EU-GMP 附录1 无菌药品 2020年02月20日修订草案 中英文对照版-2

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

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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 processing

operations

表4：最终灭菌的制备和加工操作的操作和等级示例

A 风险非常高的产品灌装 C 风险非常高的溶液配制。产品灌装 D 溶液配制和灌装前物料的准备 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 any

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associated requirements, should be identified, assessed and appropriately controlled. 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。在洁净室中，应尽量减少容易产生微粒和纤维的材料的存在。

8.10 Where possible, the use of equipment such as RABS, isolators or other systems, should be considered in order to reduce the need for critical interventions into the Grade A zone and to minimize the risk of contamination. Robotics and automation of processes can also be considered to eliminate direct human critical interventions (e.g. dry heat tunnel, automated lyophilizer loading, sterilization in place).

在可能的情况下，应考虑使用RABS、隔离器或其他系统等设备，以减少对A级区的干扰并降低污染风险。也可以考虑采用机器人技术和流程自动化来消除直接的人为干预（例如干热通道、自动冻干机装载、在线灭菌等）。

8.11 Examples of operations to be carried out in the various environmental grades are given in the Table 5.

表5载列了在不同环境等级下进行的作业的例子。

Table 5: Examples of operations and grades for aseptic preparation and processing operations

表5:无菌准备和加工操作的示例和等级

A Critical zone for 关键区域： -Aseptic assembly of filling equipment. 灌装设备的无菌组装。 -Connections made under aseptic conditions (where sterilized product contact surfaces are exposed) that are post the final sterilizing filter. These connections should be sterilized by steam-in-place whenever feasible. 在无菌条件下(产品接触表面已灭菌)进行连接，并在最后的无菌过滤器后进行连接。只要可行，这些连接应该用蒸汽在线灭菌。 -Aseptic compounding and mixing. 无菌配制和混合。 -Replenishment of sterile bulk product, containers and closures. 无菌产品、容器和密封的供应。 -Removal and cooling of unprotected (e.g. with no packaging) items from sterilizers. 将没有保护的(如无包装的)物品从灭菌器中取出并冷却。 -Staging and conveying of sterile primary packaging components. 无菌初级包装部件的准备和运输。 3

-Aseptic filling, sealing of containers such as ampoules, vial closure, transfer of open or partially stoppered vials. 无菌灌装，密封容器，如安瓿，小瓶封口，转移开口或半压盖的小瓶。 -Loading of a lyophilizer. 装入冻干机。 B Background support for the Grade A zone (when not in an isolator). A级区域的背景(当不在隔离器中时)。 -Transport, while protected from the surrounding environment, of equipment, components and ancillary items for introduction into the Grade A zone. 在不受周围环境影响的情况下，将设备、部件和附属物品运入A级区域。 C -Preparation of solutions to be filtered including weighing. 待过滤溶液的配制 D -Cleaning of equipment. 清洁设备。 -Handling of components, equipment and accessories after washing. 清洗后的零部件、设备和附件的处理。 -Assembly of cleaned components, equipment and accessories prior to sterilization. 在灭菌前组装清洁过的部件、设备和附件。 -Assembly of closed and sterilized SUS using intrinsic aseptic connectors. 使用内部无菌连接器组装封闭和灭菌的SUS（一次性系统）。 8.12 For sterile products that cannot be filtered, the following should be considered: 对于不能过滤的无菌产品，应考虑以下事项:

i.

All product and component contact equipment should be sterilized prior to use. 所有与产品和部件接触的设备在使用前都应灭菌。

ii. All raw materials should be sterilized and aseptically added or subsequently sterilized by

filtration.

所有的原料都要经过灭菌，无菌添加或除菌过滤。

iii. Bulk solutions should be sterilized by a validated process, e.g. by heat, chemical sterilization or

via sterile filtration.

散装溶液应通过经过验证的工艺进行灭菌，例如通过加热、化学灭菌或通过除菌过滤。

iv. All materials added to the sterile bulk product should be sterilized prior to addition.

添加到无菌散装产品中的所有物料应在添加前进行灭菌。

8.13 The unwrapping, assembly and preparation of sterilized equipment, components and ancillary items and the preparation and filling of the sterile product should be treated as an aseptic process and performed in a Grade A zone with a Grade B background. Where an isolator or RABS is used, the background should be in accordance with paragraphs 4.21 & 4.22.

