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Warning Letter 320-20-43
August 13, 2020
Dear Dr. Subramanian:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Wintac Limited, FEI 3003821988, at54/1 Bodhihal Village, Nelamangala, Bangalore, from February 10 to 19, 2020.
美国FDA于2020年2月10日至19日检查了你们位于印度的WintacLimited, FEI 3003821988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 response to our Form FDA 483, received March 10, 2020, in detail and acknowledge receipt of your subsequent correspondence.
我们已详细审核了你公司2020年3月10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：
1. 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 the batch has already been distributed (21CFR 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 investigation into contaminated media fillunits is inadequate in that it did not include scientifically supported conclusions, it lacked corrective actions and preventive actions (CAPA), and itfailed to address all potentially compromised lots.
你们对受污染培养基灌装瓶的调查不充分，其中没有科学依据得出结论，缺乏CAPA，未解决所有可能影响批次的问题。
In November 2019, you conducted a media fill on the (b)(4) line. On the (b)(4) of incubation, you observed morethan (b)(4) contaminated units. Your investigation into this media fillfailure was inadequate. You considered a limited portion of the (b)(4) processing train to be the potential source of the Ralstonia picketti contamination. However, your investigation lacked scientific justification forits narrow focus and for ruling out other meaningful failure modes. Your investigation did not identify any CAPA to resolve the potential root causes,and you closed the investigation without sufficiently assessing how other batches manufactured on the line may have been or will be compromised. Instead, you concluded that there was no impact to product quality, citing the passing results of subsequent 2019 media fill runs.
2019年11月，你们在XX线上进行了培养基灌装。在培养的过程中你们发现超过XX个受污染的瓶。你们对该培养基失败的调查不充分。你们认为XX加工链有限部分是皮氏罗尔斯顿氏菌污染的潜在来源。但是你们的调查缺乏科学理由，因为调查范围小，排除了其它有意义的失败模式。你们的调查并未制订CAPA来解决潜在的根本原因，没有充分评估是否同一产线上生产的其它批次是否受影响即关闭了调查。你们得出结论认为产品质量未受影响，依据的是后来2019年培养基灌装的合格结果。
Your firm’s response is inadequate. Your response stated you did “not formally document” CAPA for this investigation “because they weren’t connected to a definitive root cause and therefore not addressed.”You further stated that only a “most probable” root cause had been identified in your investigation. It is essential that your investigations identify areas for improvement even when only possible root causes are identified. Without such risk mitigation, there is no assurance that you canprevent recurrence of failures from the same sources of excessive variationthat led to the original failure. Your response did not include a retrospective evaluation of investigations to ensure CAPA have been identified and implemented when you do not find a definitive root cause.
你公司的回复不充分。你们的回复说你们“未正式记录CAPA”，“因为它们并不能与明确的根本原因建立关联，因此没有明确说明”。你们还说在你们的调查中只识别出了“最可能的”根本原因。即使只找到可能的根本原因，找出需要改进的问题也是很重要的。没有此类降低风险的措施，就不能确保你们可以防止因初次失败相同的过度波动导致的重复失败。你们的回复中没有对调查进行回顾性评估，确保在没有发现明确的根本原因时制订并实施CAPA。
Similar deficiencies were observed with your investigation into another failing media fill used to qualify your new aseptic filling line in June 2019. This investigation also did not thoroughly investigate potential root causes, include appropriate CAPA, and specify the number of contaminated units. We note this new filling line has not been used to manufacture commercially distributed products for the U.S. to date.
在另一次2019年6月新的无菌灌装线确认用培养基灌装失败调查中，我们发现有类似的缺陷。该起调查亦未对可能的根本原因进行彻底调查，包括制订适当的CAPA，并说明受污染件的数量。我们注意到新的灌装线尚未用于商业化生产销往美国的药品。
In response to this letter, provide:
在你们对本函的回复中请提交以下：
• A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, 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 unit oversight, and written procedures. Address how your firm will ensure all phases of investigations areappropriately conducted.
• 对偏差、不符合、投放、OOS结果和失败情况进行调查的全面系统所做的全面独立评估。提交一份对该系统进行补救的详细行动计划。你们的行动计划应包括但不仅限于对调查能力、范围确定、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执行了所有调查环节。
• Your updated media fill failure investigations, which include a detailed, independent, retrospective evaluation of your mediafills. Your third party should oversee your investigations to-date and provide their independent evaluation of these and other investigations which should include, but not be limited to:
• 你们更新后的培养基灌装失败调查，其中要包括对你们培养基灌装的详细独立的回顾性评估。你们的第三方应监督你们迄今为止的调查情况，并提交一份对这些调查和其它调查的独立评估，其中应包括但不仅限于：
Events of all sterility positives and out-of-specification endotoxin results for the past four years, regardless of whether the batch was shipped to the U.S.
