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
挂包钩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)
汽车钻机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 processing
operations
表4：最终灭菌的制备和加⼯操作的操作和等级⽰例
锌合金压铸工艺
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
associated 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。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。
鱼笼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
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 an
d 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
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.
产品评价⽆菌操作(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.
灌装前灭菌产品的保持时间。
vi.The aseptic processing time.
⽆菌处理时间。
vii.The filling time.
灌装时间。
viii.The maximum exposure time of sterilized containers and closures in the critical processing zone (including filling) prior to closure.
灭菌容器和封闭容器在关键加⼯区域(包括灌装)密封前的最⼤暴露时间。
8.19 Aseptic operations (including APS) should be observed at a regular basis by personnel with specific expertise in aseptic processing to verify the correct performance of operations and address inappropriate practices if detected.
具有⽆菌处理专业知识的⼈员应定期观察⽆菌操作（包括APS），以验证操作的正确性能并在发现错误后解决不适当的做法。
压力维持阀
Finishing of sterile products⽆菌产品的最终处理
8.20 Open primary packaging containers (including partially stoppered vials or prefilled syringes) should be maintained under Grade A conditions with Grade B background (e.g. Barrier Technology), or under Grade A conditions with physical segregation from operators (e.g. UDAF carts) until the stopper is fully inserted.
打开的初级包装容器（包括部分加塞的⼩瓶或预充式注射器）应在具有B级背景的A级条件下（例如屏障技术），或在与操作员物理隔离的A级条件下（例如UDAF⼿推车）保存，直到塞⼦完全插⼊。
8.21 Containers should be closed by appropriately validated methods. Containers closed by fusion, e.g. Blow-fill-seal (BFS), Form-Fill-Seal (FFS), Small and Large Volume Parenteral (SVP & LVP) bag
s, glass or plastic ampoules, should be subject to 100% integrity testing. Samples of containers closed by other methods should be taken and checked for integrity using validated methods. The frequency of testing should be based on the knowledge and experience of the container and closure systems being used.
A scientifically valid sampling plan should be utilized. The sample size should be based on information such as supplier approval, packaging component specifications and process knowledge. It should be noted that visual inspection alone is not considered as an acceptable integrity test method.
豫公网安备41160202000603
站长QQ:729038198
关于我们
投诉建议