Annex 1 : Manufacture of Sterile Products

EU GMP 附录1 无菌产品生产-2020版

1 Scope

范围

The manufacture of sterile products covers a wide range of sterile product types (active substance, sterile excipient, primary packaging material and finished dosage form), packed sizes (single unit to multiple units), processes (from highly automated systems to manual processes) and technologies (e.g. biotechnology, classical small molecule manufacturing and closed systems). This Annex provides general guidance that should be used for the manufacture of all sterile products using the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and pyrogen contamination is prevented in the final product.

无菌产品的生产涵盖了广泛的无菌药品类型（活性成分，无菌辅料，内包材和制剂），包装量（从单个单位到多个单位），工艺（从高度自动化系统到人工操作）和技术（例如生物技术，常规小分子生产以及密闭系统）。本附录运用质量风险管理(QMR)原则为所有无菌产品提供总体指导原则，用以避免最终产品中来自微生物，颗粒以及热原方面的污染。

QRM applies to this document in its entirety and will not be referred to in specific paragraphs. Where specific limits or frequencies are written, these should be considered as a minimum requirement. They are stated due to regulatory historical experience of issues that have previously been identified and have impacted the safety of patients.

本文件的全部内容均适用QRM（质量风险管理），而不是某个章节。当章节中规定特定限度或者频次时应视为最低要求，这些规定通常基于所出现问题的监管历史经验。曾经识别出这些问题，它们对病患安全造成过影响。

The intent of the Annex is to provide guidance for the manufacture of sterile products. However, some of the principles and guidance, such as contamination control strategy, design of premises, cleanroom classification, qualification, monitoring and personnel gowning, may be used to support the manufacture of other products that are not intended to be sterile such as certain liquids, creams, ointments and low bioburden biological intermediates but where the control and reduction of microbial, particulate and pyrogen contamination is considered important. Where a manufacturer elects to apply guidance herein to non-sterile products, the manufacturer should clearly document which principles have been applied and acknowledge that compliance with those principles should be demonstrated.

本附录旨在为无菌产品的生产提供指导，然而有些原则和指导，例如污染控制策略，厂房设施设计，洁净区级别，确认，监测和人员更衣，可用于支持其他非无菌产品的生产（例如特殊液体制剂，膏剂，软膏剂以及低微生物负载的生物制品中间体）,特别适应于控制和降低微生物，颗粒和热原污染非常重要的情况。当生产厂家选择将此指南应用于非无菌产品时应清晰记录所应用的原则以及这些原则的符合情况。

2 Principle

原则

2.1 The manufacture of sterile products is subject to special requirements in order to minimize risks of microbial, particulate and pyrogen contamination. The following key areas should be considered:

无菌产品的生产应符合特定要求，以减少来自微生物, 颗粒及热原方面的污染风险, 应考虑到以下关键区域：

Facility, equipment and process design should be optimized, qualified and validated according to the relevant sections of the Good Manufacturing Practices (GMP) guide. The use of appropriate technologies (e.g. Restricted Access Barriers Systems (RABS), isolators, robotic systems, rapid microbial testing and monitoring systems) should be considered to increase the protection of the product from potential extraneous sources of particulate and microbial contamination such as personnel, materials and the surrounding environment, and assist in the rapid detection of potential contaminants in the environment and product.

厂房设施，设备及工艺设计应根据良好药品生产管理规范（GMP）相关附录中的要求进行优化，确认和验证。应考虑采用适当技术手段（例如，限制进入屏障系统（RABS），隔离器，机器人系统，快速微生物测试和监测系统）以加强从潜在外来微粒和微生物污染（例如人员，物料及周边环境）中对产品进行保护，并实现对环境和产品中的潜在污染的快速识别。

Personnel should have adequate qualifications and experience, training and attitude with a specific focus on the principles involved in the protection of sterile product during the manufacturing, packaging and distribution processes.

人员应有充分资质，经验，培训和态度，能够重视用于在生产、包装及发运过程中保护无菌产品的原则。

Processes and monitoring systems for sterile product manufacture should be designed, commissioned, qualified and monitored by personnel with appropriate process, engineering and microbiological knowledge.

无菌产品的生产工艺及监测系统应由具有合适的工艺、工程以及微生物知识的人员进行设计、调试、确认和监测。

2.2 Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Where alternative approaches are used, these should be supported by appropriate rationales and risk assessment and should meet the intent of this Annex.

工艺、设备、厂房设施及生产活动应基于 QRM 原则进行管理，该原则提出了一个前瞻性的方法用于识别、科学评估及控制对质量的潜在风险。使用替代方法应经恰当依据和风险评估支持，并符合本附录目的。

QRM priorities should include good design of the facility, equipment and process in the first instance, then implementation of well-designed procedures, with monitoring systems as the final element that demonstrate that the design and procedures have been correctly implemented and continue to perform in line with expectations. Exclusively monitoring or testing does not give assurance of sterility.QRM applies to this document in its entirety and will not be referred to in specific paragraphs. Where specific limits or frequencies are written, these should be considered as a minimum requirement. They are stated due to regulatory historical experience of issues that have previously been identified and have impacted the safety of patients.

