Annex 1 : Manufacture of Sterile Products

附件1:无菌产品生产

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文档目录

Section Number
概述
章节号
1 Scope Includes additional areas (other than sterile products) where the general
范围 principles of the annex can be applied.
（除了无菌产品以外）包括适用该附件一领域的通
2 Principle General principles as applied to the manufacture of sterile products.
通则 适用于无菌产品生产的一般原则。
3 Pharmaceutical Quality Highlights the specific requirements of the PQS when applied to sterile
System (PQS) products.
药品质量体系（PQS） 强调了无菌药品中PQS的特定要求。
4 Premises General guidance regarding the specific needs for premises design and also
设施 guidance on the qualification of premises including the use of Barrier
Technology.
关于设施设计的具体需要和一般指导原则，以及设施确认和屏障技术
的应以指南。
5 Equipment General guidance on the design and operation of equipment.
设备 设备设计和运行的一般指南。
6 Utilities Guidance with regards to the special requirements of utilities such as water,
公用系统 gas and vacuum.
关于公用系统，如水、空气和真空等设施的特殊要求指南。
7 Personnel Guidance on the requirements for specific training, knowledge and skills. Also
人员 gives guidance to the qualification of personnel.
关于具体培训、知识和技能要求的指导。还对人员的资格给予指导。
Discusses the approaches to be taken with regards to aseptic and terminal
sterilization processes. Discusses approaches to sterilization of products,
Production and specific
equipment and packaging components. Also discusses different technologies
8 technologies such as lyophilization and Form Fill Seal where specific requirements apply.
生产和特定技术 讨论了关于无菌和终端灭菌过程应采取的方法。讨论了产品、设备和
包装部件的灭菌方法。还讨论了不同的技术，如BFS设备的具体要求。
This section differs from guidance given in section 4 in that the
guidance here applies to ongoing routine monitoring with regards to the
Viable and non viable design of systems and setting of action limits alert levels and reviewing
environmental and trend data.
process 本节与第4节中给出的指导意见不同，因为此处的指导意见适用
9 monitoring 于与系统设计和行动限制警报级别设置以及趋势数据审查有关的
适宜的环境和不适宜的 持续例行监控。
环境以及过程检测 The section also gives guidance on the requirements of Aseptic Process
Simulation (APS).
本节还给出了无菌工艺模拟（APS）要求的指导。
Quality control (QC) Gives guidance on some of the specific Quality Control requirements
10 relating to sterile products.
质量控制（QC） 给出与无菌产品相关的一些具体质量控制要求的指导。
Glossary Explanation of specific terminology.
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术语 特定术语的解释。

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1. Scope
范围

1.1. 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.
无菌产品生产涵盖了广泛的无菌产品类型。（活性物质，无菌赋形剂，内包装材料和成品（剂型）、
包装尺寸（从单个单位到多个单位）、流程（从高度自动化系统到手动操作）和技术（例如:生物技
术、小分子制造和封闭系统）。本附件提供了使用质量风险管理原则（QRM）生产所有无菌产品时
应使用的一般指南。以确保能够防止最终产品中的微生物、微粒和热原的污染。

1.2. 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.
QRM适用于本文档的全部内容，不会在特定段落中提及。如果规定了具体的限值或频率，则应将其
视为最低要求。它们是由于以前发现的问题的监管历史经验而提出的，这些问题影响了患者的安全。

1.3. 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.
附件的目的是为无菌产品的生产提供指导。然而，一些原则和指导，如污染控制策略、厂房设计、洁
净室分类、环境监测和人员着装，也可用于支持其他非无菌产品的生产，例如如某些液体制剂、乳膏
软膏和低生物负荷的生物中间体，但在控制和减少微生物，微粒和热原污染方面被认为很重要的产品。
如果制造商选择将本指南应用于非无菌产品，制造商应明确记录应用了哪些原则，并承认应遵守这些
原则。

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:
无菌产品的制造须符合特殊要求，以最大限度地减少微生物、微粒和热原污染。应考虑以下关键领域:

2.1.1. 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.
应优化设施、设备和工艺设计，根据《药品生产质量管理规范》（GMP）的相关章节进行有
效的确认和验证。应考虑增加对产品的保护（例如限制性屏障技术（RABS)、隔离器、机器
人系统、快速微生物测试和监测系统）使其免受人员、物料和周围环境等可能的外来颗粒物
和微生物污染，并协助快速检测环境和产品中的潜在污染物。

2.1.2. Personnel should have adequate qualifications and experience, training and attitude with aspecific
focus on the principles involved in the protection of sterile product during the manufacturing,
packaging and distribution processes.
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 人员应具备足够的资格和经验、培训和态度，人员需要特别关注在生产、包装和分销过程中
保护无菌产品所涉及的原则。

2.1.3. Processes and monitoring systems for sterile product manufacture should be designed,commissioned,
qualified and monitored by personnel with appropriate process, engineering and microbiological
knowledge.
无菌产品生产的工艺和监控系统应由具有适当工艺、工程和微生物知识的人员设计、使用、
确认和监控。

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. 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.
工艺、设备、设施及生产活动应根据QRM原则进行管理，科学评估和控制潜在的质量风险。如使用
替代办法，则应以适当的理由和风险评估来作为支持，并应符合本附件的意图。质量风险管理的优先
事项应首先包括设施、设备和工艺的良好设计，然后执行设计良好的工艺，并以监测系统作为最终要
素，证明设计工艺能够正确实施并可以继续执行且符合预期。专门的监测或检测并不能保证产品的无
菌。

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。应在整个
工厂内实施污染控制策略（CCS），以定义所有关键控制点，并评估用于管理与污染相关的风险的所
有控制措施（设计，程序，技术和组织上）的有效性和监控措施。 应积极更新CCS，并应不断改进制
造和控制方法。

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.
一系列污染控制和采取措施使微生物和颗粒物污染的风险降至最低，是一系列相继发生的事件和措施。
这些通常是单独评估，控制和监视的，但应综合考虑它们的集体有效性。

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的开发需要透彻的技术和工艺知识。潜在的污染源可归因于微生物和细胞碎片（例如，热原，内
毒素）以及颗粒物（例如，玻璃碎片以及其他可见的和次要的颗粒）。 CCS文件中应考虑的要素应包
括（但不限于）：

2.5.1. Design of both the plant and processes.

工厂和工艺的设计。

2.5.2. Premises and equipment.

房间和设备。

2.5.3. Personnel.
人员。

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 2.5.4. Utilities.
公用设施。

2.5.5. Raw material controls – including in process controls.

原材料控制 包括过程控制。

2.5.6. Product containers and closures.

产品容器和密封。

2.5.7. Vendor approval – such as keycomponent suppliers, sterilization of components and single use systems
(SUS), andservices.
供应商批准–例如关键组件的供应商，组件和一次性系统（SUS）的灭菌服务的供应商。

2.5.8. For outsourced services, such as sterilization, sufficient evidence should be provided to the contract
giver to ensure the process is operating correctly.
对于灭菌等外包服务，应向要求合同提供方提供充分的证据，以确保流程被正确运行。

2.5.9. Process risk assessment.

工艺风险评估。

2.5.10. Process validation.

工艺验证。

2.5.11. 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 设备及设施的维护保养（计划性及非计划性维护保养）应有一个标准，使之
不会带来重大的污染风险。

2.5.12. Cleaning and disinfection.

清洁消毒。

2.5.13. 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 包括评估引入科学合理的现代方法以优化环境污染检测的可行性。

2.5.14. Prevention – trending, investigation, corrective and preventive actions (CAPA), root cause
determination and the need for more comprehensive investigational tools.
预防 趋势分析、调查、纠正和预防措施（CAPA）、根本原因确定以及对更全面的调查工具
的需求。

2.5.15. Continuous improvement based on information derived from the above.

基于上述信息的持续改进。

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.
2.7. CCS应考虑污染控制及其生命周期的所有方面，进行持续和定期审查，酌情在质量体系内进行更新。

2.8. 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.
2.9. 制造商应采取所有必要的步骤和预防措施，以确保在其设施内生产的产品的无菌性。无菌或其他质量
方面的唯一依据不应放在任何终端过程或成品测试上。

3. Pharmaceutical Quality System (PQS)

药品质量体系（PQS）

3.1. The manufacture of sterile products is a complex activity that requires specific controls and measures to ensure
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 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,
无菌产品的生产是一项复杂的活动，需要采取特定的控制措施以确保所生产产品的质量。 因此，生
产商的PQS应涵盖并满足无菌产品生产的特定要求，并确保有效的控制所有活动，以使无菌产品中的
微生物，微粒和热原污染最小化。 除了GMP第1章中详述的PQS要求外，用于无菌产品生产的PQS还
应确保：

3.1.1. 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.
有效的风险管理系统已集成到产品生命周期的所有领域，旨在最大程度地减少微生物污染并
确保所生产无菌产品的质量。

3.1.2. 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.
制造商对于所制造的产品以及所使用的会影响产品质量的设备，设施和生产方法具有足够的
知识和专长。

3.1.3. 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、工艺或设备故障的根本原因进行分析，以便正确理解产品的风险，并采取适当的纠
正和预防措施（CAPA）。

3.1.4. 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.
风险管理应用于CCS的开发和维护，以识别、评估、减少/消除（如适用）和控制污染风险。
风险管理应记录在案，并应包括与降低风险和接受残余风险有关的决策的理由。

3.1.5. 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.
在变更控制和定期产品质量审查期间，应定期审查风险管理结果，作为持续质量管理的一部
分。

3.1.6. 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.
与无菌产品的整理和运输相关的过程不应危及无菌产品。应考虑的方面包括:容器的完整性、
污染的风险以及通过确保产品按照注册的储存条件进行储存和维护来避免降解。
与无菌产品的包装和运输相关的过程不应损害无菌产品。应考虑的方面包括：容器的完整性，
污染的风险和确保产品按照注册的存储条件进行存储和维护。

3.1.7. 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有适当的途径获得生产和质量信息，并在无菌产品生产及其关
键质量属性方面拥有足够的知识和经验。这是为了让这些人能够确定无菌产品是按照注册规
格生产的，并且质量符合要求。

3.2. non conformities, such as sterility test failures, environmental monitoring excursions or deviations from
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 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.
不合格，如无菌测试失败，环境监测偏差或偏离既定工艺，应进行调查。调查应确定对工艺和产品质
量的潜在影响，以及是否有任何其他工艺或批次受到潜在影响。将某一产品或批次列入或排除在调查
范围之外的理由应当明确，并记录在案。

4. Premises
设施

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.
无菌产品的制造应在适当的洁净室中进行，进入洁净室的人员、设备和物料应通过气闸进入，用于人
员进入的更衣室为人流气闸，而用于设备和物料进入气闸则作为物流气闸。 洁净室应保持在适当的
洁净级别，并应有经过适当效率过滤器过滤的空气。控制和监视应具有科学依据，并能够评估用于物
料和设备转移的洁净室，气闸和通道的环境状况。

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.
各种原料的制备、产品的制备和灌装，必须使用适当的技术和操作隔离的方式在洁净区或是设施内进
行，以防止混合和污染。

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）和隔离器有助于确保所需的条件，并最大限度减少关键区域中人工员造
成的微生物污染。在CCS中应考虑使用它们。若使用其他任何方法替代RABS或隔离器，需要证明其
合理性。

4.4. For the manufacture of sterile products there are four grades of cleanroom.
无菌产品的生产有四个级别的洁净室。

4.4.1. 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级区域：高风险操作或需要空气保护而进行无菌连接的关键区域（例如无菌生产线的灌装区
域，加塞区域，开口的安瓿瓶和小瓶）。通常这种情况是带有局部气流保护的，例如：单向
气流工作站（FFU），RABS或隔离器。应对单向气流的维持进行论证和确认，直接干预（例
如:没有屏障和手套箱技术的保护）应通过场地、设备、工艺和程序的设计，尽量减少进入A
级区操作的人员。

4.4.2. 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
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 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级区域:对于无菌制备和灌装，这是A级区域的背景洁净室（这里不是隔离器）。当使用转移
孔将灌装的密封产品转移到相邻的较低等级的洁净室时，气流可视化研究应证明空气不会从
低等级洁净室进入B级洁净室。应持续监控压差。在使用隔离器技术的情况下，可以考虑使用
低于B级的洁净室（参见章节4.22）。

4.4.3. 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级区域:这些是洁净室，用于在无菌灌装产品的生产过程中进行不太重要的阶段，但可
用于制备/灌装最终灭菌产品。（有关终端灭菌的详细信息，请参阅第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.
在洁净室中，所有暴露的表面应光滑、不渗透和无破损，以尽量减少微粒或微生物的脱落或积累，并
耐受重复使用清洁、消毒和杀芽孢剂的擦拭。

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.
为了减少灰尘的积累和便于清洁，不应存在难以有效清洁的凹槽，因此应将突出的壁架、搁架、储物
架和设备数量降至最低。门的设计应避免无法清洁的凹槽。

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

洁净室中使用的材料应尽量减少微粒的产生。

4.8. Ceilings should be designed and sealed to prevent contamination from the space above them.
天花板的设计和密封应防止来自其上方空间的污染。

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级区和B级区禁止设置水槽和地漏。在其他洁净室中，应在机器或水槽和排水管之间安装空气断阻
断。低级别洁净室的地面排水管应安装设计用于防止回流的单向阀或水封，并应定期清洁、消毒和维
护。

4.10. 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的转移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通过单向过程进行。 如有可能，应对物品进行灭菌并
通过密封在墙壁上的双端灭菌器（例如:通过双门高压灭菌器或去热原烘箱/隧道）进入该区域。 如果
无法在物品转移时进行灭菌，应验证和实施能够实现不引入污染物这一相同目标的程序（例如，使用
有效的转移消毒，隔离器或气态或液态物质的快速转移系统，微生物过滤器）。
7
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提供物理隔离，并最大程度地减少不同区域的微生物和颗粒污染，并且应为在不
同等级之间移动的物料和人员提供气闸。在可能的情况下，用于人员流动的气闸应与用于物料流动的
气闸分开。在不可行的情况下，应考虑在程序中规定人员和物料分不同时间段使用。气闸应用过滤后
的空气有效净化，以确保保持洁净室的等级。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（可行和不可行）。最好使用单独的更衣室进入和离开B级洁净室。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表示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：

4.12.1. 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.
人员气闸:用于人员进入的清洁程度不断提高的区域（例如，从D级到C级再到B级）。一般情
况下，只应在更衣室的第一阶段提供洗手设施，而不应在直接进入B级洁净室的更衣室提供洗
手设施。

4.12.2. Material airlocks: used for materials and equipment transfer.

物料气闸:用于材料和设备的转移。

4.12.2.1. 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.
仅允许在物料传送验证过程中，已列入批准清单中的物料和设备，通过气闸或通过
传递窗转移到A级区域或B级洁净室。设备和物料（用于A级区域）在通过B级洁净
室时应受到保护。任何需要转移的未批准项目应作为例外情况进行预先批准。应根
据CCS采用和适当的风险评估和风险控制措施，并进行记录，并且应包括经质量保
证批准的特定消毒和监控程序。

4.12.2.2. 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空气源进行有效净
化。

4.12.2.3. 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.
将物料或设备从较低等级或未分类区域移动到较高等级时，应根据风险和CCS进行
相应的清洁和消毒。

4.13. Both sets of doors for pass throughs and airlocks (for material and personnel) should not be opened
8
 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.
传递窗和气闸（用于材料和人员）的两组门不应同时打开。对于通向A级区域和B级区域的气闸，应
使用互锁系统。 对于通向C级和D级洁净室的气闸，应至少使用视觉和或声音报警系统。 在要求自净
的地方，应在关闭和打开互锁门之间建立时间延迟。

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，并应有效净化该区域。不同等级的相邻房间的压差应至少为10帕斯卡（指导值）。应特
别注意保护关键区域。在需要包含某些物料（例如病原性，高毒性或放射性产品或活病毒或细菌材料）
的地方，可能需要修改有关空气供应和压力的建议。修改可包括正压或负压气闸，以防止有害物质污
染周围区域。对于某些操作，可能需要对设施（例如无尘室和供暖，通风和空调（HVAC）系统）进
行消毒，并对离开清洁区域的空气进行处理。如果密闭需要空气流入临界区域，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.
洁净室和洁净区内的气流模式应可视化，以证明没有从较低等级区域进入较高等级区域。空气不会从
清洁程度较低的区域（如地板）传播，或可能将污染物转移到更高等级区域的操作人员或设备。如果
空气流动对洁净区或关键区域构成风险，则应采取纠正措施，如改进设计。气流模式研究应在静态和
动态时进行（例如模拟操作员干预）。应保留气流模式的视频记录。在建立设施的环境监测计划时，
应考虑空气可视化研究的结果。

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 hould 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.
应在洁净室和/或隔离器之间安装压差指示器。应在CCS中规定压差的设置点和关键点。应持续监测
和记录被确定为关键点的压差。建立一个警告系统，以即时指示和警告操作员任何供气故障或压力下
降。（低于关键点的设定值）.在没有评估的情况下，不得消除警告信号，并且应提供程序来概述在
警告时需要采取的步骤。如果设置了报警延迟，则应在CCS中对其进行评估并证明其合理性。应定期
监测和记录其他压差。

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
9
 designing new facilities or during refurbishment of existing facilities.
设施的设计应允许从A级区域和B级区域之外观察生产活动（例如，通过提供视窗或远程摄像头，可
对区域和工艺进行全方位观察和监督，而无需进入）。在设计新设施或翻修现有设施时应考虑到这一
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RABS技术及相关工艺的设计应能保护A级环境。应尽量减少加工过程中（和除污后）物料
的进入，最好辅以快速转移技术或转移隔离器。

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，包括内部空气质量和背景环境、物料
和部件转移、去污和/或灭菌过程、与制造操作相关的风险因素以及在关键区域内进行的操作。

4.20. he critical zone of the RABS or open iso lator 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
用于无菌工艺的RABS或开放式隔离器的关键区域应满足A级以及单向气流的要求。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和开放式隔离器的设计应确保从关键区域到所在背景环境的气流顺畅； （除非需要密闭，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）。负压隔离器仅应在认为产品包含有必要
成分并采取风险控制措施以确保关键区域不受损害的情况下使用。

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.
对于用于无菌工艺的RABS，背景环境应至少达到B级。基于风险评估，开放式隔离器的背景环境应
达到C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
键因素考虑。 如果发现了额外的工艺风险，则应考虑更高级别的背景。 有关支持的背景环境的决定
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
10
 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.
应证明用于手套系统（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任务和关键程度的方法
进行。测试应在规定的时间段内进行，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，可以根据其他条件（例如每个制造周期的
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，并在每次生产
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进行有效灭菌）。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和隔离器系统，应在规定的循环参数内验证和控制去污方法。消毒步骤之前的清洁过程是
必不可少的；残留的任何残余物都可能抑制去污过程的有效性:

4.24.1. 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，去污过程应自动化，并应包括适当形式（如气态、气溶胶或汽化形式）的杀芽
孢剂，以确保对其内部进行彻底的微生物去污。净化方法（清洗和杀芽胞消毒）应能保证隔
离器的内表面和关键区域不存在活的微生物。

4.24.2. 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，消毒应包括常规应用杀孢子剂，使用的方法已经过验证和论证，可对内部进
行强力消毒，并确保为无菌处理提供合适的环境。

4.24.3. 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.
还应提供证据，证明所使用的试剂不会对RABS或隔离器内生产的产品产生不利影响。在使用
这些系统之前，应对其保持时间进行验证。

Cleanroom and clean air equipment qualification

洁净室和洁净空气设备的检定

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.
洁净室和洁净空气设备，如单向气流装置（UDAF）RABS和隔离器，用于生产无菌产品，应根据所
需的环境特征进行限定和分类。每个生产操作都需要在操作状态下达到适当的环境洁净度水平，以便
最大限度地减少正在处理的产品或材料存在颗粒或微生物污染的风险。

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.
洁净室和洁净空气设备应使用符合附件15要求的方法进行鉴定。洁净室的鉴定（包括分类）应与操
11
 作环境监测区分开来。

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):
洁净室鉴定是评估A级洁净室或洁净空气设备与其预期用途相符程度的整个过程。作为附件15资格要
求的一部分，洁净室和洁净空气设备的资格鉴定应包括（与安装的设计/操作有关的地方）:

4.27.1. Installed filter leakage and integrity testing.

已安装的过滤器的泄漏和完整性测试。

4.27.2. Airflow measurement Volume and velocity.

空气流量、体积和速度测量。

4.27.3. Air pressure difference measurement.

气压差测量

4.27.4. Airflow direction and visualisation.

气流方向和可视化。

4.27.5. Microbial airborne and surface contamination.

空气中的微生物和表面污染。

4.27.6. Temperature measurement.

温度测量。

4.27.7. Relative humidity measurement.

相对湿度测量。

4.27.8. Recovery testing.

自净测试。

4.27.9. Containment leak testing.

密闭性泄漏测试。。

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.
洁净室分类是洁净室资格鉴定的一部分，是通过测量空气中的非活性颗粒浓度，对照洁净室或洁净空
气设备的规范评估空气洁净程度的一种方法。洁净室和洁净空气设备的分类参考可在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.
对于洁净室分类，应测量等于或大于0.5和5μm的空气中颗粒物。对于静止的A级区域和B级区域，分
类应包括对等于或大于0.5μm的颗粒进行测量； 但是，要使用更大的第二个粒径（例如 可以考虑符合
ISO 14644的1μm。 该测量应在静止和运行状态下进行。 表1列出了每个等级的最大允许空气中颗粒物
浓度。

Table 1: Maximum permitted airborne particulate concentration during classification

表1:分类过程中允许的最大空气颗粒物浓度

12
 Maximum limits for particulates Maximum limits for particulates
微粒的最高限量 微粒的最高限量
≥ 0.5 µm/m3 ≥ 5 µm/m3
Grade
at rest in operation at rest in operation
静态 动态 静态 动态
Not applicable Not applicable
A 3 520 3 520
不适用 不适用
Not applicable
B 3 520 352 000 2 900
不适用
C 352 000 3 520 000 2 900 29 000
Not defined(a) Not defined(a)
D 3 520 000 29 000
未定义 未定义

(a)
For Grade D, in operation limits are not defined. The company should establish in operation
limits based on a risk assessment and historical data where applicable.
（a）
对于D级，未定义运行限制。公司应根据风险评估和历史数据（如适用）确定控制限额。

4.30. For classification of the cleanroom, the minimum number of sampling locations and their positioning can be
found in ISO 14644 Part 1. In addition, for the aseptic processing room and the background environment
(Grade A zone and Grade B area, respectively), sample locations should also consider all critical processing
zones such as the point of fill and stopper bowls. Critical processing locations should be based on a documented
risk assessment and knowledge of the process and operations to be performed in the area.
对于洁净室的分类，可以在ISO 14644第1部分中找到最少的采样数量及其位置。此外，对于无菌加工
区和背景环境（分别为A级区域和B级区域），采样位置 还应考虑所有关键的加工区域，例如灌装点
和加塞点。关键加工位置应基于文件化的风险评估以及对该区域要执行的工艺和操作的了解。

4.31. Clean room classification should be carried out in the “at rest” and “in operation” states.
洁净室分类应在"静止"和"运行"状态下进行。

4.31.1. The definition of “at rest” state is the condition whereby the installation of all the utilities is
complete including any functioning HVAC, with the main manufacturing equipment installed as
specified and standing by for operation, without personnel in the room.
"静止"状态的定义是指所有公用设施的安装完成，包括任何运行正常的暖通空调系统，主要
生产设备已按规定安装，并处于待命状态，房间内无人员。

4.31.2. The definition of “in operation” state is the condition where the installation of the cleanroom is
complete, the HVAC system fully operational, equipment installed and functioning in the
manufacturer’s defined operating mode with the maximum number of personnel present
performing or simulating routine operational work. In operation classification may be performed
during simulated operations or during aseptic process simulations (where worst case simulation
is required).
“运行中”状态的定义是洁净室的安装完成，HVAC系统完全运行，设备已安装并以生产商定义
的运行模式运行，最大数量的人员在场执行或模拟常规操作工作的状态。 在操作中，分类可
以在模拟操作或无菌工艺模拟（需要最坏情况模拟）期间执行。

4.31.3. The particulate limits given in Table 1 above for the “at rest” state should be achieved after a
“clean up” period on completion of operations. The "clean up" period should be determined
during the classification of the rooms (guidance value of 15 to 20 minutes).
上文表1中给出的"静止"状态下的颗粒限值应在操作完成后的"清理"期间达到。"清理"时间应
在房间分类时确定（指导值为15至20分钟）。

4.32. The speed of air supplied by unidirectional airflow systems should be clearly justified in the qualification
protocol including the location for air speed measurement. Air speed should be designed, measured and
maintained to ensure that appropriate unidirectional air movement provides protection of the product and open
13
 components at the working height (e.g. where high risk operations and product and/or components are exposed).
Unidirectional airflow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance
value) at the working position, unless otherwise scientifically justified in the CCS. Airflow visualization studies
should correlate with the air speed measurement.
由单向气流系统供应的空气的速度应在鉴定协议中明确说明，包括空气速度测量的位置。 应设计，
测量和保持风速，以确保适当的单向空气流动在工作高度（例如高风险操作和暴露于产品和/或无菌
连接的地方）为产品和敞开的组件提供保护。 单向气流系统应在工作位置提供0.36 0.54 m / s（指导
值）的均匀风速，除非在CCS中有科学依据。 气流可视化研究应与风速测量相关。

4.33. The microbial concentration of the cleanrooms should be determined as part of the cleanroom qualification.
The number of sampling locations should be based on a documented risk assessment, including the results of
the classification, air visualization studies and knowledge of the process and operations to be performed in the
area. The maximum limits for microbial contamination during qualification for each grade are given in Table
2. Qualification should include both at rest and in operation states.
洁净室的微生物浓度应作为洁净室资格的一部分进行测定。取样位置的数量应基于文件化的风险评估，
包括分类的结果。空气可视化研究和在该区域执行的工艺和操作的知识。表2给出了每个等级的合格
期间微生物污染的最大限值。鉴定应包括静止状态和运行状态。

Table 2: Limits for microbial contamination during qualification

表2:鉴定期间的微生物污染限值

Settle plates Contact plates

Air sample
沉降板 接触板
Grade 空气样本
级别 (diameter 90 mm) (diameter 55mm)
CFU/m3
cfu/4 hours (a) cfu/plate
A(b) No growth(b) 无增长
B 10 5 5
C 100 50 25
D 200 100 50
(a)
Settle plates should be exposed for the duration of operations and changed as required after
4 hours. Exposure time should be based on recovery studies and should not allow desiccation of the
media used.
（a ）
沉降板应在作业期间暴露，并在4小时后按要求更换。暴露时间应以回收研究为基础，不允许
所用介质干燥。

(b)
It should be noted that for Grade A, the expected result should be no growth.
（B ）
应注意的是，对于A级，预期结果应为无增长。

 Note 1: All methods indicated for a specific Grade in the table should be used for qualifying the
area of that specific Grade. If one of the methods is not used, or alternative methods are used, the
approach taken should be appropriately justified.
注1:表中特定级别所示的所有方法均应用于限定该特定级别的面积。如果没有使用其中一
种方法，或者使用了其他方法，则所采用的方法应具有适当的合理性。

 Note 2: Limits are applied using cfu throughout the document. If different or new technologies
are used that present results in a manner different from cfu, the manufacturer should
scientifically justify the limits applied and where possible correlate them to cfu.
注2:在整个文档中，使用CFU应用限制。如果使用不同或新的技术以不同于CFU的方式呈
现结果，则制造商应科学地证明所应用的限制，并在可能的情况下将其与CFU相关联。

 Note 3: For qualification of personnel gowning, the limits given for contact plates and glove
prints in Table 7 should apply.
注3:对于人员着装的资格，应适用表7中给出的接触板和手指接触的限制。

 Note 4: Sampling methods should not pose a risk of contamination to the manufacturing
14
 operations.
注4:取样方法不应对生产操作造成污染风险。

4.34. The requalification of cleanrooms and clean air equipment should be carried out periodically following defined
procedures. The requirement for requalification of cleanroom areas is as follows:
洁净室和洁净空气设备的再验证应按照规定的程序定期进行。洁净室区域的再验证要求如下:

Table 3: Minimum test requirements for the requalification of cleanrooms

表3:洁净室再验证的最低试验要求

Determination of the
Verification of air
concentration of Integrity Test of
Airflow volume pressure difference Air Velocity
Grade airborne viable and non Terminal Filters between rooms
measurement test
级别 viable particles 终端空气过滤器
风量测量 验证房间之间的气 风速试验
空气中活性和非活性颗 的完整性试验
压差
粒浓度的测定

A Yes Yes Yes Yes Yes

B Yes Yes Yes Yes *

C Yes Yes Yes Yes *

D Yes Yes Yes Yes *

*performed according to a risk assessment documented as part of the CCS. However, required for filling zones
(e.g. when filling terminally sterilised products) and background to Grade A RABS.
*根据作为CCS一部分记录的风险评估执行。 但是，灌装区域（例如，灌装最终灭菌产品时）和A级
RABS的背景是必需的。

For Grade A & B areas, the maximum time interval for requalification is 6 months. For Grade C & D
areas, the maximum time interval for requalification is 12 months. Appropriate requalification
consisting of at least the above tests should also be carried out following completion of remedial action
implemented to rectify an out-of-compliance equipment or facility condition or after changes to
equipment, facility or processes. The significance of a change should be determined through the change
management process. Examples of changes to be considered include but are not limited to the
following:
对于A级和B级区，重新获得资格的最长时间间隔为6个月。对于C级和D级地区，重新认证的最长时
间间隔为12个月。在完成补救措施后，还应进行至少由上述测试组成的适当再认证。纠正不符合要
求的设备或设施状况，或在设备、设施或流程发生变化后进行纠正。变更的重要性应通过变更管理
流程来确定。要考虑的更改示例包括但不限于下列各项:
对于A级和B级地区，重新认证的最长时间间隔为6个月。 对于C级和D级地区，重新认证的最长时间
间隔为12个月。 在为纠正不合格设备或设施状况而采取的补救措施完成之后，或在设备，设施或工
艺发生变更后，也应进行至少由上述测试组成的适当重新认证。 变更的重要性应通过变更管理过程
来确定。 要考虑的更改示例包括但不限于以下内容：

 Change in the operational use of the cleanroom, or of the operational setting parameters of the
HVAC system.
洁净室的操作使用或HVAC系统的操作设置参数的改变。

 Interruption of air movement which affects the operation of the installation.

