1、WHO961文件附件6无菌药品良好生产规范中英文 World Health OrganizationWHO Technical Report Series, No. 961, 2011WHO技术报告丛书961，2011Annex 6WHO good manufacturing practices for sterile pharmaceutical products附件6无菌药品良好生产标准IntroductionFollowing implementation of these WHO good manufacturing practices (GMP) guidelines (1) wit
2、hin the context of the WHO Prequalication of Medicines Programme, clarifying, editorial modications have been proposed. These changes were adopted for maintenance purposes. In order to ease reading the full guideline has been reproduced again as an Annex to the current report of the WHO Expert Commi
3、ttee on Specications for Pharmaceutical Preparations.引言以下WHO药品质量管理标准GMP1指南在WHO预审药物设计、阐明、编辑修改中已经被提出。这些变更的应用以维护的目的。为了便于阅读，整篇指南已被重新编制并作为WHO药品标准专家委员会报告的一个附件。WHO good manufacturing practices for sterile pharmaceutical productsWHO无菌药品良好生产标准1. General considerations1 总则1.1 The production of sterile prepara
4、tions 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 standard of cleanliness and supplied with air that has passed through lters of the required efciency. 1.1 无菌产品的生产
5、应在洁净区进行，人员和/或设备和物料进入洁净区应通过气闸室进入。洁净区应保持适当的洁净度标准并提供经过有效的过滤的空气。1.2 The various operations of component preparation (such as those involving containers and closures), product preparation, lling and sterilization should be carried out in separate areas within the clean area. These areas are classied into
6、 four grades (see section 4).1.2 组件的准备如相关的容器和密闭包装，产品的制备、灌装和灭菌操作应在洁净区内分区域进行。这些洁净区分为四个等级见第4节。1.3 Manufacturing operations are divided here into two categories:rst, those where the product is terminally sterilized; and second, those which are conducted aseptically at some or all stages.1.3 生产操作在此可以划分为两
7、类：第一，仅在最后阶段灭菌的产品；第二，部分或全部工序采用无菌生产工艺的产品。2. Quality control2 质量控制2.1 The sterility test applied to the nished product should only be regarded as the last in a series of control measures by which sterility is assured. The test should be validated for the product(s) concerned.2.1成品的无菌检测仅作为一系列确保无菌度的控制措施的
8、最后一步。相关产品的无菌度检测应进行验证。2.2 Samples taken for sterility testing should be representative of the whole of the batch but should, in particular, include samples taken from parts of the batch considered to be most at risk of contamination, for example: for products that have been lled aseptically, samples
9、should include containers lled at the beginning and end of the batch and after any signicant interruption of work; for products that have been heat sterilized in their nal containers, consideration should be given to taking samples from that part of the load that is potentially the coolest.2.2 无菌度检测
10、取样的样品应能代表整个批次，并且应包括最容易受到污染风险的部位的样品。无菌灌装的产品，取样应包括灌装前、灌装后和有明显中断的时候。仅在在最后步骤进行高温灭菌的产品，应考虑从最凉处取样。2.3 The sterility of the nished product is assured by validation of the sterilization cycle in the case of terminally sterilized products, and by “media simulation” or “media ll” runs for aseptically processe
11、d products. Batch-processing records and, in the case of aseptic processing, environmental quality records, should be examined in conjunction with the results of the sterility tests. The sterility test procedure should be validated for a given product. Pharmacopoeial methods should be used for the v
12、alidation and performance of the sterility test. In those cases where parametric release has been authorized in place of sterility testing special attention should be paid to the validation and the monitoring of the entire manufacturing process.2.3 最终产品的无菌度检测，如果是仅在最后步骤灭菌的产品，应确保整个灭菌周期的验证，如果是无菌工艺生产的产品
13、，应确保进行了 “培养基模拟”和“培养基灌装”。批生产记录和环境质量记录无菌生产过程中的应结合无菌度检测结果进行检查。对给出的产品应进行无菌度检测验证。验证和无菌度检测应使用药典的方法。如果授权使用参数放行取代无菌度检测，应注意特别关注验证和整个生产过程的监测。2.4 For injectable products the water for injection and the intermediate, if appropriate, and nished products should be monitored for endotoxins, using an established ph
14、armacopoeial method that has been validated for each type of product. For large-volume infusion solutions, such monitoring of water or intermediates should always be done, in addition to any tests required by an approved monograph for the nished product. When a sample fails a test, the cause of the
15、failure should be investigated and necessary action should be taken. Alternative methods to those in the pharmacopoeias may be used if they are validated, justied and authorized.2.4 关于注射产品，对注射用水和中间体，如果适用，还有成品，应采用已建立的经过验证药典方法进行内毒素监测。对于大容量输液剂，除了符合专论要求的成品检测外，还应对水和中间体进行监测。当样品检测不合格时，应进行调查并采取必要的措施。也可采用经验证
16、、合理并授权的方法取代药典中的方法。2.5 The use of rapid microbiological methods to replace the traditional microbiological methods, and to obtain earlier results on the microbiological quality of, for example, water, the environment or bioburden, could be considered if appropriately validated and if a comparative as
17、sessment of the proposed rapid method is performed against the pharmacopoeial method.2.5 使用快速微生物学方法取代传统的微生物学方法，如果微生物质量可靠，并可早点获得检测结果，如：水、环境或生物负荷，是可以考虑的，但是提议的快速方法应进行了验证，并与药典方法进行比对评估。3. Sanitation3卫生3.1 The sanitation of clean areas is particularly important. They should be cleaned frequently and thoro