本文件的全部内容均适用QRM（质量风险管理），而不是某个章节。当章节中规定特定限度或者频次时应视为最低要求，这些规定通常基于所出现问题的监管历史经验。曾经识别出这些问题，它们对病患安全造成过影响。

The intent of the Annex is to provide guidance for the manufacture of sterile products. However, some of the principles and guidance, such as contamination control strategy, design of premises, cleanroom classification, qualification, monitoring and personnel gowning, may be used to support the manufacture of other products that are not intended to be sterile such as certain liquids, creams, ointments and low bioburden biological intermediates but where the control and reduction of microbial, particulate and pyrogen contamination is considered important. Where a manufacturer elects to apply guidance herein to non-sterile products, the manufacturer should clearly document which principles have been applied and acknowledge that compliance with those principles should be demonstrated.

本附录旨在为无菌产品的生产提供指导，然而有些原则和指导，例如污染控制策略，厂房设施设计，洁净区级别，确认，监测和人员更衣，可用于支持其他非无菌产品的生产（例如特殊液体制剂，膏剂，软膏剂以及低微生物负载的生物制品中间体）,特别适应于控制和降低微生物，颗粒和热原污染非常重要的情况。当生产厂家选择将此指南应用于非无菌产品时应清晰记录所应用的原则以及这些原则的符合情况。

2 Principle

原则

2.1 The manufacture of sterile products is subject to special requirements in order to minimize risks of microbial, particulate and pyrogen contamination. The following key areas should be considered:

无菌产品的生产应符合特定要求，以减少来自微生物, 颗粒及热原方面的污染风险, 应考虑到以下关键区域：

Facility, equipment and process design should be optimized, qualified and validated according to the relevant sections of the Good Manufacturing Practices (GMP) guide. The use of appropriate technologies (e.g. Restricted Access Barriers Systems (RABS), isolators, robotic systems, rapid microbial testing and monitoring systems) should be considered to increase the protection of the product from potential extraneous sources of particulate and microbial contamination such as personnel, materials and the surrounding environment, and assist in the rapid detection of potential contaminants in the environment and product.

厂房设施，设备及工艺设计应根据良好药品生产管理规范（GMP）相关附录中的要求进行优化，确认和验证。应考虑采用适当技术手段（例如，限制进入屏障系统（RABS），隔离器，机器人系统，快速微生物测试和监测系统）以加强从潜在外来微粒和微生物污染（例如人员，物料及周边环境）中对产品进行保护，并实现对环境和产品中的潜在污染的快速识别。

Personnel should have adequate qualifications and experience, training and attitude with a specific focus on the principles involved in the protection of sterile product during the manufacturing, packaging and distribution processes.

人员应有充分资质，经验，培训和态度，能够重视用于在生产、包装及发运过程中保护无菌产品的原则。

Processes and monitoring systems for sterile product manufacture should be designed, commissioned, qualified and monitored by personnel with appropriate process, engineering and microbiological knowledge.

无菌产品的生产工艺及监测系统应由具有合适的工艺、工程以及微生物知识的人员进行设计、调试、确认和监测。

2.2 Processes, equipment, facilities and manufacturing activities should be managed in accordance with QRM principles to provide a proactive means of identifying, scientifically evaluating and controlling potential risks to quality. Where alternative approaches are used, these should be supported by appropriate rationales and risk assessment and should meet the intent of this Annex.

工艺、设备、厂房设施及生产活动应基于 QRM 原则进行管理，该原则提出了一个前瞻性的方法用于识别、科学评估及控制对质量的潜在风险。使用替代方法应经恰当依据和风险评估支持，并符合本附录目的。

QRM priorities should include good design of the facility, equipment and process in the first instance, then implementation of well-designed procedures, with monitoring systems as the final element that demonstrate that the design and procedures have been correctly implemented and continue to perform in line with expectations. Exclusively monitoring or testing does not give assurance of sterility.

QRM 优先事项首先是厂房设施，设备和工艺设计的优良设计，其次是对良好设计规程的实施，最后以监测系统证明设计和规程的正确实施以及按照预期继续运行。仅监测或测试不能确保无菌性。

2.3 Quality Assurance is particularly important, and manufacture of sterile products must strictly follow carefully established and validated methods of manufacture and control. A Contamination Control Strategy (CCS) should be implemented across the facility in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organisational) and monitoring measures employed to manage risks associated with contamination. The CCS should be actively updated and should drive continuous improvement of the manufacturing and control methods.

质量保证尤为重要，无菌产品的生产必须严格遵循精心建立，并经过验证的生产和控制方法。污染控制策略（CCS）应在整个厂房设施内得到实施以确定出所有关键点并评估用于管理污染相关风险的所有控制方式（设计，规程上的，技术和组织层面）和监测措施的有效性。应积极更新 CCS，CCS 应促使生产和控制方法的持续改进。

2.4 Contamination control and steps taken to minimize the risk of contamination from microbial and particulate sources are a series of successively linked events and measures. These are typically assessed, controlled and monitored individually but their collective effectiveness should be considered altogether.

用于降低来自微生物和颗粒来源的污染风险的控制和步骤是指一系列持续关联事件及措施，通常应分别对这些控制和步骤进行评估、控制和监测，然而总体有效性应整体把握。

2.5 The development of the CCS requires thorough technical and process knowledge. Potential sources of contamination are attributable to microbial and cellular debris (e.g. pyrogen, endotoxins) as well as particulate matter (e.g. glass and other visible and sub-visible particulates). Elements to be considered within a documented CCS should include (but are not limited to):

CCS 开发需要全面的技术和工艺知识。潜在的污染源源于微生物及细胞残骸（例如热原/内毒素）以及颗粒（例如玻璃及其他可见和不可见微粒）。成文的污染控制策略应考虑的要素包含（但不限于）：

Design of both the plant and processes.