影响系统运行的空气流动中断。

 Special maintenance which affects the operation of the installation (e.g. change of final filters).
影响系统运行的特殊维护（如更换末级过滤器）。

4.35. Other characteristics, such as temperature and relative humidity, should be controlled within ranges that align
15
 with product/processing requirements and support maintenance of defined cleanliness standards (e.g. Grade
A or B).
其他特性，如温度和相对湿度，应控制在与产品/加工要求一致的范围内，并支持维护规定的洁净度
标准（如A级或B级）。

Disinfection
消毒

4.36. The disinfection of cleanrooms is particularly important. They should be cleaned and disinfected thoroughly
in accordance with a written programme. For disinfection to be effective, prior cleaning to remove surface
contamination should be performed. More than one type of disinfecting agent should be employed to ensure
that where they have different modes of action and their combined usage is effective against all bacteria and
fungi. Disinfection should include the periodic use of a sporicidal agent. Monitoring should be undertaken
regularly in order to assess the effectiveness of the disinfection program and to detect changes in types of
microbial flora (e.g. organisms resistant to the disinfection regime currently in use). Cleaning programs should
effectively remove disinfectant residues.
洁净室的消毒尤为重要。应按照书面程序彻底清洁和消毒。为使消毒有效，应事先进行清洁以去除表
面污染物。应使用一种以上的消毒剂，以确保它们具有不同的作用方式，并且它们的组合使用对所有
细菌和真菌均有效。消毒应包括定期使用杀孢子剂。应该定期进行监测，以评估消毒程序的有效性并
检测微生物菌群类型的变化（例如，对当前使用的消毒方案有抵抗力的生物）。清洁程序应有效去除
消毒剂残留物。

4.37. The disinfection process should be validated. Validation studies should demonstrate the suitability and
effectiveness of disinfectants in the specific manner in which they are used and should support the in use expiry
periods of prepared solutions.
消毒过程应经过验证。验证研究应证明消毒剂在特定使用方式下的适宜性和有效性，并应支持所配制
溶液的使用期限。。

4.38. Disinfectants and detergents used in Grade A zone and Grade B areas should be sterile prior to use
(disinfectants used in Grade C and D may also be required to be sterile). Where the disinfectants and detergents
are made up by the sterile product manufacturer, they should be monitored for microbial contamination.
Dilutions should be kept in previously cleaned containers and should only be stored for defined periods. If the
disinfectants and detergents are supplied “ready-made” then results from certificates of analysis or
conformance can be accepted subject to successful completion of the appropriate vendor qualification.
A级区域和B级区域中使用的消毒剂和清洁剂在使用前应该是无菌的（C级和D级使用的消毒剂也可能
要求是无菌的）。如果消毒剂和清洁剂是由无菌产品生产商配制的，则应对其进行微生物污染监测。
稀释液应保存在事先清洁的容器中，并且只能在规定的时间内保存。如果消毒剂和清洁剂是“现成”的，
则在成功完成相应供应商资格的前提下，可以接受检验证书或合格证书的结果。

4.39. Fumigation or vapour disinfection (e.g. Vapour phased Hydrogen Peroxide) of cleanrooms and associated
surfaces may be useful for reducing microbial contamination in inaccessible places.
洁净室和相关表面的熏蒸或蒸气消毒（例如气化氧化氢）可能有助于减少无法进行表面清洁和消毒的
地方的微生物污染。

5. Equipment
设备

5.1. A written, detailed description of the equipment design should be available (including process and
instrumentation diagrams as appropriate). This should form part of the initial qualification package and be kept
up to date as part of the ongoing review of the CCS.
应提供设备设计的书面详细说明（包括适当的工艺和仪表图）。这应成为初始软件包的一部分，并作
为CCS持续审查的一部分不断更新。

5.2. Equipment monitoring requirements should be defined in “user requirements specifications” and during early
stages of development, and confirmed during qualification. Process and equipment alarm events should be
reviewed and approved and evaluated for trends. The frequency at which alarms are assessed should be based
on their criticality (with critical alarms reviewed immediately).
16
 设备监控要求应在“用户需求说明”中以及在开发的早期阶段进行定义，并在验证过程中进行确认。
应对工艺和设备报警事件进行审查和批准并评估趋势。 评估报警的频率应基于警报的严重性（立即
审查关键报警）。

5.3. As far as practicable, equipment, fittings and services should be designed and installed so that operations,
maintenance, and repairs can be performed outside the cleanroom. If maintenance has to be performed in the
cleanroom, and the required standards of cleanliness and/or asepsis cannot be maintained, then precautions
such as restricting access to the work area to specified personnel, generation of clearly defined work
protocols and maintenance procedures should be considered. Cleaning, additional disinfection and additional
environmental monitoring should also be considered. If sterilization of equipment is required, it should be
carried out, wherever possible, after complete reassembly.
在可行的情况下，设备、配件和服务的设计和安装应使操作、维护和维修能够在洁净室外进行。如果
必须在洁净室内进行维护，并且不能维持所需的清洁度和/或无菌标准，则应考虑采取预防措施，例
如限制特定人员进入工作区域，制定明确定义的工作规程和维护程序 。 还应考虑进行清洁，额外的
消毒和额外的环境监控。 如果需要对设备进行灭菌，则应在完全重新组装后尽可能进行灭菌。

5.4. The cleaning process should be validated to:

清洁验证前应确认

5.4.1. Remove any residue or debris that would detrimentally impact the effectiveness of the
disinfecting agent used.
清除任何可能对所用消毒剂的效力产生不利影响的残留物或碎屑。

5.4.2. Minimize chemical, microbial and particulate contamination of the product during the process
and prior to disinfection.
在消毒过程中和消毒前，尽量减少产品的化学、微生物和颗粒污染。

5.5. Direct and indirect contact parts should be sterilized. Direct contact parts are those that the product passes
through, such as filling needles or pumps. Indirect product contact parts are equipment parts that come
into contact with sterilized critical items and components.
直接和间接接触部位均应消毒。直接接触部件是指产品经过的部件，如填充针或泵。间接产品接触部
件是与灭菌的关键物品和部件接触的设备部件。

5.6. All equipment such as sterilizers, air handling systems (including air filtration) and water systems should
be subject to qualification, monitoring and planned maintenance. Upon completion of maintenance, their return
to use should be approved.
所有设备如灭菌器，空气处理系统（包括空气过滤）和水系统应进行验证，监测和计划中的维护，维
修完成后，应批准其恢复使用。

5.7. Where unplanned maintenance of equipment critical to the sterility of the product is to be carried out, an
assessment of the potential impact to the sterility of the product should be performed and recorded.
对产品无菌至关重要的设备进行计划外维护时，应对产品无菌的潜在影响进行评估并记录。

5.8. A conveyor belt should not pass through a partition between a Grade A or B area and a processing
area of lower air cleanliness, unless the belt itself is continually sterilized (e.g. in a sterilizing tunnel).
传送带不应通过空气洁净度较低的A级或B级区域和A级处理区域之间的隔板，除非传送带本身持续进
行消毒（例如在灭菌隧道中）。

5.9. Particle counters, including sampling tubing, should be qualified. The tubing length should be no greater than
1 meter with a minimum number of bends and bend radius should be greater than 15 cm. Portable particle
counters with a short length of sample tubing should be used for classification purpose. Isokinetic sampling
heads should be used in unidirectional airflow systems and should be positioned as close as possible to sample
air representative of the critical location.
微粒计数器，包括取样管，应合格。管道长度应不大于1米，最小弯曲数和弯曲半径应大于15厘米。
用于洁净级别分类的采样，应使用采样管较短的便携式颗粒计数器。。应在单向气流系统中使用等速
取样头，并应尽可能靠近代表关键位置的空气取样。
17
6. Utilities
公用设施

6.1. The nature and extent of controls applied to utility systems should be commensurate with the risk to product
quality associated with the utility. The impact should be determined via a risk assessment documented as part
of the CCS.
应用于公用设施系统控制的质量属性和范围应与与公用设施相关的产品质量风险相称。应通过风险评
估确定其影响，并将其记录为CCS的一部分。

6.2. In general higher risk utilities are those that:

一般来说，风险较高的公用设施有那些:

6.2.1. Directly contact product e.g. water for washing and rinsing, gases and steam for sterilization.
直接接触产品，如用于洗涤和漂洗的水，用于灭菌的气体和蒸汽。

6.2.2. Contact materials that will ultimately become part of the product.
最终将成为产品一部分的接触物料。

6.2.3. Contact surfaces that come into contact with the product.
与产品接触的接触面。

6.2.4. Otherwise directly impact the product.

否则直接影响产品的质量。

6.3. Utilities should be designed, installed, operated, maintained and monitored in a manner to ensure that the utility
functions as expected.
公用设施的设计、安装、操作、维护和监控应确保其功能符合预期。

6.4. Results for critical parameters and critical quality attributes of high risk utilities should be subject to regular
trend analysis to ensure that system capabilities remain appropriate.
高风险设施的关键参数和关键质量属性的结果应定期进行趋势分析，以确保系统能力保持适当。

6.5. Records of utility installation should be maintained throughout the system’s life cycle. Such records should
include current drawings and schematic diagrams, construction material lists and specifications. Typically,
important information includes attributes such as:
在系统的整个生命周期中，应保留公用设施安装的记录。此类记录应包括当前图纸和示意图、施工材
料清单和规格。通常，重要信息包括以下属性:

6.5.1. Pipeline flow direction, slopes, diameter and length.

管道流向、坡度、管径和长度。

6.5.2. Tank and vessel details.

罐和容器的细节。

6.5.3. Valves, filters, drains, sampling and user points.

阀门、过滤器、排水管、取样和使用点。

6.6. Pipes, ducts and other utilities should not be present in cleanrooms. If unavoidable, then they should be
installed so that they do not create recesses, unsealed openings and surfaces which are difficult to clean.
Installation should allow cleaning and disinfection of outer surface of the pipes.
洁净室内不应存在管道、导管和其他公用设施。如果无法避免，则安装时应确保不会产生难以清洁的
凹槽、未密封的开口和表面。安装时应允许对管道外表面进行清洗和消毒。

Water systems
水系统

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6.7. Water treatment plant and distribution systems should be designed, constructed and maintained to minimize
the risk of particulates, microbial contamination/proliferation and pyrogens (e.g. sloping of piping to provide
complete drainage and the avoidance of dead legs), and prevent the formation of biofilms to ensure a reliable
source of water of an appropriate quality. Where filters are included in the system, special attention should
be given to the monitoring and maintenance of these filters. Water produced should comply with the current
monograph of the relevant Pharmacopeia.
水制备系统和分配系统的设计、建造和维护应最大限度地减少微粒，微生物污染/扩散和热原的风险
（例如，倾斜管道以提供完全的排水和避免死角），并防止生物膜的形成，以确保具有适当质量的可
靠水源。当系统中包含过滤器时，应特别注意对这些过滤器的监控和维护。产生的水应符合有关药典
的最新规定。

6.8. Water systems should be qualified to maintain the appropriate levels of physical, chemical andmicrobial control,
taking seasonal variation into account.
考虑到季节变化，水系统应保持适当的物理、化学和微生物控制水平。

6.9. Water flow should remain turbulent through the pipes to minimize the risk of microbial adhesion,and
subsequent biofilm formation.
水流在管道中应保持紊流状态，以最大限度地降低微生物粘附的风险。以及随后的生物膜形成。

6.10. Water for injections (WFI) should be produced from water meeting specifications that have been defined during
the qualification process, stored and distributed in a manner which minimizes the risk of microbial growth (for
example by constant circulation at a temperature above 70°C). Where the WFI is produced by methods
other than distillation, further techniques such as nanofiltration and ultra filtration as well as
electrodeionization (EDI) should be considered in conjunction with reverse osmosis (RO) membranes.
注射用水（WFI）的生产应使用符合验证过程中规定的规范，并以使微生物生长的风险最小化的方式
（例如，通过在70°C以上的温度持续循环）来存储和分配。 如果WFI是通过蒸馏以外的方法生产的，
则应考虑将诸如纳滤和超滤以及电去离子（EDI）的其他技术与反渗透（RO）膜结合使用。

6.11. Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters, the filters should be
sterilized and the integrity of the filter tested before installation and after removal following use.
如果WFI储罐配备有疏水性除菌过滤器呼吸器，则应在安装前和使用后拆卸前对过滤器进行消毒并测
试其完整性。则过滤器应在安装前和使用拆卸后进行消毒和完整性测试。

6.12. To minimize the risk of biofilm formation, sterilization or disinfection or regeneration of waterystems should
be carried out according to a predetermined schedule and when microbial counts exceed action limits.
Disinfection of a water system with chemicals should be followed by a validated rinsing/flushing procedure.
Water should be tested after disinfection/regeneration. The results should be approved before the water system
is returned to use.
为了最大限度地减少生物膜形成的风险，应根据预定的时间表和当微生物数量超过行动限制时，对水
系统进行灭菌或消毒或再生。使用化学品对水系统进行消毒后，应采用经过验证的漂洗/冲洗程序。
水应在消毒/再生后进行检测。在供水系统重新使用之前，应先批准检测结果。

6.13. Regular ongoing chemical and microbial monitoring of water systems should be performed. Alert levels
should be based on the qualification or a review of ongoing monitoring data that will identify an adverse
trend in system performance. Sampling programs should reflect the requirements of the CCS and include:
应定期对水系统进行化学和微生物监测。警报级别应基于正在进行的监控数据的鉴定或审查结果，这
些数据将确定系统性能的不利趋势。取样方案应反映CCS的要求，并包括:

6.13.1. All points of use, at a specified interval, to ensure that representative water samples are obtained
for analysis on a regular basis.
在规定的时间间隔内，确保定期收集有代表性的水样进行分析。

6.13.2. Potential worst case sampling locations.

潜在的最坏情况采样位置。

6.13.3. A sample from the point at the end of the distribution loop each day that the water is used.
每天用水时，从分配回路末端的点抽取一个样本。
19
 6.14. Breaches of alert levels should be documented and reviewed, and include investigation of system trends
to determine whether the breach is a single (isolated) event or if results are indicative of loss of control or
system deterioration. Each breach of action limits should be investigated to determine the root cause of the
issue and any impact on the quality of products and manufacturing processes as a result of the potential use of
the water.
应记录和审查警报级别的违规情况，并包括对系统趋势的调查，以确定违规是单个（孤立的）事件，
还是表明失控或系统恶化。应对每一项违反行动限制的行为进行调查，以确定问题的根本原因，以及
由于可能使用水而对产品质量和生产工艺造成的任何影响。

6.15. WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and
conductivity, (unless justified otherwise) as these may give a better indication of overall system performance
than discrete sampling. Sensor locations should be based on risk and the outcome of qualification.
WFI系统应包括连续监测系统，如总有机碳（TOC）和电导率（除非另有理由），因为这些系统可能
比离散采样更好地显示整体系统性能。传感器位置应基于风险和鉴定结果。

Steam used as a direct sterilizing agent

蒸汽用作直接灭菌剂

6.16. Feed water to a pure steam (clean steam) generator should be appropriately purified. Pure steam generators
should be designed, qualified and operated in a manner to ensure that the quality of steam produced meets
defined chemical and endotoxin levels.
纯蒸汽（清洁蒸汽）发生器的给水应适当净化。纯蒸汽发生器的设计、鉴定和操作应确保所产生的蒸
汽质量符合规定的化学和内毒素水平。

6.17. Steam used as a direct sterilizing agent should be of suitable quality and should not contain additives at a level
which could cause contamination of product or equipment. For a pure steam generator supplying pure steam
used for the direct sterilization of materials or product-contact surfaces (e.g. porous hard-good autoclave loads),
steam condensate should meet the current monograph for WFI of the relevant Pharmacopeia. A suitable
sampling schedule should be in place to ensure that representative pure steam samples are obtained for analysis
on a regular basis. Other aspects of the quality of pure steam used for sterilization should be assessed
periodically against validated parameters. These parameters should include the following: non-condensable
gases, dryness value (dryness fraction) and superheat.
用作直接灭菌剂的蒸汽应具有适当的质量，不应含有可能导致产品或设备污染的添加剂。对于提供用
于对物料或产品接触表面进行直接灭菌的纯蒸汽的纯蒸汽发生器（例如，多孔的硬质高压灭菌器），
蒸汽冷凝物应符合相关《药典》 WFI的最新标准。 应制定适当的采样时间表，以确保定期获取有代
表性的纯蒸汽样品进行分析。用于灭菌的纯蒸汽质量的其他方面应定期根据已验证的参数进行评估。
这些参数应包括以下内容：不凝性气体，干度值（干度分数）和过热度。

Gases and vacuum systems

气体和真空系统

6.18. Gases that come in direct contact with the product/primary container surfaces should be of appropriate chemical,
particulate and microbial quality. All relevant parameters, including oil and water content, should be specified,
taking into account the use and type of the gas, the design of the gas generation system and, where applicable,
comply with the appropriate Pharmacopoeia monographs.
与产品/主容器表面直接接触的气体应具有适当的化学，微粒和微生物质量。应规定所有相关参数，
包括油和水含量，同时考虑气体的用途和类型、气体生成系统的设计，并在适用的情况下，遵守适当
的药典专著。

6.19. Gases used in aseptic processes should be filtered through a sterilizing filter (with a nominal pore size of a
maximum of 0.22 µm) at the point of use. Where the filter is used on a batch basis (e.g. for filtration of gas
used for overlay of aseptically filled products) or as product vessel vent filter, then the filter should be integrity
tested and the results included as part of the batch certification process. Any transfer pipework or tubing that
is located after the final sterilizing filter should be sterilized. Whengases are used in the process, microbial
monitoring of the gas should be performed periodically at thepoint of use.
在使用过程中，无菌工艺中使用的气体应通过除菌过滤器（标识孔径最大为0.22 µm）进行过滤。 如
20
 果过滤器是产品使用的（例如用于过滤保护无菌灌装产品的气体）或用作产品容器排气的过滤器，那
么过滤器应进行完整性测试，其结果应作为批量验证过程的一部分。位于最终除菌过滤器之后的任何
输送管道或管道配件均应进行灭菌。在此工艺中使用气体时，应在使用时定期对气体进行微生物监测。

6.20. Where backflow from vacuum or pressure systems poses a potential risk to the product, thereshould be
mechanism(s) to prevent backflow when the vacuum or pressure system is shut off. Heating and cooling and
hydraulic systems
如果真空或压力系统的回流会对产品造成潜在风险，则应该有一种机制可以在真空或压力系统关闭时
防止回流。

Heating and cooling and hydraulic systems

加热和冷却以及液压系统

6.21. Major items of equipment associated with hydraulic, heating and cooling systems, e.g. such as those associated
with Blow-Fill-Seal equipment should, where possible, be located outside the filling room. Where they are
located inside the filling room there should be appropriate controls to contain any spillage and/or cross
contamination associated with the hydraulic system fluids. Where possible, the system should be at a lower
pressure than the processed fluid.
与液压、加热和冷却系统相关的主要设备，例如与吹灌密封设备相关的设备，应尽可能位于灌装室之
外。如果它们位于灌装室内，则应有适当的控制装置，以控制与液压系统流体相关的任何泄漏和/或
交叉污染。在可能的情况下，系统的压力应低于被处理流体的压力。

6.22. Any leaks from these systems that would present a risk to the product should be detectable (i.e. an indication
system for leakage).
这些系统中可能对产品造成风险的任何泄漏都应是可检测的（即泄漏指示系统）。

6.23. For both vacuum and cooling systems there should be periodic cleaning/disinfection as determined in the CCS.
对于真空和冷却系统，应按照CCS中的规定进行定期清洁/消毒。

7. Personnel
人员

7.1. The manufacturer should ensure that there are sufficient appropriate personnel, suitably qualified, trained and
experienced in the manufacture and testing of sterile products, and any of the specific manufacturing
technologies used in the site’s manufacturing operations, to ensure compliance with GMP applicable to the
manufacture and handling of sterile products.
生产商应确保在无菌产品的生产和检测以及现场生产操作中使用的任何特定生产技术方面，有足够的
合格的、受过培训的和有经验的适当人员，以确保无菌产品的制造和操作符合GMP要求。

7.2. Only the minimum number of personnel required should be present in cleanrooms. The maximum
number of operators in cleanrooms should be determined, documented and validated during activities
such as initial qualification and aseptic process simulations, so as not to compromise sterility assurance.
This is particularly important during aseptic processing.
洁净室中只应存在所需的最少数量的人员。在初始鉴定和无菌工艺模拟等活动期间，应确定、记录
和验证洁净室中操作员的最大人数，以免影响产品的无菌保证。这在无菌生产过程中尤为重要。

7.3. Non essential processes such as product inspection and in process testing should be conducted outside the clean
areas wherever possible.
非必要的过程，如产品检验和过程中的测试，应在可能的情况下，在清洁区之外进行。

7.4. All personnel including those performing cleaning, maintenance, monitoring and those that access
cleanrooms should receive regular training, gowning qualification and assessment in disciplines relevant
to the correct manufacture of sterile products. This training should include the basic elements of
microbiology, hygiene, with a specific focus on cleanroom practices, contamination control, aseptic
techniques and the protection of sterile products (for those operators entering the Grade B cleanrooms and/or
intervening into the Grade A zone) and the potential safety implications to the patient if product is not
sterile. The level of training should be based on the criticality of the function and area in which the personnel
21
 are working.
所有人员，包括进行清洁，维护，监控的人员和进入洁净室的人员，均应接受与正确生产无菌产品
相关的学科的定期培训，更衣确认和评估。 该培训应包括微生物学，卫生学的基本知识，并特别关
注洁净室操作，污染控制，无菌技术和无菌产品的保护（针对进入B级洁净室和/或介入A级区域的操
作员） 如果产品不是无菌的，对患者的潜在安全隐患。 培训级别应基于人员工作的职能和领域的重
要性。

7.5. The personnel working in a Grade A zone and Grade B areas should be trained for aseptic gowning and
aseptic practices. Compliance with aseptic gowning procedures should be assessed and confirmed, periodically
reassessed at least annually and should involve both visual and microbial assessment (using monitoring
locations such as hands, arms, chest and forehead. Refer to paragraph 9.30 for the expected limits). The
unsupervised access to Grade A zone and Grade B areas where aseptic operations are or will be conducted
should be restricted to appropriately qualified personnel, who have passed the gowning assessment and have
participated in a successful aseptic process simulation (APS).
在A级区域和B级区域工作的人员应接受无菌着装和无菌操作的培训。应评估和确认无菌着装程序的
符合性。至少每年定期重新评估一次，并应包括目视和微生物评估。（使用监测位置，例如手，手臂，
胸部和前额。预期限制参见章节9.30）。应适当限制无监督人员进入正在或将要进行无菌操作的A级
区域和B级区域。合格的人员，应通过了着装考核，并参加了成功的无菌工艺模拟（APS）。

