案例二
警告信发出日期
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厂家
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产品
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2022.10.31
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Abraxis Bioscience
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Abraxane
紫杉醇（无菌药品）
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链接：
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https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/abraxis-bioscience-llc-633713-10312022
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缺陷如下：
Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
贵公司未能彻底调查一批产品或其任何组件是否存在无法解释的差异或未能满足其质量标准，无论该批产品是否已分发（《联邦法规》第21卷第211.192节）。
You failed to effectively implement corrective actions and preventive actions (CAPA) and return your asepticprocessing line and manufacturing operations to a state of control. Multiple media fill failures occurred between April and October 2021, when simulating aseptic processing operations on the filling line used for your drug product Abraxane (a sterile(b)(4) drug).
贵公司未能有效实施纠正措施和预防措施(CAPA)，未能将你们的无菌生产线和生产操作恢复到受控状态。在2021年4月至10月期间，在你们药品Abraxane(一种无菌药品)的灌装线上模拟无菌工艺操作时，发生了多次培养基灌装失败。
Your firm failed to perform a sufficiently comprehensive evaluation and remediation upon this loss of state of control in your aseptic operations. In December 2021, you released batches potentially impacted by these failures following(b)(4) successful media fill run (conducted in November 2021).
贵公司未能对无菌操作中的失控状态进行足够全面的评估和补救。2021年12月，你们在xx成功灌装后放行了可能受这些故障影响的批次
Your investigations into the following media fill failures were inadequate in that they lacked sufficient rigor in determining root causes and scope of impact after the media fills revealed serious non-sterility risks in your aseptic process operations.
你们对以下培养基灌装失败的调查是不充分的，因为在培养基灌装暴露出你们无菌工艺操作中严重的非无菌风险后，你们在确定根本原因和影响范围方面缺乏足够的严谨性。
Specifically,确切地说
1) On April 20, 2021, you conducted a media fill using the(b)(4). On the (b)(4) of incubation, you observed a very high number ((b)(4)) of contaminated units. Ten different microbes were identified from samples of contaminated units including sporeforming, vegetative, gram-negative, and gram-positive microbes. Your investigation attributed the root cause to (b)(4) in the filling manifold that included a damaged (b)(4) that was contaminated during (b)(4) equipment cleaning step. The investigation indicated that the valve harbored such excessive bioburden that it apparently enabled numerous bacteria to survive the subsequent filling equipment sterilization cycle, and the contaminated valve then caused the extensive contamination of units during the media fill. The investigation failed to adequately address how not only sporeforming microbes, but also vegetative microbes with far (b)(4), presumably survived your validated sterilization cycle. Also, you did not explain whether the sterilization cycle design allows for robust (b)(4) and reproducible exposure of all equipment parts in your sterilizer loads.
2021年4月20日，使用（b）（4）进行了培养基灌装。在培养的（b）（4）中，您观察到大量（b）（4）受污染的单元。从受污染单元的样本中鉴定出10种不同的微生物，包括产(芽)孢菌类、营养菌、革兰氏阴性菌和革兰氏阳性菌。你们的调查将根本原因归咎于灌装通道中的xx，其中包括在xx设备清洗步骤中被污染的xx损坏。调查表明，阀门含有过多的生物负载，显然使许多细菌能够在随后的灌装设备灭菌循环中存活下来，而被污染的阀门在培养基灌装过程中导致了单元的广泛污染。这项调查未能充分解决孢子转化微生物，以及含有（b）（4）的营养微生物是如何在经过验证的灭菌周期中存活下来的。另外，你们没有解释灭菌周期设计是否允许你们灭菌器负载中所有设备部件的稳定和可重复暴露。
2) On July 12, 2021, you conducted a repeat media fill using the(b)(4), which revealed multiple (b)(4) contaminated units. You attributed the root cause of the media fill failure to personnel gowning, poor disinfection of the inner Restricted Access Barrier System(RABS), and contaminated forceps used during the stopper bowl interventions in your RABS. However, the CAPA did not sufficiently expand to more holistic remediation of the root causes, including but not limited to, ensuring a comprehensive evaluation of the frequency, specificity, sufficiency, and robustness of your disinfection and decontamination program for the RABS and the surrounding cleanroom(s).