厂房和工艺的设计

Premises and equipment.

厂房设施和设备

Personnel.

人员

Utilities.

 公用系统

Raw material controls – including in-process controls.

起始物料的控制-包含中间控制

Product containers and closures.

产品包装

Vendor approval – such as key component suppliers, sterilization of components and single use systems (SUS), and services.

供应商的批准-例如关键组分的供应商、部件的灭菌及一次性使用系统（SUS）和服务。

For outsourced services, such as sterilization, sufficient evidence should be provided to the contract giver to ensure the process is operating correctly.

对于委托外部的服务，例如灭菌，应将充分的证据提供给合同的委托方，以确保工艺的正确操作。

Process risk assessment.

工艺风险评估

Process validation.

工艺验证

Preventative maintenance – maintaining equipment, utilities and premises (planned and unplanned maintenance) to a standard that will not add significant risk of contamination.

预防性维护保养-设备，公用系统及设施的维护保养（计划性及非计划性维护保养）符合标准，不会加大显著的污染风险

Cleaning and disinfection.

清洁和消毒

Monitoring systems - including an assessment of the feasibility of the introduction of scientifically sound, modern methods that optimize the detection of environmental contamination.

监测系统-包括对引入检测方法的可行性评估，方法科学合理，现代化，能够优化环境污染的检测。

Prevention – trending, investigation, corrective and preventive actions (CAPA), root cause determination and the need for more comprehensive investigational tools.

预防措施-趋势分析、调查、纠正和预防措施（CAPA）、根本原因的确定以及需求更全面的调查工具

Continuous improvement based on information derived from the above.

基于来自上述衍生信息的持续改进。

2.6 The CCS should consider all aspects of contamination control and its life cycle with ongoing and periodic review resulting in updates within the quality system as appropriate.

 CCS 应考虑到污染控制的各个方面以及整个生命周期的各个方面，包含持续的周期性回顾所引起的质量体系的必要更新。

2.7 The manufacturer should take all steps and precautions necessary to assure the sterility of the products manufactured within its facilities. Sole reliance for sterility or other quality aspects should not be placed on any terminal process or finished product test.

生产厂家应采取所有必要的步骤及防范措施以确保在其设施内所生产产品的无菌性。无菌性或其他质量因素不应仅仅依靠最终工艺步骤或成品检测。

3 Pharmaceutical Quality System (PQS)

制药质量体系（PQS）

3.1 The manufacture of sterile products is a complex activity that requires specific controls and measures to ensure the quality of products manufactured. Accordingly, the manufacturer’s PQS should encompass and address the specific requirements of sterile product manufacture and ensure that all activities are effectively controlled so that microbial, particulate and pyrogen contamination is minimized in sterile products. In addition to the PQS requirements detailed in Chapter 1 of the GMPs, the PQS for sterile product manufacture should also ensure that:

无菌产品的生产是一个复杂的活动，该活动需要特定的控制和措施以确保所生产的产品质量。通常，生产企业的PQS应包括或强调无菌产品生产的具体要求以确保所有的活动均得到了有效的控制，以便使无菌产品中的微生物、粒子、热原污染最小化。除了满足GMP第一章关于PQS的要求外，无菌产品生产企业的PQS还应确保：

An effective risk management system is integrated into all areas of the product life cycle with the aim to minimize microbial contamination and to ensure the quality of sterile products manufactured.

在产品生命周期内的各个方面应用一个有效的风险管理系统，以降低微生物污染，确保所生产的无菌药品的质量。

The manufacturer has sufficient knowledge and expertise in relation to the products manufactured and the equipment, engineering and manufacturing methods employed that have an impact on product quality.

生产企业应具有足够的与所生产的产品、对产品质量有影响的设备、工程和生产方法相关的知识和专业技能。

Root cause analysis of procedural, process or equipment failure is performed in such a way that the risk to product is correctly understood and suitable corrective and preventative actions (CAPA) are implemented.

对程序、工艺或设备失败的根本原因进行分析，能够正确了解对产品产生的风险，实施适当的纠正和预防措施。

Risk management is applied in the development and maintenance of the CCS, to identify, assess, reduce/eliminate (where applicable) and control contamination risks. Risk management should be documented and should include the rationale for decisions taken in relation to risk reduction and acceptance of residual risk.

在开发和维护污染控制策略的过程中进行风险管理，以识别、评价、降低 / 消除（如适用）并控制污染风险。风险管理应有记录并包括对降低风险及接受残余风险所做出的决定的合理说明。

The risk management outcome should be reviewed regularly as part of on-going quality management, during change control and during the periodic product quality review.

风险管理的结果应作为持续质量管理的一部分在变更控制以及产品周期质量回顾时进行定期审核。

Processes associated with the finishing and transport of sterile products should not compromise the sterile product. Aspects that should be considered include: container integrity, risks of contamination and avoidance of degradation by ensuring that products are stored and maintained in accordance with the registered storage conditions.

