The Rules Governing Medicinal Products in the European Union Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use

 

欧盟药品管理法规第4卷《人用和兽用药品良好生产规范指南》

 

Annex 1

 

附录1

 

Manufacture of Sterile Medicinal Products

 

无菌药品生产

 

Deadline for coming into operation:

 

生效时间：

 

25 August 2023 : one year from the date of publication in Eudralex Volume 4

 

2023 年 8 月 25 日：发布之日起一年后生效（除8.123节外）

 

25 August 2024 : two years from the date of publication in Eudralex Volume 4 for point 8.123

 

2024 年 8 月 25 日：发布之日起两年后第 8.123 节生效

 

Document map               

 

文件目录

 

Section  Number 章节	General  overview 概述
1. Scope 范围	Includes additional areas (other than  sterile products) where the general principles of the annex can be  applied. 包括可适用本附录一般原则的其他领域（其他非无菌产品外）。
2. Principle 原则	General principles as applied to the  manufacture of sterile products. 适用于无菌产品生产的一般原则。
3. Pharmaceutical Quality System  (PQS) 药品质量体系（PQS）	Highlights the specific requirements of  the PQS when applied to sterile products. 重点介绍 PQS 在应用于无菌产品时的具体要求。
4. Premises 厂房	General guidance regarding the specific  needs for premises design and also guidance on the qualification of   premises including the use of Barrier Technology. 关于厂房设计的具体要求，以及关于厂房确认的指导，包括使用屏障技术。
5. Equipment 设备	General guidance on the design and  operation of equipment. 关于设备设计和操作的一般指导。
6. Utilities 公用系统	Guidance regarding the special  requirements of utilities such as water, gas and vacuum. 有关水，气和真空等公用系统特定要求的指南。
7. Personnel 人员	Guidance on the requirements for specific  training, knowledge and skills. Also gives guidance regarding the   qualification of personnel. 关于特定培训，知识和技能要求的指导。还就人员确认提供了指导。
8. Production and specific technologies 生产和特定技术	Guidance on the approaches to be taken  regarding aseptic and terminal sterilization processes. Guidance on the   approaches to sterilization of products, equipment and   packaging components. Also guidance on different   technologies such as lyophilization and  Form-Fill-Seal where  specific requirements apply. 关于无菌和最终灭菌工艺应采取的方法的指南。关于产品、设备和包装部件灭菌方法的指南。还就不同技术，如冻干和成型-灌装-密封，的特定要求提供指导。
9. Environmental and process monitoring 环境和过程监测	This section differs from guidance given  in section 4 in that the guidance here applies to ongoing routine  monitoring  regarding the design of systems and setting of action   limits alert levels and reviewing trend  data. The section  also gives guidance on the  requirements of Aseptic Process  Simulations  (APS). 本节与第 4 节中给出的指导不同，因为此处的指南适用于有关持续日常监测的系统设计和行动限/警戒限设置以及趋势数据回顾。 本节还就无菌工艺模拟（APS）的要求提供了指导。
10. Quality control (QC) 质量控制（QC）	Guidance on some of the specific Quality  Control requirements relating to sterile products. 关于无菌产品的一些具体质量控制要求的指南。
11. Glossary 术语	Explanation of specific terminology. 具体术语的解释。

 

1 Scope

 

范围

 

The manufacture of sterile products covers a wide range of sterile product types (active substance, 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 systems and closed systems). This Annex provides general guidance that should be used in the design and control of facilities, equipment, systems and procedures used for the manufacture of all sterile products applying the principles of Quality Risk Management (QRM), to ensure that microbial, particulate and endotoxin/pyrogen contamination is prevented in the final product.

 

无菌产品的制造涵盖广泛的无菌产品类型（活性物质，辅料，内包装材料和成品制剂），包装规格（单剂量到多剂量），工艺（从高度自动化系统到手动工艺）和技术（例如生物技术，经典小分子制造系统和密闭系统）。本附录提供了使用质量风险管理（QRM）原则应用于各类无菌产品的设施，设备，系统和程序的设计和控制的通用指导，以确保最终产品免受微生物，颗粒和内毒素/热原污染。

 

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

 

QRM适用于本文件的全部内容，通常不会在具体段落中提及。在规定具体限值、频率或范围的情况下，应将这些限制或范围视为最低要求。基于已经确定并影响患者安全的问题的历史监管经验对它们进行声明。

 

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, validation, 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 endotoxin/pyrogen contamination is considered important. Where a manufacturer elects to apply guidance herein to non-sterile products, the manufacturer should clearly document which principles have been applied and acknowledge that compliance with those principles should be demonstrated.

 

本附录的目的是为无菌产品的制造提供指导。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，确认，验证，监测和人员更衣，也可用于支持制造其他不需要无菌但有必要控制和减少微生物，颗粒物和内毒素/热原污染的产品，如某些液体，乳膏，软膏和低生物负荷生物中间体。如果制造商选择将此指南应用于非无菌产品，制造商应清楚地记录已应用的原则，并应认可证明符合这些原则。

 

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 endotoxin/pyrogen contamination. The following key areas should be considered:

 

无菌产品的制造须遵守特定要求，以尽量减少微生物、微粒和内毒素/热原污染的风险。应考虑以下关键领域：

 

i.             Facility, equipment and process should be appropriately designed, qualified and/or validated and where applicable, subjected to ongoing verification according to the relevant sections of the Good Manufacturing Practices (GMP) guidelines. The use of appropriate technologies (e.g. Restricted Access Barriers Systems (RABS), isolators, robotic systems, rapid/alternative methods and continuous monitoring systems) should be considered to increase the protection of the product from potential extraneous sources of endotoxin/pyrogen, 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 the product.

 

设施、设备和工艺应按照良好生产规范（GMP）指南的相关章节进行适当的设计、确认和/或验证，并在适用的情况下，进行持续确认。应考虑使用适当的技术（例如限制进入屏障系统（RABS）、隔离器、机器人系统、快速/替代方法和连续监测系统），以加强对产品的保护，使其免受潜在的外来内毒素/热原、颗粒物和微生物来源（如人员、物料和周围环境）污染的影响，并支持快速检测环境和产品中的潜在污染物。

 

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

 

人员应具有足够的资质和经验、培训和行为规范，并特别关注在制造、包装和运输过程中无菌产品保护的原则。

 

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

 

无菌产品制造的工艺和监测系统应由具有适当工艺、工程和微生物知识的人员进行设计、调试、确认、监测和定期回顾。

 

iv.             Raw materials and packaging materials should be adequately controlled and tested to ensure that level of bioburden and endotoxin/pyrogen are suitable for use.

 

应充分控制和测试原辅料和包装材料，以确保生物负荷和内毒素/热原水平满足使用要求。

 

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 rationale, risk assessment and mitigation, and should meet the intent of this Annex.

 

工艺、设备、设施和制造活动应按照QRM原则进行管理，以提供一种前瞻性手段来识别、科学地评估和控制潜在的质量风险。在使用替代方法时，应有适当的论证、风险评估和缓解措施的支持，并应符合本附录的目的。

 

In the first instance, QRM priorities should include appropriate design of the facility, equipment and processes, followed by the implementation of well-designed procedures, and finally application of monitoring systems as the element that demonstrates that the design and procedures have been correctly implemented and continue to perform in line with expectations. Monitoring or testing alone does not give assurance of sterility.

 

QRM的优先考虑，首先应是设施、设备和工艺的适当设计，其次是实施设计良好的程序，最后使用监测系统作为表明设计和程序已正确实施并持续如预期执行的要素。仅监测或检测并不能保证无菌。

 

2.3 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 to medicinal product quality and safety. The combined strategy of the CCS should establish robust assurance of contamination prevention. The CCS should be actively reviewed and, where appropriate, updated and should drive continual improvement of the manufacturing and control methods. Its effectiveness should form part of the periodic management review. Where existing control systems are in place and are appropriately managed, these may not require replacement but should be referenced in the CCS and the associated interactions between systems should be understood.

 

应在整个设施中实施污染控制策略（CCS），以定义所有关键控制点，并评估用于管理药品质量和安全风险的所有控制措施（设计，程序，技术和组织）和监测措施的有效性。CCS的组合策略应建立强有力的污染预防保证。CCS应动态审查，并在适当情况下进行更新，并应推动制造和控制方法的持续改进。其有效性应成为定期管理审查的一部分。如果现有的控制系统并得到适当管理，则这些系统可能不需要更换，但应在CCS中引用，并应了解系统之间的相关相互作用。

 

2.4 Contamination control and steps taken to minimize the risk of contamination from microbial, endotoxin/pyrogen and particle sources includes a series of interrelated events and measures. These are typically assessed, controlled and monitored individually but their collective effectiveness should be considered together.

 

污染控制和为最大限度减少微生物、内毒素/热原和颗粒源污染风险而采取的步骤包括一系列相互关联的事件和措施。它们通常单独评估，控制和监测，但应一起考虑其集体有效性。

 

2.5 The development of the CCS requires detailed technical and process knowledge. Potential sources of contamination are attributable to microbial and cellular debris (e.g. pyrogen, endotoxin) as well as particulate (e.g. glass and other visible and sub-visible particles).

