拒绝查看记录、拒绝拍照、限制进入房间、编辑记录，这家中国药企收到FDA警告信！

11月19日，FDA发布了对津药达仁堂京万红(天津)药业有限公司的警告信，警告信中列举了该公司限制、延迟或拒绝FDA检查，以及GMP违规的情况：

限制访问记录：

• FDA 要求提供工艺验证报告和批生产记录。尽管该公司将文件逐行翻译给 FDA 检查人员，但所提供的翻译副本分别针对批生产记录中组分的总净重和工艺验证报告中的工艺参数进行了不合理的编辑。此外，还编辑了设备确认记录，包括所有关键工艺参数，以及相应的可接受范围和记录范围。

• 该公司之所以提供编辑的副本，是因为公司最高管理层要求保护批记录、工艺验证研究和设备参数中包含的信息。当检查组解释说未能提供所要求的记录将被记录为拒绝时，该公司确认了拒绝。

• 检查组要求提供2016 年至 2024 年启动的CAPA清单；该公司仅提供了 2024 年的 CAPA 清单。

限制拍照：在检查过程中，检查人员试图对灌装机进行拍照，但是管理层表示，检查人员不允许对设备进行拍照。

限制访问区域：管理层不允许检查人员进入执行某生产操作的房间。

GMP违规：

• 检查人员在灌装机上观察到残留物，但是这两台设备都被标识为干净。

• 灌装机有几颗螺丝缺失，电机外壳面板破损，灌装机料斗没有盖子，并使用老化破损的绳子与设备绑在一起。FDA认为其设备不适合其预期用途。

• 尽管声明了生产工艺已经过验证且设备已经过确认，但是没有提交支持信息。

• 用于药品的放行和稳定性测试的分析方法没有稳定性指示能力。

• 该公司尚未进行强降解试验，以识别可能存在足够数量以需要在稳定性试验期间进行测试的降解物。

警告信翻译如下：

Warning Letter 320-25-08

October 30, 2024

Dear Mr. Zhang:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Tianjin Darentang Jingwanhong Pharmaceutical Co., Ltd., (also known as Tianjin Pharmaceutical Da Ren Tang Group Jing Wan Hong Co., Ltd.), FEI 3006283468, at No. 20 Daming Street, Xiqing, Tianjin, Tianjin, China, from March 18 to 22, 2024.

FDA 于 2024 年 3 月 18 日至 22 日检查了位于中国天津市西青市大明街 20 号的贵方药品生产工厂津药达仁堂京万红(天津)药业有限公司，位于中国天津市天津市西青市大明街 20 号，3006283468。

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

本警告信总结了对于药品现行药品生产质量管理规范 （CGMP） 法规的重大违规。请参阅21 CFR 第 210 和 211 部分。

Our investigators documented your firm limited and/or refused an FDA inspection. Under section 501(j) of the FD&C Act, 21 U.S.C. 351(j), your drugs are adulterated in that they have been manufactured, processed, packed, or held in an establishment where the owner or operator has limited inspection and/or refused inspection.

我们的检查人员记录了贵公司对 FDA 检查的限制和/或拒绝。根据FD&C 法案 第 501（j） 节（21 U.S.C. 351（j）），你们的药品因限制检查和/或拒绝检查被认定为掺假。

Additionally, because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug product is adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

此外，由于你们的制造、加工、包装或保存方法、设施或控制不符合 CGMP，你们的药品被认定为FD&C 法案 第 501（a）（2）（B） 节、21 U.S.C. 351(a)(2)(B)所指的掺假商品。

We reviewed your April 15, 2024, response to our Form FDA 483 in detail.

我们详细审查了你们于 2024 年 4月 15 日对我们的 FDA 483 的回复。

During our inspection, FDA investigators observed specific violations including, but not limited to, the following.

在我们的检查期间，FDA 检查人员观察到了具体的违规行为，包括但不限于以下：

Limiting the Inspection

限制检查

Your firm limited and refused to permit the FDA inspection as follows:

贵公司限制并拒绝允许 FDA 检查，具体如下：

Limiting Access to Records

限制访问记录

Your firm limited access to manufacturing records that our inspection team was entitled to inspect. For example, during the inspection, FDA investigators requested the process validation report for your over-the-counter (OTC) drug product “(b)(4)” and the manufacturing production batch record for Batch(b)(4). Although you translated the documents line by line to the FDA investigators, translated copies provided were unreasonably redacted for the total net weights of components in the production batch record and processing parameters in the process validation report, respectively. In addition, records of equipment qualification for the following units were also redacted: (b)(4) tank ID 447, (b)(4) tank ID 344, and (b)(4) tank ID 264. Redactions included all critical process parameters, such as (b)(4), and corresponding acceptable and recorded ranges.