7.6. Unqualified personnel (e.g. building and maintenance contractors and regulatory inspectors) should not enter
Grade B cleanrooms or Grade A zones in operation. If needed in exceptional cases, manufacturers should
establish written procedures outlining the process by which unqualified personnel are brought into the
Grade B and A areas. Access by these persons should be assessed and recorded in accordance with the PQS.
An authorized person from the manufacturer should supervise the unqualified personnel during their activities
and should assess the impact of these activities on the cleanliness of the area.
不合格人员（如建筑和维修承包商及监管检查员）不得进入正在运行的B级洁净室或A级洁净区。如
果在例外情况下需要，生产商应建立书面程序，概述将不合格人员带入B级的过程，以及A地区。应
根据PQS对这些人员的接触情况进行评估和记录。制造商的授权人员应在不合格的人员进行活动的过
程中进行监督，并应评估这些活动对区域洁净度的影响。

7.7. There should be systems in place for disqualification of personnel from entry into cleanrooms based on aspects
including ongoing assessment and/or identification of an adverse trend from the personnel monitoring
program and/or after participation in a failed APS. Once disqualified, retraining and requalification
should be completed before permitting the operator to have any further involvement in aseptic practices. For
operators entering Grade B cleanrooms or performing intervention into Grade A zone, this requalification
should include consideration of participation in a successful APS.
应建立基于以下方面的人员丧失进入洁净室资格的系统，这些方面包括不断评估和/或从人员监视计
划中识别不利趋势，以及/或者在参加失败的APS之后。 一旦取消资格，应在允许操作者进一步参与
无菌操作之前完成再培训和重新资格鉴定。 对于进入B级洁净室或对A级区域进行干预的操作员，此
重新认证应包括考虑参加成功的APS。

7.8. High standards of personal hygiene and cleanliness are essential to prevent excessive shedding or increased
risk of introduction of microbial contamination. Personnel involved in the manufacture of sterile products
should be instructed to report any specific health conditions or ailments which may cause the shedding of
abnormal numbers or types of contaminants and therefore preclude cleanroom access. Health conditions and
actions to be taken with regard to personnel who could be introducing an undue microbial hazard should be
provided by the designated competent person and described in procedures.
高标准的个人卫生和清洁对于防止过度脱落或增加引入微生物污染的风险至关重要。因此。应指示参
与无菌产品生产的人员报告任何可能导致污染的特定健康状况或疾病。从而防止进入洁净室，避免异
常数量或类型的污染物脱落。对于可能引入不适当微生物危害的人员，应由指定的称职人员提供健康
条件和应采取的措施，并在程序中加以说明。

7.9. Staff who have been engaged in the processing of human or animal tissue materials or of cultures of micro
organisms, other than those used in the current manufacturing process, or any activities that may have a
negative impact to quality (e.g. microbial contamination), should not enter clean areas unless clearly defined
and effective decontamination and entry procedures have been followed.
从事处理人类或动物组织材料或微生物培养物（当前制造过程中使用的材料除外）或任何可能对质
22
 量产生负面影响（如微生物污染）的活动的工作人员，不得进入清洁区域，除非明确规定并遵循有效
的净化和进入程序。

7.10. Wristwatches, make up, jewellery, other personal items such as mobile phones and any other non
essential items should not be allowed in clean areas. Electronic devices used in cleanrooms, e.g. mobile phones
and tablets, that are supplied by the company solely for use in the cleanrooms, may be acceptable if suitably
designed to permit cleaning and disinfection commensurate with the Grade in which they are used. The use and
disinfection of such equipment should be included in the CCS.
手表、化妆品、珠宝、其他个人物品（如手机）和任何其他非必要物品都不能进入洁净区。洁净室中
使用的电子设备，如移动电话和平板电脑，由公司提供，仅供在洁净室中使用，如果经过适当设计，
允许进行与其使用等级相称的清洁和消毒，则可以接受。这些设备的使用和消毒应包括在CCS中。

7.11. Cleanroom gowning and hand washing should follow a written procedure designed to minimize contamination
of cleanroom clothing and/or the transfer of contaminants to the clean areas.
洁净室更衣和洗手应遵循书面程序，以最大限度地减少对洁净室衣物的污染和/或污染物向洁净区的
扩散。

7.12. The clothing and its quality should be appropriate for the process and the grade of the working area.
It should be worn in such a way as to protect the product from contamination. When the type of clothing
chosen needs to provide the operator protection from the product, it should not compromise the protection
of the product from contamination. Garments should be visually checked for cleanliness and integrity
immediately prior to gowning and prior to entry to the cleanroom. Gown integrity should also be checked upon
exit. For sterilized or effectively decontaminated garments and eye coverings, particular attention should be
taken to ensure they have been processed, are within their specified hold time and that the packaging is
visually inspected to ensure it is integral before use. Reusable garments (including eye coverings) should be
replaced if damage is identified or at a set frequency that is determined during qualification studies. . Damage
to garments may not be identified by visual inspection alone, so the qualification should consider any
necessary garment testing requirements.
服装及其质量应与工作区域的工艺和等级相适应。应以保护产品不受污染的方式佩戴。当所选择的服
装类型需要为操作员提供免受产品影响的保护时，它不应能对产品造成受污染。在着装前和进入洁净
室前，应立即目视检查服装的清洁度和完整性。退场时还应检查礼服的完整性。对于已灭菌或有效净
化的服装和眼罩，应特别注意确保其已经过处理。并在使用前对包装进行目视检查，以确保其完整无
损。可重复使用的服装（包括眼罩）如果发现损坏，或在确认验证期间确定的设定频次下进行更换。.
仅凭目视检查可能无法确定服装的损坏，因此，资格审查应考虑任何必要的服装测试要求

7.13. Clothing should be chosen to prevent shedding due to operators moving excessively (when cold) or sweating
(when hot).
应选择合适的衣服，以防止因操作人员过度移动(冷的时候)或出汗(热的时候)而导致衣服脱落微粒。

7.14. The description of clothing required for each grade is given below:
每个等级所需的服装说明如下:

7.14.1. Grade A / B: Dedicated garments to be worn under a sterilized suit. Sterile headgear should enclose
all hair (including facial hair) and where separate from the rest of the gown, it should be tucked
into the neck of the sterile suit. A sterile face mask and sterile eye coverings (e.g. goggles)
should be worn to cover and enclose all facial skin and prevent the shedding of droplets and
particulates. Appropriate sterilized, non powdered, rubber or plastic gloves and sterilized footwear
(such as overboots) should be worn. Trouser legs should be tucked inside the footwear and
garment sleeves into the gloves. The protective clothing should minimize shedding of fibres or
particulate matter and retain particulates shed by the body. Garments should be packed and folded
in such a way as to allow operators to gown without contacting the outer surface of the garment.
A/B级:在灭菌套装内穿着的专用服装。无菌帽应包裹所有头发（包括面部毛发）如果与洁净
服的其他部分分开，则应将其塞进无菌服的颈部。无菌面罩和无菌眼罩（如护目镜）应佩
戴，以覆盖和封闭所有面部皮肤，并防止飞沫和微粒脱落。应戴上适当灭菌、无粉末的橡胶
或塑料手套和灭菌的鞋类（如套靴）。裤腿应塞进鞋内，衣袖应塞进手套内。防护服应尽量
减少纤维或微粒物质的脱落，并保能截留身体脱落的微粒。服装的包装和折叠方式应允许操
作者在穿着时不接触服装的外表面。
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 7.14.2. Grade C: Hair, beards and moustaches should be covered. A single or two piece trouser suit gathered
at the wrists and with high neck and appropriately disinfected shoes or overshoes should be worn.
They should minimize the shedding of fibres and particulate matter.
C级：应当将头发、胡须等相关部位遮盖，应当穿手腕处可收紧的连体服或衣裤分开的工作
服，并穿着经过适当消毒的鞋子或套鞋。工作服应当不脱落纤维或微粒。

7.14.3. Grade D: Hair, beards and moustaches should be covered. A general protective suit and
appropriately disinfected shoes or overshoes should be worn. Appropriate measures should be taken
to avoid any ingress of contaminants from outside the clean area.
应当将头发、胡须等相关部位遮盖。应当穿合适的工作服和鞋子或鞋套。应当采取适当措
施，以避免带入洁净区外的污染物。

7.14.4. Gloves should be worn in Grade C and D areas when performing activities considered to be a
contamination risk as defined by the CCS.
在C级和D级区域执行CCS定义为A级污染风险的活动时，应戴手套。

7.15. Outdoor clothing (other than personal underwear) should not be brought into changing rooms leading directly
to Grade B and C cleanrooms. Facility suits, covering the full length of the arms and the legs, and socks
covering the feet, should be worn before entry to change rooms for Grades B and C. Facility suits and socks
should not present a risk of contamination to the gowning area or processes.
户外服装（除个人内衣外）不得带入直接通往B级和C级洁净室的更衣室。进入B级和C级更衣室前，
应穿上覆盖手臂和腿部全长的工作服和覆盖脚部的袜子。工作服和袜子不应对着装区域或流程造成污
染风险。

7.16. Every operator entering Grade B or A areas should gown into clean, sterilized protective garments
(including eye coverings and masks) of an appropriate size at each entry. The maximum duration of each
garment use should be defined as part of the garment qualification.
进入B级或A级区域的每个操作员应在每个入口处穿上适当尺寸的清洁、消毒的防护服（包括眼罩和
口罩）。每件服装使用的最长期限应被定义为服装资格的一部分。

7.17. Garments and gloves should be changed immediately if they become damaged and present any risk of product
contamination. Gloves should be regularly disinfected during operations.
如果衣服和手套损坏并有可能造成产品污染，应立即更换。操作时应定期消毒手套。

7.18. Clean area clothing should be cleaned in a dedicated laundry facility using a qualified process ensuring that
the clothing is not damaged and/or contaminated by fibres and particles during the laundry process.
Inappropriate handling and use of clothing will damage fibres and may increase the risk of shedding of
particles. After washing and before packing, garments should be visually inspected for damage. The
garment management processes should be evaluated and determined as part of the garment qualification
program.
洁净区衣物应在专用洗衣设施中使用合格的流程进行清洗，以确保衣物没有损坏和/或在洗衣清洗过
程中被纤维和颗粒污染。不适当地处理和使用衣物会损坏纤维，并可能增加脱落微粒的风险。在洗涤
后和包装前，应目视检查服装是否有损坏。服装管理流程应作为服装资格认证计划的一部分进行评估
和确定。

7.19. Activities in clean areas that are not critical to the production processes should be kept to a minimum,
especially when aseptic operations are in progress. Movement of personnel should be slow, controlled and
methodical to avoid excessive shedding of particulates and organisms due to over vigorous activity. Operators
performing aseptic operations should adhere to aseptic technique at all times to prevent changes in air currents
that introduce air of lower quality into the critical zone. Movement adjacent to the critical zone should be
restricted and the obstruction of the path of the unidirectional (first air) airflow should be avoided.
Airflow visualisation studies should be considered as part of the operator’s training programme.
清洁区域中对生产过程不重要的活动应保持在最低限度。尤其是在进行无菌操作时。人员流动应当
缓慢，控制和方法，以避免过度脱落的微粒和生物体，由于过于激烈的活动。执行无菌操作的操作人
员应始终坚持无菌技术，以防止气流的变化引入空气。我们的质量进入了临界区。邻近临界区的移动
应受到限制，单向（第一空气）路径的阻碍应避免气流。应将气流可视化研究视为操作员培训计划的
24
 一部分。
在洁净区域中对生产过程不重要的活动应降低至最低水平，尤其是在进行无菌操作时。 人员的流动
应缓慢，受控和有条理，以避免由于过度剧烈活动而过多地散布微粒和微生物。 进行无菌操作的操
作的人员应始终坚持使用无菌技术，以防止气流变化而将劣质空气引入关键区域。 应限制靠近关键
区的操作，并应避免跟你说单向（第一空气）气流的路径。 气流可视化研究应被视为操作员培训计
划的一部分。

8. Production and Specific Technologies

生产和特定的技术

Terminally sterilized products

终端灭菌产品

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.
部件和材料的准备应在至少D级洁净室中进行，以限制微生物、热原和微粒污染，以使产品适合灭菌。
当产品处于微生物污染的高风险或异常风险中时（例如:该产品适合于微生物生长，产品在灌装前必
须存放很长时间，或者产品不是在封闭容器中处理的），则应在C级环境中进行制备。配制药膏、乳
膏、在终端灭菌前，悬浮液和乳状液应在C级环境中进行。

8.2. Primary packaging containers and components should be cleaned using validated processes to ensure that
particulate, pyrogen and bioburden contamination is appropriately controlled.
初级包装容器和部件应使用经过验证的工艺进行清洁，以确保适当控制微粒、热原和生物污染物。

8.3. Filling of products for terminal sterilization should be carried out in at least a Grade Cenvironment.
终端灭菌产品的灌装应在至少C级的环境中进行。

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.
如果产品处于不寻常的环境污染风险中，例如，由于灌装操作缓慢、容器是宽颈的或在密封前必须暴
露几秒钟以上，则产品应在至少具有C级背景的A级区域灌装。

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截留过滤器的过滤步骤，以尽可能减少装填到最终产品容器中
之前的生物负荷水平和微粒，并且在准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中给出了在不同等级中进行的操作的例子。

Table 4: Examples of operations and grades for terminally sterilized preparation and processing
operations
表4:最终灭菌制剂和疫苗的操作和分级示例处理操作

Filling of products, when unusually at risk.

A
高污染风险产品的灌装。
Preparation of solutions, when unusually at risk. Filling of products.
C
在高污染风险产品溶液的配制，产品的灌装；
D Preparation of solutions and components for subsequent filling.
25
 后续填充用溶液和成分的制备

Aseptic preparation and processing

无菌制备和加工

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.
无菌准备和处理是指在受控环境中处理无菌产品、容器和/或设备，在该环境中，空气供应、材料和
人员受到控制，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 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.
无菌工艺应明确规定。与无菌工艺相关的风险，以及任何相关的要求，都应该被识别、评估和适当控
制。现场CCS应明确规定这些控制的验收标准、监测要求和有效性审查。应说明和执行控制这些风险
的方法和程序。被接受的剩余风险应该被正式记录下来

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.
在无菌环境的准备过程中，在所有的加工阶段(包括散装产品灭菌前和灭菌后的阶段)，直至产品密封
在最后的容器中，应根据现场的CCS，采取预防措施，以最大限度地减少微生物、热原和微粒污染。
洁净室内应尽量减少易产生微粒及纤维的物料。

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级区进行关键干预的需
要，并将污染风险降至最低。还可以考虑机器人技术和工艺自动化，以消除直接的人类关键干预（例
如，干热隧道、自动冻干机装载、在线灭菌）。

8.11. Examples of operations to be carried out in the various environmental grades are given in the Table 5.
表5给出了在不同环境等级下进行的操作示例。

Table 5: Examples of operations and grades for aseptic preparation and processing operations
表5:无菌准备和处理操作的操作示例和洁净级别
Critical zone for
关键区
- 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
Grade A should be sterilized by steam in place whenever feasible.
- 在最终除菌过滤器之后的无菌条件下（已暴露无菌产品接触表面的地方）进
行的连接。 在可行的情况下，应对这些连接处进行蒸汽灭菌。
- Aseptic compounding and mixing.
- 无菌配制和混合。
- Replenishment of sterile bulk product, containers and closures.
- 生产过程中添加无菌产品、容器和密封的部件
26
 -。
-Removal and cooling of unprotected (e.g. with no packaging) items from
sterilizers.
- 将无保护（如无包装）的物品从消毒器中取出并冷却。
- Staging and conveying of sterile primary packaging components.
- 无菌初级包装部件的准备和输送。
- Aseptic filling, sealing of containers such as ampoules, vial closure, transfer
of open or partially stoppered vials.
- 无菌灌装容器（如安瓿瓶）的密封，安瓿瓶密封，打开或半加塞的小瓶的转
移。
- Loading of a lyophilizer.
- 冻干机的装载。
Background support for the Grade A zone (when not in an isolator).
Grade B A级区域的背景区域（当不使用隔离器时）。

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。
Grade C Preparation of solutions to be filtered including weighing.
准备要过滤的溶液，包括称量。
- Cleaning of equipment.
- 设备的清洗。
Grade D - Handling of components, equipment and accessories after washing.
- 清洗后部件、设备和附件的处理。
- Assembly of cleaned components, equipment and accessories prior to
sterilization.
- 在灭菌前装配清洁的部件、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。

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:

8.12.1. 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。

8.12.2. 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。

8.12.3. Bulk solutions should be sterilized by a validated process, e.g. by heat, chemical sterilizationor
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。

8.12.4. 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，背景应符合章节4.21和4.22。
27
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，背景应符合段落4.21和4.22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段的规定。 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段。

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，以确保与实际制造活动的一
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:
无菌准备和处理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:

8.18.1. 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。

8.18.2. 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。

8.18.3. 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。

8.18.4. The time between the start of the preparation of a product and its sterilization or filtrati on
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
28
 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。

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

灌装前灭菌产品的保持时间。

8.18.6. The aseptic processing time.

无菌处理时间。

8.18.7. The filling time.

灌装时间。

8.18.8. 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
detect
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

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) bags, 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.
容器应通过适当验证的方法进行封闭。通过熔合封闭的容器，例如吹塑填充密封（BFS）、成型填充
密封（FFS）、小容量和大容量注射剂（SVP和LVP）袋、玻璃或塑料安瓿，应进行100%完整性测试。
应对用其他方法封闭的容器取样，并用经过验证的方法检查其完整性。测试频率应基于所使用的容器
和封闭系统的知识和经验。应使用科学有效的抽样计划。样品量应基于供应商批准、包装组件规格和
工艺知识等信息。应当注意的是，仅凭目视检查并不被认为是一种可接受的完整性测试方法。

8.22. Containers sealed under vacuum (where the vacuum is necessary for the product stability) should be tested for
maintenance of vacuum after an appropriate pre determined period and during shelf life.
在真空下密封的容器（真空对产品的稳定性是必要的）应在适当的预定时间后和货架期内进行真空保
持试验。

8.23. The container closure integrity validation should take into consideration any transportation or shipping
requirements that may negatively impact the integrity of the container (e.g. by decompression or temperature
extremes).
容器密封完整性验证应考虑任何可能对容器完整性产生负面影响的运输或装运要求(例如通过减压或
极端温度)。

8.24. Where the equipment used to crimp vial caps can generate large quantities of non viable particulates, measures
to prevent particulate contamination such as locating the equipment at a physically separate station equipped
29
 with adequate air extraction should be taken.
如果用于压紧小瓶盖的设备会产生大量不可行的颗粒，则应采取措施来防止颗粒污染，例如将设备放
置在配备有足够空气的物理独立位置上。

8.25. Vial capping can be undertaken as an aseptic process using sterilized caps or as a clean process outside the
aseptic core. Where the latter approach is adopted, vials should be protected by Grade A conditions up
to the point of leaving the aseptic processing area, and thereafter stoppered vials should be protected with a
Grade A air supply until the cap has been crimped. Where capping is a manual process it should be performed
under Grade A conditions either in an appropriately designed isolator or into Grade A zone with a Grade B
background.
瓶盖可以作为无菌工艺使用无菌瓶盖或作为清洁过程以外的无菌核心。如果采用后一种方法，小瓶应
在离开无菌处理区之前受到A级条件的保护，之后加塞的小瓶应使用A级空气供应保护，直到瓶盖卷
压紧为止。如果封盖是手工操作，则应在A级条件下进行，要么在设计适当的隔离器中进行，要么在
A级区域内进行，背景为B级。

8.26. Where capping of aseptically filled sterile product is conducted as a clean process with Grade A air supply
protection, vials with missing or displaced stoppers should be rejected prior to capping. Appropriately qualified,
automated methods for stopper height detection should be in place.
如果无菌灌装无菌产品的封盖是作为具有A级空气供应保护的洁净工艺进行的，则在封盖之前，应拒
绝使用有缺失或移位塞子的小瓶。应采用适当的合格的自动方法进行塞子高度检测。

8.27. Where human intervention is required at the capping station, appropriate technological and organizational
measures should be used to prevent direct contact with the vials and to minimize microbial contamination.
如果需要在封盖站进行人为干预，应采用适当的技术和组织措施，以防止直接接触小瓶，并尽量减少
微生物污染。

8.28. RABS and isolators may be beneficial in assuring the required conditions and minimizing the microbial
contamination associated with direct human interventions into the capping operation.
RABS和隔离器可能有助于确保所需的条件，并将与封盖操作中的人类直接干预相关的微生物污染降
至最低。

8.29. All filled containers of parenteral products should be inspected individually for extraneous contamination or
other defects. Defect classification and criticality should be determined during qualification and based on risk
and historical knowledge. Factors to consider include, but are not limited to, the potential impact of the defect
to the patient and the route of administration. Different defect types should be categorized and batch
performance analysed. Batches with unusual levels of defects, when compared with routine defect numbers for
the process (based on historical and trend data), should lead to an investigation. A defect library should be
generated and maintained which captures all known classes of defects. The defect library should be used for
the training of production and quality assurance personnel. Critical defects should not be identified during any
subsequent sampling and inspection of acceptable containers. Any critical defect identified should trigger an
investigation as it indicates a possible failure of the original inspection process.
应对所有已灌装的注射用产品容器进行单独检查，以确定是否存在外来污染或其他缺陷。缺陷分类和
严重程度应在验证期间根据风险和历史知识确定。要考虑的因素包括但不限于缺陷对患者的潜在影响
和给药途径。应对不同的缺陷类型进行分类，并批量性能进行分析。当与工艺的常规缺陷数（基于历
史和趋势数据）比较时，具有异常缺陷水平的批次，应该会导致调查。应该生成并维护一个缺陷库，
该库捕获所有已知的缺陷类。缺陷库应用于生产和质量保证人员的培训。在随后对可接受容器进行的
任何抽样和检查期间，不应识别出关键缺陷。任何发现的关键缺陷都应引发调查，因为它表明最初的
检查过程可能失败。

8.30. When inspection is done manually, it should be performed under suitable and controlled conditions of
illumination and background. Inspection rates should be appropriately controlled and qualified. Operators
performing the inspection should undergo visual inspection qualification (whilst wearing corrective lenses, if
these are normally worn) at least annually. The qualification should be undertaken using appropriate samples
from the manufacturer's defect library sets and taking into consideration worst case scenarios (e.g. inspection
time, line speed where the product is transferred to the operator by a conveyor system, container size or fatigue
at the end of shift) and should include consideration of eyesight checks. Operator distractions should be
minimized and frequent breaks, of an appropriate duration, from inspection should be taken.
30
 当手动进行检查时，应在合适的和受控的照明和背景条件下进行。应适当控制检查率并确保合格。执
行检查的操作员应进行目视检查资格鉴定（如果正常佩戴矫正镜片，则应佩戴矫正镜片）。至少每年
一次。应使用制造商缺陷库中的适当样品进行鉴定，并考虑最坏情况。场景（例如：检验时间、通过
输送系统将产品传送给操作员的生产线速度、容器尺寸或轮班结束时的疲劳程度）并应考虑进行视力
检查。应尽量减少操作者的注意力分散，并应在适当的时间内经常中断检查。

8.31. Where automated methods of inspection are used, the process should be validated to detect known defects
(which may impact the product quality, safety or efficacy) and be equal to, or better than, manual inspection
methods. The performance of the equipment should be challenged using representative defects prior to start up
and at regular intervals.
在使用自动化检验方法的情况下，应对流程进行验证，以检测已知缺陷（可能影响产品质量、安全性
或有效性），且该流程应等于或优于人工检验方法。应在启动前定期使用代表性缺陷对设备的性能提
出质疑。

8.32. Results of the inspection should be recorded and defect types and numbers trended. Reject levels for the various
defect types should also be trended based on statistical principles. Impact to product on the market should be
assessed as part of the investigation when adverse trends are observed.
应记录检查结果，并对缺陷类型和数量进行趋势分析。各种缺陷类型的拒收水平也应根据统计原则进
行趋势分析。当观察到不利趋势时，作为调查的一部分，应评估产品对市场的影响。

Sterilization
灭菌

8.33. Where possible, finished product should be terminally sterilized, using a validated and controlled sterilization
process, as this provides a greater assurance of sterility than a validated and controlled sterile filtration process
and/or aseptic processing. Where it is not possible for a product to undergo terminal sterilization, consideration
should be given to using terminal bioburden reduction steps, such as heat treatments (e.g. pasteurization),
combined with aseptic process to give improved sterility assurance.
在可能的情况下，应使用经过验证和控制的灭菌工艺对成品进行最终灭菌。因为这提供了比验证和控
制的无菌过滤过程和/或无菌处理更大的无菌性保证。如果不可能对产品进行最终灭菌，则应考虑使
用最终生物负荷减少步骤，例如热处理巴氏杀菌），结合无菌工艺，以提供更好的无菌保证。

8.34. The selection, design and location of the equipment and cycle/programme used for sterilization should be based
on scientific principles and data which demonstrate repeatability and reliability of the sterilization process.
Critical parameters should be defined, controlled, monitored and recorded.
用于灭菌的设备和周期/程序的选择、设计和位置应以科学原则和数据为依据，证明灭菌过程的可重
复性和可靠性。应定义、控制、监测和记录关键参数。

8.35. All sterilization processes should be validated. Validation studies should take into account the product
composition, storage conditions and maximum time between the start of the preparation of a product or material
to be sterilized and its sterilization. Before any sterilization process is adopted, its suitability for the product
and equipment, and its efficacy in consistently achieving the desired sterilizing conditions in all parts of each
type of load to be processed should be validated notably by physical measurements and where appropriate by
biological indicators (BI). For effective sterilization, the whole of the product, and surfaces of equipment and
components should be subject to the required treatment and the process should be designed to ensure that this
is achieved.
所有灭菌过程都应经过验证。验证研究应考虑产品组成，储存条件和从准备要灭菌的产品或材料开始
到灭菌之间的最长时间。在采用任何灭菌工艺之前，其对产品和设备的适用性，并且应验证其在待处
理的每种装载的所有部分中持续达到所需灭菌条件的效力。可通过物理测量，并在适当情况下通过生
物指标（BI）.为了有效灭菌，整个产品，设备和部件的表面应进行所需的处理，工艺设计应确保这
一点。

8.36. Particular attention should be given when the adopted sterilization method is not described in the current edition
of the Pharmacopoeia, or when it is used for a product which is not a simple aqueous solution. Where possible,
heat sterilization is the method of choice.
当所采用的灭菌方法在现行药典中没有描述时，或当它用于非简单水溶液的产品时，应特别注意。在
可能的情况下，热灭菌是首选的方法。
31
8.37. Validated loading patterns should be established for all sterilization processes and should be subject to periodic
revalidation. Maximum and minimum loads should also be considered as part of the overall load validation
strategy.
应为所有灭菌过程建立经验证的装载模式，并应定期进行再验证。最大和最小负载也应作为总体负载
验证策略的一部分加以考虑。

