WHO961文件-附件6无菌药品良好生产规范(中英文).doc

LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO.,LTD 丽珠集团福州福兴医药有限公司丽珠集团福州福兴医药有限公司 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO., LTD. ADD: Jiangyin Industrial Zone, Fuqing, Fujian, 350309, P. R. China TEL:+86-591-85966928; +86-591-85966932; FAX:+86-591-85966925 E-MAIL:xmdongwei; fuxingra; regulation WEBSITE: Page 1 of 45 World Health Organization WHO Technical Report Series, No. 961, 2011 WHO 技术报告丛书 961，2011 Annex 6 WHO good manufacturing practices for sterile pharmaceutical products 附件附件 6 无菌无菌药药品良好生品良好生产规产规范范 Introduction Following implementation of these WHO good manufacturing practices (GMP) guidelines (1) within the context of the WHO Prequalifi cation of Medicines Programme, clarifying, editorial modifi cations 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 Committee on Specifi cations for Pharmaceutical Preparations. 引言 以下 WHO 药品质量管理规范（GMP）（1）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。 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO.,LTD 丽珠集团福州福兴医药有限公司丽珠集团福州福兴医药有限公司 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO., LTD. ADD: Jiangyin Industrial Zone, Fuqing, Fujian, 350309, P. R. China TEL:+86-591-85966928; +86-591-85966932; FAX:+86-591-85966925 E-MAIL:xmdongwei; fuxingra; regulation WEBSITE: Page 2 of 45 WHO good manufacturing practices for sterile pharmaceutical products WHO 无菌无菌药药品良好生品良好生产规产规范范 1. GENERAL CONSIDERATIONS.3 1 总则总则.3 2. QUALITY CONTROL.3 2 质质量控制量控制.3 3. SANITATION.4 3 卫卫生生.4 4. MANUFACTURE OF STERILE PREPARATIONS.5 4 无菌无菌产产品的生品的生产产.5 5. STERILIZATION.19 5.灭灭菌菌.19 6. TERMINAL STERILIZATION.20 6. 最最终灭终灭菌菌.20 7. ASEPTIC PROCESSING AND STERILIZATION BY fi LTRATION.24 7. 无菌操作和无菌操作和过滤灭过滤灭菌菌.24 8. ISOLATOR TECHNOLOGY.26 8. 隔离技隔离技术术.26 9. BLOW/fi LL/SEAL TECHNOLOGY.27 9. 吹吹/灌灌/封技封技术术.27 10. PERSONNEL.28 10. 人人员员.28 11. PREMISES.30 11.厂房厂房.30 12. EQUIPMENT .33 12. 设备设备.33 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO.,LTD 丽珠集团福州福兴医药有限公司丽珠集团福州福兴医药有限公司 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO., LTD. ADD: Jiangyin Industrial Zone, Fuqing, Fujian, 350309, P. R. China TEL:+86-591-85966928; +86-591-85966932; FAX:+86-591-85966925 E-MAIL:xmdongwei; fuxingra; regulation WEBSITE: Page 3 of 45 13. FINISHING OF STERILE PRODUCTS.34 13. 无菌无菌产产品完成品完成.34 1. General considerations 1 总则总则 1.1 The production of sterile preparations 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 fi lters of the required effi ciency. 1.1 无菌产品的生产应在洁净区进行，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, fi lling and sterilization should be carried out in separate areas within the clean area. These areas are classifi ed into 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: fi 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 control 2 质质量控制量控制 2.1 The sterility test applied to the fi 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. LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO.,LTD 丽珠集团福州福兴医药有限公司丽珠集团福州福兴医药有限公司 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO., LTD. ADD: Jiangyin Industrial Zone, Fuqing, Fujian, 350309, P. R. China TEL:+86-591-85966928; +86-591-85966932; FAX:+86-591-85966925 E-MAIL:xmdongwei; fuxingra; regulation WEBSITE: Page 4 of 45 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 fi lled aseptically, samples should include containers fi lled at the beginning and end of the batch and after any signifi cant interruption of work; for products that have been heat sterilized in their fi 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 fi nished product is assured by validation of the sterilization cycle in the case of terminally sterilized products, and by “media simulation” or “media fi ll” runs for aseptically processed 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 validation 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，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 fi LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO.,LTD 丽珠集团福州福兴医药有限公司丽珠集团福州福兴医药有限公司 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO., LTD. ADD: Jiangyin Industrial Zone, Fuqing, Fujian, 350309, P. R. China TEL:+86-591-85966928; +86-591-85966932; FAX:+86-591-85966925 E-MAIL:xmdongwei; fuxingra; regulation WEBSITE: Page 5 of 45 nished products should be monitored for endotoxins, using an established pharmacopoeial 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 fi nished product. When a sample fails a test, the cause of the failure should be investigated and necessary action should be taken. Alternative methods to those in the pharmacopoeias may be used if they are validated, justifi ed 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、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 assessment 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. Sanitation 3 卫卫生生 3.1 The sanitation of clean areas is particularly important. They should be cleaned frequently and thoroughly 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 different 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， LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO.,LTD 丽珠集团福州福兴医药有限公司丽珠集团福州福兴医药有限公司 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO., LTD. ADD: Jiangyin Industrial Zone, Fuqing, Fujian, 350309, P. R. China TEL:+86-591-85966928; +86-591-85966932; FAX:+86-591-85966925 E-MAIL:xmdongwei; fuxingra; regulation WEBSITE: Page 6 of 45 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 defi ned periods unless sterilized. Disinfectants and detergents used in Grade A and B areas should be sterile before use. 