 

CCS的制订需要详细的技术和工艺知识。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（例如玻璃和其他可见和亚可见颗粒（不溶性微粒））。

 

Elements to be considered within a CCS should include (but are not limited to):

 

CCS中需要考虑的要素应包括（但不限于）：

 

i.             Design of both the plant and processes including the associated documentation.

 

工厂和工艺的设计，包括相关文件。

 

ii.             Premises and equipment.

 

厂房和设备

 

iii.             Personnel.

 

人员

 

iv.             Utilities.

 

公用系统

 

v.             Raw material controls – including in-process controls.

 

原辅料控制-包括过程控制

 

vi.             Product containers and closures.

 

产品容器和密封部件

 

vii.             Vendor approval – such as key component suppliers, sterilisation of components and single use systems (SUS), and critical service providers.

 

供应商审批 – 例如关键组分供应商、组件和一次性系统（SUS）的灭菌以及关键服务提供商。

 

viii.             Management of outsourced activities and availability/transfer of critical information between parties, e.g. contract sterilisation services.

 

外包活动管理以及各方之间关键信息的可获得性/传递，例如合同灭菌服务。

 

ix.             Process risk management.

 

工艺风险管理

 

x.             Process validation.

 

工艺验证

 

xi.             Validation of sterilisation processes.

 

灭菌工艺验证

 

xii.             Preventative maintenance – maintaining equipment, utilities and premises (planned and unplanned maintenance) to a standard that will ensure there is no additional risk of contamination.

 

预防性维护 – 以确保没有额外的污染风险的标准对设备、公用系统和厂房进行维护（计划内和计划外维护）。

 

xiii.             Cleaning and disinfection.

 

清洁和消毒

 

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

 

监测系统—包括评估采用科学合理的替代方法以优化环境污染检测的可行性。

 

xv.             Prevention mechanisms – trend analysis, detailed investigation, root cause determination, corrective and preventive actions (CAPA) and the need for comprehensive investigational tools.

 

预防机制 – 趋势分析、详细调查、根本原因分析、纠正和预防措施（CAPA）以及综合调查工具的需要。

 

xvi.             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 with ongoing and periodic review resulting in updates within the pharmaceutical quality system as appropriate. Changes to the systems in place should be assessed for any impact on the CCS before and after implementation.

 

CCS应考虑污染控制的各个方面，并进行持续和定期的审查，从而在药品质量体系内酌情更新。对现有系统的变更应在实施前后评估其对CCS的影响。

 

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

 

制造商应采取一切必要的步骤和预防措施，以确保在其设施内制造的产品的无菌性。对无菌性或其他质量方面，不应仅依赖任何终端过程或成品测试。

 

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 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 the risk of microbial, particulate and endotoxin/pyrogen contamination is minimized in sterile products. In addition to the PQS requirements detailed in Chapter 1 of the GMP guidelines (Part I - Basic Requirements for Medicinal Products), the PQS for sterile product manufacture should also ensure that:

 

无菌产品的制造是一项复杂的活动，需要特定的控制和措施来确保所制造产品的质量。因此，制造商的PQS应涵盖并解决无菌产品制造的特定要求，并确保有效控制所有活动，以最大限度减少无菌产品中微生物，颗粒物和内毒素/热原污染的风险。除了GMP指南（第一部分 - 药品基本要求）第1章中详述的PQS要求外，无菌产品制造的PQS还应确保：

 

i.             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.

 

将有效的风险管理体系整合到产品生命周期的所有领域，旨在最大限度地减少微生物污染，并确保所制造的无菌产品的质量。

 

ii.             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.

 

制造商在所制造的产品以及采用的影响产品质量的设备，工程和制造方法方面有足够的知识和专业技能。

 

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

 

对程序、工艺或设备故障的根本原因分析以正确识别和理解产品风险的方式进行，以便实施适当的纠正和预防措施（CAPA）。

 

iv.             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.

 

将风险管理应用于CCS的制订和维护，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，并应包括就降低风险和接受剩余风险作出决定的理由。

 

v.             Senior management should effectively oversee the state of control throughout the facility and product lifecycle. Risk management outcome should be reviewed regularly as part of the on- going quality management, during change, in the event of a significant emerging problem, and during the periodic product quality review.

 

高级管理层应有效监督整个设施和产品生命周期的受控状态。在变更期间，在出现重大问题时，以及在定期产品质量回顾期间，风险管理结果应作为持续质量管理的一部分定期审查。

 

vi.             Processes associated with the finishing, storage 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.

 

与无菌产品的最终处理、储存和运输相关的过程不应损害无菌产品。应考虑的方面包括：容器完整性，污染风险以及通过确保产品按照注册存储条件进行储存和维护来避免降解。

 

vii.             Persons responsible for the certification/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 the associated critical quality attributes. This is in order to allow such persons to determine if the sterile products have been manufactured in accordance with the registered specifications and approved process and are of the required quality.

 

负责无菌产品认证/放行的人员可适当获取生产和质量信息，并在无菌产品的生产和相关的关键质量属性方面拥有足够的知识和经验。以使这些人员能够确定无菌产品是否按照注册标准和批准的工艺生产，并具有所需的质量。

 

3.2 All non-conformities, such as sterility test failures, environmental monitoring excursions or deviations from established procedures should be adequately investigated before certification/release of the batch. 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.

 

在批认证/放行之前，应充分调查所有不符合项，例如无菌测试失败，环境监测超标或不符合既定程序的偏差。调查应确定对工艺和产品质量的潜在影响，以及任何其他工艺或批次是否受到潜在影响。将某一产品或批次纳入调查或排除在外的原因应明确说明理由并记录在案。

 

4 Premises

 

厂房

 

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

 

无菌产品的制造应在适当的洁净室进行，（人员、设备、物品等）应通过change rooms进入，这些change rooms充当人员、设备和物料的气闸。洁净室和change rooms应保持适当的洁净度标准，并提供通过适当效率过滤器的空气。控制和监测应科学论证，并应有效评估洁净室、气闸和传递窗的环境条件的状况。

 

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.

 

组分制备，产品配制和灌装的各种操作应在洁净室或设施内采取适当的技术性和操作性隔离措施，以防止混淆和污染。

 

4.3 Restricted Access Barrier Systems (RABS) or isolators are beneficial in assuring required conditions and minimizing 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.

 

限制进入屏障系统（RABS）或隔离器有助于确保所需条件并最大限度地减少与关键区域直接人为干预相关的微生物污染。在CCS中应考虑它们的使用。任何替代RABS或隔离器的方法都应进行论证。

 

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

 

对于无菌产品的制造，有四个等级的洁净室/区域。

 

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

 

l  A级：高风险操作的关键区域（例如无菌加工线，灌装区，胶塞斗，未密闭的内包装材料或在第一空气的保护下进行无菌连接）。通常，这些条件由局部气流保护提供，例如RABS或隔离器中的单向流工作站。应证实和确认整个A级区域内单向流的维持。应通过厂房、设备、工艺和程序设计最大限度减少操作人员对A级区域的直接干预（例如，在没有屏障和手套箱技术的保护下）。

 

l  Grade B: For aseptic preparation and filling, this is the background cleanroom for grade A (where it is not an isolator). Air pressure differences should be continuously monitored. Cleanrooms of lower grade than grade B can be considered where isolator technology is used (see paragraph 4.20 ).

 

l  B级：对于无菌配制和灌装，B级为A级（隔离器除外）的背景区域。应持续监测压差。在使用隔离器技术的情况下，可以考虑低于B级的洁净室（见4.20）。

 

l  Grade C and D: These are cleanrooms used for carrying out less critical stages in the manufacture of aseptically filled sterile products or as a background for isolators. They can also be used for the preparation/filling of terminally sterilised products. (See section 8 for the specific details on terminal sterilisation activities).

 

l  C级和D级：用于在无菌灌装无菌产品的制造中执行不太关键的阶段，或作为隔离器的背景。还可用于最终灭菌产品的配制/灌装。（有关最终灭菌活动的具体细节，请参阅第8节）。

 

4.5 In cleanrooms and critical zones, all exposed surfaces should be smooth, impervious and unbroken in order to minimize the shedding or accumulation of particles or micro-organisms.

 

在洁净室和关键区域，所有暴露的表面应光滑、无渗漏、不破损，以最大限度减少颗粒或微生物的脱落或积聚。

 

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. Sliding doors may be undesirable for this reason.

 

为了减少灰尘的积聚并便于清洁，不应有难以有效清洁的凹槽，因此应最大限度减少突出的窗台，架子，柜子和设备。门的设计应避免无法清洁的凹槽。由于这个原因，滑动门可能是不可取的。

 

4.7 Materials used in cleanrooms, both in the construction of the room and for items used within the room, should be selected to minimize generation of particles and to permit the repeated application of cleaning, disinfectant and sporicidal agents where used.

 

洁净室使用的材料，无论是在房间的建造中还是在房间内使用的物品，都应选择以尽量减少颗粒的产生，并允许重复使用清洁、消毒剂和杀孢子剂。

 

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上方空间的污染。

 

4.9 Sinks and drains should be prohibited in the grade A and grade B areas. 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.

