近期收到FDA警告信的企业汇总

2017年04月11日，FDA官网挂出对全球仿制药巨头 迈兰（Mylan）制药 的警告信，缺陷主要涉及数据可靠性问题，包括：

• 无效OOS率约72%，但没有充分的调查来确定根本原因

• 未能监测和调查计算机化系统所产生的错误信号

• 删除检验数据、进针结果、色谱图等

• 多个OOS（数据丢失）归咎为供电中断、连接问题（网线或电源线中断）、和仪器失灵。一周有7次因数据采集中断导致原始结果丢失。

具体如下：

Mr. Rajiv Malik

President

Mylan Pharmaceuticals, Inc.

迈兰制药有限公司

1000 Mylan Boulevard

Canonsburg, PA 15317

Dear Mr. Malik:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Mylan Laboratories Limited at F-4 & F-12, MIDC, Malegaon Taluka, Sinnar District, Nashik 422 113, Maharashtra, India, from September 5 to 14, 2016.

FDA与2016年9月5~14日检查了你们位于印度马哈拉施特拉邦纳克西422113西纳尔街马莱冈的迈兰实验室有限公司。

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.

本警告信概况了成品CGMP条款重大违规。见21CFR第210部分和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).

因为你们的方法，设施，或者生产、加工、包装或者保存的控制不符合CGMP，你们的药品被认定为掺假。

We reviewed your October 5, 2016, response in detail and acknowledge receipt of your subsequent correspondence.

我们详细审阅了你们于2016年10月5日及之后的回复。

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

检查期间，我们的检查员发现的具体违规包括但不限于，如下：

1.    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).

未能彻底调查批产品或其组分与其既定标准的任何不明原因的差异或不符，不管该批是否已经被放行。

From January 1 to June 30, 2016, your firm invalidated 101 out of 139 (about 72 percent) initial out-of-specification (OOS) assay results without sufficient investigation to determine the root cause of the initial failure.

从2016年6月1日到30日，贵司判定139个含量结果OOS里面有101个为无效OOS（约72%），但是没有充分的调查来确定最初失败的根本原因。

For example, you opened laboratory investigation report PR 908027 for an initial OOS six-month stability assay result of (b)(4) percent (specification (b)(4)–(b)(4) percent) for (b)(4) mg tablets, lot (b)(4). You invalidated the initial failing result without adequate investigation, performed re-testing, and then reported the (b)(4) results of these replicate re-tests ((b)(4) percent). Your investigation did not reach an assignable cause, nor did you take appropriate corrective actions and preventive actions to ensure that the significant “analytical bias” to which you ultimately attributed the initial failure would not affect other analytical work in your laboratory.

例如，你们对XX mg片剂，批次XX六个月稳定性含量结果XX%（标准：XX~XX%）的初始OOS结果开展实验室调查报告PR908027。你们判定原来的不合格结果无效，没有进行充分的调查，而是重复检验，并报告了重复检验的XX%的XX结果。你们的调查没有确定原因，也没有采取适当的纠正和预防措施来确保你们最终确定的导致原先不合格结果的“分析偏差”不会影响其他你们实验室的其他分析工作。

In your response, you state that laboratory decisions are to be made on the basis of scientific evaluation, and that they are to determine whether OOS laboratory results are the result of the laboratory process or the manufacturing process. However, in the example above, your investigation assumed “analytical bias” in your laboratory process but failed to determine how this apparently significant error in your analyses could be eliminated or mitigated in the future.

在你们的回复中，你们说实验室决策将基于科学评价，并说将确定实验室OOS结果是实验室过程引起还是生产过程引起。但是，在以上的例子中，你们的调查认定为实验室过程引起的“分析偏差”而没有确定在实验室过程中如此明显的重大错误在将来将如何被消除或减少。

Your response is inadequate because you failed to implement a corrective action and preventive action (CAPA) plan to mitigate errors that you attribute to laboratory process. Further, you did not include these improperly invalidated OOS results in your analysis of laboratory investigation trends. According to your Laboratory Investigation Report procedure MLLNSK-SOP-QA-GMP-0138, version 6, only “confirmed” root causes are to be identified and trended in laboratory investigation reports. Because your laboratory investigations frequently invalidate initial failures without cause, your laboratory trending excludes a large proportion of data that would otherwise alert you to problems in your laboratory system. Failure to identify trends in OOS investigations is a repeat observation from the previous FDA inspection, March 19 to 26, 2015.

