近日，FDA发布了对Aspen Pharmacare Holdings Limited的警告信，其中提及大量的无菌生产操作缺陷，如下：

 

产品放行和稳定性测试中未测试某杂质，该公司表示杂质限度是根据客户的要求确定的，并且放行标准对此没有任何限值。并提供了客户的健康危害评估（HHE），该评估得出的结论：高达标签含量（b）（4）%的杂质的稳定性水平，不会对按照说明使用产品的用户造成任何安全风险。FDA不认同该HHE 评估，并得出结论，在推荐剂量下，（b）（4）% 的杂质水平可能会对患者安全构成风险。

 

无菌操作不良

 

操作人员将戴手套的手直接放在未加塞的无菌瓶子上从而堵塞了第一空气，而未将其从无菌灌装线中清除。

 

操作人员使用戴手套的手而未使用适当的无菌工具来清除卡住的瓶子。

 

关键区域的操作人员移动并不总是缓慢和小心翼翼的。

 

操作人员使用的护目镜有许多开孔，因此在生产线装配和无菌生产过程中会暴露皮肤。

 

培养基灌装批次中发现了污染，确定了不良无菌行为的根本原因。这些污染事件以及检查期间观察到的不良无菌实践表明，无菌生产操作可能缺乏足够的控制。

 

开门干预需要打开一个很大的门。在许多情况下，门会长时间保持打开状态，但生产线仍在运行。打开时，门暴露在 ISO 7 区域，关闭时，存在较低质量的空气卷入到 ISO 5 无菌生产区域的重大风险。未加塞的空玻璃瓶位于离这个门非常近的地方。此外，操作人员没有对打开的门进行充分的消毒。在（b）（4）上喷洒消毒剂时，操作人员没有考虑生产线上未加塞的玻璃瓶，使其面临潜在污染。

 

烟雾研究和洁净室设计不足

 

烟雾研究缺乏对无菌生产线装配、动态操作和无菌生产操作期间发生的干预的模拟。

 

烟雾的产生不足以证明单向气流。

 

操作人员和传送带上开放的玻璃瓶之间没有物理屏障。你们的生产操作人员一直在 ISO 5 无菌加工区域内，坐在或站在输送未加塞玻璃瓶的传送带旁边。

 

对无菌生产线及其暴露的无菌药品和容器/瓶塞进行了大量的人工干扰。

 

操作人员在多次过滤器完整性测试失败后只收集并打印了合格结果。操作人员没有记录或打印失败的结果。

 

没有对操作人员一直在里面清除掉落的瓶子的 ISO 5 区域中的空气和表面进行微生物监测。

 

在线粒子探头放置位置存在缺陷

 

缺陷翻译如下：

 

1. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).

 

贵公司未能建立实验室控制措施，包括科学合理且适当的规范、标准、取样计划和测试程序，以确保组件、药品容器、瓶盖、生产物料、标签和药品符合适当的特性、强度、质量和纯度标准 （21 CFR 211.160（b））。

 

Your firm did not establish appropriate specifications or test your sterile over-the-counter (OTC)(b)(4) drug products to monitor impurities at release and throughout expiry. For example:

 

贵公司未制定适当的标准或未能测试无菌药品以监测在放行时和整个有效期内的杂质。例如：

 

You did not perform impurity testing prior to release and     during stability for (b)(4).

 

你们在放行前和稳定性试验期间未进行杂质检测。

 

You did not establish scientifically justified specifications     to monitor impurities during stability testing of drug products containing     Naphazoline Hydrochloride or Tetrahydrozoline Hydrochloride active     pharmaceutical ingredient (API).

