FDA警告信：印度 Apotex Research Private Limited

恨我不成钢

Warning Letter 320-18-69          August 9, 2018

Dr. Ravinder Kumar, Managing Director

Apotex Research Private Limited

Plot 1 & 2, Bommasandra Industrial Area, 4th Phase, Jigani Link Road, Bangalore—560 099, Karnataka,India

Dear Dr. Kumar:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Apotex Research Private Limited at Plot 1 & 2,Bommasandra Industrial Area, 4th Phase, Jigani Link Road, Bangalore, from November 6 to 17, 2017.

美国FDA于2017年11月6-17日检查了你们位于印度班加洛尔的ApotexResearch Private Limited生产场所。

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

本警告信总结了制剂生产严重违反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 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).

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21U.S.C. 351(a)(2)(B)被认为是掺假药品。

We reviewed your December 11, 2017, response in detail and acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司2017年12月11日的回复，并此告知已收悉后续函件。

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

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 firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or anyof its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).你公司未能彻底调查所有放行或未放行销售批次或其组分无法解释的不一致情况，或不符合其质量标准的情况。(21CFR 211.192)

Your investigations into out-of-specification (OOS) laboratory results and manufacturing deviations are insufficient and do not include scientifically-supported conclusions. For example:

你们对化验室OOS结果和生产偏差的调查是不充分的，并未包括有受科学支持的结论。例如：

A.    You tested (b)(4) for (b)(4) capsule samples collected at (b)(4) locations during the manufacture of (b)(4) capsules, (b)(4) mg, batch (b)(4). The relative standarddeviation (RSD) was OOS: (b)(4)% (specification is not more than (b)(4)%).You then tested reserve capsules and obtained additional OOS results for this batch. One unit assayed at (b)(4)% (specification is (b)(4)–(b)(4)%), and the RSD was (b)(4)% (specification is not more than (b)(4)%).Your firm excluded the individual sub potent assay OOS result and recalculated the RSD results as passing with a new value of (b)(4)%.

你们在XX胶囊XXmg的XX批次生产期间对XX位置所取样品进行了XX检测。相对标准偏差（RSD）值为OOS：XX%（标准要求不得过XX%）。然后你们检测了留样胶囊，得到了该批次更多的OOS结果。一个单位含量为XX%（标准为XX-XX%），RSD为XX%（标准为不得过XX%）。你们公司排除了单个含量不合格的OOS结果重新计算RSD结果为合格，重新计算结果为XX%。

You did not test the reserve capsules and investigate the failing (b)(4) capsule (b)(4) results until approximately one and a half months after you used the same batch of (b)(4) capsules for in-vivo bioavailability studies on December 17, 2016.

直到2016年12月17日你们将相同批次XX胶囊用于体内生物等效性研究之后一个半月，你们才检查了留样胶囊，并调查不合格的XX胶囊XX结果。

Your response is inadequate. You attributed this failure toan “unknown lab error.” You claimed that the low individual assay test resultwas an outlier and that the most probable root cause was analytical error.Outlier tests have no applicability in cases where the variability in theproduct is what is being assessed, such as for (b)(4). You did notprovide sufficient justification for disregarding the low result or supporting your unspecific conclusion of unknown laboratory root cause.

你们的回复是不充分的。你们将此不合格归因于“未知化验室错误”。你们声称单个含量值偏低的检测结果是离群结果，最可能的根本原因是检验错误。如果产品本身的波动性是受评估的对象，如XX，那么离群测试是不适用的。你们并未提交足够的论证用以支持忽略低含量结果或支持你们未知化验室根本原因的非特定原因。           

B.     You initiated an investigation into OOS and out-of-trend (OOT) assay results for (b)(4) tablets, (b)(4)mg and (b)(4) mg, three-month stability samples (batches (b)(4) and (b)(4)). Your May 2017 investigation states that you also obtained low OOT assay values at the one-month time point. You concluded the OOS and OOT results were due to analyst error during sampling preparation but lacked data to support your conclusion. Your testing associated with the investigation did not demonstrate that sample preparation caused the aberrant results as assay values did not differ substantially when you varied sample preparation.

你们启动了对XXmg和XXmg的XX片剂3个月稳定性样品（批号XX和XX）的OOS和OOT含量结果的调查。你们在2017年5月的调查声称你们在1个月的时间点亦得到了较低的OOT含量值。你们做出结论说该OOS和OOT结果是由于化验员的取样制备错误，但缺乏数据来支持你们的结论。你们与调查有关的检测并未证明样品制备会导致异常结果，因为当你们改变样品制备时含量值并未发现有显著差异。

You did not extend the investigation to manufacturing, although your Site Incident Response Committee requested initiation of this part of the investigation. Notably, you performed the manufacturing phase of the investigation after our inspection.

