重磅，瑞士药监局 发布 EU GMP附录1《无菌药品生产》官方解读！

Interpretation of GMP Annex 1 2022 (Rev. 1) 

GMP 附件 1 2022（修订版 1）释义

1 Purpose and scope 目的和范围

This technical interpretation focuses on some of the most important main changes of the revision 2022 of Annex 1 and also covers aspects that were already included in the previous version of this guideline and that repeatedly gave rise to questions. This technical interpretation is intended to reflect the general opinion of the Swiss Inspectorates on these topics and to serve as a support during the inspection of manufacturers of sterile medicinal products.

本技术解释侧重于附件 1 修订版 2022 中一些最重要的主要变化，也涵盖了本指南上一 版中已包含但反复出现问题的方面。本技术解释旨在反映瑞士检查机构对这些主题的总体意见，并在对无菌医药产品制造商进行检查时提供支持。

2 Basics 基础知识

The Revised Annex 1 to the PIC/S GMP Guide (PE 009), about manufacture of sterile medicinal products, adopted on 9 September 2022 by the PIC/S Committee and came into force on 25 August 2023 (with the exception of point 8.123, which will become binding from 25 August 2024).

PIC/S GMP 指南（PE 009）经修订的附件 1 涉及无菌药品的生产。

PIC/S委员会于2022年9月9日通过了《国际植物保护公约》第8.123条，该条于2023年8月25日生效（第8.123条除外，该条将于2024年8月25日生效）。

3 Definitions and abbreviations 定义和缩写

n.a.

4 Interpretation: Questions and Answers 问题与答案

4.1 Scope (Annex 1, Chapter 1) 范围（附件 1，第 1 章）

Q&A No. 问答编号	Paragraph No. 章节编号	Questions 问题	Answers 答案
1	Chapter 1 (Scope) 第 1 章（范围）	Does Annex 1 apply without restriction also to ATMPs or are only defined aspects of Annex 1 to be followed for some specific product types, such as for exam ple the allogeneic and autologous cell therapy products? 附件 1 是否也不受限制地适用于 ATMP，还是只有某些特定类型的产品，如异体和自体细胞治疗产品，才需要遵守附件 1 的规定？	It is recognised that ATMPs cover a very heterogeneous range of products and that for some of these products, due to their nature and manufacturing technology, specific considerations are required. This certainly applies, for example, to the allogeneic and autologous cell therapy products, which are to be manufactured under conditions suitable to avoid microbial contaminations, but which usually cannot be terminally sterilised or sterile filtered. In addition, such products are made from unsterile patient material. Specifically with regard to cellular therapy, Annex 2A, paragraph 5.29(b), requires that aseptic processing be maintained from the time of procurement of cells through manufacturing and administration back into the patient. Annex 2A refers to Annex 1 several times (e.g., in connection with the requirements for the provision of systems for closed processing), but implies the possibility of exceptions from applying the requirements of Annex 1. It must also be taken into account that Annex 2A became valid in May 2021, i.e., more than one year before the publication of the new Annex 1 version. It is expected that ATMP manufacturers, based on the knowledge of their manufacturing processes and the execution of detailed risk analyses covering all process steps, materials and systems, develop and implement Contamination Control Strategies suitable to avoid or largely minimise risks of product contaminations. Justification must be given for any exceptions to the requirements of Annex 1. 人们认识到，ATMP涵盖的产品种类繁多，其中一些产品由于其性质和制造技术，需要特别考虑。这当然适用于异体和自体细胞治疗产品，这些产品的生产条件应能避免微生物污染，但通常无法进行终末消毒或无菌过滤。此外，这类产品是用未经消毒的病人材料制成的。具体到细胞疗法，附件2A第5.29(b)段要求，从细胞的采购、制造到回输到病人体内，都必须保持无菌处理。附件2A几次提到附件1（例如，关于提供封闭式处理系统的要求），但也暗示有可能不执行附件1的要求。还必须考虑到，附件2A于2021年5月生效，即在新版附件1发布前一年多。 ATMP 生产商应根据对其生产工艺的了解以及对所有工艺步骤、材料和系统的详细风险分析，制定并实施适当的污染控制策略，以避免或在很大程度上降低产品污染的风险。附件 1 的要求如有例外，必须说明理由。

