact plates接触皿diam. 55mmcfu/plateglove pri
31、nt手套5 fingers5个手指cfu/gloveA 1 1 1 1B 10 5 5 5C 100 50 25 -D 200 100 50 -(a) These are average values.(a) 此为平均值(b) Individual settle plates may be exposed for less than 4 hours.(b) 单个沉降皿放置的时间可以少于4小时6. Appropriate alert and action limits should be set for the results of particulate and microbiological
32、 monitoring. If these limits are exceeded operating procedures should prescribe corrective action.对尘埃粒子和微生物的监控结果，要设置适当的警戒限度和措施限度。当超出这些限度时，操作规程应说明需要采取的措施。Isolator technology 隔离技术7. The utilisation of isolator technology to minimise human interventions in processing areas may result in a significant d
33、ecrease 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 for the respective zones
34、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.The transfer of materials into and out of the unit is one of
35、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.The air classification required for the background environment
36、 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.在生产区采用人员方面的隔离技术，在无菌产品的生产中，会显著降低周围环境微生物污染的风险。有很多隔离和传递设施可供选择，隔离和背景环境的设计，必须保证各区域相应的空气质量要求。隔离设施的建造材料，多少有些易于穿孔和泄漏。传递设施可以是单门、双门或结合无菌机制的全封闭系统。原材料的进出是污染的最大来源之一。尽管人们已经认
37、可，层流罩不可能存在于所有隔离设施的工作区内，但是，通常隔离区内是高风险操作的局部区域。背景环境的洁净级别，视隔离区的设计和应用而定。要控制无菌生产的背景环境，并且最低为D级。8. Isolators should be introduced only after appropriate validation. Validation should take into account all critical factors of isolator technology, for example the quality of the air inside and outside (backgro
38、und) the isolator, sanitisation of the isolator, the transfer process and isolator integrity.在经过适当的验证之后，隔离室才能使用。验证必须将隔离技术的所有关键因素考虑在内，如：隔离室的内外部空气质量、隔离室的消毒，传递过程和隔离室的完整性。9. Monitoring should be carried out routinely and should include frequent leak testing of the isolator and glove/sleeve system.必须进行常规
39、监控，包括隔离室和手套/袖系统的泄漏检查。Blow/fill/seal technology吹/灌/封技术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 used for aseptic pr
40、oduction 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/fill/seal equipmen
41、t 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 reproducibility of cleanin
42、g-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.吹/灌/封单元都安装在一台专用的设备上，连续运转完成从热塑材料吹成容器、然
43、后灌装、密封一次自动完成。吹/灌/封设备用于配备了有效的A 级空气流的无菌生产时，假如使用A/B级的工作服，设备可以安装在最低C级的环境里。静态时环境必须符合可行限度和非可行限度，动态时只要求符合可行限度。用于生产终端灭菌产品时，吹/灌/封设备必须安置在最低D 级环境中。对此设备，要特别注意如下几点：设备设计和验证，现场清洁消毒的验证和可重复性，设备安装环境，人员的培训和服装，设备关键区域的设备连接，包括灌装前的无菌装置。Terminally sterilised products 最终灭菌产品11. Preparation of components and most products sh
44、ould 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 actively supports microbial gro
45、wth 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 be carried out in at least a grade C environment.Where the produ
46、ct 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 zone with at least a grade C background. Pre
47、paration and filling of ointments, creams, suspensions and emulsions should generally be carried out in a grade C environment before terminal sterilisation.为了降低微生物和微粒污染的风险，原材料和大部分产品的处理，应在最低D级的环境里进行，适用于过滤和灭菌。如果产品的微生物污染的风险很高（如产品易生菌、或灭菌前要长时间存放，生产过程要在开口容器中进行），生产应在C 级环境进行。最终灭菌产品的灌装最低要在C级环境进行。如果产品受到环境污染的风
48、险高，例如：灌装速度慢，使用大口容器，或密封前要暴露几秒钟，灌装要在C级环境中的A级区域进行，背景环境最低为 C级。在灭菌前，软膏、霜剂、混悬剂、栓剂的制备和灌装应在C级环境进行。Aseptic preparation 无菌制备12. Components after washing should be handled in at least a grade D environment. Handling of sterile starting materials and components, unless subjected to sterilisation or filtration t
49、hrough 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 sterile filtered during the process should be done in a grade C environment; if not filtered, the preparation of materials and products should be done ina 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 grade B background.Prior to the completion of stoppering, transfer of partially closed containers, as used in freeze
