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[FDA国外警告信] FDA警告信:印度 Emcure 20190802

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发表于 2019-8-24 21:25:40 | 显示全部楼层 |阅读模式

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Warning Letter 320-19-32        August 2, 2019
Mr. Satish Mehta, CEO, Emcure Pharmaceuticals, Ltd.
Plot No. P-1, P-2, I.T.B.T. Park, Phase II, M.I.D.C.,Hinjwadi, Pune, Maharashtra, 411057 India
Dear Mr. Mehta:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Emcure Pharmaceuticals Limited atPlot No. P-1 & P-2, I.T.B.T. Park, Phase II, M.I.D.C., Hinjwadi, Pune, Maharashtra, from February 11 to 20, 2019.
美国FDA于2019年2月11日至20日检查了你们位于印度的Emcure Pharmaceuticals 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与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,你们的药品根据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 March 13, 2019, response in detailand acknowledge receipt of your subsequent correspondence.
我们已详细审核了你公司2019年3月13日的回复,并此告知已收到后续通信。
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:
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). 你公司未彻底调查所有已销售或未销售的产品或其组份有未经解释的差异或不符合其质量标准的情形21 CFR 211.192)。
You failed to adequately investigate the following sterility failures obtained during routine batch release testing:
你们未能充分调查以下常规批放行检测中的无菌失败情形:
•      (b)(4) Injection, (b)(4)mg(b)(4)mL, Batch (b)(4) Sterility testing performed on June 4, 2018, reported Bacillus cereus growth
•      XX注射剂XXmgXXml,XX批次无菌检测于2018年6月4日执行,报告有蜡样芽孢杆菌生长
•      (b)(4) Injection, (b)(4)gm(b)(4)ml (b)(4) Batch (b)(4) Sterility testing performed on November 24, 2017, reported Lysinbacillus fusiformis growth.
•      XX注射剂XXmgXXml,XX批次无菌检测于2017年11月24日执行,报告有纺锤形赖氨酸芽孢杆菌生长
According to your sterility failure investigations, the most probable root cause for both events was laboratory error. Your firm’s investigations substantially addressed the potential for microbial contamination during sterility testing, but deemphasized potential manufacturing causes.
根据你们的无菌失败调查,两起事件的最可能根本原因为实验室错误。你公司的调查非常强调无菌检测过程中可能有微生物污染,但对可能的生产原因一笔带过。
Your sterility failure investigations lacked sufficient data to support its conclusions. For example:
你们的无菌失败调查缺乏足够的数据来支持其结论。例如
•      Sterility testing was performed using a closed testing system inside an ISO 5 laminarair flow environment. These conditions minimize the potential introduction of adventitious contamination during a sterility test. The investigation did not adequately address the specific breaches that could have occurredin such a closed testing system.
•      无菌测试是在ISO5级层流环境内的密闭测试系统里执行的。这些条件使得无菌测试过程中异物污染的可能性大大减少。调查未充分说明具体的问题为什么可能在如此密闭检测系统中发生的原因。
•      No microbial contamination was observed in the negative controls.
•      在阴性控制中未发现微生物污染。
•      Environmental monitoring data in the ISO 5 environment did not show microbiological contamination during performance of the sterility test.
•      在ISO5级环境中的环境监测数据并未显示无菌测试期间有微生物污染。
•      Your investigation did not identify aseptic breaches during the sterility tests.
•      你们的调查未识别出无菌测试期间有无菌问题。
•      Your investigation did not identify faults in the testing procedure, material, ortechnique used in conducting the sterility tests.
•      你们的调查未发现无菌检测过程所用检测程序、物料或技术问题。
•      Potential manufacturing failure modes were not adequately assessed.
