FDA警告信：检查30分钟后即开始造假！重复测试一次又一次！

近日，FDA发布了对印度Windlas Healthcare Private Limited的警告信 ，警告信描述的检查现场几乎是一个活生生的造假现场 ：

• 进厂API的GC残留溶剂检测期间峰检测功能被关闭了数次，检查员对色谱的审核发现该公司未按程序规定报告亦未积分这些未知峰。随后检查员要求你公司重新处理样品序列，结果显示有>XX%的总未知杂质峰。
  

• 有关物质分析方法验证期间，同样未报告亦未积分未知峰。

• 该公司 将根本原因归结为实验室人员“知识和意识不足” 。还声称另一个可归结原因是“外源峰识别没有适当的SOP”。但是未论证为何化验员没有遵守规程对已知和未知峰进行积分。该公司同样未回复未知峰的根本原因。

• 在18个月有关物质检测中取消了一个检测序列。调查说取消该序列是因为“柱温箱泄漏故障”。 初始运行色谱图显示杂质会得出OOS结果。初次运行被宣布无效，然后重新配制样品并检测。复测时RSD不合格，又宣布第二次运行无效。然后又制备了第三份样品并重新检测，第三次检测中样品溶液RSD仍然不合格，又宣布运行无效。然后，第四次制备了样品溶液。这次检测得到了合格数据。只报告了最后这次合格数据。

• 声称可能是因为用作检测方法一部分和流动相配制的溶液受污染。但是缺少足够证据来证明溶液的可能污染是OOS的根本原因。也并未讨论为何在相同序列多个样品明显都未受到影响。

• 实验室事件（LI）检测结果的调查不充分。

• 检测准确性、方法精密度或中间精密度参数有 无数LI（实验室事件）相关的失败 。这些LI的可能根本原因被归结到污染和化验员错误。

• 声称缺乏足够的LI调查是因为程序培训不充分，化验员未遵守程序，以及质量监管不够和高级管理层不重视。

• 在检查员到达公司宣布检查后才30分钟，就发现大量员工在将装有切碎和撕掉的文件与文件夹的垃圾袋往厂外装运。检查后发现有批平衡表、清洁和分料日志、培训评估和秤打印件。

• 在检查后期，FDA检查员在该公司的 监控录像 上发现生产员工快速地在文件上签名并传递给另一人。检查员要求前去生产员工所在的位置，但被带到了另一个地方。

March 10, 2020

Warning Letter 320-20-28

Dear Mr. Windlass:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Windlas Healthcare Private Limited,FEI 3005339091, at Plot No. 183 & 192, Mohabewala Industrial Area, Dehradun, from August 26 to 30, 2019.

美国 FDA 于 2019 年 8 月 26 日至 29 日检查了你们位于印度的 Windlas Healthcare Private Limited （ FEI3005339091 ）生产场所。

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).

本警告信总结了制剂生产严重违反 CGMP 的行为。参见 21CFR 第 210 与 211 部分。

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

由于你们的制剂生产、加工、包装或保存的方法、场所或控制不符合 CGMP 要求，你们的药品根据 FDCA 的 501(a)(2)(B) 以及 21 U.S.C. 351(a)(2)(B) 被认为是掺假药品。

We reviewed your September 20, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司 2019 年 9 月 20 日对 FDA483 表的回复，并此告知已收到后续通信。

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

检查期间，我们的调查人员发现的具体问题包括但不仅限于以下：

1. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards (21 CFR 211.194(a)). 你公司未能确保实验室记录中包括有为确保符合既定标准所需检测中得到的完整数据（ 21 CFR 211.194(a) ）。

Your firm did not maintain complete and accurate data from all laboratory testing. Without reliable laboratory data, you cannot assure appropriate decisions regarding batch release, product stability, andother drug aspects of quality. For example:

你公司并未保存所有实验室检测的完整准确数据。没有可靠的实验室数据，你们就无法确保做出适当的批放行决策、产品稳定性及其它药品质量方面决策。例如：

a. On May 19, 2018, the peak detection function was disabled multiple times during the gas chromatography (GC) residual solvent testing of your incoming active pharmaceutical ingredient (API), (b)(4) batch (b)(4) . After reviewing the chromatograms, our investigators noted unknown peaks that were not reported or integrated as required per your procedure.