与无菌产品的完成和运输相关的过程不应对无菌产品造成危害。需要考虑的方面包括：容器完整性、受污染风险以及产品按照其注册的储存条件储存时如何避免降解。

Persons responsible for the quality release of sterile products have appropriate access to manufacturing and quality information and possess adequate knowledge and experience in the manufacture of sterile products and their critical quality attributes. This is in order to allow such persons to ascertain that the sterile products have been manufactured in accordance with the registered specifications and are of the required quality.

负责无菌产品质量放行的人员能够获得足够的生产及质量信息，并具备足够的无菌产品生产和关键质量属性方面的知识和经验，以便能够确保无菌产品是按照注册的质量标准被生产出来并具有所要求质量。

3.2 All non-conformities, such as sterility test failures, environmental monitoring excursions or deviations from established procedures should be investigated. The investigation should determine the potential impact upon process and product quality and whether any other processes or batches are potentially impacted. The reason for including or excluding a product or batch from the scope of the investigation should be clearly justified and recorded.

应对不符合项进行调查，例如无菌检查失败或环境监测超标或与已建立的程序存在偏差。调查需要确定对工艺和产品质量的潜在影响，以及对其他工艺或批次的潜在影响。对于在调查范围内涵盖或排除的产品的原因，应有合理说明并记录。

4 Premises

厂房

4.1 The manufacture of sterile products should be carried out in appropriate cleanrooms, entry to which should be through changing rooms that act as airlocks for personnel and airlocks for equipment and materials. Cleanrooms should be maintained to an appropriate cleanliness standard and supplied with air which has passed through filters of an appropriate efficiency. Controls and monitoring should be scientifically justified and capable of evaluating the state of environmental conditions for cleanrooms, airlocks and pass-throughs used for material and equipment transfer.

无菌产品的生产应在适当的洁净室内进行，人员通过更衣用的气闸进入洁净区而设备以及物料需要通过气闸间进入洁净区。洁净室应维护在一个合适的洁净度标准，并供应通过合适效率过滤器的空气。控制和监视应具有科学依据，并能够评估洁净室、气闸和用于物料、设备转移的传递窗的环境状况。

4.2 The various operations of component preparation, product preparation and filling should be carried out with appropriate technical and operational separation measures within the cleanroom or facility to prevent mix up and contamination.

部件的准备、产品的配制以及灌装的不同操作应在洁净室或者设施内通过合适的技术及操作隔离方式来防止混淆和污染。

4.3 Restricted Access Barrier Systems (RABS) and isolators are beneficial in assuring the required conditions and minimizing the microbial contamination associated with direct human interventions in the critical zone. Their use should be considered in the CCS. Any alternative approaches to the use of RABS or isolators should be justified.

限制进入障碍系统（RABS）和隔离器有利于确保所需的条件，并能最大程度地减少关键区域中与人为直接干预相关的微生物污染。 在 CCS（污染控制策略）中应考虑使用它们。任何替代 RABS 或隔离器的其他方法应证明其合理性。

4.4 For the manufacture of sterile products there are four grades of cleanroom.

无菌产品生产所需的洁净室可分为以下 4 个级别：

Grade A zone: The critical zone for high risk operations or for making aseptic connections by ensuring protection by first air (e.g. aseptic processing line, filling zone, stopper bowl, open ampoules and vials). Normally, such conditions are provided by a localised airflow protection, such as unidirectional airflow work stations, RABS or isolators. The maintenance of unidirectional airflow should be demonstrated and qualified across the whole of the Grade A zone. Direct intervention (e.g. without the protection of barrier and glove port technology) into the Grade A zone by operators should be minimized by premises, equipment, process and procedural design.

A       级：高风险操作区，如灌装区、胶塞加料盘、敞口的安瓿和西林瓶、无菌对接。通常情况下，该条件下应设有局部单向流保护，例如层流操作台或隔离器。整个 A 级区域的单向流的维护应被证明或验证。应通过设施、设备、工艺及过程的设计来最小化操作人员进入 A 级区的直接干涉活动（例如在没有限制系统和手套箱技术的保护下）的次数。

Grade B area: For aseptic preparation and filling, this is the background cleanroom for the Grade A zone (where it is not an isolator). When transfer holes are used to transfer filled, closed products to an adjacent cleanrooms of a lower grade, airflow visualization studies should demonstrate that air does not ingress from the lower grade cleanrooms to the Grade B. Pressure differentials should be continuously monitored. Cleanrooms of lower grade than Grade B can be considered where isolator technology is used (refer to paragraph 4.22).

B 级：对于无菌配制和灌装等高风险操作， B 级区是 A 级洁净区所处的背景洁净室。当使用传递孔来进行传递灌封密闭产品至相邻的低级别房间时，此处的气流流行试验应该证明低级别房间的空气不会倒灌至 B 级别的房间。 此处的压差需要连续监测。如果使用了隔离器技术，可以考虑比 B 更低级别（参照条款 4.22）。

Grade C and D area: These are cleanrooms used for carrying out less critical stages in the manufacture of aseptically filled sterile products but can be used for the preparation /filling of terminally sterilized products. (See section 8 for the specific details on terminal sterilization activities).

C 级和 D 级：指用于执行无菌填充产品生产过程不太关键的操作步骤的洁净区， 但可用于制备/灌装最终灭菌产品。（有关最终灭菌活动的详细信息，请参见第 8 节）。

4.5 In cleanrooms, all exposed surfaces should be smooth, impervious and unbroken in order to minimize the shedding or accumulation of particulates or micro-organisms and to permit the repeated application of cleaning, disinfectant and sporicidal agents where used.

