近日，FDA发布了Global Calcium Pvt. Limited的警告信，其中提及各类记录造假、厂房维护和杂质控制问题：

FDA检查该公司批记录和设备日志，发现两个产品的生产活动在同一设备上同时发生。

在检查期间删除了多个电子记录。例如，在检查的第一天早上，检查人员在工厂的某生产办公室的台式计算机上看到了 Microsoft Excel 文件：包括但不限于“XX清洁验证样品”、“XX生产详细信息-2024”、“2024 年 6 月 工厂-XX生产报告”和“2024 年 6 月-计划”。第二天，检查人员返回该生产办公室审查这些文件。但是，所有文件都已被删除，并且在检查期间无法恢复。

该公司承认生产主管指示伪造生产记录来编排 API 生产活动，以便可以就XX工厂的生产索取奖励。

该公司表示删除 Microsoft Excel 文件是为了“避免与检查人员进行不必要的对话”，并补充说有问题的计算机是“个人使用以记录日常活动”。

检查人员观察到一个房间地板有一个洞，里面中装有XX液体。类似的液体从这个房间的天花板管道连接处滴落。液体滴落在标已清洁和待使用的生产设备上。

未能对制造过程进行全面评估以识别所有潜在杂质。某API的杂质概况仅列出了USP中描述的那些杂质，而没有考虑特定于工艺和物料来描述典型批次中的其他杂质。此外，未能对每个已识别的杂质进行充分分类。在稳定性研究期间没有监测杂质。

警告信缺陷翻译如下：

1. Failure of your quality unit to prepare, review, and approve documents related to the manufacturing of APIs in accordance with written procedures.

质量部门未能按照书面程序准备、审查和批准与 API 制造相关的文件。

You provided production records for two different APIs that showed manufacturing activities occurred simultaneously on the same equipment. For example, your batch records and equipment logbooks show the same equipment including, but not limited to,(b)(4) were used at the same time to manufacture (b)(4) USP and (b)(4) USP.

你们为两个不同的 API 提供了生产记录，其中显示：这两个API的生产活动在同一设备上同时发生。例如，你们的批记录和设备日志显示相同的设备，包括但不限于（b）（4） 同时用于制造XX USP 产品和xx USP产品。

Additionally, you deleted multiple electronic records during the inspection. For example, on the initial morning of the inspection, investigators observed Microsoft Excel documents on a desktop computer in the Plant (b)(4) production office including, but not limited to, “(b)(4) Cleaning validation samples,” “(b)(4) Production Details-2024,” “Plant-(b)(4) production Report Jun-2024,” and “Planning June-2024.” On the second day, investigators returned to the production office to review these files. However, all files had been deleted and could not be recovered during the inspection. Without access to the files, the investigators were unable to determine their purpose and adequately evaluate your adherence to CGMP.

此外，你们在检查期间删除了多个电子记录。例如，在检查的第一天早上，检查人员在工厂 的某生产办公室的台式计算机上看到了 Microsoft Excel 文件：包括但不限于“XX清洁验证样品”、“XX生产详细信息-2024”、“2024 年 6 月 工厂-XX生产报告”和“2024 年 6 月-计划”。第二天，检查人员返回该生产办公室审查这些文件。但是，所有文件都已被删除，并且在检查期间无法恢复。由于无法访问这些文件，检查人员无法确定其目的并充分评估你们的CGMP 符合性。

In your response, you acknowledge your production head directed the creation of falsified manufacturing records to misrepresent API production activities so incentives could be claimed regarding production in plant (b)(4). Additionally, you state a lack of training and other factors resulted in deficient documentation control, then explain you have revised your SOP for document issuance and control. You also state Microsoft Excel files were deleted to “avoid unwanted conversation” with the investigators, and add the computers in question are for “personal use to record day to day activities” so there is no impact on product quality. We also acknowledge you performed a product quality impact assessment.

在你们的回复中，你们承认生产主管指示伪造生产记录来编排 API 生产活动，以便可以就XX工厂的生产索取奖励。此外，你们指出缺乏培训和其他因素导致文件控制不足，然后解释你们已经修改了文件发布和控制的 SOP。你们还表示删除 Microsoft Excel 文件是为了“避免与检查人员进行不必要的对话”，并补充说有问题的计算机是“个人使用以记录日常活动”，因此不会影响产品质量。我们还知道你们执行了产品质量影响评估。

Your response is inadequate. Your product quality impact assessment relies, in part, on data generated by your facility’s deficient documentation practices, and therefore is inherently unreliable. Furthermore, you do not adequately evaluate how widespread the practice of record fabrication extends throughout your facility, and you do not share in sufficient detail how you will prevent, detect, and investigate non-contemporaneously prepared records. You also do not adequately explain which, if any records were legitimate and pertain to actual product produced on your equipment. Considering your response states you created records that “falsely attributed” production activities to claim incentives, FDA is concerned about the adequacy of your remediation efforts given you have not sufficiently reconciled all CGMP records.