8.38. The validity of the sterilizing process should be reviewed and verified at scheduled intervals based on risk. Heat
sterilization cycles should be revalidated with a minimum frequency of at least annually.
灭菌过程的有效性应根据风险按预定的时间间隔进行审查和验证。热灭菌周期应至少每年重新验证一
次。

8.39. Routine operating parameters should be established and adhered to for all sterilization processes, e.g. physical
parameters and loading patterns.
应为所有灭菌过程建立并遵守常规操作参数，例如物理参数和装载模式。

8.40. There should be mechanisms in place to detect a sterilization cycle that does not conform to the validated
parameters. Any failed sterilization or sterilization that deviated from the validated process (e.g. have longer or
shorter phases such as heating cycles) should be investigated.
应该有相应的机制来检测不符合验证参数的灭菌周期。任何失败的灭菌或灭菌偏离验证过程(如有较
长或较短的阶段，如加热周期)应进行调查。

8.41. Suitable BIs placed at appropriate locations may be considered as an additional method to support the validation
of the sterilization process. BIs should be stored and used according to the manufacturer’s instructions. Where
BIs are used to support validation and/or to monitor a sterilization process (e.g. for ethylene oxide), positive
controls should be tested for each sterilization cycle. If BIs are used, strict precautions should be taken to avoid
transferring microbial contamination to the manufacturing or other testing processes. BI results in isolation do not
give assurance of sterilization and should not be used to override other critical parameters and process design
elements.
可以考虑将放置在适当位置的合适的BIS作为支持灭菌过程验证的附加方法。BIS应按照制造商的说明
进行储存和使用。其中BIS用于支持验证和/或监控灭菌过程（例如环氧乙烷）此外，应为每个灭菌周
期测试阳性对照。如果使用BIS，应采取严格的预防措施，以避免将微生物污染转移到制造或其他测
试过程中。隔离的BI结果不能保证灭菌，不应用于覆盖其他关键参数和工艺设计元素。

8.42. The reliability of BIs is important. Suppliers should be qualified and transportation and storage conditions
should be controlled in order that BI quality is not compromised. Prior to use of a new batch/lot of BIs, the
population and identity of the indicator organism of the batch/lot should be verified. For other critical
parameters, e.g. D value, Z value, the batch certificate provided by the qualified supplier can normally be used.
BIS的可靠性很重要。供应商应具备资格，运输和储存条件应得到控制，以确保BI质量不受影响。在
使用新批/批次BIS之前，应核实该批/批次的指示生物的种群和身份。对于其他关键参数，如D值、Z
值，可正常使用合格供方提供的批次证。

8.43. There should be a clear means of differentiating products, equipment and components, which have not been
subjected to the sterilization process from those which have. Containers used to carry products such as baskets
or trays, items of equipment and/or components should be clearly labelled (or electronically tracked) with the
material name, product batch number and an indication of whether or not it has been sterilized. Indicators such
as autoclave tape, or irradiation indicators may be used, where appropriate, to indicate whether or not a batch
(or sub batch) has passed through a sterilization process. However, these indicators show only that the
sterilization process has occurred, they do not indicate product sterility or achievement of the required sterility
assurance level.
应该有一种明确的方法来区分产品、设备和部件，未经过灭菌处理的与经过灭菌处理的。用于装载产
品的容器，如篮子或托盘，设备和（或）部件应清楚地贴上标签（或电子跟踪）有物料名称、产品批
号和是否灭菌的说明。在适当的情况下，可以使用诸如高压灭菌带或辐照指示器之类的指示器来指示
一批（或子批）已经经过了消毒过程。然而，这些指标只表明发生了灭菌过程，它们不表示产品无菌
或达到要求的无菌保证水平。

8.44. Sterilization records should be available for each sterilization run. Each cycle should have a unique identifier.
32
 They should be reviewed and approved as part of the batch certification procedure.
每次灭菌都应有灭菌记录。每个周期应该有一个唯一的标识符。它们应作为批认证程序的一部分进行
审查和批准。

8.45. Where possible, materials, equipment and components should be sterilized by validated methods appropriate
to the specific material. Suitable protection after sterilization should be provided to prevent recontamination. If
sterilized items are not used immediately after sterilization, these should be stored using appropriately sealed
packaging. A maximum hold time should also be established. Where justified, components that have been
packaged with multiple sterile packaging layers need not be stored in a cleanroom if the integrity and
configuration of the sterile pack allows the items to be readily disinfected during transfer by operators into the
Grade A zone, (e.g. by the use of multiple sterile coverings that can be removed at each transfer from lower to
higher grade). Where protection is achieved by containment in sealed packaging, this packaging process should
be undertaken prior to sterilization.
在可能的情况下，物料、设备和部件应通过适用于特定材料的经验证的方法进行灭菌。灭菌后应提供
适当的保护，以防止再污染。如果灭菌后的物品没有立即使用，应使用适当的密封包装储存。还应规
定最长保留时间。在合理的情况下，已经用多个无菌包装层包装的部件不需要存储在洁净室中，如果
无菌包允许物品在操作人员转移到A级区域期间容易消毒。例如使用多层无菌覆盖物，每次从低等级
转到高等级时可将其去除）。在通过密封包装实现保护的情况下，应在灭菌之前进行这一包装过程。

8.46. Where materials, equipment, components and ancillary items are sterilized in sealed packaging and then
transferred into the Grade A zone, this should be done using appropriate, validated methods (for example,
airlocks or pass through hatches) with accompanying disinfection of the exterior of the sealed packaging. The
use of rapid transfer port technology should also be considered. These methods should be demonstrated to
effectively control the potential risk of contamination of the Grade A zone and Grade B area and, likewise, the
disinfection procedure should be demonstrated to be effective in reducing any contamination on the packaging
to acceptable levels for entry of the item into the Grade B and Grade A areas.
物料、设备、部件和附属物经密封包装灭菌后转入A级区的，应使用适当的、经过验证的方法（例如
气闸或传递窗）进行此项工作。同时对密封包装的外部进行消毒。还应考虑使用快速传输端口技术。
应证明这些方法可有效控制A级区和B级区的潜在污染风险，应证明灭菌程序能有效地将包装上的任
何污染降低到可接受的水平，以供TH进入。以减少任何污染的包装上的可接受水平的项目进入B级和
A级地区。

8.47. Where materials, equipment, components and ancillary items are sterilized in sealed packaging or containers,
the packaging sealing process should be validated. The validation should consider the integrity of the sterile
protective barrier system and the maximum hold time before sterilization and maximum shelf life assigned to
the sterilized items. The integrity of the sterile protective barrier system for each of the sterilized items should
be confirmed prior to use.
在密封包装或容器中对物料、设备、部件和附属物品进行灭菌的，应当对包装密封过程进行验证。验
证应考虑无菌保护屏障系统的完整性、灭菌前的最长保存时间以及分配给已灭菌物品的最长保存期。
在使用前，应确认每个已灭菌物品的无菌保护屏障系统的完整性。

8.48. For materials, equipment, components and ancillary items that are necessary for aseptic processing but cannot
be sterilized, an effective and validated disinfection and transfer process should be in place. These items, once
disinfected, should be protected to prevent recontamination. These items, and others representing potential
routes of contamination, should be included in the environmental monitoring program.
对于无菌工艺所必需但不能灭菌的材料、设备、部件和附属物品，应建立有效和经验证的消毒和转移
流程。这些物品一旦灭菌后，应加以保护，防止再次污染。这些物品和其他代表潜在污染途径的物品，
应列入环境监测计划。

Sterilization by heat
热力灭菌

8.49. Each heat sterilization cycle should be recorded either electronically or by hardcopy, on equipment with suitable
accuracy and precision. Monitoring and recording systems should be independent of the controlling system (e.g.
by the use of duplex/double probes).
每个热灭菌周期应以适当的准确度和精确度的传感器在设备上进行电子记录或硬拷贝记录。监控和记
录系统应独立于控制系统（例如，通过使用双工/双探头）。
33
8.50. The position of the temperature probes used for controlling and/or recording should be determined during the
validation which should include heat distribution and penetration studies and, where applicable, also checked
against a second independent temperature probe located at the same position.
用于控制和/或记录的温度探头的位置应在验证期间确定，验证应包括热分布和穿透研究，并且在适
用的情况下，还应对照位于同一位置的第二个独立温度探头进行检查。

8.51. Sufficient time should be allowed for the whole of the load to reach the required temperature before
measurement of the sterilizing time period starts. For sterilization cycles controlled by using a reference probe
within the load, specific consideration should be given to ensuring the load probe temperature is controlled
within defined temperature range prior to cycle commencement.
在开始测量灭菌时间之前，应使整个负载有足够的时间达到所需的温度。 对于在负载内使用参考探
头控制的灭菌周期，应特别考虑确保在周期开始之前将负载探头的温度控制在规定的温度范围内

8.52. After completion of the high temperature phase of a heat sterilization cycle, precautions should be taken against
contamination of a sterilized load during cooling. Any cooling liquid or gas that comes in contact with the
product or sterilized material should be sterilized.
在完成热灭菌周期的高温阶段后，应采取预防措施，防止在冷却过程中被灭菌的物品受到污染。与产
品或灭菌物品接触的任何冷却液体或气体都应进行灭菌。

8.53. In those cases where parametric release has been authorized, a robust system should be applied to the product
lifecycle validation and the routine monitoring of the manufacturing process. This system should be periodically
reviewed. Further guidance regarding parametric release is provided in Annex 17.
在已批准参数发布的情况下，应将稳定的系统应用于产品生命周期验证和制造过程的常规监视。 该
系统应定期审查。 附件17提供了有关参数释放的更多指南。

Moist heat sterilization

湿热灭菌

8.54. Moist heat sterilization utilises steam or superheated water, typically at lower temperatures and shorter duration
than dry heat processes, in order to sterilize a product or article. Moist heat sterilization of hard goods or porous
loads is primarily effected by latent heat of condensation of clean steam and the quality of steam is therefore
important to provide consistent results. For aqueous liquid filled containers, energy from moist heat is
transferred through conduction and/or convection to the content of the container without direct contact with the
autoclave steam. In these cases, time and temperature are the key parameters and steam quality does not have
the same impact to the process. Moist heat sterilization processes may be utilized to sterilize or control
bioburden (for non sterile applications) of thermally stable materials, articles or products and is the preferred
method of sterilization, where possible. Moist heat sterilization can be achieved using steam, (direct or indirect
contact), but also includes other systems such as superheated water systems. Superheated systems are typically
used for the terminal sterilization of product in flexible containers where the pressure differentials associated
with the steam would cause damage to the primary container.
湿热灭菌利用蒸汽或过热水，通常比干热灭菌温度低，持续时间短。为了对产品或物品进行消毒。硬
质物品或多孔物的湿热灭菌主要受清洁蒸汽的冷凝潜热和蒸汽质量的影响。因此，提供一致的结果很
重要。对于水液体填充的容器，来自湿热的能量通过传导和/或对流传递到容器的内容物，而不与高
压釜直接接触蒸汽。在这些情况下，时间和温度是关键参数，而蒸汽品质对过程的影响并不相同。湿
热灭菌过程可用于灭菌或控制生物菌（对于非无菌应用）。对热稳定的材料、物品或产品进行消毒，
并在可能的情况下作为首选的消毒方法。可使用蒸汽（直接或间接接触）进行湿热灭菌。，还包括过
热水系统等其他系统。过热系统通常用于对柔性容器中的产品进行终端灭菌，其中压力差蒸汽会对主
容器造成损坏。

8.55. For porous cycles (hard goods) time, temperature and pressure should be used to monitor the process. Each
item sterilized should be inspected for damage, packaging material integrity and moisture on removal from
the autoclave. Any item found not to be fit for purpose should be removed from the manufacturing area and
an investigation performed.
对于多孔循环（硬货物），应使用时间、温度和压力来监控过程。在从高压灭菌器中取出时，应检查
灭菌的每个物品是否损坏、包装材料是否完整以及是否受潮。任何发现不适合使用的物品都应从制造
区域移走，并进行调查。
34
8.56. For autoclaves fitted with a drain at the bottom of the chamber, the temperature should be recorded at this
position throughout the sterilization period. For steam in place systems, the temperature should be recorded at
condensate drain locations throughout the sterilization period.
对于在灭菌室底部装有排水管的高压灭菌器，应在整个灭菌期间记录该位置的温度。对于蒸汽就地系
统，在整个灭菌期间，应记录冷凝水排放位置的温度。

8.57. Validation of porous cycles should include a calculation of equilibration time, exposure time, correlation of
pressure and temperature and maximum temperature range during exposure. Validation of fluid cycles should
include temperature, time and/or Fo. These critical processing parameters should be subject to defined limits
(including appropriate tolerances) and be confirmed as part of the sterilization validation and routine cycle
acceptance criteria.
多孔循环的验证应包括平衡时间、暴露时间、压力和温度的相关性以及暴露期间的最大温度范围的计
算。流体循环的验证应包括温度、时间和/或FO。这些关键工艺参数应符合规定的限值（包括适当的
公差），并作为灭菌验证和常规周期验收标准的一部分加以确认。

8.58. Leak tests on the sterilizing system should be carried out periodically (normally weekly) when a vacuum phase
is part of the cycle or the system is returned, post sterilization, to a pressure lower than the environment
surrounding the sterilized system.
当真空阶段是循环的一部分或灭菌后系统返回到低于灭菌系统周围环境的压力时，应定期（通常每周）
对灭菌系统进行泄漏测试。

8.59. There should be adequate assurance of air removal prior to and during sterilization when the sterilization
process includes air purging (e.g. porous autoclave loads, lyophilizer chambers). For autoclaves, this should
include an air removal test cycle (normally performed on a daily basis) or an air detector system. Loads to be
sterilized should be designed to support effective air removal and be free draining to prevent the build up of
condensate.
当灭菌过程包括空气吹扫（如多孔高压灭菌器负载、冻干器室）时，应充分保证灭菌前和灭菌期间的
空气去除。对于高压灭菌器，这应包括空气去除试验循环（通常每天进行）或空气检测系统。要消毒
的负载应设计为支持有效的空气去除，并可自由排放，以防止冷凝水的积聚。

8.60. The items to be sterilized, other than products in sealed containers, should be dry, wrapped in a material which
allows removal of air and penetration of steam and prevents recontamination after sterilization. All loaded items
should be dry upon removal from the sterilizer. Load dryness should be confirmed by visual inspection as a
part of the sterilization process acceptance.
除密封容器中的产品外，待消毒的物品应干燥，并用一种可排除空气和蒸汽渗透的材料包裹，以防止
消毒后再次污染。所有装载的物品从消毒器中取出后应保持干燥。作为灭菌过程验收的一部分，应通
过目视检查来确认负载的干燥度。

8.61. If it is necessary to wet equipment using WFI (e.g. ultrafiltration membrane) prior to the sterilization process,
then a risk based assessment should be carried out to demonstrate the acceptable dryness level that will not
impact the sterility of the equipment sterilized and the product sterility assurance level. The hold time between
the wetting phase and sterilization should be justified and validated.
如果有必要在灭菌过程之前使用WFI（如超滤膜）湿润设备，则应进行基于风险的评估，以证明可接
受的干燥水平不会影响灭菌设备的无菌和产品的无菌保证水平。润湿阶段和灭菌之间的保持时间应合
理并经过验证。

8.62. Distortion and damage of non rigid containers that are terminally sterilized, such as containers produced by
Blow Fill Seal or Form Fill Seal technologies, should be prevented by appropriate cycle design and control (for
instance setting correct pressure, heating and cooling rates and loading patterns).
应通过适当的循环设计和控制（例如，设定正确的压力、加热和冷却速率以及装载模式）来防止最终
灭菌的非刚性容器（如吹填密封或模装密封技术生产的容器）的变形和损坏。

8.63. Where steam in place systems are used (e.g. for fixed pipework, vessels and lyophilizer chambers), the system
should be appropriately designed and validated to assure all parts of the system are subjected to the required
treatment. The system should be monitored for temperature, pressure and time at appropriate locations during
routine use to ensure all areas are effectively and reproducibly sterilized. These locations should be
35
 demonstrated as being representative of, and correlated with, the slowest to heat locations during initial and
routine validation. Once a system has been sterilized by steam in place it should remain integral and held under
positive pressure prior to use.
使用蒸汽就地系统（例如，用于固定管道、容器和冻干器室）此外，应对系统进行适当的设计和验证，
以确保系统的所有部件都经过所需的处理。应监测系统的温度，在常规使用过程中，在适当的位置施
加压力和时间，以确保所有区域都得到有效和可重复的消毒。应证明这些位置具有代表性，并与之相
关。在初始和常规验证期间，加热位置最慢。一旦系统被蒸汽就地消毒，在使用前应保持完整并在正
压力下保持。

8.64. For systems using superheated water rather than steam, as the sterilizing agent, the heated water should
consistently reach all of the required contact points. Initial qualification studies should include temperature
mapping of the entire load. There should be routine checks on the equipment to ensure that nozzles (where the
water is introduced) are not blocked and drains remain free from debris.
对于使用过热水而不是蒸汽作为消毒剂的系统，热水应始终达到所有要求的接触点。初始鉴定研究应
包括整个载荷的温度图。应对设备进行常规检查，以确保喷嘴（水引入处）未堵塞，排水管无杂物。

8.65. For the qualification of superheated systems it should be demonstrated that all parts of the load meet the
minimum required temperature and that routine monitoring probes are located in the worst case positions
identified during the qualification process.
对于过热系统的鉴定，应证明负荷的所有部分均满足最低要求温度，且常规监测探头位于鉴定过程中
确定的最坏情况位置。

Dry heat sterilization

干热灭菌

8.66. Dry heat sterilization is of particular use in the removal of thermally robust contaminants such as pyrogens and
is often used in the preparation of components for aseptic filling. The combination of time and temperature to
which product, components and equipment are exposed should produce an adequate and reproducible level of
lethality and/or pyrogen (endotoxin) inactivation/removal when operated routinely within the established limits.
干热灭菌特别适用于去除热敏污染物，如热原，并经常用于无菌灌装的部件制备。产品、部件和设备
暴露的时间和温度组合应在规定限度内常规操作时产生足够的和可再现的致死性和/或热原（内毒素）
灭活/去除水平。

8.67. Dry heat sterilization/depyrogenation tunnels should be configured to ensure that airflow protects the integrity
and performance of the Grade A sterilizing zone by maintaining pressure differentials and airflow through the
tunnel from the higher grade area to the lower grade area. Airflow patterns should be visualised and correlated
with temperature studies. The impact of any airflow change should be assessed to ensure the heating profile is
maintained. All air supplied to the tunnel should pass through at least a HEPA filter and periodic tests should
be performed to demonstrate air filter integrity (at least biannually). Any tunnel parts that come into contact
with sterilized components should be appropriately sterilized or disinfected. Critical process parameters that
should be considered during validation and/or routine processing should include, but may not be limited to:
应配置干热灭菌/脱热通道，以确保气流保护A级消毒剂的完整性和性能通过保持压力差和气流通过隧
道从较高等级区域到较低等级区域来形成加热区。气流模式应可视化，并与温度研究相关联。应评估
任何气流变化的影响，以确保维持加热剖面。所有供应至隧道的空气应至少通过一个高效空气过滤器，
并应定期进行测试，以证明空气过滤器的完整性。（至少每年两次）.任何与灭菌部件接触的隧道部
件都应进行适当的灭菌或消毒。验证和/或例行处理期间应考虑的关键工艺参数应包括但不限于:

8.67.1. Belt speed or dwell time within the sterilizing zone.

在消毒区内的带速或停留时间。

8.67.2. Temperature – minimum and maximum temperatures.

温度 最低和最高温度。

8.67.3. Heat penetration of the material/article.

材料/物品的热渗透。

8.67.4. Heat distribution/uniformity.

36
 热分布/均匀性

8.67.5. Airflows – correlated with the heat distribution and penetration studies.
气流——与热分布和穿透研究相关。

8.68. When a thermal depyrogenation process is used for any component or product contact equipment, validation
studies should be performed to demonstrate that the process provides a suitable Fh value and results in a
minimum 3 log reduction in endotoxins concentration.
当热脱气工艺用于任何部件或产品接触设备时，应进行验证研究，以证明该工艺可提供合适的FH值，
并可使内毒素浓度至少降低3个对数。

8.69. Containers inoculated with endotoxin should be used during validation and should be carefully managed with
a full reconciliation performed. Containers should be representative of the materials normally processed.
Endotoxin quantification and recovery efficiency should also be demonstrated through biological measurement.
在验证期间应使用接种内毒素的容器，并应进行仔细管理，进行全面核对。容器应代表正常加工的材
料。内毒素定量和回收效率也应通过生物测量来证明。

8.70. Dry heat ovens are typically employed to sterilize or depyrogenate primary packaging components, finished
materials or active substances but may be used for other processes. They should be maintained at a positive
pressure relative to lower grade areas throughout the sterilization and post sterilization hold process. All air
entering the oven should pass through a sterilizing filter. Critical process parameters that should be considered
in qualification and/or routine processing should include, but may not be limited to:
干热烘箱通常用于对初级包装部件进行消毒或脱热，成品材料或活性物质，但可用于其他工艺。在整
个灭菌和灭菌后保持过程中，它们应保持相对于较低等级区域的正压。所有进入烤箱的空气都应经过
消毒过滤器。在鉴定和/或例行处理中应考虑的关键工艺参数应包括但不限于:

8.70.1. Temperature.
温度。

8.70.2. Exposure period/time.

曝光周期/时间。

8.70.3. Chamber pressure (for maintenance of over pressure).

燃烧室压力（用于维持过压）。

8.70.4. Air speed.

空速。

8.70.5. Air quality within the oven.

烤箱内的空气质量。

8.70.6. Heat penetration of material/article (slow to heat spots).

材料/物品的热渗透（慢至热斑）。

8.70.7. Heat distribution/uniformity.

热分布/均匀性

8.71. For dry heat sterilization of starting materials and intermediates, the same principles should be applied.
Consideration should also be given to factors affecting heat penetration such as the container type, size and
packing matrix.
对于起始原料和中间体的干热灭菌，应采用相同的原则。还应考虑影响热渗透的因素，如容器类型、
尺寸和包装基质。

Sterilization by radiation
辐射灭菌

8.72. Guidance regarding ionising radiation sterilization can be found within Annex 12.
37
 关于电离辐射灭菌的指导可在附件12中找到。

8.73. Sterilization by radiation is used mainly for the sterilization of heat sensitive materials and products. Ultraviolet
irradiation is not an acceptable method of sterilization.
辐射灭菌主要用于热敏性材料和产品的灭菌。紫外线照射不是一种可接受的消毒方法。

8.74. Validation procedures should ensure that the effects of variations in density of the product and packages are
considered.
验证程序应确保考虑到产品和包装密度变化的影响。

Sterilization with ethylene oxide

环氧乙烷灭菌

8.75. This method should only be used when no other method is practicable. During process validation, it should be
shown that there is no damaging effect on the product and that the conditions and time allowed for degassing
result in the reduction of any residual ethylene oxide (EO) gas and reaction products to defined acceptable
limits for the given product or material.
只有在没有其他方法可行的情况下，才应使用这种方法。在工艺验证期间，应表明对产品没有损害作
用，且脱气的条件和时间允许将任何残留的环氧乙烷（EO）气体和反应产物减少到给定产品或材料
的规定的可接受限度。

8.76. Direct contact between gas and microbial cells is essential, precautions should be taken to avoid the presence
of organisms likely to be enclosed in material such as crystals or dried protein. The nature, porosity and quantity
of packaging materials can significantly affect the process.
气体和微生物细胞之间的直接接触是必不可少的，应采取预防措施，避免可能存在于晶体或干蛋白等
物质中的有机体的存在。包装材料的性质、孔隙率和数量会显著影响工艺。

8.77. Before exposure to the gas, materials should be brought into equilibrium with the humidity and temperature
required by the process. The time required for this should be balanced against the opposing need to
minimize the time before sterilization.
在暴露于气体之前，应使材料与工艺所需的湿度和温度达到平衡。这方面所需的时间应与尽量缩短绝
育前时间的相反需要相平衡。

8.78. Each sterilization cycle should be monitored with suitable BIs, using the appropriate number of test units
distributed throughout the load at defined locations that have been shown to be worst case during validation.
每个灭菌周期应使用适当的BIS进行监控，使用适当数量的测试单元分布在整个负载的规定位置，这
些位置在验证期间已被证明为最坏情况。

8.79. Critical process variables that could be considered as part of the sterilization process validation and routine
monitoring include, but are not limited to:
作为灭菌工艺验证和例行监控的一部分，可考虑的关键工艺变量包括但不限于:

8.79.1. EO gas concentration.

EO气体浓度

8.79.2. EO gas pressure.

EO气体压力。

8.79.3. Amount of EO gas used.

环氧乙烷气体的使用量。

8.79.4. Relative humidity.

相对湿度。

8.79.5. Temperature.
温度。

38
 8.79.6. Exposure time.
曝光时间。

8.80. After sterilization, the load should be aerated to allow EO gas and/or its reaction products to desorb from the
packaged product to predetermined levels. Aeration can occur within a sterilizer chamber and/or in a separate
aeration chamber or aeration room. The aeration phase should be validated as part of the overall EO sterilization
process validation.
灭菌后，应对装载物进行充气，以使EO气体和/或其反应产物从包装产品中解吸至预定水平。曝气可
以发生在灭菌器室内和/或单独的曝气室或曝气室中。曝气阶段应作为总体环氧乙烷灭菌工艺验证的
一部分进行验证。

Filter sterilization of products which cannot be sterilized in their final container

不能在最终容器中灭菌的产品的过滤灭菌

8.81. If the product cannot be sterilized in the final container, solutions or liquids should be sterilized by filtration
through a sterile sterilizing grade filter (with a nominal pore size of 0.22 µm (or less) that has been appropriately
validated to obtain a sterile filtrate) and subsequently aseptically filled into a previously sterilized container.
The selection of the filter used should ensure that it is compatible with the product and as described in the
marketing authorization (refer to paragraph 8.125).
如果产品不能在最终容器中消毒，溶液或液体应通过无菌级过滤器过滤消毒。（公称孔径为0。22µm
（或更小），已适当验证可获得无菌滤液）随后无菌填充到预先消毒的容器中。所用过滤器的选择应
确保与产品兼容，并符合营销授权书中的说明。（参见PARAG）拉斐尔8。125)

8.82. Suitable bioburden reduction prefilters and/or sterilizing grade filters may be used at multiple points during the
manufacturing process to ensure a low and controlled bioburden of the liquid prior to the primary sterilizing
grade filter. Due to the potential additional risks of a sterile filtration process, as compared with other
sterilization processes, a second filtration through a sterile sterilizing grade filter, immediately prior to filling,
should be considered as part of an overall CCS.
在制造过程中，可在多个点处使用适当的生物负荷减少预滤器和/或消毒级滤器，以确保在初级消毒
级滤器之前液体的生物负荷低且受控制。由于与其他灭菌工艺相比，无菌过滤工艺存在潜在的额外风
险，因此，在灌装之前，通过无菌消毒级过滤器进行的第二次过滤应被视为整个CCS的一部分。

