FDA警告信：印度Mylan制药

Dear Ms. Bresch:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Mylan Laboratories Limited, Unit 7,FEI 3003227156, at Plot No. 14, 99, & 100, Phase-II, IDA, Pashamylaram,Patancheru (M), Sangareddy District, India, from February 24 to 28, 2020.
美国FDA于2020年2月24日至28日检查了你们位于印度的MylanLaboratories Limited, Unit 7, FEI 3003227156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 March 20, 2020, 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2020年3月20日对FDA483表的回复，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 have adequate cleaning procedures to prevent contamination or carry-over of a material that would alter the qualityof the API. 没有足够的清洁方法用于防止可能改变API质量的污染或物料残留。
Inadequate Cleaning Records for Bulk Storage Tanks 散装贮罐清洁记录不充分
Your firm manufactures (b)(4) and other(b)(4). You use numerous storage tanks to hold various materials, including mother liquids, fresh solvents, and recovered solvents.
你公司生产XX和其它XX。你们使用了许多贮罐来存放不同物料，包括母液、新鲜溶剂和回收溶剂。

Your firm did not have adequate cleaning records for approximately (b)(4) non-dedicated bulk storage tanks. You used these tanks in numerous API manufacturing processes across your (b)(4) non-dedicated manufacturing blocks. Our investigators requested cleaning records for these tanks. Your firm management provided some records for activities conducted after October 2019 but stated that cleaning, storage, and usage records for storage tanks were not documented or maintained prior to October 2019.
你公司约XX个非专用散装贮罐并没有足够的清洁记录。你们将这些贮罐用于你们XX非专用生产车间的多个API生产工艺。我们的检查员索取这些贮罐的清洁记录时，你公司管理人员提供了一些2019年10月之后所做的工作记录，声称2019年10月之前贮罐的清洁、存贮和使用没有记录。

During the inspection our investigators queried your firm on the quality of recovered solvents held in these storage tanks.Your firm management stated that complete impurity profiles of recovered solvents were not performed during the initial evaluation of your solvent recovery contract manufacturing organizations (CMO). Coupled with inadequate cleaning records, there are limited assurances that your non-dedicated equipment would not contribute to cross-contamination or carry-over of residual impurities.
在检查期间，我们检查员询问你公司这些贮罐中所存放的回收溶剂的质量情况，你公司管理人员声称在对你们的溶剂回收外包生产机构（CMO）初次评估期间未对回收溶剂的杂质概况进行研究。加上清洁记录不足，实际上你们的非专用设备几乎完全无法保证不会造成交叉污染和残留杂质带入。

Some recovered solvents used at your site are processed by CMOs. One CMO you used for solvent recovery is (b)(4) which was added to Import Alert 66-40 on (b)(4) and was issued Warning Letter (b)(4).The firm was cited for inadequate impurity profiles of recovered solvents, which included unknown peaks observed in more than (b)(4) lots of (b)(4) between 2018 and 2019. Your firm received, stored in non-dedicated bulk tanks, and used multiple (b)(4) lots from this CMO, including one lot in which an unknown peak was identified by your firm. You used these lots in the manufacturing of (b)(4) API in one of your (b)(4) non-dedicated API manufacturing blocks. Numerous other API intended for the United States market were also manufactured in these non-dedicated blocks.
你们工厂所用的一些回收溶剂是由CMO加工的。你们有一个溶剂回收CMO是XX，该公司已于XX时间被放进进口禁令66-40中，并被签发了警告信。该公司的回收溶剂杂质概况研究不充分，其中包括2018-2019年间有多批XX被发现存在未知峰。你们公司从该CMO处接受了多批XX，存贮在非专用贮罐中并使用，其中有一批你公司亦发现有未知峰。你们在一个XX非专用API生产车间里XX API生产中使用了这些批次回收溶剂。有许多销售至美国市场的其它API亦是在这些非专用车间生产的。

Inadequate Cleaning Validation and Verification Program 清洁验证和确认程序不足
In addition to your lack of cleaning records, your cleaning validation and verification program for non-dedicated manufacturing and storage equipment are inadequate. Specifically, during the review of cleaning method validation of (b)(4) our investigator observed that your method was not adequately validated to ensure it was capable of detecting and appropriately quantitating (b)(4) impurities such as (b)(4). An inadequate scope of impurity analysis, in combination of non-dedicated equipment, lack of cleaning records, and introduction of elevated unknown impurities, increase the risk potential for API and API intermediate cross-contamination.
除了没有清洁记录外，你们的非专用生产和存贮设备清洁验证和确认程序是不充分的。具体来说，在检查清洁方法验证时，我们检查员发现你们的方法未得到充分验证，无法确保该清洁方法能够检出并恰当定量XX杂质，如XX。杂质分析范围不足，加上非专用设备，缺少清洁记录，以及引入了相关未知杂质，增加了API和API中间体交叉污染的潜在风险。

