昨夜，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。