 

在对含有盐酸萘甲唑啉或盐酸四氢唑啉活性药物成分（API）的药品进行稳定性检测时，你们未制定科学合理的标准来监测杂质。

 

In your response, you state that the impurity limits were established based on your customer’s requirements and that no limits were included for release testing. You provide your customer’s health hazard evaluation (HHE) which concluded that the presence of Impurity(b)(4) at stability levels of up to (b)(4)% of the labeled (b)(4) content would not pose any safety risk for those that use the products according to directions. The Agency disagrees with the HHE assessment and concludes that the presence of impurity levels at (b)(4)% may pose a risk to patient safety at the recommended dosage. It is your responsibility to ensure that appropriate specifications are established to monitor impurities throughout the expiry period.

 

在回复中，你们表示杂质限度是根据客户的要求确定的，并且放行标准对此没有任何限值。你们提供了客户的健康危害评估（HHE），该评估得出的结论：高达标签含量（b）（4）%的杂质（b）（4）的稳定性水平，不会对按照说明使用产品的用户造成任何安全风险。FDA不认同该HHE 评估，并得出结论，在推荐剂量下，（b）（4）% 的杂质水平可能会对患者安全构成风险。你们有责任确保建立适当的标准，以在整个有效期内监测杂质。

 

Your response is inadequate. You lack adequate scientific rationale for the current impurity specifications of your drug products. A similar deficiency for the lack of impurity specifications for release and stability testing for(b)(4) API containing products was also identified during the 2016 inspection. However, this deficiency has not been fully addressed to date. Additionally, your risk assessment does not include an evaluation of reserve samples of potentially impacted product batches distributed to the United States.

 

你们的回复是不充分的。你们目前的药品杂质标准缺乏足够的科学依据。在 2016 年的检查中，还发现了类似的缺陷，即缺乏用于 （b）（4） API 产品放行和稳定性测试的杂质标准。然而，这一缺陷迄今尚未得到完全解决。此外，你们的风险评估不包括对已分销的潜在受影响产品批次的留样样品的评估。

 

Drug product batches must be tested for identity, strength, quality, and purity prior to release. Insufficient release and stability testing to appropriately detect impurities in your drug products could potentially impact product quality and patient safety.

 

药品批次在放行前必须进行鉴定、剂量、质量和纯度测试。如果放行和稳定性检测不足，无法正确检测药品中的杂质，可能会影响产品质量和患者安全。

 

2. Your firm failed to 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)).

 

贵公司未能遵循适当的书面程序，以防止声称无菌的药品受到微生物污染，包括验证所有无菌和灭菌工艺（21 CFR 211.113（b））。

 

Poor Aseptic Practices

 

无菌操作不良

 

During the inspection of your facility, we observed poor practices and behaviors in ISO 5 areas during the manufacturing of sterile(b)(4) drug products. These poor practices included, but were not limited to:

 

在检查期间，我们观察到无菌药品生产过程中 ISO 5 区域中的不良操作和行为。这些不良操作包括但不限于：

 

Operators blocked first air by placing their gloved hands     directly over open sterilized bottles without clearing them from the     aseptic filling line.

 

操作人员将戴手套的手直接放在未加塞的无菌瓶子上从而堵塞了第一空气，而未将其从无菌灌装线中清除。

 

Operators used their gloved hands instead of using appropriate     sterile tools to remove jammed bottles.

 

操作人员使用戴手套的手而不是使用适当的无菌工具来清除卡住的瓶子。

 

Operator movements in the critical areas were not always slow     and deliberate.

 

关键区域的操作人员移动并不总是缓慢和小心翼翼的。

 

Operators used goggles that had numerous open holes and     therefore had exposed skin during line set-up and aseptic processing.

 

操作人员使用的护目镜有许多开孔，因此在生产线装配和无菌生产过程中会暴露皮肤。

 

In 2022, your firm identified contamination in two media fill batches one on the “(b)(4)” aseptic filling line and another on the “(b)(4)” aseptic filling line. You identified the root cause as poor aseptic behavior. These contamination events along with the poor aseptic practices observed during our inspection indicate your aseptic manufacturing operations may lack adequate control. Your firm did not perform a sufficiently comprehensive evaluation of aseptic behavior of operators as part of this recurrent trend.