你们的回复是不充分的。你们的产品质量影响评估在一定程度上依赖于你们的工厂有缺陷的文件实践所产生的数据，因此本质上是不可靠的。此外，你们没有充分评估记录伪造在整个设施中的泛滥程度，并且你们没有足够详细地分享你们将如何预防、检测和调查非同步准备的记录。你们也没有充分解释哪些记录（如有）是合规并与你们设备生产的实际产品相关的。考虑到你们的回复表明你们伪造记录“编排”生产活动以申请奖励，鉴于你们没有充分核对所有 CGMP 记录，FDA 担心你们的补救工作是否充分。

2. Failure to properly maintain buildings and facilities used in the manufacture of APIs.

未能妥善维护用于制造 API 的厂房和设施。

You failed to maintain your facility in an acceptable state of repair. For example, investigators observed a room with (b)(4) liquid in a floor cavity surrounding the exit pipe of a (b)(4). A similar liquid was dripping from a ceiling pipe junction in the (b)(4) area below this room. The liquid was dripping onto processing equipment labeled as clean and ready for use.

你们未能将你们的设施保持在可接受的维护状态。例如，检查人员观察到一个房间，在 （b）（4） 的出口管道周围的地板有一个洞，里面中装有（b）（4）液体。类似的液体从这个房间（b）（4）区域的天花板管道连接处滴落。液体滴落在标已清洁和待使用的生产设备上。

It is essential your facility is in a good state of repair, and sanitary conditions are maintained to ensure ongoing suitability for drug manufacturing.

你们的设施必须处于良好的维护状态，并保持卫生条件，以确保持续适合药品生产。

In your response, you state no production activities were taking place in the (b)(4) area, as it was partially shut down to make various upgrades, and you state the damaged flooring has since been repaired. You also state personnel did not display proper signage in the area, as required by your procedure, and a change control had been initiated. Additionally, your deviation report submitted with your response states personnel were not aware of ongoing maintenance activities in Plant (b)(4).

在你们的回复中，你们表示 （b）（4） 区域没有进行生产活动，因为它已部分关闭以进行各种升级，并且你们表示损坏的地板已经修复。你们还指出，操作人员没有按照你们的程序要求在该区域展示适当的标识，并且已经启动了变更控制。此外，你们与回复一起提交的偏差报告指出，操作人员不知道工厂（b）（4）正在进行的维护活动。

3. Failure to establish an impurity profile for identified and unidentified impurities.

未能确定已鉴定和未鉴定杂质的杂质概况

You failed to conduct a comprehensive evaluation of your manufacturing processes to identify all potential impurities. For example, the impurity profile you provided for (b)(4) USP, only listed those impurities described in the United States Pharmacopeia (USP), without considering your unique processes and materials to describe additional impurities in a typical lot. Furthermore, you failed to sufficiently classify each identified impurity. Our inspection also noted impurities are not monitored during stability studies.

你们未能对制造过程进行全面评估以识别所有潜在杂质。例如，你们为 （b）（4） USP产品提供的杂质概况仅列出了USP中描述的那些杂质，而没有考虑特定于你们工艺和物料来描述典型批次中的其他杂质。此外，你们未能对每个已识别的杂质进行充分分类。我们的检查还注意到，在稳定性研究期间没有监测杂质。

In your response, you include impurity profiles and data from forced degradation studies, which you state was provided to investigators on the final day of the inspection. We acknowledge you also include updated impurity profiles with further details completed since the inspection. You also state drug product manufacturers who you supply perform testing of the drug products for impurities, and you have not received any returned APIs due to quality issues.

在你们的回复中，你们提供了杂质概况和来自强制降解研究的数据，你们声称这些数据是在检查的最后一天提供给检查人员的。我们确认你们还提供了更新的杂质概况，以及自检查以来完成的更多详细信息。你们还应声明，你们供应的药品制造商对药品进行杂质检测，你们还没有收到任何因质量问题退回的API。

Your response is inadequate. Our inspection found you have received at least two lots of returned product due to quality issues in the last two years. You also received a complaint for one lot of (b)(4) USP that failed the customer’s identity testing. Furthermore, you do not provide a retroactive risk assessment of distributing APIs with incomplete impurity profiles, and you lack evidence that you communicated your updated impurity profiles to your customers who you state test the drug products for impurities. Additionally, your APIs are distributed to (b)(4) who typically do not test components for compliance with quality specifications, including impurity testing.

你们的回复是不充分的。我们的检查发现，在过去两年中，你们至少收到了两批因质量问题而退回的产品。你们还收到了关于一批 （b）（4） USP产品经客户鉴定检查不合格的投诉。此外，你们没有提供分销杂质分析不完整的API 的追溯风险评估，并且你们缺乏证据表明你们将更新的杂质分析传达给你们声明对药品进行杂质测试的客户。此外，你们的API 将分发给 （b）（4），他们通常不测试组件是否符合质量标准，包括杂质测试。