印度MEGAFINE的FDA警告信节译

julia朱玉姣

警告信原文网址：http://www.fda.gov/ICECI/Enforce ... /2016/ucm503699.htm

The U.S. Food and Drug Administration (FDA) inspected your drugmanufacturing facility, Megafine Pharma Limited at No. 201, Village Lakhmapur,Dindori, Nashik, from May 11-15, 2015.

FDA于2015年5月11-15日对你工厂进行了检查。

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

此警告信中列出了原料药重大CGMP缺陷。

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

由于你们生产、加工、包装或保存的方法、设施或控制不符合CGMP要求，你们的原料药被认为是掺假。

We reviewed your firm’s June 3, 2015, response in detail and acknowledgereceipt of subsequent responses.

我们已详细审核了你公司于2015年6月3日发来的回复，也收到了之后的回复。

Our investigator observed specific deviations during the inspection,including, but not limited to, the following:

我们的调查人员在检查期间发现了一些特定的缺陷，包括但不仅限于以下：

1.     Failure to ensure that, for each batch ofintermediate and API, appropriate laboratory tests are conducted to determineconformance to specifications.

未能确保每批中间体和原料药均进行恰当的实验室测试来确定符合质量标准。

One of your analysts acknowledged falsifying test data for (b)(4)stability batch (b)(4) in August 2012. The analyst substituted areference standard chromatogram in place of the 12-month stability intervalchromatogram. You also submitted this data to FDA in support of drug masterfile (DMF) (b)(4).

你们的一个化验员知道2012年8月间某稳定性批次检测数据做假。化验员替换了12个月稳定性测试的对照谱图。你们还将此数据提交给FDA用以支持某产品的DMF。

In your response, you stated that laboratory management did not discoverthe discrepancy until the 24-month stability interval. You also stated that thebatch quality is unaffected because subsequent test results met specificationsat the 24-month and 36-month stability intervals.

在你们的回复中，你们说化验室管理人员直到24个月稳定性时间点时才发现此问题。你们还说，批质量并未受到影响，因为之后在24个月和36个月的稳定性时间点的检测结果仍符合质量标准。

Your response is inadequate because it does not address the extent of thedata falsification that could exist in your laboratory. You have not providedthe results of any investigation to determine the accuracy of the test data forother batches of drugs and the corrective actions that should be implemented toensure the quality of the drugs intended for U.S. distribution.

你们的回复是不充分的，因为其中并没有说明在你们化验室所存在的数据造假的程度。你们没有提供任何调查的结果来确定其它药品批次的检测数据准确性，也没有提交所实施的纠正措施来确保要在美国销售的药品的质量。

In response to this letter, conduct a complete review of all datasubmitted to the agency in support of DMF (b)(4) and provide a detailedassessment of any discrepancies found. Also provide a review of all testresults for any (b)(4) batch released for U.S. distribution withinexpiry.

在回复此函时，请对所有提交给药监支持某产品DMF的数据进行完整审核，提交所发现的差异的详细评估。还要提交一份销售到美国仍在有效期内某产品所有批次的检测结果审核。

2.     Failure to prevent unauthorized access orchanges to data and to provide adequate controls to prevent manipulation andomission of data.

未能防止未经授权进入或改变数据，以提供足够的控制来防止数据篡改和遗漏。

Multiple analysts, testing multiple drugs, deleted unknown peaks withoutjustification. These manipulations made the drugs appear to meet theirspecifications. Of concern, one of these unknown peaks was for a residual solventknown to be a (b)(4) impurity.   

检测多个药品的多个化验员删除了未知峰，没有任何论证。这些篡改过数据的药品貌似并不符合其质量标准。其中，有一个未知峰是一个残留溶剂的某杂质。

In response to this letter, provide the residual solvent results performedby an independent laboratory for all lots of drugs distributed to the UnitedStates.

在回复此函时，请提供由独立化验室对所有销售到美国的药品批次检测的残留溶剂结果。

3.     Inadequate investigation of critical deviationsor a failure of a batch to meet its specifications or quality standards.

对关键偏差和批不合格调查不充分。

Your quality unit released (b)(4) batch (b)(4) fordistribution despite its failure to meet the specification for (b)(4), a(b)(4) and (b)(4) impurity. Your impurity specification is notmore than (b)(4) parts per million (ppm). However, the batch had aresult of (b)(4) ppm.

你们的质量部门放行了某产品某批次用于销售，不管这批其实未能符合某项目某杂质的规格。你们的杂质规格是不超过XXppm，而这些结果为YYppm。

In your response, you indicated that the batch had been reprocessed andyielded a result of (b)(4) ppm for the impurity. However, thechromatograms that you provided as evidence of passing results were dated April28, 2014, almost (b)(4) after the batch was distributed.

在你们的回复中，你们说该批经过返工，重新检测杂质结果为ZZppm。但是你们所提供作为合格证据的图谱日期为2014年4月28日，是在该批销售之后差不多一年。

In response to this letter, retain an independent laboratory to conducttesting for all known (b)(4) and/or (b)(4) impurities that may bepresent in your drugs distributed to the United States. Provide a summary ofthe lab’s findings and actions you take in response to any out-of-specification(OOS) results.