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. 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 preparations 4 无菌无菌产产品的生品的生产产 4.1 Clean areas for the manufacture of sterile products are classifi ed according 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 environmental 4.1 生产无菌产品的洁净区根据所需环境特点划分。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 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO.,LTD 丽珠集团福州福兴医药有限公司丽珠集团福州福兴医药有限公司 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO., LTD. ADD: Jiangyin Industrial Zone, Fuqing, Fujian, 350309, P. R. China TEL:+86-591-85966928; +86-591-85966932; FAX:+86-591-85966925 E-MAIL:xmdongwei; fuxingra; regulation WEBSITE: Page 7 of 45 of air, surfaces, etc., is not given in these guidelines. ISO 14644-1 (2) should be used for classifi cation of cleanliness according to concentration of airborne particles (determination of number of sample locations, calculation of sample size and evaluation of classifi cation from the data obtained). Table 1 should also be used to defi ne 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表面等的微生物和微粒洁净度的详细检测方法。 依据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 14644-1（2）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. fi lling and making aseptic connections. Normally such conditions are achieved by using a unidirectional airfl ow workstation. Unidirectional airfl ow systems should provide a homogeneous air speed of 0.360.54 m/s (guidance value) at a defi ned test position 1530 cm below the terminal fi lter or air distributor system. The velocity at working level should not be less than 0.36 m/s. The uniformity and effectiveness of the unidirectional airfl ow should be demonstrated by undertaking airfl ow visualization tests. Grade B: In aseptic preparation and fi lling, this is the background environment for the Grade A zone. Grades C and D: Clean areas for carrying 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 airfl ow and lower velocities may be used in closed isolators 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。 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO.,LTD 丽珠集团福州福兴医药有限公司丽珠集团福州福兴医药有限公司 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO., LTD. ADD: Jiangyin Industrial Zone, Fuqing, Fujian, 350309, P. R. China TEL:+86-591-85966928; +86-591-85966932; FAX:+86-591-85966925 E-MAIL:xmdongwei; fuxingra; regulation WEBSITE: Page 8 of 45 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 为了达到 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-effi ciency particulate air (HEPA) fi lters should be subjected to an installed fi lter leakage 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 fi lter media, fi lter frame and fi lter seal are free from leaks. The aerosol selected for HEPA leak testing should not support microbial growth and should be composed of a suffi cient number or mass of particles. HEPA fi lter patching is allowed at the fi lter manufacturer and in situ operation provided that the patch sizes and procedures follow the recommendations of ISO 1822-4 (4). 4.5 高效空气过滤器（HEPA）应根据 ISO14644-3（3）进行过滤器试漏检测，建议间隔为 6 个月， 但不超过 12 个月。进行常规试漏试验是为了确保过滤介质、滤框和过滤器密闭性无泄漏。用 于试漏试验的气溶胶应不支持微生物的生长并应由足够数量的质量微粒组成。HEPA 过滤器 可以在生产厂家和原位进行修补，修补尺寸和步骤应符合 ISO1822-4（4）。 Clean room and clean-air device classifi cation 洁净洁净室和空气室和空气净净化化设备设备分分类类 4.6 Clean rooms and clean-air devices should be classifi ed in accordance with ISO 14644 (23, 5 7). 4.6 洁净室和空气净化设备分类应符合 ISO14644（2-3，5-7） 4.6.1 Classifi cation should be clearly differentiated from operational process environmental monitoring. The maximum permitted airborne particle concentration for each grade is given in 4.6.1 分级应与操作过程中的环境监测清楚区分。表 1 中给出了每个等级所允许的最大悬浮 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO.,LTD 丽珠集团福州福兴医药有限公司丽珠集团福州福兴医药有限公司 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO., LTD. ADD: Jiangyin Industrial Zone, Fuqing, Fujian, 350309, P. R. China TEL:+86-591-85966928; +86-591-85966932; FAX:+86-591-85966925 E-MAIL:xmdongwei; fuxingra; regulation WEBSITE: Page 9 of 45 粒子浓度。 Table 1 Maximum permitted airborne particle concentrat a. The “at rest” state is the condition where the installation is complete with equipment installed and operating in a manner agreed upon by the customer and supplier, but with no personnel present. b The “in operation” state is the condition where the installation is functioning in the defi ned operating mode and the specifi ed number of personnel is present. The areas and their associated environmental control systems should be designed to achieve both the “at rest” and “in operation” states. 表 1 表表 1 允允许许的最大的最大悬悬浮粒子浮粒子浓浓度度 悬浮粒子最大允许数/m3（大于或等于表中的大小） 静态 a 动态 b 等级 0.5m5.0m0.5m5.0m A3,520203,52020 B3,52029352,0002,900 C352,0002,9003,520,00029,000 D3,520,00029,000 未规定未规定 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO.,LTD 丽珠集团福州福兴医药有限公司丽珠集团福州福兴医药有限公司 LIVZON GROUP FUZHOU FUXING PHARMACEUTICAL CO., LTD. ADD: Jiangyin Industrial Zone, Fuqing, Fujian, 350309, P. R. China TEL:+86-591-85966928; +86-5