 

2022 年，贵公司在两个培养基灌装批次中发现了污染，一个在“（b）（4）”无菌灌装线上，另一个在“（b）（4）”无菌灌装线上。你们确定了不良无菌行为的根本原因。这些污染事件以及我们在检查期间观察到的不良无菌实践表明，你们的无菌生产操作可能缺乏足够的控制。贵公司没有对操作人员的无菌行为进行足够全面的评估，以作为这种反复出现的趋势分析的一部分。

 

We also note that open door interventions required a large door to be opened. On numerous occasions, the door remained opened for extended periods of time while the line was still in-operation. When opened, the door was exposed to the ISO 7 area, and when being closed, there was a significant risk of the lower quality room air sweeping into the ISO 5 aseptic processing area. Empty sterile containers were located extremely close to the door. In addition, operators did not adequately disinfect the open door. While spraying disinfectant on the(b)(4), operators failed to consider open sterilized bottles on the line, exposing them to potential contamination.

 

我们还注意到，开门干预需要打开一个很大的门。在许多情况下，门会长时间保持打开状态，但生产线仍在运行。打开时，门暴露在 ISO 7 区域，关闭时，存在较低质量的空气卷入到 ISO 5 无菌生产区域的重大风险。未加塞的空玻璃瓶位于离这个门非常近的地方。此外，操作人员没有对打开的门进行充分的消毒。在（b）（4）上喷洒消毒剂时，操作人员没有考虑生产线上未加塞的玻璃瓶，使其面临潜在污染。

 

Inadequate Smoke Studies and Cleanroom Design

 

烟雾研究和洁净室设计不足

 

Your smoke studies did not adequately demonstrate unidirectional air flow in the ISO 5 classified areas used for the aseptic filling of ophthalmic drug products on the “(b)(4)” and “(b)(4)” aseptic filling lines. For example:

 

你们的烟雾研究未充分证明无菌灌装线上用于无菌灌装的 ISO 5 区域中的单向气流。例如：

 

Your smoke studies lacked simulation of aseptic line set-up,     dynamic operations, and interventions that occur during aseptic     manufacturing operations.

 

烟雾研究缺乏对无菌生产线装配、动态操作和无菌生产操作期间发生的干预的模拟。

 

Generation of smoke was not sufficient to demonstrate     unidirectional air flow.

 

烟雾的产生不足以证明单向气流。

 

We also note that there were multiple aspects of your cleanroom and aseptic processing line design which represented fundamental contamination risks:

 

我们还注意到，你们的洁净室和无菌加工生产线的设计有多个方面存在污染风险：

 

There was no physical barrier between the operator and the     open (b)(4)-sterilized bottles on the conveyor. Your     production operator remained inside the ISO 5 aseptic processing area,     sitting or standing next to the conveyor line where open, exposed bottles     pass.

 

操作人员和传送带上开放的玻璃瓶之间没有物理屏障。你们的生产操作人员一直在 ISO 5 无菌加工区域内，坐在或站在输送未加塞玻璃瓶的传送带旁边。

 

There were extensive manual interactions with the aseptic     processing line and its exposed sterile drug product and     containers/closures.

 

对无菌生产线及其暴露的无菌药品和容器/瓶塞进行了大量的人工干扰。

 

Operators performed multiple manual interventions during     filling by (b)(4) or (b)(4) due to (b)(4) not     being installed on these (b)(4). These interventions may pose     inherent risks to your aseptic processes.

 

由于未将（b）（4） 安装在（b）（4） 上，因此操作人员在通过 （b）（4） 或 （b）（4） 进行灌装期间执行了多次人工干预。这些干预措施可能会给你们的无菌工艺带来固有的风险。

 

The ISO 5 area is critical because sterile product is exposed and therefore vulnerable to contamination. Your aseptic filling process should be designed, and operations executed, to prevent contamination hazards to your sterile product. The flawed design of the filling line and execution of the aseptic operations promote influx of contamination into the critical filling areas.