18、ughly in accordance with an approved written programme. Where disinfectants are used, more than one type should be employed. Monitoring should be regularly undertaken to detect contamination or the presence of an organism against which the cleaning procedure is ineffective. Interactions between diff
19、erent cleaning materials should be validated. Appropriate cleaning validation should be carried out to ensure disinfectant residuals can be detected and are removed by the cleaning process.3.1 洁净区的环境卫生极为重要。应根据批准的书面规程定期并彻底地清洁。使用清洁剂时，应不止一种。应定期进行监测以检测污染或清洁程序对之无效的生物体。应确定不同清洁材料之间的相互作用。应进行适当的清洁验证，确保能检测到清洁
20、剂残留并能通过清洁程序去除。3.2 Disinfectants and detergents should be monitored for microbial contamination; dilutions should be kept in previously cleaned containers and should only be stored for dened periods unless sterilized. Disinfectants and detergents used in Grade A and B areas should be sterile before u
21、se.3.2 消毒剂和清洁剂应进行微生物污染监测；稀释剂应保存在预先清洁的容器中并按规定的期限储存，除非被消毒灭菌。在A级和B级洁净区使用的消毒剂和清洁剂应在使用前应进行灭菌。3.3 A disinfectant programme should also include a sporicidal agent since many common disinfectants are ineffective against spores. The effectiveness of cleaning and disinfectant procedures should be demonstrated
22、.3.3 消毒程序还应包括杀孢子剂，因为通常的消毒剂对孢子是无效的。应证明清洁和消毒程序是有效的。3.4 Fumigation of clean areas may be useful for reducing microbial contamination in inaccessible places.3.4 洁净区熏蒸法对于减少死角的微生物污染有效。4. Manufacture of sterile preparations4 无菌产品的生产4.1 Clean areas for the manufacture of sterile products are classied accord
23、ing to the required characteristics of the environment. Each cleanliness in the operational state to minimize the risks of particulate or microbial contamination of the product or materials being handled. manufacturing operation requires an appropriate level of environmental4.1 生产无菌产品的洁净区根据所需环境特点划分。
24、操作阶段每个生产操作都需要相适应的洁净水平以减少产品或物料处理时微粒或微生物污染的风险。4.2 Detailed information on methods for determining the microbiological and particulate cleanliness of air, surfaces, etc., is not given in these guidelines.ISO 14644-1 (2) should be used for classication of cleanliness according to concentration of airbor
25、ne particles (determination of number of sample locations, calculation of sample size and evaluation of classication from the data obtained). Table 1 should also be used to dene the levels to be used as the basis for monitoring clean areas for airborne particles.4.2 本指南没有给出空气或外表等的微生物和微粒洁净度的详细检测方法。依据
26、空气中悬浮粒子的浓度确定样品监测位置数目、计算取样量和根据活的的数据进行几倍划分评估，参考ISO 14644-12划分洁净等级。表1也应用于定义监测洁净区空气中悬浮粒子的依据。4.3 For the manufacture of sterile pharmaceutical preparations, four grades of clean areas are distinguished as follows: Grade A: The local zone for high-risk operations, e.g. lling and making aseptic connections
27、. Normally such conditions are achieved by using a unidirectional airow workstation. Unidirectional airow systems should provide a homogeneous air speed of 0.360.54 m/s (guidance value) at a dened test position 1530 cm below the terminal lter or air distributor system. The velocity at working level
28、should not be less than 0.36 m/s. The uniformity and effectiveness of the unidirectional airow should be demonstrated by undertaking airow visualization tests. Grade B: In aseptic preparation and lling, this is the background environment for the Grade A zone. Grades C and D: Clean areas for carrying
29、 out less critical stages in the manufacture of sterile products or carrying out activities during which the product is not directly exposed (i.e. aseptic connection with aseptic connectors and operations in a closed system).A unidirectional airow and lower velocities may be used in closed isolators
30、 and glove boxes.4.3 对无菌产品的生产，洁净区可以分为以下四个等级：A级：高风险操作的局部区域，如：灌装和无菌操作连接。通常这些情况是通过单向气流工作站实现的。单向气流系统应在规定的终端过滤器或空气分配器系统下方15-30cm的位置提供一个速度为0.360.54m/s指导值的均匀气流。工作时的速度应不小于0.36m/s。单向气流的均一性和有效性应在气流可视化试验下证明。B级：在无菌配制和灌装中作为A级区域的背景环境。C级和D级：较少的关键阶段或生产中产品没有直接暴露的生产活动如：无菌连接器的无菌连接和密闭系统的操作在此洁净区进行。封闭的隔离器或手套箱可采用单向气流和较低的速
31、度。4.4 In order to reach the B, C and D air grades the number of air changes should be appropriate for the size of the room and the equipment and personnel present in it.4.4 为了到达B、C和D的空气等级，换气次数应符合房间大小和里面的设备和人员要求。4.5 High-efciency particulate air (HEPA) lters should be subjected to an installed lter l
32、eakage test in accordance with ISO 14644-3 (3) at a recommended interval of every 6 months, but not exceeding 12 months. The purpose of performing regular leak tests is to ensure the lter media, lter frame and lter seal are free from leaks. The aerosol selected for HEPA leak testing should not support microbial growth and should be composed of a sufcient number or mass of particles. HEPA lter patching is allowed at the lter manufacturer and in situ operation provided t
