FDA警告信中微生物污染案例-案例一

缺陷如下：

Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).

贵公司未能建立并遵循适当的书面程序，该程序旨在防止无菌的药品的微生物污染，并包括所有无菌和灭菌工艺的验证(21 CFR 211.113(b))。

Media Fill Contamination Incidents 培养基灌装污染事件

You failed to appropriately evaluate a pattern of media fill failures in your facility and afford sufficient attention to potential correlations among these contamination events. Between February 2021 and March 2022, there were multiple aborted and contaminated media fills on(b)(4) filling lines (b)(4) and (b)(4) (solution and suspension lines). For example,

未能恰当地评估培养基灌装失败，并对这些污染事件之间的潜在相关性给予足够的关注。在2021年2月至2022年3月期间，在溶液线和混悬剂线上的培养基灌装存在多次终止和污染事件。例如,

In September 2021, you isolated a gram-negative microbe, Ralstonia picketii, from multiple media     fill (b)(4) of Batch # (b)(4) manufactured     on the (b)(4) suspension line. You identified multiple     deviations such as damaged filter housing, choked (b)(4),     dislocation of the filter, and ineffective (b)(4) processes.

2021年9月，从混悬剂线上多批培养基灌装批次中，分离出一种革兰氏阴性微生物，皮氏罗尔斯顿式菌。你们发现了多个偏差，如过滤器外壳损坏、堵塞(b)(4)过滤器错位和过程中失效。

In November 2021, you isolated Pseudomonas     stutzeri from one (b)(4) of media fill     Batch # (b)(4) manufactured on the (b)(4) suspension     line. This media fill (Batch # (b)(4)) was performed as part     of the initial qualification of the suspension line and as a corrective     action for a previously failed media fill on the same line (Batch #(b)(4)).     You identified Pseudomonas stutzeri to be a gram-negative     opportunistic pathogen. Your investigation, reviewed during the inspection     and further described in your response, indicated this contamination was     due to a puncture in the body of the (b)(4) by a (b)(4) during     handling or movement of the filled samples, storage, or visual inspection,     prior to incubation. However, you lacked adequate evidence that described     mishandling of (b)(4). Further, your investigation also does     not include comprehensive steps to prevent future mishandling of incubated     units, and indicates use of (b)(4) will still be     permitted. Your QU approved the investigation and the media fill run for     Batch # (b)(4), and you used this media fill as one of three     successful runs required to qualify filling line (b)(4) for     suspension products.

2021年11月，从（b）（4）混悬剂线上培养基灌装中的一个批次（b）（4）中分离出斯氏假单胞菌。该培养基灌装（批次#（b）（4））是作为混悬剂线初始确认的一部分进行的，也是对同一管线上先前失败的培养基灌装的纠正措施（批次#）。你们鉴定了斯氏假单胞菌是革兰氏阴性条件致病菌。你们的调查，在检查期间进行了审核，并在你们的回复中进一步描述，表明该污染是由于在处理或移动灌装样品、储存或培养前的目视检查期间，xx在xx体内穿孔造成的。然而，你们缺乏足够的证据来描述xx的不当处理。此外，你们的调查也没有包括全面的步骤来防止未来对培养工序的不当操作，并表明使用(b)(4)仍将被允许。您的QU批准了批次#的调查和培养基灌装继续进行(b)(4)，并且您将该培养基灌装作为合格悬浮液产品灌装线（b）和（4）所需的三次成功运行之一。

In March 2022, you isolated Stenotrophomonas maltophilia in     multiple media fill (b)(4) of Batch # (b)(4).     You identified Stenotrophomonas maltophilia to be a     drug-resistant gram-negative emerging global opportunistic pathogen with a     known propensity for biofilm formation. You determined the root cause to     be a leakage caused by a damaged valve gasket and deformed filter.

2022年3月，你分离了嗜麦芽窄食单胞菌在培养基灌装中(b)(4)批次号(b)(4)。你们确定嗜麦芽窄养单胞菌是一种耐药革兰氏阴性新出现的全球机会性病原体，已知具有生物膜形成倾向。你们确定根本原因是由阀门垫圈损坏和过滤器变形引起的泄漏。

You failed to appropriately investigate root causes and implement effective CAPAs to prevent recurrence of contamination events. For example, you failed to substantively evaluate the personnel and environmental monitoring (EM) data obtained during the production of these media fill batches, and to comprehensively assess additional historical data from the manufacturing area.

你们未能适当调查根本原因并实施有效的CAPA以防止污染事件再次发生。例如，你们未能实质性地评估这些培养基灌装批生产期间人员和环境监测(EM)数据，也未能全面评估生产区域的其他历史数据。

Your response is inadequate because there is no overall assessment of these atypical invalidations of media fills, explanation of the adverse pattern of gram-negative microbe findings in your aseptic processing operational environment, or major improvements to ensure more reliable aseptic operational design and equipment maintenance.

你们的回复是不充分的，因为你们没有对这些培养基灌装的非典型失效进行全面评估，没有解释你们无菌模拟中发现革兰氏阴性微生物，也没有进行重大改进以确保更可靠的无菌操作设计和设备维护。

The presence of any highly pathogenic microorganism in your aseptic processing environment presents a heightened risk to patients who are, for example, immunocompromised, have cystic fibrosis, or have chronic obstructive airway disease. Presence of such microbes should receive urgent investigation and effective remediation. Further, it is critical to ensure appropriate equipment design and maintenance, as equipment failures may not be easily observable and contamination events during commercial manufacturing may go undetected for substantial periods of time.

无菌加工环境中任何高致病性微生物的存在，对免疫功能低下、囊性纤维化或慢性阻塞性气道疾病的患者都有更高的风险。这些微生物的存在应该得到紧急调查和有效的补救。此外，确保适当的设备设计和维护是至关重要的，因为设备故障可能不容易观察到，并且在商业化生产期间的污染事件可能在很长一段时间内无法检测到。

It is essential to address potential contamination hazards in your manufacturing environment in a timely manner. Any adverse microbiological trends and potential routes of contamination should be identified promptly, allowing for implementation of appropriate follow-up measures to prevent contamination. It should also be noted that finished product testing alone cannot establish sterility of all units because contamination is typically episodic and not uniformly distributed.

及时处理你们生产环境中的潜在污染危害是至关重要的。任何不利的微生物趋势和潜在的污染途径应及时确定，以便实施适当的后续措施，以防止污染。还应注意的是，成品检测本身不能确定所有单位的无菌性，因为污染通常是偶发的，而且分布不均匀。

总结：培养基灌装屡次出现的微生物污染事件，未进行深入、全面的研究，以及执行有效的CAPA，未进行微生物污染的趋势分析。

整改建议：

1. 1.      微生物污染事件首次发生时，需进行深入彻底、全面的分析评估，分离鉴定菌株，找出真正的污染源，对期间涉及批次进行调查，必要时进行召回；

2. 2.      针对污染事件，根据调查的原因，制定出有效的解决措施以及预防措施，避免类似事件的发生；

3. 3.      针对类似或重复出现的污染事件，定期对生产线环境监控、水系统、物料包材和产品结果，及设备设施维护状态进行回顾分析，防患于未然。