FDA警告信：验证失败，部分批次能否放行？

11月24日，FDA公布一封针对美国企业(AuroLife Pharma, LLC，总部位于印度)的警告信。主要的缺陷项涉及OOS调查不充分、厂房维护不利、设施设备的清洁问题和针对工艺变更的验证不足。

为缩短工艺时间，该公司对三种片剂产品的生产工艺进行了变更，并执行了工艺性能确认(PPQ)。验证时，由于出现了均匀性不合格的问题，该公司拒放了某些批次，但放行了其余批次。FDA认为，公司没有数据来说明新工艺处于受控状态，因此对那些放行批次提出了质疑。为此，在483表格的回复中，该公司决定召回使用新工艺生产的所有PPQ批次，但FDA认为公司的答复是不充分的，因为公司提出的验证策略存在问题，需要提供有关验证计划的详细摘要及相关程序。

WARNING LETTER

CMS# 607087

警告信

CMS＃607087

清洁问题
3. Your firm failed to establish and follow written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).

3.你们公司未建立并遵循适当的书面程序，来清洁和维护设备(21 CFR 211.67(b))。

During the inspection, our investigators observed surfaces covered in powder throughout your facility including API sampling rooms, raw material dispensing rooms, common production corridor areas, granulation rooms, and compression rooms.

在检查过程中，我们的调查员观察到整个设施表面都被粉末覆盖，包括API取样室、原料称量间、公共生产通道区域、造粒间和压缩空气室。

For example, in a (b)(4) granulation room documented as “major”-cleaned, we observed a powder residue coating the surface of the (b)(4) panel, the floor of the room, and the control panel of a (b)(4).

例如，在记录为“主要”清洁的XX造粒间中，我们观察到粉末残留物覆盖了XX面板的表面，房间的地板和XX控制面板。

The visible powder observed in numerous areas of your facility could lead to cross-contamination of your finished drug products. Notably, the hazard posed by this deviation is heightened because you manufacture high potency drug products.

在工厂的许多区域观察到可见粉末，可能会导致成品制剂的交叉污染。值得注意的是，由于你们生产高活性的药品，这种偏差带来的危险会加增。

In your response, you stated you will revise your cleaning procedures and train your personnel. Your response failed to address the root cause of inadequate powder control in your facility and propose adequate corrections.

在答复中，你们表示将修改清洁程序，并培训人员。你们的答复未能解决你们设施中粉末控制不足的根本原因，也没有提出了适当的纠正措施。

In your response to this letter, provide:

针对此信，请提供：

• Your CAPA plan to ensure that you have effective powder control (e.g., exhaust) systems in your facility.

•你们的CAPA计划，确保你们的设施中具有有效的粉末控制(例如，排风)系统。

• A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies in facility design, cleaning procedures, or cleaning practices. It should encompass each production room and piece of manufacturing equipment used to manufacture more than one product.

•对清洁效果进行全面、独立的回顾性评估，以评估交叉污染危害的范围。包括残留物的识别，可能未正确清洁的其它生产设备，并评估放行分发的产品是否可能发生了交叉污染。评估应确定设施设计、清洁程序或清洁实践中的任何不足之处。这应涵盖每个用于多个产品生产的房间和设备。

工艺变更验证不足
4. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

4.公司未建立用于生产和过程控制的书面程序，以确保你所生产的药品具有其声称或代表拥有的鉴别、强度、质量和纯度(21 CFR 211.100(a))。

To reduce the manufacturing process time for three strengths of acetaminophen and codeine phosphate tablets, you implemented a manufacturing process change. Using this new process, you manufactured (b)(4) process performance qualification (PPQ) batches. You rejected (b)(4) batches for uniformity failures (e.g., blend, content uniformity) and released the remaining (b)(4) batches.

为了减少三种对乙酰氨基酚和磷酸可待因片剂的生产工艺时间，你们实施了生产工艺变更。使用此新工艺，你们生产了XX个工艺性能确认(PPQ)批次。由于均匀性失败(例如，混合、含量均匀性)，你们拒放了XX个批次，但放行了其余XX个批次。

You did not have data to support that your process was in a state of control prior to releasing those (b)(4) batches.

在放行那些XX批次之前，你们没有数据来支持你们的工艺处于受控状态。

Your evaluation of the process change after implementation concluded that the new process resulted in a non-uniform blend, your previous manufacturing process was more consistent and robust, and the remaining batches should be held pending further discussion. Eight months after this initial evaluation you made the decision to revert to the old process. However, your firm determined that the quarantined batches could be distributed.

对于实施后的工艺变更，你们的评估得出结论，即：新工艺导致混合不均匀，你们以前的生产工艺更加一致且稳定，剩余批次应等待进一步讨论。在此初始评估的八个月后，你们决定恢复到旧工艺。但是，你们公司决定可以分发之前隔离的那些批次。

In your response, you wrote that you would review these lots and recall if necessary.