洁净室内，所有暴露的表面应光滑、无渗漏且无破损以尽可能降低微粒或微生物的脱落或积聚，并可耐受清洗剂、消毒剂和杀孢子剂的重复使用。

4.6 To reduce accumulation of dust and to facilitate cleaning there should be no recesses that are difficult to clean effectively therefore projecting ledges, shelves, cupboards and equipment should be kept to a minimum. Doors should be designed to avoid recesses that cannot be cleaned.

为减少尘埃积聚并便于清洁，不应存在无法有效清洁的死角，因此支腿、货架、柜子、设备的突出部位应最小化。门的设计应当避免难清洁的凹陷。

4.7 Materials used in cleanrooms should be selected to minimize generation of particles.

应该选择洁净室中使用的材料，以最大程度地减少颗粒的产生。

4.8 Ceilings should be designed and sealed to prevent contamination from the space above them.

吊顶的设计和密封应能防止来自其上部空间的污染。

4.9 Sinks and drains are prohibited in Grade A zone and Grade B area. In other cleanrooms, air breaks should be fitted between the machine or sink and the drains. Floor drains in lower grade cleanrooms should be fitted with traps or water seals designed to prevent back flow and should be regularly cleaned, disinfected and maintained.

A/B 级洁净区内禁止设置水池和地漏。在其它洁净室内，设备或水池和排水之间应装有

气密封。低级别房间内的地漏应配置存水弯或水封以防止倒灌，并应定期进行清洁、消毒和维护。

4.10 The transfer of equipment and materials into and out of the cleanrooms and critical zones is one of the greatest potential sources of contamination. Any activities with the potential to compromise the cleanliness of cleanrooms or the critical zone should be assessed and if they cannot be eliminated, appropriate controls should be implemented.

设备和物料进出洁净室和关键区域是最大的潜在污染源之一。 应评估可能危害洁净室或关键区域清洁度的任何活动，如果不能消除这些活动，则应实施适当的控制措施。

4.11 The transfer of materials, equipment, and components into an aseptic processing area should be carried out via a unidirectional process. Where possible, items should be sterilized and passed into the area through double-ended sterilizers (e.g. through a double-door autoclave or depyrogenation oven/tunnel) sealed into the wall. Where sterilization on transfer of the items is not possible, a procedure which achieves the same objective of not introducing contaminant should be validated and implemented, (e.g. using an effective transfer disinfection, rapid transfer systems for isolators or, for gaseous or liquid materials, a bacteria-retentive filter).

将物料，设备和组件转移到无菌处理区域中应采用单向的过程。 如有可能，应对物品进行灭菌并通过封闭在墙壁中的双开的灭菌器（例如通过双扉高压灭菌器或去热原烘箱/隧道）进入无菌区域。 如果无法在物品转移时进行灭菌，则应验证并实施达到不引入污染物的相同目标的程序（例如，使用有效的消毒传递，隔离器或气态或液态物质的快速转移系统，除菌滤芯）。

4.12 Airlocks should be designed and used to provide physical separation and to minimize microbial and particulate contamination of the different areas, and should be present for material and personnel moving between different grades. Wherever possible, airlocks used for personnel movement should be separated from those used for material movement. Where this is not practical, time-based separation of movement (personnel /material) by procedure should be considered. Airlocks should be flushed effectively with filtered air to ensure that the grade of the cleanroom is maintained. The final stage of the airlock should, in the “at rest” state, be of the same cleanliness grade (viable and non-viable) as the cleanroom into which it leads. The use of separate changing rooms for entering and leaving Grade B cleanrooms is desirable. Where this is not practical, time-based separation of activities (ingress/egress) by procedure should be considered. Where the CCS indicates that the risk of cross-contamination is high, separate changing rooms for entering and leaving production areas should be considered. Airlocks should be designed as follow:

气闸的设计和使用应能提供物理隔离以最大限度地降低不同区域的微生物和微粒污染，并为物料和人员在不同级别之间的移动提供通道。如果可能，用于人流的气闸间应当与用于物流的气闸间分开。如果不能实现，应该考虑按时间分别执行人流、物流的程序。气闸应能被经过滤的空气有效地吹扫来确保洁净级别的维持。气闸的最后阶段在静态状态下应与其通向的洁净室的洁净度相同（活性和非活性颗粒）。进入和离开 B 级洁净室的更衣室期望独立设置。在不可行的情况下，应考虑按程序将活动（进/出）基于时间的分隔。如果 CCS（污染控制策略） 指出交叉污染的风险很高，则应考虑进入和离开生产区域的单独更衣室。气闸的设计应如下：

Personnel airlocks: Areas of increasing cleanliness used for entry of personnel (e.g. from Grade D to Grade C to Grade B). In general hand washing facilities should be provided only in the first stage of the changing room and not be present in changing rooms directly accessing Grade B cleanrooms.

人流气闸室。人员进入更高级别洁净度的区域（例如，从D 级到 C 级到 B 级）。通常来讲，洗手设施只能在更衣室的第一阶段提供， 并且直接进入 B 级别的更衣室不能有洗手设施。

Material airlocks: used for materials and equipment transfer.