4.2 Premises (Annex 1, Chapter 4) 厂房（附件 1，第 4 章）

Q&A No. 问答编号	Paragraph No. 章节编号	Questions 问题	Answers 答案
2	4.1, 4.11 & 4.12	Are grade A and B cleanrooms required to have separate airlocks for material and personnel and must the flows in such airlocks be strictly unidirectional? A 级和 B 级洁净室是否需要为材料和人员设置单独的气闸，气闸中的气流是否必须是严格的单向流动？	In general, it is expected that new facilities have for grade A and B zones segregated airlocks for personnel and material and that the flows in such airlocks are unidirectional (i.e., separate MALs for transport into and out of the cleanroom and separate PALs for personnel entry and exit). Existing facilities that do not have such airlock separation must ensure that, as a minimum, temporary separation of the flows in the airlocks is guaranteed and that the situation is covered by scientifically sound risk analysis also assessing the need of additional technical or organizational measures. The rationale for not applying physical separation of the above-mentioned flows through segregated airlocks and the risk assessment on which it is based must be integrated in the overall contamination control strategy. 一般来说，新设施的A级和B级区域应设有隔离人员和材料的气闸，并且气闸中的气流是单向的（即进出洁净室的运输有单独的 MAL，人员进出有单独的 PAL）。 没有这种气闸隔离措施的现有设施必须确保至少保证气闸中的气流临时隔离，并通过科学合理的风险分析，评估是否需要采取额外的技术或组织措施。不通过隔离气闸对上述气流进行物理隔离的理由及其所依据的风险评估必须纳入总体污染控制战略。
3	4.12	Paragraph 4.12, point ii, states that only materials and equipment that are on an approved list and that have been assessed during validations of the transfer process, should be transferred into grade A or grade B areas via airlocks or pass-through hatches. What does “validation of the transfer process” mean, for example for the material transfer into an isolator? 第 4.12 段第 ii 点规定，只有列入核准清单并在转移过程验证中经过评估的材料和设 备，才能通过气闸或通过式舱口转移到 A 级或 B 级区域。例如，'转移过程验证 '对于将材料转移到隔离器中是什么意思？	As mentioned in paragraph 4.10 of Annex 1, the transfer of materials, equipment or components into and out of a cleanroom (incl. the critical zone within a grade A environment), represents one of the greatest potential sources and risks of contamination. In order to minimise such risks, great care must be taken in particular when defining the technical and procedural measures associated with the transfer of materials/equipment into an aseptic processing area. Only in relatively rare cases it is possible to bring materials into an isolator before it is sealed and biodecontaminate them together with the isolator using a validated VHP treatment (only possible for small batches and if materials are resistant to VHP). In the majority of cases, however, it is necessary to transfer materials to an isolator that has already been decontaminated. For this, all materials must first be sterilised and then moved through the physical barrier of the isolator in such a way that the sterility of the goods and the integrity of the isolator are maintained. Regardless of the technology used (e.g., usage of double-door sterilisers upstream of the isolator, use of transfer isolators or of rapid transfer port technology), the entire transfer process must be considered within detailed risk analysis and be part of the overall contamination control strategy. In addition, appropriate control mechanisms must be defined to monitor the maintenance of the integrity and functionality of the systems (e.g., measurement of differential pressure and control of door interlocks between adjacent zones of the transfer system). The technical solutions must be covered by appropriate equipment/system qualifications (incl. Smoke studies if applicable) and sterilisation validations and the suitability of the entire transfer process must be verified through APS (validations and also regular APS). Appropriate qualification measures and APS must also be used to demonstrate that the egress of materials from the isolator does not affect the maintenance of the grade A zone requirements. The arrangement of the installations, the processes carried out in it and the material movements must also be considered when defining the points to be sampled during PQ activities or during routine or event based environmental monitoring. 如附件1第4.10段所述，材料、设备或部件进出洁净室（包括A级环境中的临界区）是最大的潜在污染源和风险之一。 为了最大限度地降低这种风险，在确定与将材料/设备转移到无菌加工区有关的技术和程序措施时，必须特别小心。只有在相对罕见的情况下，才有可能在隔离器密封之前将材料带入隔离器，并通过有效的VHP处理对材料和隔离器进行生物消毒（只有在小批量和材料对VHP有抵抗力的情况下才有可能）。但在大多数情况下，必须将材料转移到已经去污的隔离器中。为此，必须首先对所有材料进行灭菌，然后通过隔离器的物理屏障进行转移，以保持货物的无菌性和隔离器的完整性。无论使用哪种技术（如在隔离器上游使用双门灭菌器、使用转移隔离器或快速转移端口技术），都必须在详细的风险分析中考虑整个转移过程，并将其作为整体污染控制战略的一部分。此外，还必须确定适当的控制机制，以监测系统完整性和功能性的维护情况（例如，测量压差和控制传送系统相邻区域之间的门联锁）。技术解决方案必须经过适当的设备/系统鉴定（包括烟雾研究，如适用）和灭菌验证，整个转移过程的适用性必须通过 APS（验证和定期 APS）进行验证。还必须采取适当的鉴定措施和 APS，以证明材料从隔离器中流出不会影响维持 A 级区的要求。 在确定PQ活动或例行或事件性环境监测期间的采样点时，还必须考虑设备的布置、设备中的工艺流程以及材料的流动情况。
4	4.12	Is it always required to strictly adhere to the area cleanliness cascade (i.e., respecting the sequential order of cleanroom classes) for material transfer through airlocks or pass-through hatches or is it possible to skip a grade (e.g., moving from CNC directly to class C) under certain circumstances? 通过气闸或通过式舱口进行材料转移时，是否始终需要严格遵守区域洁净度级联（即遵守洁净室等级的先后顺序），或者在某些情况下是否可以跳级（例如从 CNC 直接转到 C 级）？	Compliance with the cleanroom sequence for the transfer of materials via airlocks or pass-through hatches is expected to be fulfilled for zones A and B (exceptions from this rule are possible for sterility test rooms). For cleanroom areas with lower classification, it is principally feasible for materials to be transferred from one low zone (CNC) through an airlock or pass-through hatch directly into an area with two grades higher classification (grade C area), provided that suitable technical and/or procedural measures are established ensuring fulfilment of the cleanroom specifications in the respective areas. The adequacy of the established systems/procedures needs to be demonstrated by appropriate qualification activities and the results of regular environmental monitoring. The defined measures and the risk analyses on which they are based must be part of the CCS. 对于A区和B区（无菌测试室可例外），通过气闸或通过舱口转移材料时应遵守洁净室顺序。对于分级较低的洁净室区域，只要制定了适当的技术和/或程序措施，确保满足相应区域的洁净室规格，则通过气闸或穿堂风舱口将材料从一个低级区域（CNC）直接转移到一个高两级分级的区域（C级区域）基本上是可行的。需要通过适当的资格认证活动和定期环境监测结果来证明所建立的系统/程序的适当性。所确定的措施及其所依据的风险分析必须是综合控制系统（CCS）的一部分。
5	4.20	What are the expectations for older barrier technology systems that do not meet all the requirements according to the new Annex 1? By when do they have to be replaced or upgraded? 对不符合新附件 1 所有要求的旧屏障技术系统有何期望？何时需要更换或升级？	The company has to perform an in-depth internal evaluation of the current barrier technology and assess whether the installation, its cleanroom background and all related systems/procedures meet the requirements of the new Annex 1 or whether technical measures are required. If necessary, a project has to be initiated for example to upgrade the cleanroom used as background and install additional airlocks. From August 25th 2023, all barrier technology equipment not complying with the revised Annex 1 are considered deficient and deviations will be issued upon findings during inspections. Depending on the CAPA plan and interim risk reducing measures defined, an additional implementation timeline of approx. one year may be acceptable. 公司必须对当前的屏障技术进行深入的内部评估，并评估安装、洁净室背景和所有相关系统/程序是否符合新附件1的要求，或是否需要采取技术措施。如有必要，必须启动一个项目，例如升级用作背景的无尘室并安装额外的气闸。从2023年8月25日起，所有不符合修订后的附件1的阻隔技术设备都将被视为不合格设备，并将在检查中发现后发出偏差通知。根据所定义的 CAPA 计划和临时风险降低措施，额外的约一年实施时间可能是可以接受的。
6	4.20	What is meant in paragraph 4.20 by the need to take into consideration, among others, the “extent of automation” when carrying out CCS related risk assessments of an isolator? 第 4.20 段中说，在对隔离装置进行与二氧化碳捕获和储存有关的风险评估时，除 其他外，需要考虑 '自动化程度'，这是什么意思？	This refers to the inclusion in such CCS risk assessments of an evaluation of all automated functionalities and processes associated with the use of the isolator and the activities taking place in it (from cleaning and disinfection of the equipment, to the transport of materials into the isolator, their handling and the product filling, to the capping and removal of the filled containers). The use of a well-designed, automated, recipecontrolled and possibly robotised system, equipped with appropriate control and alarm systems, can increase the reproducibility of the operations and minimise both errors and manual interventions. Ideally, such risk analyses should already be carried out as part of the design or selection of the isolator system and should be revised or supplemented during the lifecycle of the equipment, as knowledge and experience increases or in the event of changes to be implemented. 这指的是在这种二氧化碳捕获和储存风险评估中纳入对所有自动与使用隔离器有关的功能和过程，以及在隔离器中进行的活动（从设备的清洁和消毒，到材料运入隔离器、材料的处理和产品的灌装，到灌装容器的封盖和移除）。 使用精心设计的、自动化的、受控的，甚至可能是机器人的系统、配备适当的控制和警报系统，可以提高操作的可重复性，最大限度地减少错误和人工干预。理想情况下，此类风险分析应作为隔离系统设计或选择的一部分来进行，并应在设备的生命周期内，随着知识和经验的增长，或在要实施变更时进行修订或补充。
7	4.22	Are manual operations accepted for bio-decontamination? 生物净化是否接受人工操作？	The decontamination process for an isolator should always be an automatic process. However, paragraph 4.22 refers to both RABS and isolators, and manual decontamination processes are most commonly encountered for RABS. Such manual processes must be designed in such a way to be reproducible and to cover the entire surface area of the equipment, and their robustness and effectiveness must be demonstrated by appropriate validation and by regular monitoring. 隔离装置的洗消程序应始终是自动程序。然而，第 4.22段同时提到了RABS和隔离器，RABS最常见的是手工净化程序。这种手工程序的设计必须具有可重复性，并能覆盖设备的整个表面区域，而且必须通过适当的验证和定期监测来证明其稳健性和有效性。
8	4.22	“ 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”. How should this be demonstrated? '还应提供证据证明所使用的清洁剂和生物去污剂不会对 RABS 或隔离器内生产的产品产生不利影响'。应如何证明这一点？	The cleaning or bio-decontamination procedure should include steps designed to effectively remove cleaning agent or disinfectant (including sporicidal agent) residues from direct and indirect product contact surfaces within the RABS/isolator. The effectiveness of these steps should be demonstrated based on validation data. For isolators, validation data should be available to demonstrate that the residual amount of sporicidal agent is below the concentration that could be detrimental to the product quality and stability at the end of the sporicidal cycle. Control mechanisms must be defined to ensure that the conditions prevailing during validation are also maintained during routine production (e.g., compliance with the time after completion of the sporicidal cycle, resp. measurement of the peroxide concentration). The extent to which samples of the surfaces are to be taken during validation and analysed for disinfectant/cleaning agent residues can be defined based on a risk assessment, taking into account the risk of transferring such residues to the product or a product contacting surface of a packaging component. 清洁或生物去污程序应包括旨在有效去除 RABS/隔离器内直接和间接产品接触面上的清洁 剂或消毒剂（包括杀菌剂）残留物的步骤。应根据验证数据证明这些步骤的有效性。对于隔离器，应提供验证数据，以证明杀菌剂的残留量低于杀菌周期结束时可能损害产品质量和稳定性的浓度。必须确定控制机制，以确保在常规生产过程中也能保持验证期间的条件（例如，遵守杀 孢剂周期结束后的时间，以及过氧化物浓度的测量）。 可以根据风险评估来确定在验证过程中对表面取样并分析消毒剂/清洁剂残留的程度，同时考虑到将这些残留转移到产品或包装部件的产品接触表面的风险。
9	4.30	Is it acceptable that for barrier technology systems with unidirectional air flow other air speed and speed measurement positions are defined than those mentioned in Annex 1? 对于单向气流的屏障技术系统，除了附件 1 中提到的位置外，是否还可以定义其他气流速度和速度测量位置？	The most important requirement for barrier technology systems stated in paragraph 4.30 is that the air velocity in unidirectional airflow systems must be defined in such a way that unidirectional and uniform airflow conditions prevail at the working positions where high-risk operations take place, suitable to protect the product and open components (e.g., containers) from contamination. The air speed range of 0.36 - 0.54 m/s is, as stated in the above paragraph itself, merely a guideline value that has been encountered in the pharmaceutical industry for decades. Annex 1, however, clearly allows for the establishment of alternative air speed ranges or measurements at different heights in the system than the working position, provided this is “scientifically justified in the CCS” . It is important that the suitability of the defined airflow conditions is proven by airflow visualisation studies (part of the system qualification) covering the entire system and that these are correlated with the respective defined air speed range at specified height/position. The air speed must be measured continuously during operations and kept within this defined range. 第 4.30 段中对阻隔技术系统最重要的要求是，单向气流系统中的气流速度必须确保在进行高风险操作的工作位置上保持单向和均匀的气流条件，以保护产品和开放式部件（如容器）免受污染。 如上段所述，0.36 - 0.54 m/s 的气流速度范围只是制药行业几十年来一直使用的指导值。 不过，附件 1 明确允许在系统中不同于工作位置的高度确定其他气流速度范围或测量值，但前提是 '在综合控制系统中有科学依据'。重要的是，所定义的气流条件的适用性要通过气流可视化研究（系统鉴定的一部分）来证明，研究要覆盖整个系统，并与指定高度/位置上各自定义的气流速度范围相关联。在运行过程中必须连续测量气流速度，并将其保持在规定范围内。