In your response, you referred to corrective actions implemented as a result of Warning Letter 320-20-06 issued on November5, 2019, to your Mylan Unit 8 facility. We still remain concerned with some of the practices found in your facility both at the time of the inspection and after that Warning Letter was issued, particularly around control of recovered solvents.
在你们的回复中，你们引用了应对2019年11月5日对MYLAN第8单元场所警告信320-20-06所执行的纠正措施。我们在检查时和签发警告信之后均很担心在你们场所发现的许多做法，尤其是回收溶剂的控制问题。

You determined that the cleaning validation and verification program was adequate based upon the absence of out-of-specification investigations, lack of complaints, and undetected impurity testing. Your response is inadequate. Cross-contamination cannot be assumed to be uniformly distributed. Testing alone is insufficient to mitigate the observed contamination hazards. 
你们认为该清洁验证和确认程序不足是因为未进行OOS调查、缺少投诉和未检出杂质检测。你们的回复是不充分的。你们不能假定交叉污染是均匀分布的。仅是检测本身不足以缓解所发现的污染危害。

In response to this letter, provide the following: 在回复本函时，请提交以下：
Written confirmation that you no longer use (b)(4) to supply materials for your drug manufacturing operations.
书面确认你们不会再使用XX给你提供药品生产操作用物料

A comprehensive, third-party retrospective assessment of your cleaning     effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product.  
一份全面的第三方对你们清洁有效性的回顾性评估，评价交叉污染危害的范围。在其中要包括残留识别，其它可能清洁不当的生产设备，并评估是否有受交叉污染的产品被放行销售。评估中应识别所有清洁程序和做法不充分，列明每台非专用生产设备

As one element of the risk assessment, describe whether you will be  testing all API manufactured on non-dedicated equipment for impurities      such as nitrosamines due to your deficient systems for cross-contamination prevention and cleaning. The risk assessment should      support your response to this item.
作为风险评估的一个要素，说明你们是否准备检测所有在非专用设备上生产的API中的由于防止交叉污染和清洁缺陷而存在的杂质，例如亚硝胺。风险评估应支持你们对此问题的回复。

Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:
对你们的清洁验证程序进行恰当的改进，要特别注意在你们药品生产操作中识别为最差情形的条件。其中应包括但不仅限于识别和评估所有最差情形

· drugs with higher toxicities
· 高毒性药品
· drugs with higher drug potencies
· 高效价药品
· drugs of lower solubility in their cleaning solvents
· 在清洁溶剂中溶解度较低的药品
· drugs with characteristics that make them difficult to clean
· 因特性不易清洁的药品
· swabbing locations for areas that are most difficult to clean
· 最难清洁的擦拭取样位置
· maximum hold times before cleaning
· 清洁之前最长存放时间

In addition, describe the steps that must be takenin your change management system before introduction of new manufacturing equipment or a new product.
此外，说明在引入新的和平设备或新产品之前你们变更管理系统中必须采取的措施

· A summary of updated SOPs that ensure an appropriate program is in place for verification and validation of cleaning procedures for products, processes, and equipment.
· 一份更新后的SOP摘要，确保有恰当的产品、工艺和设备清洁方法确认和验证程序

· Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
· 你们对设施和设备实施日常、谨慎操作管理的CAPA计划。该计划应确保（除其它措施以外）提高发现设备/设施性能问题的能力，有效进行修理，遵守恰当维保计划，对设备/设施硬件及时进行技术升级，以及经过改进的持续管理审评系统

2. Failure to control and monitor procedures to recover solvents to ensure that they meet appropriate standards before reuse. 未能检测和监控回收溶剂的程序，从而确保在重新使用之前其符合恰当的标准
Your firm failed to implement procedures to evaluate and control impurity risks associated with solvents used in your API manufacturing operations. This includes adequate testing of all incoming raw materials to confirm their suitability for manufacturing processes in which they may be used, establishing an impurity profile for solvents to ensure that they meet appropriate standards, and maintaining an ongoing program for monitoring process controls to ensure stable manufacturing and prevent unanticipated impurities.
你公司未能执行程序评估和控制你们API生产操作中所用溶剂的杂质风险。其中要包括对所有进厂原料的充分检测，从而确认其适用于其将被用于的生产工艺，建立溶剂的杂质概况，从而确保其符合恰当的标准，保持持续的工艺控制监测，从而确保稳定的生产，防止产生意外杂质。

For example, during a review of incoming raw material acceptance testing between 2015 to 2019, the impurity profiles did not match for multiple lots of recovered (b)(4) from (b)(4) when compared to the impurity profile of (b)(4) solvent. Specifically, unknown peaks were detected in the recovered solvent. Your firm management stated that only the main peak is evaluated during analysis. Your firm failed to evaluate the unknown peaks observed during analytical testing of recovered solvents. Unknown peaks observed in chromatograms may represent unanticipated impurities and should be thoroughly evaluated, and if necessary, investigated.
例如，在比较XX溶剂的杂质概况时发现，2015-2019年间的进厂原料接收检测得到的杂质概况与来自XX的多批回收XX是不一样的。具体来说，在回收溶剂中发现有未知峰。你公司管理人员声称在分析时只会评估主峰。你公司未能评估回收溶剂检测期间发现的未知峰。在色谱图中发现的未知峰可能表示有意外杂质，应进行彻底评估，必要时应进行调查。