8.83. The selection of components for the filtration system and their interconnection and arrangement within the
filtration system, including pre filters, should be based on the critical quality attributes of the product, justified
and documented. The filtration system should minimize the generation of fibres and particulates, not cause or
contribute to unacceptable levels of impurities, or possess characteristics that otherwise alter the quality and
efficacy of the product. Similarly, the filter characteristics should be compatible with the fluid and not be
adversely affected by the product to be filtered. Adsorption of product components and extraction/leaching of
filter components should be evaluated (refer to paragraph 8.125).
过滤系统部件的选择及其在过滤系统内的相互连接和布置，包括预过滤器；应以产品的关键质量属性
为基础，证明合理并记录在案。过滤系统应最大限度地减少纤维和微粒的产生，不会导致或促成不可
接受的杂质水平。或具有以其他方式改变产品质量和功效的特性。同样，过滤器特性应与流体相容，
不受待过滤产品的不利影响。应评估产品组分的吸附和过滤组分的萃取/沥滤（参见第8.125段）

8.84. The filtration system should be designed to:

过滤系统应设计为:

8.84.1. Allow operation within validated process parameters.

允许在已验证的工艺参数范围内操作。

8.84.2. Maintain the sterility of the filtrate.

保持滤液的无菌。

8.84.3. Minimize the number of aseptic connections required between the sterilizing filter and the final filling
of the product.
最大限度地减少灭菌过滤器和产品最终灌装之间所需的无菌连接数量。

39
 8.84.4. Allow cleaning procedures to be conducted as necessary.
允许必要时进行清洁程序。

8.84.5. Allow sterilization procedures, including sterilization in place, to be conducted as necessary.

允许在必要时进行消毒程序，包括就地消毒。

8.84.6. Permit in place integrity testing, of the 0.22 µm sterilizing filter, preferably as a closed system, prior
to filtration as necessary. In place integrity testing methods should be selected to avoid any adverse
impact on the quality of the product.
必要时，在过滤之前，允许对0.22微米的消毒过滤器（最好作为封闭系统）进行完整性测试。
应选择适当的完整性测试方法，以避免对产品质量产生任何不利影响。

8.85. Sterile filtration of liquids should be validated in accordance with European (or other relevant) Pharmacopeia
requirements. Validation can be grouped by different strengths or variations of a product but should be done
under worst case conditions. The rationale for grouping should be justified and documented.
液体的无菌过滤应根据欧洲（或其他相关）药典要求进行验证。验证可以按产品的不同强度或变体进
行分组，但应在最坏的情况下进行。分组的理由应该是合理的，并应记录在案。

8.86. During filter validation, wherever possible, the product to be filtered should be used for bacterial retention
testing of the sterilizing filter. Where the product to be filtered is not suitable for use in bacterial retention
testing, a suitable surrogate product should be justified for use in the test. The challenge organism used in the
bacterial retention test should be justified.
在过滤器验证过程中，只要有可能，应将待过滤的产品用于灭菌过滤器的细菌保留测试。如果要过滤
的产品不适合用于细菌保留试验，则应证明合适的替代产品可用于该试验。在细菌保留试验中使用的
挑战生物应该是合理的。

8.87. Filtration parameters that should be considered and established in validation and monitored in routine
processing should include, but are not limited to:
在验证中应考虑和建立的过滤参数以及在常规处理中应监控的过滤参数应包括但不限于:

8.87.1. The wetting fluid used for filter integrity testing should be based on the filter manufacturer’s
recommendation or the fluid to be filtered. The appropriate integrity test value specification should be
established.
用于过滤器完整性测试的润湿液应基于过滤器制造商的建议或要过滤的流体。应建立适当的
完整性测试值规范。

8.87.2. If the system is flushed or integrity tested in situ with a fluid other than the product, appropriate actions
are taken to avoid any deleterious effect on product quality.
如果使用产品以外的流体对系统进行现场冲洗或完整性测试，则应采取适当措施以避免对产
品质量造成任何有害影响。

8.87.3. Filtration process conditions including:

过滤工艺条件包括:

8.87.3.1. Fluid pre filtration holding time and effect on bioburden.

流体预滤保持时间及其对生物膜的影响。

8.87.3.2. Filter conditioning, with fluid if necessary.

过滤器调节，必要时使用液体。

8.87.3.3. Maximum filtration time/total time filter is in contact with fluid.

最大过滤时间/过滤器与流体接触的总时间。

8.87.3.4. Maximum operating pressure.

最大工作压力。

8.87.3.5. Flow rate.

40
 流量。

8.87.3.6. Maximum filtration volume.

最大过滤容积。

8.87.3.7. Temperature.
温度。

8.87.3.8. The time taken to filter a known volume of bulk solution and the pressure difference to be
used across the filter.
过滤已知体积的大量溶液所需的时间和过滤器所用的压差。

Note: Results of these checks should be included in the batch record. Any significant difference in parameters
from those validated to those observed during routine manufacturing should be noted and investigated.
注:这些检查的结果应包括在批记录中。应注意并调查常规制造过程中验证的参数与观察到的参数之间的任何
显著差异。

8.88. The integrity of the sterilized filter assembly should be verified by integrity testing before use, to check for
damage and loss of integrity caused by the filter preparation prior to use. A sterilizing grade filter that is used
to sterilize a fluid should be subject to a non destructive integrity test post use prior to removal of the filter from
its housing. Test results should correlate to the microbial retention capability of the filter established during
validation. Examples of tests that are used include bubble point, diffusive flow, water intrusion or pressure hold
test. It is recognized that pre use post sterilization integrity testing (PUPSIT) may not always be possible after
sterilization due to process constraints (e.g. the filtration of very small volumes of solution). In these cases, an
alternative approach may be taken providing that a thorough risk assessment has been performed and
compliance is achieved by the implementation of appropriate controls to mitigate any risk of non sterility. Points
to consider in such a risk assessment should include but are not be limited to:
在使用前，应通过完整性测试来验证消毒过滤器组件的完整性。检查过滤器的损坏和完整性损失，在
使用前进行准备。用于对流体进行消毒的消毒级过滤器在去除F之前，应在使用后进行无损完整性测
试。滤器从它的外壳。测试结果应与验证期间建立的过滤器的微生物保留能力相关。使用的测试示例
包括泡点、扩散流、水侵入或压力保持测试。使用前和灭菌后完整性测试（PUPSIT）由于工艺的限
制（例如，过滤极少量的溶液），在灭菌后可能不总是可行的。在这些情况下，如果已经进行了彻底
的风险评估，并且通过实施以下措施实现了合规性，则可以采用另一种方法适当的控制措施，以减轻
任何不育的风险。此类风险评估中要考虑的要点应包括但不限于:

8.88.1. In depth knowledge and control of the sterilization process to ensure that the potential for damage to
the filter is minimized.
深入了解和控制杀菌过程，以确保将损坏过滤器的可能性降至最低。

8.88.2. In depth knowledge and control of the supply chain to include:

对供应链的深入了解和控制包括:

8.88.2.1. Contract sterilization facilities.

合同消毒设施。

8.88.2.2. Defined transport mechanisms.

定义的传输机制。

8.88.2.3. Packaging of the sterilized filter, to prevent damage to the filter during transportation and
storage.
灭菌过滤器的包装，以防止在运输和储存过程中损坏过滤器。

8.88.3. In depth process knowledge such as:

深入的工艺知识，如:

8.88.3.1. The specific product type, including particulate burden and whether there exists any risk of
impact on filter integrity values, such as the potential to alter integrity testing values and
41
 therefore prevent the detection of a non integral filter during a post use filter integrity test.
具体的产品类型，包括颗粒负荷，以及是否存在影响过滤器完整性值的任何风险，
例如改变完整性测试值的可能性，从而防止在使用后过滤器完整性测试期间检测到
非完整的过滤器。

8.88.3.2. Pre filtration and processing steps, prior to the sterilizing filter, which would remove
particulate burden and clarify the product prior to the sterile filtration.
在灭菌过滤器之前的预过滤和处理步骤，这将在无菌过滤之前去除颗粒负担并澄清
产品。

8.89. The integrity of critical sterile gas and air vent filters (that are directly linked to the sterility of the product)
should be verified by testing after use, with the filter remaining in the filter assembly.
关键的无菌气体和空气通风过滤器（与产品的无菌直接相关）的完整性应通过使用后的测试进行验证，
且过滤器应保留在过滤器组件中。

8.90. The integrity of non critical air or gas vent filters should be confirmed and recorded at appropriate intervals.
Where gas filters are in place for extended periods such as vent filters, integrity testing should be carried out
pre and post use. The maximum duration of use should be specified and monitored based on risk (e.g.
considering the maximum number of uses and sterilization cycles permitted).
应在适当的时间间隔内确认和记录非临界空气或气体通风过滤器的完整性。如果气体过滤器（如通风
过滤器）安装时间较长，则应在使用前和使用后进行完整性测试。应根据风险（例如，考虑允许的最
大使用次数和绝育周期）规定和监测最长使用期限。

8.91. For gas filtration, attention should be paid to avoiding unintended moistening or wetting of the filter or filter
equipment. This can be achieved by the use of hydrophobic filters.
对于气体过滤，应注意避免过滤器或过滤设备被无意弄湿或弄湿。这可以通过使用疏水过滤器来实现。

8.92. If the sterilizing filtration process has been validated as a system consisting of multiple filters to achieve the
sterility for a given fluid, the filtration system is considered to be a single sterilizing unit and all filters within
the system should satisfactorily pass integrity testing after use.
如果灭菌过滤过程已被验证为一个由多个过滤器组成的系统，以实现对给定流体的无菌，则该过滤系
统被认为是一个单一的灭菌单元，且该系统中的所有过滤器在使用后均应令人满意地通过完整性测试。

8.93. In a redundant filtration system (where a second filter is present as a backup but the sterilizing process is
validated as only requiring one filter), post use integrity test of the primary sterilizing filter should be performed
and if demonstrated to be integral, then a post use integrity test of the secondary filter is not necessary. However,
in the event of a failure of the post use integrity test on the primary filter, a risk assessment should be carried
out to determine the acceptability of performing a post use integrity test on the secondary (redundant) filter.
在冗余过滤系统中（有第二个过滤器作为备用，但灭菌过程经验证只需要一个过滤器），应对初级消
毒过滤器进行使用后的完整性测试，如果证明是完整的，则无需对次级过滤器进行使用后完整性测试。
但是，如果主过滤器的后使用完整性测试失败，应进行风险评估，以确定对二次（冗余）进行使用后
完整性测试的可接受性。过滤器。

8.94. Bioburden samples should be taken from the bulk product and immediately prior to the final sterile filtration.
Systems for taking samples should be designed so as not to introduce contamination.
应在最终无菌过滤之前立即从散装产品中提取生物膜样品。取样系统的设计应避免引入污染。

8.95. Liquid sterilizing filters should be discarded after the processing of a single lot and the same filter should not
be used for more than one working day unless such use has been validated.
液体消毒过滤器应在处理完一批后丢弃，且同一过滤器不应使用超过一个工作日，除非这种使用已得
到验证。

8.96. Where campaign manufacture of a product has been appropriately justified in the CCS and validated, the filter
user should:
如果在CCS中对产品的生产活动进行了适当的论证并进行了验证，则过滤器用户应:

8.96.1. Assess and document the risks associated with the duration of filter use for the sterile filtration process
42
 for a given fluid.
评估并记录与特定流体的无菌过滤过程中使用过滤器的持续时间相关的风险。

8.96.2. Conduct and document effective validation and qualification studies to demonstrate that the duration
of filter use for a given sterile filtration process and for a given fluid does not compromise performance
of the sterilizing filter or filtrate quality.
进行并记录有效的验证和鉴定研究，以证明用于特定无菌过滤过程和特定流体的过滤器使用
时间不会影响消毒过滤器的性能或滤液质量。

8.96.3. Document the maximum validated duration of use for the filter and implement controls to ensure that
filters are not used beyond the validated maximum duration. Records of these controls should be
maintained.
记录过滤器的最长验证使用期限，并实施控制以确保过滤器的使用不超过验证的最长期限。
应保持这些控制措施的记录。

8.96.4. Implement controls to ensure that filters contaminated with fluid or cleaning agent residues, or
considered defective in any other way, are removed from use.
实施控制，以确保从使用中清除被液体或清洁剂残留物污染的过滤器，或被认为有缺陷的任
何其他方式。

Form Fill Seal

8.97. Form Fill Seal (FFS) units include blow moulding from thermoplastic granulate and thermoforming from
thermoplastic film, typically known as Blow Fill Seal (BFS) and Vertical Form Fill Seal (VFFS), respectively.
VFFS process is an automated filling process, typically for terminally sterilized products, that may utilize a
single or dual web system which constructs the primary container out of a flat roll of thermoplastic film while
simultaneously filling the formed bags with product and sealing the filled bags in a continuous process. All
such containers are considered to be closed through sealing by fusion and, as such, fall under the requirement
to perform 100% integrity testing (refer to paragraph 8.21).
填表密封（FFS）设备包括热塑性颗粒的吹塑和热塑性薄膜的热成型，通常称为吹塑填充密封
（BFS）。和垂直形式填充密封件（VFFS）。VFFS工艺是一种自动灌装工艺，通常用于终端灭菌产
品。其可以利用单幅或双幅系统，该系统在同时填充的同时从热塑性薄膜的平卷构造主容器在连续的
过程中，将成型的袋子与产品一起包装，并将填充的袋子密封。所有这些容器都被认为是通过熔合密
封的，因此，符合执行100%完整性测试的要求（参见第8段。21)

8.98. Process parameters relating to seal integrity should be qualified and appropriately controlled.
与密封完整性相关的工艺参数应合格并得到适当控制。

8.99. Critical parameters include, but are not limited to:

关键参数包括但不限于:

8.99.1. Seal strength.

密封强度。

8.99.2. Seal uniformity.

密封均匀性。

8.99.3. Sealing temperatures.

密封温度。

8.99.4. Sealing pressures.

密封压力。

8.99.5. Sealing times.

密封次数。

8.99.6. Dwell time for filling.

43
 填充的停留时间。

8.100. Seal strength and uniformity should be monitored routinely.

应定期监测密封强度和均匀性。

8.101. The controls identified during qualification should be in alignment with the site’s CCS. Aspects to be considered
include but are not limited to:
鉴定期间确定的控制措施应与现场的CCS保持一致。需要考虑的方面包括但不限于:

8.101.1. Determination of the boundaries of the critical zone.

确定临界区的边界。

8.101.2. Environmental control and monitoring, both of the machine and the background in which it is placed.
环境控制和监控，包括机器和放置机器的背景。

8.101.3. Integrity testing of the product filling lines.

产品灌装线的完整性测试。

8.101.4. Integrity testing of the cooling system.

冷却系统的完整性测试。

8.101.5. Duration of the batch or filling campaign.

批处理或填充活动的持续时间。

8.101.6. Control of polymer starting material (including resin pellets).

聚合物原料（包括树脂颗粒）的控制。

8.101.7. Cleaning in place and sterilization in place of equipment in direct contact to the formulation (product
filling lines); sterilization in place of sterile air pathways.
对直接接触制剂的设备（产品灌装线）进行就地清洗和灭菌；以消毒代替无菌空气通道。

Blow Fill Seal

8.102. Blow Fill Seal (BFS) units are purpose built machines in which, in one continuous operation, containers are
formed from a thermoplastic granulate, filled and then sealed by one automatic machine. Air that makes contact
with critical surfaces of the container during extrusion, formation or sealing of the moulded container should
undergo appropriate filtration.
吹塑填充密封（BFS）装置是一种专门制造的机器，在一次连续操作中，容器由热塑性颗粒形成，填
充，然后由一台自动机器密封。在模塑容器的挤压、成型或密封过程中与容器的关键表面接触的空气
应经过适当的过滤。

8.103. For shuttle type equipment used for aseptic filling, the area between parison cutting and mould sealing should
be covered by a flow of filtered air to provide Grade A conditions at the critical zone. The equipment should
be installed in at least a Grade C environment, provided that Grade A/B clothing is used. The filling
environment should meet Grade A for viable and non viable limits at rest and the viable limit only when in
operation.
对于用于无菌灌装的梭式设备，型坯切割和模具密封之间的区域应由过滤空气流覆盖，以在临界区提
供A级条件。设备应至少安装在C级环境中，前提是使用A/B级服装。充填环境在静止时应满足可行和
不可行极限的A级，仅在操作时满足可行极限的A级。

8.104. For rotary type equipment, used for aseptic filling, the filling environment should be designed to meet Grade A
conditions. Other sterility assurance controls such as monitoring of critical parameters and alarms during each
batch and parison support filter integrity testing should be considered.
对于旋转式设备，用于无菌灌装，应将灌装环境设计为满足A级条件。应考虑其他无菌保证控制措施，
如在每批和型坯支持过滤器完整性测试期间监控关键参数和警报。

8.105. The environmental control and monitoring program should take into consideration the moving parts and
44
 complex airflow paths generated by the BFS process and the effect of the high heat outputs of the process, e.g.
by performing smoke studies and/or other equivalent studies. Environmental monitoring should be applied
taking into consideration elements such as air filter configuration, air filter integrity, cooling systems integrity,
equipment design and installation.
环境控制和监测计划应考虑由BFS工艺产生的移动部件和复杂的气流路径以及工艺的高热输出的影响，
例如通过进行烟雾研究和/或其他等效研究。在进行环境监测时，应考虑空气过滤器配置、空气过滤
器完整性、冷却系统完整性、设备设计和安装等因素。

8.106. Blow Fill Seal equipment used for the manufacture of products which are terminally sterilized should be
installed in at least a Grade D environment. The conditions at the point of fill should comply with the
environmental requirements of paragraphs 8.3 and 8.4.
用于生产终端灭菌产品的吹灌封设备应安装在至少D级环境中。灌注点的条件应符合第8.3和8.4段的
环境要求。

8.107. External particulate and microbial contamination of the polymer should be prevented by appropriate design,
control, and maintenance of the polymer storage, sampling and distribution systems. The capability of the
extrusion system to provide appropriate sterility assurance for the moulded container should be fully understood
and validated. The sampling frequency, the bioburden and, where applicable, endotoxins levels of the raw
polymer should be defined and controlled within the CCS.
应通过对聚合物储存、取样和分配系统的适当设计、控制和维护来防止聚合物的外部微粒和微生物污
染。应充分了解和验证挤压系统为模制容器提供适当无菌保证的能力。应在CCS中规定和控制取样频
率、生物负荷和（如适用）原聚合物的内毒素水平。

8.108. Interventions requiring cessation of filling and/or extrusion, moulding and sealing and, where required, re
sterilization of the filling machine should be clearly defined and well described in the aseptic filling procedure,
and included in the APS (refer to paragraphs 9.36, 9.37 and 9.38).
要求停止灌装和/或挤压、模塑和密封的干预措施，以及必要时对灌装机进行重新消毒的干预措施，
应在无菌灌装程序中明确规定和详细描述，并包含在APS中（参见第9.36、9.37和9.38段）。

8.109. The moulds used to form containers are considered critical equipment and any changes or modification to
moulds should result in an assessment of finished product container integrity, and should be supported by
validation.
用于形成容器的模具被视为关键设备，对模具的任何更改或修改都应导致对成品容器完整性的评估，
并应得到验证的支持。

Lyophilization
冻干

8.110. Lyophilization is a critical process step and all activities that can affect the sterility of the product or material
need to be regarded as extensions of the aseptic processing of the sterilized product. The lyophilization
equipment and its processes should be designed to ensure that product or material sterility is maintained during
lyophilization by preventing microbial and particulate contamination between the filling of products for
lyophilization, and completion of lyophilization process. All control measures in place should be determined
by the site’s CCS.
冻干是一个关键的工艺步骤，所有可能影响产品或材料无菌的活动都需要被视为扩展。消毒产品的无
菌工艺。冻干设备及其工艺的设计应确保产品或材料在冻干过程中保持无菌防止冻干产品灌装和冻干
过程完成之间的微生物和颗粒污染。所有控制措施应由现场的CCS确定。

8.111. The sterilization of lyophilizers and associated equipment, (e.g. trays, vial support rings) should be validated
and holding times between sterilization cycles appropriately challenged during aseptic process simulations. The
lyophilizer should be sterilized regularly, based on system design. Re sterilization should be performed
following maintenance or cleaning. Sterilized lyophilizers and associated equipment should be protected from
contamination after sterilization.
应验证冻干机和相关设备（例如托盘、小瓶支撑环）的灭菌，并在无菌工艺模拟期间适当地挑战灭菌
周期之间的保持时间。根据系统设计，冻干机应定期消毒。应在维护或清洁后进行再消毒。灭菌后的
冻干机和相关设备应防止污染。

45
8.112. Lyophilizers that are manually loaded or unloaded should normally be sterilized before each load. For
lyophilizers loaded by automated closed systems or located within systems that exclude operator intervention,
the frequency of sterilization should be justified and documented as part of the CCS.
手动装载或卸载的冻干机通常应在每次装载之前进行消毒。对于由自动封闭系统装载的冻干机或位于
排除操作员干预的系统内的冻干机，灭菌频率应合理，并作为CCS的一部分进行记录。

8.113. The integrity of the lyophilizer system should be maintained following sterilization and during use. The filter
used to maintain lyophilizer integrity should be sterilized before each use of the system and its integrity testing
results should be part of the batch certification. The frequency of vacuum/leak integrity testing of the chamber
should be documented and the maximum permitted leakage of air into the lyophilizer should be specified and
checked at the start of every cycle.
冻干机系统的完整性应在灭菌后和使用过程中保持。用于保持冻干机完整性的过滤器应在每次使用该
系统之前进行消毒，其完整性测试结果应作为批次认证的一部分。应记录真空室的真空/泄漏完整性
测试的频率，并应规定进入冻干机的空气的最大允许泄漏量，并在每个周期开始时进行检查。

8.114. Lyophilization trays should be checked regularly to ensure that they are not misshapen or damaged.
冻干托盘应定期检查，以确保其不变形或损坏。

8.115. Points to consider for the design of loading (and unloading, where the lyophilised material is not in a sealed
container (e.g. open tray dried materials), include but are not limited to:
荷载设计应考虑的要点（和卸载，其中冻干材料不在密封容器中（例如，开放式托盘干燥材料），包
括但不限于:

8.115.1. The loading pattern within the lyophilizer should be specified and documented.
冻干机内的装载模式应加以规定和记录。

8.115.2. The transfer of partially closed containers to a lyophilizer should be undertaken under Grade A
conditions at all times and handled in a manner designed to minimize direct operator intervention.
Technologies such as conveyor systems, portable transfer systems (e.g. clean air transfer carts, portable
unidirectional airflow workstations) should be used to ensure that the cleanliness of the system used to
transfer the partially closed containers is maintained). Alternatively, where supported by validation,
containers closed in the Grade A zone and not reopened whilst in the Grade B may be used to protect
partially stoppered vials (e.g. sealed sterilized trays).
将部分封闭的容器转移至冻干机时，应始终在A级条件下进行，并按设计的方式进行处理。最
大限度地减少操作员的直接干预。技术，如输送机系统、便携式传送系统（如清洁空气传送
推车、便携式单向气流工作站）以确保用于转移部分封闭容器的系统保持清洁）。或者，在
验证支持的情况下，在A级区域关闭且在B级区域未重新开启的容器可用于保护部分加塞的小
瓶。（e）密封消毒托盘）

8.115.3. Airflow patterns should not be adversely affected by transport devices and venting of the loading zone.
气流模式不应受到运输装置和装载区通风的不利影响。

8.115.4. Unsealed containers (such as partially stoppered vials) should be maintained under Grade A conditions
and should normally be separated from operators by physical barrier technology or any other
appropriate measures.
未密封的容器（如部分加塞的小瓶）应保持在A级条件下，通常应通过物理屏障技术或任何其
他适当措施与操作人员隔离。

8.115.5. Where seating of the stoppers is not completed prior to opening the lyophilizer chamber, product
removed from the lyophilizer should remain under Grade A conditions during subsequent handling.
如果在打开冻干机室之前未完成塞子的安装，则从冻干机中取出的产品在随后的处理过程中
应保持在A级条件下。

8.115.6. Utensils used during transfer to and loading and unloading of the lyophilizer (such as trays, bags,
placing devices, tweezers, etc.) should be subject to a validated sterilization process.
在转移到冻干机和装卸冻干机期间使用的器具（如托盘、袋、放置装置、镊子等）应经过验
证的灭菌过程。
46
Closed systems
封闭系统

8.116. Closed systems can be single use systems (i.e. disposable systems) and fixed systems (such as vessels with
fixed pipework). Guidance in this section is equally applicable to both systems.
封闭系统可以是一次性使用系统（即一次性系统）和固定系统（例如具有固定管道系统的容器）。本
节中的指导同样适用于两个系统。

8.117. The use of closed systems can reduce the risk of extraneous contamination such as microbial, particulate and
chemical from the adjacent environment. Closed systems should always be designed to reduce the need for, and
complexity of manual interventions.
使用封闭系统可减少来自邻近环境的微生物、微粒和化学品等外来污染的风险。封闭系统应始终设计
为减少人工干预的必要性和复杂性。

8.118. It is critical to ensure the sterility of all product contact surfaces of closed systems used for aseptic processing.
The design and selection of any closed system used for aseptic processing should ensure maintenance of sterility.
Connection of sterile equipment (e.g. tubing / pipework) to the sterilized product pathway after the final
sterilizing filter should be designed to be connected aseptically (e.g. by intrinsic aseptic connectors or fusion
systems).
确保用于无菌工艺的封闭系统的所有产品接触面的无菌是至关重要的。用于无菌工艺的任何封闭系统
的设计和选择应确保保持无菌。在最终灭菌过滤器之后，无菌设备（例如，管道）与灭菌产品通道的
连接应设计为无菌连接（例如，通过内部无菌连接器或熔合系统）。

8.119. Appropriate measures should be in place to ensure the integrity of components used in aseptic connections. The
means by which this is achieved should be determined and captured in the CCS. Appropriate system integrity
tests should be considered when there is a risk of compromising product sterility. Supplier assessment should
include the collation of data in relation to potential failure modes that may lead to a loss of system sterility.
应采取适当措施，以确保无菌连接中使用的部件的完整性。应当确定实现这一目标的手段，并将其纳
入综合传播战略。当存在危及产品无菌的风险时，应考虑进行适当的系统完整性测试。供应商评估应
包括整理与可能导致系统失效的潜在故障模式相关的数据。

