法国Quali-Controle &Quali-Controle警告信

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julia Julia法规翻译Warning Letter 320-18-38

Quali-Controle &Quali-Controle C.E.BAC

29 Rue Paul Vaillant-Couturier,Meru 60110, France

Dear Mr. Souhaut:

The U.S. Food and DrugAdministration (FDA) inspected your drug contract testing laboratory,Quali-Controle & Quali-Controle C.E.BAC, at 29 Rue Paul Vaillant-Couturier,Meru, from September 14 to 15, 2017.

美国FDA于2017年9月14-15日检查了你们位于法国梅吕的合同检测化验室Quali-Controle & Quali-ControleC.E.BAC。

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

本警告信总结了制剂检测严重违反CGMP的行为。参见21CFR第210和211部分。

Because your methods,facilities, or controls for manufacturing, processing, packing, or holding donot conform to CGMP, your drugs are adulterated within the meaning of section501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21U.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，你们的制剂根据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 6,2017, response in detail and acknowledge receipt of your subsequentcorrespondence. We note that your response lacks sufficient corrective actions.

我们已详细审核了你公司2017年10月6日的回复，并此告知已收悉后续回复。我们注意到你们的回复缺陷足够的纠正措施。

During our inspection, ourinvestigator observed specific violations including, but not limited to, thefollowing.

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 firmfailed to establish and document the accuracy, sensitivity, specificity, andreproducibility of its test methods (21 CFR 211.165(e)). 你公司未能建立和记录其检测方法的准确度、灵敏度、专属性和重现性(21 CFR211.165(e))。

For example, yournon-compendial test methods used to analyze your customers’ drug products hadnot been validated.

例如，你们使用未经验证的非药典方法分析你们客户的药品。

In your response, youindicated that a comment has been added to your Certificate of Analysis (CoA)to inform your customer that the analyses are conducted using unvalidated testmethods. You also committed to inform your customers that all future test methodswill need to be properly transferred or validated to legitimize the resultsobtained in your laboratory.

在你们的回复中，你们说已经在COA上增加了一个备注，告知你们客户该分析是使用了未经验证的检测方法测试的。你们还承诺会通知你们客户未来所有检测方法都要进行适当转移或验证，使得你们化验室获得的结果合法化。

Your response was inadequate.It is essential for a contract test laboratory to use validated or verifiedmethods to ensure that results of pharmaceutical analyses subject to CGMP areaccurate. Accountability in the supply chain is compromised when a CoA reportsthat results conform to specification without assurance that the test methodsused were reliable. Including a disclaimer does not release you from the CGMPrequirement to ensure that your test methods are validated and suitable fortheir intended use.

你们的回复是不充分的。合同检测化验室有必要使用经过验证或确认的方法，以确保CGMP要求下药物分析的结果是准确的。如果一份COA报告的结果是符合质量标准，但不保证所用检测方法是可靠的，则供应链的可靠度就受到损害。包括一份免责声明并不能让你们免除确保你们的检测方法要经过验证并适合其既定用途的GMP要求。

Further, although you statedthat you would advise your customers about the requirement for validationand/or transfer of test methods for future analyses, your response didnot address how you will review the results of all analyses you have previouslyconducted using unvalidated non-compendial methods or how you will communicatewith your customers about these non-compliant analyses.

另外，虽然你们声称你们将告诉你们的客户在将来分析中关于检验方法验证和/或转移的要求，但你们的回复并未说明你们要如何审核你们之前使用未经验证的非药典方法所执行的所有分析的结果，也没有说明你们要如何与你们的客户沟通这些不合规的分析。

In response to this letter,provide the following: 在回复此函时请提交以下内容：

• Protocol and timelines for the validation or method transfer of all non-compendial methods, and verification of all compendial methods used at your facility to test products for release.
• 在你们场所用于药品放行测试的所有非药典方法验证或方法转移，以及所有药典方法确认的方案和时间表
• An assessment of the use of unvalidated and unverified methods on products released to the U.S. market, and your plans to communicate with your customers regarding previously tested drugs for which you used unvalidated or unverified methods.
• 对放行至美国市场的药品使用未经验证和未经确认方法的评估，以及你们与你们客户沟通之前你们使用未经验证或未经确认方法检测药品情况的沟通计划
• Your procedure to assure that all future non-compendial methods used in your facility are properly validated or transferred, and all compendial methods are verified prior to use.
• 你们用以确保将来你们场所所有非药典方法会在使用前经过适当验证或转移，所有药典方法会在使用前经过确认的程序
  
  

2.    Your firmfailed to thoroughly investigate any unexplained discrepancy or failure of abatch or any of its components to meet any of its specifications, whether ornot the batch has already been distributed (21 CFR 211.192).你公司未能彻底调查已销售和未销售批次及其成分与其质量标准间所有非预期的差异或不合格（21 CFR 211.192）。

Your original atomicabsorption analysis of (b)(4) sample 15/0871 was out-of-specification(OOS). A retest of the sample was also OOS. A third sample was retested andfound within specifications. You invalidated the OOS results withoutjustification or documented investigation.

你们对XX样品15/0871的原始原子吸收分析结果不合格OOS，对该样品复测结果也是OOS。第三个样品进行了复测，发现符合质量标准。你们宣布OOS结果无效，但没有论证或书面调查。

In your response, you statedthat dirty glassware used in all prior preparations and tests was the root causefor the failures; you claimed that rinsing the glassware before testingresolved the problem.

在你们的回复中，你们声称不合格的根本原因是在所有之前的样品制备和检测中使用了脏的玻璃仪器，你们声称在测试前淋洗玻璃仪器解决了此问题。

Your response was inadequatebecause you have no scientific justification for the assigned root cause, norhave you implemented adequate corrective actions and preventive actions (CAPA).