•      未充分说明潜在生产失败模式。
Regarding the latter, your investigation did not thoroughly investigate potential manufacturing root causes. For example, while the organisms isolated during the failing sterility tests had been recovered in the laboratory facility in the past, the same microorganisms were also recovered in the production area in a six-month timeframe prior to the sterility failures. Lysinbacillus fusiformis, recovered on November 24, 2017, from the sterility testing of (b)(4) Inj. USP, (b)(4)gm (b)(4)ml, batch (b)(4) was recovered in the filling line ((b)(4) flow area) on September 1, 2017. Similarly, Bacillus cereus, recovered on June 4, 2018 from the sterility testing of (b)(4) injectionUSP(b)(4)mg(b)(4)mL, batch (b)(4) was recovered in the vial filling room on December 2, 2017.
关于后者,你们的调查并未彻底调查潜在生产根本原因。例如,在失败的无菌检测中分离出的菌过去曾在实验室场所有发现过,在无菌失败之前6个月时间内在生产区域亦发现有相同菌。在2017年11月24日在某USP注射剂无菌测试中发现过纺锤形赖氨酸芽孢杆菌,2017年9月在灌装线(XX流区域)XX批次中亦有发现。类似地,2018年6月4日曾在某USP注射剂中发现蜡样芽孢杆菌,2017年12月2日亦在西林瓶灌装间发现该菌。
Your review of environmental data was insufficient in that it relied too heavily on findings in the laboratory. You concluded that data indicated potential contamination control risks in the testing facility, but did not sufficiently address production failure modes. Specifically, your  investigation failed to thoroughly address container-closure integrity hazards, including but not limited to robustness of the vial sealing process. Your written response provided a table with a retrospective review of container closure integrity test (CCIT) results, but it lacked a comprehensive evaluation of discrepancies, deviations, complaints, and investigations related to a potential container-closure integrity failure mode.
你们对环境数据的审核不充分,过于依赖实验室发现的问题。你们得出结论说数据显示测试设施中有潜在污染控制风险,并未充分说明生产失败模式。具体来说,你们的调查未能彻底说明密闭容器完整性风险,包括但不仅限于西林瓶密封工艺稳健性。你们的书面回复中有一份表格,对容器密闭器完整性测试(CCIT)结果进行了回顾性审核,但其中缺少对与潜在容器密闭器完整性失效模式的差异、偏差、投诉和调查的全面评估。
Notably, your film has recalled products in the past due to container-closure integrity failures in batches of products that originally passed CCIT studies. Integrity of container-closure systems is critical to ensure product sterility.
值得注意的是你们公司曾经因为容器密闭器完整性失败而召回过原来通过了CCIT研究的产品。容器密闭器系统完整性对于确保产品无菌性至为关键。
You rejected a portion (sub-lot) of each batch and released the remaining sub-lots for distribution to the United States.
你们拒收了每批中的一部分(子批次),将剩下的子批次放行销售至美国。
We acknowledge your firm's decision to recall the distributed sub-lots after discussion with FDA, and your decision to install a sterility test isolator. We also acknowledge your commitment to conduct a further review of these failures and evaluate procedures for microbiological out-of--specification investigations to ensure they provide appropriate details in documenting root cause as well as adequate impact assessments with respect to other lots (or sub-lots) that may be impacted.
我们已知晓你公司在与FDA讨论之后决定召回已销售的子批次,你们还决定要安装无菌检测隔离器。我们亦知晓你们承诺要对这些失败执行进一步审核,评估微生物OOS调查程序,以确保其能提供适当的详细信息记录根本原因,对可能受影响的其它批次(或子批次)方面进行充分的影响性评估。
In response to this letter, provide:
在回复此函时请提交
•      An assessment of your overall system for investigations of deviations, atypical events, complaints, out-of-specification results, and failures. Your corrective action and preventive action (CAPA) plan should include, but not be limited to, improved rigor in reviewing the sources of variation in your operation that may cause deviations, failures, or defects. Also include your process for evaluating CAPA effectiveness.
•      对你们偏差、异常事件、投诉、OOS结果和失败调查的整体系统的评估。你们的CAPA应包括但不仅限于提高审核你们操作中可能导致偏差、失败或缺陷的波动来源的严谨性。亦要包括你们评估CAPA有效性的流程。
•      A comprehensive, third-party evaluation of records relating to discrepancies, deviations, complaints, maintenance, detailed batch defect history, and investigations related to potential sealing variability and container-closure integrity issues. Include all lots since July 2016 in the review. Based on this evaluation, provide an updated retrospective review to assess the robustness of your sealing process and container-closure systems.