8.120. The background in which closed systems are located should be based on their design and the processes
undertaken. For aseptic processing and where there are any risks that system integrity may be compromised,
the system should be located in a Grade A zone. If the system can be shown to remain integral at every usage
(e.g. via pressure testing and/or monitoring) then a lower classified area may be used. If the closed system is
opened (e.g. for maintenance of a bulk manufacturing line) then this should be performed in a classified area
appropriate to the materials (e.g. Grade C for terminally sterilization processes, or Grade A for aseptic
processing) or be subject to further cleaning and disinfection (and sterilization in case of aseptic processes).
封闭系统所处的背景应基于其设计和所采取的流程。对于无菌工艺和存在系统完整性受损风险的情况，
系统应位于A级区域。如果系统在每次使用时（例如通过压力测试和/或监控）都能保持完整，则可以
使用较低分类的区域。如果封闭系统被打开（例如，用于批量生产线的维护）则应在与材料相适应的
分类区域执行此操作。（例如:C级用于最终灭菌过程，或A级用于无菌过程）或进行进一步的清洁和
消毒（如果是无菌工艺，则进行灭菌）

Single use systems (SUS)

一次性使用系统（SUS）

8.121. SUS are those technologies used in manufacture of sterile products which are used as an alternative to reusable
equipment. SUS can be individual components or made up of multiple components such as bags, filters, tubing,
connectors, valves, storage bottles and sensors.
SUS是指那些用于制造无菌产品的技术，它们被用作可重复使用设备的替代品。SUS可以是单独的组
件，也可以由多个组件组成，如袋、过滤器、管道、连接器、阀门、储存瓶和传感器。

8.122. There are some specific risks associated with SUS which should be assessed as part of the CCS. These risks
include but are not limited to:
有一些与SUS相关的特定风险应作为CCS的一部分进行评估。这些风险包括但不限于:
47
 8.122.1. The interaction between the product and product contact surface (such as adsorption, or the formation
of leachables and extractables).
产品与产品接触面之间的相互作用（如吸附，或形成浸出物和萃取物）。

8.122.2. The fragile nature of the system compared to fixed reusable systems.
与固定的可重复使用的系统相比，系统的脆弱性。

8.122.3. The increase in the number and complexity of manual operations (including inspection and handling
of the system) and connections made.
人工操作（包括检查和处理系统）和连接的数量和复杂性增加。

8.122.4. The complexity of the assembly.

大会的复杂性。

8.122.5. The performance of the pre use integrity test for sterilizing grade filters (refer to paragraph 8.88).
灭菌级过滤器使用前完整性测试的性能（参见第8.88段）。

8.122.6. The risk of holes and leakage.

孔洞和渗漏的风险。

8.122.7. The potential for compromising the system at the point of opening the outer packaging.
在打开外包装时可能危及系统安全。

8.122.8. The risk of particulate contamination.

颗粒污染的风险。

8.123. Sterilization processes for SUS should be validated and shown to have no adverse impact on system
performance.
应验证SUS的灭菌过程，并证明其对系统性能没有不利影响。

8.124. Assessment of suppliers of disposable systems including sterilization is critical to the selection and use of
these systems. For sterile SUS, verification of sterility should be performed as part of the supplier
qualification and on receipt and use of each unit.
对包括灭菌在内的一次性系统供应商的评估对于这些系统的选择和使用至关重要。对于无菌SUS，应
作为供应商资格的一部分，并在接收和使用每个单元时进行无菌验证。

8.125. The adsorption and reactivity of the product with product contact surfaces should be evaluated under process
conditions.
应在工艺条件下评价产品与产品接触面的吸附性和反应性。

8.126. The extractable and leachable profile of the SUS and any impact on the quality of the product especially where
the system is made from polymer based materials should be evaluated. An assessment should be carried out for
each component to evaluate the applicability of the extractable profile data. For components considered to be
at high risk from leachables, including those that may absorb processed materials or those with extended
material contact times, an assessment of leachable profile studies, including safety concerns, should be taken
into consideration. If applying simulated processing conditions, these should accurately reflect the actual
processing conditions and be based on a scientific rationale.
SUS的可提取性和可浸出性概况以及对产品质量的任何影响，特别是当该系统由基于聚合物的M应对
材料进行评估。应对每个组成部分进行评估，以评价可提取的剖面数据的适用性。对于被认为来自可
沥滤物的高风险部件，包括可能吸收处理过的材料或材料接触时间延长的材料，评估可沥滤的概况研
究，包括安全问题，都应加以考虑。如果应用模拟的处理条件，这些标准应准确反映实际的加工条件，
并以科学的理论为基础。

8.127. SUS should be designed to maintain integrity throughout processing under the intended operational conditions.
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 Attention to the structural integrity of the single use components is necessary where these may be exposed to
more extreme conditions (e.g. freezing and thawing processes) either during routine processing or
transportation. This should include verification that intrinsic aseptic connections (both heat sealed and
mechanically sealed) remain integral under these conditions.
SUS应设计为在预期操作条件下在整个处理过程中保持完整性。在常规加工或运输过程中，如果一次
性使用部件可能暴露于更极端的条件（例如冷冻和解冻过程），则必须注意这些部件的结构完整性。
这应包括验证内在无菌连接（热密封和机械密封）在这些条件下保持完整。

8.128. Acceptance criteria should be established and implemented for SUS corresponding to the risks or criticality of
the products and its processes. On receipt, each piece of SUS should be checked to ensure that they have been
manufactured, supplied and delivered in accordance with the approved specification. A visual inspection of the
outer packaging (e.g. appearance of exterior carton, product pouches), label printing, and review of attached
documents (e.g. certificate of conformance and proof of sterilization) should be carried out and documented
prior to use.
应为SUS建立和实施与产品及其过程的风险或关键程度相对应的验收标准。在接收时，应检查每一件
SUS，以确保它们是制造的。按照批准的规格供应和交付。外部包装的目视检查（如外部纸箱、产品
小袋的外观）、标签打印和附加文件的审核（例如，符合性证书和灭菌证明）应在使用前进行并记录。

8.129. Critical manual handling operations of SUS such as assembly and connections should be subject to appropriate
controls and verified during the APS.
在APS期间，应对SUS的关键手动操作（如装配和连接）进行适当的控制和验证。

9. Viable and non viable environmental & process monitoring

可行和不可行的环境和过程监测

General
一般的

9.1. The site’s environmental and process monitoring program forms part of the overall CCS and is used to monitor
the controls designed to minimize the risk of microbial and particulate contamination. It should be noted that
the reliability of each of the elements of the monitoring system (viable, non viable and APS) when taken in
isolation is limited and should not be considered individually to be an indicator of asepsis. When considered
together, their reliability is dependent on the design, validation and operation of the system that they are
monitoring.
现场的环境和过程监控计划是整个CCS的一部分，用于监控旨在最小化RIS的控制措施K微生物和颗
粒污染。应当指出，监测系统的每一个要素（可行、不可行和APS）的可靠性当采取隔离是有限的，
不应被视为一个单独的无菌指标。当综合考虑时，它们的可靠性取决于它们所监测的系统的设计、验
证和运行。

9.2. This program is typically comprised of the following elements:

该计划通常由以下要素组成:

9.2.1. Environnemental monitoring – non viable particles.

环境监测 非活性颗粒。

9.2.2. Environmental and personnel monitoring – viable particles.

环境和人员监测 活性粒子。

9.2.3. Aseptic process simulation (aseptically manufactured product only).

无菌工艺模拟（仅适用于无菌制造的产品）。

9.3. The information from these systems should be used for routine batch certification and for periodic assessment
during process review or investigation. This applies for both terminal sterilization and aseptic processes,
however, the criticality of the impact may differ depending upon the product and process type.
来自这些系统的信息应用于常规批次认证和过程审查或调查期间的定期评估。这适用于终端灭菌和无
菌工艺，但是，影响的严重程度可能因产品和工艺类型而异。

49
Environmental monitoring
环境监测

9.4. Risk assessments should be performed in order to establish a comprehensive environmental

应进行风险评估，以建立全面的环境

9.5. monitoring program, i.e. sampling locations, frequency of monitoring, monitoring method used and incubation
conditions (e.g. time, temperature(s), aerobic and/or anaerobic conditions). These risk assessments should be
conducted based on detailed knowledge of; the process inputs and final product, the facility, equipment, specific
processes, the operations involved, historical monitoring data, monitoring data obtained during qualification
and knowledge of typical microbial flora isolated from the environment. Consideration of other information
such as air visualization studies should also be included. These risk assessments should be reviewed regularly
in order to confirm the effectiveness of the site’s environmental monitoring program. The monitoring program
should be considered in the overall context of the trend analysis and the CCS for the site.
监测计划，即采样地点、监测频率、所用监测方法和培养条件（例如时间、温度）有氧和/或厌氧条
件）。这些风险评估应在以下方面的详细知识的基础上进行:过程输入和最终产品、设施、设备特定
流程、涉及的操作、历史监控数据从环境中分离的典型微生物区系鉴定和知识期间获得的监测数据。
还应考虑其他信息，如空气可视化研究。应定期审查这些风险评估，以确认现场环境监测计划的有效
性。应在趋势分析和场址的CCS的总体背景下考虑监测方案。

9.6. Routine monitoring of cleanrooms, clean air equipment and personnel should be performed in operation
throughout all critical stages, including equipment set up.
在包括设备安装在内的所有关键阶段，应对操作中的洁净室、洁净空气设备和人员进行常规监测。

9.7. The monitoring of Grade A zones should demonstrate the maintenance of aseptic processing conditions during
critical operations. Monitoring should be performed at locations posing the highest risk of contamination to the
sterile equipment surfaces, container, closures and product. The selection of monitoring locations and the
orientation and positioning of sampling devices should be justified and appropriate to obtain reliable data from
the critical zones.
对A级区域的监控应证明关键操作期间无菌工艺条件的维护。应在对无菌设备表面、容器、封盖和产
品造成最大污染风险的位置进行监测。监测地点的选择以及取样装置的定向和定位应当合理和适当，
以便从关键地带获得可靠的数据。

9.8. Sampling methods should not pose a risk of contamination to the manufacturing operations.
取样方法不应对生产操作造成污染风险。

9.9. Appropriate alert levels and action limits should be set for the results of viable and non viable particle
monitoring. Alert levels should be established based on results of cleanroom qualification tests or trend data
and should be subject to periodic review.
应为可行和不可行粒子监测的结果设定适当的警报级别和行动限制。应根据洁净室合格测试的结果或
趋势数据确定警报级别，并应定期进行审查。

9.10. Alert levels for Grade A (non viable particles only) Grade B, Grade C and Grade D should be set such that
adverse trends (e.g. a numbers of events or individual events that indicate a deterioration of cleanliness) are
detected and addressed.
应设定A级（仅指不能存活的颗粒）、B级、C级和D级的警报级别，以检测并解决不利趋势（例如，
表明清洁度恶化的多个事件或单个事件）。

9.11. Monitoring procedures should define the approach to trending. Trends can include, but are not limited to:
监控程序应定义趋势分析的方法。趋势可包括但不限于:

9.11.1. Increasing numbers of action limit or alert level breaches.

违反行动限制或警报级别的次数增加。

9.11.2. Consecutive breaches of alert levels.

连续突破警戒级别。

50
 9.11.3. Regular but isolated breaches of action limits that may have a common cause, for example single
excursions that always follow planned preventative maintenance.
可能有共同原因的常规但孤立的违反操作限制，例如，始终遵循计划的预防性维护的单次偏
移。

9.11.4. Changes in microbial flora type and numbers and predominance of specific organisms. Particular
attention should be given to objectionable organisms or those that can be difficult to control such as
spore forming microorganisms.
微生物区系类型和数量的变化以及特定生物体的优势。应特别注意有害微生物或难以控制的
微生物，如形成孢子的微生物。

9.12. The monitoring of Grade C and D cleanrooms in operation should be performed based on data collected during
qualification and historical data to allow effective trend analysis. The requirements of alert levels and action
limits will depend on the nature of the operations carried out. Action limits may be more stringent than those
listed in Table 6 and Table 7.
运行中的C级和D级洁净室的监测应根据鉴定期间收集的数据和历史数据进行，以便进行有效的趋势
分析。警戒级别和行动限制的要求将取决于所开展行动的性质。作用限度可能比表6和表7所列的更为
严格。

9.13. If action limits are exceeded, operating procedures should prescribe a root cause investigation, an assessment
of the potential impact to product and requirements for corrective and preventive actions. If alert levels are
exceeded, operating procedures should prescribe assessment and follow up, which should include consideration
of an investigation and/or corrective actions to avoid any further deterioration of the environment.
如果超过措施限制，操作程序应规定根本原因调查、对产品潜在影响的评估以及纠正和预防措施的要
求。如果超过警戒级别，操作程序应规定进行评估和跟踪，其中应包括考虑进行调查和/或采取纠正
措施，以避免环境进一步恶化。

9.14. Results from environmental monitoring should be considered when reviewing batch documentation for finished
product batch certification.
在审查批次时应考虑环境监测的结果成品批认证的文件。

Environmental monitoring non viable particles

环境监测非活性粒子

9.15. Non viable particulate monitoring systems should be established to obtain data for assessing potential
contamination risks and to ensure the maintenance of the environment for sterile operations in a qualified state.
应建立不可行的微粒监测系统，以获得评估潜在污染风险的数据，并确保无菌操作环境保持在合格状
态。

9.16. The limits for environmental monitoring of airborne particulate concentrations for each graded area are given
in Table 6.
各分级区域大气颗粒物浓度环境监测限值见表6。

Table 6: Limits for airborne particulate concentration for the monitoring of non viable contamination. 表6:监
测非活菌污染的空气颗粒物浓度限值。

Maximum limits for particulates Maximum limits for particulates

微粒的最高限量 微粒的最高限量
Grade
≥ 0.5 μm/m3 ≥ 5 μm/m3
级别 at rest in operation at rest in operation

A 3 520 3 520 29 29

B 3 520 352 000 29 2 900

51
 C 352 000 3 520 000 2 900 29 000

D 3 520 000 Not defined(a) 29 000 Not defined(a)

(a)
For Grade D, in operation limits are not defined. The company should establish in operation limits based
on a risk assessment and on historical data, where applicable.
(a)
对于D级，未定义运行限制。公司应根据风险评估和历史数据（如适用）确定运营限额。

Note 1: The particulate limits given in the table for the “at rest” state should be achieved after a short
“clean up” period (defined during qualification with a guidance value of 15 to 20 minutes) in an unmanned
state, after the completion of operations (refer to paragraph 4.30 and 4.31).
注1:表中给出的"静止"状态下的微粒限值应在无人状态下完成操作（参见第4.30和4.31段）后经过短暂
的"清理"时间（在鉴定期间定义，指导值为15至20分钟）后达到。

Note 2: With regards to the monitoring of airborne particulates ≥5 μm particulate concentration, the limit
of 29 (Grade A) is selected due to the limitations of monitoring equipment. Alert levels should be set based
on historical data, such that frequent sustained counts below the action limit which may be indicative of
system contamination or deterioration should trigger an investigation. For the Grade A zone and Grade B
area the importance of monitoring the ≥5 μm particulates is to identify negative trends as defined in the
manufacturer's CCS.
注2:大气颗粒物≥5μm颗粒物浓度监测，限值为29（A级）由于监控设备的限制而被选择。应根据历史
数据设置警报级别，这样，如果经常持续计数低于作用极限（这可能表明系统污染或恶化），则应触
发调查。继承。对于A级区和B级区，监测≥5μm颗粒物的重要性在于确定《国家大气污染物排放标准》
中规定的负面趋势。ER的CCS。

9.17. For the Grade A zone, particulate monitoring should be undertaken for the full duration of critical processing,
including equipment assembly.
对于A级区，应在整个关键加工期间（包括设备组装）进行颗粒监测。

9.18. The Grade A zone should be monitored continuously (for particulates ≥0.5 and ≥5 µm) and with a suitable
sample flow rate (at least 28 litres (1ft3) per minute) so that all interventions, transient events and any system
deterioration is captured. The system should frequently correlate each individual sample result with the limits
in Table 6 at such a frequency that any potential excursion can be identified and responded to in a timely manner.
Alarms should be triggered if alert levels are exceeded. Procedures should define the actions to be taken in
response to alarms including the consideration of additional microbial monitoring.
A级区应连续监测（对于≥0.5和≥5µm的颗粒物），并采用适当的样品流速（至少28升（1英尺3英寸））
每分钟），以便捕获所有干预、瞬态事件和任何系统恶化。系统应以这样的频率频繁地将每个单独的
样本结果与表6中的限制相关联，该频率使得任何潜在的偏移都可以得到及时识别和响应。如果超过
警报级别，则应触发警报。程序应规定应对警报采取的行动，包括考虑额外的微生物监测。

9.19. It is recommended that a similar system be used for Grade B area although the sample frequency may be
decreased. The Grade B zone should be monitored at such a frequency and with suitable sample size that the
programme captures any increase in levels of contamination and system deterioration. If alert or action levels
are exceeded, alarms should be triggered.
建议对B级区域使用类似的系统，尽管采样频率可能会降低。B级区域应以适当的频率和样本量进行
监测，以使方案能够捕捉到污染程度的任何增加和系统的恶化。如果超过警报或行动级别，则应触发
警报。

9.20. The selection of the monitoring system should take i n t o account any risk presented by the materials used
in the manufacturing operation (for example, those involving live organisms, powdery products or
radiopharmaceuticals) that may give rise to biological or chemical hazards.
监测系统的选择应考虑到制造作业中使用的材料（例如，涉及活生物体、粉状产品或放射性药物的材
料）可能引起生物或化学危害的任何风险。

52
 9.21. In the case where contaminants are present due to the processes involved and would potentially damage the
particle counter or present a hazard (e.g. live organisms, powdery products and radiation hazards), the frequency
and strategy employed should be such as to assure the environmental classification both prior to and post
exposure to the risk. An increase in viable particle monitoring should be considered to ensure comprehensive
monitoring of the process. Additionally, monitoring should be performed during simulated operations. Such
operations should be performed at appropriate intervals. The approach should be defined in the CCS.
在由于所涉及的过程而存在污染物的情况下，污染物可能会损坏颗粒计数器或造成危险（例如:活生
物体、粉末状产品和辐射危害），所采用的频率和策略应确保在暴露于风险之前和之后进行环境分类。
应考虑增加可行的粒子监测，以确保对该过程进行全面监测。此外，应在模拟操作期间进行监测。此
类操作应在适当的时间间隔内进行。应在综合传播战略中界定这一方法。

9.22. The size of monitoring samples taken using automated systems will usually be a function of the sampling rate
of the system used. It is not necessary for the sample volume to be the same as that used for formal classification
of cleanrooms and clean air equipment. Monitoring sample volumes should be justified.
使用自动系统采集的监测样本的大小通常是所用系统的采样率的函数。样品量不必与洁净室和洁净空
气设备正式分类所用的样品量相同。监测样品量应合理。

9.23. The occasional indication of macro particulate counts, especially ≥ 5 µm, may be considered to be false counts
due to electronic noise, stray light, coincidence, etc. However, consecutive or regular counting of low levels
may be indicative of a possible contamination event and should be investigated. Such events may indicate early
failure of the room air supply filtration system, filling equipment failure, or may also be diagnostic of poor
practices during machine set up and routine operation.
偶尔显示的宏观颗粒计数，特别是≥5µm，可能被认为是由于电子噪声、杂散光巧合等。然而，连续
或定期计数的低水平可能表明可能的污染事件，应进行调查。这类事件可能表明房间送风过滤系统的
早期故障、灌装设备故障或者也可以在机器设置和日常操作期间诊断不良操作。

9.24. Monitoring conditions such as frequency, sampling volume or duration, alert levels and action limits and
corrective actions (including an investigation) should be established in each manufacturing area based on data
generated during the initial qualification process, ongoing routine monitoring and periodic review of data.
应根据初始鉴定过程中产生的数据、正在进行的例行监控和数据的定期审查，在每个制造区域建立监
控条件，如频率、取样量或持续时间、警报级别和行动限制以及纠正措施（包括调查）。

Environmental and personnel monitoring viable particles

环境和人员监测有活力的粒子

9.25. Where aseptic operations are performed, microbial monitoring should be frequent using a combination of
methods such as settle plates, volumetric air sampling, glove, gown and surface sampling (e.g. swabs and
contact plates). The method of sampling used should be justified within the CCS and should be demonstrated
not to have a detrimental impact on Grade A and B airflow patterns.
进行无菌操作时，应经常使用沉降板、容积空气取样、手套、长袍和表面取样（如棉签和接触板）等
方法的组合进行微生物监测。所使用的取样方法应在CCS范围内合理，并应证明不会对A级和B级气
流模式产生有害影响。

9.26. Monitoring should include sampling of personnel at periodic intervals during the process. Sampling of
personnel should be performed in such a way that it will not compromise the process. Particular consideration
should be given to monitoring personnel following involvement in critical interventions and on each exit from
the Grade B cleanroom.
监测应包括在过程中定期对人员进行抽样。人员抽样应以不损害流程的方式进行。应特别考虑在B级
洁净室的每个出口进行关键干预后对人员进行监控。

9.27. Viable particle monitoring should also be performed within the cleanrooms when normal manufacturing
operations are not occurring (e.g. post disinfection, prior to start of manufacturing, on completion of the batch
and after a shutdown period), and in associated rooms that have not been used, in order to detect potential
incidents of contamination which may affect the controls within the cleanrooms. In case of an incident,
additional sample locations may be used as a verification of the effectiveness of a corrective action (i.e. cleaning
and disinfection).

53
 在A级区进行连续的空气监测（如空气采样或沉降板）应在整个关键工艺过程中进行，包括设备（无
菌装置）装配和灌装操作。对于B级洁净室，应根据影响无菌工艺的风险，考虑采用类似的方法。应
以这样一种方式进行监测，瞬态事件和任何系统恶化都将被捕获，并且避免了因监控操作的干预而导
致的任何风险。

9.28. Continuous viable air monitoring in the Grade A zone (e.g. air sampling or settle plates) should be undertaken
for the full duration of critical processing, including equipment (aseptic set up) assembly and filling operations.
A similar approach should be considered for Grade B cleanrooms based on the risk of impact on the aseptic
processing. The monitoring should be performed in such a way that all interventions, transient events and any
system deterioration would be captured and any risk caused by interventions of the monitoring operations is
avoided.
当正常的生产操作没有发生时，也应该在洁净室内进行可行的颗粒监测。（例如:后消毒，在生产开
始前、批次完成时和停工期后），以及尚未使用的相关房间，以便检测可能影响洁净室内控制的潜在
污染事件。在发生事故的情况下，可以使用额外的取样位置来验证纠正措施的有效性（即:（清洁及
消毒）

9.29. The adoption of suitable rapid or automated monitoring systems should be considered by manufacturers in
order to expedite the detection of microbiological contamination issues and to reduce the risk to product. These
rapid and automated microbial monitoring methods may be adopted after validation has demonstrated their
equivalency or superiority to the established methodology.
制造商应考虑采用合适的快速或自动监测系统，以加快微生物污染问题的检测，并降低产品的风险。
这些快速和自动化的微生物监测方法可在验证证明其与已建立的方法学的等效性或优越性后采用。

9.30. Sampling methods and equipment used should be fully understood and procedures should be in place for the
correct operation and interpretation of results obtained. The recovery efficiency of the sampling methods chosen
should be qualified.
应充分了解所使用的取样方法和设备，并应制定正确操作和解释所获结果的程序。所选采样方法的回
收率应合格。

9.31. Action limits for viable particle contamination are shown in Table 7
活性粒子污染的作用限值见表7。

Table 7: Maximum action limits for viable particle contamination

Glove print,
Settle plates Contact plates Including 5 fingers
Air sample (diam. 90 mm) (diam. 55mm) 接触 on both hands
Grade
空气样本 沉降板（直径90毫 板（直径55mm）, cfu/ glove手套印，
级别
cfu/m3 米）cfu/4 hours (a) cfu/ plate (c) 包括双手5个手指
CFU/手套
No growth(b) 无增
A 长（B）
B 10 5 5 5
C 100 50 25
D 200 100 50
(a)
Settle plates should be exposed for the duration of operations and changed as required after4 hours (exposure
time should be based on validation including recovery studies and it should not have any negative effect on the
suitability of the media used). Individual settle plates may be exposed for less than 4 hours.
（a ）
沉降板应在操作期间暴露，并在4小时后根据需要进行更换（暴露时间应基于验证，包括回收研究，
且不应对所用介质的适用性产生任何负面影响）。个别沉降板的暴露时间可少于4小时。

(b) It
should be noted that for Grade A, any growth should result in an investigation.
（B ）
应当指出，就A级而言，任何增长都应导致调查。

(c) Contact
plate limits apply to equipment room and gown surfaces within the Grade A zone and Grade B area.
Routine gown monitoring is not normally required for Grade C and D areas, depending on their function.
54
 （C ）
接触板限制适用于A级区域和B级区域内的设备室和外套表面。对于C级和D级区域，根据其功能，
通常不需要常规的长袍监测。

Note 1: It should be noted that the types of monitoring methods listed in the table above are examples and other
methods can be used provided they meet the intent of providing information across the whole of the critical
process where product may be contaminated (e.g. aseptic line set up, filling and lyophilizer loading).
注1:应注意，上表中列出的监测方法类型仅为示例，如果其他方法满足提供产品可能受到污染的整个
关键过程的信息的意图（例如，无菌线设置、灌装和冻干机装载），则可以使用这些方法。

Note 2: Limits are applied using cfu throughout the document. If different or new technologies are used that
present results in a manner different from cfu, the manufacturer should scientifically justify the limits applied
and where possible correlate them to cfu.
注2:在整个文档中，使用CFU应用限制。如果使用了不同的或新的技术，以不同于CFU的方式呈现结
果，制造商应科学地证明所应用的限制，并在可能的情况下将其与CFU相关联。

9.32. Microorganisms detected in Grade A zone and Grade B area should be identified to species level and the
potential impact of such microorganisms on product quality (for each batch implicated) and overall state of
control should be evaluated. Consideration should also be given to the identification of microorganisms
detected in Grade C and D areas (for example where action limits or alert levels are exceeded or where atypical
or potentially objectionable microorganisms are recovered). The approach to organism identification and
investigation should be documented.
在A级区和B级区检测到的微生物应鉴定到物种水平，以及这些微生物对产品的潜在影响。UCT质量
（涉及的每个批次）并应评估总体控制状况。还应考虑对C级和D级地区检测到的微生物进行鉴定。
（例如，其中的操作限制或警报）含量超标或回收了非典型或可能有害的微生物）.有机体识别和调
查的方法应记录在案。

9.33. Personnel gloves (and any part of the gown that may potentially have direct impact on the product sterility (e.g.
the sleeves if these enter a critical zone) should be monitored for viable contamination after critical operations
and on exit from the cleanroom. Other surfaces should be monitored at the end of an operation.
人员手套（以及任何可能直接影响产品无菌的长袍部分（例如，进入关键区域的袖子）应在关键操作
后和从洁净室出口时进行监测，以确定是否存在污染。其他表面应在操作结束时进行监测。

