来自：JULIA法规翻译

Warning Letter 320-20-39
June 17, 2020
Dear Mr. Kurre:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Vega Life Sciences Private Limited, FEI 3015658387, at Plot No. D-15, 16, 21 & 22, Phase-I, I.D.A.Pashamylaram, Patencheru (M), Sangareddy District, Telangana, from November 25 to 28, 2019.

美国FDA于2019年11月25日至28日检查了你们位于印度的Vega Life Sciences Private Limited（FEI 3015658387）生产场所。

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
本警告信总结了原料药生产严重违反CGMP的行为。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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21 U.S.C.351(a)(2)(B)被认为是掺假药品。

We reviewed your December 19, 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12月19日对我们FDA483表格的回复，并此告知已收到后续通信。

During our inspection, our investigators observed specific deviations 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. Failure to control and monitor solvent recovery procedures to ensure that solvents meet appropriate standards before reuse in API manufacturing. 未能控制和监测溶剂回收程序，从而确保溶剂在重新用于API生产之前符合适当的标准。

Our inspection found that your firm acts as acontract solvent recovery facility for your customer’s (b)(4) API manufacturing operations. Solvents recovered at your facility include (b)(4).
我们检查发现你公司受委托为你们客户的XX API生产操作回收溶剂。在你们场所回收的溶剂包括XX。

Your firm failed to establish and follow procedures to evaluate and control impurity risks associated with your solvent recovery operations. For example:
你公司未能建立和遵守评估和控制与你们溶剂回收操作有关的杂质风险的程序。例如
Inadequate Testing of Recovered Solvents 对回收溶剂检测不充分

Your firm failed to follow your gas chromatography (GC) test method procedure for recovered (b)(4). The procedure requiresuse of a standard for ensuring the batch meets the Identification by GC recovered solvent specification. We reviewed analytical data packages for approximately (b)(4) batches of recovered (b)(4) processed by your firm in 2019 and found they lacked chromatograms representing the use of a standard. Furthermore, your firm stated to the investigators that standards were never run during GC analysis of recovered (b)(4) in 2018 and 2019.

你公司未能遵守你们对回收XX的GC检测方法。该方法要求使用一种对照品确保批次符合回收溶剂质量标准中的GC鉴别。我们审核了你公司在2019年约XX批次回收XX的分析数据包，发现其中缺少使用对照品的图谱。另外，你公司向检查员承诺2018-2019年间在GC分析时从未使用对照品运行GC分析。

In your response, you provided no explanation for this deviation and made no commitment to investigate the scope of this deficiency to determine if other test methods or procedures were not followed. Your response also lacked a risk assessment to determine potential product impact.
在你们的回复中，你们没有为该偏差提交解释，亦未承诺要调查该缺陷的范围，从而确定是否未遵守其它检测方法或程序。你们的回复亦未进行风险评估来确定对产品的潜在影响。

Failure to Establish an Impurity Profile for Recovered Solvents or Investigate Extraneous Peaks in Chromatograms
未能建立回收溶剂的杂质概况或调查色谱图中的外源峰

Your firm failed to establish an impurity profilefor recovered solvents and maintain appropriate oversight of your operations for the control of unknown impurities. Extraneous peaks were observed in morethan (b)(4) batches of recovered (b)(4) processed at your facility between 2018 and 2019. The batches were released by your firm without investigation and you failed to inform your customer of any potential impurities. You stated that your customer instructed you to focus only on the peak representing the recovered solvent, however this is not adequate. Unknown peaks observed in chromatograms of recovered solvents may represent unanticipated impurities that can impact the quality of your customer’s API and should be thoroughly investigated.

你公司未能建立回收溶剂杂质谱，并对你们操作中未知杂质的控制进行适当监管。在2018-2019年间在你们场所加工的多个批次回收XX中发现有外源峰。你们未进行调查就放行这些批次，你们未将潜在杂质问题通知给你们客户。你们声称你们的客户指令你们仅关注回收溶剂峰，但这是不够的。回收溶剂色谱图中的未知峰可能代表了意外杂质，可能会影响你们客户API的质量，应进行彻底调查。

Your response is inadequate. Your evaluation of the extraneous peaks observed in recovered solvent chromatograms was not comprehensive and did not include a thorough manufacturing evaluation to determine if your solvent recovery operations contributed impurities to the recovered solvent.