2018 年 5 月 19 日，进厂 API 的 GC 残留溶剂检测期间峰检测功能被关闭了数次 ，我们检查员对色谱的审核注意到你们未按程序规定报告亦未积分这些未知峰。

Our investigators requested your firm to reprocess the sample set sequence, which subsequently showed > (b)(4) % total unknown impurity peaks. You used this batch of API to manufacture multiple batches of (b)(4) tablets which were released to the U.S. market.

我们检查员要求你公司重新处理样品序列，之后显示有 >XX% 的总未知杂质峰。你们使用该批 API 生产了多批 XX 片，并放行至美国市场。

This was not an isolated incident. Our investigators also noted unknown peaks which were not reported or integrated during the method transfer of related compounds testing for (b)(4) USP API batch (b)(4) . Your firm did this study to support the (b)(4) for (b)(4) tablets.

这并不是孤立事件。我们检查员还发现在 XX USP API 批次 有关物质分析方法验证期间，未报告亦未积分未知峰。 你公司进行该项试验是为了支持 XX 片剂的 XX 。

In your response, you attributed the root cause to "inadequate knowledge and awareness" by your laboratory personnel. You also stated that a contributing root cause was "the unavailability of a proper SOP on identification of extraneous peaks." Your response was inadequate. You did not discuss why your analysts did not follow your procedure to integrate known and unknown peaks. Your response also failed to identify the cause of the unknown peaks.

在你们的回复中，你们 将根本原因归结为你们实验室人员“知识和意识不足” 。你们还 声称另一个可归结原因是“外源峰识别没有适当的 SOP ” 。你们的回复是不充分的。你们并未讨论为何你们的化验员没有遵守你们的程序对已知和未知峰进行积分。你们的回复亦未找出未知峰的根本原因。

b. On April 16, 2019, you cancelled a test sequence during 18-month related substances testing that included (b)(4) mg tablets batch (b)(4) . Your investigation stated the cancellation was due to "oven leak error." The chromatogram for this initial run showed impurities that would yield an out-of-specifications (OOS) result. The initial run was invalidated, and you prepared and tested a new sample solution on April 17, 2019. The retest failed percent relative standard deviation (RSD) and you invalidated this second run too. On April 22, 2019, you prepared a third sample solution and repeated the test. The third sample solution also failed percent RSD and again you invalidated the run. On April 29, 2019, you prepared a fourth sample solution. This test yielded passing data. You reported the final, passing data after multiple testing failures. You did not adequately investigate the failing results as required by your laboratory incidents (LI) procedure. Your firm also did not identify clear root causes for the repeated analytical problems that caused you to invalidate the first three analyses.

2019 年 4 月 16 日，你们在 18 个月有关物质检测中取消了一个检测序列，其中包括 XXmg 片剂批次 XX 。 你们的调查说取消该序列是因为“柱温箱泄漏故障”。初始运行色谱图显示杂质会得出 OOS 结 果 。 初次运行被宣布无效，你们在 2019 年 4 月 17 日重新配制样品并检测。复测时 RSD 不合格，你们又宣布第二次运行无效。 2019 年 4 月 22 日，你们制备了第三份样品并重新检测，第三次检测中样品溶液 RSD 仍然不合格，你们又宣布运行无效。 2019 年 4 月 29 日，你们第四次制备了样品溶液。这次检测得到了合格数据。你们在多次检测合格之后报告了最后这次合格数据。 你们并未对失败结果按你们的实验室事件（ LI ）程序进行充分调查。你公司亦未找出导致你们宣布前面三次分析过程中反复发生的分析问题的明确根本原因。

In your response, you confirmed that batch (b)(4) was OOS, and stated it was potentially due to contaminated (b)(4) solution used as part of the test method and mobile phase preparation. However, you lacked adequate evidence demonstrating how the potential contamination of the (b)(4) solution was the root cause of the OOS. You did not discuss how, in the same sequence multiple samples were apparently not compromised. In addition, you lacked adequate· evidence concerning the scope and potential impact that these laboratory errors may have on other laboratory tests and results.

在你们的回复中，你们确认 XX 批次为 OOS ，并声称可能是因为用作检测方法一部分和流动相配制的 XX 溶液受污染。但是你们 缺少足够证据来证明 XX 溶液的可能污染是 OOS 的根本原因 。你们并未讨论为何在相同序列多个样品明显都未受到影响。另外，你们亦缺乏足够证据证明实验室错误的范围及其可能对其它实验室检测和结果产生的潜在影响。

In your response to this letter provide the following:

在你们对本函的回复中请提交以下：

• A retrospective, independent, assessment of your OOS investigation into the 18-month related substances testing for (b)(4) mg tablets batch (b)(4) .

