2025上海医疗器械创新展谈ECA:关于欧盟无菌附录1的问答

1 Scope Annex 1 1 附录1的范围

Is there a formal process for identifying to which scope the Annex 1 needs to be applied to API manufacturing? How does it have to be applied during the API manufacturing and how to make those decisions systematic?

是否有一个正式流程来确定附录1需要应用到API制造的范围？它在API制造期间如何被应用，以及如何系统地做出这些决定？

It depends if the API is claimed sterile, it falls under the requirements of Annex 1. For APIs (e.g., claimed “low bioburden” / controlled endotoxin level), Annex 1 provides guidance for stateof-the-art manufacturing whenever contamination control is required. It targets at the control of microbial, endotoxin, particulate contamination. As outlined in the Scope of Annex 1 “…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.“ The application of the requirements and recommendations of Annex 1 can also be helpful for the manufacture of non-sterile products such as ointments etc.

这取决于API是否声称无菌，它属于附录1的要求范围。对于API（例如，声称“低生物负荷”/控制内毒素水平），附录1为需要控制污染的最先进的制造提供了指导。它针对微生物、内毒素、颗粒污染的控制。正如附录1的范围所概述的“……一些原则和指导，如污染控制策略、场所设计、洁净室分级、确认、验证、监测和人员更衣，可以用来支持制造其他不打算无菌的产品，如某些液体、乳膏、软膏和低生物负荷的生物中间体，但控制和减少微生物、颗粒和内毒素/热原污染被认为是重要的。”附录1的要求和建议的应用对制造非无菌产品如软膏等也有帮助。

Will also authorities of non-EU countries adopt Annex 1 (e.g. US-FDA)?

非欧盟国家的当局也会采用附录1吗（例如美国FDA）？

According to EMA representative, Annex 1 is expected to become applicable in all ICH member states. This is also supported by the fact that the new PIC/S document published recently on sterile medicinal products is identical to Annex 1. WHO was also involved in the revision and follows Annex 1 in its documents on sterile production.

根据EMA代表的说法，预计附录1将在所有ICH成员国适用。这也得到了最近PIC/S关于无菌药品的新文件与附录1相同的事实的支持。WHO也参与了修订，并在其无菌生产的文件中遵循附录1。

Difference between aseptic and terminally sterilised product: Annex 1 is not very clear what is applicable for what product group. Should we identify the GAPs the same for both but risk assess it differently since it is aseptic or a terminally sterilized product? Or is there just not as much difference anymore between the two (aseptic and terminally sterilized process)?

无菌和最终灭菌产品的区别：附录1对于适用的产品组并不十分清楚。我们应该为两者识别相同的GAPs，但由于它是无菌的或最终灭菌的产品而不同地进行风险评估吗？还是说两者（无菌和最终灭菌过程）之间已经没有太大的区别了？

Unfortunately, it is true that there are requirements in Annex 1, for which the attribution to either aseptic manufacturing or terminal sterilization technique is not explicitly stated. Thus, the only answer that can be provided is: QRM has to be applied to define the adequate solution for the individual process.

不幸的是，确实附录1中有要求，对于归因于无菌制造或最终灭菌技术并没有明确说明。因此，唯一可以提供的回答是：必须应用QRM来定义各个过程的适当解决方案。

Is there a relation between Part IV – GMP requirements for Advanced Therapy Medicinal Products and the Annex 1 requirements?

第IV部分 – 先进治疗药品的GMP要求与附录1的要求之间有关系吗？

Annex 1 applies for ATMPs only if explicit reference is made in EU-GMP Part IV, which is the case in the context of sterilization. Otherwise, from a formal point of view, Annex 1 is not applicable for ATMPs. However, it is advisable to consider Annex 1 requirements as state-of-the-art in general sterile manufacturing.

只有当欧盟GMP第IV部分明确提及时，附录1才适用于ATMPs，这在灭菌的背景下是适用的。否则，从形式上讲，附录1不适用于ATMPs。然而，建议将附录1的要求视为一般无菌制造的最新技术。

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2 Utilities 2 公用设施

Is the examination of all parameters in return loop of WFI needed?

Thinking about the nonhomogenously distribution of (micro)biology in a water loop while chemical and physical parameters are homogeneous distributed. In other words, is online monitoring at the return loop sufficient or is offline monitoring additionally needed?