物流气闸：用于物料和设备的传递

Only materials and equipment that have been included on an approved list, developed during validation of the transfer process, should be allowed to be transferred into the Grade A zone or Grade B cleanroom via an airlock or pass-through hatch. Equipment and materials (intended for use in the Grade A zone) should be protected when transiting through the Grade B cleanroom. Any unapproved items that require transfer should be pre-approved as an exception. Appropriate risk assessment and mitigation measures should be applied and recorded as per the manufacturer's CCS and should include a specific disinfection and monitoring programme approved by quality assurance.

只有包含在确认列表部分中并且经过传递验证的的物料和设备方可通过气锁或通道转移进 A/B 级区域；当在 A级区使用的设备、 物料从 B 级区转移时， 应该被保护起来。 任何未经批准的物料需要转移都属于需要预先批准的异常情况。应根据生产商污染控制策略进行适当的风险评估和降低措施，并予以记录，应包含由质量保证部门批准的特定的消毒和监测程序。

Pass-through hatches should be designed to protect the higher grade environment, for example by effective flushing with an active filtered air supply.

传递窗的设计应能保护较高等级的环境，例如通过使用主动过滤的空气进行有效风淋

The movement of material or equipment from lower grade or unclassified area to higher grade clean areas should be subject to cleaning and disinfection commensurate with the risk and in line with the CCS.

将物料从低级别或未定级区域移至更高等级的洁净区域时，应进行与其风险相称清洁和消毒并符合 CCS（污染控制策略）。

4.13 Both sets of doors for pass-throughs and airlocks (for material and personnel) should not be opened simultaneously. For airlocks leading to a Grade A zone and Grade B areas, an interlocking system should be used. For airlocks leading to Grade C and D cleanrooms, a visual and/or audible warning system should be operated as a minimum. Where required to maintain zone segregation, a time delay between the closing and opening of interlocked doors should be established.

气闸和传递窗两端的门不得被同时打开。通向 A 级区和 B 级区的气闸应使用互锁系统，

并能防止有超过一扇的门被同时打开；对于通向 C 级区与 D 级区的互锁，应至少有一个可

视和/或可听的报警系统运行。当需要维持区域隔离时，应建立互锁门开关时间的延迟（即互锁门关闭只有需要隔一段时间才能重新打开）。

4.14 Cleanrooms should be supplied with a filtered air supply that maintains a positive pressure and/or an airflow relative to the background environment of a lower grade under all operational conditions and should flush the area effectively. Adjacent rooms of different grades should have pressure differentials of a minimum of 10 pascals (guidance value). Particular attention should be paid to the protection of the critical zone. The recommendations regarding air supplies and pressures may need to be modified where it is necessary to contain certain materials (e.g. pathogenic, highly toxic or radioactive products or live viral or bacterial materials). The modification may include positively or negatively pressurized airlocks that prevent the hazardous material from contaminating surrounding areas. Decontamination of facilities (e.g. the cleanrooms and the heating, ventilation, and air conditioning (HVAC) systems) and the treatment of air leaving a clean area, may be necessary for some operations. Where containment requires air to flow into a critical zone, the source of the air should be from an area of the same grade.

洁净室应提供经过过滤的空气，该空气供应在所有操作条件下均相对于较低等级的背景环境保持正压和/或气流， 并能有效冲洗该区域。不同洁净级别的相邻房间之间应维持至少 10 帕（指导值）的压差。应特别注意对风险级别最高的区域的保护，如包括一些物料， 如致病性的、高毒性、放射性或活病毒或细菌物料或产品，与送风和压差相关的建议可能需要调整， 调整可包括正压或负压气闸，以防止有害物质污染周围区域。 设施净化，如洁净室和空调系统，以及在某些操作时对排出洁净区的空气的处理可能是有必要的。 如果防止外泄需要空气流入关键区域，则空气来源应来自相同等级的区域。

4.15 Airflow patterns within cleanrooms and zones should be visualised to demonstrate that there is no ingress from lower grade to higher grade areas and that air does not travel from less clean areas (such as the floor) or over operators or equipment that may transfer contaminant to the higher grade areas. Where air movement is shown to be a risk to the clean area or critical zone, corrective actions, such as design improvement, should be implemented. Airflow pattern studies should be performed both at rest and in operation (e.g. simulating operator interventions). Video recordings of the airflow patterns should be retained. The outcome of the air visualisation studies should be considered when establishing the facility's environmental monitoring program.

洁净室和区域内的气流流形应进行可视化研究，以证明从低等级区域到较高等级区域没有倒灌，并且空气不会从较不洁净的区域（例如地板）或经过操作员或设备将污染传递至高级别的区域。 其他需要证明气流流型的区域应通过风险评估来进行。气流流型的研究应在动态条件下进行。记录气流流型的视频应保存。 当建立设施的环境监测计划时，应考虑气流可视化研究的结果。

4.16 Indicators of pressure differences should be fitted between cleanrooms and/or isolators. Set-points and the criticality of pressure differentials should be documented within the CCS. Pressure differentials identified as critical should be continuously monitored and recorded. A warning system should be in place to instantly indicate and warn operators of any failure in the air supply or reduction of pressure differentials (below set limits for those identified as critical). The warning signal should not be overridden without assessment and a procedure should be available to outline the steps to be taken when a warning signal is given. Where alarm delays are set, these should be assessed and justified within the CCS. Other pressure differentials should be monitored and recorded at regular intervals.