虽然你们的工厂事件响应委员会要求启动生产部分调查，但你们并未将该调查延伸至生产。值得注意的是，你们在我们检查之后执行了生产阶段调查。

Your response explains that a third party performed a retrospective review of nine invalidated OOS investigations and that in “all cases, the investigations were found to be thorough and robust and the findings were sufficiently justified.” However, this is not fully consistent with your third-party report. Regarding this specific OOS investigation, your third-party report says it “did not believe sufficient scientific evidence was presented in the laboratory OOS investigation process to justify retesting. Only retesting and obtaining passing results are the basis of conclusions.”

你们的回复解释说一个第三方单位对9个被宣布无效的OOS调查进行了回顾性审核，“在所有案例中均发现调查是彻底可靠的，发现的问题经过了科学论证”。但是，这与你们的第三方报告并不完全一致。关于此具体的OOS调查，你们的第三方报告说他们“并不认为在化验室OOS调查过程中有足够的科学证据来对复验进行支持。结论的基础只有复验和获得的合格结果”。

C.     Variance investigation checklists (VIC) and variance investigation reports (VIR) used to investigate poor chromatography and failing results are inadequate. These VIC and VIR investigations are not subject to your OOS investigational procedures, and you do not track and trend them. Our inspection identified that you used test results obtained with your VIC and VIR investigations to replace original results. Further, your personnel stated that they retested a sample as part of a VIR investigation because they did not want to show low results to a customer.

用于调查不良色谱和不合格结果的差异调查检查清单（VIC）和差异调查报告（VIR）不充分。这些VIC和VIR调查未遵守你们的OOS调查程序，你们并未追踪并进行趋势分析。我们在检查中发现你们使用了你们VIC和VIR调查中所获得的检测结果来取代原始结果。另外，你们的人员声称他们作为VIR调查的一部分对一份样品进行了复测，因为他们不想给客户显示出低结果。

Your response is inadequate. You have not provided the retrospective review of all VIC and VIR investigations.

你们的回复是不充分的，你们并未提交对所有VIC和VIR调查的回顾性审核。

D.    On August 8 and 9, 2017, you observed capped and edge-worn tablets in two batches of (b)(4) tablets, (b)(4)mg. You rejected a substantial number of units from each batch due to these defects. You opened an investigation, which closed September 7, 2017, and concluded the most probable root cause was high (b)(4) force. You lackedscientific evidence to support this root cause as other batches had been successfully produced in that range. After observing a third batch with capped (b)(4) tablets, (b)(4) mg, inOctober 2017, you initiated another investigation.

在2017年8月8日和9日，你们发现XX片剂XXmg两个批次中有已顶裂以及边缘破损的片子。由于该缺陷，你们拒收了每个批次中相当多的数量。你们开启了一个调查，该调查于2018年9月7日关闭，结论是最可能的根本原因是高XX力。你们缺乏科学证据来支持该根本原因，因为在该范围内成功生产其它批次。在2017年10月发现第三批顶裂XX片剂XXmg之后，你们启动了另一个调查。

Your response acknowledges that the tablet defects may be due to multiple root causes and you continue to investigate the issue. However, your response lacks a detailed update on the investigations into the capped tablets. You also did not include corrective action and preventive actions (CAPA) initiated in association with the investigations.

你们的回复说知晓片剂缺陷可能是由于多个根本原因，你们将继续调查此问题。但是，你们的回复缺乏对顶裂片剂的调查情况的更新细节。你们亦未包括在相关调查中启动的CAPA。

In response to this letter:在回复此函时：

• Explain why (b)(4) mg capsule batch (b)(4) was shipped and used for your bioequivalence studies before testing and investigational activities were completed. Also, describe whether your procedures require all testing and investigations to be completed prior to batch release.
• 请解释为何在完成检测和调查活动之前已将XXmg胶囊批次XX发运，并用于你们的生物等效性研究。亦请说明你们的程序是否要求在批放行之前完成所有检测和调查。
• Perform a three-year retrospective review to determine whether outlier tests have been used in previous OOS investigations, and determine whether you used them to improperly invalidate OOS results.
• 对过去三年进行回顾性审核以确定在之前的OOS调查中是否有使用离群检查，并确定你们是否使得它们来不恰当地宣布了OOS结果无效。
• Provide the report and associated CAPAs for your retrospective review of all VIRs and VICs initiated since January 1, 2015. Include a third-party assessment of each of the VIRs and VICs, and of your firm’s final report.
• 请提交一份对自2015年1月1日开始所有VIR和VIC的回顾性审核的报告和相关CAPA。在其中包括一份第三方对每份VIR和VIC的评估，以及对你们公司最终报告的评估。
• Assess the procedures you use to evaluate (b)(4) uniformity, including collecting and testing samples and evaluating results.
• 对你们用于评估XX均一性的程序的评估，包括样品采集和检测以及对结果的评估。
• Provide a comprehensive, independent assessment of your overall system for investigations of laboratory and manufacturing-related deviations, discrepancies, complaints, OOS results, and failures. Your CAPA plan should include but not be limited to improvements in investigation competencies, root cause analysis, written procedures, and quality unit oversight. Also, include an improved process for evaluating CAPA effectiveness.
• 提交一份对你们化验室和生产相关偏差、不符合、投诉、OOS结果和不合格调查的总体系统的全面独立评估。你们的CAPA计划应包括但不仅限于对调查能力、根本原因分析、书面程序和质量部门监管的改进。还应包括改进后的CAPA有效性评估程序。
  