需要检查WFI回环中的所有参数吗？考虑到水循环中（微生物）学的不均匀分布，而化学和物理参数是均匀分布的。换句话说，回环中的在线监测是否足够，还是还需要额外的离线监测？

Online monitoring in general determines TOC / conductivity. TOC can be an indicator for a microbiological contamination. CFU needs to be determined offline. Of course, parameters such as temperature or flow rate can also be measured. Sampling locations and frequency should be determined based on risk assessments.

一般而言，在线监测决定了TOC/电导率。TOC可以作为微生物污染的指标。CFU需要离线确定。当然，也可以测量诸如温度或流速等参数。采样位置和频率应基于风险评估来确定。

Modern alternative methods for online measurement of all viable counts are now available, but the results cannot yet be correlated with the cfu results of the offline methods, i.e. comparability cannot be proven. Therefore Sec. 6.13 in conjunction with sec. 6.15 clarifies, that daily sampling (off-line) is required at worst-case location and this is to be performed in addition to continuous TOC/conductivity in-line monitoring. 6.13 …. 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. 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.

现在可以在线测量所有活菌计数的现代替代方法，但结果尚不能与离线方法的cfu结果相关联，即无法证明可比性。因此，第6.13节与第6.15节明确指出，在最坏情况下的位置需要每天采样（离线），并且这需要在连续的TOC/电导率在线监测之外进行。6.13 … … 采样计划应基于确认数据，应考虑潜在的最坏情况采样位置，并应确保每天至少包括一个用于生产过程的水的代表性样品。6.15 WFI系统应包括连续监测系统，如总有机碳（TOC）和电导率，因为这些可能比离散采样更好地指示整体系统性能。传感器位置应基于风险。

WFI produced using R/O and distributed using cold loop: Is this acceptable if the site is using electro-deionisation (EDI), ultra/micro-filtration, ozonation and UV treatment and periodic thermal sanitization?

使用反渗透（R/O）生产的WFI并使用冷环分配：如果现场使用电去离子（EDI）、超/微过滤、臭氧处理和UV处理以及定期热消毒，这是可以接受的吗？

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. Ozonation, UV treatment and periodic thermal sanitization could be part of a company’s biofilm-management. This management is general required but no technical solutions are given. Annex 1 does not define technical solutions or requirements on RO water systems. For technical support on this topic there is a EMA Q&A paper (EMA/INS/GMP/443117/2017).

WFI应通过蒸馏或等同于蒸馏的纯化过程生产。这可能包括与其它适当技术如电去离子（EDI）、超滤或纳滤相结合的反渗透。臭氧处理、UV处理和定期热消毒可以是公司生物膜管理的一部分。这种管理通常是必需的，但没有给出技术解决方案。附录1没有定义RO水系统的技术解决方案或要求。有关此主题的技术支持，有一份EMA问答文件（EMA/INS/GMP/443117/2017）。

Chapter 6 Steam: Does this also apply for autoclaves? (not used for terminally sterilised product but within aseptic manufacturing with sterilised equipment)

第6章 蒸汽：这也适用于灭菌器吗？（不用于最终灭菌的产品，而是用于无菌制造中已灭菌的设备）

Annex 1 says in No. 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).”

附录1在第6.17节中说：“用作直接灭菌剂的蒸汽应具有适当的质量，并且不应包含可能造成产品或设备污染的添加剂。对于供应用于材料或产品接触表面（例如多孔硬质灭菌器负载）直接灭菌的纯蒸汽的发生器，蒸汽冷凝水应符合相关药典的当前WFI专题（蒸汽冷凝水的微生物检测不是强制性的）。”

What frequency is microbiological testing of gases used in processes expected to be? Currently we have a risk assessment, which states that due to filters used in process, this is not required. Is it now an absolute requirement to do the testing?

在流程中使用的气体进行微生物测试的频率是多少？目前我们有一份风险评估，指出由于流程中使用的过滤器，这不是必需的。现在进行测试是绝对要求吗？

Testing should be done at least annually, but the depends of usage of gases. There is no frequency defined in Annex 1, however, “no testing” is not an option, as sec. 6.19 clearly requires periodic monitoring at the point of use. Monitoring frequency is to be defined, but depends on the manufacturer’s experience, frequency of use, existing monitoring data and – as a general requirement – should be based on QRM principles.

