12月24日，FDA发布了Viatris, Inc.（Viatris为Mylan(迈兰)和Pfizer(辉瑞)子公司Upjohn(普强)合并而成的新公司，中文名为晖致）的警告信，其中记录了严重的数据完整性和实验室调查不当问题，并在随后发现工厂的现场质量负责人、质量控制负责人、质量保证负责人、调查负责人和负责包材实验室的经理违反了数据完整性政策，并被该公司辞退，FDA批评该公司质量体系为无效的质量体系：

 

组件（包材）放行检测存在数据完整性问题。检查人员查看了四张记录并发现了异常。

 

该公司的考勤记录为生物识别访问记录，其中记录了包材检测人员在检测期间没有实际出现在工厂。尽管他们不在，但他们记录了测试过程和结果，就好像他们已经进行了检测一样。随后该公司表示已查明出勤记录无法支持分析人员在场完成他们所签名的检测。

 

在检查之后，该公司扩大了调查范围，发现工厂的现场质量负责人、质量控制负责人、质量保证负责人、调查负责人和负责包材实验室的经理违反了数据完整性政策，并被该公司辞退。

 

在18个月和3个月的长期稳定性时间点的HPLC溶出度试验中分别出现OOS和OOT结果。分析人员在咨询其主管后，在没有提供充分论证的情况下中止了HPLC样品组序列。也缺乏证据来证实根本原因。

 

将含量均匀性OOT结果归因于HPLC柱泄漏。然而，仪器的审计追踪并没有记录该问题（HPLC柱泄漏），并且使用了另一个的样品和仪器进行了复测。

 

FDA批评该公司质量体系为无效的质量体系：除了对实验室操作缺乏有效的管理监督外，质量部门无法行使适当的权力和/或没有充分履行其职责。

 

FDA提醒该公司有责任纠正在质量保证程序审计（包括自检）中发现的缺陷。

 

FDA要求该公司对过去五年内所有质量保证程序审计（包括自检）和检查进行回顾，并提供完成审计中确定的所有相关纠正措施的时间表。认证和/或时间表应由Viatris，Inc.的首席执行官签署。

 

警告信翻译如下：

 

Dear Mr. Smith:

 

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Mylan Laboratories Limited, Inc., “a Viatris company,” FEI 3010453141, located at Plot No. 11, 12 & 13, Indore SEZ Pharma Zone, Phase-II, Sector-III, Pithampur, Dhar, Madhya Pradesh, India, from June 14 to 26, 2024.

 

FDA于2024年6月14日至26日检查了你们的药品生产工厂Mylan Laboratories Limited， Inc.(“Viatris公司”，注册号FEI 3010453141，位于印度中央邦达尔Pithampur印度经济特区制药区ii期iii区第11、12和13号地块。

 

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).

 

本警告信总结了成品药品严重违反现行良好生产规范（CGMP）规定的情况。参见21 CFR第210和211部分。

 

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are 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).

 

由于你们的生产、加工、包装或保存的方法、设施或控制不符合CGMP，你们的药品根据FD&C Act第501(a)(2)(B)条，21 U.S.C. 351(a)(2)(B)条被认定为掺假。

 

We reviewed your July 18, 2024, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

 

我们详细审查了你们2024年7月18日对FDA表格483的回复，并确认收到了你们随后的来信。

 

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

 

在我们的检查中，检查人员发现了具体的违规行为，包括但不限于以下情况。

 

1. Your firm failed to establish adequate written responsibilities and procedures applicable to the quality control unit and to follow written procedures applicable to the quality control unit (21 CFR 211.22(d)).

 

贵公司没有建立足够的适用于质量控制部门的书面职责和程序，也没有遵循适用于质量控制部门的书面程序（21 CFR 211.22(d)）。

 

You failed to ensure the reliability and integrity of quality control data during component release testing at your facility. Our investigators identified anomalies in four worksheets that reported passing results for(b)(4) identification testing by chemical analysis.

 

你们未能确保组件放行检测期间的质量控制数据的可靠性和完整性。我们的检查人员在四张记录中发现了异常，这些记录报告了通过化学分析进行xx鉴定测试的合格结果。

 

Biometric access records documented that the responsible analysts were not physically present at the facility during testing. Despite their absence, they documented both the testing process and results as if they had conducted the analyses.