9.34. Microbial monitoring of personnel in the Grade A zone and Grade B area should be performed to assess their
aseptic behaviour. Where filling operations are manual in nature e.g. hand filling, the process in its entirety may
be considered as one critical intervention. In these cases, the frequency of microbial monitoring of gowning
should be based on scientific principles and justified as part of the CCS. Where monitoring is routinely
performed by manufacturing personnel, consideration should be given to periodic monitoring under the
supervision of the quality unit.
应对A级区域和B级区域的人员进行微生物监测，以评估其无菌行为。如果灌装操作本质上是人工操
作，例如手工灌装，则整个过程可被视为一种关键干预。在这些情况下，对长袍进行微生物监测的频
率应基于科学原则，并作为CCS的一部分加以证明。在由制造人员例行执行监控的情况下，应考虑在
质量部门的监督下进行定期监测。

Aseptic process simulation (APS) (also known as media fill)

无菌工艺模拟（APS）（也称为介质填充）

9.35. Periodic verification of the effectiveness of the controls in place for aseptic processing should include a process
simulation test using a sterile nutrient media and/or surrogate in place of the product. Selection of an appropriate
nutrient media should be made based on the ability of the media and/or surrogate to imitate product
characteristics at all processing stages. Where processing stages may indirectly impact the viability of any
introduced microbial contamination, (e.g. sterile aseptically produced semi solids, powders, solid materials,
microspheres, liposomes and other formulations where product is cooled or heated or lyophilized), alternative
procedures that represent the operations as closely as possible can be developed and justified. Where surrogate
materials, such as buffers, are used in parts of the process simulation, the surrogate material should not inhibit
the growth of any potential contamination.
无菌工艺控制措施有效性的定期验证应包括使用无菌NU进行工艺模拟试验。替代产品的Trient介质和
/或替代品。应根据培养基和/或替代品模仿产品特性的能力来选择合适的营养培养基。l加工阶段。如
55
 果加工阶段可能间接影响任何引入的微生物污染的生存能力，（例如:无菌生产的半固体，粉末，固
体材料，微球，脂质体和其他制剂（其中产品被冷却或加热或冻干）此外，还可以制定尽可能接近业
务的替代程序，并证明其合理性。在工艺模拟的某些部分使用替代材料（如缓冲剂）时，替代材料不
应抑制任何潜在污染物的增长。

9.36. The process simulation test should imitate as closely as possible the routine aseptic manufacturing process and
include all the critical manufacturing steps, specifically:
工艺模拟试验应尽可能地模拟常规无菌生产工艺，并包括所有关键的生产步骤，特别是:

9.36.1. Process simulation tests should assess all aseptic operations performed subsequent to the sterilization
and decontamination cycles of materials utilised in the process to the point where the container is sealed.
工艺模拟试验应评估在对工艺中使用的材料进行灭菌和去污循环之后进行的所有无菌操作，
直至容器密封。

9.36.2. For non filterable formulations, any additional aseptic steps should be assessed.

对于不可过滤的制剂，应评估任何额外的无菌步骤。

9.36.3. Where aseptic manufacturing is performed under an inert atmosphere, the inert gas should be
substituted with air in the process simulation unless anaerobic simulation is intended.
如果无菌制造是在惰性气氛下进行的，则在工艺模拟中应使用空气代替惰性气体，除非打算
进行厌氧模拟。

9.36.4. Processes requiring the addition of sterile powders should use an acceptable surrogate material in
containers identical to those used in the process under evaluation.
需要添加无菌粉的工艺应使用可接受的替代材料，其容器应与正在评估的工艺中使用的容器
相同。

9.36.5. Separate simulations of individual unit operations (e.g. processes involving drying, blending, milling
and subdivision of a sterile powder) should generally be avoided. Any use of individual simulations
should be supported by a documented justification and ensure that the sum total of the individual
simulations continues to fully cover the whole process.
通常应避免单独模拟单个单元操作（例如，涉及无菌粉末的干燥、混合、研磨和细分的过
程）。单独模拟的任何使用都应得到书面证明的支持，并确保单独模拟的总和继续完全覆盖
整个流程。

9.36.6. The process simulation procedure for lyophilized products should represent the entire aseptic
processing chain including filling, transport, loading, chamber dwell, unloading and sealing under
specified, documented and justified conditions representing worst case operating parameters.
冻干产品的工艺模拟程序应代表整个无菌工艺链，包括在规定、记录和证明的条件下的灌装、
运输、装载、室停留、卸载和密封，这些条件代表最坏情况下的操作参数。

9.36.7. The lyophilization process simulation should duplicate all aspects of the process, except those that may
affect the viability or recovery of contaminants. For instance, boiling over or actual freezing of the
solution should be avoided. Factors to consider in determining APS
冻干工艺模拟应复制工艺的所有方面，除了那些可能影响污染物的生存能力或回收的方面。
例如，应避免煮沸或溶液的实际冻结。决定认可人士时须考虑的因素

9.36.8. dsign include, where applicable:

9.36.9. 在适用的情况下，包括:

9.36.9.1. The use of air to break vacuum instead of nitrogen.

用空气代替氮气打破真空。

9.36.9.2. Replicating the maximum interval between sterilization of the lyophilizer and its use.
复制冻干机灭菌和使用之间的最大间隔。

56
 9.36.9.3. Replicating the maximum period of time between sterilization and lyophilization.
重复灭菌和冻干之间的最大时间间隔。

9.36.9.4. Quantitative aspects of worst case situations, e.g. loading the largest number of trays,
replicating the longest duration of loading where the chamber is open to the environment.
最坏情况的定量方面，例如装载最多数量的塔板，在腔室向环境开放的情况下重复
最长的装载持续时间。

9.37. The process simulation testing should take into account various aseptic manipulations and interventions known
to occur during normal production as well as worst case situations, including:
工艺模拟试验应考虑正常生产过程中已知的各种无菌操作和干预以及最坏情况，包括:

9.37.1. Inherent interventions representative of the routine process at the maximum accepted frequency per
number of filled units (e.g. loading of vials into a lyophilizer).
固有的干预，代表每填充单位数量的最大可接受频率的常规过程（例如，将小瓶装入冻干
机）。

9.37.2. Corrective interventions, that occur frequently during routine production, in a representative number
and with the highest degree of acceptable intrusion (e.g. correcting jammed stoppers).
纠正干预，在日常生产中经常发生，具有代表性的数量和最高程度的可接受的干扰（例如，
纠正塞子堵塞）。

9.38. Interventions should not be designed or selected to justify poor process or facility design or to assess
unacceptable interventions that rarely occur and which should lead to a thorough investigation and product
assessment when they do occur.
干预措施的设计或选择不应为不良的流程或设施设计辩护，也不应评估很少发生的不可接受的干预措
施，如果确实发生，则应进行彻底调查和产品评估。

9.39. In developing the process simulation test plan, consideration should be given to the following:
在制定过程模拟试验计划时，应考虑以下几点:

9.39.1. Identification of worst case conditions covering the relevant variables, such as container size and line
speed, and their impact on the process. The outcome of the assessment should justify the variables
selected.
确定最坏情况条件，包括相关变量，如集装箱大小和生产线速度，以及它们对流程的影响。
评估结果应证明所选择的变量是合理的。

9.39.2. Determining the representative sizes of container/closure combinations to be used for validation.
Bracketing or matrix approach may be considered for validation of the same container/closure
configuration for different products where process equivalence is scientifically justified.
确定用于验证的容器/封盖组合的代表性尺寸。在工艺等效性得到科学证明的情况下，对于不
同产品的相同容器/封盖配置的验证，可以考虑使用方括号或矩阵方法。

9.39.3. The volume filled per container, which should be sufficient to ensure that the media contacts all
equipment and component surfaces that may directly contaminate the sterile product. The volume used
should provide sufficient headspace to support potential microbial growth and ensure that turbidity can
be detected during inspection.
每个容器的装载量，应足以确保介质接触到所有可能直接污染无菌产品的设备和部件表面。
所使用的体积应提供足够的顶部空间，以支持潜在的微生物生长，并确保在检查过程中可以
检测到浊度。

9.39.4. Maximum permitted holding times for sterile product and associated sterile components and equipment
exposed during the aseptic process.
无菌产品及相关无菌部件和设备在无菌过程中暴露的最大允许保持时间。

9.39.5. The method of detection of microbial contamination should be scientifically justified to ensure that any
contamination is detectable.
57
 检测微生物污染的方法应该是科学合理的，以确保任何污染都是可检测的。

9.39.6. The selected nutrient media should be capable of growing a designated group of reference
microorganisms as described by the relevant pharmacopeia and suitably representative local isolates
and supporting recovery of low numbers of these microorganisms.
所选择的营养培养基应能够培养相关药典中描述的指定参考微生物群和具有适当代表性的当
地分离物，并支持回收少量的这些微生物。

9.39.7. The requirement for substitution of any inert gas used in the routine aseptic manufacturing process by
air unless anaerobic simulation is intended. In these situations, inclusion of
要求用空气代替常规无菌生产过程中使用的任何惰性气体，除非打算进行厌氧模拟。在这些
情况下，列入

9.39.8. occasional anaerobic simulations as part of the overall validation strategy should be considered (refer
to paragraph 9.35 point iii).
应考虑将偶尔的厌氧模拟作为总体验证策略的一部分（参见第9.35段第III点）。

9.39.9. The process simulation should be of sufficient duration to challenge the process, the operators that
perform interventions, shift changes and the capability of the processing environment to provide
appropriate conditions for the manufacture of a sterile product.
工艺模拟应具有足够的持续时间，以挑战工艺、执行干预的操作员、换班和加工环境的能力，
从而为无菌产品的生产提供适当的条件。

9.39.10. Where the manufacturer operates different shifts then the APS should be designed to capture specific
factors (e.g. for those manufacturing during a night or extended shift, fatigue should be considered).
如果制造商运行不同的轮班，则应设计APS以捕获特定因素（例如，对于在夜间或延长轮班
期间进行的制造，应考虑疲劳）。

9.39.11. Simulating normal aseptic manufacturing interruptions where the process is idle (e.g. shift changeovers,
recharging dispensing vessels, introduction of additional equipment, etc.).
在工艺空闲的情况下模拟正常的无菌生产中断（例如换班、再充装分配容器、引入附加设备
等）。

9.39.12. Ensuring that environmental monitoring is conducted as required for routine production, and
throughout the entire duration of the process simulation.
确保在整个工艺模拟过程中，按照日常生产的要求进行环境监测。

9.39.13. Where campaign manufacturing occurs, such as in the use of Barrier Technologies or manufacture of
sterile active substances, consideration should be given to designing and performing the process
simulation so that it simulates the risks associated with both the beginning and the end of the campaign
and demonstrating that the campaign duration does not pose any risk. The performance of "end of
production or campaign APS" may be used as additional assurance or investigative purposes; however,
their use should be justified in the CCS and should not replace routine APS. If used, it should be
demonstrated that any residual product does not negatively impact the recovery of any potential
microbial contamination.
在使用阻隔技术或生产无菌活性物质等突击性生产的情况下，应考虑设计和执行流程模拟，
以便它模拟与开始和执行过程相关的风险d活动结束，并证明活动持续时间不构成任何风险。
"生产或活动APS结束"的性能可用作额外的保证或调查目的；然而，它们的使用应在综合传播
战略中得到证明，不应取代常规的行动方案。如果使用，应证明任何残留产品不会对任何潜
在微生物污染的恢复产生负面影响。

9.40. For sterile active substances, batch size should be large enough to represent routine operation, simulate
intervention operation at the worst case, and cover potential contact surfaces. In addition, all the simulated
materials (surrogates or growth medium) should be subjected to microbial evaluation. The simulation materials
should be sufficient to satisfy the evaluation of the process being simulated and should not compromise the
recovery of micro organisms.
对于无菌活性物质，批量应足够大，以代表常规操作，模拟最坏情况下的干预操作，并覆盖潜在的接
58
 触面。此外，所有模拟材料（代用品或生长培养基）均应进行微生物评价。模拟材料应足以满足对所
模拟过程的评估，且不应影响微生物的恢复。

9.41. Process simulation tests should be performed as part of the initial validation, with at least three consecutive
satisfactory simulation tests that cover all working shifts that the aseptic process may occur in, and after any
significant modification to operational practices, facilities, services or equipment (e.g. modification to the
HVAC system, equipment, major facility shut down, changes to process, number of shifts and numbers of
personnel etc.). Normally, process simulation tests (periodic revalidation) should be repeated twice a year
(approximately every six months) for each aseptic process, each filling line and each shift. Each operator should
participate in at least one successful APS annually. Consideration should be given to performing an APS after
the last batch prior to shut down, before long periods of inactivity or before decommissioning or relocation of
a line.
过程模拟测试应作为初始验证的一部分进行，通过至少三次连续的满意的模拟试验，覆盖无菌过程可
能发生的所有工作班次，以及在对操作做法、设施、服务或设备进行任何重大修改之后（e）HVAC
系统的改造、设备、主要设施关闭、工艺变更、班次和人员数量等）。通常，工艺模拟试验（定期再
验证）应每年重复两次（大约每六个月一次）对于每个无菌过程，每个灌装线和每个班次。每个运营
商每年至少应参加一次成功的APS。应考虑在关闭之前的最后一个批处理之后执行APS，在长期不活
动之前或在线路退役或搬迁之前。

9.42. Where manual operation (e.g. aseptic compounding or filling) occurs, each type of container, container closure
and equipment train should be initially validated with each operator participating in at least 3 consecutive
successful APS and revalidated with one APS approximately every 6 months for each shift. The APS batch size
should mimic that used in the routine aseptic manufacturing process.
当发生手动操作（如无菌混合或灌装）时，应对每种类型的容器、容器封闭和设备培训进行初始验证，
每个操作员至少参加3次连续成功的APS，并且每个班次大约每6个月进行一次APS的再验证。APS批
次大小应与常规无菌生产工艺中使用的批次大小相似。

9.43. The number of units processed (filled) for APS tests should be sufficient to effectively simulate all activities
that are representative of the aseptic manufacturing process. Justification for the number of units to be filled
should be clearly captured in the PQS. Typically, a minimum of 5000 to 10000 units are filled. For small batches
(e.g. those under 5000 units), the number of containers for media fill should at least equal the size of the
production batch.
为APS试验处理（填充）的单元数量应足以有效地模拟代表无菌制造过程的所有活动。应在PQS中明
确说明要填充的单元数量的理由。通常，至少填充5000到10000个单元。对于小批量（例如5000单位
以下），用于介质填充的容器数量应至少等于生产批次的大小。

9.44. Filled APS units should be agitated, swirled or inverted before incubation to ensure contact of the media with
all interior surfaces in the container. Units with cosmetic defects or those who have gone through non
destructive in process control checks should be identified and incubated. Units discarded during the process
simulation and not incubated should be comparable with units discarded during a routine fill. Examples may
include those normally discarded after the set up process or due to an intervention or where the integrity of the
unit is compromised as would be identified by the routine inspection process for the product.
填充的APS单元应该被搅动，培养前旋转或倒置，以确保培养基与容器的所有内表面接触。应对存在
外观缺陷或已通过非破坏性过程控制检查的部件进行识别和孵化。在工艺模拟过程中丢弃且未孵化的
单位应与常规填充过程中丢弃的单位相当。示例可包括通常在建立过程之后或由于干预而被丢弃的部
件，或在以下情况下损坏部件的完整性的部件:将由产品的常规检查过程来确定。

9.45. Where processes have materials that contact the product contact surfaces but are then discarded, the discarded
material should be simulated with nutrient media and be incubated as part of the APS, unless it can be clearly
demonstrated that this waste process would not impact the sterility of the product.
如果工艺中的材料与产品接触面接触，但随后被丢弃，则应使用营养培养基模拟丢弃的材料，并将其
作为APS的一部分进行培养，除非可以明确证明该废弃工艺不会影响产品的无菌。

9.46. Filled APS units should be incubated in a clear container to ensure visual detection of microbial growth. Where
the product container is not clear (i.e. amber glass, opaque plastic), clear containers of identical configuration
may be substituted to aid in the detection of contamination. When a clear container of identical configuration
cannot be substituted, a suitable method for the detection of microbial growth should be developed and validated.
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 Microorganisms isolated from contaminated units should be identified to at least genus, and to the species level
when practical, to assist in the determination of the likely source of the contaminant. The selection of the
incubation conditions and duration should be scientifically justified and validated to provide an appropriate
level of sensitivity of detection of microbial contamination.
填充的APS单元应在透明容器中培养，以确保直观检测微生物的生长。产品容器不透明的地方（即琥
珀色玻璃、不透明塑料），可替换相同构造的透明容器，以帮助检测污染。当无法替换相同配置的
Clear容器时，应开发和验证检测微生物生长的合适方法。从受污染单元分离的微生物应至少鉴定到
属，在可行的情况下鉴定到种水平。协助确定污染物的可能来源。孵育条件和孵育时间的选择应经过
科学论证和验证，以提供适当的敏感性水平。微生物污染的检测。

9.47. Filled APS units should be incubated without unnecessary delay to achieve the best possible recovery of
potential contamination.
填充的APS单元应在没有不必要延迟的情况下进行培养，以实现潜在污染的最佳恢复。

9.48. On completion of incubation:

孵化完成后:

9.48.1. Filled APS units should be inspected by staff, who have been trained and qualified in the visual
inspection procedures, under conditions similar to those for visual inspection, that facilitate the
identification of any microbial contamination.
应由受过目视检查程序培训并有资格的工作人员在类似于目视检查的条件下检查已灌装的
APS单元，以便于识别任何微生物污染。

9.48.2. Samples of these units should undergo positive control by inoculation with a suitable range of reference
organisms and local isolates.
这些单位的样本应通过接种适当范围的参考生物体和当地分离物进行阳性控制。

9.49. The target should be zero growth. Any contaminated unit should result in a failed process simulation and the
following actions should occur:
目标应该是零增长。任何被污染的装置都应导致流程模拟失败，并应采取以下措施:

9.49.1. An investigation to determine the most probable root causes.

确定最可能的根本原因的调查。

9.49.2. Determination and implementation of appropriate corrective measures.

确定并实施适当的纠正措施。

9.49.3. A sufficient number of successful, consecutive repeat media fills (normally a minimum of 3) should
be conducted in order to demonstrate that the process has been returned to a state of control.
应进行足够次数的成功连续重复介质填充（通常最少3次），以证明工艺已返回到控制状态。

9.49.4. A prompt review of all appropriate records relating to aseptic production since the last successful APS.
The outcome of the review should include a risk assessment of potential sterile breaches in batches
manufactured since the last successful process simulation. All other batches not released to the market
should be included in the scope of the investigation. Any decision regarding their release status should
consider the investigation outcome.
及时审查自上次成功的APS以来与无菌生产相关的所有适当记录。审查结果应包括对自上一
次成功的工艺模拟以来生产的批次中潜在的无菌违规的风险评估。其他未投放市场的批次均
应纳入调查范围。关于释放他们的任何决定都应考虑到调查结果。

9.49.5. All products that have been manufactured on a line subsequent to a process simulation failure should
be quarantined until a successful resolution of the process simulation failure has occurred.
工艺模拟失败后在生产线上生产的所有产品都应隔离，直到工艺模拟失败得到成功解决。

9.49.6. Production should resume only after completion of successful revalidation.

只有在成功完成重新验证后，才能恢复生产。

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 9.50. APS should be carefully observed by personnel with specific expertise in aseptic processing to assess the correct
performance of operations and address inappropriate practices if detected.
APS应由具有无菌工艺专门知识的人员仔细观察，以评估操作的正确性能，并在发现时解决不适当的
做法。

9.51. Where results indicate that an operator may have failed qualification, actions to limit the operator’s activities,
until retrained and requalified, should be taken.
如果结果表明操作员可能未通过资格认证，则应采取措施限制操作员的活动，直到重新培训和重新获
得资格认证为止。

9.52. An aseptic process or filling should be subject to a repeat of the initial validation when:
在下列情况下，无菌工艺或灌装应重复初始验证:

9.52.1. The specific aseptic process has not been in operation for an extended period of time.
特定的无菌工艺在很长一段时间内没有运行。

9.52.2. There is a change to the process, equipment, procedures or environment that has the potential to affect
the aseptic process or an addition of new product containers or container closure combinations.
工艺、设备、程序或环境的改变有可能影响无菌工艺，或增加新的产品容器或容器密封组合。

9.53. All process simulation runs should be fully documented and include a reconciliation of units processed (e.g.
units filled, incubated, not incubated, and rejected). All interventions performed during the process simulations
should be recorded, including the start and end of each intervention. All microbial monitoring data as well as
other testing data should be recorded in the APS batch record.
所有流程模拟运行都应完整记录，并包括处理的单位（例如，已填充、已孵化、未孵化和已拒绝的单
位）的对账。应记录在流程模拟期间执行的所有干预，包括每次干预的开始和结束。所有微生物监测
数据以及其他检测数据均应记录在APS批记录中。

10. Quality Control (QC)

质量控制（QC）

10.1. It is important that there are personnel with appropriate training and experience in microbiology and knowledge
of the process to support the design of the manufacturing process, environmental monitoring regime and any
investigation assessing the impact of microbiologically linked events to the safety of the sterile product.
重要的是，要有受过适当培训、具有微生物方面经验和工艺知识的人员，以支持制造工艺的设计、环
境监测制度和评估微生物相关事件对无菌产品安全性的影响的任何调查。

10.2. Specifications for raw materials, components and products should include requirements for microbial quality
when the need for this has been indicated by monitoring and/or by the CCS.
原材料、部件和产品的规格应包括微生物质量的要求，如果监测和/或CCS表明需要这样做的话。

10.3. The bioburden assay should be performed on each batch for both aseptically filled product and terminally
sterilized products and the results considered as part of the final batch review. There should be defined limits
for bioburden immediately before the sterilizing filter or the terminal sterilization process, which are related to
the efficiency of the method to be used. Samples should be taken to be representative of the worst case scenario
(e.g. at the end of hold time). Where overkill sterilization parameters are set for terminally sterilized products,
bioburden should be monitored at suitable scheduled intervals.
无菌灌装产品和最终灭菌产品的每批产品都应进行生物菌检验，并考虑检验结果。d作为最后一批审
查的一部分。在灭菌过滤器或终端灭菌过程之前，应该有明确的生物负荷限值。这与要使用的方法的
效率有关。取样应代表最坏的情况（例如，在保持时间结束时）。在为最终灭菌产品设置过杀灭菌参
数的情况下，应按适当的预定时间间隔监测生物负荷。

10.4. A pre sterilization bioburden monitoring program for the product and components should be developed to
support parametric release. The bioburden should be performed for each batch. The sampling locations of filled
units before sterilization should be based on a worst case scenario and be representative of the batch. Any
organisms found during bioburden testing should be identified and their impact on the effectiveness of the
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 sterilizing process determined. Where appropriate, the level of pyrogen (endotoxins) should be monitored.
应开发产品和部件的预灭菌生物负载监控程序，以支持参数放行。应对每个批次执行生物负载。灭菌
前灌装单位的取样位置应基于最坏情况，并代表该批次。在生物负荷试验中发现的任何微生物都应进
行鉴定，并确定其对灭菌过程有效性的影响。在适当情况下，应监测热原（内毒素）水平。

10.5. The sterility test applied to the finished product should only be regarded as the last in a series of control
measures by which sterility is assured. It cannot be used to assure sterility of a product that does not meet its
design, procedural or qualification parameters. The test should be validated for the product concerned.
对成品的无菌检查只应视为保证无菌的一系列控制措施中的最后一项。它不能用于保证不符合其设计、
程序或鉴定参数的产品的无菌。应对相关产品的测试进行验证。

10.6. The sterility test should be performed under aseptic conditions. 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:
无菌检查应在无菌条件下进行。无菌检测所取的样品应代表整个批次，但应特别包括从被认为最有污
染风险的批次中的部分所取的样品，例如:

10.6.1. For products which have been filled aseptically, samples should include containers filled at the
beginning, middle and end of the batch and after any significant intervention (e.g. interventions where
the integrity of a barrier is breached (open door)) or an operator intervention into critical zones.
对于无菌灌装的产品，样品应包括在批次开始、中间和结束时以及在任何重大干预（例如，
屏障完整性被破坏（打开门）的干预）或操作员干预进入关键区域后灌装的容器。

10.6.2. For products which have been heat sterilized in their final containers, samples taken should be
representative of the worst case locations (e.g. the potentially coolest or slowest to heat part of each
load).
对于已在最终容器中加热灭菌的产品，所取样品应代表最坏情况的位置（例如，每批货物中
可能最冷或加热最慢的部分）。

10.6.3. For products that are lyophilized, samples taken from different lyophilization loads.Note: Where the
manufacturing process results in sub batches (e.g. for terminally sterilized products) then sterility
samples from each sub batch should be taken and a sterility test for each sub batch performed.
Consideration should also be given to performing separate testing for other finished product tests.
对于冻干的产品，样品取自不同的冻干负载。注:如果生产过程产生子批（例如，对于最终灭
菌的产品），则应从每个子批中抽取无菌样品，并对每个子批进行无菌试验。还应考虑对其
他成品测试进行单独测试。

10.7. For some products it may not be possible to perform a sterility test prior to release because the shelf life of the
product is too short to allow completion of a sterility test. In these cases, the CCS should clearly capture the
identified risks, the additional considerations of design of the process and additional monitoring required to
mitigate the identified risks.
对于某些产品，可能无法在发布前进行无菌测试，因为产品的保质期太短，无法完成无菌测试。在这
些情况下，综合传播战略应清楚地掌握已查明的风险、程序设计的额外考虑因素以及为减轻已查明的
风险所需的额外监测。

10.8. Any process (e.g. Vaporized Hydrogen Peroxide or VH202, Ultra Violet) used to decontaminate the external
surfaces of sterility samples prior to testing should not negatively impact the sensitivity of the test method.
在试验前，用于净化无菌样品外表面的任何工艺（例如，蒸发的过氧化氢或VH202，紫外线）不应对
试验方法的灵敏度产生负面影响。

10.9. Media used for environmental monitoring and APS should be tested for its growth promotion capability, in
accordance with a formal written program.
用于环境监测的介质和APS应根据正式的书面程序测试其生长促进能力。

10.10. Environmental monitoring data and trend data generated for classified areas should be reviewed as part of
product batch certification. A written plan should be available that describes the actions to be taken when data
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 from environmental monitoring are found out of trend or exceeding the established limits. For products with
short shelf life, the environmental data for the time of manufacture may not be available; in these cases, the
certification should include a review of the most recent available data. Manufacturers of these products should
consider the use of rapid monitoring systems.
分类区域产生的环境监测数据和趋势数据应作为产品批次认证的一部分进行审查。应提供一份书面计
划，说明当发现环境监测数据超出趋势或超出时应采取的行动。既定的限制。对于保质期短的产品，
可能无法获得制造时的环境数据；在这些情况下，认证应包括对最新可用数据的审查。这些产品的制
造商应考虑使用快速监测系统。

