In a recent Warning Letter, the FDA outlined its view on the topic of cleaning validation. What is it about?
在最近的一封警告信中，FDA概述了其对清洁验证主题的看法。这是怎么回事？
An API manufacturer from India has been criticized for lacking procedures on the topics of cleaning and equipment maintenance. During their inspection, FDA investigators found "spalling" of the inner surface and incrustations on equipment components. Furthermore, residues were also found on an inner surface of one piece of equipment.
印度一家原料药制造商因缺乏有关清洁和设备维护的程序而受到批评。在检查过程中，FDA检查人员发现内表面“剥落”和设备部件结垢。此外，在一台设备的内表面上也发现了残留物。
Responses to the 483
483答复
The manufacturer stated that the residues remaining were non-significant and non-reactive. Furthermore, the manufacturer wanted to implement preventive measures regarding the update of a work instruction and regarding the handling of the "spalled" material. Additionally, a verification checkpoint is to be established.
制造商表示，这些残留物不重要且无反应性。此外，制造商希望就更新操作规程和“剥落”材料的处理方面采取预防措施。此外，还将建立一个确认检查点。
FDA's responses in the Warning Letter to the inspected company's replies
FDA在警告信中对此答复的回复
This is not sufficient for the FDA! The FDA demands an evaluation of the potential risk of "spalling" for all APIs that are manufactured there.
It also criticizes the inspected company for not providing evidence that the retained material does not react with other APIs. Additionally, a gap analysis on the cause of the cleaning deficiencies is requested.
这对FDA来说是不够的！FDA要求对所有在美国生产的原料药进行“剥落”的潜在风险评估。它还批评被检查公司没有提供证据证明残留的物料不会与其他原料药发生反应。此外，要求对清洁缺陷的原因进行差距分析。
Specifically, the FDA is asking for:
具体来说，FDA要求：
A summary, retrospective review of cleaning effectiveness with respect to cross-contamination risks. The identities of residues, equipment other than those previously considered that may also have been inadequately cleaned, and a consideration of whether cross-contaminated products may have been released are to be included. The consideration should include any inadequate cleaning procedures and practices and any equipment item in which more than one product is manufactured.
关于交叉污染风险的清洁有效性的回顾性总结。应包括残留物的鉴定、其他可能也未充分清洁的设备，以及是否可能已经放行了受到交叉污染的产品的考虑。考虑因素应包括任何不适当的清洁程序和做法以及任何多产品共享的设备。
Based on this retrospective review, a CAPA plan shall then be developed regarding the cleaning programme. This should identify corrective actions to the cleaning process and activities and provide timelines to implementation. Furthermore, the FDA would like to see a summary of weaknesses in the life cycle management of cleaning. Improvements to the cleaning programme, including improvements to cleaning efficiency and improved continued verification of cleaning execution of all products and equipment, should be described.
根据这一回顾性审查，应制定有关清洁计划的CAPA计划。应确定清洁工艺和活动的纠正措施，并提供实施时间表。此外，FDA希望看到清洁生命周期管理中的弱点摘要。应说明清洁计划的改进情况，包括提高清洁效率以及改进对所有产品和设备的清洁执行情况的持续确认。
The cleaning validation programme should be improved to consider worst case scenarios, regarding:
应改进清洁验证程序，考虑最差情况，包括：
Medicinal products with higher toxicities
毒性较高的药品
Medicinal products with higher API contents
API含量较高的药品
Medicinal products with low solubility in the cleaning reagent
在清洁剂中溶解度低的药品
Medicinal products with properties that make them difficult to clean
较难清洁的药品
Swab sampling sites to locations that are most difficult to clean
对最难清洁的位置进行擦拭采样
Standing time before cleaning
脏的保持时间
Adjustments to the change management system when new equipment or products are introduced
引入新设备或产品时的变更管理
Overview of updated standard operating procedures (SOPs) to ensure that an adequate cleaning process verification and validation programme is in place for products, processes, and the equipment.
更新标准操作程序 （SOP）以确保为产品、工艺和设备制定适当的清洁验证和确认计划。
A holistic review of cleaning operations and associated cleaning validation strategy for each piece of equipment to determine if similar deficiencies exist.
对每台设备的清洁操作和相关清洁验证策略进行全面审查，以确定是否存在类似缺陷。
Conclusion: "Simple responses" to inspection deficiencies to the FDA are often inadequate. FDA typically wants to see that the deficiencies found are evaluated retrospectively and described proactively as to what corrective actions will prevent the deficiencies in the future (CAPA).
结论：对FDA检查缺陷的“简单答复”往往是不够的。FDA通常希望看到对发现的缺陷进行回顾性评估，并主动描述哪些纠正措施将防止未来的缺陷(CAPA)。