 

生物识别访问记录记录了负责的分析人员在检测期间没有实际出现在工厂。尽管他们不在，但他们记录了测试过程和结果，就好像他们已经进行了检测一样。

 

Data integrity is critical throughout the CGMP data life cycle, including in the creation, modification, processing, maintenance, archival, retrieval, transmission, and disposition of data after the record’s retention period ends.

 

数据完整性在整个CGMP数据生命周期中是至关重要的，包括数据的创建、修改、处理、维护、存档、检索、传输和在记录保存时间结束后的处置。

 

In your response, you “…confirmed that certain test data generated in the Packaging Material Laboratory were not reliable…” and “…determined that attendance records did not support that the analyst was present to complete the testing for which they signed.” You commit to implement a Data Integrity Remediation Plan, which includes appointing a Data Integrity Lead to oversee and enhance compliance efforts.

 

在你们的回复中，你们“……确认在包材实验室产生的某些测试数据不可靠……”并“……已查明出勤记录无法支持分析人员在场完成他们所签名的检测。”你们承诺实施数据完整性补救计划，其中包括任命一名数据完整性主管来监督和加强合规工作。

 

We acknowledge that you suspended testing in the Packaging Material Laboratory, and initiated reserve sample testing for components. We also acknowledge that after the inspection, you expanded your investigations, which identified that the facility’s Site Head of Quality, Head of Quality Control, Head of Quality Assurance, Head of Investigations, and the Manager responsible for the packaging materials laboratory had violated your data integrity policies and were removed from your organization.

 

我们知道你们暂停了在包材实验室的测试，并开始了对组件的留样样品进行测试。我们也知道，在检查之后，你们扩大了调查范围，发现工厂的现场质量负责人、质量控制负责人、质量保证负责人、调查负责人和负责包材实验室的经理违反了你们的数据完整性政策，并被你们的组织辞退。

 

Your response is inadequate. It fails to provide sufficient details regarding the extent of the identified data integrity issues, and the thoroughness of your proposed corrective and preventive actions (CAPAs) is unclear.

 

你的答复是不充分的。它未能提供关于已识别数据完整性问题程度的足够细节，并且不清楚你们所提议的纠正和预防措施（CAPA）的彻底性。

 

In subsequent communications following the inspection, you disclosed that both your site and global quality organization became aware of the data integrity issues related to component testing in January 2024. FDA is concerned that you did not adequately investigate or begin to implement holistic corrective actions until after the subsequent FDA inspection.

 

In response to this letter, provide:

 

在检查后的后续沟通中，你们披露你们的工厂和全球质量组织都在2024年1月意识到与组件测试相关的数据完整性问题。FDA担心你们在有FDA检查之后才充分调查或开始实施整体纠正措施。

 

2. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).

 

你们公司未能彻底调查批次或其任何成分出现的任何无法解释的差异或不符合标准，无论该批次是否已经放行（21 CFR 211.192）。

 

Your investigations into discrepancies and out-of-specification (OOS) results lacked adequate scientific rationale to support root cause determinations. Specifically,

 

你们对差异和OOS结果的调查缺乏足够的科学依据来支持根本原因的确定。具体的,

 

A.(b)(4) mg tablets, batches (b)(4) and (b)(4), exhibited OOS and out-of-trend (OOT) results during the dissolution test by high-performance liquid chromatography (HPLC) at the 18-month and 3-month long-term stability timepoints, respectively. The analyst, after consulting their supervisor, aborted the HPLC sample set sequence without providing adequate justification. You also lacked evidence to substantiate the root cause of improper (b)(4) of (b)(4).

 

(b)(4) mg片剂、批号XX和xx在18个月和3个月的长期稳定性时间点的高效液相色谱（HPLC）溶出度试验中分别出现OOS和OOT结果。分析人员在咨询其主管后，在没有提供充分论证的情况下中止了HPLC样品组序列。你们也缺乏证据来证实根本原因。

 

B. You invalidated OOT assay results and during retest subsequently dismissed an anomalous content uniformity result for(b)(4) mg Capsules, batch (b)(4), attributing the original issue to HPLC column leakage. However, the equipment's audit trail did not document such an error, and you conducted retesting using different samples and equipment.