In your response, you provided some corrective actions and improvements that were implemented prior to this inspection. You state these were based upon learnings from Mylan Unit 8 which had similar issues. You determined the recovered solvents utilized at this facility had minimal impact on API and API intermediates based upon the absence of out-of-specification investigations, lack of complaints, and undetected impurity testing. Your response is inadequate. Your evaluation of the unknown peaks observed in recovered solvent chromatograms was not comprehensive and did not include a thorough manufacturing evaluation to determine if your solvent recovery process contributed impurities to the recovered solvent.
在你们的回复，你们提交了一些检查之前已实施的纠正措施和改进情况。你们声称这是基于MYLAN第8单元场所类似问题得到的教训。你们认为在此场所使用的回收溶剂对API和API中间体只有很小的影响，因为没有OOS调查，没有投诉，没有检出杂质。你们的回复是不充分的。你们对回收溶剂色谱图中发现的未知峰的评估是不全面的，其中没有进行全面生产评估，以确保你们的溶剂回收工艺是否会在回收溶剂中引入杂质。

In response to this letter, provide the following: 在回复本函时请提交以下：
· A detailed plan describing how you will implement an ongoing program for monitoring unknown impurities from fresh solvents (e.g., stabilizers/additives, contaminants from transport, etc.) which may pose a risk for carry over into the API.
· 一份详细的计划，说明你们准备如何实施新鲜溶剂未知杂质持续监测计划（例如，稳定剂/添加剂，运输中的污染物等），这些杂质可能会被带入API中

· A detailed plan describing how you will implement an ongoing program for monitoring process control to ensure stable manufacturing and prevention of unanticipated impurities during solvent recovery operations.
· 一份详细的计划，说明你们准备如何实施工艺控制进行持续监测计划，从而确保稳定的生产，防止在溶剂回收操作中产生意外杂质

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

· An updated procedure for evaluating unknown peaks in chromatograms,  including a discussion on the level at which an impurity would need to be identified. Provide scientific justification for your decision.
· 一份更新后色谱图中未知杂质评估程序，其中要包括需要进行鉴别的杂质水平的讨论。请提交一份你们决策的科学论证。

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 API operations to assist your firm in meeting CGMP requirements.
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。

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for fully 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。

Additional API CGMP Guidance 其它APICGMP指南
FDA considers the expectations outlined in ICH Q7 when determining whether API are manufactured in conformance with CGMP. See FDA’s guidance document Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients for guidance regarding CGMP for the manufactureof API at https://www.fda.gov/media/71518/download.
FDA在确定API生产是否符合CGMP要求时考虑的是ICH Q7中的要求。参见FDA的Q7指南。

Repeat Deviations at Multiple Sites 多场所重复缺陷
FDA cited similar CGMP deviations at another facility in your company’s network.
FDA在你公司网络的另一场所中引用了相似的CGMP偏差。

On November 5, 2019, Mylan Laboratories Limited –Unit 8, FEI No. 3002785310, was issued Warning Letter 320-20-06 for, amongother things, failure to have adequate written procedures for receipt, identification, testing, and handling of raw materials and a failure to clean equipment and utensils to prevent contamination or carry-over of material. The poor controls of recovered solvents at this facility led to contamination of drugs with (b)(4) impurities.
2019年11月5日，MYLAN实验室有限公司第8单元场所FEI号3002785310被签发了警告信320-20-06，除其它违规情形外，警告信中缺陷包括在原料接收、标识、检测和处置的书面程序不足，以及未能清洁设备和工器具从而防止污染或物料残留。该场所对回收溶剂的控制不善忆导致药品受到XX杂质的污染。
We observed similar deficiencies related to inadequate storage and handling of recovered solvents utilized at your Unit 7 API manufacturing operations. These repeated failures at multiple sites manufacturing API demonstrate that your company’s oversight and control overthe manufacture of drugs is inadequate. You should immediately and comprehensively assess your company’s global manufacturing operations to ensurethat systems and processes, and ultimately, the products manufactured, conformto FDA requirements at all your sites.
我们在你们的第7单元API生产操作中发现所用回收溶剂存贮和处置不足。这些多场所API生产的重复缺陷显示你公司对药品生产的监管和控制是不充分的。你们应立即全面评估你公司的全球生产操作，以确保你们所有场所的体系和工艺最终是所生产的产品符合FDA要求。

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。

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 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 result in the FDA refusing admission of articles manufactured at Mylan Laboratories Limited, Unit 7, at Plot No. 14, 99, & 100, Phase-II, IDA, Pashamylaram, Patancheru (M), Sangareddy District 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 usedin 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 3003227156and ATTN: Joseph Lambert, Pharm.D.

Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
cc:
Mr. P. Jayachandra Prasad, Vice President of Manufacturing Services
Mylan Laboratories Limited – Unit 7
Plots 14, 99, 100; IDA
Pashamylaram II, Patancheru Medak District, Hyderabad Telangana, 502319
India

       文章来源：蒲公英

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