Warning Letter 320-20-31

March 25, 2020

Dear Mr. Bourla:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Pfizer Healthcare India Private Limited, FEI 3008316085, at Plots 116-117-118-119-111-123 (part), Jawaharlal Nehru Pharma City, Parawada, Visakhapatnam, Andhra Pradesh, India, from August29 to September 6, 2019.

美国FDA于2019年8月29日至9月6日检查了你们位于印度的Pfizer Healthcare India Private Limited（辉瑞印度工厂）生产场所。

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (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 September 27, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

我们已详细审核了你公司2019年9月27日对FDA483表的回复，并此告知已收到后续通信。

During our inspection, our investigator 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). 你公司未彻底调查已销售和未销售批次产品或其组份未经解释的差异或不符合其标准（21 CFR 211.192）。

Your facility manufactures (b)(4) injectable products. Your firm failed to conduct adequate investigations, including timely implementation of effective corrective action and preventive action (CAPA) plans.

你们场所生产XX注射剂。你公司未进行充分的调查，包括及时实施有效CAPA计划。

Failed Sterility Testing 无菌性检测不合格

You did not adequately investigate root causes and implement CAPA to address deficiencies regarding your sterility testing (b)(4). For example, in February 2019, you investigated the sterility failure of (b)(4) injection batch (b)(4). You determined the most probable root cause of this sterility failure was the “lack of robust (b)(4) integrity testing and possible non-integral drug product vials.” You also stated that the source of the microbial contamination may have been a faulty (b)(4). This batchwas rejected. However, you continued to use the same (b)(4) and performed sterility testing for a substantial number of additional batches before you made corrections, including replacing the suspect (b)(4).

你们并未对根本原因进行充分调查，并执行CAPA解决你们无菌检测XX的缺陷。例如，2019年2月，你们调查了XX注射剂批次XX的无菌检查不合格情况。你们认为最可能的根本原因是“缺乏稳健的XX完整性测试，药品西林瓶可能不完整”。你们还声称微生物污染来源可能是错误XX。该批次被拒。但你们在整改包括替换可疑的XX之前继续使用相同的XX，并对另外几批进行了大量无菌检测。

Your response stated that you will implement automated (b)(4) integrity testing, which is planned for July 2020. Previously, you lacked an automated integrity test, and instead relied on avisual check that was insufficient on its own to reliably detect (b)(4).

你们的回复声称你们将使用自动化XX进行完整性检测，计划实施时间为2020年7月。之前，你们缺少自动完整性检测，而是依赖于人工目视检查，仅靠人工目检无法可靠检出XX。

You also indicated that, effective January 2020, you would inspect sterility test samples for integrity before introduction to the sterility (b)(4).

你们还说自2020年1月起，你们会在引入无菌XX之前对无菌性检测样品进行检查。

The timeliness of the CAPA to resolve these significant root causes was insufficient. Your response did not adequately address the delay in CAPA implementation. Your response also indicated that you had made revisions to the investigation and that these revisions were completed on September 27, 2019. However, your response lacked the revised investigation and the status of your CAPA progress.

解决这些重大根本原因的CAPA时间限是不充分的。你们的回复中并未充分说明为何延迟执行CAPA。你们的回复亦说你们已对调查进行了修订，这些修订已于2019年9月27日完成。但是你们的回复中没的修订后的调查内容，以及你们的CAPA进度。

Environmental Monitoring Program 环境监测程序

You did not adequately investigate serious deficiencies in microbiology laboratory conditions and practices. Among the deficiencies were excessive occurrences of negative control plate contamination, high levels of contamination in environmental monitoring (EM) samples of the sterility test (b)(4), and disregarded EM data because of delayed plate readings. More specifically:

你们并未对微生物实验室条件和操作的严重缺陷进行充分调查。这些缺陷中，有阴性控制碟污染反复发生、无菌性检测XX环境监测（EM）样品有高水平污染、由于碟计数延迟弃除EM数据。更为具体的内容如下：

•      You did not thoroughly investigate negative environmental trends observed in the (b)(4) used to support sterility testing. Repeated recoveries were observed in the (b)(4), including excessively high levels (e.g., (b)(4), too-numerous-to-count (TNTC)CFU/m3), in some cases, over a three month period.

•      你们并未对支持无菌性检测的XX中发现的不良环境趋势进行彻底调查。有过3个月时间里，在XX中观察到重复回收，包括有些检测中发现微生物水平超高（例如XX，太多无法计数（TNTC）CFU/m3）。

•      You did not adequately investigate numerous instances over a one year period of microbial growth on negative control plates. These plates were used to support the EM program in both your production and laboratory areas.