2021年7月12日，您使用（b）（4）重复进行了一次培养基灌装，结果显示有多个受污染的单元。您将培养基灌装失败的根本原因归因于工作人员穿着、RABS系统内部消毒不充分以及在RABS中的胶塞加料盘过程中使用的钳子被污染。然而，CAPA没有充分扩展到更全面的根本原因补救，包括但不限于确保对RABS和周围洁净室的消毒和去污计划的频率、特异性、充分性和耐用性进行全面评估。
3) On October 5, 2021, you conducted a media fill using(b)(4) as part of your process improvement. Although you aborted the run due to “unloading equipment failure,” you again observed a high number ((b)(4)) of contaminated units. Your firm observed this contamination, which was present in (b)(4) shelves, while unloading the units from the (b)(4). You attributed the root cause to (b)(4) and stated that the bacterial contamination was introduced via the (b)(4) performed with (b)(4) apparatus that consists of a (b)(4) for purposes of sample collection. Notably, your process has incorporated multiple pieces of (b)(4) equipment on your sterile processing line rather than traditional reusable equipment. As with traditional equipment, high standards for robustness and integrity are essential for each of the (b)(4) elements of your sterile operation.
在2021年10月5日，你们使用xx进行了培养基灌装，作为你们工艺优化的一部分。虽然你们因“卸载设备故障”而中止了运行，但你们再次观察到高数量的污染单元。你们公司在从xx货架上卸下产品时发现了该污染，该污染存在于xx货架上。你们声明细菌污染是通过xx采样设备引入的，该设备由xx组成，用于样品采集。值得注意的是，您的工艺在无菌加工线上包含了多个（b）（4）设备，而不是传统的可重复使用的设备。与传统设备一样，高标准的稳定性和完整性对无菌操作的每一个（b）（4）要素都至关重要。
The investigation of the(b)(4) failure was insufficient. For example, it lacked sufficient evaluation of the ruggedness of these disposable systems, which your firm states are intended to be “(b)(4)” while adding that they can be contaminated by the operator manipulations in the ISO 7 (Grade B) environment. While the investigation acknowledges “vulnerability of the syringe sampling system” and inadequate instructions for use of the (b)(4) as factors contributing to the contamination of the sterile product process stream, the CAPA did not include a broader review of suitability for their intended use of other (b)(4) equipment, adequacy of their instructions, and potential hazards posed when sterile (b)(4) are exposed to lower area classifications than ISO 5 (Grade A).
对（b）（4）失败的调查不够充分。例如，它缺乏对这些一次性系统的坚固性的充分评估，贵公司表示，这些系统旨在“（b）（4）”，同时补充说，它们可能会被ISO 7（b级）环境中的操作员操作所污染。虽然调查承认“注射器取样系统的脆弱性”和（b）（4）使用说明不充分是导致无菌产品工艺流污染的因素，但CAPA没有包括对其他xx设备预期用途的适用性、说明书的充分性以及无菌xx暴露于低于ISO 5 (a级)的区域分类时所造成的潜在危害的更广泛的审查。
4) On November 15, 2021, you conducted a media fill using the(b)(4), as part of qualification of this new system. You observed one turbid vial on the (b)(4) of incubation. You attributed the contamination to inadequate disinfection of the area below the work surface that contaminated the pump apparatus after equipment changeover, which in turn may have contaminated RABS gloves used for unplanned mechanical interventions. However, you did not address the extent of other equipment underneath the filling line worksurface that can pose a contamination risk due to insufficient disinfection.
在2021年11月15日，你们使用xx进行了培养基灌装，作为新系统确认的一部分。你们在培养的xx上观察到一个混浊的小瓶。你们将污染归因于工作台面以下区域消毒不充分，在设备转换后污染了泵设备，这反过来可能污染了用于计划外机械干预的RABS手套。但是，你们没有说明由于消毒不足而可能造成污染风险的灌装线工作台面以下的其他设备的范围。
These(b)(4) media fill contaminations indicate your aseptic manufacturing operations were not in control. Without a comprehensive assessment of contamination hazards, and a CAPA that builds more holistic risk mitigation into your operational design, there is no assurance that you can prevent recurrence of sterility problems due to various latent or active failure modes in your operation.