  

For more information about handling failing,out-of-specification, out-of-trend, or other unexpected results and documentation of your investigations, see FDA’s guidance document, InvestigatingOut-of-Specification (OOS) Test Results for Pharmaceutical Production, athttps://www.fda.gov/downloads/drugs/guidances/ucm070287.pdf.

更多信息参见FDA官网OOS调查指南。

2.      Your firm failed to establish valid in-process specifications (21 CFR 211.110(b)).你公司未建立有效的中控标准（21 CFR 211.110(b)）。

Your firm failed to establish appropriate in-process specifications to ensure the quality of (b)(4). During our inspection, your management explained that (b)(4) could not be tested (b)(4) because the material was not (b)(4) and could fail assay specifications. OOS (b)(4) should not be (b)(4) with other batches for the purpose of meeting specifications.

你公司未能建立适当的中控质量标准，以确保XX的质量。在我们检查期间，你们的管理人员解释说XX不能检测XX，因为该物料不是XX，含量可能不符合标准。OOS的XX不应与其它批次XX以达成符合质量标准的目的。

Your response included a process flow diagram which showsthat (b)(4) of (b)(4) undergo separate dispensing, (b)(4), and (b)(4) steps, and are not tested separately (b)(4). You stated that assay testing at the (b)(4) stage is not a critical quality attribute because the (b)(4) is incomplete. You also acknowledged thatyou did not perform this (b)(4) testing during process validation studies.This response is inadequate. (b)(4) should be individually tested and found to meet appropriate specifications (b)(4).

你们的回复包括有一个工艺流程图，其中显示了XX的XX有分散、XX和XX步骤，且并未分别检测XX。你们声称在XX步骤的含量检测并不是关键质量属性，因为XX是不完整的。你们亦知晓你们在工艺验证期间并未执行此XX检测。该回复是不充分的。XX应该单独检测并应符合适当的质量标准XX。

In response to this letter, remediate your current procedures to ensure that (b)(4) are tested for appropriate quality attributes (b)(4). Provide us with any updates made to your procedures.Provide a list of all products manufactured in a similar manner and include an assessment of the effects on any batches produced in this manner which are within expiry.

在回复此函时，请对你们当前程序进行弥补以确保检测XX的适当质量属性XX。向我们提供你们程序所做的所有更新。提交一份以类似方式生产的所有产品清单，并包括一份对所有以此方式生产且仍在效期内批次的影响性评估。

Quality Unit Authority 质量部门权力

Your inspectional history indicates that your quality unit does not fully exercise authority, such as ensuring that appropriate investigations are performed with sound conclusions, identifying root causes,and supporting scientific justification. Your firm must provide your quality unit with appropriate authority, sufficient resources, and staff to carry out its responsibilities and consistently ensure drug quality.

你们的检查历史显示你们质量部门并不具有全面的履责权力，例如确保进行适当的调查并得出合理结论、识别根本原因，以及支持性科学论证。你公司必须为你们质量部门提供适当的权力、足够的权力和人员来履行其职责，持续确保药品质量。

Quality Systems质量体系

Your firm’s quality systems are inadequate. For guidance onestablishing and following CGMP compliant quality systems, see FDA’s guidancefor industry:

你们公司的质量体系是不充分的。建立和遵守符合CGMP要求的质量体系请参见FDA行业指南Q8/Q9/Q10

• Q8(R2) Pharmaceutical Development,     athttps://www.fda.gov/downloads/drugs/guidances/ucm073507.pdf;
• Q9 Quality Risk Management,     athttps://www.fda.gov/downloads/Drugs/Guidances/ucm073511.pdf; and
• Q10 Pharmaceutical Quality System,     athttps://www.fda.gov/downloads/drugs/guidances/ucm073517.pdf.
  
