ISPE：清洁验证，生命周期有哪三个阶段？

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清洁可以说是药品生产中的关键工艺。传统的清洁验证程序只关注于单一的验证，来证明清洁方法可以按预期工作。然而，随着行业实践的发展，更好的方法是将清洁验证视为一个生命周期，将其重点从单一的清洁验证扩展到清洁开发阶段和持续清洁验证阶段，涉及到清洁方法使用的整个生命期间。

2020年，ISPE发布了清洁验证方面新的指南，名为“清洁验证生命周期——应用、方法和控制”。在该指南中，对于“清洁验证生命周期”这一概念进行了阐述。

生命周期的模型

The cleaning validation lifecycle follows the model defined by FDA, the concepts defined in the EMA Process Validation Guideline, and other regulatory bodies for process validation.

清洁验证生命周期可以遵循工艺验证的概念，这来自FDA界定的模型、EMA工艺验证指南和其它监管机构界定的概念。

“Although the rigor of process design and the timing of implementation for some ‘stages’ may differ, the science and risk-based methodology described in the FDA guidance is equally applicable to cleaning processes.”

“尽管工艺设计的严谨性和某些“阶段”的实施时间可能不同，但FDA指南中描述的科学和基于风险的方法同样适用于清洁工艺。"

For existing operations and processes, the introduction of new products or residues may require an assessment of the suitability of existing cleaning method designs, rather than forcing a new design of cleaning methods.

对于现有的操作和工艺，引入新产品或残留物可能需要评估现有清洁方法设计的适用性，而不是强制采用新的清洁方法设计。

The main elements of the FDA lifecycle model are illustrated in Figure below. The lifecycle model adopts the principles of Quality by Design, which states that quality cannot be assessed by testing alone. Therefore, processes need to be developed, critical parameters need to be identified, and the cleaning process monitored to verify ongoing performance and ensure quality output. The quality output expected from a cleaning process is the achievement of consistent cleaning of manufacturing product contact surfaces at a target cleanliness level that represents no harm to patients or impact to product quality (safety, identity, strength, potency).

FDA生命周期模型的主要要素如下图所示。生命周期模型采用“质量源于设计”原则，该原则指出不能仅通过测试来评估质量。因此，需要开发工艺，需要确定关键参数，并监测清洁工艺以验证持续性能并确保质量输出。清洁工艺的预期质量输出是：在目标清洁度水平上实现对生产产品接触面的一致清洁，对患者无害或对产品质量（安全性、鉴别、强度、活性）无影响。

图：FDA工艺验证生命周期模型

The lifecycle approach for cleaning validation is more comprehensive than the traditional approach as application of the lifecycle ensures that the cleaning process remains in a state of control and provides a logical progression for gaining knowledge for process improvements.

与传统方法相比，清洁验证的生命周期方法更为全面，因为生命周期的应用可确保清洁工艺保持可控状态，并为获得工艺改进的知识提供了逻辑进展。

Implementing a lifecycle approach can be challenging for legacy products where the development of the cleaning process may not be fully documented. However, a company can benefit from understanding the cleaning process parameters and design constraints when dealing with cleaning method changes or investigating failures. Better knowledge of the cleaning process provides the tools necessary to assess potential manufacturing cross- contamination risks and helps to ensure a compliant and effective cleaning program.

对于可能未充分记录清洁工艺开发的旧产品，实施生命周期方法可能具有挑战性。然而，在处理清洁方法变更或调查故障时，公司可以从了解清洁工艺参数和设计限制中获益。对清洁工艺的更深入了解，为评估潜在的生产交叉污染风险提供了必要的工具，并有助于确保清洁计划的合规性和有效性。

阶段1-清洁工艺设计

Stage 1 – Cleaning Process Design: Typical activities include creating a cleaning validation plan, selecting cleaning agents, determining Health-Based Exposure Limits (HBEL), defining critical parameters following Quality Risk Management principles, characterizing residues, evaluating parameter interactions, completing recovery studies, selecting validated analytical methods, reviewing equipment design, grouping equipment, defining limits and acceptance criteria.

阶段1-清洁工艺设计：典型活动包括创建清洁验证计划、选择清洁剂、确定基于健康的暴露限度（HBEL）、根据质量风险管理原则界定关键参数、表征残留物、评估参数相互作用、完成回收率研究、选择已验证的分析方法、审核设备设计、分组设备、界定限度和可接受标准。

阶段2-清洁工艺确认

Stage 2 – Cleaning Process Qualification: Typical activities include conducting next phases of the validation plan, qualifying equipment, reviewing utilities readiness, qualifying suppliers, selecting sampling site, justifying number of qualification runs, creating a cleaning qualification protocol, training personnel, executing the cleaning qualification protocol, and issuing the final validation report.

阶段2-清洁工艺确认：典型活动包括执行验证计划的下一阶段、确认设备、审核公用设施准备情况、确认供应商、选择取样点、确认运行次数、创建清洁确认方案、培训人员、执行清洁确认方案和发布最终验证报告。

Knowledge gained during this stage may require going back to Stage 1 for further development. Otherwise, proceed to Stage 3.

在此阶段获得的知识可能需要返回阶段1进行进一步开发。否则，进行阶段3。

阶段3-持续清洁确认

Stage 3 – Continued Cleaning Verification (Ongoing Cleaning Verification): Typical activities include establishing periodic reviews, determining extension of PV sampling and testing, monitoring process capabilities, reviewing deviations and changes.

阶段3-持续清洁确认：典型活动包括建立定期回顾、确定PV取样和检测的扩展、监测工艺能力、审查偏差和变更。

Knowledge gained during this stage may require going back to Stage 1 for further development or for revalidation at Stage 2.

在该阶段获得的知识可能需要返回阶段1，进行进一步开发；或在阶段2进行再验证。

It is possible to introduce changes to previous stages in the lifecycle model based on knowledge gained during the execution of each stage. Risk-based approaches and assessments are conducted throughout the lifecycle, especially during Stage 1 and Stage 2 of the model.

可以根据每个阶段执行过程中获得的知识，在生命周期模型的早期阶段引入变更。基于风险的方法和评估在整个生命周期中进行，特别是在模型的第1阶段和第2阶段。

参考：

Cleaning Validation Lifecycle Applications, Methods, and Controls. August, 2020. International Society for Pharmacoepidemiology (ISPE).

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