洁净室和/或隔离器之间应安装压差指示器。 设定点和压差的临界值应在 CCS（污染控制策略）文件化。 被确定为关键压差的应得到连续监测和记录。 应建立警告系统以便立即向操作员指示并警告气体供应出现任何故障或压差降低（低于确定为关键的限度值）。 未经评估，不得摒弃报警信号，并且应提供程序概述发出警告信号时应采取的步骤。 如果设置了警报延迟，则应在 CCS 内对其进行评估和证明。 其他压力差应定期监测和记录。

4.17 Facilities should be designed to permit observation of production activities from outside the Grade A zone and Grade B area (e.g. through the provision of windows or remote cameras with a full view of the area and processes to allow observation and supervision without entry). This requirement should be considered when designing new facilities or during refurbishment of existing facilities.

设施的设计应允许从 A 级区域和 B 级区域以外的地方观察生产活动（例如，通过提供窗户

或远程摄像头全面观察该区域和过程，以便无需进入即可进行观察和监督）。 在设计新设施或翻新现有设施时，应考虑此要求。

Barrier Technologies

屏障技术

4.18 Isolator or RABS technologies, and the associated processes, should be designed to provide protection of the Grade A environment. The entry of materials during processing (and after decontamination) should be minimized and preferably supported by rapid transfer technologies or transfer isolators.

隔离器或限制进入屏障系统（RABS）技术，以及相关工艺，应设计为对 A 级区环境提供保护。在处理过程中（以及净化后），应尽量减少物料进入，最好由快速转移技术或转移隔离器来支持。

4.19 The design of the RABS or isolator should take into account all critical factors associated with these technologies including the quality of the air inside and the background environment, the materials and component transfer, the decontamination and/or sterilization processes, the risk factors associated with the manufacturing operations and the operations conducted within the critical zone.

RABS 或隔离器的设计应考虑与这些技术相关的所有关键因素，包括室内空气质量以及背景环境、 物料及部件传递、净化、和/或灭菌处理，与生产操作和物料相关的风险因素、以及在关键区域中进行的操作。

4.20 The critical zone of the RABS or open isolator used for aseptic processes should meet Grade A requirements with unidirectional airflow. In closed isolator systems where airflow may not be unidirectional, it should provide Grade A conditions and be demonstrated to provide adequate protection for exposed products during processing. The design of the RABS and open isolators should ensure a positive airflow from the critical zones to the supporting background environment; (unless containment is required in which case localized air extraction is required to prevent contamination transfer to the surrounding room). Negative pressure isolators should only be used when containment of the product is considered essential and risk control measures are applied to ensure the critical zone is not compromised.

用于无菌工艺的 RABS 或开放隔离器的关键区域应满足 A 级区单向气流要求。 在气流可能不是单向的封闭式隔离器系统中，应提供 A 级条件，并应证明在加工过程中为暴露的产品提供足够的保护。RABS 和开放隔离器的设计，应保证气流从关键区域流向周边区域(除非需要控制外泄，在这种情况下需要局部抽气以防止污染物转移到周围的房间)。负压隔离室应仅在必须对产品进行隔离的时候使用， 并采取风险控制措施以确保关键区域不受损害。

4.21 For RABS used for aseptic processing, the background environment should meet at least Grade B. The background environment for open isolators should meet Grade C or D, based on a risk assessment. Airflow studies should be performed to demonstrate the absence of air ingress during interventions, such as door openings.

对于 RABS，背景环境应满足 B 级区要求，根据风险评估，开放隔离器的背景环境应达到C 级或 D 级。 应当进行气流研究，以证明在干预过程中（例如门打开）没有空气进入。

4.22 The background environment of a closed isolator should correspond to a minimum of Grade D. The disinfection/decontamination programme should be included as a key consideration when performing the risk assessment for the CCS of an isolator. Where additional process risks are identified, a higher grade of background should be considered. The decision as to the supporting background environment should be documented in the CCS.

封闭式隔离器的背景环境应至少达到 D 级。在进行隔离器 CCS 风险评估时，应将消毒/净化程序作为关键考虑因素。 如果确定了其他过程风险，则应考虑更高级别的背景。 有关背景环境的决定应记录在 CCS中 。

4.23 The materials used for glove systems (for both RABS and isolators), as well as other parts of an isolator, should be demonstrated to have good mechanical and chemical resistance. Integrity testing of the barrier systems, and leak testing of the glove system and the isolator should be performed using a methodology demonstrated to be suitable for the task and criticality. The testing should be performed at defined periods, at a minimum at the beginning and end of each batch, and should include a visual inspection following any intervention that may affect the integrity of the system. For single unit batch sizes, integrity may be verified based on other criteria, such as the beginning and end of each manufacturing session. RABS gloves used in Grade A zone should be sterilized before installation and sterilized (or effectively decontaminated by a validated method which achieves the same objective) prior to each manufacturing campaign. The frequency of glove replacement should be defined within the CCS.