 

应禁止在A级和B级区域使用水槽和排水管。在其他洁净室中，应在设备或水槽与排水管之间安装空气隔断。低级别洁净室的地漏应安装存水弯或水封，以防止回流，并应定期清洁，消毒和维护。

 

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

 

设备和物料进出洁净室和关键区域是最大的潜在污染源之一。任何可能损害洁净室或关键区域洁净度的活动都应进行评估，如果无法消除，则应实施适当的控制措施。

 

4.11 The transfer of materials, equipment, and components into the grade A or B areas should be carried out via a unidirectional process. Where possible, items should be sterilised and passed into these areas through double-ended sterilisers (e.g. through a double-door autoclave or depyrogenation oven/tunnel) sealed into the wall. Where sterilisation upon transfer of the items is not possible, a procedure which achieves the same objective of not introducing contamination should be validated and implemented, (e.g. using an effective transfer disinfection process, rapid transfer systems for isolators or, for gaseous or liquid materials, a bacteria-retentive filter). The removal of items from the grade A and B areas (e.g. materials, waste, environmental samples) should be carried out via a separate unidirectional process. If this is not possible, time-based separation of movement (incoming/exiting material) by procedure should be considered and controls applied to avoid potential contamination of incoming items.

 

物料、设备和组件向A级或B级区域的转移应通过单向过程进行。在可能的情况下，应对物品进行灭菌，并通过密封在墙上的双开口灭菌器（例如通过双扉门高压灭菌器或去热原烘箱/隧道）进入这些区域。如果无法在转移物品时进行灭菌，则应验证和实施实现不引入污染的相同目标的程序（例如，使用有效的转移消毒程序，隔离器的快速转移系统，或对于气体或液体物料，使用除菌级过滤器）。从A级和B级区域传出物品（例如物料，废弃物，环境样品）应通过单独的单向过程进行。如果无法做到这一点，应考虑按程序对这种转移（传入/传出）进行基于时间的分离，并采取控制措施，以避免对传入物料/物品的潜在污染。

 

4.12 Airlocks should be designed and used to provide physical separation and to minimize microbial and particle 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 total particle) as the cleanroom into which it leads. The use of separate change rooms for entering and leaving the grade B area 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 contamination is high, separate change rooms for entering and leaving production areas should be used. Airlocks should be designed as follows:

 

气闸的设计和使用应提供物理分隔，并最大限度地减少不同区域的微生物和颗粒污染，并且应用于在不同等级之间移动的物料和人员。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。如无法实现，应考虑按时间将移动（人员/物料）分开的程序。气闸应使用经过滤的空气有效冲洗，以确保保持该洁净室的等级。在气闸的最后阶段，在“静态”下，应与其进入的洁净室具有相同的洁净度等级（活性粒子和总粒子）。使用单独的更衣室进出B级区域是可取的。如无法做到，应考虑按程序对活动（进/出）进行基于时间的分离。如果CCS表明污染风险很高，则应使用单独的更衣室进出生产区域。气闸应设计如下：

 

i.             Personnel airlocks: Areas of increasing cleanliness used for entry of personnel (e.g. from the grade D area to the grade C area to the grade B area). 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 the grade B area.

 

人员气闸：用于人员进入的洁净度越来越高的区域（例如，从D级区域到C级区域再到B级区域）。一般来说，洗手设施应仅在更衣室的第一阶段提供，而不应出现在直接进入B级区域的更衣室中。

 

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

 

物料气闸：用于物料和设备的转移。

 

l  Only materials and equipment that have been included on an approved list and assessed during validation of the transfer process should be transferred into the grade A or grade B areas via an airlock or pass-through hatches. Equipment and materials (intended for use in the grade A area) should be protected when transiting through the grade B area. 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.

 

l  只有已列入批准清单并在转移验证期间进行评估的物料和设备才能通过气闸或传递窗转移到A级或B级区域。在通过B级区域时，应对设备和物料（打算在A级区域使用）进行保护。任何需要转移的未经批准的物品都应作为例外情况预先获得批准。应根据制造商的CCS使用和记录适当的风险评估和缓解措施，并应包括质量保证部门批准的具体消毒和监测计划。

 

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

 

l  传递窗的设计应保护更高级别的环境，例如通过主动过滤空气供应进行有效冲洗。

 

l  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.

 

l  将物料或设备从较低等级或未分类区域移动到较高等级的洁净区域时，应进行与风险相称并符合CCS的清洁和消毒。

 

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

 

 对于传递窗和气闸（用于物料和人员），不应同时打开入口和出口的门。对于通向A级和B级区域的气闸，应使用联锁系统。对于通往C级和D级区域的气闸，应至少使用声光报警系统。如果需要保持区域隔离，则应在互锁门的关闭和打开之间建立时间延迟。

 

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 an air pressure difference 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 or higher grade.

 

洁净室应配备经过滤的送风，在所有操作条件下保持相对于较低等级的背景环境的正压和/或气流，并应有效冲洗该区域。不同等级的相邻房间的气压差应至少为10帕斯卡（指导值）。应特别注意保护关键区域。在需要含有某些物料（例如致病性、剧毒或放射性产品或活病毒或细菌物料）的情况下，可能需要修改有关送风和压力的建议。这种修改可能包括正压或负压气闸，以防止危险物质污染周围区域。对于某些操作，可能需要对设施（例如洁净室和HVAC系统）进行净化以及处理排风。如果密闭要求空气流入关键区域，则空气源应来自相同或更高等级的区域。

 

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 contamination to the higher grade areas. Where unidirectional airflow is required, visualisation studies should be performed to determine compliance, (see paragraphs 4.4 & 4.19). When filled, closed products are transferred to an adjacent cleanroom of a lower grade via a small egress point, airflow visualization studies should demonstrate that air does not ingress from the lower grade cleanrooms to the grade B area. Where air movement is shown to be a contamination 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 documented and considered when establishing the facility's environmental monitoring programme.

 

 应将洁净室和区域内的气流流型可视化，以证明没有从较低等级区域进入到较高等级区域，并且空气不会从不太干净的区域（如地板）或通过操作人员或设备将污染物转移到较高等级区域。需要单向流时，应进行可视化研究以确定符合性（见第4.4和4.19段）。充填后，已密封的产品通过一个小的出口转移到相邻的较低等级的洁净室，气流可视化研究应证明空气不会从较低等级的洁净室进入B级区域。如果气流对洁净区域或关键区域构成污染风险，则应采取纠正措施，例如设计改进。气流流型研究应在静态和动态下（例如，模拟操作员干预）进行。应保留气流流型的视频记录。在制订环境监测计划时，应记录和考虑空气可视化研究的结果。

 

4.16 Indicators of air pressure differences should be fitted between cleanrooms and/or between isolators and their background. Set points and the criticality of air pressure differences should be considered within the CCS. Air pressure differences identified as critical should be continuously monitored and recorded. A warning system should be in place to instantly indicate and warn operators of any failure in the air supply or reduction of air pressure differences (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 air pressure differences should be monitored and recorded at regular intervals.

 

应在洁净室和/或隔离器与其背景之间安装压差指示器。在CCS中应考虑设置点和此压差的关键性。应持续监测和记录被确定为关键的压差。应建立报警系统，以立即向操作人员指示和警告送风的任何故障或压差的降低（低于确定为关键的限值）。警告信号不应在未经评估的情况下被覆盖，并应提供程序来概述在发出警告信号时应采取的步骤。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 and B areas (e.g. through the provision of windows or remote cameras with a full view of the area and processes to allow observation and supervision without entry). This requirement should be considered when designing new facilities or during refurbishment of existing facilities.

 

设施的设计应允许从A级和B级区域之外观察生产活动（例如，通过提供窗口或远程摄像机，可以全面查看该区域和过程，以便在不进入的情况下进行观察和监督）。在设计新设施或翻新现有设施时，应考虑这一要求。

 

Barrier Technologies

 

屏障技术

 

4.18 Isolators or RABS, which are different technologies, and the associated processes, should be designed to provide protection through separation of the grade A environment from the environment of the surrounding room. The hazards introduced from entry or removal of items during processing should be minimized and supported by high capability transfer technologies or validated systems that robustly prevent contamination and are appropriate for the respective technology.

 

隔离器或RABS是不同的技术和工艺，应设计为通过将A级环境与周围房间的环境分开来提供保护。在加工过程中，应尽量减少因进入或移除物品而造成的危害，并得到高能力转移技术或经验证可有效防止污染的系统的支持，并适用于相应的技术。

 

4.19 The design of the technology and processes used should ensure appropriate conditions are maintained in the critical zone to protect the exposed product during operations.

 

所用技术和工艺的设计应确保在关键区域保持适当的条件，以便在操作过程中保护暴露的产品。

 

i.             Isolators:

 

隔离器

 

a)        The design of open isolators should ensure grade A conditions with first air protection in the critical zone and unidirectional airflow that sweeps over and away from exposed products during processing.