测试至少应该每年进行一次，但这取决于气体的使用情况。附录1中没有定义频率，然而，“不进行测试”不是一个选项，因为第6.19节明确要求在使用点进行定期监测。监测频率需要定义，但取决于制造商的经验、使用频率、现有监测数据 – 作为一般要求 – 应基于QRM原则。

3 Single Use Systems 3 一次性使用系统

How do you distinguish between SUS (Single Use Systems) and closed systems? (As the terms are often used identical)

如何区分SUS（一次性使用系统）和封闭系统？（因为这些术语通常被相同地使用）

There is no one-to-one correlation between SUS and “closed system”: a. Closed systems do not necessarily have to be SUS, e.g. also isolators, bioreactors, transfer vessels can be closed systems and b. SUSs does not necessarily have to be a closed systems.

SUS和“封闭系统”之间没有一一对应的关系：a. 封闭系统不一定必须是SUS，例如隔离器、生物反应器、转移容器也可以是封闭系统 b. SUS不一定必须是封闭系统。

The definition of single use systems and closed systems are given in the glossary of Annex 1. 一次性使用系统和封闭系统的定义在附录1的术语表中给出。

What is meant by large volume containers in integrity testing chapter? Does it also include SUS used in manufacturing?

完整性测试章节中所说的大体积容器是什么意思？它也包括在制造中使用的SUS吗？

CCIT requirements related large volume containers (>100mL) refer to the volume of the primary packaging. For details, refer to Section 8.22. However, this section does not describe requirements for SUS.

CCIT要求相关的大体积容器（>100mL）是指初级包装的体积。详情参见第8.22节。然而，这一节没有描述SUS的要求。

Many suppliers for SUS apply only ISO 9001:2015 standards. We cannot force them to apply Annex 1 expectations during manufacturing SUS, is this correct?

许多SUS供应商只应用ISO 9001:2015标准。我们不能强迫他们在制造SUS期间应用附录1的期望，这是正确的吗？

Annex 1 is not applicable for suppliers of SUS. It is the responsibility of the pharmaceutical manufacturing company to select qualified supplier according to their needs taking EU GMP guideline Chapter 7 into consideration. However, there are ISO standards for the manufacture under biocontamination control, e.g. ISO 14698: Cleanrooms and associated controlled environments — Biocontamination control

附录1不适用于SUS供应商。根据他们的需求选择合格的供应商是制药公司的责任，同时要考虑欧盟GMP指南第7章。然而，有ISO标准用于生物污染控制下的制造，例如ISO 14698：洁净室和相关受控环境 – 生物污染控制。

4 Barrier Systems 4 屏障系统

Question about RABS/Isolators: open=RABS and closed = Isolator (vials in/out not robotics): asking because of background of Isolator: is Zone D sufficient for isolators (not robotics)?

关于RABS/隔离器的问题：开放=RABS，封闭=隔离器（西林瓶进出不是机器人）：由于隔离器的背景：D区对隔离器（非机器人）足够吗？

For closed isolators, grade D is sufficient, for open isolators, grade C is required. RABS require grade B background. Risk from background environment is mainly caused by material being introduced into the isolator/RABS.

对于封闭隔离器，D级足够，对于开放隔离器，需要C级。RABS需要B级背景。背景环境的风险主要是由引入隔离器/RABS的材料引起的。

What would be a suitable way to perform an isolator glove integrity test for both, nitrile gloves and latex gloves? We face problems with a self-sealing effect of latex gloves, any tips?

对丁腈手套和乳胶手套进行隔离器手套完整性测试的合适方法是什么？我们面临乳胶手套的自密封效果问题，有什么建议吗？

Usually for isolator intervention, neither latex nor nitrile gloves used in production isolators. Generally, for isolator gloves two tests in combination are industry’s standard: Pressure drop test and visual check for integrity. Typical materials for isolator gloves are EPDM (steam sterilizable) or CSM. Latex and nitrile are used for single use gloves. e.g. when gowning. However, these are then visually checked and often two pairs are worn on top of each other. 通常用于隔离器干预的手套既不是乳胶也不是丁腈手套。通常，结合两种测试是行业标准的隔离器手套：压力下降测试和完整性视觉检查。隔离器手套的典型材料是EPDM（可蒸汽灭菌）或CSM。乳胶和丁腈用于一次性手套，例如穿衣时。然而，这些通常会被视觉检查，并且通常两层手套叠在一起穿。

Is there any requirement for room classification of a QC Microbiological laboratory? Do Isolators used for (sterility) testing need a grade D background?

QC微生物实验室的房间分级有什么要求吗？用于（无菌）测试的隔离器需要D级背景吗？

There is explicit requirement for the room grade in Annex 1. Ph.Eur. 5.1.9 “Guidelines for using the test for sterility” says: “Aseptic conditions for performance of the test can be achieved using, for example, a class A laminar-air-flow cabinet located within a class B clean room, or an isolator“, without specifying the background. However, for the isolators applied for sterility testing, it is common practice to locate those in grade D environment.