 

ISO 5 区域至关重要，因为无菌产品暴露在其中，因此容易受到污染。你们的无菌灌装工艺应经过精心设计，并应以防止对无菌产品造成污染风险的方式操作。灌装线的缺陷设计和无菌操作不良加剧了污染物流入关键的灌装区域。

 

In your response, you indicate that you temporarily suspended manufacturing on the “(b)(4)” aseptic filling line. You acknowledge that the design of your aseptic filling lines is not optimal and indicate that an independent review of your design and remediation plans for both “(b)(4)” and “(b)(4)” aseptic filling lines will be performed. You also commit to perform new smoke studies under static and dynamic conditions and evaluate associated risks. You indicate that you have engaged a third-party consultant to assist in improving aseptic practices.

 

在你们的回复中，你们表示暂时停止了“（b）（4）”无菌灌装线的生产。你们承认你们的无菌灌装线的设计并非最佳，并表示将对你们的 “（b）（4）” 和 “（b）（4）” 无菌灌装线的设计和补救计划进行独立审查。你们还承诺在静态和动态条件下进行新的烟雾研究，并评估相关风险。你们表示已聘请第三方顾问协助改进无菌实践。

 

Your response is inadequate because it does not sufficiently address the lack of oversight of aseptic behavior of operators. Further, you do not adequately investigate poor aseptic practices to determine the impact on sterile drug products manufactured and aseptic processing areas. You also do not clearly specify how you will improve your smoke studies, including what interventions will be included, and how you will address potential deficiencies.For additional guidance on aseptic processing see FDA’s guidance document,Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing at https://www.fda.gov/media/71026/download.

 

你们的回复是不充分的，因为它没有充分解决对操作人员无菌行为缺乏监督的问题。此外，你们没有充分调查不良的无菌实践，以确定对无菌药品生产和无菌加工区域的影响。你们也没有明确说明将如何改进烟雾研究，包括将包括哪些干预，以及将如何解决潜在的缺陷。有关无菌加工的其他指南，请参阅 FDA 指南文件《无菌加工生产的无菌药品 -现行药品生产质量管理规范》：https://www.fda.gov/media/71026/download。

 

3. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

 

贵公司未能对计算机或相关系统进行适当的控制，以确保只有经授权人员才能更改主生产和控制记录或其他记录 （21 CFR 211.68（b））。

 

Your Production and QU did not review electronic raw data and audit trails to ensure data integrity prior to batch release. Your operators obtained and printed a passing result after multiple production filter integrity tests failed. Your operators did not record or print the failing results. For example:

 

你们的生产和质量部门在批放行之前未审查电子原始数据和审计追踪以确保数据完整性。你们的操作人员在多次过滤器完整性测试失败后只收集并打印了合格结果。你们的操作人员没有记录或打印失败的结果。例如：

 

On August 8, 2024, two operators performed four post-use     sterilizing filter integrity tests for (b)(4) batch (b)(4).     The four tests included three failing results and the final passing     result. Your operators only reported the passing result.

 

2024 年 8 月 8 日，两名操作人员对（b）（4）批次进行了4次使用后除菌过滤器完整性测试。这四次测试包含 3 次不合格结果和最终合格结果。你们的操作人员只报告了合格的结果。

 

On July 25, 2024, two operators performed nine filter integrity     tests associated with (b)(4), bulk batch (b)(4).     The nine tests included five failing results, three aborted tests, and the     final passing result. Your operators only reported the passing result.

 

2024 年 7 月 25 日，两名操作人员进行了9 次过滤器完整性测试。这 9 个测试包括 5 个失败的结果、3 个中止的测试以及最终的合格结果。你们的操作人员只报告了合格的结果。

 

In your response, you acknowledge the deficiency and commit to perform a full audit trail review of your production equipment. You also indicate that you are completing the investigations into anomalous filter integrity tests.