 

你们判定OOT测定结果无效，随后在复测期间，你们驳回了xx批次xx mg胶囊的异常含量均匀性结果，并将最初的问题归因于HPLC柱泄漏。然而，仪器的审计追踪并没有记录该问题（HPLC柱泄漏），并且你们使用了另一个的样品和仪器进行了复测。

 

In your response, you acknowledge your inadequate laboratory investigations and data handling practices. Additionally, you commit to perform an extended evaluation across the rest of the laboratory to evaluate your laboratory practices and controls.

 

在你们的回复中，你们承认你们的实验室调查和数据处理不充分。另外，你们承诺在实验室的其余部分执行扩大评估，以评估你们的实验室实践和控制。

 

Your response is inadequate. The conclusions of your OOS investigations lack the necessary rigor and scope to thoroughly identify root causes, assess the extent of deviations, and evaluate their impact on drug products. You repeatedly accepted these conclusions, despite insufficient justification.

 

你们的答复是不充分的。你们OOS调查的结论缺乏必要的严谨性和范围，无法彻底识别根本原因，评估偏差的程度，并评估其对药品的影响。你一再接受这些结论，尽管没有充分的理由。

 

For more information about handling failing, out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s current guidance documentInvestigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production at https://www.fda.gov/media/158416/download.

 

有关处理不合格、不符合标准、不符合趋势或其他意外结果和调查文件的更多信息，请参阅FDA当前的指导文件调查药品生产不符合规格（OOS）的测试结果，网址为https://www.fda.gov/media/158416/download。

 

Ineffective Quality Systems

 

无效的质量体系

 

Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP. In addition to the lack of effective management oversight of your laboratory operations, we found your QU is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities. Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements.

 

此函中的重要发现证明你们公司没有按照CGMP运行有效的质量体系。除了对你们的实验室操作缺乏有效的管理监督外，我们还发现你们的质量部门无法行使适当的权力和/或没有充分履行其职责。执行管理层应立即全面评估你们公司的全球生产运营，以确保你们的体系、流程和产品符合FDA的要求。

 

CGMP Consultant Recommendation

 

CGMP顾问推荐

 

We strongly recommend that your firm engage a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

 

我们强烈建议你们公司聘请符合21 CFR 211.34规定的顾问来协助你们公司满足CGMP要求。你们使用顾问并不解除你们公司遵守CGMP的义务。你们公司的执行管理层仍然有责任解决所有缺陷和系统性不足，以确保持续的CGMP符合性。

 

Data Integrity Remediation

 

数据完整性修复

 

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance documentData Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers.

 

你们的质量体系不能充分确保数据的准确性和完整性，以支持你们生产的药品的安全性、有效性和质量。关于建立和遵循CGMP合规数据完整性实践的指导，请参阅FDA指南：数据完整性和药品CGMP合规性，网址为https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers。

 

Quality Assurance Program Audits

 

质素保证程序审计

 

FDA reminds Viatris, Inc. of their responsibility as a matter of CGMP to correct deficiencies found during quality assurance program audits, also referred to as “internal audits” in your correspondence with the FDA.

 

FDA提醒Viatris， Inc.有责任纠正在质量保证程序审计中发现的缺陷，在你们与FDA的通信中也被称为“内审”。

 

In response to this letter, conduct a review of all quality assurance program audits and inspections within the last five years at all Viatris, Inc. facilities. Provide written certification that required corrective actions for such audits and inspections have been taken. If, upon your review or the review by any pertinent party working on your behalf, it is determined that actions have not been taken, provide a timeline for completion for all related corrective actions identified in the audits. The certification and/or timeline should be signed by the CEO of Viatris, Inc.

 

回复此函，对过去五年内所有Viatris， Inc.工厂的所有质量保证程序审计和检查进行回顾。提供书面证明，证明已对此类审计和检查采取了纠正措施。如果经贵司或代表贵司工作的任何相关方回顾确定未采取措施，请提供完成审计中确定的所有相关纠正措施的时间表。认证和/或时间表应由Viatris， Inc.的首席执行官签署。