首页 > 资讯 > 课前预习 PDA 无菌工艺要点与欧盟无菌附录

出自识林

2023-11-06

以下文章来源于IPEM ，作者IPEM

PDA于2003年首次发布了“Points to Consider for Aseptic Processing“，并于2015年和2016年分别发布了Points to Consider for Aseptic Processing parts 1和2。2023年10月，PDA更新了“Points to Consider No.1 Aseptic Processing”，本次修订取代了2015和2016文件中讨论的话题。

这份新文件共7个章节，总计71个话题，每个话题下的内容包括：

• Recommendation / 建议

• Rationale / 理由

• References / 参考文献

PDA新文件与欧盟无菌附录的关联

PDA这份新文件指出，文件修改的原因是技术和监管进步了，特别是欧盟无菌附录修订版的发布（【全文翻译】欧盟 GMP 附录1《无菌药品生产》最新版）。从内容上看，多数话题可以与欧盟无菌附录的相应条款对应上，部分话题则未在欧盟无菌附录中体现，具体对应关系如下，建议学员课前提前阅读相应附录条款：

PDA在附录征求意见期间发表了什么修改建议，是否都接受了？

欧盟在2017年和2020年分别发布了两版无菌附录征求意见稿，与之前的版本相比，2017版是一份全新的无菌附录，并不是旧版的修订版（欧盟无菌附录（草案）变化详解），征求意见期间总计收到来自140家企业/组织/个人/作者的约6200条意见，其中PDA反馈了115条建议。至2020版征求意见，总计收到约2000条意见，其中PDA反馈了78条建议。

以气流速度为例，欧盟2022版的要求为：

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.

4.30 应在确认方案中明确论证单向流系统送风速度的合理性，包括风速的测定位置。风速应经过设计、测定和维持，以确保在工作区域（例如，在进行高风险操作的区域以及产品和/或组件暴露的区域）有合适的单向气流为产品和开放组件提供保护。除非在CCS中另有科学论证，否则单向流系统应在工作区域提供0.36-0.54m/s（指导值）范围内的均匀风速。气流可视化研究应与风速测定相关联。

在征求意见稿中，2017版和2020版的描述，以及PDA提出的反馈意见为：

• 2017版原文：

5.3 For the manufacture of sterile medicinal products 4 grades of clean room can be distinguished.

Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open ampoules and vials, making aseptic connections. Normally, such conditions are provided by a localised air flow protection, such as laminar air flow work stations or isolators. Unidirectional air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value), the point at which the air speed measurement is taken should be clearly justified in the protocol. During initial qualification and requalification air speeds may be measured either close to the terminal air filter face or at the working height, Where ever the measurement is taken it is important to note that the key objective is to ensure that air visualization studies should correlate with the airspeed measurement to demonstrate air movement that supports protection of the product and open components with unidirectional air at the working height, where high risk operations and product and components are exposed. The maintenance of unidirectional airflow should be demonstrated and validated across the whole of the grade A area. Entry into the grade A area by operators should be minimized by facility, process and procedural design.

• PDA对2017版的反馈意见如下：

Comment: Section 5.3 states prescriptive guidance for air speed as well as an expectation for justification of sampling distance. Air velocity guidance may or may not be appropriate for unidirectional flow in all cases and at all points within the Grade A zone. ISO 14644-3 clearly indicates that the test for unidirectional air flow and referencing 0.4 – 0.6 m/s should be taken within 150-300 mm of the filter face. While using the ISO guidance for qualification or re-qualification may be suitable, implication that the guidance velocity values have any validity elsewhere in the Grade A zone is not accurate. The prescription of a standard velocity is not necessary, and should depend on line and process configuration. The requirement for individual determination of standard measuring distance is not necessary, if a standard distance is already available.

意见：第 5.3 节阐述了对风速的规定性指导以及对取样距离合理性的期望。风速指导可能适用于也可能不适用于A级区内所有情况下所有点的单向流。ISO 14644-3明确指出，参照0.4-0.6 m/s的单向气流测试应在距过滤器表面150-300 mm范围内进行。虽然使用ISO指南进行确认或再确认可能是合适的，但理解为该指导风速值在A级区的其它地方也有效是不准确的。标准风速的规定不是必需的，应取决于生产线和工艺配置。如果已有标准距离，则不需要单独确定标准测定距离。

Proposed change: Remove recommended velocity, but add guidance recommendation for measurement distance. "Unidirectional air flow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value), the point at which the air speed measurement is taken should be clearly justified in the protocol. During initial qualification and requalification air speeds may be measured either close to the terminal air filter face or at the working height, Airflow systems that are designed to be unidirectional should provide a homogeneous air velocity as measured within 150 – 300mm of the filter face that is adequate to prevent the ingress of particulate from the less-clean surrounding environment into the working area.

拟议变更：删除建议的风速，但增加测定距离的指导建议。“单向气流系统应提供0.36-0.54 m/s（指导值）范围内的均质风速，风速测定的点应在方案中明确论证。在初始确认和再确认期间，风速可以在靠近末端空气过滤器表面处或在工作高度测定。单向气流设计的系统应提供均匀风速，在距离过滤器表面150–300 mm范围内测定，即，足以防止微粒从不太洁净的周围环境进入工作区域。

• 2020版原文：

4.32 The speed of air supplied by unidirectional airflow systems should be clearly justified in the qualification protocol including the location for air speed measurement. Air speed should be designed, measured and maintained to ensure that appropriate unidirectional air movement provides protection of the product and open components at the working height (e.g. where high risk operations and product and/or components are exposed). Unidirectional airflow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position, unless otherwise scientifically justified in the CCS. Airflow visualization studies should correlate with the air speed measurement.