这些培养基灌装污染表明你们的无菌生产操作没有得到控制。如果没有对污染危害的全面评估，以及在操作设计中构建更全面的风险缓解的CAPA，则无法保证您可以防止由于操作中各种潜在或主动失效模式而导致的无菌问题的再次发生。
We acknowledge that your firm took significant steps in response to the media fill failures, including a Field Alert Report, batch rejections, and suspension of operations.
我们承认贵公司采取了重大措施来应对培养基灌装失败，包括现场警报报告、批次拒绝和暂停运营。
Your firm’s response is inadequate. You state that “... the media fill investigations determined root cause of each media fill event, supported the establishment of CAPA to prevent future recurrence as well as the decisions made in relation to the product under scope of the events.” However, you continued to observe contaminated units in subsequent media fills. The recurring incidents of contaminated units in media fills are an indicator of an adverse trend in your aseptic filling line. You did not provide a comprehensive assessment of contamination risk factors in your aseptic processing operations that support robust and holistic remediations to your aseptic processing operation design. Systemic remediations are essential to address a pattern of recurring contamination events and ensure sustainable control of your aseptic processing operations.
贵公司的回复不充分。您声明“……培养基灌装调查确定了每个培养基灌装事件的根本原因，支持建立CAPA以防止未来再次发生，以及与事件范围内的产品相关的决策。”然而，您在随后的培养基灌装中继续观察到受污染的单元。培养基灌装中重复发生的受污染单元事件表明无菌灌装线存在不良趋势。您没有对无菌加工操作中的污染风险因素进行全面评估，从而支持对无菌加工设计进行稳健和全面的补救。系统补救对于解决重复发生的污染事件模式和确保无菌加工操作的可持续控制至关重要。
The response also lacks adequate justification to support the sufficiency of your CAPA activities. For example, regarding the October 5, 2021, media fill, your response fails to adequately explain how your CAPA will ensure the(b)(4) syringe in your (b)(4) will no longer cause contamination of the sterile product pathway. This type of fragility questions the basic functionality and selection of a system that is explicitly designed to maintain sterility. You also did not adequately address whether you intend to revisit the area classification, the (b)(4) equipment choice or supplier of this system considering the media fill finding.
您的回复也缺乏足够的理由来支持你们CAPA活动的充分性。例如，关于2021年10月5日的培养基灌装，你们的回复未能充分解释你们的CAPA将如何确保你们xx中的xx注射器不会再对无菌产品通路造成污染。这种类型的脆弱性对系统的基本功能和选择提出了质疑，而系统的设计明确是为了保持无菌性。你们也没有充分说明考虑到培养基灌装发现，决定是否打算重新审视区域分类、设备选择或该系统的供应商。
总结：从2021年4月到11月在培养基灌装中，屡次出现微生物污染事件，并且根据调查，污染的来源有损坏设备的污染，人员带入，消毒不充分等，屡次发生的污染事件，证明未执行有效的CAPA，
整改措施：
1.微生物污染事件应深究根本原因，扩大调查范围，举一反三，针对此案例中多次出现因设备而出现的微生物污染事件，初次所执行的CAPA应不止针对于污染涉及设备，应扩大范围，制定出更为有效的预防措施；
2.对于微生物高单位污染单元，应进行微生物的分离鉴定，以更好的确定污染源；
3.所制定的CAPA应是科学有效，能够避免类似事件的再发生，
如：
针对设备所导致的微生物污染，解决措施不应补仅限于表面补救，应充分评估污染来源，甚至评估设备的适用性，必要时进行设备维护、更新，甚至是更换。
针对于案例中所提及的消毒不充分所导致的污染事件，一方面应是加强人员培训，保证消毒操作的规范性，另一方面需评估消毒计划的有效性，是否能够满足消毒的要求，以及从监管的角度强化管理。
4.对于屡次发生的污染事件，需对不良趋势进行深入分析，评估前后污染事件的相关性，研究此前制定的CAPA是否充分有效，是否需要制定新的预防措施来保证无菌操作。