灭菌设备、部件和附属物品的拆卸、装配和制备以及无菌产品的制备和灌装应作为无菌工艺处理，并在具有B级背景的A级区域内进行。当使用隔离器或RABS时，背景应符合4.21和4.22章节要求。

8.14 Preparation and filling of sterile products such as ointments, creams, suspensions and emulsions should be performed in a Grade A zone with a Grade B background when the product and components are exposed to the environment and the product is not subsequently filtered (via a sterilizing filter) or terminally sterilized. Where an isolator or RABS is used, the background should be in accordance with

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paragraphs 4.21 & 4.22.

当产品和成分暴露在环境中且随后未对产品进行过滤（通过除菌过滤器）或最终灭菌时，应在具有B级背景的A级区域进行无菌产品（如软膏、乳膏、悬浮液和乳剂）的制备和灌装。当使用隔离器或RABS时，背景应符合4.21和4.22章节的要求。

8.15 Aseptic connections should be performed in a Grade A zone with a Grade B background unless subsequently sterilized in place or conducted with validated intrinsic sterile connection devices that minimize any potential contamination from the immediate environment. Where an isolator or RABS is used, the background should be in accordance with paragraphs 4.21 & 4.22. Aseptic connections should be appropriately assessed and their effectiveness verified. For requirements regarding intrinsic sterile connection devices refer to paragraph 8.120.

无菌连接应在具有B级背景的A级区域中进行，除非随后进行在线灭菌或使用经过验证的固有无菌连接设备进行，以最大程度地减少对周围环境的潜在污染。如果使用隔离器或RABS，则背景应符合第4.21和4.22章节的规定。应当适当评估无菌连接并验证其有效性。有关固有无菌连接设备的要求，请参见第8.120章节。

8.16 Aseptic manipulations (including non-intrinsic aseptic connections) should be minimized through the use of engineering design solutions such as preassembled and sterilized equipment. Whenever feasible, product contact piping and equipment should be pre-assembled, and sterilized in place.

无菌操作(包括非固有的无菌连接)应尽量减少使用工程设计解决方案，如预先组装和灭菌设备。在可行的情况下，产品接触管道和设备应预先组装，并在线灭菌。

8.17 There should be an authorized list of allowed interventions, both inherent and corrective, that may occur during production. The procedures listing the types of inherent and corrective interventions, and how to perform them, should be updated, as necessary to ensure consistency with the actual manufacturing activities. In the event that an unauthorized intervention is required, details of the intervention conducted should be recorded and fully assessed under the manufacturer's PQS.

应该有一份在生产过程中可能发生的，允许的干预措施的授权清单，包括固有干预措施和纠正措施。列出固有和纠正性干预的类型以及如何执行的程序应根据需要进行更新，以确保与实际生产活动的一致性。如果需要未经授权的干预，则应记录进行的干预的详细信息，并根据制造商的PQS进行全面评估。

8.18 The duration of each aspect of aseptic preparation and processing should be limited to a defined and validated maximum time, including:

无菌准备和加工的每个方面的持续时间应限制在规定和验证的最长时间内，包括:

i.

The holding time between equipment, component, and container cleaning, drying and sterilization.

设备、部件和容器清洗、干燥和灭菌之间的保持时间。

ii. The holding time for sterilized equipment, components, and containers before use and during

filling/assembly.

灭菌设备、部件和容器在使用前和灌装/装配期间的保持时间。

iii. The holding time for a decontaminated environment, such as the RABS and isolator before and

during filling /assembly.

在灌装/组装之前和过程中，用于净化环境（如RABS和隔离器）的保持时间。

iv. The time between the start of the preparation of a product and its sterilization or filtration through

a microorganism-retaining filter (if applicable), through to the end of the aseptic filling process. There should be a maximum permissible time for each product that takes into account its composition and the prescribed method of storage.

从产品开始制备到通过除菌过滤器（如果适用）进行除菌或过滤直到无菌灌装过程结束之间的时间。考虑到产品的成分和规定的存储方法，每种产品应有最大允许时间。

v. The holding time for sterilized product prior to filling.

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