 

开放式隔离器的设计应确保A级条件，在关键区域有第一空气保护，在加工过程中单向气流扫过暴露的产品，然后远离。

 

b)        The design of closed isolators should ensure grade A conditions with adequate protection for exposed products during processing. Airflow may not be fully unidirectional in closed isolators where simple operations are conducted. However, any turbulent airflow should not increase risk of contamination of the exposed product. Where processing lines are included in closed isolators, grade A conditions should be ensured with first air protection in the critical zone and unidirectional airflow that sweeps over and away from exposed products during processing

 

密闭式隔离器的设计应确保在加工过程中对暴露的产品提供足够保护的A级条件。在进行简单操作的封闭隔离器中，气流可能不是完全单向的。但是，任何湍流气流都不应增加暴露产品污染的风险。如果工艺流程中包含在密闭式隔离器中，则应确保A级条件，在关键区域提供第一空气保护，并在加工过程中单向气流扫过暴露的产品，然后远离

 

c)        Negative pressure isolators should only be used when containment of the product is considered essential (e.g. radiopharmaceutical products) and specialized risk control measures should be applied to ensure the critical zone is not compromised.

 

只有当产品隔离（例如放射性药物产品）被认为必要时，才应使用负压隔离器，并应采取专门的风险控制措施以确保关键区域不受损害。

 

ii.             RABS:

 

RABS：

 

The design of RABS should ensure grade A conditions with unidirectional airflow and first air protection in the critical zone. A positive airflow from the critical zone to the supporting background environment should be maintained.

 

RABS的设计应确保具有单向气流的A级条件和在关键区域的第一空气保护。应保持从关键区域到支持背景环境的正向气流。

 

4.20 The background environment for isolators or RABS should ensure the risk of transfer of contamination is minimized.

 

隔离器或RABS的背景环境应确保将污染转移的风险降至最低。

 

i.             Isolators:

 

隔离器

 

a)        The background environment for open isolators should generally correspond to a minimum of grade C. The background for closed isolators should correspond to a minimum of grade D. The decision on the background classification should be based on risk assessment and justified in the CCS.

 

开放式隔离器的背景环境通常应符合C级的最低要求。密闭式隔离器的背景应与最低 D 级相对应。关于背景级别的决定应以风险评估为基础，并在CCS中说明理由。

 

b)        Key considerations when performing the risk assessment for the CCS of an isolator should include (but are not limited to); the bio-decontamination programme, the extent of automation, the impact of glove manipulations that may potentially compromise ‘first air’ protection of critical process points, the impact of potential loss of barrier/glove integrity, transfer mechanisms used and activities such as set-up or maintenance that may require the doors to be opened prior to the final bio-decontamination of the isolator. Where additional process risks are identified, a higher grade of background should be considered unless appropriately justified in the CCS.

 

对隔离器CCS进行风险评估时的关键考虑因素应包括（但不限于）：生物净化程序，自动化程度，手套操作可能对关键工艺点的“第一空气”保护造成潜在损害的影响、屏障/手套完整性的潜在损失的影响、所使用的可能需要在隔离器最终生物净化之前开门的传递机制以及装机或维护等活动。当发现其他工艺风险，应考虑更高级别的背景，除非CCS中已适当证明其合理性。

 

c)        Airflow pattern studies should be performed at the interfaces of open isolators to demonstrate the absence of air ingress.

 

开放式隔离器的接口应进行气流流型研究，以证明没有空气进入。

 

ii.             RABS:

 

RABS：

 

The background environment for RABS used for aseptic processing should correspond to a minimum of grade B and airflow pattern studies should be performed to demonstrate the absence of air ingress during interventions, including door openings if applicable.

 

用于无菌处理的RABS的背景环境应最低与B级相对应，并应进行气流流型研究，以证明干预期间没有空气进入，包括开门（如适用）。

 

4.21 The materials used for glove systems (for both isolators and RABS), should be demonstrated to have appropriate mechanical and chemical resistance. The frequency of glove replacement should be defined within the CCS.

 

用于手套系统（隔离器和RABS）的材料应证明具有适当的机械和耐化学性。手套的更换频率应在CCS内定义。

 

i.             Isolators:

 

隔离器

 

a)        For isolators, leak testing of the glove system should be performed using a methodology demonstrated to be suitable for the task and criticality. The testing should be performed at defined intervals. Generally glove integrity testing should be performed at a minimum frequency of the beginning and end of each batch or campaign. Additional glove integrity testing may be necessary depending on the validated campaign length.

 

对于隔离器，应使用一种被证明适合该任务和关键性的方法进行手套系统的泄漏测试。测试应以规定的时间间隔进行。一般来说，手套完整性测试应至少在每批或每个生产周期的开始和结束进行。根据已验证的生产周期长度，可能需要额外的手套完整性测试。

 

b)        Glove integrity monitoring should include a visual inspection associated with each use and following any manipulation that may affect the integrity of the system.

 

手套完整性监测应包括在每次使用和任何可能影响系统完整性的操作后进行目视检查。

 

c)        For manual aseptic processing activities where single unit or small batch sizes are produced, the frequency of integrity verification may be based on other criteria, such as the beginning and end of each manufacturing session.

 

对于生产单件或小批量的人工无菌工艺活动，完整性确认的频率可能基于其他标准，如每个生产环节的开始和结束。

 

d)        Integrity / leak testing of isolator systems should be performed at defined intervals.

 

隔离器系统的完整性/泄漏测试应以规定的时间间隔进行。

 

ii.             RABS:

 

RABS：

 

For RABS, gloves used in the grade A area should be sterilised before installation and sterilised or effectively bio-decontaminated by a validated method prior to each manufacturing campaign. If exposed to the background environment during operation, disinfection using an approved methodology following each exposure should be completed. Gloves should be visually examined with each use, and integrity testing should be performed at periodic intervals.

 

对于RABS，在A级区域使用的手套应在安装前进行灭菌，并在每次制造活动之前通过经验证的方法进行灭菌或有效消毒。如果在操作过程中暴露于背景环境，则应在每次暴露后使用批准的方法进行消毒。每次使用时应目视检查手套，并应定期进行完整性测试。

 

4.22 Decontamination methods (cleaning and bio-decontamination, and where applicable inactivation for biological materials) should be appropriately defined and controlled. The cleaning process prior to the bio-decontamination step is essential; any residues that remain may inhibit the effectiveness of the decontamination process. Evidence should also be available to demonstrate that the cleaning and bio-decontamination agents used do not have adverse impact on the product produced within the RABS or isolator.

 

应适当界定和控制去污方法（清洁和生物净化，以及在适用的情况下对生物材料进行灭活）。生物净化步骤之前的清洁过程至关重要;残留的任何残留物都可能抑制去污过程的有效性。还应提供证据证明所使用的清洁剂和生物净化剂不会对RABS或隔离器内生产的产品产生不利影响。

 

i.             For isolators

 

对于隔离器

 

The bio-decontamination process of the interior should be automated, validated and controlled within defined cycle parameters and should include a sporicidal agent in a suitable form (e.g. gaseous or vaporized form). Gloves should be appropriately extended with fingers separated to ensure contact with the agent. Methods used (cleaning and sporicidal bio-decontamination) should render the interior surfaces and critical zone of the isolator free from viable microorganisms.

 

隔离器内部的生物净化过程应在既定的循环参数内自动化，验证和控制，并应包括合适形式（例如气态或汽态）的杀孢剂。手套应适当伸展，手指分开，以确保与杀孢子剂接触。使用的方法（清洁和杀孢生物净化）应使隔离器的内表面和关键区域没有活的微生物。

 

ii.             For RABS

 

对于RABS

 

The sporicidal disinfection should include the routine application of a sporicidal agent using a method that has been validated and demonstrated to robustly include all areas of the interior surfaces and ensure a suitable environment for aseptic processing.

 

杀孢子消毒应包括杀孢剂的日常使用，使用经验证和证明的方法，以有效地包含内表面的所有区域，并确保无菌处理的合适环境。

 

Cleanroom and clean air equipment qualification

 

洁净室和洁净空气设备确认

 

4.23 Cleanrooms and clean air equipment such as unidirectional airflow units (UDAFs), RABS and isolators, used for the manufacture of sterile products, should be qualified 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 contamination of the product or materials being handled. Appropriate cleanliness levels in the “at rest” and “operational” states should be maintained.

 

用于制造无菌产品的洁净室和洁净空气设备，如单向气流单元（UDF）、RABS和隔离器，应按照所需的环境特性进行确认。每个生产操作都需要在动态条件下具有适当的环境洁净度水平，以最大限度地降低所处理的产品或物料受到污染的风险。应保持在“静态”和“动态”状态的适当洁净度水平。

 

4.24 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录15要求的方法进行确认。洁净室确认（包括分级）应与生产环境监测明确区分开来。

 

4.25 Cleanroom and clean air equipment 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):

 

洁净室和洁净空气设备确认是评估已分级洁净室或洁净空气设备适合其预期用途的总体过程。作为附录15确认要求的一部分，洁净室和洁净空气设备的确认应包括（在设计/运行有关）：

 

i.             Installed filter system leakage and integrity testing.

 

已安装过滤系统泄漏和完整性测试。

 

ii.             Airflow tests - volume and velocity.

 

气流测试-风量和风速

 

iii.             Air pressure difference test.

 

压差测试

 

iv.             Airflow direction test and visualisation.

 

气流方向测试和可视化

 

v.             Microbial airborne and surface contamination.

 

空气微生物和表面微生物

 

vi.             Temperature measurement test.

 

温度测试

 

vii.             Relative humidity test.

 

相对湿度测试

 

viii.             Recovery test.

 

恢复测试

 

ix.             Containment leak test.

 

隔离泄漏测试

 

Reference for the qualification of the cleanrooms and clean air equipment can be found in the ISO 14644 series of standards.