  

Repeat Violations and Deviations at Multiple Sites多个工厂重复违规和偏差

FDA has cited similar CGMP violations and deviations at this and other facilities in your company’s network. In the last five years, FDA has taken the following actions in response to CGMP violations and deviations at Apotex facilities.

FDA在你们公司网络中此工厂和其它工厂发现了类似的CGMP违规和偏差情况。在过去5年内，FDA已经采取了以下措施来响应APOTEX工厂的CGMP违规和偏差情况：

1.      FDA placed Apotex Pharmachem India Private Limited on Import Alert on April 1, 2014, and issued a warning letter on June 16, 2014, which cited failure to investigate and document OOS results.FDA于2014年4月1日将Apotex PharmachemIndia Private Limited置于进口禁令中，并于2014年6月16日签发了警告信。

2.      FDA placed Apotex Research Private Limited on Import Alert on September 22, 2014, and issued a warning letter on January 30, 2015, which cited failure to follow written procedures applicable to the quality control unit. FDA于2014年9月22日将Apotex Research Private Limited置于进口禁令中，并于2015年1月30日签发了警告信，其中引用了不遵守质量部门所适用书面程序的问题。

FDA has previously communicated about the need for appropriate and global quality oversight to Apotex senior management during several regulatory meetings.These repeated failures at multiplesites demonstrate that management oversight and control over the manufacture of drugs is inadequate.

FDA之前在几次法规会议中已与APOTEX的高级管理层沟通过需要有适当的全球质量监管事宜。这些在多个工厂发现的重复违规情况说明管理层对药品生产的监管和控制是不充分的。

Your quality system has not implemented effective correctiveactions to ensure the accuracy and integrity of the data generated at your facility, which is necessary to ensure the safety, effectiveness, and quality of the drug products you manufacture. There will be additional communications from CDER’s Office of Pharmaceutical Quality regarding theseissues. The Office of Generic Drugs may subsequently provide comment regarding the effect of these findings on (b)(4) if needed.

你们的质量体系并未执行有效的纠正措施来确保在你们工厂所产生的数据的准确性和完整性，而这些数据是确保你们所生产药品的安全性、有效性与质量所必须的。CDER的药品质量办公室将就此问题进行另外的沟通。必要时，仿制药办公室可能会在后续提供对这些缺陷的看法。

CGMP consultant recommended  CGMP顾问建议

Because you failed to correct repeat violations, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34, to assist your firm in meeting CGMP requirements. Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance, and evaluate the completion and effectiveness of any corrective actions and preventive actions you have implemented before you pursue resolution of your firm’s compliance status with FDA. Your firm’s executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance.

由于你们未能纠正重复的违规情况，我们强烈建议你们使用一位有21 CFR211.34所述资质的顾问来协助你们公司符合CGMP要求。我们还建议具备资质的顾问对你们全面操作进行CGMP合规性综合审计，并在你公司寻求符合FDA法规要求解决方案之前评估所有已实施CAPA的完整性和有效性。你们公司的高级管理层仍负有义务全面解决所有缺陷，确保持续CGMP符合性。

Conclusion 结论

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

此函中所引用的违规并不是全部。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 thatyou contact CDER’s Drug Shortages Staff immediately, at drugshortages@fda.hhs.gov, so that FDA can work with you on the most effectiveway to bring your operations into compliance with the law. Contacting the DrugShortages Staff also allows you to meet any obligations you may have to reportdiscontinuances 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 dependon your products.

如果你们在考虑要采取的措施可能会导致你们工厂所生产的药品供应中断，FDA要求你立即联系CDER药品短缺负责人员，这样FDA可以与你们一起采用最为高效的方式引导你们的操作符合法规要求。联系药品短缺负责人员还能让你满足依据21 U.S.C. 356C(b)你可能必须报告你们药品中止或中断的义务，让FDA尽快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。

FDA placed your firm on Import Alert 66-40 on April 12,2018.

FDA已于2018年4月12日将你置于进口禁令66-40项下。

Until you correct all violations completely and we confirmyour compliance with CGMP, FDA may withhold approval of any new applications orsupplements 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 violations may also result in FDAcontinuing to refuse admission of articles manufactured at Apotex ResearchPrivate Limited at Plot 1 & 2, Bommasandra Industrial Area, 4thPhase, Jigani Link Rd., Bangalore, into the United States under section801(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 andcontrols used in their manufacture do not appear to conform to CGMP within themeaning 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 inwriting within 15 working days. Specify what you have done since our inspectionto correct your violations and to prevent their recurrence. If you cannotcomplete corrective actions within 15 working days, state your reasons fordelay 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:

Brooke K. Higgins

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 3006076314.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research