附录1中没有对房间分级的明确要求。Ph.Eur. 5.1.9 “使用无菌测试的指南”说：“可以使用例如位于B级洁净室中的A级层流柜或隔离器来实现测试的无菌条件”，并没有指定背景。然而，对于用于无菌测试的隔离器，通常的做法是将其放置在D级环境中。

Regarding Barrier systems: Is it required to perform a smoke study to prove egress, pressure cascade in a pass-through panel from a C to D grade in a low bioburden facility?

关于屏障系统：是否需要进行烟雾研究来证明从一个C级到D级的传递面板中的出口，压力级联在低生物负荷设施中？

a. Usually, smoke studies (airflow visualisation) are performed, where unidirectional airflow shall be achieved or a backflush prevention (mouseholes at an open isolators) needs to be shown. Between rooms of different cleanroom grades, in general differential pressure is measured instead of performing a smoke study

通常，进行烟雾研究（气流可视化），需要实现单向气流或需要显示防止反冲洗（开放隔离器的小孔）。在不同洁净室等级的房间之间，通常测量压差而不是进行烟雾研究。

b. Annex 1, e.g. sec. 4.15, 7.18, 8.109 define, in which cases airflow visualization studies have to be performed. Furthermore, in case of changes to rooms and equipment, which might impact the airflow situation, visualization studies would also be required in context with requalification.

附录1，例如第4.15节、第7.18节、第8.109节定义了在哪些情况下必须进行气流可视化研究。此外，如果房间和设备发生变化，可能会影响气流情况，那么在重新确认的背景下也需要进行可视化研究。

Use of VHP is not considered as sterilization method for gloves, However, by autoclaving then VHP, the gloves become sticky and shorten the usage span of glove. Is autoclaving really a good practice?

使用VHP不被认为是手套的灭菌方法，然而，通过高压灭菌然后VHP，手套变得粘稠并缩短了手套的使用寿命。高压灭菌真的是一个好习惯吗？

a. For isolators gloves are not exchanged frequently. For RABS It is rather recommended to change glove material (EPDM = steam sterilizable) or supplier to still use steam sterilisation in an autoclave on them rather than changing the process of bioburden reduction to an inferior process （消毒/清洁与灭菌）。

对于隔离器手套不经常更换。对于RABS，更推荐更换手套材料（EPDM = 可蒸汽灭菌）或供应商，以便在高压灭菌器中仍然使用蒸汽灭菌，而不是将生物负荷降低过程改为较差的过程。

How to deal with significant incident (e.g. breakage and blockage of line) within isolator during critical operations?

在关键操作期间隔离器内发生重大事故（例如线路破损和堵塞）如何处理？

Usually this could only be solved by opening of the isolator which leads to ending the batch and campaign due to its non-integrity. Breakage of single vials, cartridges etc. may need no intervention. Time needs to be recorded and correlated to the vial/cartridge count. That section of the filled containers is specifically inspected for glass particles and if necessary discarded. This should be assessed upfront in the CCS. This is industry practice of e.g. insulin manufacturing, where a filling campaign may last week(s). If there is a complete blockage of the line, the isolator needs to be opened and batch is over.

通常，这只能通过打开隔离器来解决，这会导致批次和活动由于其不完整性而结束。单个西林瓶、注射器等的破损可能不需要干预。需要记录时间并与西林瓶/注射器计数相关联。那部分已灌装容器要特别检查玻璃颗粒，如果必要，要丢弃。这应该在CCS中预先评估。这是例如胰岛素制造行业的实践，灌装活动可能持续数周。如果线路完全堵塞，隔离器需要打开，批次结束。

5 CCIT 5 流通蒸汽灭菌

Regarding CCIT (§ 8.20 – 8.29). How to perform CCIT at prefilled syringes?