在答复中，你们写道，你们将审查这些批次，并在必要时召回。

You also wrote that only the first (b)(4) consecutive “successfully manufactured” PPQ validation batches can be considered for release into the market and that any prior failed PPQ batches can be considered “(b)(4).” You added if any failure is observed in PPQ batches “with unassignable root cause then the failed batch and the batches manufactured prior to the failed batch shall not be released in to the market.” Your response is inadequate, because your proposed validation strategy fails to ensure all PPQ batches are properly evaluated when determining whether or not your process is in an initial state of control.

你们还写道，只有前XX个连续“成功生产”的PPQ验证批次才可以考虑投放市场，而任何先前失败的PPQ批次都可以考虑为“XX”。你们补充道，如果在PPQ批次中发现任何失败，“根本原因无法确定时，则该失败批次和之前生产的批次将不会投放市场。” 你们的答复不充分，因为在确定你们的工艺是否处于初始控制状态时，你们提出的验证策略无法确保正确评估所有PPQ批次。

We acknowledge you have recently made the decision to recall the PPQ batches made using the new process.

你们最近决定召回使用新工艺生产的PPQ批次，对此我们已经知晓。

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and ensure the quality of raw material inputs, in-process materials, and finished drugs. Failure to conduct these studies can result in product quality attribute failures. Process qualification studies determine whether an initial state of control has been established. Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.

工艺验证会评估整个工艺生命周期中设计的合理性和控制状态。生产工艺中的每个重要阶段都必须进行适当的设计，并确保原材料输入、在制品和成品制剂的质量。未能进行这些研究可能会导致产品质量属性失败。工艺确认研究确定是否已建立初始控制状态。商业放行之前，必须进行成功的工艺确认研究。此后，有必要对工艺性能和产品质量进行持续的监控，以确保你们在整个产品生命周期中保持稳定的生产操作。

See FDA’s guidance document Process Validation: General Principles and Practices for general principles and approaches that FDA considers appropriate elements of process validation at https://www.fda.gov/media/71021/download.

请参阅FDA的指南《工艺验证：一般原则和实践》，就FDA考虑的工艺验证适当要素，获取一般原则和方法。

In response to this letter, provide:

针对此信，请提供：

• A detailed summary of your validation program for ensuring a state of control throughout the product lifecycle, along with associated procedures. Describe your program for process performance qualification, and ongoing monitoring of both intra-batch and inter-batch variation to ensure a continuing state of control.

•有关验证计划的详细摘要（确保整个产品生命周期中的控制状态），以及相关程序。描述你们的计划，以进行工艺性能确认(PPQ)，并持续监控批内和批间变化，以确保持续的控制状态。

• A determination of whether the PPQ for each of your marketed drug products was properly executed and used the appropriate criteria.

#推荐使用CGMP顾问

Consultant recommended

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements.

根据我们发现的违规行为的性质，我们强烈建议聘请符合21 CFR 211.34规定的合格顾问，来协助你们公司满足CGMP要求。

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

你们聘用顾问并不能免除公司遵守CGMP的义务。你们公司的执行管理层仍然负责解决所有缺陷和系统性缺陷，以确保持续符合CGMP。


结论
Conclusion

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.

本信函中引用的违规行为并非旨在列出与你们产品相关的所有违规行为。你们有责任调查和确定这些违规的原因，并防止其再次发生或发生其它违规情况。

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

如果你们正在考虑可能会导致你们的工厂生产的药物供应中断的行动，则FDA要求你们立即联系CDER的药物短缺人员(drugshortages@fda.hhs.gov)，以便FDA可以与你们以最有效的方式使你们的运营符合法律规定。与药品短缺人员联系还可以使你们履行报告21 USC 356C(b)规定的药品生产中断或暂停的义务。这也使FDA可以尽快考虑可能需要采取什么措施，以避免短缺和保护依赖你们产品的患者的健康。

Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.

及时纠正此信中引用的违规行为。不及时纠正这些违法行为，可能会导致采取法律行动(恕不另行通知)，包括但不限于：扣押和强制令。此警告信中未解决的违反行为也可能阻止其它联邦机构给予合同。

FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.

FDA还可能拒绝批准出口证书申请，对于新药申请或补充申请，也不会批准将你们的工厂列为供应商或生产商，直到上述违法行为得到纠正。我们可能会重新检查，以确认你们已完成纠正措施。

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

收到这封信后，请在15个工作日内以书面形式答复FDA办公室。说明自我们检查以来，你们所做的事情，以纠正你们违规行为，并防止其再次发生。如果你们无法在15个工作日内完成纠正措施，请说明延误原因和完成时间表。

If you believe that your products are not in violation of the FD&C Act (or you have complied with FDA regulations), include your reasoning and any supporting information for our consideration.

如果你们认为你们产品未违反FD＆C法案(或你们已遵守FDA法规)，请提供你们理由和任何支持信息，以供我们考虑。

Ref.: [FDA][2020-11-24]WARNING LETTER-Aurolife Pharma, LLC

       文章来源：PharmLink

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