贵公司限制了我们检查组对有权检查的生产记录的访问。例如，在检查期间，FDA 检查人员要求提供您的XX药品的工艺验证报告和XX批次的批生产记录。尽管你们将文件逐行翻译给 FDA 检查人员，但所提供的翻译副本分别针对批生产记录中组分的总净重和工艺验证报告中的工艺参数进行了不合理的编辑。此外，还编辑了XX罐 ID 447、XX罐ID 344 和 XX罐 ID 264的设备确认记录。编辑包括所有关键工艺参数，例如（b）（4）以及相应的可接受范围和记录范围。

Your firm provided redacted copies because you stated that you are required by the firm’s top management to protect the information included in batch records, process validation studies, and equipment parameters. Your firm’s actions during this inspection significantly hindered FDA from fully assessing your compliance with CGMP. When our inspection team explained that your failure to provide the requested records would be documented as a refusal, you acknowledged the refusal.

贵公司之所以提供编辑的副本，是因为你们声明公司的最高管理层要求你们保护批记录、工艺验证研究和设备参数中包含的信息。贵公司在此次检查期间的行为严重阻碍了FDA 全面评估你们对 CGMP 的符合性。当我们的检查组解释说，你们未能提供所要求的记录将被记录为拒绝时，你们确认了拒绝。

Our inspection team documented other instances in which your firm limited the inspection by providing some, but not all, of the records requested that FDA had authority to inspect. For example, the inspection team requested the list of corrective actions and preventive actions (CAPAs) initiated from 2016 to 2024; however, you limited the inspection by providing the list of CAPAs issued in 2024 only.

我们的检查组记录了贵公司通过提供部分（而不是全部）FDA 有权检查的记录来限制检查的其他情况。例如，检查组要求提供2016 年至 2024 年启动的CAPA清单；但是，你们仅提供 2024 年的 CAPA 清单。

Limiting Photography

限制拍照

During the inspection, our inspection team attempted to take photos of the filling machines ID-192, and ID-197, which were observed to be dirty and in an apparent state of disrepair, despite the equipment status being identified as clean. This equipment is currently used to manufacture a drug intended for U.S. distribution. Your management stated that the investigators were not allowed to take photographs of the equipment as part of the inspection. When our inspection team explained that failure to allow photography would be documented as a refusal, you acknowledged the refusal.

在检查过程中，我们的检查组试图对灌装机 ID-192 和 ID-197 进行拍照，尽管设备状态被确定为干净，但观察到它们很脏并且明显处于年久失修的状态。该设备目前用于生产在美国分销的药物。你们的管理层表示，检查人员不允许对设备进行拍照来作为检查的一部分。当我们的检查人员解释说，不允许拍照将被记录为拒绝时，你们确认了拒绝。

Limiting Access to Areas

限制访问区域

Your management did not permit our inspection team to access the manufacturing room where(b)(4) and (b)(4) are performed. When our inspection team explained that failure to allow FDA to access and evaluate manufacturing equipment and operations would be documented as a refusal, you acknowledged the refusal.

你们的管理层不允许我们的检查团队进入执行XX和XX操作的房间。当我们的检查团队解释说，不允许FDA 访问和评估生产设备和操作将被记录为拒绝时，你们确认了拒绝。

Delaying, Denying, Limiting, or Refusing a Drug Inspection

延迟、限制或拒绝药品检查

When an owner, operator, or agent delays, denies, limits, or refuses an inspection, the drugs may be deemed adulterated under section 501(j) of the FD&C Act. See FDA’s guidance document:Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection (June 2024) at https://www.fda.gov/media/86328/download.

当持有人、经营者或代理人延迟、限制或拒绝检查时，根据FD&C法案第501（j）条，这些药物可能被视为掺假。请参阅 FDA 指南：构成延迟、限制或拒绝药品或器械检查的情况（2024 年 6 月）。

GMP Violations

GMP违规

1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

贵公司未能根据药品的性质对设备和器具进行适当的清洁、维护和/或消毒，以防止出现改变药品安全性、特性、剂量、质量或纯度超出官方或其他既定标准的故障或污染 （21 CFR 211.67（a））。

You failed to demonstrate that your cleaning practices are adequate to remove contaminants from equipment used to manufacture your topical drug product, "(b)(4)." On March 19, 2024, our investigators observed residues on filling machines ID-192 and ID-197, despite both being identified as clean.

