Annex 1 : Manufacture of Sterile Products无菌药品的生产Document map 目录8 Production and Specific Technologies生产与具体技术 (2)Terminally sterilized products 最终灭菌产品 (2)Aseptic preparation and processing 无菌准备和处理 (2)Finishing of sterile products无菌产品的最终处理 (6)Sterilization 灭菌 (8)Sterilization by heat 热力灭菌 (10)Moist heat sterilization 湿热灭菌 (11)Dry heat sterilization 干热灭菌 (13)Sterilization by radiation 辐射灭菌 (15)Sterilization with ethylene oxide环氧乙烷灭菌 (15)Filter sterilization of products which cannot be sterilized in their final container非最终灭菌药品的无菌过滤 (16)Form-Fill-Seal 成型-灌-封 (20)Blow-Fill-Seal 吹-灌-封 (20)Lyophilization 冻干 (22)Closed systems 密封系统 (23)Single use systems (SUS) 一次性使用系统 (24)9 Viable and non-viable environmental & process monitoring 活性和非活性环境和工艺监测 (26)General 综述 (26)Environmental monitoring 环境检测 (26)Environmental monitoring- non-viable particles 非活性粒子的环境检测 (27)Environmental and personnel monitoring-viable particles 环境和人员的监测—活粒子 (29)Aseptic process simulation (APS) (also known as media fill) 无菌模拟灌装 (31)10 Quality Control (QC) 质量控制 (38)Glossary 术语 (40)8 Production and Specific Technologies生产与具体技术Terminally sterilized products 最终灭菌产品8.1 Preparation of components and materials should be performed in at least a Grade D cleanroom in order to limit the risk of microbial, pyrogen and particulate contamination, so that the product is suitable for sterilization. Where the product is at a high or unusual risk of microbial contamination (e.g. the product actively supports microbial growth, the product must be held for long periods before filling or the product is not processed mostly in closed vessels), then preparation should be carried out in a Grade C environment. Preparation of ointments, creams, suspensions and emulsions should be carried out in a Grade C environment before terminal sterilization.部件和物料的准备工作至少应在D级洁净室中进行，以限制微生物、热原和微粒污染的风险，以便使产品适合灭菌。
如果产品存在微生物污染的高风险或异常风险（例如产品适宜微生物的生长，必须在灌装之前将产品放置很长时间，或者产品大多不在密闭容器中生产），应在C级环境中进行准备工作。
在最终灭菌之前，应在C级环境中制备软膏，霜剂，混悬剂和乳剂。
8.2 Primary packaging containers and components should be cleaned using validated processes to ensure that particulate, pyrogen and bioburden contamination is appropriately controlled.应使用经过验证的工艺清洁初级包装容器和组件，以确保适当地控制颗粒，热原和生物负载污染。
8.3 Filling of products for terminal sterilization should be carried out in at least a Grade C environment. 终端灭菌产品的填充应至少在C级环境中进行。
8.4 Where the product is at an unusual risk of contamination from the environment because, for example, the filling operation is slow, the containers are wide necked or are necessarily exposed for more than a few seconds before closing, then the product should be filled in a Grade A zone with at least a Grade C background.当产品存在异常的环境污染风险，如，灌装操作缓慢，广口容器或是必须要在密封前需暴露数秒钟，或是产品需要在最终灭菌前需要存放较长时间，则产品灌装需要C级背景下的A级环境8.5 Processing of the bulk solution should include a filtration step with a microorganism retaining filter, where possible, to reduce bioburden levels and particulates prior to filling into the final product containers and there should be a maximum permissible time between preparation and filling.散装溶液的处理应包括一个带有微生物保留过滤器的过滤步骤，以在灌装到最终产品容器中之前降低生物负荷水平和微粒，并且在制备和灌装之间应有最大允许的时间。
8.6 Examples of operations to be carried out in the various grades are given in Table 4.表4给出了各种等级的操作示例。
Table 4: Examples of operations and grades for terminally sterilized preparation and processingoperations表4：最终灭菌的制备和加工操作的操作和等级示例Aseptic preparation and processing 无菌准备和处理8.7 Aseptic preparation and processing is the handling of sterile product, containers and/or devices in a controlled environment in which the air supply, materials and personnel are regulated to prevent microbial, pyrogenic and particulate contamination.无菌准备和处理是在受控环境中对无菌产品、容器和/或设备进行处理，在该环境中对空气、物料和人员进行管理以防止微生物、热原和微粒污染。
8.8 The aseptic process should be clearly defined. The risks associated with the aseptic process, and anyassociated requirements, should be identified, assessed and appropriately controlle d. The site’s CCS should clearly define the acceptance criteria for these controls, requirements for monitoring and the review of their effectiveness. Methods and procedures to control these risks should be described and implemented. Accepted residual risks should be formally documented.应当明确定义无菌过程。
应当确定、评估和适当控制与无菌过程以及任何相关要求有关的风险。
现场的CCS应该明确定义这些控件的接受标准，监视要求和有效性审查。
应描述和实施控制这些风险的方法和程序。
可接受的残留风险应正式记录在案。
8.9 Precautions to minimize microbial, pyrogenic and particulate contamination should be taken, as per the site’s CCS, during the preparation of the aseptic environment, during all processing stages (including the stages before and after bulk product sterilization), and until the product is sealed in its final container. The presence of materials liable to generate particulates and fibres should be minimized in cleanrooms. 根据现场的CCS，在无菌环境的准备过程中，所有加工阶段（包括大宗产品灭菌前后的阶段）以及密封产品之前，应采取预防措施，以尽量减少在最终包装中微生物、热原和颗粒的污染。