重磅，瑞士药监局 发布 EU GMP附录1《无菌药品生产》官方解读！

近日，瑞士药监局发布了EU GMP附录1《无菌药品生产》（同时也是PIC/S和WHO GMP附录1）的解读文件，该文件侧重于新版EU、PIC/S和WHO GMP附录1的一些最重要的变化，也涵盖了长期以来反复引起问题的方面。反映了检查员对这些主题的一般意见，并在无菌药品制造商检查期间提供支持。

文件包含内容如下：

1 Purpose and scope

目的和范围

2 Basics

基本情况

3 Definitions and abbreviations

定义和缩写

4 Interpretation: Questions and Answers

解读：问答

4.1 Scope (Annex 1, Chapter 1)

范围（附录1，第1章）

4.2 Premises (Annex 1, Chapter 4)

厂房（附录1，第4章）

4.3 Utilities (Annex 1, Chapter 6)

公用系统（附录1，第6章）

4.4 Personnel/Training (Annex 1, Chapter 7)

人员/培训（附录1，第7章）

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

生产和特定技术（附录1，第8章）

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

环境和过程监测（附录1，第9章）

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

质量控制（QC）（附录1，第10章）

5 Changes to the previous version

对先前版本的变更

在厂房设施方面，关于是否必须严格遵循洁净梯度，是否允许从一般区（CNC区域）直接进入C级，文件给出了意见：

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?

是否总是要求严格遵守区域洁净度梯度（即，按照洁净室级别的顺序）通过气闸或传递舱进行物料传递，或者在某些情况下是否可以跳过一个级别（例如，从CNC直接进入到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级和B级，通过气闸或传递舱传递物料要求符合洁净室梯度（无菌检查室可能例外）。对于级别较低的洁净室区域，物料通过气闸或传递舱直接转移到高两个级别的区域（C级区域）基本上是可行的，前提是建立了适当的技术和/或程序措施，确保满足相应区域的洁净室规。需要通过适当的确认活动和定期环境监测的结果来证明已建立的系统/程序的充分性。所定义的措施及其所依据的风险分析必须是CCS的一部分。

文件提及对于不能满足新版附录1所有要求的旧屏障技术（RABS或隔离器）系统，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/程序是否符合新版附录1 的要求，或者是否需要采取技术措施。如有必要，必须启动一个项目，例如升级背景洁净室并安装额外的气闸。从 2023 年8月 25 日起，所有不符合新版附录 1 的屏障技术设备均被视为有缺陷，并将在检查期间发现偏差（缺陷）时发布偏差（缺陷）。根据CAPA计划和确定的临时风险降低措施，可以接受大约一年的额外实施时间表。

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?

对于不能满足新版附录1所有要求的旧屏障技术系统，有何期望？什么时候必须更换或升级它们？

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 com plying 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/程序是否符合新版附录1 的要求，或者是否需要采取技术措施。如有必要，必须启动一个项目，例如升级背景洁净室并安装额外的气闸。从 2023 年 8 月 25 日起，所有不符合新版附录 1 的屏障技术设备均被视为有缺陷，并将在检查期间发现偏差（缺陷）时发布偏差（缺陷）。根据CAPA计划和确定的临时风险降低措施，可以接受大约一年的额外实施时间表。

关于风速标准和测量位置，文件给出如下意见：

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?

对于具有单向流的屏障技术系统，定义了其他风速和风速测量位置，而不采用附录1中提到的要求，是否可以接受？

 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 sys tem 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款所述的屏障技术系统的最重要要求是，单向流系统中的风速必须以这样一种方式，即在发生高风险操作的工作位置上普遍存在单向和均匀的气流条件，适合保护产品和打开的部件（例如容器）免受污染。0.36 - 0.54 m/s 的风速范围，如上段所述，只是制药行业几十年来遇到的一个指导值。然而，附录1明确允许在系统中与工作位置不同的高度建立替代风速范围或测量值，前提是这“在 CCS 中具有科学合理性”。重要的是，通过涵盖整个系统的气流可视化研究（系统确认的一部分）来证明所定义的气流条件的适用性，并且这些研究与指定高度/位置下各自定义的风速范围相关联。在运行过程中必须连续测量风速，并保持在此定义的范围内。

关于工艺气体的监测位置，文件指出，对工艺气体的监测应尽可能靠近除菌过滤器前端（上游）进行(除菌前的污染程度应得到控制，以保证气体除菌过程的效率)。

Where should process gas be monitored?

工艺气体应该在哪里监测？

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).

对工艺气体的监测应尽可能靠近除菌过滤器前端进行(除菌前的污染程度应得到控制，以保证气体除菌过程的效率)。

关于灭菌柜首次验证和周期性再验证的装载模式：

Sterilisation: what are the required loading patterns for initial and periodic autoclave (re-) validations?

灭菌：灭菌柜首次和定期（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-vali dated. A theoretical reference load is not acceptable, as 8.36 states that “each type of load” needs to be validated.

首次验证必须验证每个装载模式。必须每年对每种装载模式进行再验证。如果可以确定合适的最差情况装载（相同的材料、相同的装载模式、相同的程序）进行再验证（有数据备份），则并非该材料的每个装载都需要再验证。理论上的参考装载是不可接受的，因为 8.36款规定“每种类型的装载”都需要验证。

关于新版附录1中提出的除菌级过滤器使用前/灭菌后完整性测试（“PUPSIT”）是否强制要求，文件表示期望使用PUPSIT来确认除菌过滤器组件的完整性。然而，第8.87款允许在风险分析支持并包含在CCS中的合理情况下有一定的灵活性。

Is a pre-use / post-sterilisation integrity testing (“PUPSIT”) of sterilising grade filters used in aseptically processes mandatory?

在无菌工艺中使用的除菌级过滤器进行使用前/灭菌后的完整性测试（“PUPSIT”）是否强制要求？

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.

期望使用PUPSIT来确认除菌过滤器组件的完整性。然而，第8.87款允许在风险分析支持并包含在CCS中的合理情况下有一定的灵活性。

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