近日，FDA在Empower Clinic Services, LLC dba Empower Pharma的警告信中提及多项环境监测偏差处理相关的缺陷：

 

该公司在 ISO 5 生产区域内的环境监测（EM）检测到阳性微生物生长，但还是放行了该批无菌药品。

 

该公司此后答复：已修改了EM响应计划程序，要求：在最终无菌过滤和灌装期间，在 ISO 5区域内检测到微生物将导致相关批次的拒签。但是FDA认为该回复不充分并表示：该修订仅限于无菌灌装和过滤的两个生产步骤。

 

FDA发现该公司ISO 5 层流罩内部有缝隙和小孔。该公司的气流流型研究未包括缝隙和小孔对气流的影响。

 

该公司ISO 5层流罩的非活性粒子超出行动限。该公司的调查表明，可能导致偏差的因素是机器或操作人员，并得出结论：没有已知的产品影响，并放行了整批产品，但它没有提供放行整个批次的充分理由。FDA在警告信中表示：任何超过既定行动限的偏差都可能影响产品质量。

 

该公司在操作人员的手指采样中检查到一种真菌，即 浆果红酵母菌（Rhodotorula bacarum）。该公司的调查表明最可能的原因是操作人员更衣或无菌技术不良。因此，操作人员被取消了无菌生产资格，并且该批次被拒绝。然而，调查并不充分，因为它缺乏对操作人员在 EM 结果出来之前生产的所有批次的评估。

 

此外，该公司在 2023 年 8 月16 日至 9 月 14 日期间启动了大约14 个不符合项 （NC） 来调查EM偏移。在短短20天内，大约报告了 32 次 EM 偏移。大量 EM 偏差“引起了对无菌生产设施内整体受控状态的担忧。

 

在更衣间的日常环境监测样本中发现了木犀草假单胞菌，同一天XX批产品被无菌灌装。产品被放行。

 

缺陷翻译如下：

 

1. Your firm released a batch of a drug product intended to be sterile even though positive microbial growth was detected during environmental monitoring (EM) within the ISO 5 production area. You did not provide an adequate product impact assessment for Pyridoxine HCL lot 609763 compounded on April 18, 2024, when our investigators identified the observation during the inspection. As noted above, we acknowledge your recall of this lot on September 5, 2024. Your response stated you have revised your EM response program procedure to include the requirement that any recovery of a microorganism within an ISO 5 area during final aseptic filtration and filling shall result in the rejection of the associated batch. However, your revision was limited to only two processing steps for aseptic filling and filtration, although any operation in the ISO 5 area has the potential to be affected. Your responses did not provide an investigation update for the microbial failure in which 1 CFU of Bacillus altitudinis/pumilus/safensis was recovered on a surface contact plate inside the ISO 5 laminar airflow hood (LAFH) during aseptic filling. You identified the likely root cause as man (human) and a contributing factor as method due to sampling error, but your investigation did not include any documented preventive actions regarding proper aseptic technique and proper sampling.

 

贵公司在 ISO 5 生产区域内的环境监测（EM）检测到阳性微生物生长，但还是放行了该批无菌药品。你们未对609763批次的盐酸吡哆醇进行适当的产品影响评估，直到2024 年 4 月 18 日我们的检查人员在检查期间发现该结果。我们知道你们于2024 年 9 月 5 日召回此批产品。你们回复表示，已修改了EM 响应计划程序，以包括以下要求：在最终无菌过滤和灌装期间，在 ISO 5区域内检测到微生物将导致相关批次的拒签。尽管在ISO 5 区域的任何操作都有可能被（EM阳性）影响，但是，你们的修订仅限于无菌灌装和过滤的两个生产步骤。你们的回复没有提供微生物偏差的调查更新，其中在无菌灌装期间，在ISO 5 层流罩 （LAFH） 内的表面接触皿上检测到 1 CFU 的高地芽孢杆菌/短小芽孢杆菌/沙福芽孢杆菌。你们确定了可能的根本原因是人为因素（采样错误），但你们的调查不包括任何关于适当无菌技术和正确采样的书面预防措施。

 