过去4年所有无菌阳性和内毒素OOS结果，无论这些批次是否发送至美国
Media fill failures for the past four years
过去4年的培养基灌装失败
Identification of all potential failure modes associated with these events
找出这些事件中的所有潜在失败模式
A detailed description of each aseptic connection made (b)(4) of the (b)(4) for line(b)(4), including but not limited to the connections made before and after the (b)(4)tank and on the filling line
产线XX的每个无菌连接的详细说明，包括但不限于在XX罐前后的连接和灌装线上的连接
你公司未遵守适当的书面程序，设计用于防止既定无菌的药品微生物污染，并包括所有无菌和灭菌工艺的验证（21 CFR 211.113(b)）。
Inadequate Smoke Studies
烟雾试验不充分
Smoke studies performed for your (b)(4) aseptic processing operation lacked simulation of interventions and other related activities that occurred during aseptic manufacturing operations.
你们XX无菌加工操作所做的烟雾试验缺少干预模拟和无菌生产操作期间的其它相关活动。
We also note that there were multiple aspects of both your cleanroom and aseptic processing line design which represent fundamental contamination risks. Your smoke studies demonstrated that:
我们亦注意到你们的清洁间和无菌加工线设计有多个问题，可能会带来重大污染风险。你们的烟雾试验显示：
• There is minimal protection of the aseptic processing line.
• 无菌加工线缺乏足够的保护
• There are extensive manual interactions with the aseptic processing line and its exposed sterile drug product and containers/closures.
• 无菌生产线人为干预过多，导致无菌药品和容器/密闭器暴露
• There is non-unidirectional airflow within the (b)(4) area, and limited space around the critical (b)(4) processing area.
• 在XX区内有非单向流，关键XX加工区周边空间有限
• Personnel are inadvertently in contact with the interior of the (b)(4) used to access the area which houses the (b)(4) aseptic processing area.
• 人员与用于进入该保护XX无菌加工区域的XX内表有无意接触
• When these (b)(4), there is a profound change in airflow that causes excessive turbulence.
• 在XX时，气流会产生重大变化，导致严重的乱流
While we have noted these deficiencies and the lack of adequate qualification, it is unclear whether your firm has undertaken efforts to remediate your cleanroom and processing line design.
虽然我们已注意到这些缺陷，以及缺乏足够的确认，但我们不清楚你公司是否已尽力补救你们的洁净区和加工线设计问题。
Your firm’s response is inadequate. You noted inyour response that you performed additional smoke studies and concluded that airflow patterns were unidirectional. These smoke studies are inadequate. For example:
你公司的回复不充分。在回复中你们提到你们已执行了另外的烟雾试验，结论是气体流形是单向流。这些烟雾试验不充分。例如：
• Smoke studies did not provide adequate visualization of airflow of the aseptic processing operation.
• 烟雾试验没有将无菌加工操作气流进行充分可视化
• Smoke studies were not performed under dynamicconditions, as incorrectly identified in your report.
• 烟雾试验不是在动态情况下执行，你们报告中的说明不正确
• You did not address smoke which travels along the gaps between the ceiling HEPA filters and mixes with first air.
• 你们未能说明烟雾流入HEPA过滤器之间的间隔区，并与新风混合的问题
The (b)(4) area is critical because sterile products are exposed and therefore vulnerable to contamination. Your aseptic manufacturing process should be designed, and operations executed, to prevent contamination hazards to your sterile product.
XX区域是关键区域，因为无菌药品在这里暴露，易于受到污染。你们的无菌生产工艺设计和所执行的操作应能防止无菌药品受到污染危害。
Flaws in the design of cleanrooms and aseptic processing lines, or improper execution of aseptic operations, can promote influx of contamination into the critical (b)(4) processing area.
洁净室和无菌加工线设计的缺陷，或无菌操作执行不当可能会导致污染涌入关键XX加工区域。
Inadequate Media Fills
培养基灌装不充分
Media fills should accurately simulate commercial operations. Our inspection found that interventions and other operations simulated during media fills were not sufficiently representative of commercial aseptic manufacturing.