4.3 Utilities (Annex 1, Chapter 6) 公用工程（附件 1，第 6 章）

Q&A No. 问答编号	Paragraph No. 章节编号	Questions 问题	Answers 答案
10	6.12	Water generation reverse osmosis system: What are the requirements regarding the sanitization (disinfection) of the system? 反渗透制水系统：对系统的消毒有什么要求？	Paragraph 6.12 gives detailed guidance on the requirements. It is important that the system is designed to allow for routine sanitization / disinfection and a procedure is in place defining this regular preventive sanitization or disinfection of the RO-system. It should also include a regular change of membranes. The frequency of sanitization should be determined based on quality risk management principles and on the data gathered during the qualification of the system, and it should be reviewed at least annually taking into consideration the routine monitoring data. The system must continuously be maintained meaning that the sanitization also has be performed when no production is running or when no water is used for production. 第 6.12 段提供了有关要求的详细指导。重要的是，系统的设计应允许进行例行消毒/杀菌，并制定程序，对反渗透系统进行定期的预防性消毒或杀菌。程序还应包括定期更换膜。消毒频率应根据质量风险管理原则和系统鉴定期间收集的数据来确定，并应至少每年审查一次，同时考虑到日常监测数据。 系统必须持续维护，这意味着在不生产或不用水时也必须进行消毒。
11	6.13	What are the sampling requirements for regular ongoing monitoring of Water for Injection? 定期持续监测注射用水的采样要求是什么？	A suitable sampling schedule should be in place to ensure that representative water samples are obtained for analysis on a regular basis. For WFI distribution system sampling plans are more important because microbial control must be much more stringent. In general, water sampling for microbial and bacterial endotoxin testing is expected to occur daily somewhere in the system, with each outlet being sampled periodically to characterize the quality of the water. The use of cold loops requires a much closer microbiological monitoring and special sanitization measures. Quality control sampling locations in the main distribution system should include all POUs, having also process control sampling be located before the first and after the last POU and at other specified worst-case locations. POU sampling plans should rotate through all use points on the system, with the expectation that samples are collected on a daily basis from various use points, and that all use points are sampled on a rotational basis. The loop return should be sampled each day of use of the system in order to provide additional assurance of the quality of water utilized in the manufacturing processes. For WFI, it is an expectation that water samples should be taken daily from a minimum of one POU, with all point of use tested weekly during the qualification phase. The final phase of qualification may form the basis for the ongoing sampling frequencies with the goal of ensuring that the system is maintained in a validated state. However, it has become good industry practice to continue to utilize the same sampling frequency beyond the completion of the performance qualification to collect sufficient historical data in order to justify adjusting the sampling frequency. The use of risk analysis tools coupled with stringent periodic data review may be used to alter the frequency of sampling. Any decrease of the sampling frequency for routine monitoring should be based on historical data and should only occur when a large number of historical data is available to allow statistical analysis. Based on the outcome of analysis of data and on the regular review of the performance of the point of use or the system, and if operational SOPs are in place which ensure also an increase of the sampling frequency if indicated and regular maintenance activities, e.g. for all outlets, a less frequent sampling can be justified. The risk assessment should consider the fact that decreased sampling frequencies also results in a higher number of batches that will be put at risk and a problem may have a serious impact on supply of products for patients. 应制定适当的取样计划，以确保定期获取具有代表性的水样进行分析。 对于 WFI 配水系统来说，取样计划更为重要，因为微生物控制必须严格得多。一般来说，微生物和细菌内毒素检测的水样采集工作应每天在系统的某个地方进行，并定期对每个出水口进行采样，以确定水质的特征。 使用冷循环系统需要更严密的微生物监测和特殊的消毒措施 主输水系统中的质量控制取样位置应包括所有 POU，同时在第一个和最后一个 POU 之前以及其他指定的最坏情况位置进行过程控制取样。POU 取样计划应在系统的所有使用点轮流进行，每天从不同的使用点采集样品，并轮流对所有使用点进行取样。在系统使用的每一天都应对循环回水进行取样，以便为生产过程中使用的水质提供额外的保证。对于 WFI 来说，预计每天应至少从一个 POU 提取水样，并在鉴定阶段每周对所有使用点进行检测。最后的鉴定阶段可作为持续采样频率的基础，目的是确保系统保持在验证状态。 不过，在性能鉴定完成后继续使用相同的取样频率，以收集足够的历史数据，从而证明调整取样频率是合理的，这已成为良好的行业惯例。风险分析工具的使用加上严格的定期数据审查可用于改变取样频率。任何例行监测采样频率的降低都应以历史数据为基础，并且只有在有大量历史数据可供统计分析时才可进行。根据数据分析的结果和对使用点或系统性能的定期审查，如果操作标准作业程序 （SOP）已到位，并确保在有指示的情况下增加取样频率和定期维护活动（如所有出口）， 则减少取样频率是合理的。风险评估应考虑到，减少抽样频率也会导致更多批次的产品面临风险，出现问题可能会严重影响对患者的产品供应。
12	6.19	Where should process gas be monitored? 应在何处监测工艺气体？	The monitoring of process gas should be performed as close as possible before the sterilization filter (the level of contamination before sterilization should be under control to ensure the efficiency of the gas sterilization process). 应尽可能在灭菌过滤器之前对工艺气体进行监测（应控制灭菌前的污染程度，以确保气体灭菌工艺的效率）。