 

在你们的回复中，你们承认存在缺陷并承诺对生产设备进行全面的审计追踪审查。你们还表明正在完成对异常过滤器完整性测试的调查。

 

Your response is inadequate as you do not provide details of the investigation outcome or explain whether effective corrective actions and preventive actions (CAPAs) have been implemented. Further, you do not provide the scope and time period of the retrospective review to ensure all batches potentially affected are part of the assessment.

 

你们的回复是不充分的，因为没有提供调查结果的详细信息或解释是否已实施有效的纠正措施和预防措施（CAPA）。此外，你们没有提供回顾性审查的范围和时间段，以确保所有可能受影响的批次都被评估。

 

4. Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas (21 CFR 211.42(c)(10)(iv)).

 

贵公司未能建立适当的系统来监测无菌加工区域的环境条件 （21 CFR 211.42（c）（10）（iv））。

 

You did not establish an adequate system for monitoring environmental conditions on the “(b)(4)’ aseptic filling line. For example:

 

你们没有建立适当的系统来监测“（b）（4）”无菌灌装线的环境条件。例如：

 

You did not conduct viable monitoring of the air and surfaces     in ISO 5 areas where an operator was continuously present removing fallen     bottles.

 

你们没有对操作人员一直在里面清除掉落的瓶子的 ISO 5 区域中的空气和表面进行微生物监测。

 

You did not place the non-viable particle monitoring (NVPM)     probes in representative ISO 5 areas where the product and primary     components were exposed. Our investigators noted the following:

 

你们没有将非活性颗粒子监测（NVPM） 探头放置在产品和主要组件暴露的代表性 ISO 5 区域。我们的检查人员注意到以下内容：

 

The NVPM probe closest to the (b)(4) was located     approximately (b)(4) above the level of the (b)(4).

 

最靠近 （b）（4） 的 NVPM 探头位于     （b）（4） 水平上方约 （b）（4） 的位置。  

 

The NVPM probe nearest to the sterile cap (b)(4) was     located approximately (b)(4) above the level of the (b)(4).

 

最靠近无菌铝盖（b）（4）的 NVPM 探头位于（b）（4）水平上方约 （b）（4） 处。

 

Your operators routinely placed mobile NVPM devices in     locations different from those specified in your procedures to monitor the     ISO 5 areas. As such, NVPM data may not accurately represent the critical     areas in operation.

 

你们的操作人员通常会将移动 NVPM 设备放置在与你们的程序中指定的位置不同的位置，以监控 ISO 5 区域。因此，NVPM 数据可能无法准确代表生产中的关键区域。

 

In your response, you commit to upgrade your “(b)(4)” aseptic filling line and perform a Quality Risk Assessment for NVPM in Suite(b)(4).

 

在你们的回复中，你们承诺升级“（b）（4）”无菌灌装线，并对NVPM 进行质量风险评估。

 

Your response is inadequate. While you commit to conducting a Quality Risk Assessment for NVPM to identify, assess, and mitigate all gaps, you have not provided any updates on the status of risk assessment. Vigilant and responsive environmental monitoring programs should be designed to provide meaningful information on the state of control of your aseptic processing environment. Operations that include highly manually intensive aseptic activities warrant a more extensive environmental and personnel monitoring program, including but not limited to, heightened emphasis on well-timed sampling to appropriately monitor batch manufacturing conditions.

 

你们的回复是不充分的。虽然你们承诺对 NVPM 进行质量风险评估以识别、评估和缓解所有差距，但尚未提供有关风险评估状态的任何更新。应设计警惕且反应迅速的环境监测计划，以提供有关无菌加工环境控制状态的有意义信息。包括高度手动密集型无菌活动的操作需要更广泛的环境和人员监测计划，包括但不限于，更加强调及时采样，以适当监测批次生产条件。