培养基灌装应准确模拟商业化操作。我们检查发现培养基灌装期间的干预和其它模拟操作不能充分代表商业化无菌生产情况。
We disagree with your initial response that indicated your media fills studies have been representative of commercial manufacturing operations. You did not provide a comprehensive retrospective review of all interventions and activities performed proximal to the aseptic processing line during commercial operations to fully remediate your media fill simulations.
我们不同意你们初次回复中你们培养基灌装试验能够代表商业化生产操作的说法。你们并未提交对商业操作期间所有干预行为和接近无菌加工线所执行的活动的全面回顾性审核报告，从而全面补救你们的培养基模拟灌装。
If a media fill program fails to incorporate contamination risk factors and closely simulate actual drug product exposure,the state of process control and sterility assurance cannot be accurately assessed.
如果培养基灌装程序未能包括污染风险因素，尽可能模拟实际药品暴露情况，则工艺控制和无菌保证的状态可能无法得到准确评估。
In response to this letter, provide:
在回复本函时请提交：
• Smoke studies under dynamic conditions, with thorough and complete evaluations of aseptic interventions and operator positioning within the critical filling areas. After you remediate your aseptic operation, provide smoke studies that visualize airflow and critically evaluate unidirectional airflow. Include a video of your dynamic smoke studies.
• 动态条件下的烟雾试验，包括对无菌干预和操作员在关键灌装区域内所在位置的彻底全面评估。在你们补救了无菌操作之后，请提交气流可视化烟雾试验，对单向流进行批判性评估。要提交一份你们动态烟雾试验的视频。
• A risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities, including an independent assessment that includes, but is not limited to:
• 一份对你们无菌工艺设备和设施的所有污染危害的风险评估，要包括但不仅限于对以下要素的独立评估：
All human interactions within the (b)(4) area
XX级区域内的所有人为干预
Equipment placement and ergonomics
设备更换情况和工效学设计说明
Air quality in the (b)(4) area and surrounding room
XX级区和周围房间的空气质量
Facility layout
设施平面布局
Building management systems (e.g., address insufficiencies in differential pressure recording frequency)
建筑管理系统（例如，解决压差记录频次不够问题）
Personnel flows and material flows throughout all rooms used to conduct and support sterile operations
人流和物流（用于执行和支持无菌操作的所有房间内）
• A detailed remediation plan based on review and recommendations by a third party, with timelines, to address the findings ofthe contamination hazards risk assessment. Describe how you will significantly improve aseptic processing operation design and control. In particular, include comprehensive improvements in the design of both your aseptic processing lines and cleanrooms. Also describe your plans for qualification and validation of your extensively remediated operations.
• 基于第三方审核和建议制订的详细补救计划和时间表，解决污染危害风险评估的发现的问题。说明你们要如何显著改进无菌加工操作设计和控制。尤其要包括全面改进你们无菌生产线和洁净间设计的全面改进。亦要说明你们确认和验证你们大面积补救操作的计划。
• An update on the third-party assessment of your media fill program. Provide your third party’s assessment of the updated media fills, and your plan for implementing the recommendations in the assessment.
• 第三方对你们培养基灌装程序的更新。提交你们第三方对更新后培养基灌装的评估，以及你们实施评估后建议的计划。
• An update on the media fills you committed to perform on your (b)(4) manufacturing lines, and your assessment of frequency and duration of interventions performed. Describe improvements made to more accurately and appropriately simulate interventions and activities nextto the (b)(4) zone that occur during production.
• 你们所承诺的XX生产线的培养基灌装的更新，以及你们对所实施干预的频次和时长的评估。说明所做的改进，更准确恰当地模拟干预和生产期间接近XX区的活动。
Additional Guidance on Aseptic Processing
其它无菌加工指南
See FDA’s guidance document Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing athttps://www.fda.gov/media/71026/download.
参见FDA指南文件“无菌工艺生产的无菌药品CGMP”。
CGMP Consultant Recommended
CGMP顾问建议
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 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 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。
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商的新申报和增补申报的批准。
Failure to correct these violations may also resultin the FDA refusing admission of articles manufactured at Wintac Limited, FEI3003821988, at 54/1 Bodhihal Village, Nelamangala, Bangalore into the UnitedStates 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 thatthe 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 to CDER-OC-OMQ-Communications@fda.hhs.gov. Identify your response with FEI3003821988 and ATTN: Brooke K. Higgins.
Sincerely,
/S/
Francis Godwin
Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research
cc: Sunil Gundewar, Chief Operating Officer
文章来源：允咨GMP制药技术
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