你们的回复是不充分的，因为你们没有实施纠正措施和预防措施计划来减少你们所归咎为实验室过程引起的错误。而且，在你们的实验室调查趋势分析中没有包括这些被误判为无效的OOS结果。根据你们的实验室调查报告规程，MLLNSK-SOP-QA-GMP-0138，第六版，只有“确定的根本原因”才会在实验室调查报告中被认定和趋势分析。因为你们的实验室调查经常判定一开始的不合格结果无效而没有原因，你们的实验趋势分析将一大部分本可能警戒实验室系统问题的数据排除在外。未能分析OOS调查的趋势是2015年3月19~26日上次FDA检查发现的重复缺陷。

2.    Your firm failed to establish an adequate quality control unit with the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated (21 CFR 211.22(a)).

贵司未能建立一个充分的质量控制部门，使其有权审核生产记录以确保没有错误发生，或者在发生错误后，能够被充分调查。

Your quality unit failed to monitor and investigate error signals generated by the computerized systems that you use for high performance liquid chromatography and gas chromatography. These signals indicated the loss or deletion of original CGMP analytical data. However, your quality unit did not comprehensively address the error signals or determine the scope or impact of lost or deleted data until after these problems were reviewed during our inspection.

你们的质量部门未能监测和调查由高效液相（HPLC）和气相（GC）所用的计算机化系统所产生的错误信号。这些信号显示了原始CGMP分析数据的丢失或删除。然而，你们的质量部门没有彻底处理这些错误信号，或确定所丢失或删除的数据的范围和影响，直到这些问题在我们检查期间被发现。

For example, our investigator reviewed audit trails from August 2016 assay testing on (b)(4) batch (b)(4) and dissolution testing for (b)(4) tablets batch (b)(4). The audit trail for these tests included the message, “deleted result set,” but neither of these two incidents were recorded in the analytical packages for these batches of drug products, nor were they reviewed or investigated by the quality unit.

例如，我们的检查员审阅了2016年8月XX产品XX批次的含量检测和XX片剂XX批次的溶出检测的审计追踪。这些检验的审计追踪均提示“删除结果集”，但是这两个事件均没有在他们的药品批次分析包中记录，也没有被质量部门审核或调查。

In addition, during the inspection, our investigator observed that your Empower 3 system audit trail displayed many instances of a “Project Integrity Failed” message, which indicates that injections were missing from the results of analytical testing. For example, in (b)(4) analysis for (b)(4) tablets batch (b)(4) conducted on June 20, 2016, no chromatogram was rendered for the initial run of testing. The data package for this testing clearly shows that the initial run is missing, but your quality unit did not investigate the incident.

另外，在检查期间，我们的检查员发现你们的Empower 3系统审计追踪显示有很多“项目完整性失败”的提示，这些提示表示分析检验结果中的进针缺失。例如，在2016年6月20日所进行的XX片剂XX批次的XX分析中， 没有绘制一开始检验的色谱图。该次检验的数据包清楚显示一开始的检验已经缺失，但是你们的质量部门没有调查该事件。

Although you showed our investigator isolated examples of interrupted, missing, deleted, and lost data for which you had opened investigations, you reached similar conclusions in many of these investigations regarding the root cause of your loss of data integrity but failed to take appropriate corrective action and preventive action in response. Our investigator observed that you attributed numerous incidents to power interruptions, connectivity problems (disconnection of the Ethernet or power cord), and instrument malfunctions. You could not explain why these events occurred with frequency in your laboratory, nor had you undertaken a comprehensive investigation into the problem or sought to correct it and prevent its recurrence.

尽管你们给我们的检查员展示了你们已经开展调查的中断、缺失、删除，和丢失数据的个例，在这些调查中有很多你们就数据可靠性问题的根本原因得出了相似的结论，但是没有采取适当的纠正和预防措施。我们的检查员发现你们将很多问题归咎为供电中断、连接问题（网线或电源线中断）、和仪器失灵。你们未能解释为什么这些问题在你们的实验室频繁出现，也没有对问题采取全面的调查或力求纠正它并预防再次发生。

In your written response dated February 17, 2017, you identified seven samples from a single week of testing for which original results were lost following data acquisition interruptions at the time of initial analysis. Instead of uniformly initiating an investigation into the root cause of each interruption when it occurred or even documenting it for later review and investigation by the quality unit, you explained in your response that you retested the samples immediately after the interruptions.