4.4 Personnel/Training (Annex 1, Chapter 7) 人员/培训（附件 1，第 7 章）

Q&A No. 问答编号	Paragraph No. 章节编号	Questions 问题	Answers 答案
13	7.4	This paragraph requires that all personnel accessing grade A and B areas be trained in aseptic gowning and aseptic behaviors. It also stipulates that compliance with the gowning procedure must be confirmed by means of assessments and periodic reassessments on an annual basis, covering both visual and microbiological checks (monitoring of gloved fingers, forearms, etc.). Are these assessments to be covered by staff participation in APS? Paragraphs 9.38 and 9.39 mention staff participation in APS only in the context of staff requalification. Do APSs also have to take place during the initial qualification of employees? Does every employee have to perform every manual intervention in APS in order to be qualified or requalified? 该段规定，所有进入 A 级和 B 级区域的人员都必须接受穿无菌工作服和无菌行为的培训。该段还规定，必须通过评估和每年定期重新评估来确认是否遵守了穿衣程序，包括目视检查和微生物检查（监测戴手套的手指、前臂等）。 这些评估是否包括在员工参与 APS 的范围内？第 9.38 和 9.39 段只在员工重新获得资格的情况下提及员工参与 APS。APS 是否也必须在员工初次获得资格时进行？是否每个员工都必须在 APS 中进行每次人工干预，才能获得资格或重新获得资格？	To ensure product quality, adequate training of employees working in grade B and A areas or involved in aseptic processes (incl. the necessary preparatory activities) is essential. The qualification must be adapted to the respective activities of the single employee and, after initial training (initial qualification), must also include regular requalification / retraining. Annex 1 requires that each employee qualified and involved in aseptic processes participates in a successful APS at least annually (or every six months if the aseptic processes are manual) as part of his requalification. However, Annex 1 is not specific about the scope of the initial employee qualification, but indicates in paragraph 7.4 that the relevant training must cover theory and knowledge transmission as well as practical aspects and that evidence of training effectiveness is required through assessments using both visual and personnel monitoring examinations. Although not explicitly required in Annex 1, the expectation for the initial qualification of an employee for the aseptic area is that practical process simulations, including manual interventions, are carried out under the supervision of qualified trainers/QA and are followed by personnel monitoring as training verification. It is at the discretion of the respective pharmaceutical company to define and justify whether these process simulations need to be conducted separately (but under similar conditions as an APS) or can be integrated within an APS. It is important that the representativeness of the activities to be performed by the trainee for the actual processes is justified and that the simulations cover each critical activity to be carried out by the respective employee. Equivalent representative interventions can be grouped for staff qualification. All operators should perform one intervention per year from each group of equivalent representative interventions. 为确保产品质量，必须对在 B 级和 A 级区域工作的员工进行充分培训，或参与无菌工艺（包括必要的准备活动）的员工必须具备相应的资格。资格认证必须与单个员工的相关活动相适应，在初始培训（初始资格认证）之后，还必须包括定期的再认证/再培训。 附件 1 要求参与无菌工艺的每名合格员工至少每年（如果无菌工艺是手工操作，则每 六个月）参加一次成功的 APS，作为其重新认证的一部分。 然而，附件 1 并没有具体说明员工初始资格的范围，但在第 7.4 段中指出，相关培训必须包括理论和知识传授以及实 践方面，并要求提供培训效果的证据 通过目测和人员监测检查进行评估。 尽管附件 1 中没有明确要求，但对无菌区员工初始资格的期望是，在合格培训师/质 量保证人员的监督下，进行包括人工干预在内的实际工艺模拟，并在随后进行人员监测， 作为培训验证。 各制药公司可自行决定是否需要单独进行这些工艺模拟（但条件应与工艺模拟类似），并说明理由。 APS），也可将其整合到 APS 中。重要的是，受训人员要执行的活动对实际流程的代表性要合理，模拟要涵盖相关员工要执行的每项关键活动。可将具有代表性的等效干预活动进行分组，以便对员工进行资格认证。所有操作人员每年都应从每组具有代表性的等效操作中进行一次操作。