• 对你们 XX 批 XXmg 片剂 18 个月有关物质检测中 OOS 调查的独立回顾评估

• A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

• 一份对你们实验室规范、程序、方法、仪器、文件和化验员能力的全面独立评估。根据这些审核，提交一份详细的 CAPA 计划用于补救你们实验室系统的有效性。

• Your corrective action and preventive action (CAPA) plan to implement routine, vigilant quality management oversight of laboratory equipment. This plan should ensure, among other things, prompt detection of equipment performance issues, effective execution of repairs, and adherence to appropriate preventive maintenance schedules.

• 你们对实验室设备执行日常严格质量管理监管的 CAPA 计划。该计划应确保（除其它事情外）快速发现设备性能问题、有效进行维修，并遵守适当的预防性维护计划。

• See the Data Integrity Remediation heading below. Part C requests a corrective action plan to ensure the reliability and completeness of all the data you have submitted to FDA in your approved and pending drug applications. It is essential that this retrospective review include an independent evaluation of raw data used for these application submissions.

• 参见以下数据完整性补救措施项。第 C 部分要求制订整改计划以确保你们在你们已批准和审评中药品申报资料里提交给 FDA 的所有数据的可靠性和完整性。必须保证该回顾性审核包括对这些申报资料中所用原始数据的独立评估。

• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality unit oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

• 一份对你们偏差、差异、投诉、 OOS 结果和失败调查的全面系统的全面独立评估。提交一份详细的行动计划以补救该系统。你们的行动计划应包括但不仅限于对调查能力、范围界定、根本原因评估、 CAPA 有效性、质量部门监管和书面程序的重大改进。说明你们公司要如何确保恰当地执行了所有调查阶段。

• An independent assessment and remediation plan for your CAPA program. Provide a report that evaluates if it includes staff with proper investigation competencies, effectively conducts root cause analysis, assures CAPA effectiveness, regularly reviews investigations trends, implements improvements to the CAPA program when needed, ensures appropriate quality unit decision rights, and is fully supported by executive management.

• 一份你们 CAPA 程序的独立评估及补救计划。提交一份报告评估其是否包括员工具备适当的调查能力、有效执行根本原因分析、确保 CAPA 有效性、定期审核调查趋势、必要时对 CAPA 程序进行改进，确保质量部门具备适当的决策权力，并得到高级管理层的全面支持。

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). 你公司未彻底调查已销售和未销售批次产品或其组份未经解释的差异或不符合其标准（ 21 CFR 211.192 ）。

Your investigations into laboratory incidents (LI) testing results are inadequate. Multiple LI investigations lacked adequate scientific rationale for root cause determination. Without adequate scientific rationale, your firm invalidated the failing OOS results that were included in these LI. You subsequently reported the passing retest results.

你们对实验室事件（ LI ）检测结果的调查是不充分的。多个 LI 调查中根本原因确定中缺乏足够的科学合理性。在没有足够的科学合理性情况下，你公司宣布在这些 LI 中的不合格 OOS 结果无效。你们随后报告了合格的复测结果。

For example, during your analytical method verification for residual solvent for (b)(4) API, your firm initiated numerous LI concerning failures of the test's accuracy, method precision, or intermediate precision parameters. The probable root causes of these LI were attributed to contamination and analyst error. We note your retesting plans did not specify retesting by an analyst other than the one who performed the original test. In addition, samples were retested until passing results were achieved. Your CAPA for these LI stated "training on standard operating procedure (SOP) of 'Good laboratory practices of QC laboratory' shall be imparted to concern person [sic]." Your method verification report was approved on May 3, 2018. We note that on May 19, 2018, unknown peaks were observed using this test method which were not identified or integrated as discussed in Charge 1 of this letter.