在你们日期为2017年2月17日的书面回复中，你们在一周的检验里面确定了7个在一开始分析时由于数据采集中断导致原始结果丢失的例子 。你们在你们的回复中解释说你们在中断后立即重新测试了样品，而不是对每一次中断在其发生时都进行一个根本原因调查，或至少记录它们以进行后续审核并由质量部门调查。

Your response is inadequate because you have not identified and investigated each instance in which data acquisition was interrupted. While you assessed a limited number of error codes from a seven day period, you did not evaluate the effects of other error codes identified in your simulation exercise report on the reliability, accuracy, or completeness of the data you use to evaluate the quality of your drugs.

你们的回复是不充分的，因为你们没有确定和调查每一个数据采集中断的情况。在你们评估了为期一周的有限数量的错误代码之后，你们没有在你们的模拟演练报告中评价你们所确定的其他错误代码对你们用于评价你们药品质量的数据的可靠性、准确性、或完整性的影响。

2017年04月25日，FDA官网挂出对仿制药巨头梯瓦制药中国萧山工厂的警告信，缺陷包括 关键工艺参数未监控、产品质量反复不合格、根本原因分析和CAPA无效、未能建立一个科学合理的取样计划、工艺验证取样不合理、未描述持续工艺确认计划如何确保质量属性持续符合并且批批一致

具体如下：

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, Chinafrom September 26 to 29, 2016.

FDA于2016年9月26-29日检查了你们位于杭州萧山的梯瓦医药化工有限公司生产基地。

This warning letter summarizes significant deviationsfrom current good manufacturing practice (CGMP) for active pharmaceuticalingredients (API).

本警告信概述了原料药生产严重违反CGMP的行为。

Because your methods, facilities, or controls formanufacturing, processing, packing, or holding do not conform to CGMP, your APIare 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).

由于你们原料药的生产、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)被认定为掺假。

We reviewed your October 21, 2016 response in detailand acknowledge receipt of your subsequent correspondence.

我们详细审阅了你们公司于2016年10月21日及之后的回复。

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

我们的检查人员发现的具体问题包括但不仅限于以下：

1.      Failure to establishwritten procedures to monitor the progress and control the performance of processing steps that may cause variability in the quality characteristics ofyour 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 2016failed to meet the (b)(4) impurity limit. During this period, anadditional 10 percent of batches yielded out-of-trend (OOT) results for (b)(4).You have reprocessed rejected out-of-specification OOS batches but failed toimplement effective corrective and preventive actions (CAPA) to correct processdesign and control flaws that lead to excessive formation of this impurityduring 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 analysisfound that impurity failures appear to be related to insufficient control of (b)(4).You committed to monitor (b)(4) specific process parameters in the newprocess 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. Yourresponse does not commit to monitor future batches for all parameters thatimpact quality, and may contribute to the failure of a batch of intermediatesor 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 notinclude the risk assessment and related scientific rationale to ensure thatcontrols implemented for all batches will detect upstream processing variationand ensure final API quality. You also acknowledged in March 2017correspondence that additional lots have failed since you resumed commercialmanufacture of (b)(4) API. Recurrence of product quality failuresfollowing the completion of your investigation and process re-qualificationindicate 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.

未能建立一个科学合理的取样计划

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.

我们的检查员发现了你们对XX API的验证取样计划的缺陷。你们在工艺性能确认阶段没有进行充分的监测和检验以评价每一批次的产品质量是否一致。你们只在干燥步骤评估了水分含量的均匀性。

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，你们确认了在生产工艺再验证期间的一个高水平的取样显示XX的残留溶剂和粒度分布存在一些批内差异。

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，因为没有描述你们的持续工艺确认计划如何确保质量属性持续符合并且批批一致。关于一致性，仅仅使用XX样品来确认可能在批内显著变异的属性是不足以确保你们的工艺保持在一个持续受控状态的。

In response to this letter:

回复此函：

Specify how you will improve batch sampling of (b)(4) API to ensure that you detect intra- and inter-batch variability during commercial manufacturing.

详细说明你们将如何改善XX API的批取样来确保你们可以在商业生产过程中发现批内和批间变异。

Evaluate other API produced by your firm for adequacy of sampling plans.

评价贵司生产的其他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.

提供质量体系的总体改善以确保贵司执行的所有取样都能具有代表性并能够检测到可能发生变异的质量属性的不一致性。