•      一份与差异、偏差、投诉、维护、详细批缺陷历史记录,以及与潜在密封波动性和容器密闭器完整性问题有关调查的第三方全面评估。审核要包括自2016年7月以来的所有批次。根据评估结果,提供一份更新后的回顾性审核,评估你们密封工艺和容器密闭器系统的稳健性。
•      Your plans and procedures to ensure that future sterility failure investigations include a comprehensive evaluation of potential vulnerabilities in the manufacturing operation, specifically but not limited to a review of uniformity of biological lethality in your sterilizer as well as container-closure system integrity.
•      你们用于确保未来无菌失败调查会包括全面评估生产操作中潜在弱点的计划与程序,包括但不仅限于对你们杀菌剂生物杀灭力均一性的审核,以及容器密闭器系统完整性的审核。
•      Due to your finding of turbid samples during multiple additional sterility tests since 2017 beyond those discussed in this letter, provide a comprehensive third-party review of your sterility test methods. Special emphasis should be placed on improving method robustness to eliminate the root causes of the variations that led to the apparent false turbid readings.
•      由于你们在2017年多起附加无菌检测中发现样品混浊不在本警告信讨论范围内,请提交一份对你们无菌检测的第三方全面审核。特别要强调提高方法耐用性,消除导致明显错误浊度结果波动的根本原因。
•      A third-partyreview of your sterilizer reliability, with emphasis on uniformity of heat distribution and lethality throughout your sterilizers. This review should fully assess both physical and biological data and include analysis of current F-value and Z-value data, and any related assumptions incorporated into your sterilization cycle justifications. Include detailed analysis of temperature mapping/load studies, D-value determinations for each biological indicator lot,and causes of any positive biological indicator results. Specify the (b)(4) (or positions that had widest variation) identified in each of your validation studies since 2017.
•      第三方对你们灭菌剂可靠性的审核,强调温度分布均一性和你们灭菌剂的杀灭力。该审核应全面解释物理数据和生物数据,并包括目前的F值和Z值数据分析,以及你们灭菌循环论证中所含的任何相关假设。应包括详细的温度分布/装载研究分析、每个生物指示剂批次的D值计算,以及所有阳性生物指示剂结果原因。说明在你们2017年以来验证研究中所发现的XX(或有很大波动的位置)。
Repeat Observations at Facility 工厂重复缺陷
In a previous inspection, dated August 7 to 17,2017, FDA cited similar CGMP observations in which you inadequately performed microbiological investigations. Repeated failures demonstrate that executive management oversight and control over the manufacture of drugs is inadequate.
在之前2017年8月7-17日的检查中,FDA引用了类似的CGMP缺陷,也讲到你们微生物调查不充分。重复缺陷证明高级管理层对药品生产的监管和控制是不充分的。
Your executive management remains responsible for fully resolving all deficiencies, and ensuring ongoing CGMP compliance. You should immediately and comprehensively assess your company's manufacturing operations to ensure that systems and processes, and ultimately, the products manufactured conform with CGMP requirements.
你们的高级管理人员负有全面解决所有缺陷以及确保持续CGMP合规的义务。你们应立即全面评估你公司的生产操作,以确保系统和工艺和最终所生产的产品符合CGMP要求。
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.
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,防止你们设施内其它偏差的发生。
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 that you 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 Drug Shortages Staff also allows you to meet any obligations you may have to reportdis continuances 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 depend on 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。
Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements 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 resultin FDA continuing to refuse admission of articles manufactured at Emcure Pharmaceuticals Limited at Plot No. P-1 & P-2, I.T.B.T. Park, Phase II,M.I.D.C., Hinjwadi, Pune, Maharashtra 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 and controls used in their manufacture do not appear to conform to CGMP within the meaning 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 in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. 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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药徒
发表于 2021-7-24 21:27:04 来自手机 | 显示全部楼层
第一,进来参观一下。顺便看看情况。
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