关于CCIT（第8.20 – 8.29节）。如何在预灌装注射器中执行CCIT？

a. Usually, it is performed offline. Based on Annex 1 risk-based sampling during routine production. Method based on process, determination risk-based

通常，它是离线执行的。基于附录1在常规生产中基于风险的采样。基于过程的方法，基于风险的确定

b. The requirements are: – Validated method – Frequency based on knowledge & experience – Scientifically justified sampling plan – Justification for sample size (e.g. supplier management, packaging components, process knowledge)

要求是：– 验证过的方法 – 基于知识和经验的频率 – 科学合理的抽样计划 – 样品大小的理由（例如供应商管理、包装组件、过程知识）

What is mean with 100% CCIT Control? 100% CCIT控制是什么意思？

a. 100% CCIT is required only for small volume parenterals (< 100ml) closed by fusion. a. 仅对小容量注射剂（<100ml）通过融合封闭的需要100% CCIT。

b. Large volume parenterals closed by fusion see Annex 1, sec. 8.22: “Where final containers are closed by fusion, e.g. Blow-Fill-Seal (BFS), Form-Fill-Seal (FFS), Small and Large Volume Parenteral (SVP & LVP) bags, glass or plastic ampoules, the critical parameters and variables that affect seal integrity should be evaluated, determined, effectively controlled and monitored during operations. Glass ampoules, BFS units and small volume containers (≤100 ml) closed by fusion should be subject to 100% integrity testing using validated methods. For large volume containers (>100 ml) closed by fusion, reduced sampling may be acceptable where scientifically justified and based on data demonstrating the consistency of the existing process, and a high level of process control. It should be noted that visual inspection is not considered as an acceptable integrity test method.”

参见附录1，第8.22节，大容量注射剂通过融合封闭：“当最终容器通过融合封闭时，例如吹灌封（BFS）、成型-灌装-密封（FFS）、小容量和大容量注射剂（SVP & LVP）袋、玻璃或塑料安瓿瓶，影响密封完整性的关键参数和变量应在操作过程中进行评估、确定、有效控制和监测。玻璃安瓿瓶、BFS单元和小容量容器（≤100 ml）通过融合封闭的应使用验证过的方法进行100%完整性测试。对于大容量容器（>100 ml）通过融合封闭的，如果科学上有道理并基于证明现有过程的一致性和高水平的过程控制的数据，可以接受减少采样。需要注意的是，目视检查不被认为是可接受的完整性测试方法。”

c. Products closed by other than fusion technique see Annex 1, sec. 8.23 or question 1

通过非融合技术封闭的产品参见附录1，第8.23节或问题1

Is it a requirement to have your process challenged end by end, so from the point sterile filtration until closure of the container? Or can you split up the process, so for example formulation and filling separately challenged?

是否需要将您的流程从端到端进行挑战，从无菌过滤点直到容器封闭？或者您可以将流程分开，例如配方和灌装分别进行挑战吗？

a. Related to aseptic process simulation, it should only be the exception to subdivide the process into separate unite operations. If so, then you need to have a documented justification (annex 1, sec. 9.33 v. “Separate simulations of individual unit operations (e.g. processes involving drying, blending, milling and subdivision of a sterile powder) should be avoided. Any use of individual simulations should be supported by a documented justification and ensure that the sum total of the individual simulations continues to fully cover the whole process”)

与无菌模拟灌装相关，应该只有例外将流程细分为单独的单元操作。如果是这样，那么你需要有一个文件化的论证（附录1，第9.33节v。“应避免将单独的单元操作（例如涉及干燥、混合、粉碎和无菌粉末细分的过程）单独模拟。任何单独模拟的使用都应该由文件化的论证支持，并确保各个单独模拟的总和继续完全覆盖整个过程”）

b. For manufacture you should validate these activities “end by end”, which are performed automatic without interruption by product separation.

对于制造，您应该验证这些“端到端”活动，这些活动是自动执行的，产品不会中断分离。

Is the issue with CCIT in Annex 1 also relevant for the pharmacy production or are here other regulations, for example ApoBetrO relevant? 附录1中与CCIT有关的问题是否也与药房生产相关，或者这里有其他规定，例如ApoBetrO是否相关？

a. This cannot be answered uniformly at European level, as national legislation plays a role here. Germany, for example: If the registered pharmacy or hospital pharmacy also manufactures for third parties, it requires a manufacturing authorization and falls under the GMP guidelines and Annex1. If this is not the case, the German ApoBetrO applies. Interpretations of additional national law (e.g. ApoBetrO) needs to be agreed with the national competent authority.

这不能在欧洲层面统一回答，因为国家立法在这里起作用。例如德国：如果注册药房或医院药房也向第三方生产，它需要制造授权并属于GMP指南和附录1。如果不是这样，那么适用德国ApoBetrO。需要与国家主管当局商定对额外国家法律（例如ApoBetrO）的解释。

 

文章来源： BasicPharma搬砖工