例如，在你们的 XX API 残留溶剂分析方法确认过程中，你公司对检测准确性、方法精密度或中间精密度参数有 无数 LI（实验室事件） 相关的失败 。这些 LI 的可能根本原因被 归结到污染和化验员错误 。我们注意 到 你们的复测计划并未指定由原化验员以外的化验员进行复测。还有你们对样品一直复测直到获得合格结果。你们对这些 LI 的 CAPA 说“应该为相关人员进行《 QC 实验室的优良实验室规范》 SOP 培训”。你们的方法确认报告是在 2018 年 5 月 3 日批准的，我们发现在 2018 年 5 月 19 日，采用该方法时发现有未知峰，但对这些未知峰并未进行鉴别或积分。见本函第 1 条缺陷所述。

In your response, you stated that the lack of adequate LI investigations was due to inadequate training on procedures, analysts not following procedures, and inadequate quality oversight and visibility to senior management. You committed to perform a retrospective evaluation of LI.

在你们的回复中， 你们声称缺乏足够的 LI 调查是因为程序培训不充分，化验员未遵守程序，以及质量监管不够和高级管理层不重视。 你们承诺会对 LI 进行回顾性评估。

However, your response failed to assess your entire laboratory system to ensure the competency of analysts. You also failed toprovide a retrospective review of all your drug products to determine if you are attributing root cause appropriately, reporting OOS results correctly, and implementing adequate CAPA to prevent recurrence.

但是你们的回复中并未对你们整个实验室系统进行评估，以保证化验员的能力。你们亦未提交对你们药品的回顾性审核，从而确定你们是否找到了正确的根本原因，正确地报告了 OOS 结果，以及实施了足够的 CAPA 防止其再次发生。

For more information about handling failing, out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FD A's guidance document Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production , at https://www.fda.gov/media/71001/download .

关于不合格、 OOS 、 OOT 或其它非预期结果和调查文件记录，参见 FDA 指南“药物生产中 OOS 结果调查”。

In your response to this letter provide the following:

在你们对本函的回复中请提交以下：

• A retrospective, independent review of all invalidated laboratory incidents and OOS (including in-process and release/stability testing) results for U.S. products irrespective of whether the batch was ultimately distributed in the U.S. and a report summarizing the findings of the analysis, including the following for each OOS:

• 对所有美国产品的宣布无效的实验室事件和 OOS （包括中控和放行 / 稳定性测试）结果的独立回顾审核，无论这些产品是否最终销售至美国，并提交一份报告总结分析中发现的情况，包括每个 OOS 的以下信息：

• Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.

• 确定宣布无效的 OOS 结果的科学论证和证据是否可得出结论支持可归因的实验室错误

• For investigations that conclusively establish laboratory root cause, provide rationale and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.

• 对于可得出实验室根本原因的调查，提交理由并确保识别出所有其它易受到类似根本原因影响的实验室方法并进行补救

• For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history). Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.

• 对于回顾审核中发现的所有 OOS 结果，在实验室未找到根本原因或不能得出结论的，要包括一份对生产（例如批生产记录，生产步骤是否充分，设备 / 设施适用性，原料波动性，工艺能力，偏差历史，投诉历史，批不合格历史）的彻底审核。提交一份每个调查潜在生产根本原因的总结，以及所有生产操作改进措施。

• A comprehensive review and remediation plan for your OOS result investigation systems.

• 一份对你们 OOS 结果调查系统的全面审核和补救计划。

The CAPA should include but not be limited to addressing the following:

该 CAPA 应包括但不仅限于说明以下问题：

• Define what constitutes a laboratory incident or OOS.

• 规定实验室事件或 OOS 的形成要素

• Quality unit oversight of laboratory investigations.

• 质量部门对实验室调查的监管

• Identification of adverse laboratory control trends.

• 不良实验室控制趋势的识别

• Resolution of causes of laboratory variation.

• 实验室波动原因的解决方案

• Initiation of thorough investigations of potential manufacturing causes whenever a laboratory cause cannot be conclusively identified.

• 无论是否可发现可归结实验室原因，均要对潜在生产原因启动彻底调查

• Adequately scoping of each investigation and its CAPA.

• 对每个调查及其 CAPA 范围进行充分界定

• Revised OOS investigation procedures with these and other remediations.