2. Our investigators observed 6-inch horizontal gaps below the back wall of the ISO 5 LAFH and the bar holes on the side wall of the ISO 5 E2150 LAFH. Your smoke study from June 26, 2023, was not conducted under dynamic conditions to demonstrate unidirectional airflow to include the impact of the gaps and bar holes on your aseptic process in your ISO 5 LAFHs, and to show that airflow could exit through the gaps in the back wall, which could prevent airflow from the ISO 7 cleanroom from entering the ISO 5 LAFH. We acknowledge that you executed an addendum to the original protocol and provided a summary table within document number B-REP-QAL-0168. However, your response did not include an executed protocol per B-PROT-QAL-0069 with documentation completed nor a video with your visual airflow study for review. Your response also lacked an assessment on product impact on lots within expiry made since the smoke study was performed to mitigate any potential concerns until your addendum was completed.

 

我们的检查人员观察到 ISO 5 层流罩内的后下方有 6 英寸的缝隙，以及侧壁上有小孔。你们于 2023 年 6 月 26 日烟雾研究不是在动态条件下进行的，包括那些缝隙和小孔对 ISO 5层流罩无菌工艺的影响，以证明气流是单向的，并证明气流会通过这些缝隙和小孔对外排出，以防止ISO 7 洁净室的气流进入 ISO 5 层流罩。我们确认你们执行了原始方案的附录，并在文件编号B-REP-QAL-0168 中提供了汇总表。但是，你们的回复不包括根据 B-PROT-QAL-0069执行的方案的已完成文件，也没有包含你们的气流可视化研究以供审查的视频。你们的回复也缺乏对产品对有效期内批次影响的评估。

 

3. Your firm exceeded your action level of non-viable particles in the ISO 5 hood during the production of Ascorbic Acid Preserved 500 mg/mL Injection 30 mL lot(b)(4) filled on June 17, 2024. The (b)(4) system (b)(4) counter recorded a total plate count (TPC) that exceeded the action level for particles greater than or equal to (b)(4) microns, according to your internal specification. Your investigation stated the likely contributing factor to the failure was the machine or operator. Your investigation concluded no known product impact, and you released the full batch of Ascorbic Acid Preserved 500 mg/mL Injection 30 mL lot (b)(4). Your investigation stated the operator was properly gowned and maintained proper aseptic practices, but it did not provide an adequate rationale for releasing the whole batch. Your investigation also did not adequately assess the impact of the failure to the ISO 5 environment, for example investigating other operations that had occurred in the ISO 5 area. Any excursion that exceeds an established action level could potentially affect product quality. This is a repeat violation that was discussed during the May 4, 2023, regulatory meeting regarding your failure to establish and follow appropriate written procedures to prevent microbiological contamination.

 

贵公司在 2024 年 6 月17 日灌装的30 mL抗坏血酸保鲜注射液500 mg/mL批次 （b）（4） 的生产过程中， ISO 5 层流罩的非活性粒子超出行动限。根据你们的内部标准，（b）（4） 系统 （b）（4） 计数器记录的TPC结果超出行动限。你们的调查表明，可能导致偏差的因素是机器或操作人员。你们的调查得出结论，没有已知的产品影响，并且你们放行了整批30 mL抗坏血酸保鲜液注射液 500 mg/mL批次 （b）（4）。你们的调查表明，操作人员穿着适当的洁净服并保持了适当的无菌操作，但它没有提供放行整个批次的充分理由。你们的调查也没有充分评估偏差对 ISO 5 环境的影响，例如，调查在 ISO 5 区域中发生的其他操作。任何超过既定行动限的偏差都可能影响产品质量。

 

4. Your firm’s investigation of EM out of specification (OOS) results during aseptic batch processing was inadequate. The investigators noted that a fungus,Rhodotorula bacarum, was identified on fingertip samples from an operator during the filling operations on May 4, 2023, of Lipo-B/Methionine/Choline Chloride/Cyanocobalamin 25/50/1 mg/mL, lot (b)(4). Your firm investigated this issue under non-conformance (NC)-000518, but did not determine a definitive root cause. The most probable cause was identified as inadequate gowning or aseptic technique by the operator. Consequently, the operator was disqualified from aseptic production and the batch was rejected. However, the investigation was inadequate as it lacked an assessment on any batches the operator produced before the EM results were available. Also, your investigation stated this employee was working as your (b)(4) equipment lead operator, “which increases the risk of a potential impact to the final product.” Your investigation did not include an assessment of potential other batches involving this operator that utilized the (b)(4) equipment before the EM results were available.