 

有关洁净室和洁净空气设备确认的参考，请参见 ISO 14644 系列标准。

 

4.26 Cleanroom classification is part of the 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 total particle concentration. Classification activities should be scheduled and performed in order to avoid any impact on process or product quality. For example, initial classification should be performed during simulated operations and reclassification performed during simulated operations or during aseptic process simulation (APS).

 

洁净室级别确认是洁净室确认的一部分，是通过测量总粒子浓度来根据洁净室或洁净空气设备的规范评估空气洁净度水平的方法。应安排和执行级别确认活动，以避免对工艺或产品质量产生任何影响。例如，初始级别确认应在模拟操作期间执行，级别再确认可在模拟操作或无菌工艺模拟（APS）期间进行。

 

4.27 For cleanroom classification, the total of particles equal to or greater than 0.5 and 5 µm should be measured. This measurement should be performed both at rest and in simulated operations in accordance with the limits specified in Table 1.

 

对于洁净室级别确认，应测量等于或大于0.5和5μm的粒子总数。该测量应根据表1中规定的限值在静态和模拟动态中进行。

 

Table 1: Maximum permitted total particle concentration for classification

 

表1:用于分级的最大允许总粒子浓度

 

Grade 级别	Maximum  limits for total particle 总粒子最大限度		Maximum  limits for total particle 总粒子最大限度
	≥  0.5 µm/m3		≥  5 µm/m3
	at  rest 静态	in  operation 动态	at  rest 静态	in  operation 动态
A	3  520	3  520	Not  specified (a) 不作规定	Not  specified (a) 不作规定
B	3  520	352  000	Not  specified (a) 不作规定	2  930
C	352  000	3  520 000	2  930	29  300
D	3  520 000	Not predetermined  (b) 未设定	29  300	Not predetermined  (b) 未设定

 

a)        Classification including 5µm particles may be considered where indicated by the CCS or historical trends.

 

根据CCS或历史趋势，可考虑5 μ m粒子的级别。

 

b)        For grade D, in operation limits are not predetermined. The manufacturer should establish in operation limits based on a risk assessment and routine data where applicable.

 

对于D级，（本文件）未预先确定动态标准。制造商应根据风险评估和日常数据(如适用)建立动态标准。

 

4.28 For classification of the cleanroom, the minimum number of sampling locations and their positioning can be found in ISO 14644 Part 1. For the aseptic processing area and the background environment (the grade A and grade B areas, respectively), additional sample locations should be considered and all critical processing areas such as the point of fill and container closure feeder bowls should be evaluated. Critical processing locations should be determined by documented risk assessment and knowledge of the process and operations to be performed in the area.

 

对于洁净室的级别确认，可以在ISO 14644第1部分中找到采样点的最小数量及其位置。对于无菌加工区域和背景环境（分别为A级和B级区域），应考虑额外的取样位置，并应评估所有关键处理区域，例如灌装点和容器密封部件给料斗。关键处理位置应通过书面的风险评估和对该区域所执行的工艺和操作的了解来确定。

 

4.29 Cleanroom classification should be carried out in the “at rest” and “in operation” states.

 

4.29 洁净室级别确认应在“静态”和“动态”状态下进行。

 

i.             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 but not operating and without personnel present in the room.

 

“静态”状态的定义是所有公用设施的安装已完成，包括任何正常运行的HVAC，主要生产设备按既定安装但不运行并且没有人员在房间内的条件。

 

ii.             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.

 

“动态”状态的定义是洁净室的安装完成，HVAC系统完全运行，设备在制造商定义的操作模式下安装和运行，并且具有执行或模拟日常操作工作的最大人员数量的条件。

 

iii.             The total particle limits given in Table 1 above for the “at rest” state should be achieved after a “clean up” period on completion of operations and line clearance/cleaning activities. The "clean up" period (guidance value of less than 20 minutes) should be determined during the qualification of the rooms, documented and adhered to in procedures to reinstate a qualified state of cleanliness if disrupted during operation.

 

上文表1中给出的“静态”条件的总粒子限度应在完成操作和生产线清除/清场活动后的“自净”期后达到。“自净”期（指导值小于20分钟）应在房间的确认期间确定，并在操作期间中断时记录并遵守程序，以恢复已确认的洁净状态。

 

4.30 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 components at the working position (e.g. where high-risk operations occur and where 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.

 

单向流系统提供的气流速度应在确认方案中明确证明，包括风速测量的位置。应设计、测量和维护气流速度，以确在工作位置（例如，发生高风险操作以及产品和/或组件暴露的位置）有足够的单向气流为产品和暴露的组件提供保护。单向流系统应在工作位置提供 0.36 – 0.54 m/s（指导值）范围内的均匀气流速度，除非 CCS 中另有科学论证。气流可视化研究应与风速相关联。

 

4.31 The microbial contamination level 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 and the results obtained from room 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.

 

洁净室的微生物污染水平应作为洁净室确认的一部分来确定。采样点的数量应基于书面的风险评估和从房间级别确认，气流可视化研究以及有关在该区域执行的工艺和操作的知识中获得的结果。每个级别的确认过程中微生物污染的最大限值见表2。确认应包括“静态”和“动态”状态。

 

Table 2: Maximum permitted microbial contamination level during qualification

 

表2：确认期间最大允许微生物污染水平

 

Grade 级别	Air  sample CFU/m3 浮游菌 CFU/立方	Settle  plates (diameter  90 mm) CFU/4  hours (a) 沉降菌（直径90mm） CFU/4小时	Contact  plates (diameter  55 mm) CFU/plate 接触皿（直径55mm） CFU/皿
A	No  growth 无生长
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 a maximum of 4 hours. Exposure time should be based on recovery studies and should not allow desiccation of the media used.

 

沉降皿应在操作期间进行暴露，并在最多4小时后根据需要更换。暴露时间应基于回收率研究，并且不应使所用的培养基干燥。

 

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 tabulated is not used, or alternative methods are used, the approach taken should be appropriately justified.

 

注1：表中为各洁净级别所指定的所有方法应应用于确认该级别的领域。如未使用表中的任一方法，或者使用了替代方法，则应适当证明所采用的方法的合理性。

 

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：在整个文件中使用了单位为CFU 的限度。如果使用其他的或新的技术，以不同于CFU的方式呈现结果，制造商应科学证明所使用的限度的合理性，并在可能的情况下将其与CFU相关联。

 

Note 3: For the qualification of personnel gowning, the limits given for contact plates and glove prints in Table 6 should apply.

 

注3：对于人员更衣的确认，应使用表6中给出的接触皿和手套的限度。

 

Note 4: Sampling methods should not pose a risk of contamination to the manufacturing operations.

 

注4：取样方法不应对生产操作造成污染风险。

 

4.32 The requalification of cleanrooms and clean air equipment should be carried out periodically following defined procedures. The requalification should include at a minimum the following:

 

洁净室和洁净空气设备应按照规定的程序定期进行再确认。再确认至少应包括以下内容：

 

l  Cleanroom classification (total particle concentration).

 

l  洁净室级别确认（总粒子浓度）

 

l  Integrity test of final filters.

 

l  终端过滤器完整性测试

 

l  Airflow volume measurement.

 

l  风量测试

 

l  Verification of air pressure difference between rooms.

 

l  不同房间之间的压差确认

 

l  Air velocity test (Note: For grade B, C and D the air velocity test should be performed according to a risk assessment documented as part of the CCS. However, it is required for filling zones supplied with unidirectional airflow (e.g. when filling terminally sterilised products or background to grade A and RABS). For grades with non-unidirectional airflow, a measurement of recovery testing should replace velocity testing).

 

l  风速测试（注：对于B级，C级和D级，应根据CCS中记录的风险评估进行风速测试。但是，对于提供单向流的灌装区域（例如，最终灭菌产品的灌装或A级和RABS背景）是必须的。对于非单向流的洁净区域，可用恢复测试取代风速测试）。

 

The maximum time interval for requalification of grade A & B areas, is 6 months.

 

A级和B级区域再确认的最大时间间隔为6个月。

 

The maximum time interval for requalification of grade C & D areas, is 12 months.

 

C&D级区域再确认的最大时间间隔为12个月。

 

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 as appropriate. 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:

 

在为纠正设备或设施不合规状况而采取的补救措施完成后，或在适当的设备、设施或工艺变更之后，也应进行适当的再确认，至少包括上述测试。变更的重要性应通过变更管理流程来确定。需要考虑的变更示例包括但不限于以下：

 

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

 

l  影响设备操作的空气流动中断。

 

l  Change in the design of the cleanroom or of the operational setting parameters of the HVAC system.

 

l  改变洁净室的设计或HVAC系统的运行设置参数。

 

l  Special maintenance which affects the operation of the installation (e.g. change of final filters).

 

l  影响设备操作的特殊维护（例如更换终端过滤器）。

 

Disinfection

 

消毒

 

4.33 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. Cleaning programmes should effectively remove disinfectant residues. More than one type of disinfecting agent should be employed to ensure that where they have different modes of action, their combined usage is effective against 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 programme and to detect changes in types of microbial flora (e.g. organisms resistant to the disinfection regime currently in use).

