FDA警告信：杭州泰华（TEVA）

Warning Letter 320-17-33

April 5, 2017

Mr. Quanmin Ye
General Manager
Teva Pharmaceutical and Chemical (Hangzhou) Co. Ltd.
No.1889, Jingliu Road, Linjiang Industrial Zone,
Xiaoshan, Hangzhou, Zhejiang, China 311228

Dear Mr. Ye:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Teva Pharmaceutical and Chemical (Hangzhou) Co. Ltd., 1889 Jingliu Road, Xiaoshan, Hangzhou, Zhejiang, China from September 26 to 29, 2016.

美国FDA于2016年9月26-29日检查了你们位于杭州萧山的泰华医药化工有限公司生产场所。

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).

  本警告信总结了原料药生产严重违反CGMP的行为。

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

  由于你们的原料药生产、加工、包装或保存的方法、场所或控制不符合CGMP要求，你们的原料药根据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 October 21, 2016 response in detail and acknowledge receipt of your subsequent correspondence.

  我们详细审核了你们公司2016年10月21日及之后的回复。

During our inspection, our investigator observed specific deviations including, but not limited to, the following.

  我们的调查人员发现的具体问题包括但不仅限于以下：

1.      Failure to establish written procedures to monitor the progress and control the performance of processing steps that may cause variability in the quality characteristics of your API.

未能建立书面程序以监控工艺步骤进程及表现，因此可能会导致你们API的质量特性的波动。

Our inspection found that approximately 10 percent of (b)(4) API batches produced at your facility from December 2014 to September 2016 failed to meet the (b)(4) impurity limit. During this period, an additional 10 percent of batches yielded out-of-trend (OOT) results for (b)(4). You have reprocessed rejected out-of-specification OOS batches but failed to implement effective corrective and preventive actions (CAPA) to correct process design and control flaws that lead to excessive formation of this impurity during processing.

我们检查发现你工厂自2014年12月至2016年9月生产的约有10%的某API批次不符合某杂质限度要求。在此期间，同一产品另有10%批次质量超趋势（OOT）。你们对OOS批准进行了返工，但未实施有效的CAPA来纠正工艺设计，控制工艺中导致此杂质过量生产的工艺瑕疵。

According to your response, a new root cause analysis found that impurity failures appear to be related to insufficient control of (b)(4). You committed to monitor (b)(4) specific process parameters in the new process performance qualification batches of (b)(4) API and the first (b)(4) commercial batches. However, these proposed parameters differ from the “critical process parameters” monitored by your firm in the last three years. They also do not include all of the parameters that you categorized as “critical and significant” in the most recent process qualification study. Your response does not commit to monitor future batches for all parameters that impact quality, and may contribute to the failure of a batch of intermediates or API to meet specifications.

根据你们的回复，在新的根本原因分析中发现杂质失败貌似与对XX控制不充分有关。你们承诺会在该API新的工艺性能确认批次及首次XX商业批次中监测该特定工艺参数。但是，这些所提出的参数并不是你们公司在过去三年所监测的“关键工艺参数”。他们也不包括所有的你们在最近工艺确认研究中定为“关键和重要”的参数。你们的回复没有承诺在将来监测所有影响质量、可能会与中间体或API不符合质量标准有关的参数。

Your response is also inadequate because it did not include the risk assessment and related scientific rationale to ensure that controls implemented for all batches will detect upstream processing variation and ensure final API quality. You also acknowledged in March 2017 correspondence that additional lots have failed since you resumed commercial manufacture of (b)(4) API. Recurrence of product quality failures following the completion of your investigation and process re-qualification indicate that your root cause analysis and CAPA were ineffective.

你们的回复不充分还因为其中未包括风险评估以及相关的科学合理性，以确保对所有批次所实施的控制能检出上游工艺波动，确保最终API质量。你们在2017年3月的信函中告知我们自从你们恢复某API的商业生产以来，又有一些批次不合格。在你们完成调查和工艺再确认之后，产品质量又发生不合格表明你们的根本原因分析和CAPA是无效的。

In response to this letter:

在回复此函件时：

• Provide an updated investigation into the root cause(s) of (b)(4) OOS results and an improved CAPA plan. Include provisions to ensure CAPA effectiveness.
• 请提交更新后的某OOS结果根本原因调查，以及改进后的CAPA计划。包括确保CAPA有效性的条款。
• Specify if the presumed root causes for failures were actually observed in the failed (b)(4) batches.
• 说明在不合格的XX批次中是否实际观察到了所假定的根本不合格原因。
• Describe why some finished (b)(4) API batches yielded OOS results for the bis-ether impurity, but passed testing for this same impurity at the (b)(4) stage.
• 说明为什么有些某API批次产生二醚杂质OOS结果，但却能通过在某工艺步骤中该相同杂质的检测。
• List the past and current process parameters for (b)(4) API. Explain their role in the process, the potential impact on quality, the limits used, and your justification if you plan to cease monitoring and controlling any parameter during commercial batch manufacture.
• 列出过去和现在的某API工艺参数。解释在工艺中各参数的作用、对质量的潜在影响、所使用的限度以及如果你们计划停止在商业批次生产中监测和控制任一参数时你们的论证。
• Explain your systems for incorporating reprocessing activities into Drug Master Files.
• 解释你们将返工活动整合入DMF文件的系统。
• Provide procedures that ensure that reprocessed lots and process performance qualification lots are included in your stability program.
• 提供程序确保返工批次和工艺性能确认批准被放入你们的稳定性计划中。
  