4.5 Production and Specific Technologies (Annex 1, Chapter 8)

Q&A No. 问答编号	Paragraph No. 章节编号	Questions 问题	Answers 答案
14	8.36 & 8.38 / 8.39	Sterilisation: what are the required loading patterns for initial and periodic autoclave (re-) validations? 灭菌：高压灭菌器初始验证和定期（再）验证所需的装载模式是什么？	Initially each loading pattern must be validated. Re-validation of each loading pattern must be done annually. If a suitable worst-case load (the same material, same loading pattern, same cycle) for re-validation (backed up with data) can be identified, not every load of this material needs to be re-validated. A theoretical reference load is not acceptable, as 8.36 states that “each type of load” needs to be validated. 最初必须验证每种装载模式。必须每年对每种装载模式进行重新验证。 如果可以确定一个合适的最坏情况载荷（相同的材料、相同的加载模式、相同的周期）进行重新验证（有数据支持），则不需要对该材料的每个载荷都进行重新验证。理论参考载荷是不可接受的，因为 8.36 规定 '每种载荷 '都需要验证。
15	8.63	Moist heat sterilisation: is it expected that routine re-validation includes a temperature mapping for systems where steam in place is used for sterilization? 湿热灭菌：对于使用蒸汽就地灭菌的系统，常规重新验证是否应包括温度分布图？	Yes, routine (or periodic) validation should include tests providing evidence that the positions used for temperature monitoring throughout the sterilization process are still representative of and correspond to the slowest to heat locations during sterilisation. 是，例行（或定期）验证应包括测试，以证明在整个灭菌过程中用于温度监测的位置仍具有代表性，并与灭菌过程中加热最慢的位置相对应。
16	8.128	Is the sterility of the product-contacting surface of a closed system ensured if the system is opened in a cabinet with laminar airflow (LAF)? 如果在层流气流柜（LAF）中打开封闭系统，是否能确保产品接触面的无菌？	Opening a sterile, closed system should be avoided whenever possible. In general, a closed system that needs to be opened should be returned to the sterile state by carrying out a validated sterilization process (if required, preceded by cleaning). If a sterilisation of the system after opening is not possible, the system’s opening could be performed in a decontaminated isolator (provided that the introduction of the closed system to be opened or relevant parts of it into the isolator does not compromise the isolator’s decontamination status and can be considered covered by successful APS). Opening the system in an LAF with classification A and background B could possibly be an alternative to the isolator but rather to be envisaged in exceptional cases only as the risks of introducing contamination from the environment are higher and require appropriate consideration and risk mitigating measures. 应尽可能避免打开无菌封闭系统。一般来说，需要打开的封闭系统应通过有效的灭菌过程（如有必要，应先进行清洗）恢复到无菌状态。 如果无法在打开系统后对其进行灭菌处理，则可在经过消 毒处理的隔离器中打开系统（条件是将要打开的封闭系统或其相关部分引入隔离器不会危及隔离 器的消毒状态，并可被视为已被成功的 APS 所覆盖）。 在 A 类和 B 类背景的 LAF 中打开系统可能是隔离器的替代办法，但只能在特殊情况下 考虑，因为从环境中引入污染的风险较高，需要适当考虑并采取风险缓解措施。
17	8.128	Are non-aseptic connections allowed to be carried out for coupling closed systems if a sterilization cycle (SIP) occurs prior to use? 如果在使用前进行了消毒循环 (SIP)，是否允许对耦合封闭系统进行非无菌连接？	Yes, such an approach is possible, provided that the SIP process used is appropriately validated. 是的，这种方法是可行的，只要所使用的 SIP 程序经过适当验证。
18	8.128	Is the use of sterile aseptic connectors purchased from qualified suppliers permitted as suitable strategy to connect sterile equipment to each other and may the end-user rely on the sterility documentation (sterilisation validation) provided by the respective supplier? 是否允许使用从合格供应商处购买的无菌无菌连接器作为无菌设备相互连接的适当策略，最终用户是否可以依赖各供应商提供的无菌文件（灭菌验证）？	Provided the supplier of the aseptic connector in question was covered by comprehensive qualification activities and the validation package/data provided by the supplier for the connector (e.g., validation of the gamma irradiation process, data on microbial challenge tests, etc.) have been checked and found to be sound, the end-user can rely on such data, but must cover this equipment and its handling during his manufacturing process APS activities. See also paragraph 4.6.4 on single-use systems. If single-use connectors that are sterilised by the end-user (e.g., by autoclaving) are used for coupling sterile systems, this sterilisation process must be validated. It must also be ensured that single-use connectors are suitable for sterilisation and that the latter does not impact their functionality or integrity (e.g., by causing the material of construction to become more porous). 如果有关无菌连接器的供应商参加了全面的资格认证活动，而且供应商为连接器提供的验证包/数据（如伽马辐照过程的验证、微生物挑战测试数据等）已经过检查并被认定是可靠的，则最终用户 最终用户可以信赖这些数据，但必须在生产过程中对这些设备及其处理进行 APS 活动。另见关于一次性使用系统的第 4.6.4 段。 如果由最终用户消毒（如高压灭菌）的一次性使用连接器用于连接无菌系统，则必须对消毒过程进行验证。还必须确保一次性使用连接器适合灭菌，并且灭菌不会影响其功能或完整性（例如，导致结构材料变得更加多孔）。
19	8.128	Is it considered acceptable to introduce small amounts of product or cells into a sterile closed system with a syringe fitted with a needle through a septum? Can the system be considered closed after piercing of the septum? 用装有针头的注射器穿过隔膜将少量产品或细胞引入无菌封闭系统是否可以接受？ 刺穿隔膜后，系统是否可视为封闭系统？	Such a practice should be avoided for aseptic steps, as piercing a septum with a needle is to be regarded as a breach of the sterile barrier. In aseptic processes where the above approach is used, measures must be taken to re-design and optimise the procedure accordingly. If the process concerned cannot be improved and adapted immediately, consideration should be given, as a temporary measure, to minimise the risk of contamination, as to whether the syringe should be left with the needle inserted in the septum after completion of the material addition and appropriately secured in this position. In addition, it should be considered that the top of the septum (prior to piercing) be protected by a sterile film, which is removed just prior to insertion of the syringe needle to reduce the risk of contaminants on the septum surface entering the process and avoiding treating the septum with a disinfectant, which may also pose a risk of contamination of the product (by disinfectant residues). 在无菌步骤中应避免这种做法，因为用针刺穿隔膜会被视为破坏无菌屏障。在使用上述方法的无菌工艺中，必须采取措施重新设计和优化相应的程序。 如果不能立即改进和调整有关程序，作为临时措施，为尽量减少污染风险，应考虑在完成材料添加后，注射器是否应将针头留在隔膜中，并在此位置适当固定。此外，应考虑在隔膜顶部（穿刺前）贴上一层无菌薄膜，在插入注射器针头前撕下，以减少隔膜表面的污染物进入加工过程的风险，并避免用消毒剂处理隔膜，因为消毒剂残留也可能造成产品污染的风险。
20	8.128	Is tubing welding considered a suitable strategy for aseptically connecting equipment parts maintaining the closed status of a system? 管道焊接是否被认为是无菌连接设备部件以保持系统封闭状态的合适方法？	Welding equipment and processes must be qualified/validated. If such processes are used in sterile or aseptic filling processes, they must be covered also by APS. However, as tubing welding processes are both less monitorable and entail risks of undetected integrity deficiencies, such practices should be avoided and more reliable systems should be used, which should be taken into account whenever possible already during facility and process design. 焊接设备和工艺必须合格/经过验证。如果在无菌或无菌灌装过程中使用此类工艺，则也必须遵守《操作规程》。 然而，由于管道焊接工艺的可监控性较低，且存在未被发现的完整性缺陷的风险，因此应避免此类做法，而应使用更可靠的系统。
21	8.129	Closed systems: in case of using single-use systems, can system integrity tests performed by the respective suppliers be leveraged without having to carry out own tests? 封闭系统：在使用一次性使用系统的情况下，是否可以利用相关供应商进行的系统完整性测试，而无需自己进行测试？	Whenever possible, the integrity of critical single-use systems should be tested by the enduser on site (i.e., before use in production). It is acknowledged that such an integrity test, e.g., by means of a pressure hold test using an inert gas, is difficult to establish for small single-use bags/containers and is also only reliable to a limited extent. However, the decision in this respect must be justified by well-founded measures and considerations, be verified by risk assessments and must be included in the CCS. The possibility of relying for single-use materials (such as bags) on integrity test results provided by the respective suppliers requires a detailed assessment of the situation, taking into account, among other things, the criticality of possible integrity deficiencies on the manufacturing processes/product quality and their detection probability during the process. The adoption of integrity results from the vendor requires an in-depth qualification of the supplier and must also take into account the risks of subsequent damage to the single-use material during its delivery and installation in production. 只要有可能，关键一次性使用系统的完整性应由最终用户进行现场测试（即在用于生产之前）。我们承认，对于小型一次性使用袋/容器来说，很难进行这种完整性测试，例如使用惰性气体进行保压测试，而且这种测试的可靠性也很有限。不过，这方面的决定必须有充分的措施和考虑，并通过风险评估加以验证，而且必须纳入综合控制系统。 对于一次性使用材料（如包装袋），是否可以依赖相关供应商提供的完整性测试结果，需要对情况进行详细评估，除其他事项外，还要考虑到可能存在的完整性缺陷对生产流程/产品质量的影响及其在生产流程中的检测概率。 采用供应商提供的完整性结果需要对供应商进行深入的资格审查，还必须考虑到一次性使用材料在交付和安装到生产过程中的后续损坏风险。
22	8.134	Single-use systems: what are the expectations placed on the assessment of such suppliers and what must it comprise? 一次性使用系统：对此类供应商的评估有何要求，必须包括哪些内容？	The supplier assessment should be understood as a comprehensive qualification of the singleuse systems (SUS) supplier. This assessment/qualification should cover not only the supplier delivering the SUS but in particular the SUS manufacturer (or each relevant manufacturing site, if the SUS in question is produced at several sites) as well as any sub-contractors involved in critical services or processes (e.g., sterilisation of the SUS). The supplier assessment/qualification should be carried out in parallel with the evaluation of the SUS material and should play a crucial role in the SUS selection decision. For all SUS that the end-user intends to use in his manufacturing process and that will have direct contact with the product, intermediates, process solutions or starting materials/raw materials, a Quality Agreement should be concluded with the respective supplier. This Quality Agreement should cover the SUS specifications as well as quality relevant service conditions (e.g., requirement to manufacture SUS in cleanrooms) and regulate, among other things, the terms relevant for the notification of planned changes and their approval by customers, the procedures in the event of major/critical deviations impacting delivered SUS, the terms in case of customer complaints and the oversight responsibility for sub-contractors. Supplier qualifications must include an assessment of the supplier's quality systems, a comprehensive review of all relevant technical documentation received (incl. for example drawings, documentation of components used such as filters, aseptic connectors, tubings etc., certificates and validation/study packages), and audits. It is expected that audits cover all systems, relevant processes and control strategies (e.g., sterilisation process and its validation, subcontractor qualification, etc.) considered critical for the respective SUS and these contents must be comprehensibly documented in the respective audit report. 供应商评估应被理解为对一次性使用系统（SUS）供应商的全面鉴定。这种评估/资格鉴定不仅应包括提供一次性使用系统的供应商，还应特别包括一次性使用系统的制造商（或每个相关的生产场所，如果有关一次性使用系统是在多个场所生产的话），以及参与关键服务或流程（如一次性使用系统的灭菌）的任何分包商。供应商评估/资格鉴定应与 SUS 材料评估同时进行，并应在 SUS 选择决策中发挥关键作用。 对于最终用户打算在其生产过程中使用的所有 SUS，以及将与产品、中间体、工艺溶液或起始材料/原材料直接接触的 SUS，应与相关供应商签订质量协议。该质量协议应涵盖 SUS 规格以及与质量相关的服务条件（例如，要求在洁净室中生产 SUS），并规定计划变更通知和客户批准的相关条款、出现影响已交付 SUS 的重大/关键偏差时的程序、客户投诉时的条款以及对分包商的监督责任等。 供应商资格审查必须包括对供应商质量体系的评估、对收到的所有相关技术文件（包括图纸、所用组件（如过滤器、无菌连接器、管子等）的文件、证书和验证/研究包）的全面审查以及审核。预计审核将涵盖所有系统、相关流程和控制策略（如灭菌流程及其验证、分包商资质等），这些内容被认为对各自的 SUS 至关重要，必须在各自的审核报告中以可理解的方式记录下来。