你们的回复是不充分的。你们对回收溶剂色谱图中外源峰的评估不全面，其中未包括彻底的生产评估，从而确定你们的溶剂回收操作是否影响了回收溶剂的杂质。

During the inspection, your firm provided a written statement indicating that you had terminated processing recovered solvents for customers. However in your response you indicated that all future customer products would include quality agreements, which suggests that you may resume such operations in the future. Your firm has not provided sufficient details or procedures to demonstrate the capability of predicting, controlling, testing, and preventing impurities or cross contamination associated with your solvent recovery processes.

在检查期间，你们公司提交了一份书面声明，说你们已停止为客户回收溶剂。但是在你们的回复中，你们说所有未来客户产品会包括有质量协议，这表示你们未来可能恢复此类操作。你公司未提交足够详细的信息或程序，来证明你们预测、控制、检测和预防溶剂回收工艺杂质与交叉污染的能力。

In response to this letter, provide the following: 在回复本函时请提交以下资料

• A comprehensive investigation into your firm’sfailure to follow internal procedures including test methods. Include a detailed description of the scope and root causes of your lapses and list all associated corrective actions with timeframes for completion.

• 一份对你们公司未遵守内部程序，包括检测方法的全面调查。包括对你们问题范围和根本原因的详细描述，以及所有相关纠正措施和完成时限的清单

• A detailed plan describing how you will implement an ongoing program for evaluating the effectiveness of your solvent recovery operations monitoring process control to ensure stable manufacturing and prevention of unanticipated impurities during solvent recovery operations.

• 一份详细的计划，说明你们会持续评估你们溶剂回收操作有效性，监测工艺控制，以确保生产的稳定性，防止溶剂回收操作中的意外杂质

• A procedure requiring an impurity profile analysis and risk assessment for all solvent recovery operations. The scope of the procedure should include recovered solvents for internal and external use.

• 一份要求进行杂质概况分析，对所有溶剂回收操作进行风险评估的程序。程序的范围应包括内部和外部使用的回收溶剂。

• An updated procedure for handling unknown peaks in chromatograms.

• 一份处理色谱中未知峰的程序

2. Failure to have adequate cleaning procedures to prevent contamination or carry-over of a material that would alter the quality of the API. 未制订足够的清洁程序，防止可能改变API质量的污染或物料残留

The cleaning of your nondedicated manufacturing equipment used to recover customer solvents including (b)(4) is inadequate. Your firm failed to ensure that your cleaning procedure was sufficient to prevent carryover or contamination for nondedicated equipment used to recover spent solvents. Your firm stated during the inspection that these requirements were not met. Additionally, your firm stated that there were no records to document cleaning of nondedicated equipment used to process recovered solvents including product changeover cleaning.

你们用于回收客户溶剂的非专用生产设备的清洁包括XX是不充分的。你公司未能确保你们的清洁程序足以防止用于回收废溶剂的非专用设备的残留或污染。你公司在检查期间声称不符合这些要求。另外，你公司声称没有记录回收溶剂的非专用设备的清洁，包括更换产品的清洁。

In your response, you provided examples of equipment cleaning records but did not include an explanation or justification regarding why you told our investigators during the inspection that these documents did not exist.

在你们的回复中，你们提交了一份设备清洁记录的例子，但并未解释或说明为何你们在检查期间告诉我们检查员没有记录。

Your response also failed to include a thorough evaluation designed to ensure that all equipment including nondedicated storage, receiving, and charging tanks were properly cleaned according to approved procedures.

你们的回复亦未对设计用以确保所有设备包括非专用存贮、接收和加料罐未能按已批准程序进行恰当清洁进行彻底评估。

In response to this letter, provide the following:

在回复本函时请提交以下资料：

• A corrective action and preventive action (CAPA) plan, based on the retrospective assessment, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Providea detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program including enhancements to cleaning effectiveness, improved ongoing verification of proper cleaning execution for all products and equipment, and all other needed remediations.

• 一份基于回顾性评估的CAPA计划，其中要包括对你们清洁工艺和做法的适当补救，以及完成时限。提交一份对你们工艺在设备清洁生命周期管理中的薄弱点。说明对你们清洁程序的改进，包括改进清洁有效性，改进所有产品和设备执行适当清洁的持续确认，以及其它所需补救措施

• Appropriate improvements to your cleaning program,with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or new manufacturing operations.
• 对你们清洁程序的适当改进，特别要强调你们药品生产操作的最差情形。另外，说明你们变更管理体系中在引入新的生产设备或新的生产操作之前必须采取的措施

• A summary of updated SOPs that ensure an appropriate program is in place for cleaning procedures for products, processes, and equipment.
• 一份更新后的SOP摘要，确保制订有适当的产品、工艺和设备清洁程序