你们的回复是不充分的，因为你们所归结的根本原因并没有科学论证，你们也未实施充分的CAPA。

As a contract laboratory, youmust comply with the CGMP regulations that apply to operations you perform,including but not limited to those that address the operations of your qualitycontrol unit, laboratory, investigation systems, documentation systems, andother facets of your operation. As set forth in FDA’s guidance forindustry, Investigating Out-of-Specification (OOS) Test Results forPharmaceutical Production (available athttp://www.fda.gov/downloads/Drugs/.../Guidances/ucm070287.pdf), following anOOS result, the laboratory should conduct an initial assessment to determinewhether there was a meaningful error in the analytical method. Followingsuch assessment, “[f]or contract laboratories, the laboratory should convey itsdata, findings, and supporting documentation to the manufacturing firm’squality control unit...”

作为合同化验室，你们必须符合适用你们所执行的操作的CGMP法规，包括但不仅限于说明你们质量控制部门、化验室、调查系统、文件记录系统和其它方面的法规。正如FDA指南所要求，在OOS结果之后，化验室应执行初始评估以确定是否在分析方法中有重大错误。在此评估之后，“化验室或合同化验室应将其数据、发现的情况和支持性文件转交给生产公司的质量部门……”。

FDA considers contractors asextensions of the manufacturer’s own facility. Your failure to comply with CGMPmay affect the quality, safety, and efficacy of the products you test for yourclients. It is essential that you understand your responsibility to operate infull compliance with CGMP, and to inform all of your customers of significantproblems encountered during the testing of these drugs. Your clients (e.g.,drug manufacturers, application sponsors), in turn, must provide you with allof the scientific data and information needed to support reliable methodimplementation.

FDA认为合同商是生产商自己工厂的延伸。你们未遵守CGMP可能会影响你们为客户所测试的药品的质量、安全和有效性。你们有必要了解你们全面按照CGMP进行操作的职责，并通知你们所有客户在这些药品测试中所遇到的重大问题。你们的客户（例如，药品生产商、申办人）则必须为你们提供所有科学数据和信息支持可靠的方法实施。

Your procedures must includeuse of validated methods for each analysis subject to CGMP. It is critical thatyou provide all test results for evaluation and consideration in final productdisposition decisions. When your investigation of out-of-specification resultsdoes not determine an assignable cause, all test results should be reported tothe customer on the certificate of analysis. We also recommend providing yourOOS reports to your customers, and including steps in your procedures to obtaincritical information from your customers about the products you test that couldaffect the suitability of the methods you use.

你们的程序必须包括依CGMP要求为每个分析使用经过验证的方法。你们提交所有检测结果供最终产品处置决策评估和考量是至关重要的。在你们调查OOS结果未确定可归结原因时，所有测试结果均应在COA上报告给客户。我们还建议将你们的OOS报告提供给你们的客户，在你们的程序中包括从你们客户那里获取关于你们所检药品的关键信息的步骤，这些信息可能会影响你们所用方法的适当性。

In your response to thisletter, provide the following:

在回复此函时，请提交以下内容：

• Retrospective review of all OOS test results     to determine if results were invalidated without scientific justification.     Your review should also identify those instances where a documented     investigation was not performed, and your plans for communicating these     deviations with your clients. Submit a report of your review with the     findings, and your CAPA plan to prevent recurrence.
• 所有OOS检测结果的回顾审核以确定是否有结果在没有科学论证情况下即被宣布无效。你们的审核还应识别出未进行有记录的调查的案例，以及你们与你们客户沟通这些偏差的计划。提交一份你们审核及发现问题的报告，以及你们防止再次发生的CAPA计划。
• Your revised written procedure for OOS investigations.
• 你们修订后的书面OOS调查程序
  
  

Quality Agreement 质量协议

You and your customer, (b)(4),have a quality agreement specifying the testing method that must be used foryour drug product. Your firm failed to follow the procedure set forth in yourquality agreement regarding the use of the United States Pharmacopeia for drugcomponent testing. You also failed to obtain prior approval from your customerbefore changing the test method, as required in your quality agreement.

你和你的客户XX有质量协议，其中写明了你们必须用于你们制剂检测的方法。你公司未遵守在你们质量协议中设定的使用USP方法测定药品成分的规定。你们亦未在变更该方法之前依你们质量协议的要求获得你们客户的批准。

For more information on howquality agreements may be helpful for defining, establishing, and documentingresponsibilities for CGMP activities, see FDA’s guidance document, ContractManufacturing Arrangements for Drugs: Quality Agreements, athttp://www.fda.gov/downloads/dru ... nces/ucm353925.pdf.

参见FDA指南文件“药品合同生产安排：质量协议”。

Conclusion 结论

Violations cited in this letterare not intended as an all-inclusive list. You are responsible forinvestigating these violations, for determining the causes, for preventingtheir recurrence, and for preventing other violations in all your facilities.

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，防止所有场所中这些偏差的再次发生，防止其它偏差的发生。

Until you correct all violationscompletely and we confirm your compliance with CGMP, FDA may withhold approvalof any new applications or supplements listing your firm as a drugmanufacturer.

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 theseviolations may also result in FDA refusing admission of articles manufacturedat Quali-Controle & Quali-Controle C.E.BAC at 29 Rue PaulVaillant-Couturier, Meru, into the United States under section 801(a)(3) of theFD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may besubject to refusal of admission, in that the methods and controls used in theirmanufacture do not appear to conform to CGMP within the meaning of section501(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 havedone since our inspection to correct your violations and to prevent theirrecurrence. 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。

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