你们未能证明清洁方法足以去除用于制造外用药品 （b）（4） 设备中的污染物。2024 年 3 月19 日，我们的检查人员在灌装机 ID-192 和 ID-197 上观察到残留物，但是这两台设备都被标识为干净。

In addition, your filling machines were not adequately maintained and were observed to be in a state of disrepair. For example, the filling machine ID-192 had several missing screws and a broken motor housing panel, and filling machine ID-197 lacked a cover for the(b)(4) bowl and was observed with degraded and cracked (b)(4) bands apparently holding the equipment together. As such, your equipment was not suitable for their intended use.

此外，你们的灌装机没有得到充分维护，并且被发现处于年久失修的状态。例如，灌装机 ID-192有几颗螺丝缺失，电机外壳面板破损，灌装机 ID-197 没有XX斗的盖子，并且观察到使用老化破损的XX绳与设备绑在一起。因此，你们的设备不适合其预期用途。

In your response, you acknowledge the incomplete cleaning of filling machine ID-192 and state that the equipment’s cleaning procedure is revised. You also state that the conditions identified above filling machine ID-197 are repaired.

在你们的回复中，你们承认灌装机 ID-192 的清洁不完整，并声明设备的清洁程序已修改。你们还声明上述灌装机ID-197 的状况已修复。

Your response is inadequate because you did not implement sufficient corrective actions related to the status and cleaning of all equipment used in the manufacture of drugs intended for the U.S. market. You also failed to evaluate the potential impact of your filling machines’ condition and inadequate cleaning on the quality of your distributed drug batches.

你们的回复是不充分的，因为你们没有对所有设备的状态和清洁采取足够的纠正措施。你们也未能评估灌装机的状况和清洁不足对分销药品批次质量的潜在影响。

2. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

贵公司未能建立适当的生产和工艺控制的书面程序，以确保贵公司生产的药品具有其声称或声称拥有的特性、剂量、质量和纯度 （21 CFR 211.100（a））。

Based on the limitation of the inspection described above, you failed to provide data to demonstrate that you adequately validated your manufacturing processes used to manufacture your OTC drug product and to demonstrate that your processes are reproducible and controlled to consistently yield drugs of uniform character and quality.

基于上述的检查限制，你们未能提供数据来证明你们充分验证了用于生产药品的制造工艺，并证明工艺具有可重复性和可控性，无法始终如一地生产出具有一致特性和质量的药品。

Although you state your manufacturing process is validated and equipment is qualified, you do not submit supporting information.

尽管你们声明生产工艺已经过验证并且设备已经确认，但你们没有提交支持信息。

3. You firm failed to establish required laboratory control mechanisms (21 CFR 211.160(a)), including those related to stability studies (21 CFR 211.166).

贵公司未能建立所需的实验室控制机制 （21 CFR 211.160（a）），包括与稳定性研究相关的机制 （21 CFR 211.166）。

The analytical method used for the release and stability testing of your drug product “(b)(4)” is not stability indicating.

用于XX药品的放行和稳定性测试的分析方法没有稳定性指示能力。

Also, your firm has not performed forced degradation studies to identify degradants that may be present in sufficient quantities to require testing during stability studies.

此外，贵公司尚未进行强降解试验，以识别可能存在足够数量以需要在稳定性试验期间进行测试的降解物。

In your response, you commit to conduct an “impact factor” and accelerated test to assess the impact of different factors on your drug product stability. You also committed to test three batches per production schedule.

在回复中，你们承诺进行“影响因子”和加速测试，以评估不同因素对药品稳定性的影响。你们还承诺每个生产计划测试三个批次。

Your response is inadequate because you did not provide details of your “impact factor” and accelerated test plan and how they relate to the lack of degradation studies. Your plan also fails to include a retrospective evaluation of batches that have been released and are currently within expiry in the U.S. market.

你们的回复是不充分的，因为没有提供“影响因子”和加速测试计划的详细信息，以及它们与缺乏降解试验的关系。你们的计划也未能包括对已放行且在效期内的批次进行回顾性评估。