23	8.138	What aspects should be taken into account by the end-user when determining the acceptance criteria of the respective SUS and in which form should they be specified? 最终用户在确定各自 SUS 的验收标准时应考虑哪些方面，应以何种形式加以规定？	Acceptance criteria should be defined taking into account the intended use of the particular SUS in the manufacturing process, the criticality of its use/impacted process, existing process knowledge, as well as available SUS experience. Acceptance criteria should encompass quality aspects (e.g., sterility, biocompatibility, visible particles testing by compendial method, integrity tests, certificates, etc.), functionality (e.g., inserts and components required, temperature resistance in operating range, autoclaving or freezing resistance, chemical compatibility, substainable pressure, packaging requirements, etc.) as well as validation/qualification requirements to be fulfilled by the SUS and its supplier. According to Annex 1, paragraph 8.132, the use of SUS and the associated risks should be also assessed as part of the Contamination Control Strategy, taking into account the fragile nature and potential complexity of the SUS in question, possible interactions of the SUS surfaces with the product, risks associated with manual operations/connections and risks of holes or particle contaminations. The resulting conclusions from these assessments and any risk mitigating measures should be taken into account, if appropriate, when establishing the SUS acceptance criteria and the expectations placed on the SUS suppliers. To comply with the requirements of paragraph 8.138, according to which the conformity of the SUS with the approved specification has to be checked upon good receipt, the quality requirements should be defined in a written specification (including or referencing a technical drawing of the material). The other expectations regarding the functionality of the SUS or the expected validation / qualification/study package to be made available by the supplier and to be agreed with the supplier, can be defined in another document, such as a SUS user requirement document, an annex to the Quality Agreement, or similar. 验收标准的定义应考虑到特定 SUS 在生产过程中的预期用途、其使用/受影响过程的关键性、现有的过程知识以及现有的 SUS 经验。验收标准应包括质量方面（如无菌性、生物相容性、按药典方法进行的可见微粒测试、完整性测试、证书等）、功能方面（如所需的插入物和组件、工作范围内的耐温性、耐高压或冷冻性、化学相容性、可承受的压力、包装要求等）以及 SUS 及其供应商应满足的验证/资格要求。根据附件 1 第 8.132 段，SUS 的使用及相关风险也应作为污染控制策略的一部分进行评估，同时考虑到 SUS 的易碎性和潜在复杂性、SUS 表面与产品可能产生的相互作用、与手工操作/连接相关的风险以及孔洞或颗粒污染的风险。在制定 SUS 验收标准和对 SUS 供应商的期望时，应酌情考虑这些评估得出的结论和任何降低风险的措施。根据第 8.138 段的要求，在收货时必须检查 SUS 是否符合核准的规格，为遵守这 一要求，应在书面规格中规定质量要求（包括或参考材料的技术图纸）。其他关于 SUS 功能的其他预期或供应商提供并与供应商商定的预期验证/鉴定/研究包，可在另一份文件中定义，如 SUS 用户要求文件、质量协议附件或类似文件。
24	8.138 & 8.134	What should the incoming goods inspection at the end-user include to comply with paragraph 8.138 & 8.134? 在最终用户处进行的进货检查应包括哪些内容，才能符合第8.138 & 8.134?	Due to the special nature of SUS and their delivery in packaging that serves to protect them from damage but does not allow for a full visual inspection of the materials, the scope of a feasible routine incoming inspection program upon receipt is generally very limited. Immediately upon receipt, in accordance with paragraph 8.138, an initial documented inspection of the shipment should be performed, consisting primarily of a review of the documents provided by the supplier, a visual check of the integrity of the outer packaging, label printing, and a reasonably cursory verification of the contents of the shipment (without complete unpacking of the SUS to avoid the risk of damages). On the basis of a positive result of this first incoming check, the SUS can be released, allowing its transfer to the production area to be subjected to a more thorough examination. This examination must consist at least of a deep visual inspection of the SUS by qualified employees according to an established procedure, and the results of which must be documented as part of the batch record. The visual inspection should include verification of the compliance of the SUS with approved technical drawings, the presence of gamma irradiation points (if applicable and as evidence of the sterilization), and a visual examination for integrity (e.g., inspection of the welds, connectors, absence of critical scratches, etc.) as well as for the absence of particulates. If technically practicable and indicated, the integrity of the single-use system should be verified by means of a pressure hold test. 由于 SUS 的特殊性，以及 SUS 在交付时的包装可以保护其免受损坏，但无法对材料进行全面的目视检查，因此可行的收货时例行进货检查程序的范围通常非常有限。 根据第 8.138 段的规定，在收到货物后，应立即对货物进行有记录的初步检查，主要包括审查供应商提供的单据、目视检查外包装的完整性、标签印刷和对货物内 容进行合理的粗略核查（不完全拆开 SUS 包装，以避免损坏的风险）。 如果第一次进货检查结果良好，则可以放行 SUS，将其转运到生产区进行更彻底的检查。这种检查必须至少包括由合格员工按照既定程序对 SUS 进行深度目视检查，检查结果必须作为批次记录的一部分记录在案。目视检查应包括核查 SUS 是否符合经批准的技术图纸、是否存在伽马辐照点（如适用，并作为灭菌的证据）、目视检查是否完整（如检查焊缝、连接器、是否存在关键划痕等）以及是否存在微粒。如果技术上可行并有说明，应通过压力保持测试来验证一次性使用系统的完整性。
25	8.134	Is it considered acceptable that some study or validation data provided by SUS suppliers (e.g., validation packages incl. sterilization or material chemical and biological compatibility data) are incorporated by the end-user into his own assessments without the need to carry full stuies/validations on his own? 最终用户将 SUS 供应商提供的某些研究或验证数据（如包括消毒或材料化学和 生物兼容性数据在内的验证包）纳入自己的评估，而无需自己进行全面的研究/ 验证，这种做法是否可以接受？	When looking at the wording in the paragraphs on single-use systems (SUS), it can be concluded that Annex 1 allows principally the adoption by the end-user of data received from qualified suppliers. However, this requires that the en user confirms through a detailed review of the respective documentation that its contents meet the user's standards and that the conditions used by the suppliers when generating the data are representative (or worst-cases) for its own actual production conditions. The extent of the enduser's own studies/verifications or validations activities depends on the representativeness of the supplier data, the criticality of the intended SUS use in the process, established control strategies at the end-user which allow detection of possible SUS deficiencies (e.g.,pressure hold test, extensive program of microbiological testing during the process), etc. For example, an end-user operating in the biotech area must verify with own studies or assessments whether possible leachables emitted from the films of a single-use bioreactor can negatively affect the growth of cells and it is also the responsibility of the end-user to verify or provide data to prove whether absorption effects of its product on the SUS surface are possible, resulting in an impact on product quality (see paragraph 8.132, «…These risks include but are not limited to: i. the interaction between the product and product contact surface (such as adsorption, or leachables and extractables) »). When SUS are used in the sterile production, it is mandatory that they are covered by APS, as required in paragraph 8.139. For cell culture (or fermentative) processes, the end-user should evaluate the need to perform a process simulation before starting routine production to confirm the suitability, integrity, and handling of the SUS equipment. 从有关一次性使用系统（SUS）的段落中的措辞可以得出结论，附件 1 主要允许最终用户采用合格供应商提供的数据。不过，这要求最终用户通过详细审查相关文件，确认其内容符合用户的标准，并确认供应商在生成数据时所使用的条件对其实际生产条件具有代表性（或最坏情况）。最终用户自身的研究/核查或验证活动的程度取决于供应商数据的代表性、工艺中 SUS 预期用途的关键性、最终用户已建立的可检测 SUS 可能缺陷的控制策略（例如，压力保持测试、工艺过程中的大量微生物测试程序）等。 例如，在生物技术领域开展业务的最终用户必须通过自己的研究或评估来验证一次性使用生物反应器薄膜中可能释放的可浸出物是否会对细胞的生长产生负面影响，最终用户也有责任验证或提供数据来证明其产品是否可能对 SUS 表面产生吸收效应，从而对产品质量造成影响（见第 8.132 段，'......这些风险可能会影响产品的质量'）。132 段，'......这些风险包括但不限于：i. 产品与产品接触面之间的相互作用（如吸附、可浸出物和可萃取物）'）。 在无菌生产中使用 SUS 时，必须按照第 8.139 段的要求将其纳入 APS 的覆盖范围。对于细胞培养（或发酵）工艺，最终用户应评估是否需要在开始常规生产前进行工艺模拟，以确认 SUS 设备的适用性、完整性和处理。
26		Do end users have to carry out their own extractable studies or can they use the supplier's data and when is it necessary to execute leachable studies? 最终用户是否必须自行开展可萃取性研究，还是可以使用供应商的数据？	Most SUS suppliers provide comprehensive extractable studies packages to end-users. In recent years, efforts have been undertaken by international industry working groups to harmonize and standardize the conditions for extractions and analysis of extractables. Additionally, many suppliers also provide certificates covering the product contact films, e.g., Biological Reactivity Test in Vivo per USP <88>, Class VI. It is expected that based on the package of extractables data obtained, the end-users evaluate the adequacy of the data provided, potentially “add together” data from different SUS components, and define the need for additional extractables studies to simulate process-specific worstcase conditions and perform health safety assessments, as appropriate. The decision to carry out leachable studies with the respective product is usually based on a comprehensive evaluation of the possible risks of administering leachables in doses that may be of concern when using the respective drug product. In addition to the results of the extractable data and any resulting safety assessments, the decision regarding the need for a leachable study should take into account the route of administration of the respective drug (e.g., oral, parenteral, subcutaneous), the dosing frequency to a patient, the use of the respective SUS in the process (e.g., use in early or late manufacturing step) and the contact time of the process solution/product with SUS surface. Based on an assessment of such aspects, the company may justify that no leachable studies are performed for products that are still in the clinical phase and/or are only administered infrequently (e.g., vaccines). Since extractable/leachable studies are part of the filing dossier for marketing authorization, it is necessary to align the strategy with the requirements of the marketing authorization or, if necessary, with the respective regulatory authority. 大多数 SUS 供应商向最终用户提供全面的萃取物研究包。近年来，国际行业工作组一直在努力协调萃取和萃取物分析的条件并使之标准化。此外，许多供应商还提供涵盖产品接触膜的证书，例如根据 USP <88>, Class VI 进行的体内生物反应性测试。 预计最终用户将根据所获得的整套萃取物数据，评估所提供数据的充分性，可能将来自不同 SUS 组成部分的数据 '加在一起'，并确定是否需要进行额外的萃取物研究，以模拟特定工艺的最坏情况，并酌情进行健康安全评估。 在决定对相关产品进行可浸出物研究时，通常会对使用相关药物产品时可能出现的可浸出物剂量风险进行综合评估。除了可提取数据的结果和由此产生的任何安全性评估外，在决定是否需要进行可浸出物研究时，还应考虑到相关药物的给药途径（如口服、肠外、皮下注射）、患者的给药频率、相关 SUS 在工艺中的使用（如在早期或晚期生产步骤中的使用）以及工艺溶液/产品与 SUS 表面的接触时间。 在对这些方面进行评估的基础上，对于仍处于临床阶段和/或仅不经常使用的产品（如疫苗），公司可以证明不进行可浸出研究是合理的。由于可提取/可浸出研究是上市许可申报材料的一部分，因此有必要根据上市许可的要求调整策略，或在必要时与相关监管机构保持一致。
27	8.80	Is it expected that there are two redundant sterilizing filtration steps in the process before aseptic filling? 在无菌灌装之前的流程中是否会有两个多余的灭菌过滤步骤？	Annex 1 encourages an additional filtration through a sterile sterilising grade filter, as close to the point of fill as possible. The installation of such a redundant sterile filter significantly reduces the risk of a product quality impact in the event of a failed filter integrity test, which is why this risk-minimising measure is to be considered state of the art process and should be used especially for new processes. The risks and impacts of filter integrity failures of prefill point sterile filters should be assessed as part of the CCS evaluations and the decision not to install a redundant sterilising filter be justified in the CCS. Even in the case of using two sterilising filters, any filter integrity failure that may have occurred should be investigated. 附件 1 鼓励在尽可能靠近灌装点的地方用无菌消毒级过滤器进行额外过滤。安装这种多余的无菌过滤器可大大降低过滤器完整性测试失败时影响产品质量的风险，因此这种风险最小化措施被认为是最先进的工艺，尤其应在新工艺中使用。 作为中央监控系统评估的一部分，应评估预填点消毒过滤器完整性故障的风险和影响，并在中央监控系统中说明不安装多余消毒过滤器的决定的理由。 即使在使用两个消毒过滤器的情况下，也应调查可能发生的任何过滤器完整性故障。
28	8.83 / 8.84	Paragraph 8.83 makes reference to the relevant Pharmacopeia requirements in relation to the validation of sterile filtration of fluids. Which paragraph of the Pharmacopeia should be considered for this purpose? 第 8.83 段提到《药典》中关于液体无菌过滤验证的相关要求。为此应考虑药典中的哪一段？	Relevant guidance can be found in Ph. Eur. 5.1.1, paragraph “ Membrane filtration/Filtration effectiveness” and in guideline EMA/CHMP/CVMP/QWP/850374/2015. Useful details and expected data/methods can also be found in PDA TR26 “Sterilizing filtration of liquids” . 相关指南见 Ph. Eur.5.1.1，'膜过滤/过滤效果 '段和 EMA/CHMP/CVMP/QWP/850374/2015 号指南。 PDA TR26 '液体灭菌过滤 '中也提供了有用的详细信息和预期数据/方法。
29	8.91 / 8.92 / 8.93	Is a pre-use / post-sterilisation integrity testing (“PUPSIT”) of sterilising grade filters used in aseptically processes mandatory? 是否必须对无菌流程中使用的灭菌级过滤器进行使用前/灭菌后完整性测试（'PUPSIT'）？	The expectation is that PUPSIT be applied to verify the integrity of the sterilized filter assembly. However, paragraph 8.87 allows some flexibility in justified cases supported by risk analysis and covered in the CCS. 我们希望使用 PUPSIT 来验证灭菌过滤器组件的完整性。 然而，第 8.87 段允许在有风险分析支持和综合传播战略涵盖的合理情况下有一定的灵活性。