2.      Failure to establish a sampling plan based on scientifically-sound sampling practices.

未能根据科学合理的取样规范建立取样计划。

Our investigator documented deficiencies in your validation sampling plan for (b)(4) API. You did not conduct adequate monitoring and testing during process performance qualification stage to evaluate whether product quality was uniform throughout each batch. You only assessed water content at the drying step for homogeneity.

我们调查人员记录下了你们某API验证取样计划中的缺陷。你们在工艺性能确认阶段没有实施足够的监测来评估是否产品质量在每一批中都是均一的。你们只是在干燥步骤评估了水份的均匀性。

In your response, you acknowledged that a higher level of sampling during the revalidation of the manufacturing process revealed some inter-batch variability in residual solvents and particle size distribution of (b)(4).

在你们的回复中，你们说在生产工艺重新验证中有一个更高水平的取样计划，揭示出XX产品在残留溶剂和粒径分布方面有一些批内差异。

Your response is inadequate because it did not describe how your continued process verification program assures that quality attributes continue to be met batch-to-batch, as well as uniformly throughout each batch. Regarding uniformity, using only (b)(4) samples for attributes that may significantly vary within a batch is insufficient to ensure that your process remains in an ongoing state of control.

你们的回复是不充分的，因为回复没有说明你们的持续工艺确认计划是如何确保批次持续满足质量属性，以及批内的均匀性。关于均匀性，仅使用XX样品检测其在批内可能产生重大波动的属性是不足以确保你们的工艺维持在持续受控状态的。

In response to this letter:

在回复此函时：

• Specify how you will improve batch sampling of (b)(4) API to ensure that you detect intra- and inter-batch variability during commercial manufacturing.
• 请说明你们将如何改进某API的批取样以确保你们能发现商业生产中批内和批间波动。
• Evaluate other API produced by your firm for adequacy of sampling plans.
• 评估你们工厂生产的其它API取样计划的充分性。
• Provide overall quality system improvements to ensure all sampling performed by your firm is representative and able to detect non-uniformity of the quality attributes that may vary within a batch.
• 提交全面质量体系改进计划，以确保你们工厂实施的所有取样操作均具有代表性，可以发现批内可能会产生差异的质量属性的不均匀性。
  

Conclusion 结论

Deviations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these deviations, for determining the causes, for preventing their recurrence, and for preventing other deviations.

在此函中所引用的偏差并不是全部。你们有责任对这些偏差进行调查，确定原因，防止其再次发生，防止其它偏差的发生。

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b) and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

如果你们正在考虑可能会导致你们工厂所生产的药品供应中断的措施，FDA要求你们立即通过上述邮箱联系CDER药物短缺办公室，使得FDA可以与你们一起，以最高效的方式将你们的运行带回符合的轨道。与药物短缺办公室联系还能让你们完成所你们所承担的报告你们药品生产中断的义务，使得FDA尽可能快地考虑是否需要采取何种措施来避免短缺，保护依赖于你们药品的患者健康。

Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug manufacturer.

在贵公司未能完成所有偏差纠正并且由我们确认你们符合CGMP之前，FDA可能会搁置所有将你公司列为药品生产的新申报和增补申报的批准。

Failure to correct these deviations may also result in FDA refusing admission of articles manufactured at Teva Pharmaceutical and Chemical (Hangzhou) Co. Ltd., 1889 Jingliu Road, Xiaoshan, Hangzhou, Zhejiang into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

未能纠正这些偏差可能还会导致FDA依据FDCA第801(a)(3)条和21 U.S.C. 381(a)(3)拒绝接受在上述地址生产的产品进入美国。

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your deviations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

在收到此函后，请在15个工作日内回复至本办公室。在回复中说明自从检查后，你们做了哪些工作来纠正你们的偏差，防止其再次发生。如果不能在15个工作日内完成纠正措施，说明延迟的原因以及完成计划。

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:

      Rebecca Parrilla

      Compliance Officer

      U.S. Food and Drug Administration

      White Oak Building 51, Room 4359

      10903 New Hampshire Avenue

      Silver Spring, MD 20993

      USA

Please identify your response with FEI 3009271645.

Sincerely,

/S/

Thomas J. Cosgrove, J.D.

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

感谢楼主分享，辛苦