 

洁净室的消毒尤为重要。应按照书面程序彻底清洁和消毒。为了使消毒有效，应在此之前进行清洁以去除表面污染。清洁程序应有效去除消毒剂残留。应使用一种以上的消毒剂，以确保在它们具有不同作用机理且它们的组合使用对细菌和真菌有效。消毒应包括定期使用杀孢子剂。应定期进行监测以评估消毒程序的有效性，并监测微生物菌群类型的变化（例如，对当前使用的消毒模式耐受的生物体）。

 

4.34 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 on the type of surface material, or representative material if justified, and should support the in-use expiry periods of prepared solutions.

 

应验证消毒过程。验证研究应以具体使用方式和表面材料类型或代表性材料（如经论证）证明消毒剂的适用性和有效性，并应支持所制备溶液的使用有效期。

 

4.35 Disinfectants and detergents used in grade A 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 determined in the CCS. Where the disinfectants and detergents are diluted / prepared by the sterile product manufacturer, this should be done in a manner to prevent contamination and they should be monitored for microbial contamination. Dilutions should be kept in previously cleaned containers (and sterilized where applicable) and should only be stored for the defined period. 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.

 

在A级和B级区域使用的消毒剂和清洁剂在使用前应无菌。在C级和D级中使用的消毒剂也可能在CCS中要求是无菌的。如消毒剂和清洁剂由无菌产品制造商稀释/制备，则应以防止污染的方式进行，并应监测微生物污染。（消毒液）稀释液应保存在预先清洁的容器中（并在适当时进行灭菌），并且只应储存在规定的期限内。如使用“市售现成”消毒剂和清洁剂，那么在成功完成适当的供应商确认后，分析或合格证书的结果可以接受。

 

4.36 Where fumigation or vapour disinfection (e.g. Vapour-phase Hydrogen Peroxide) of cleanrooms and associated surfaces are used, the effectiveness of any fumigation agent and dispersion system should be understood and validated.

 

在对洁净室和相关表面进行熏蒸或蒸汽消毒(例如，汽化过氧化氢)时，应了解和验证任何熏蒸剂和分散系统的有效性。

 

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.

 

应提供设备设计的书面详细描述（包括适当的过程和仪表图）。这应作为初始确认的一部分，并保持最新状态。

 

5.2 Equipment monitoring requirements should be defined in “user requirements specifications” during early stages of development, and confirmed during qualification. Process and equipment alarm events should be acknowledged and evaluated for trends. The frequency at which alarms are assessed should be based on their criticality (with critical alarms reviewed immediately).

 

设备监测需求应在开发的早期阶段在“用户需求规范”中定义，并在验证期间确认。应确认过程和设备报警事件并评估其趋势。评估警报的频率应基于其严重性（严重警报立即审查）。

 

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. Additional cleaning, disinfection and environmental monitoring should also be considered. If sterilisation of equipment is required, it should be carried out, wherever possible, after complete reassembly.

 

如可行，设备，配件和服务应设计和安装以在洁净室外进行操作，维护和维修。如果必须在洁净室内进行维护，并且无法保持所需的洁净度和/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。还应考虑额外的清洁、消毒和环境监测。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 be able to:

 

清洁过程应验证能够：

 

i.             Remove any residue or debris that would detrimentally impact the effectiveness of the disinfecting agent used.

 

清除任何会对所用消毒剂的有效性产生不利影响的残留或杂物。

 

ii.             Minimize chemical, microbial and particulate contamination of the product during the process and prior to disinfection.

 

在清洁过程中和消毒之前，最大限度地减少产品的化学、微生物和颗粒污染。

 

5.5 For aseptic processes, direct and indirect product contact parts should be sterilised. Direct product contact parts are those that the product passes through, such as filling needles or pumps. Indirect product contact parts are equipment parts that do not contact the product, but may come into contact with other sterilised surfaces, the sterility of which is critical to the overall product sterility (e.g. sterilised items such as stopper bowls and guides, and sterilised components).

 

对于无菌工艺，应对产品直接和间接接触的部件进行灭菌。直接接触产品的部件是产品通过的部件，例如灌装针头或泵。间接产品接触部件是指不接触产品但可能与其他灭菌表面接触的设备部件，其无菌性对产品的整体无菌至关重要（例如，灭菌物品，如胶塞斗和导轨，以及已灭菌组件）。

 

5.6 All equipment such as sterilisers, 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，都应进行确认、监测和计划性维护。维护完成后，其恢复使用应经批准。

 

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.

 

如果要对产品无菌性至关重要的设备进行计划外维护，则应评估对产品无菌性的潜在影响。

 

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 sterilised (e.g. in a sterilising tunnel).

 

传送带不应穿过 A 级或 B 级区域与空气洁净度较低的加工区域之间的隔板，除非传送带本身连续灭菌（例如在灭菌隧道中）。

 

5.9 Particle counters, including sampling tubing, should be qualified. The manufacturer’s recommended specifications should be considered for tube diameter and bend radii. Tube length should typically be no longer than 1m unless justified and the number of bends should be minimized. Portable particle counters with a short length of sample tubing should be used for classification purposes. Isokinetic sampling heads should be used in unidirectional airflow systems. They should be oriented appropriately and positioned as close as possible to the critical location to ensure that samples are representative.

 

粒子计数器，包括采样管，应经确认。应考虑制造商对管径和弯曲半径的建议标准。采样长度通常不应超过1m（否则应进行论证）且应最大限度减少弯曲次数。应使用采样管长度较短的便携式粒子计数器进行级别确认。应使用等动力采样头应用于单向流系统。它们应有适当的方向并尽可能靠近关键位置，以确保样品具有代表性。

 

6 Utilities

 

公用系统

 

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 and documented as part of the CCS.

 

适用于公用系统的控制的性质和程度应与公用系统相关的产品质量风险相称。应通过风险评估确定影响，并作为CCS的一部分进行记录。

 

6.2 In general, higher risk utilities are those that:

 

一般而言，高风险公用系统是指：

 

i.             Directly contact product e.g. water for washing and rinsing, gases and steam for sterilisation.

 

直接接触产品，例如用于清洗和漂洗的水，用于灭菌的气体和蒸汽。

 

ii.             Contact materials that will ultimately become part of the product.

 

接触物料，最终将成为产品的一部分。

 

iii.             Contact surfaces that come into contact with the product.

 

与产品接触的表面。

 

iv.             Otherwise directly impact the product.

 

其他直接影响产品的系统。

 

6.3 Utilities should be designed, installed, qualified, operated, maintained and monitored in a manner to ensure that the utility system functions as expected.

 

公用系统的设计、安装、确认、运行、维护和监测应确保公用系统如预期运行。

 

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.

 

高风险公用系统的关键参数和关键质量属性的结果应定期进行趋势分析，以确保系统保持适当的能力。

 

6.5 Records of utility system installation should be maintained throughout the system’s life-cycle. Such records should include current drawings and schematic diagrams, construction material lists and system specifications. Typically, important information includes attributes such as:

 

应在系统的整个生命周期内保存公用系统安装记录。此类记录应包括当前图纸和原理图、建筑材料清单和系统规范。通常，重要信息包括以下属性：

 

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

 

管道流向、坡度、直径和长度。

 

ii.             Tank and vessel details.

 

罐和容器详细信息

 

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

 

阀门、过滤器、排水管、取样点和使用点。

 

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.

 

管道和其他公用设施不应存在于洁净室中。如果不可避免，则应安装以免产生凹槽，未密封的开口和难以清洁的表面。安装应允许清洁和消毒管道的外表面。

 

Water systems

 

水系统

 

6.7 Water treatment plant and distribution systems should be designed, constructed, installed, commissioned, qualified, monitored and maintained to prevent microbiological contamination and to ensure a reliable source of water of an appropriate quality. Measures should be taken to minimize the risk of presence of particulates, microbial contamination/proliferation and endotoxin/pyrogen (e.g. sloping of piping to provide complete drainage and the avoidance of dead legs). Where filters are included in the system, special attention should be given to their monitoring and maintenance. Water produced should comply with the current monograph of the relevant Pharmacopeia.

 

应设计、建造、安装、调试、确认、监测和维护水处理和分配系统以防止微生物污染，并确保适当质量的可靠水源。应采取措施尽量减少颗粒物、微生物污染/增殖和内毒素/热原存在的风险（例如，倾斜管道以完全排水和避免死角）。如果系统中包含过滤器，则应特别注意其监控和维护。产生的水应符合相关药典的现行标准。

 

6.8 Water systems should be qualified and validated to maintain the appropriate levels of physical, chemical and microbial control, taking the effect of seasonal variation into account.

 

水系统应经确认和验证，以保持适当的物理、化学和微生物控制水平，同时考虑到季节变化的影响。

 

6.9 Water flow should remain turbulent through the pipes in water distribution systems to minimize the risk of microbial adhesion, and subsequent biofilm formation. The flow rate should be established during qualification and be routinely monitored.

 

水流通过配水系统中的管道应保持湍流，以尽量减少微生物粘附和随后生物膜形成的风险。应在确认期间确定流速，并进行日常监测。

 

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 (e.g. by constant circulation at a temperature above 70°C). WFI should be produced by distillation or by a purification process that is equivalent to distillation. This may include reverse osmosis coupled with other appropriate techniques such as electrodeionization (EDI), ultrafiltration or nanofiltration.