• PDA对2020版的反馈意见如下：

Comments: As currently written, the section may be mis-interpreted as requiring the prescribed guidance value. In addition, as currently written, the section may be misinterpreted as requiring air velocity measurement for non-Grade A zones. In addition, some of the language referring to air speed requires clarification.

意见：按照目前所写内容，该部分可能被误解为需要规定的指导值。此外，正如目前所写，该部分可能被误解为需要对非A级区进行风速测定。此外，一些提到风速的语言需要澄清。

Suggested text: The speed acceptable range for velocity of air supplied by Grade A unidirectional airflow systems should be clearly justified in the qualification protocol including the location for air speed measurement. Airflow speed velocity should be designed, measured and maintained to ensure that appropriate unidirectional air movement provides protection of the product and open components at the working height (e.g. where high risk operations and product and/or components are exposed). Unidirectional airflow systems should provide a homogeneous air speed in a range of 0.36 – 0.54 m/s (guidance value) at the working position, unless otherwise scientifically justified in the CCS. Airflow visualization studies should correlate with the air speed measurement. Grade A Unidirectional airflow velocity should be correlated to airflow visualization studies.

建议的内容：应在确认方案中明确论证A级单向流系统送风速度的可接受范围，包括风速测定的位置。风速应经过设计、测定和维持，以确保在工作高度（例如，在进行高风险操作的区域以及产品和/或组件暴露的区域）有合适的单向气流为产品和开放组件提供保护。除非在CCS中另有科学论证，否则单向流系统应在工作区域提供0.36-0.54m/s（指导值）范围内的均匀风速。气流可视化研究应与风速测定相关联。A级单向气流速度应与气流可视化研究相关联。

Justification: "Speed" has been replaced with "velocity" or velocity related terms, because it refers to a vector quality including both speed and direction. "Grade A" has been inserted in the section, because unidirectional flow may pertain to other than Grade A areas; therefore, it should be clear that these requirements are meant for Grade A and not necessarily for any and all unidirectional airflow system. The section stating the guidance range has been removed, because it may be considered by some to be a prescribed range and limit. Airflow velocity should be designed, measured and maintained to ensure that, where it is specified, appropriate unidirectional air movement provides protection of the product and open components at the working height. However, the most suitable velocity range is highly dependent on several factors other than airflow velocity. These include:

o the individual production equipment calling for Grade A protection

o the individual Unidirectional Air Flow Device, UDAF, supplying air

o the geometries of the room in which the equipment and UDAF is situated

Prescribing air flow velocity ranges changes focus from the importance of understanding and evaluating the effectiveness of the flow in terms of protecting the product and critical surfaces. Note that the target interval is a historic one that does not align with current ISO guidance. The proof of concept for the airflow velocity is in the air flow visualization. The correlation between velocity measurements and visualization is key when velocity is used to verify continued compliance with the visualized airflow.

理由：“速度（speed）”已被“速度（velocity）”或与velocity相关的术语取代，因为velocity是指包括速度（speed）和方向的矢量特征。在该部分中插入“A级”，因为单向流可能涉及A级以外的区域；因此，应明确这些要求仅适用于A级，不一定适用于任何单向流系统。说明指导范围的部分已被删除，因为可能会有人认为它是规定的范围和限制。风速应经过设计、测定和维持，以确保（如规定）在工作高度有合适的单向气流为产品和开放组件提供保护。然而，最合适的速度范围在很大程度上取决于风速以外的几个因素。其中包括：

o 需要A级保护的单个生产设备

o 送风的单个单向流装置（UDAF）

o 设备和UDAF所在房间的几何形状

规定风速范围时的重点改变了，不再关注理解和评估气流在保护产品和关键表面方面的有效性。请注意，目标间隔是过去的，与当前的ISO指南不一致。风速概念的验证在气流可视化中。当使用速度来确认与可视化气流的持续一致性时，速度测定和可视化之间的相关性是关键。

• 小结

PDA在两轮意见反馈中，对气流速度相关的要点，如测定位置、风速的描述和测定范围等，都进行了说明，其关注要点在新修订的文件中也有体现，保持了PDA对该问题的一贯认知。

带着问题来讨论

欧盟无菌附录的修订，从2015年发布概念性文件起，到2022年发布最终定稿，经历了多轮的讨论，我们可以从公开的意见反馈看到行业的关注点，但遗憾的是，无菌附录的修订小组没有公开对行业意见的回应文件。

各位读者学习过PDA的报告，以及PDA过去对欧盟无菌附录的两轮意见反馈，对PDA的观点有深入了解后，不妨来听一听欧盟无菌专家Ian Thrussell本月10-11号对这份PDA报告的解读（研讨课 | PDA 无菌工艺要点与欧盟无菌附录），并带着问题来与行业专家进行讨论。

欢迎大家扫描下方二维码或点击报名课程并提出您的问题。