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，F(xiàn)DA概述了其對清潔驗(yàn)證主題的看法。這是怎么回事？
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.
印度一家原料藥制造商因缺乏有關(guān)清潔和設(shè)備維護(hù)的程序而受到批評。在檢查過程中，F(xiàn)DA檢查人員發(fā)現(xiàn)內(nèi)表面“剝落”和設(shè)備部件結(jié)垢。此外，在一臺設(shè)備的內(nèi)表面上也發(fā)現(xiàn)了殘留物。
Responses to the 483
483答復(fù)
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，這些殘留物不重要且無反應(yīng)性。此外，制造商希望就更新操作規(guī)程和“剝落”材料的處理方面采取預(yù)防措施。此外，還將建立一個(gè)確認(rèn)檢查點(diǎn)。
FDA's responses in the Warning Letter to the inspected company's replies
FDA在警告信中對此答復(fù)的回復(fù)
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.
這對FDA來說是不夠的！FDA要求對所有在美國生產(chǎn)的原料藥進(jìn)行“剝落”的潛在風(fēng)險(xiǎn)評估。它還批評被檢查公司沒有提供證據(jù)證明殘留的物料不會與其他原料藥發(fā)生反應(yīng)。此外，要求對清潔缺陷的原因進(jìn)行差距分析。
Specifically, the FDA is asking for:
具體來說，F(xiàn)DA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.
關(guān)于交叉污染風(fēng)險(xiǎn)的清潔有效性的回顧性總結(jié)。應(yīng)包括殘留物的鑒定、其他可能也未充分清潔的設(shè)備，以及是否可能已經(jīng)放行了受到交叉污染的產(chǎn)品的考慮。考慮因素應(yīng)包括任何不適當(dāng)?shù)那鍧嵆绦蚝妥龇ㄒ约叭魏味喈a(chǎn)品共享的設(shè)備。
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.
根據(jù)這一回顧性審查，應(yīng)制定有關(guān)清潔計(jì)劃的CAPA計(jì)劃。應(yīng)確定清潔工藝和活動的糾正措施，并提供實(shí)施時(shí)間表。此外，F(xiàn)DA希望看到清潔生命周期管理中的弱點(diǎn)摘要。應(yīng)說明清潔計(jì)劃的改進(jìn)情況，包括提高清潔效率以及改進(jìn)對所有產(chǎn)品和設(shè)備的清潔執(zhí)行情況的持續(xù)確認(rèn)。
The cleaning validation programme should be improved to consider worst case scenarios, regarding:
應(yīng)改進(jìn)清潔驗(yàn)證程序，考慮最差情況，包括：
Medicinal products with higher toxicities
毒性較高的藥品
Medicinal products with higher API contents
API含量較高的藥品
Medicinal products with low solubility in the cleaning reagent
在清潔劑中溶解度低的藥品
Medicinal products with properties that make them difficult to clean
較難清潔的藥品
Swab sampling sites to locations that are most difficult to clean
對最難清潔的位置進(jìn)行擦拭采樣
Standing time before cleaning
臟的保持時(shí)間
Adjustments to the change management system when new equipment or products are introduced
引入新設(shè)備或產(chǎn)品時(shí)的變更管理
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.
更新標(biāo)準(zhǔn)操作程序 （SOP）以確保為產(chǎn)品、工藝和設(shè)備制定適當(dāng)?shù)那鍧嶒?yàn)證和確認(rèn)計(jì)劃。
A holistic review of cleaning operations and associated cleaning validation strategy for each piece of equipment to determine if similar deficiencies exist.
對每臺設(shè)備的清潔操作和相關(guān)清潔驗(yàn)證策略進(jìn)行全面審查，以確定是否存在類似缺陷。
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).
結(jié)論：對FDA檢查缺陷的“簡單答復(fù)”往往是不夠的。FDA通常希望看到對發(fā)現(xiàn)的缺陷進(jìn)行回顧性評估，并主動描述哪些糾正措施將防止未來的缺陷(CAPA)。
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