4.6 Environmental & Process monitoring (Annex 1, Chapter 9)

Q&A No. 问答编号	Paragraph No. 章节编号	Questions 问题	Answers 答案
30	9.4	What is deemed regularly (“These risk assessments should be reviewed regularly”)? How often does the risk assessment need to be reviewed? 什么是定期进行的（“这些风险评估应定期进行审查”）？风险评估需要多久被审查一次？	It is not possible to give definitive guidance here, because, as ICH Q9 (R1) states, the frequency of Risk Review should be based on the level of risk. The frequency or timing of a Risk Review exercise may be based on the type and number of risks identified during an earlier Risk Assessment exercise, and on the extent of risk control that was required to mitigate risks. It may also depend on the level of uncertainty (i.e. lack of knowledge) that was present during an earlier risk assessment. The higher the level of uncertainty in relation to risk estimates and the related risk-based decisions, the greater the need to review those estimates and decisions at an early timepoint once such uncertainties have been reduced. An environmental monitoring trend report will be compiled every year and depending on the results, the risk assessment might be reviewed. It should be assessed annually if the review of the risk assessment is required. Swissmedic recommends to review the risk assessment regularly, e.g. for a new plant it is recommended to reassess the RA after one year when more experience and knowledge have been gained. 在此不可能给出明确的指导，因为正如 ICH Q9 (R1) 所述，风险审查的频率应基于风险水平。风险审查工作的频率或时间可能基于先前的风险评估工作中确定的风险类型和数量，以及为降低风险所需的风险控制程度。它还可能取决于先前风险评估中存在的不确定程度（即缺乏知识）。与风险估计和基于风险的相关决定有关的不确定程度越高，就越有必要在不确定程度降低后尽早审查这些估计和决定。 每年将编制环境监测趋势报告，并根据结果对风险评估进行审查。如果需要对风险评估进行审查，则应每年进行一次评估。瑞士美迪公司建议定期审查风险评估，例如，对于新工厂，建议一年后在获得更多经验和知识后重新评估风险评估。
31	9.9	When do we expect more stringent action limits? 我们何时才能期待更严格的行动限制？	More stringent action limits might be necessary if the trend data shows very low levels of detection of total particles and viable particles with no action limit excursions over a longer time period (e.g. one year). 如果趋势数据显示总微粒和可存活微粒的检测水平非常低，且在较长时间内（如一年）未出现行动限值超标，则可能有必要制定更严格的行动限值。
32	9.10	What statistics do we expect for establishing alert levels? 在确定警报级别时，我们需要哪些统计数据？	For a new process where limited data and experience for environmental monitoring data is available, it is acceptable e.g., to calculate the alert level limit based as 50% of the action level limit. When more data becomes available the alert level limits should be statistically from the environmental monitoring data to ensure that the alert setting takes into account its own recent historical behaviour. Traditionally the “2 or 3 standard deviation rule” (alert level = Average value + 2 x SD) which assumes the data is normally distributed, has been applied. As environmental monitoring data are usually not normally distributed, other statistical approaches such as a nonparametric approach based on 99.9Th or 99.99th percentiles, a non parametric tolerance limit approach, or a cutoff Value approach (e.g., at 59th or 99th percentiles) should be used. Alert level limits should be reviewed regularly by the company and be adapted, if necessary, based on the actual performance. Performance based alert levels that are well below the action limits should be considered as a confirmation of solid microbial control of the environment. . Test for interferences to be addressed, e.g., by disinfectants, materials or product Operational Approach: Implementation / Alarm Handling Concept Supportive data: Collection and evaluation of data in a production area grade C and D Identification of microorganisms must be performed as it is essential to determine the (possible) root cause of a contamination and evaluate the risk of the contamination for the drug product. If an action limit exceedance occurs, the agar plate from the system must be incubated in order to isolate associated CFUs and to allow identification of species for further investigation and impact assessment of product quality. 对于环境监测数据和经验有限的新工艺，可以接受的做法是，将警戒水平限值计算为行动水平限值的 50%。当获得更多数据时，应根据环境监测数据对警报水平限值进行统计，以确保警报设置考虑到其最近的历史行为。 传统上，'2 或 3 标准差规则'（警戒水平 = 平均值 + 2 x 标准差）假定数据呈正态分布。 由于环境监测数据通常不呈正态分布，因此应采用其他统计方法，如基于第 99.9 个百分位数或第 99.99 个百分位数的非参数方法、非参数容限方法或截止值方法（如第 59 个百分位数或第 99 个百分位数）。 公司应定期审查警报级别限制，必要时根据实际情况进行调整。基于性能的警报级别如果远低于行动限值，则应视为对环境微生物控制的确认。 .检测需要处理的干扰，如消毒剂、材料或产品的干扰 操作方法：实施/警报处理概念 辅助数据：在 C 级和 D 级生产区收集和评估数据 必须进行微生物鉴定，因为这对于确定污染的（可能）根本原因和评估污染对药品的风险至关重要。如果出现行动限值超标的情况，则必须对系统中的琼脂平板进行培养，以分离出相关的 CFU，并对物种进行鉴定，以便进一步调查和评估对产品质量的影响。
34	9.34	What means “frequency” here? Absolute number of interventions or how often they occur during a certain time interval? 这里的 '频率 '是指什么？是干预的绝对次数，还是在某个时间间隔内干预发生的频率？	Frequency means that the absolute number of interventions that occur during the routine aseptic process should be included in the APS. 频率是指在常规无菌流程中发生的干预的绝对数量，应纳入 APS。
35	9.34	What interventions should be included in the APS for the annual operator’s requalification? 年度操作员重新认证的 APS 中应包括哪些干预措施？	Each operator should perform each intervention. The worst case must be covered, which means that the interventions are independent of the lot size and the duration of the production. See in more detail in the Chapter above about Personnel (Annex 1, paragraph 7.4). 每个操作员都应执行每次干预。必须涵盖最坏的情况，这意味着干预措施与批量大小和生产持续时间无关。更多详情请参见上文有关人员的章节（附件 1，第 7.4 段）。
36	9.36ii	What does “same container/closure configuration” mean? 相同的容器/封闭配置 '是什么意思？	“Same container/closure configuration” refers to the dimensions, (e.g. diameter of opening) shape and material of the container and closure, like e.g. vial/stopper. E.g. has a stopper for lyophilisation a different form than a stopper for liquid products, this is therefore considered a different container/closure system. '相同的容器/封口结构 '是指容器和封口（如小瓶/瓶塞）的尺寸（如开口直径）、形状和材 料。例如，用于冻干的瓶塞与用于液体产品的瓶塞形式不同，因此被视为不同的容器/封闭系统。
37	9.36ii	There is a filling line with subsequent lyophilisation. Can the liquid filling with subsequent lyophilization be considered as worst case, so that APS of liquid filling with lyophilization would cover as well liquid filling process without lyophilization? 有一条随后进行冻干的灌装线。液体灌装和后续冻干是否可视为 在最坏的情况下，有冻干功能的液体灌装的 APS 是否也包括无冻干功能的液体灌装过程？	No, liquid filling and lyophilisation are different processes on the same line, with different paths. 不，液体灌装和冻干是同一条生产线上的不同工序，有不同的路径。
38	9.36ii	When can a bracketing or matrix approach be applied? 何时可以采用括号法或矩阵法？	If equivalence can be shown between e.g. glassware and stoppers a bracketing approach can be applied for the APS. New materials must be validated and an APS is part of the validation. 如果可以证明玻璃器皿和瓶塞之间的等效性，则可以对 APS 采用括号法。新材料必须经过验证，而 APS 是验证的一部分。
39	9.36xii & xiii	Does the APS of campaign manufacturing require the simulation of the maximal number of batches and duration of a campaign? 批量生产的 APS 是否需要模拟批量生产的最大数量和持续时间？	This is a complex question and the scenario depends on many factors. 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 the campaign duration does not pose any risk. The start of campaign (including aseptic assemblies if the case) AND end-of-campaign studies should be conducted in any case. 这是一个复杂的问题，方案取决于许多因素。应考虑设计和执行过程模拟，以便模拟与活动开始和结束相关的风险，并证明活动持续时间不会造成任何风险。在任何情况下，都应进行活动开始（包括无菌装配，如果有的话）和活动结束研究。
40	9.46	Can we differentiate between 1 CFU and >1 CFU like in ISO 134081 (2015) for 5’000 10’000 and > 10’000 units filled: if 1 CFU is detected, investigation, and consideration of one APS, if > 1 CFU, investigation, corrective measures and repetition of validation with 3 APS runs? 能否像 ISO 134081 (2015) 中的 5'000 一样，区分 1 CFU 和 >1 CFU？ 10'000 和 > 10'000 个填充单位：如果检测到 1 个 CFU，则进行调查，并考虑一次 APS；如果 > 1 个 CFU，则进行调查，采取纠正措施，并通过 3 次 APS 运行重复验证？	No. The new Annex 1 is stricter than the ISO 134081 (2015). Any contaminated unit with a contamination > 0 CFU results in a failed APS and actions according to chapter 9.46 should be followed. 新附件 1 比 ISO 134081 (2015) 更严格。任何污染大于 0 CFU 的污染单元都会导致 APS 不合格，应按照第 9.46 章的规定进行处理。
41	9.46	With identification of root cause and corrective actions implemented, would it be acceptable to resume production (with batches at risk if a positive) prior to the 14-day reads off test and completion of successful growth promotion? Release of batches could only resume after completion of successful revalidation (3x APS)? 确定了根本原因并实施了纠正措施后，是否可以在 14 天读取关闭测试和成功完成生长促进之前恢复生产（如果呈阳性，则批次有风险）？只有在成功完成再验证（3 倍 APS）后，才能恢复批量放行？	No, as it clearly states, that PRODUCTION should resume only after completion of successful revalidation (9.46 vii) 否，因为它明确规定，只有在成功完成重新验证后才能恢复生产（9.46 vii)