10.11. Where rapid and automated microbial methods are used for general manufacturing purposes, these methods
should be validated for the product(s) or processes concerned.
当快速和自动化微生物方法用于一般制造目的时，这些方法应针对相关产品或工艺进行验证。

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11. Glossary
词汇表

11.1. Airlock – An enclosed space with interlocked doors, constructed to maintain air pressure control between
adjoining rooms (generally with different air cleanliness standards). The intent of an airlock is to preclude
ingress of particulate matter and microorganism contamination from a lesser controlled area.
气闸室 具有联锁门的封闭空间，用于保持相邻房间之间的空气压力控制（通常具有不同的空气清洁
标准）。气闸的目的是防止颗粒物和微生物污染从较小的控制区进入。

11.2. Action limit – An established relevant measure (e.g. microbial, or airborne particulate limits) that, when
exceeded, should trigger appropriate investigation and corrective action based on the investigation.
行动限度–既定的相关措施（如微生物或空气中的微粒限度），当超过该限度时，应启动适当的调查，
并根据调查结果采取纠正措施。

11.3. Alert level – An established relevant measure (e.g. microbial, or airborne particulate levels) giving early
warning of potential drift from normal operating conditions and validated state, which does not necessarily give
grounds for corrective action but triggers appropriate scrutiny and follow up to address the potential problem.
Alert levels are established based on historical and qualification trend data and periodically reviewed. The alert
level can be based on a number of parameters including adverse trends, individual excursions above a set limit
and repeat events.
警戒级别 既定的相关测量（如微生物或空气中的颗粒物水平）对偏离正常工作条件和验证状态的潜
在漂移进行预警，这不一定给出采取纠正行动的理由，但会引发适当的审查和后续行动，以解决潜在
的问题。警报级别是根据历史和鉴定趋势数据确定的，并定期审查。警报级别可基于多个参数，包括
不利趋势、超过设定限值的个别偏移和重复事件。

11.4. Aseptic processing room – A room in which one or more aseptic activities or processes are performed.
无菌处理室 进行一项或多项无菌活动或工艺的房间。

11.5. Aseptic Process Simulation (APS) –A simulation of the entire aseptic formulation and filling process in order
to determine the capability of the process to assure product sterility.
无菌工艺模拟（APS） 对整个无菌配方和灌装工艺进行模拟，以确定工艺能力，确保产品无菌。

11.6. Asepsis – A state of control attained by using an aseptic work area and performing activities in a manner that
precludes microbial contamination of the exposed sterile product.
无菌 通过使用无菌工作区域并以防止微生物污染暴露的无菌产品的方式进行活动而达到的控制状态。

11.7. Bacterial retention testing – This test is performed to validate that a filter can remove bacteria from a gas or
liquid. The test is usually performed using a standard organism, such as Brevundimonas diminuta at a minimum
concentration of 107 Colony Forming Units/cm2.
细菌滞留测试 该测试用于验证过滤器是否能够去除气体或液体中的细菌。通常使用标准生物体，如
107菌落形成单位/cm2的最小浓度的缩小短波单胞菌（Brevundimonas diminuta）进行试验。

11.8. Barrier – A physical partition that affords aseptic processing area (usually Grade A) protection by separating
it from the background environment. Such systems frequently use in part or totally the Barrier Technologies
known as RABS or isolators.
屏障—通过将无菌加工区域（通常为A级）与背景环境分隔开来提供保护的物理分区。这类系统经常
部分或全部使用称为RABS或隔离器的屏障技术。

11.9. Bioburden – The total number of microorganisms associated with a specific item such as personnel,
manufacturing environments (air and surfaces), equipment, product packaging, raw materials (including water),
in process materials, or finished products.
生物负荷–与特定项目相关的微生物总数，例如人员，生产环境（空气和表面），设备，产品包装，
原材料（包括水），加工材料或成品。

11.10. Biological Indicator (BI) – A population of microorganisms inoculated onto a suitable medium (e.g. solution,
container or closure) and placed within a sterilizer or load or room locations to determine the sterilization or
disinfection cycle efficacy of a physical or chemical process. The challenge microorganism is selected and
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 validated based upon its resistance to the given process. Incoming lot D value, microbiological count and purity
define the quality of the BI.
生物指示剂（BI） 接种到合适的介质（如溶液、容器或封闭物）上并放置在消毒器或负载或房间位
置内的微生物种群，以确定物理或化学过程的灭菌或消毒循环功效。根据其对给定工艺的抗性来选择
和验证挑战微生物。输入的批次D值、微生物计数和纯度定义了BI的质量。

11.11. Blow Fill Seal (BFS) – A technology in which containers are formed from a thermoplastic granulate, filled
with product, and then sealed in a continuous, integrated, automatic operation. The two most common types of
BFS machines are the Shuttle type (with Parison cut) and the Rotary type (Closed Parison) types.
吹塑填充密封（BFS）–一种技术，其中容器由热塑性颗粒形成，填充产品，然后在连续、集成、自
动操作中密封。两种最常见的BFS机器是梭式（带有型坯切割）和旋转式（闭合型坯）类型。

11.12. Classified area – An area that contains a number of cleanrooms (see cleanroom definition). Cleaning – A
process for removing contamination e.g. product residues and disinfectant residues.
分类区域 包含若干洁净室的区域（参见洁净室定义）。清洁 去除污染的过程，如产品残留和消毒剂
残留。

11.13. Clean area – An area with defined particulate and microbiological cleanliness standards usually containing a
number of joined cleanrooms.
洁净区——具有规定的微粒和微生物清洁标准的区域，通常包含若干个联合洁净室。

11.14. Cleanroom – A room designed, maintained, and controlled to prevent particulate and microbial contamination
of drug products. Such a room is assigned and reproducibly meets an appropriate air cleanliness level. Grade A
will be referred to as Grade A zone.
洁净室 为防止微粒和微生物污染药品而设计、维护和控制的房间。这样的房间被分配并可重复地满
足适当的空气清洁度水平。A级将被称为A级区。

11.15. Cleanroom classification – 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.
洁净室分级 一种通过测量空气中的非活性颗粒浓度，根据洁净室或洁净空气设备的规范评估空气洁
净程度的方法。

11.16. Cleanroom qualification – A method of assessing the level of compliance of a classified cleanroom or clean
air equipment with its intended use.
洁净室鉴定 一种评估分类洁净室或洁净空气设备与其预期用途相符程度的方法。

11.17. Closed system – A system in which the sterile product is not exposed to the surrounding environment. For
example, this can be achieved by the use of bulk products holders (such as tanks or bags) that are connected to
each other by pipes or tubes as a system, with the system being sterilized after the connections are made.
Examples of these can be (but are not limited to) large scale reusable systems, such as those seen in active
substance manufacturing, or disposable bag and manifold systems, such as those seen in the manufacture of
biological products. Closed systems, when used in this document, does not refer to systems such as RABS or
isolator systems which are referred to as Barrier Technologies.
封闭系统 无菌产品不暴露于周围环境的系统。例如，这可以通过使用散装产品容器（如罐或袋）来
实现。它们通过管道或管子彼此连接成一个系统，连接完成后系统将被消毒。这些示例可以是（但不
限于）大规模可重复使用的系统，例如在活性物质生产中看到的系统，或一次性袋子和歧管系统，例
如在制造生物产品中看到的情况。在本文中使用封闭系统时，不是指RABS或隔离器系统等称为屏障
技术的系统。

11.18. Colony Forming Unit (CFU) – A microbiological term that describes a single detectable colony that originates
from one or more microorganisms. Colony forming units are typically expressed as cfu per ml for liquid samples,
and cfu per cm2 for samples captured on solid medium such as settle or contact plates.
菌落形成单位（CFU） 微生物学术语，描述来源于一种或多种微生物的单个可检测菌落。对于液体
样品，菌落形成单位通常表示为每毫升CFU，对于在固体培养基（例如沉降板或接触板）上捕获的样
品，菌落形成单位表示为每平方厘米CFU。

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11.19. Contamination – The undesired introduction of impurities of a microbiological nature (quantity and type of
microorganisms, pyrogens), or of foreign particulate matter, into or onto a raw material, intermediate, active
substance or drug product during production, sampling, packaging or repackaging, storage or transport with the
potential to adversely impact product quality.
污染 在生产、取样、包装或重新包装、储存或运输过程中，将微生物性质的杂质（微生物、热原的
数量和类型）或外来颗粒物质不希望地引入到原材料、中间体、活性物质或药品中或其上，可能对产
品质量产生不利影响。

11.20. Contamination Control Strategy (CCS) – A planned set of controls for microorganisms, pyrogens and
particulates, derived from current product and process understanding that assures process performance and
product quality. The controls can include parameters and attributes related to active substance, excipient and
drug product materials and components, facility and equipment operating conditions, in process controls,
finished product specifications, and the associated methods and frequency of monitoring and control.
污染控制策略（CCS） 一套有计划的微生物、热原和微粒控制措施；基于对当前产品和工艺的理解，
确保工艺性能和产品质量。控制可以包括与活性物质、赋形剂和药物产品材料和成分相关的参数和属
性，设施和设备的操作条件，过程控制，成品规格，以及监测和控制的相关方法和频率。

11.21. Corrective intervention – An intervention that is performed to correct or adjust an aseptic process during its
execution. These may not occur with the same frequency in the routine aseptic process. Examples include such
as clearing component jams, stopping leaks, adjusting sensors, and replacing equipment components.
Corrective measures should be taken to reduce their extent and frequency.
纠正干预–在无菌工艺执行过程中纠正或调整无菌工艺的干预。在常规无菌工艺中，这些可能不会以
相同的频率发生。例如清除部件堵塞、停止泄漏、调整传感器和更换设备部件。应采取纠正措施，减
少其范围和频率。

11.22. Critical surfaces – Surfaces that may come directly into contact with, or directly affect, a sterile product or its
containers or closures. Critical surfaces are rendered sterile prior to the start of the manufacturing operation,
and sterility is maintained throughout processing.
关键表面 可能直接接触或直接影响无菌产品或其容器或封盖的表面。关键表面在制造操作开始之前
是无菌的，并且在整个加工过程中保持无菌。

11.23. Critical zone – A location within the aseptic processing area in which product and critical surfaces are exposed
to the environment.
关键区域 无菌加工区域内产品和关键表面暴露于环境的位置。

11.24. Critical intervention – An intervention (corrective or inherent) into the critical zone.
关键干预–对关键区域的干预（纠正性干预或固有干预）。

11.25. D value – The value of a parameter of sterilization (duration or absorbed dose) required to reduce the number
of viable organisms to 10 per cent of the original number.
D值——灭菌参数的值（持续时间或吸收剂量），用于将存活生物体的数量减少到原数量的10%。

11.26. Dead leg – Length of non circulating pipe (where fluid may remain static) that is greater than 3 internal pipe
diameters.
死管——非循环管道（流体可能保持静止）的长度大于3倍的内部管道直径。

11.27. Decommission – When a process, equipment or cleanroom are closed where they will not be used again.
退役 当一个过程，设备或洁净室被关闭，它们将不再被使用。

11.28. Decontamination – The overall process of removal or reduction of any contaminants (chemical, waste, residue
or microorganisms) from an area, object, or person. The method of decontamination used (e.g. cleaning,
disinfection, sterilization) should be chosen and validated to achieve a level of cleanliness appropriate to the
intended use of the item decontaminated.
去污 从一个区域、物体或人身上去除或减少任何污染物（化学物质、废物、残留物或微生物）的整
个过程。应选择并验证所使用的去污方法（如清洗、消毒、灭菌），以达到与去污物品的预期用途相
适应的清洁度。
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11.29. Depyrogenation – A process designed to remove or inactivate pyrogenic material (e.g. endotoxins) to a
specified minimum quantity.
去热原 一种旨在将热原物质（如内毒素）去除或灭活至规定的最小量的工艺。

11.30. Disinfection – The process by which the reduction of the number of microorganisms is achieved by the
irreversible action of a product on their structure or metabolism, to a level judged to be appropriate for a defined
purpose.
消毒–通过产品对其结构或代谢的不可逆作用，将微生物数量减少到被判断为适合特定目的的水平的
过程。

11.31. Endotoxin – A pyrogenic product (e.g. lipopolysaccharide) present in the bacterial cell wall. Endotoxin can
lead to reactions in patients receiving injections ranging from fever to death.
内毒素——存在于细菌细胞壁中的热原产物（如脂多糖）。内毒素可导致接受注射的患者出现从发热
到死亡的反应。

11.32. Extractables Chemical entities that migrate from the surface of the process equipment, exposed to an
appropriate solvent at extreme conditions, into the product or material being processed.
在极端条件下暴露于适当的溶剂中，从工艺设备表面迁移到正在加工的产品或材料中的可提取化学实
体。

11.33. First Air – Refers to filtered air that has not been interrupted by items (such as operators) with the potential to
add contamination to the air prior to reaching the critical zone.
第一空气 指在到达临界区之前，未被有可能增加空气污染的物品（如操作员）干扰的过滤空气。

11.34. Form Fill Seal (FFS) – Similar to Blow fill Seal, this involves the formation of a large tube formed from a
flexible packaging material, in the filling machine, and generally the tube is filled to form the bags.
形式填充密封（FFS） 类似于吹塑填充密封，这涉及到在灌装机中形成由软包装材料形成的大管，并
且通常填充该管以形成袋。

11.35. Gowning qualification – A program that establishes, both initially and on a periodic basis, the capability of an
individual to don the complete sterile gown in an aseptic manner.
更衣确认——一项计划，最初和定期建立个人以无菌方式穿着完整无菌长袍的能力。

11.36. Grade A air supply – Air which is passed through a filter qualified as capable of producing Grade A non viable
quality air, but where there is no requirement to perform continuous non viable monitoring or meet Grade A
viable monitoring limits and the area itself is not classified. Specifically used for the protection of fully
stoppered vials where the cap has not been crimped and the equipment and engineering systems that have a
direct impact on product quality.
A级空气供应 通过过滤器的空气，经鉴定能够产生A级非活性质量空气，但不要求进行连续非活性监
测或满足A级活性监测限值，且该区域本身未被分类。专门用于保护瓶盖未卷曲的完全加塞的小瓶以
及对产品质量有直接影响的设备和工程系统。

11.37. HEPA filter High efficiency particulate air filter with 0.3 µm particulate retaining efficiency of no less than
99.95 percent according to the relevant norms (e.g. EN 1822)..
HEPA过滤器高效微粒空气过滤器，根据相关规范（例如EN 1822），0.3μm微粒截留效率不低于
99.95%。

11.38. Inherent interventions – An intervention that is an integral part of the aseptic process and is required for either
set up, routine operation and/or monitoring (e.g. aseptic assembly, container replenishment, environmental
sampling, etc.). Inherent interventions are required by procedure or work instruction for the execution of the
aseptic process.
固有干预 是无菌过程的组成部分，并且是设置、常规操作和/或监控（例如，无菌装配、容器补充、
环境取样等）所需的干预。程序或作业指导书要求内在干预，以执行无菌工艺。

11.39. Integrity test A test to confirm that a filter (product, gas or HVAC filter) retain their retentive properties and
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 have not been damaged during handling, installation or processing.
完整性测试确认过滤器（产品、气体或HVAC过滤器）在搬运、安装或加工过程中保持其保持性能且
未被损坏的测试。

11.40. Intrinsic Sterile Connection device – A device that reduces the risk of contamination during the connection
process; these can be mechanical or fusion sealing.
内在无菌连接装置–在连接过程中减少污染风险的装置；这些可以是机械密封或熔合密封。

11.41. Isokinetic sampling head – A sampling head designed to disturb the air as little as possible so that the same
particulates go into the nozzle as would have passed the area if the nozzle had it not been there i.e. the sampling
condition in which the mean velocity of the air entering the sample probe inlet is nearly the same (± 20 percent)
as the mean velocity of the airflow at that location.
等速取样头 取样头设计为尽可能少地扰动空气，以使进入喷嘴的颗粒与不存在喷嘴时通过该区域的
颗粒相同，即进入样品探针入口的空气平均速度与该位置的气流平均速度几乎相同（±20%）的取样
条件。

11.42. Isolator – A decontaminated unit, with an internal work zone meeting Grade A conditions that provides
uncompromised, continuous isolation of its interior from the external environment (e.g. surrounding cleanroom
air and personnel). There are two major types of isolators
隔离器 净化单元，其内部工作区满足A级条件，能够将其内部与外部环境（例如，洁净室周围的空气
和人员）完全、连续地隔离。有两种主要类型的隔离器

11.42.1. Closed isolator systems exclude external contamination of the isolator’s interior by accomplishing
material transfer via aseptic connection to auxiliary equipment, rather than use of openings to the
surrounding environment. Closed systems remain sealed throughout operations.
封闭的隔离器系统通过无菌连接至辅助设备来完成材料转移，而不是使用通向周围环境的开
口，从而排除隔离器内部的外部污染。在整个行动中，封闭系统始终处于密封状态。

11.42.2. Open isolator systems are designed to allow for the continuous or semi continuous ingress and/or egress
of materials during operations through one or more openings. Openings are engineered (e.g. using
continuous overpressure) to exclude the entry of external contaminant into the isolator.
开放式隔离器系统的设计允许在操作过程中材料通过一个或多个开口连续或半连续地进入和/
或排出。设计开口（例如，使用连续过压）以防止外部污染物进入隔离器。

11.43. Leachables – Chemical entities that migrate into products from the product contact surface of the process
equipment or containers under normal condition of use and/or storage.
可浸出物 在正常使用和/或储存条件下，从工艺设备或容器的产品接触面迁移到产品中的化学实体。

11.44. Local Isolates – Suitably representative microorganisms of the site that are frequently recovered through
environmental monitoring within the classified zone/areas especially Grade A zone and Grade B area,
personnel monitoring or positive sterility test results.
本地分离株 通过分类区/区域（特别是A级区和B级区）内的环境监测、人员监测或阳性无菌试验结果，
经常回收的现场具有适当代表性的微生物。

11.45. Lyophilization – A physical chemical drying process designed to remove solvents, by way of sublimation,
from both aqueous and non aqueous systems, primarily to achieve product or material stability. Lyophilization
is synonymous to the term freeze drying.
冻干–一种物理化学干燥过程，旨在通过升华从含水和非含水体系中除去溶剂，主要是为了实现产品
或材料的稳定性。冻干是冷冻干燥的同义词。
11.46. Manual Filling – A filling process where operator intervention is required to complete the filling of each
container (e.g. as occurs during aseptic compounding operations).
手动灌装 需要操作员干预以完成每个容器的灌装过程（例如，在无菌混合操作过程中）。

11.47. Operator Any individual participating in the processing operation, including line set up, filler, maintenance,
or other personnel associated with manufacturing activities.
操作员参与加工操作的任何个人，包括生产线安装、填料、维护或与制造活动相关的其他人员。
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11.48. Overkill sterilization – A process that is sufficient to provide at least a 12 log reduction of microorganisms
having a minimum D value of 1 minute.
过度杀菌 一种足以将微生物减少至少12倍的工艺，最小D值为1分钟。

11.49. Pass through hatch – Synonymous with airlock (refer to airlock definition) but typically smaller in size.
通过舱口 与气闸舱同义（参考气闸舱定义），但通常尺寸较小。

11.50. Pyrogen – A substance that induces a febrile reaction in a patient.

热原——一种引起病人发热反应的物质。

11.51. Rapid transfer system (RTP) – A System used for the transfer of items into RABS and isolators that minimize
the risk to the critical zone. An example would be a rapid transfer container with an alpha/beta port.
快速传输系统（RTP）–用于将物品传输到RAB和隔离器的系统，可最大限度地降低对关键区域的风
险。一个例子是具有alpha/beta端口的快速传输容器。

11.52. Raw material – Any ingredient intended for use in the manufacture of a sterile product, including those that
may not appear in the final drug product.
原料 用于生产无菌产品的任何成分，包括可能不会出现在最终药品中的成分。

11.53. Restricted Access Barrier System (RABS) – System that provides an enclosed, but not sealed, environment
meeting defined cleanroom conditions (for aseptic processing Grade A, (but where used for non sterile
applications can be lesser grade) and using a rigid wall enclosure and air overspill to separate its interior from
the surrounding environment. The inner surfaces of the RABS are disinfected and decontaminated with a
sporicidal agent. Operators use gloves, half suits, rapid transfer
限制进入屏障系统（RABS） 提供封闭但不密封的环境，满足规定的洁净室条件的系统（对于无菌处
理为A级，（但用于非无菌应用时可为较低级别），并使用硬壁封闭和空气溢流将其内部与周围环境
隔开。RABS的内表面使用杀孢子剂进行消毒和净化。操作员使用手套、半套衣服、快速转移

11.54. systems (RTPs) and other integrated transfer ports to perform manipulations or convey materials to the interior
of the RABS. Depending on the design, doors are rarely or never opened:
系统（RTPS）和其他集成传输端口，以执行操作或将材料传送到RAB内部。根据设计，门很少或从
不打开:

11.54.1. Active RABS: integral HEPA filtered air supply.

主动式RABS:集成HEPA过滤空气供应。

11.54.2. Passive RABS: air supply by ceiling mounted HEPA filters.

被动式RABS:通过安装在天花板上的HEPA过滤器提供空气。

11.54.3. Closed RABS: where the air is vented in return ducts within the cabinet.
闭合拉布:在机柜内的回流管道中排放空气的地方。

11.54.4. Open RABS: Where there are vents in the barrier that allow air to move from the Grade A zone to the
Grade B area.
开式挡板:挡板上有通风口，允许空气从A级区域进入B级区域。

11.55. Single Use Systems (SUS) – Systems in which product contact components are used only once (i.e. single use
components) to replace reusable equipment such as stainless steel transfer lines or bulk containers. SUS covered
in this document are those that are used in manufacturing processes of sterile products (e.g. sterile active
substance, sterile bio bulk, sterile finished dosage), and are typically made up of disposable components such
as bags, filters, tubing, connectors, storage bottles and sensors.
一次性使用系统（SUS）—产品接触部件仅使用一次的系统（即一次性使用部件）更换可重复使用的
设备，如不锈钢传输线或散装容器。本文件中涉及的SUS是无菌产品生产过程中使用的SUS。（例如:
无菌活性物质、无菌生物散装、无菌成品剂量），通常由袋、过滤器、管道、连接器、储存瓶和传感
器等一次性部件组成。

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11.56. Sporicidal agent – An agent that destroys bacterial and fungal spores when used in sufficient concentration for
specified contact time. It is expected to kill all vegetative microorganisms.
杀孢子剂——在规定的接触时间内，以足够的浓度使用，可以杀死细菌和真菌孢子。它有望杀死所有
的营养微生物。

11.57. Sterile Product – For purpose of this guidance, sterile product refers to one or more of the sterilized elements
exposed to aseptic conditions and ultimately making up the sterile active substance or finished sterile product.
These elements include the containers, closures, and components of the finished drug product. Or, a product
that is rendered sterile by a terminal sterilization process.
无菌产品 就本指南而言，无菌产品是指一个或多个暴露于无菌条件下并最终构成无菌活性物质或成
品的灭菌元件。这些要素包括容器、封盖和成品药物的成分。或者，通过终端灭菌过程使之无菌的产
品。

11.58. Sterilizing grade filter – A filter that, when appropriately validated, will remove a defined microbial challenge
from a fluid or gas producing a sterile effluent. Usually such filters have a pore size equal or less than 0.22 µm
(for the purposes of this document 0.2 µm and 0.22 µm are used interchangeably and deemed equivalent).
灭菌级过滤器–经过适当验证的过滤器，可从产生无菌流出物的流体或气体中去除规定的微生物挑战。
通常，此类过滤器的孔径等于或小于0.22微米（就本文件而言，0.2微米和0.22微米可互换使用，并视
为等效）。

11.59. Terminal Sterilization – The application of a lethal sterilizing agent or conditions to a product within a sealed
container to achieve a predetermined sterility assurance level (SAL) of 10⁻⁶ or better (i.e. the theoretical
probability of there being a single viable microorganism present on or in a sterilized unit is equal to or less than
1 x 10 6 (one in a million)).
终端灭菌 对密封容器内的产品应用致命灭菌剂或条件，以达到10或更高的预定无菌保证水平（Sal）
（即在已灭菌的设备上或设备中存在单一存活微生物的理论概率等于或小于1×106（百万分之一））。

11.60. Turbulent airflow – Air that is not unidirectional. Turbulent air in cleanrooms should flush the cleanroom via
mixed flow dilution and ensure maintenance of acceptable air quality.
紊流气流——不是单向的空气。洁净室中的湍流空气应通过混流稀释冲洗洁净室，并确保维持可接受
的空气质量。

11.61. Unidirectional airflow – An airflow moving in a single direction, in a robust and uniform manner, and at
sufficient speed, to reproducibly sweep particulates away from the critical processing or testing area.
单向气流——气流以稳定和均匀的方式以足够的速度沿单一方向移动，从而可重复地将颗粒从关键处
理或测试区域扫走。

11.62. Unidirectional Airflow Unit (UDAF) – A cabinet supplied with filtered unidirectional airflow (previously
referred to as a Laminar Airflow Unit or LAF).
单向气流单元（UDAF）–提供经过过滤的单向气流的机柜（以前称为层流气流单元或LAF）。

11.63. Vertical Form Fill Seal (VFFS) – An automated filling process, typically for terminally sterilized products,
that may utilize a single or dual web system which constructs the primary container out of a flat roll of
thermoplastic film while simultaneously filling the formed bags with product and sealing the filled bags in a
continuous process.
垂直形式填充密封（VFFS） 一种自动填充过程，通常用于最终灭菌产品，可能利用单幅或双幅系统，
该系统在连续过程中，用热塑性薄膜的平卷构造主容器，同时用产品填充形成的袋并密封填充的袋。

11.64. Worst case – A set of conditions encompassing processing limits and circumstances, including those within
standard operating procedures, that pose the greatest chance of process or product failure (when compared with
ideal conditions). Such conditions have the highest potential to, but do not necessarily always induce, product
or process failure.
最坏情况—一组包含处理限制和环境的条件，包括标准操作程序中的条件，与理想条件相比，这些条
件最有可能导致过程或产品失败。这种情况最有可能导致产品或工艺失败，但不一定总是导致产品或
工艺失败。

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11.65. Water system – A system for producing, storing and distributing water, usually compliant to a specific
pharmacopeia grade e.g. purified and water for injection (WFI).
水系统 生产、储存和分配水的系统，通常符合特定的药典等级，如纯化水和注射用水（WFI）。

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