•      你们并未对1年多时间里空白控制碟的大量事件进行充分调查。这些碟被用于支持你们生产和实验室区域的EM程序。

•      You invalidated microbial results without adequate scientific justification. Between September 26 and December 23, 2018, your biological quality laboratory allowed EM and testing plates used for monitoring your facility to be incubated beyond the days established in procedures. You attributed this recurring issue to a lack of qualified personnel. These plates included but are not limited to EM of the (b)(4), negative control plates, and product bioburden analysis. The testing results were repeatedly invalidated as the counts were considered unreliable, although the risks posed by the potentially valid contamination findings and related impact were not sufficiently addressed. Approximately (b)(4) batches were made during this period.

•      你们宣布微生物结果无效，却没有充分的科学论证。在2018年9月26日至12月23日之间，你们的生物质量实验室允许EM和检测碟用于监测你们要进行培养的设施，超出了程序中规定的天数。你们将该情况的发生归因于缺乏具备资质的人员。这些碟包括但不仅限于XX的EM、空白控制碟和产品生物负载分析。虽然存在实际可能被污染的风险，并且也没有对相关影响进行科学说明，但你们因为认为计数不可靠而反复宣布检测结果无效。

Your investigation into the extended incubation of plates indicates that they were being read on a “(b)(4)” basis. While you indicate you were reading plates (b)(4), you lacked documentation of earlier readings performed before the extended incubation times. The investigation also discusses the commingling of media plates in the same bag that were overgrown to the point that one plate may have contaminated another plate.

你们对延长碟培养时间的调查说你们在XX基础上进行计数。虽然你们说你们对碟进行了计数，但你们缺少在延长培养时间之前的计数文件记录。调查还讨论了培养碟混装在相同袋子里，碟之间可能会接触而相互污染。

Laboratory data accuracy deficiencies were also cited in our September 2018 inspection.

实验室数据准确性问题在2018年9月我们的检查中已有指出。

In your response, you indicated there are ongoing investigations to address the root causes of the recurring growth on negative control plates. You indicated that you have taken initial measures such as adding a new media vendor and improving incubator maintenance.

在你们的回复中，你们说还在继续调查找出阴性控制碟反复长菌的根本原因。你们说你们已采取初步措施如增加新的培养基供应商和改进培养箱维护。

Regarding the significant adverse environmental monitoring trends in your sterility testing (b)(4), your response stated that no additional EM excursions had occurred in your (b)(4) since you initiated your CAPA. The CAPA steps included addition of a (b)(4) to the (b)(4), better disinfection of supplies, slower (b)(4) movements, and retraining.

关于你们无菌检测XX中的严重不良环境监测趋势，你们的回复说自从启动CAPA以来，在你们的XX中并未发生其它的EM超标。该CAPA步骤包括增加XX至XX，对物品进行更好消毒，减慢XX动作和重新培训。

You also stated that you are improving overall laboratory capabilities and investigations systems.

你们还声称你们正在改进整体实验室能力和调查体系。

However, your response did not fully address how deficient laboratory controls, inadequate investigations, and delays in implementing CAPA compromised your firm’s microbiological control program.

但是你们的回复并未全面说明有缺陷的实验室控制、不充分的调查以及CAPA执行延迟对你公司的微生物控制程序有何不良影响。

In response to this letter, provide the following:

在回复本函时请提交以下内容：

•      A comprehensive assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-limit results,out-of-specification results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

•      一份对你们偏差、差异、投诉、OOS结果和失败调查的全面系统的全面独立评估。提交一份详细的行动计划以补救该系统。你们的行动计划应包括但不仅限于对调查能力、范围界定、根本原因评估、CAPA有效性、质量部门监管和书面程序的重大改进。说明你们公司要如何确保恰当地执行了所有调查阶段。

•      An assessment and remediation plan for your CAPA program. Provide a report that evaluates whether your firm effectively conducts root cause analysis, ensures CAPA effectiveness, regularly reviews investigations trends, implements improvements to the CAPA program when needed, ensures appropriate quality assurance decision rights, and is fully supported by executive management.

•      对你们CAPA程序的评估和补救计划。提交一份报告评估你们公司是否有效执行了根本原因分析，确保CAPA有效性、定期审核调查趋势、必要时对CAPA程序进行改进、确保适当的质量保证决策权，以及执行管理层的全面支持。

•      A complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.

•      一份在你们生产和实验室操作中所用的文件体系的完整评估，确定哪些文件记录做法不充分。要包括一份详细的CAPA计划，全面补救你们公司的文件记录规范，确保你们保持你们所有操作记录的可追溯性、清晰、完整性、原始性、准确度和同步性。

•      A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, analyst competencies, and resources. Regarding the latter, the assessment should address the adequacy of qualified staff needed to produce reliable results within appropriate timelines as well as your practices for managing the tracking of samples and timely reading of test results. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

•      一份对你们实验室规范、程序、方法、设备和文件记录、化验员能力和资源的全面独立评估。关于后者，评估应说明在适当时间限内得到可靠结果所需的具备资质的员工的充分性，以及你们管理样品追踪和及时读取检测结果的规范。根据该审核，提交一份详细的计划补救和评估你们实验室系统的有效性。

•      Your revised investigations regarding the sterility failure and the loss of environment control in the sterility testing (b)(4).The updated investigations should include, but not be limited to:

•      你们修订后的无菌性不合格以及无菌性检测中环境控制缺失的调查。更新后的调查应包括但不仅限于：

A final summary of all factors that may have compromised (b)(4) integrity, corrective actions, and your re-qualification results.