• A comprehensive investigation into your firm’s CGMP documentation practices. Include a detailed description of the scope and root causes of your documentation lapses and list all associated corrective actions with timeframes for completion.
• 一份对你们公司CGMP文件规范的全面调查。包括一份对你们文件问题范围和根本原因的详细描述，以及所有相关纠正措施的清单及完成时限

3. Failure to exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data andfailure to have adequate controls to prevent omission of data. 未能对计算机化系统进行足够的控制从而防止未经授权进入或改变数据，未能充分防止数据遗漏

Your firm failed to implement adequate controls toensure the integrity of data generated at your facility including:
你公司未能实施足够的控制，从而确保在你们工厂所生产的数据的完整性，包括：

• Missing raw data files associated with recovered solvent testing were observed in folders on the local hard drive of the operating system connected to the GC instrument. Your firm indicated that the files appear to have been deleted.

• 在连接GC仪器的操作系统的本地硬盘文件夹中发现与回收溶剂检测有关的原数据文件缺失，你公司说文件已删除

• Quality Control analysts shared the same user nameand password for the operating system on each workstation and the analyticalsoftware for the GC.
• QC化验员共用工作站操作系统和GC分析软件的用户名和密码

• Recovered solvent data on the stand-alone computerized system for the GC were not backed up as required per your approved procedure.
• 单机版本计算机化系统中的回收溶剂GC分析数据未按你们已批准的程序备份

• Your firm did not have a procedure governing the audit trail or its retention. During the inspection, the GC analytical software was configured to retain the audit trail for only (b)(4).
• 你公司没有程序对审计追踪及其保存情况进行管理。在检查期间，GC分析软件的参数设置为审计追踪仅保存XX

Your firm failed to include a comprehensive, systematic plan for evaluating your practices and procedures to ensure data integrity controls are applied throughout your firm. Additionally, you failed to conduct a risk assessment addressing potential impacts to product as a result of the inadequate data integrity controls.

你公司未包括一份评估你们做法和程序的全面系统化计划，从而确保在整个公司对数据完整性进行了控制。另外，你们未能执行风险评估，解决数据完整性控制不充分对产品的潜在影响问题。

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. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/data-integrity-and-compliance-drug-cgmp-questions-and-answers-guidance-industry.

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”指导建立和遵守CGMP合格数据完整性规范。

We strongly recommend that you retain a qualified consultant to assist in your data integrity remediation. In response to this letter, provide the following:
我们强烈建议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。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的全面调查。其中要包括一份对你们数据完整性问题范围和根本原因的详细说明。

• 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 includesthe details of your global CAPA 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。应有一份详细的CA计划，说明你们准备如何确保你们生成的所有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的数据。

CGMP Consultant Recommended CGMP顾问建议

Based upon the nature of the deviations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations and to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S.market. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA.

鉴于我们在你公司所发现的违规情况，我们强烈建议你们使用一位有21 CFR 211.34所述资质的顾问来协助你们公司符合CGMP要求。我们亦建议该具备资质的顾问对你们整体运营情况进行药品CGMP合规情况全面审计，并由其在你们寻求满足FDA合规要求之前对你们CAPA的完成情况和有效性进行评估。

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

你们使用顾问并不能解除你们公司符合CGMP的义务。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。
Solvent Recovery Operations Terminated 停止溶剂回收操作

We acknowledge your commitment to terminate processing recovered solvents for customers at this facility for the U.S.market. If you plan to resume producing recovered solvents for the U.S. supply chain, notify this office in writing.

我们了解到你们承诺会停止在该场所为美国市场客户回收溶剂。如果你们计划继续为美国供应链回收溶剂，请书面通知本办公室。

Conclusion 结论

The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility.You are responsible for investigating and determining the causes of these deviations and for preventing their recurrence or the occurrence of other deviations.

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。
FDA placed your firm on Import Alert 66-40 on April14, 2020.

FDA已于2020年4月14日将你公司置于进口禁令66-40中。

Until you correct all deviations 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商的新申报和增补申报的批准。

Failure to correct these deviations may also resultin the FDA continuing to refuse admission of articles manufactured at Vega Life Sciences Private Limited at Plot No. D-15, 16, 21 & 22, Phase-I, I.D.A.Pashamylaram, Patencheru (M), Sangareddy District, Telangana 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 deviations 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 to CDER-OC-OMQ-Communications@fda.hhs.gov
Please identify your response with FEI 3015658387and ATTN: Rory Geyer.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research