 

注射用水（WFI）应由符合既定确认标准的水生产，并以尽量减少微生物生长风险的方式储存和分配（例如，通过在高于70°C的温度下恒温循环）。WFI应通过蒸馏或相当于蒸馏的纯化过程产生。这可以包括反渗透联合其它适当的技术，例如电去离子（EDI），超滤或纳滤。

 

6.11 Where WFI storage tanks are equipped with hydrophobic bacteria retentive vent filters, the filters should not be a source of contamination and the integrity of the filter tested before installation and after use. Controls should be in place to prevent condensation formation on the filter (e.g. by heating).

 

如果WFI储罐配有疏水性细菌截留通风过滤器（呼吸过滤器），则过滤器不应成为污染源，并且在安装前和使用后测试过滤器的完整性。应采取适当的控制措施（例如通过加热），以防止在过滤器上形成冷凝。

 

6.12 To minimize the risk of biofilm formation, sterilisation, disinfection or regeneration of water systems should be carried out according to a predetermined schedule and as a remedial action following out-of-limit or specification results. Disinfection of a water system with chemicals should be followed by a validated rinsing/flushing procedure. Water should be tested after disinfection/regeneration. Chemical testing results should be approved before the water system is returned to use and microbiological/endotoxin results verified to be within specification and approved before batches manufactured using water from the system are considered for certification/release.

 

为最大限度地降低生物膜形成的风险，应按照预定的时间计划进行水系统的灭菌，消毒或再生，并在超限或超标结果后作为补救措施。使用化学品对水系统进行消毒后，应遵循经验证的冲洗/冲洗程序。消毒/再生后应测试水质。水系统恢复使用前，化学检测结果得到批准，微生物/内毒素结果则应在使用该水系统所生产的批次被放行前确认符合标准并得到批准。

 

6.13 Regular ongoing chemical and microbial monitoring of water systems should be performed to ensure that the water continues to meet compendial expectations. Alert levels should be based on the initial qualification data and thereafter periodically reassessed on data obtained during subsequent re-qualifications, routine monitoring, and investigations. Review of ongoing monitoring data should be carried out to identify any adverse trend in system performance. Sampling programmes should reflect the requirements of the CCS and should include all outlets and points of use, at a specified interval, to ensure that representative water samples are obtained for analysis on a regular basis. Sample plans should be based on the qualification data, should consider the potential worst case sampling locations and should ensure that at least one representative sample is included every day of the water that is used for manufacturing processes.

 

 应定期对水系统进行化学和微生物监测，以确保水持续符合药典标准。警戒限应基于初始确认数据，然后根据在随后的再确认、日常监测和调查期间获得的数据定期重新评估。应审查持续监测数据以发现系统性能的任何不良趋势。取样方案应反映CCS的要求，并应在规定的时间间隔内包括所有出口和使用点，以确保定期获得具有代表性的水样进行分析。取样计划应基于确认数据，应考虑潜在的最差情况取样位置，并应确保每天至少包括一个用于制造过程的水的代表性样品。

 

6.14 Alert level excursions should be documented and reviewed, and include an investigation to determine whether the excursion is a single (isolated) event or if results are indicative of an adverse trend or system deterioration. Each action limit excursion should be investigated to determine the probable root causes and any potential impact on the quality of products and manufacturing processes as a result of the use of the water.

 

应记录和审查警戒级别的偏移，并包括调查以确定偏移是个别（孤立的）事件，还是表面不良趋势或系统恶化。应调查每个行动限偏移，以确定可能的根本原因以及由于使用（超行动限的）水而对产品质量和制造过程的任何潜在影响。

 

6.15 WFI systems should include continuous monitoring systems such as Total Organic Carbon (TOC) and conductivity, as these may give a better indication of overall system performance than discrete sampling. Sensor locations should be based on risk.

 

WFI系统应包括连续监测系统，如总有机碳（TOC）和电导率，因为这些系统可能比离线取样更好地表面整体系统性能。传感器位置应基于风险。

 

Steam used as a direct sterilising agent

 

用作直接灭菌剂的蒸汽

 

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（洁净蒸汽）发生器的给水应适当净化。纯蒸汽发生器的设计、确认和运行方式应确保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 sterilising agent should be of suitable quality and should not contain additives at a level that could cause contamination of product or equipment. For a generator supplying pure steam used for the direct sterilisation 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 (microbial testing is not mandatory for steam condensate). A suitable sampling schedule should be in place to ensure that representative pure steam is obtained for analysis on a regular basis. Other aspects of the quality of pure steam used for sterilisation should be assessed periodically against validated parameters. These parameters should include the following (unless otherwise justified): non-condensable gases, dryness value (dryness fraction) and superheat.

 

用作直接灭菌剂的蒸汽应具有合适的质量，并且不应含有可能导致产品或设备污染的添加剂。对于供应用于物料或产品接触表面（例如，多孔坚硬高压灭菌器负载）直接灭菌的纯蒸汽发生器，蒸汽冷凝水应符合相关药典WFI的现行标准（蒸汽冷凝水的微生物测试不是强制的）。应制定适当的取样计划，以确保定期获得具有代表性的纯蒸汽进行分析。用于灭菌的纯蒸汽质量的其他方面应根据经验证的参数定期进行评估。这些参数应包括以下内容（除非另有说明）：不凝性气体，干燥度值（干燥度分数）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 current monograph of the relevant Pharmacopeia or the product quality requirement.

 

与产品/内包装容器表面直接接触的气体应具有适当的化学、颗粒和微生物质量。应指定所有相关参数，包括油分和水分，同时考虑到气体的用途和类型，气体制备系统的设计，并在适用的情况下，符合相关药典的现行标准或产品质量要求。

 

6.19 Gases used in aseptic processes should be filtered through a sterilising grade 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 reviewed as part of the batch certification/release process. Any transfer pipework or tubing that is located after the final sterilising grade filter should be sterilised. When gases are used in the process, microbial monitoring of the gas should be performed periodically at the point of use.

 

无菌工艺中使用的气体应在使用点通过除菌级过滤器（标称孔径最大为0.22μm）进行过滤。如果过滤器按批使用（例如，用于无菌灌装产品覆盖层气体的过滤器）或作为产品容器通风过滤器，则应对过滤器进行完整性测试并审查结果作为批放行过程的一部分。在终端除菌级过滤器之后的任何管道都应进行灭菌。当在工艺中使用气体时，应在使用点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, there should be mechanism(s) to prevent backflow when the vacuum or pressure system is shut off.

 

如果来自真空或压力系统的回流对产品构成潜在风险，则应有机制在真空或压力系统关闭时防止回流。

 

Heating and cooling and hydraulic systems

 

加热，冷却和液压系统

 

6.21 Major items of equipment associated with hydraulic, heating and cooling systems should, where possible, be located outside the filling room. There should be appropriate controls to contain any spillage and/or cross contamination associated with the system fluids.

 

与液压、加热和冷却系统有关的主要设备应尽可能位于灌装室外。应有适当的控制措施，以控制与系统流体相关的任何溢出和/或交叉污染。

 

6.22 Any leaks from these systems that would present a risk to the product should be detectable (e.g. an indication system for leakage).

 

这些系统对产品构成风险的任何泄漏都应可检测（例如，泄漏指示系统）。

 

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.

 

制造商应确保有足够的适当人员，在无菌产品的生产和检验以及现场生产操作中使用的任何特定生产技术方面经适当的确认、培训并有经验，以确保符合适用于无菌产品生产和加工的GMP。

 

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 considered during activities such as initial qualification and APS, so as not to compromise sterility assurance.

 

洁净室中应尽量配备最少数量的人员。在初始确认和APS等活动中，应确定，记录和考虑洁净室中的最大操作人员数量，以避免对无菌保证的损害。

 

7.3 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 and 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 grade A) and the potential safety implications to the patient if the product is not sterile. The level of training should be based on the criticality of the function and area in which the personnel are working.

 

所有人员，包括进行清洁、维护、监测的人员和其他进入洁净室的人员，都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。培训应包括微生物学和卫生的基本要素，特别关注洁净室实践，污染控制，无菌技术和无菌产品的保护（适用于进入B级洁净室和/或对A级进行干扰的操作人员）以及如果产品长菌，对患者的潜在安全影响。培训的水平应基于人员工作的职能和领域的重要性。

 

7.4 The personnel accessing grade A and B areas should be trained for aseptic gowning and aseptic behaviours. Compliance with aseptic gowning procedures should be confirmed by assessment and periodic reassessment at least annually, and should involve both visual and microbial assessment (using monitoring locations such as gloved fingers, forearms, chest and hood (facemask / forehead). See paragraph 9.30 for the expected limits). The unsupervised access to the grade A 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 APS.

 

进入A级和B级区域的人员应接受无菌更衣和无菌行为培训。应至少每年通过评估和定期重新评估来确认无菌更衣程序的合规性，并且应包括视觉和微生物评估（使用监测位置，例如手套手指，前臂，胸部和头罩（面罩/前额）。预期标准见第9.30段）。在无人监督的情况下进入正在或将要进行无菌操作的A级和B级区域时，应只允许已通过更衣评估并已成功参与APS的经适当确认的人员。

 

7.5 Unqualified personnel should not enter grade B cleanrooms or grade A 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. 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. Access by these persons should be assessed and recorded in accordance with the PQS.