用于手套系统（用于 RABS 和隔离器）以及隔离器其他部分的材料应证明具有良好的机械和

化学耐性。屏障系统的完整性测试以及手套系统和隔离器的泄漏测试应使用经证明适合于该任务和临界值的方法进行。测试应在规定的时间周期进行，至少在每批的开始和结束时进行，并应在任何可能影响系统完整性的干预措施后进行目视检查。对于单个单位批次大小而

言，可以根据其他条件（例如每个生产阶段的开始和结束）来验证完整性。在安装之前应对

A 级区域中使用的 RABS 手套进行灭菌，并在每次阶段制造活动之前对其进行灭菌（或通过

达到相同目的的经过验证的方法）。手套的更换频率应在 CCS 中规定。

4.24 For RABS and isolator systems, decontamination methods should be validated and controlled within defined cycle parameters. The cleaning process prior to the disinfection step is essential; any residues that remain may inhibit the effectiveness of the decontamination process: 对于 RABS 和隔离系统，规定净化的循环参数应经过验证。 消毒步骤之前的清洁是基本要

求，任何残留物可能会影响净化过程的有效性：

For isolators, the decontamination process should be automated and should include a sporicidal agent in a suitable form (e.g. gaseous, aerosolized or vaporized form) to ensure thorough microbial decontamination of its interior. Decontamination methods (cleaning and sporicidal disinfection) should render the interior surfaces and critical zone of the isolator free of viable microorganisms.

对于隔离器，净化过程应该是自动化的，并且应包括适当形式的杀孢子剂（例如气态，气溶胶或气化形式），以确保对其内部进行彻底的微生物净化。 净化方法（清洁和杀孢子灭菌）应使隔离器的内表面和关键区域不含活菌。

For RABS systems, the disinfection should include the routine application of a sporicidal agent using a method that has been validated and demonstrated to robustly disinfect the interior and ensure a suitable environment for aseptic processing.

对于 RABS 系统，消毒应包括常规杀孢子剂的使用，该方法已通过验证并证明可以对内表面进行稳定有效的消毒，并确保为无菌处理提供合适的环境。

Evidence should also be available to demonstrate that the agent used does not have adverse impact on the product produced within the RABS or isolator. The holding time before use of these systems should be validated.

还应有证据表明所用试剂对 RABS 或隔离器内生产的产品没有不利影响。 使用这些系统之前的保持时间应经过验证。

Cleanroom and clean air equipment qualification

洁净室和空气净化设备的确认

4.25 Cleanrooms and clean air equipment such as unidirectional airflow units (UDAFs), RABS and isolators, used for the manufacture of sterile products, should be qualified and classified according to the required characteristics of the environment. Each manufacturing operation requires an appropriate environmental cleanliness level in the operational state in order to minimize the risk of particulate or microbial contamination of the product or materials being handled.

用于无菌产品生产的洁净室和空气净化设备例如单向气流单元（UDAFs）、 RABS 和隔离器， 应根据环境要求进行确认和定级。各生产操作在操作状态下都要求合适的环境洁度，以尽可能降低因处理产品或物料而产生的颗粒或微生物污染风险。

4.26 Cleanrooms and clean air equipment should be qualified using methodology in accordance with the requirements of Annex 15. Cleanroom qualification (including classification) should be clearly differentiated from operational environmental monitoring.

洁净室和空气净化设备应按照欧盟 GMP 附件 15 要求进行确认。 洁净室确认（包括分类）应与日常环境监控区分开来。

4.27 Cleanroom Qualification is the overall process of assessing the level of compliance of a classified cleanroom or clean air equipment with its intended use. As part of the qualification requirements of Annex 15, the qualification of cleanrooms and clean air equipment should include (where relevant to the design/operation of the installation):

洁净室确认是评估定级的洁净室或洁净空气设备与其预期用途的符合性水平的总体过程。 作为附件 15 确认要求的一部分，洁净室和洁净空气设备的确认应包括（与设备的设计/运行有关）：

i. Installed filter leakage and integrity testing.

已安装过滤器捡漏和完整性测试

Airflow measurement - Volume and velocity.

气流测试—风量和流速

Air pressure difference measurement.

压差测试

Airflow direction and visualisation.

气流流型

Microbial airborne and surface contamination.

空气微生物和表面微生物

Temperature measurement.

温度测试

Relative humidity measurement.

相对湿度测试

Recovery testing.

恢复测试

Containment leak testing.

泄漏率测试

4.28 Cleanroom classification is part of a cleanroom qualification and is a method of assessing the level of air cleanliness against a specification for a cleanroom or clean air equipment by measuring the non-viable airborne particulate concentration. Reference for the classification of the cleanrooms and clean air equipment can be found in the ISO 14644 series of standards.

洁净室分级是洁净室确认的一部分，并且是通过测量空气中非活性的悬浮颗粒物浓度来根据洁净室或洁净空气设备的标准评估空气洁净度的方法。 洁净室和洁净空气设备的分类可在 ISO 14644 系列标准中找到。

4.29 For cleanroom classification, the airborne particulates equal to or greater than 0.5 and 5 µm should be measured. For Grade A zone and Grade B at rest, classification should include measurement of particles equal to or greater than 0.5 µm; however, measurement using a second, larger particle size, e.g. 1 µm in accordance with ISO 14644 may be considered. This measurement should be performed both at rest and in operation. The maximum permitted airborne particulate concentration for each grade is given in Table 1.

洁净室分级，应测量大于或等于 0.5µm 和 5µm 的尘埃粒子数。 对于静态的 A 级区域和B 级，分级测试应包括对等于或大于 0.5 µm 的颗粒进行测量； 但是，可以考虑使用更大的第二个粒径，例如符合 ISO 14644 的 1 µm。该测量应在静态和运行状态下进行。每个级别允许的最大尘埃粒子浓度在表 1 中给出。