• 包括上述要求及其它补救措施的修订后 OOS 调查程序

3.Your firm failed to establish an adequate quality control unit with the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging materials, labeling, and drug products (21 CFR 211.22(a)). 你公司未建立足够的质量部门，使其具备职责与权力可批准或拒收所有组份、药品容器密闭器、中间体、包装材料、标签和药品（ 21 CFR 211.22(a) ）。

Your firm's quality unit (QU) failed to provide adequate oversight of your manufacturing activities. For example:

你公司的 QU 未对你们的生产活动执行充分监管，例如：

When our investigators arrived at your firm just 30 minutes after announcing our inspection, they observed numerous employees in the process of moving off-site cartloads of trash bags containing shredded and tom documents and binders. Upon closer examination, the investigators discovered batch reconciliation forms, cleaning and dispensing logs, training assessments, and scale balance printouts.

当我们检查员到达你们公司宣布我们检查后才 30 分钟，他们就发现大量员工在将装有切碎和撕掉的文件与文件夹的垃圾袋往厂外装运。 检查员接近检查后发现有批平衡表、清洁和分料日志、培训评估和秤打印件。

In your response, your firm acknowledged that your employees violated your documentation procedure. You identified the root causeas inadequate awareness of data integrity principles, training and education, supervision, and problem-solving capabilities. Your response was inadequate in that it did not fully evaluate the scope of this deficiency. You also did not adequately address the major failure of operations management and quality unit management to conduct proper oversight over documentation and data integrity.

在你们的回复中，你公司承认你们员工违反了你们的文件记录程序。你们将根本原因归结于数据完整性原则意识，培训和教育、监管和问题解决能力不够。你们的回复是不充分的，其中并未全面评估该缺陷的范围。你们亦未充分解决操作管理和质量部门管理未能对文件记录和数据完整性进行适当监管的重大问题。

Later in the inspection, our investigator noted that your live-feed cameras showed production staff expediently signing and passing documents to one another. Our investigator requested to visit the production staff location; however, our investigator was routed to an incorrect area. This incident delayed our investigator and prevented contemporaneous verification of the activities being performed.

在检查后期，我们检查员发现你们的实时录像显示生产员工快速地在文件上签名并传递给另一人。我们的检查员要求查看生产员工位置，但我们的检查员被带到了错误地方。该事件拖延了我们的检查员，使得他们未能在该活动正在进行时进行同步核查。

In your response, you stated that your firm's procedure for camera locations was incorrect. Your response is inadequate. You failed to address why two QU personnel reviewed and approved an incorrect camera location procedure approximately one week before the start of this inspection.

在你们的回复中，你们声称你公司的录像机放置位置的程序是不正确的。你们的回复是不充分的，

In response to this letter provide the following:

在回复本函时请提交以下内容：

• A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function.The assessment should also include, but not be limited to:

• 一份确认你们 QU 被赋予权力和资源可有效运转的全面评估和补救计划。评估还应包括但不仅限于：

• A determination of whether procedures used by your firm are robust and appropriate.

• 确定你公司所用程序是否稳健恰当

• Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.

• QU 对你们整个操作进行监管并评估其是否遵守适当规范的条款

• A complete and final review of each batch and its related information before the QU disposition decision.

• 在 QU 批处置决策前对每个批次及其相关信息的完整最终审核

• Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.

• 对调查的监管和批准，履行所有其它 QU 职责以确保所有产品的鉴别、含量、质量和纯度

Also describe how top management supports quality assurance and reliable operations; including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and to assure a continuing state of control.

亦要说明高级管理层是如何支持质量保证和可靠操作的，包括但不仅限于及时提供资源，积极解决新发现的生产 / 质量问题，确保持续受控状态。

• A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm's documentation practices to ensure you retain attributable, legible, complete, original, accurate, and contemporaneous records throughout your operation.

• 一份你们整个生产和实验室操作所用文件的完整评估，以确定哪些文件记录规范不够充分。在其中要包括一份详细的 CAPA 计划，全面补救你公司的文件记录规范，确保你们保存了你们所有操作中可追溯的、清晰的、完整的、原始的、准确的和同步记录。

Data Integrity Remediation 数据完整性补救措施

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 document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/97005/download .

你们的质量体系不能充分确保数据的准确性和完整性，无法支持你们生产的药品的安全性、有效性和质量。参见 FDA 指南文件“数据完整性和药品 GMP 合格”指导建立和遵守 CGMP 合格数据完整性规范。

In response to this letter, provide the following:

在回复此函时请提交以下信息：

A. A comprehensive investigation into the extent ofthe inaccuracies in data records and reporting. Your investigation should include:

一份对数据记录和报告不准确性程度的全面调查。你们的调查应包括

• A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.