 

未经确认的人员不得进入正在操作中的B级洁净室或A级洁净室。在特殊情况下，如果需要，制造商应制定书面程序，概述将未经确认人员带入B级和A级区域的流程。制造商的授权人员应在活动期间监督未经确认的人员，并应评估这些活动对该区域洁净度的影响。这些人员的进入应根据PQS进行评估和记录。

 

7.6 There should be systems in place for the disqualification of personnel from working in or given unsupervised entry into cleanrooms that is based on aspects including ongoing assessment and/or identification of an adverse trend from the personnel monitoring programme and/or after being implicated 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, this requalification should include consideration of participation in a successful APS.

 

应建立制度，根据以下方面取消人员在洁净室工作或在无人监督的情况下进入洁净室的权限，包括持续评估和/或从人员监测计划中发现不良趋势和/或失败的APS后。权限一旦取消，应在允许操作人员进一步参与无菌操作之前完成再培训和再确认。对于进入B级洁净室或进行A级干预的操作人员，这种再确认应包括考虑参与成功的APS。

 

7.7 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 that 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防止增加微生物污染风险至关重要。参与无菌产品生产的人员应被指示报告任何可能导致异常数量或类型污染物脱落并因此应避免进入洁净室的特定健康状况或疾病。应由指定的主管人员提供可能引入不适当微生物危害的人员健康状况和应采取的行动，并在程序中加以说明。

 

7.8 Personnel 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 and documented.

 

从事人类或动物组织材料加工或微生物培养（除当前制造过程中已使用的物料外），或从事任何可能对质量产生负面影响（例如微生物污染）的活动的人员，不应进入洁净区，除非已遵循明确定义和有效的去污染和进入程序并形成文件。

 

7.9 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 manufacturer 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）和任何其他非必需品不得带入洁净区。洁净室中使用的电子设备，例如移动电话和平板电脑，如果制造商提供的电子设备仅用于洁净室，如果经过适当设计以允许与其使用等级相称的清洁和消毒，则可以接受。此类设备的使用和消毒应包括在CCS中。

 

7.10 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洁净服的污染和/或污染物向洁净区域的转移。

 

7.11 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 and after gowning. Gown integrity should also be checked upon exit. For sterilised garments and eye coverings, particular attention should be taken to ensure they have been subject to the sterilisation process, 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. The qualification of garments should consider any necessary garment testing requirements, including damage to garments that may not be identified by visual inspection alone.

 

洁净服及其质量应适合工作区域的工艺和洁净级别。其穿戴方式应能保护产品免受污染。当所选的洁净服类型需要为操作人员提供产品防护时，不应损害产品的污染保护。在更衣之前和之后，应立即对洁净服进行目视检查，以确保洁净度和完整性。退出洁净室时也应检查洁净服的完整性。对于灭菌的洁净服和眼罩，应特别注意确保其在使用前已经过灭菌，并在其规定的保存期限内，并且其包装经过目视检查以确保其完整。可重复使用的洁净服（包括眼罩）一旦发现损坏，应进行更换，或以确认研究期间确定的设定频率进行更换。洁净服的确认应考虑任何必要的洁净服测试要求，包括仅通过目视检查可能无法识别的服装损坏。

 

7.12 Clothing should be chosen to limit shedding due to operators’ movement.

 

洁净服应选择以限制因操作人员移动而导致的（颗粒）脱落。

 

7.13 A description of typical clothing required for each cleanliness grade is given below:

 

下面给出了每个洁净等级所需的典型服装的描述：

 

i.             Grade B (including access / interventions into grade A): appropriate garments that are dedicated for use under a sterilised suit should be worn before gowning (see paragraph 7.14). Appropriately sterilised, non-powdered, rubber or plastic gloves should be worn while donning the sterilised garments. 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 facemask and sterile eye coverings (e.g. goggles) should be worn to cover and enclose all facial skin and prevent the shedding of droplets and particles. Appropriate sterilised footwear (e.g. over-boots) should be worn. Trouser legs should be tucked inside the footwear. Garment sleeves should be tucked into a second pair of sterile gloves worn over the pair worn while donning the gown. The protective clothing should minimize shedding of fibres or particles and retain particles shed by the body. The particle shedding and the particle retention efficiencies of the garments should be assessed during the garment qualification. Garments should be packed and folded in such a way as to allow operators to don the gown without contacting the outer surface of the garment and to prevent the garment from touching the floor.

 

B级（包括进入/干预A级）：在穿戴洁净服之前，应穿戴专用于已灭菌洁净服下使用的适当服装（见第7.14段）。在穿上已灭菌的衣服时，应戴上适当灭菌的，无粉橡胶或塑料手套。无菌头罩应将所有毛发（包括面部毛发）封闭起来，如果与洁净服的其余部分分开，则应将其塞入无菌套装的颈部。应佩戴无菌面罩和无菌眼罩（例如护目镜）以覆盖和封闭所有面部皮肤，并防止飞沫和颗粒脱落。应穿适当的已灭菌的鞋（例如靴子）。裤腿应塞在鞋内。服装袖子应塞进第二副无菌手套中，戴在穿洁净服时戴的那双手套之上。洁净服应尽量减少纤维或颗粒的脱落，并截留自身体脱落的颗粒。在洁净服确认期间，应评估洁净服的颗粒脱落和颗粒截留效率。洁净服的包装和折叠方式应允许操作人员在不接触洁净服外表面的情况下穿上，并防止洁净服接触地板。

 

ii.             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 particles.

 

C级：应遮盖头发和胡须。应穿连体或分体式裤衫，手腕处收紧，高领，穿经适当消毒的鞋子或套鞋。它们应该尽量减少纤维和颗粒的脱落。

 

iii.             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.

 

D级：应遮盖头发和胡须。应穿通用防护服和适当消毒的鞋子或套鞋。应采取适当措施，避免任何污染物从洁净区以外进入。

 

iv.             Additional gowning including gloves and facemask may be required 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级区域进行CCS所定义的被认为存在污染风险的活动时，可能需要额外的洁净服，包括手套和口罩。

 

7.14 Cleanroom gowning should be performed in change rooms of an appropriate cleanliness grade to ensure gown cleanliness is maintained. Outdoor clothing including socks (other than personal underwear) should not be brought into changing rooms leading directly to grade B and C areas. Single or two-piece facility trouser suits, covering the full length of the arms and the legs, and facility 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.

 

洁净室更衣应在适当洁净等级的更衣室进行，以确保保持洁净服的洁净度。包括袜子（个人内衣除外）在内的户外服装不应带入直接通往B级和C级区域的更衣室。在进入B级和C级更衣室之前，应穿覆盖整个胳膊和腿的分体式或连体式套装，以及覆盖脚的洁净袜。套装和洁净袜不应对更衣区域或工序造成污染风险。

 

7.15 Every operator entering grade B or A areas should gown into clean, sterilised protective garments (including eye coverings and masks) of an appropriate size at each entry. The maximum period for which the sterilised gown may be worn before replacement during a shift should be defined as part of the garment qualification.

 

每个进入B级或A级区域的操作人员每次进入时，都应穿上适当尺寸的干净、已灭菌的洁净服（包括眼罩和口罩）。无菌洁净服在一个班次的最长穿戴时间应作为洁净服确认的一部分进行定义。

 

7.16 Gloves should be regularly disinfected during operations. Garments and gloves should be changed immediately if they become damaged and present any risk of product contamination.

 

操作期间应定期对手套进行消毒。如果衣服和手套损坏并存在任何产品污染的风险，应立即更换。

 

7.17 Reusable clean area clothing should be cleaned in a laundry facility adequately segregated from production operations, using a qualified process ensuring that the clothing is not damaged and/or contaminated by fibres or particles during the repeated laundry process. Laundry facilities used should not introduce risk of contamination or cross-contamination. Inappropriate handling and use of clothing may damage fibres and increase the risk of shedding of particles. After washing and before packing, garments should be visually inspected for damage and visual cleanliness. The garment management processes should be evaluated and determined as part of the garment qualification programme and should include a maximum number of laundry and sterilisation cycles.

 

可重复使用的洁净区衣服应在与生产操作充分分离的洗衣房中清洗，使用经确认的工艺，确保衣服在重复的清洗过程中不会损坏和/或被纤维或颗粒污染。所使用的洗衣设施不应引入污染或交叉污染的风险。衣服的不当处理和使用可能会损坏纤维并增加颗粒脱落的风险。应在清洗之后和包装之前目视检查衣服的损坏和目视清洁度。洁净服管理过程应作为洁净区确认的一部分进行评估和确定，并应包括最大清洗和灭菌次数。

 

7.18 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 particles 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 may 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. A review of airflow visualisation studies should be considered as part of the training programme.

 

应最大限度减少对生产过程不重要的洁净区活动，特别是在无菌操作进行时。人员的移动应缓慢，可控和有条不紊，以避免由于过度剧烈的活动而过度脱落颗粒和生物体。执行无菌操作的操作人员应始终坚持使用无菌技术，以防止气流变化而导致质量较低的空气进入关键区域。应限制与关键区域相邻的运动，并应避免阻挡单向流（第一空气）的路径。对气流可视化研究的阅览应被视为培训计划的一部分。

 

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