4.7 Quality Control (QC) (Annex 1, Chapter 10)

Q&A No. 问答编号	Paragraph No. 章节编号	Questions 问题	Answers 答案
42	10.1	To support the design of manufacturing activities, environmental monitoring regime etc., Annex 1 requires that personnel with appropriate training and experience in microbiology and sterility assurance should be available. What is considered appropriate training and experience? 为支持生产活动和环境监测制度等的设计，附件 1 要求应配备在微生物学和无菌保证方面接受过适当培训并具有相关经验的人员。什么是适当的培训和经验？	Microbiological knowledge (incl. sterility assurance) can be acquired by education, training and experience. The best prerequisite for the involvement of a person as an expert, for example in CCS assessments, the definition of resulting measures or in investigations on microbial contaminations, is an education (in particular a university degree or an equivalent diploma e.g. an institution of higher technical education) in the field of microbiology (or possibly other natural sciences, or medicine). However, a good understanding of the manufacturing processes concerned is also required. 微生物学知识（包括无菌保证）可以通过教育、培训和经验获得。 作为专家参与二氧化碳捕获和储存评估、制定相应措施或微生物污染调查等工作的最 佳前提条件是拥有微生物学（或可能是其他自然科学或医学）领域的教育背景（特别是大 学学位或同等文凭，如高等技术教育机构）。 不过，还需要对相关生产工艺有很好的了解。
43	10.2	What limits do we expect for specifications for raw materials, components and products? What is typical? 我们对原材料、部件和产品规格的要求有哪些限制？ 什么是典型？	The need for microbiological testing of raw materials and the limits to be defined for such testing should take into account the nature of the raw materials (e.g., if of biological origin and whether they can be considered growth promoting) and their use in the respective process. The relevant chapters and monographs in the Pharmacopeia, the requirements as defined in the marketing authorisation and other regulations should be considered. Raw materials, components and products and their handling should be assessed as part of the CCS. The specifications should be justified. 对原料进行微生物检测的必要性以及为这种检测确定的限度应考虑到原料的性质 （如是否源于生物，是否可被视为促进生长）及其在相关工艺中的用途。应考虑《药典》中的相关章节和专论、上市许可中规定的要求及其他法规。 原材料、部件和产品及其处理应作为综合控制系统的一部分进行评估。 规格应说明理由。
44	10.3	Should bioburden be tested on each batch of raw material as incoming control AND on the compounding solution in which it is formulated before sterile filtration? 是否应对作为进货控制的每批原料进行生物负载测试，并在无菌过滤前对 配制的复配溶液进行生物负载测试？	Yes 是
45	10.6 iii	What does “different lyophilization loads” actually mean? First and last? Different lyophilizers? Worst cases? Does that mean each sample from a different lyophilizer or samples from different batches in the same lyophilizer? 不同的冻干负荷 '究竟是什么意思？第一次和最后一次？不同的冻干机？最差情况？是指来自不同冻干机的每个样品，还是来自同一冻干机不同批次的样品？	Lyophilization load means loads for each lyophilizer for each batch, if e.g. more than one lyophilizer is used. 冻干负荷是指每个冻干机对每个批次的负荷，如果使用的冻干机不止一个。
46	10.10	How should situations for products with short shelf life be handled when data exceeds the established limits (including OOS for sterility, see 10.) only after product batch certification? 在产品批次认证后，如果数据超出规定限值（包括无菌 OOS，见 10.），应如何处理保质期短的产品？	A procedure should be in place in case a postrelease OOS should be obtained to inform physicians, patient and health authorities, to assess the risk for the patient and to define remediation steps as needed. See also Annex 3: 45 and 46 应制定一套程序，以备在释放后出现 OOS 时通知医生、病人和卫生当局，评估病人面临的风险，并根据需要确定补救措施。 另见附件 3：45 和 46

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