 

贵公司对无菌批处理过程中 EM 不合格 （OOS） 结果的调查不充分。检查人员指出，在 2023 年 5 月 4 日的灌装操作期间，在操作人员的手指采样中检查到一种真菌，即 浆果红酵母菌（Rhodotorula bacarum）。贵公司根据不合格项 （NC） -000518 调查了此偏差，但未确定明确的根本原因。最可能的原因是操作人员更衣或无菌技术不良。因此，操作人员被取消了无菌生产资格，并且该批次被拒绝。然而，调查并不充分，因为它缺乏对操作人员在 EM 结果出来之前生产的所有批次的评估。此外，你们的调查表明，该操作人员是 （b）（4） 设备的主操员，“这增加了对最终产品产生潜在影响的风险”。你们的调查不包括对涉及该操作人员的其他潜在批次的评估，该操作人员在 EM 结果出来之前使用了（b）（4） 设备。

 

In addition, your firm opened approximately fourteen non-conformances (NCs) to investigate EM excursions between August 16 through September 14, 2023. According to your investigation report NC-000673, there were approximately thirty-two NCs for EM excursions reported between August 24 through September 14, 2023. Your investigation report stated the presence of a significant number of EM excursions spanning this period “raises concerns regarding the overall state of control within the 503B aseptic processing suites.”

 

此外，贵公司在 2023 年 8 月16 日至 9 月 14 日期间启动了大约14 个不符合项 （NC） 来调查EM偏移。根据你们的调查报 NC-000673，在 2023 年 8 月 24 日至9 月 14 日期间，大约报告了 32 次 EM 偏移。你们的调查报告指出，在此期间存在大量 EM 偏差“引起了对 503B 无菌生产设施内整体受控状态的担忧”。

 

During a view of the combined NC investigation for these EM excursions, your firm failed to extend the investigation to other batches produced. For example, your firm did not include injectable drug product Glutathione 200mg/mL, lot(b)(4); however this lot was manufactured on August 16, 2023. In addition, Pseudomonas luteola was identified in a routine EM sample collected from the gowning room on August 16, 2023, the same day this lot was aseptically filled. Your response did not include an investigation regarding lot (b)(4). You stated you have revised your Environmental Monitoring Excursion Response Program procedure to extend investigations to other products and lots that may be impacted by the EM excursion. However, it does not appear that your firm is taking a holistic approach to this topic by only making updates to the EM response program procedure. We acknowledge your investigation into these EM excursions stated that most of the referenced batches will be rejected, however we remain concerned with your investigations not always extending to other batches and processes that may be affected. This has been a reoccurring concern from the last inspection and this violation was discussed with you during the May 4, 2023, regulatory meeting.

 

在审查针对这些 EM 偏移的调查期间，贵公司未能将调查扩展到所生产的其他批次。例如，贵公司未包括注射产品谷胱甘肽200 毫克/毫升，批次 （b）（4）;然而，这个批次是在 2023 年8 月 16 日制造的。此外，在 2023 年 8 月 16 日从更衣间的日常环境监测样本中发现了木犀草假单胞菌，同一天该批次被无菌灌装。你们的回复不包括对批次 （b）（4） 的调查。你们表示，已修订了环境监测偏移响应程序，以将调查范围扩大到可能受EM 偏移影响的其他产品和批次。贵公司似乎并没有通过更新EM响应程序来采取整体方法来解决这个问题。我们知道你们对这些EM 偏差的调查表明，大多数相关的批次都将被拒绝，但我们仍然担心你们的调查并不总是扩展到可能受影响的其他批次和工艺。

来源：GMP办公室

关键词： 环境监测 无菌药品