所有可能导致XX完整性、整改措施和你们重新确认结果的所有因素的最后总结。

Further explanation of the potential product container-closure integrityroot cause that appears to have been ruled out as a cause of the sterility failure. Provide a detailed summary of the defect and deviation rates that are relevant to container-closure integrity from your batch records over the last two years. In addition, explain the atypical manufacturing conditions that could impact container-closure integrity.

对你们将可能的产品容器密闭器完整性根本原因排除是无菌性不合格原因的进一步解释。提交一份过去2年中你们批记录里与容器密闭器完整性有关的缺陷和偏差率的详细汇总。另外，解释一下可能影响容器密闭器完整性的异常生产条件。

•      A summary of your completed negative control plate investigations that were ongoing at the close of the inspection.

•      一份你们已完成的阴性控制碟调查的总结。在检查结果时你们正在进行该调查。

•      Your response concerning extended incubation of media plates leading to the invalidation of EM results. Include a summary worksheet that documents the date that each plate was read, the date each plate was scheduled to be read, and the difference in the number of days between the actual date and the scheduled date. Clarify if you read and document microbial plates samples more than once during the incubation period and whether you document the results each time. Also provide your investigation for the TNTC result documented in PR#2466588. Include the methods used for bioburden, dilutions, and counting of microbes.

•      你们关于延长培养碟培养时长导致EM结果无效的回复。包括一份记录每个碟计数的日期、每个碟计划计数日期以及实际计数与计划计数之间相关天数的表格汇总。说明你们在培养期间是否多次读取并记录了微生物碟样品计数结果，以及你们是否每次都记下结果。还请提交一份你们对PR#2466588中所记录的TNTC结果的调查，包括生物负载、稀释和微生物计数的方法。

Data Integrity Remediation 数据完整性补救措施

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. For guidance on establishing and following CGMP compliant data integrity practices, see FDA’s guidance documents Data Integrity and Compliance With Drug CGMP at https://www.fda.gov/downloads/DRUGS/GuidanceComplianceRegulatoryInformation/Guidances/UCM495891.pdf and Questions and Answers on Current Good Manufacturing Practices—Laboratory Controls at https://www.fda.gov/DRUGS/Guidances-Drugs/Questions-And-Answers-Current-Good-Manufacturing-Practices-Laboratory-Controls#17.

你们的质量体系不能充分确保数据的准确性和完整性，无法支持你们生产的药品的安全性、有效性和质量。参见FDA指南文件“数据完整性和药品GMP合规”及实验室控制CGMP问答指导建立和遵守CGMP合格数据完整性规范。

We acknowledge that you engaged a consultant to audit your operation and assist in meeting FDA requirements.

我们知悉你们正聘用顾问对你们的操作进行审计并协助你们符合FDA要求。

In response to this letter, provide the following:

在回复此函时请提交以下信息：

•      A comprehensive investigation into the extent of the inaccuracies in data records and reporting including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.

•      一份对数据记录和报告不准确性程度，包括销售至美国的药品的数据审核结果，的全面调查，要有一份对你们数据完整性问题范围与根本原因详细的描述。

•      A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.

•      你们药品质量中所发现的不合格情况的潜在影响的当前风险评估。你们的评估应包括由于受到数据完整性问题影响的药品放行导致的患者风险的分析，以及持续运营所具有的风险。

•      A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

•      你们公司的管理策略，包括你们全球CAPA计划详细情况。详细的纠正措施计划应说明你们准备如何确保你公司所生成的所有数据的可靠性与完整性，包括微生物和分析数据、生产记录和提交给FDA的所有数据。

Conclusion 结论

The violations cited in this letter are not intended to be an all-inclusive list of violations that exist at your facility.You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of 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 effective way 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 report discontinuances or interruptions in your drug manufacture under 21 U.S.C.356C(b). This also 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 drug 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 result in the FDA refusing admission of articles manufactured at Pfizer Healthcare India Private Limited, FEI 3008316085, at Plots 116-117-118-119-111-123 (part),into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C.381(a)(3). Articles under this authority 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。

Send your electronic reply toCDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:

Michael Klapal

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4235

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Please identify your response with FEI 3008316085.

Sincerely,

/S/

Francis Godwin

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

CC:

(b)(6)

Site Leader

Pfizer Healthcare India Private Limited

Plots 116-117-118-119-111-123 (part)

Jawaharlal Nehru Pharma City, Parawada

Visakhapatnam, Andhra Pradesh, 531019

India

【本文来源： Julia法规翻译 】