在回复此函时，请让一个独立实验室对所有可能存在于你们销往美国的药品中的已知XX和/或YY杂质进行检测。请提供一份实验室缺陷和你们对OOS结果所采取的行动的摘要。

For more information about the proper handling of out-of-specificationresults and documentation of your investigations, please refer to InvestigatingOut-of-Specification (OOS) Test Results for Pharmaceutical Production at http://www.fda.gov/downloads/Drugs/.../Guidances/ucm070287.pdf

关于适当处理OOS结果，和调查文件记录方面的更多信息，请参见上述网址药品生产OOS检测结果调查。

Data Integrity Remediation

数据完整性补救

Your quality system does not adequately ensure the adequacy and integrityof data to support the safety, effectiveness, and quality of drugs youmanufacture. We acknowledge that you are using a consultant to audit youroperation and assist in meeting FDA requirements. In response to this letter,provide the following:

你们的质量体系不足以确保用以支持你们所生产药品的安全、有效性和质量的数据的充分性和完整性。我们知道你们聘请了顾问来审计你们的操作，协助你们符合FDA要求。在回复此函时，请提供以下内容：

1.     A comprehensive investigation into the extentof the inaccuracies in data records and reporting. Your investigation shouldinclude:

对数据记录和报告不准确程度的全面调查。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.
• 详细的调查方案和方法学，评估所包括的所有实验室、生产操作和系统的汇总，你们拟排除的操作的所有部分的论证。
• Interviews of current     and former employees to identify the nature, scope, and root cause of data     inaccuracies. We recommend that these interviews be conducted by a     qualified third party.
• 与现行和之前员工进行面谈，找出数据不准确的性质、范围和根本原因。我们建议这些面谈由有资质的第三方进行。
• An assessment of the     extent of data integrity deficiencies at your facility. Identify     omissions, alterations, deletions, record destruction, non-contemporaneous     record completion, and other deficiencies. Describe all parts of your     facility’s operations in which you discovered data integrity lapses.
• 对你们工厂数据完整性缺陷的评估。找出遗漏、篡改、删除、记录销毁、不同步记录和其它缺陷。描述你们发现的有数据完整性问题的工厂操作所有部分。
• A comprehensive     retrospective evaluation of the nature of the data integrity deficiencies.     We recommend that a qualified third party with specific expertise in the     area where potential lapses were identified should evaluate all data     integrity lapses.
• 关于数据完整性缺陷的性质的全面回顾性评估。我们建议采用具备相关领域专业知识的有资质第三方来评估所有数据完整性问题。
  

2.     A current risk assessment of the potentialeffect of the observed failures on the quality of your drugs. Your assessmentshould include analyses of the risks to patients caused by the release of drugsaffected by a lapse in data integrity, and risks posed by ongoing operations.

对你们药品质量所发现的不合格的潜在影响进行同步风险评估。你们的评估应包括受到数据完整性问题影响的药品放行对患者造成的风险的分析，以及持续运行所产生的风险的分析。

3.     A management strategy that includes the detailsof your global corrective action and preventive action plan. Your strategyshould include:

管理策略，包括你们全球CAPA计划的详细内容。你们的策略应包括：

• The detailed     corrective action plan that describes how you intend to ensure the     reliability and completeness of all of the data you generate, including     analytical data, manufacturing records, and all data submitted to the FDA.
• 详细的纠正措施计划，描述你们要如何确保你们所产生数据的可靠性和完整性，包括分析数据、生产记录和所有提交给FDA的申报数据。
• A comprehensive     description of the root causes of your data integrity lapses, including     evidence that the scope and depth of the current action plan is     commensurate with the findings of the investigation and risk assessment.     Indicate whether individuals responsible for data integrity lapses remain     able to influence CGMP-related or drug application data at your firm.
• 全面描述你们数据完整性问题的根本原因，包括现行措施计划的范围和深度与调查和风险评估发现相称的证据。说明是否对数据完整性问题有责任的人员仍可以对你公司CGMP相关或药品申报相关数据产生影响。
• Interim measures     describing the actions you have taken or will take to protect patients and     to ensure the quality of your drugs, such as notifying your customers,     recalling product, conducting additional testing, adding lots to your     stability programs to assure stability, drug application actions, and     enhanced complaint monitoring.
• 临时措施，描述你们已采取或将采取的措施，用以保护患者，确保你们药品的质量，例如，通知你们的客户、召回产品、实施额外检测、增加你们稳定性试验计划批次以确保稳定性、药品申报行动、加强投诉监控。
• Long-term measures     describing any remediation efforts and enhancements to procedures,     processes, methods, controls, systems, management oversight, and human     resources (e.g., training, staffing improvements) designed to ensure the     integrity of your company’s data.
• 长期措施，描述所有补救努力，对程序、工艺、方法、控制、系统、管理监管和人力资源（例如培训、员工配置改进）的强化，用以确保你公司数据的完整性。
• A status report for     any of the above activities that are already underway or completed.
• 在实施中和已完成的上述措施状态报告。
  

北重楼

数据完整性是主因，遗漏、篡改、删除、记录销毁、不同步记录……血的教训

zysx01234

印度阿三，你们的甘地大神在天上准备接你走

无药可救，罪该万死。

xiaoshihdl

哎。。每次看完一篇FDA的回信，我都头大。。

Trevor

卧槽，这样的企业也敢把药卖出去，草菅人命呀。

道路漫长黑暗

这个有资质的第三方具体指什么样的资质呢，国内有没有被认可的第三方。

kslam

道路漫长黑暗 发表于 2016-6-2 11:56
这个有资质的第三方具体指什么样的资质呢，国内有没有被认可的第三方。

顾问资质具备 21 CFR 211.34


Consultants advising on the manufacture, processing, packing, or holding of drug products shall have sufficient education, training, and experience, or any combination thereof, to advise on the subject for which they are retained.