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昨夜，FDA官网发出对湖北省宜城市共同药业有限公司的警告信，根据该警告信总结缺陷如下：
该警告信翻译如下：
Warning Letter: 320-18-65 July 26, 2018
Mr. Michael Zou Chief Marketing Officer Yicheng Goto Pharmaceuticals Co., Ltd. 宜城市共同药业有限公司 5th Floor, East Gate of Building #2 2号楼东门5A Servo Industrial Park, 1st Qilin Road 麒麟路1号伺服工业园 Xiangyang 襄阳 Hubei Province, 441021 湖北省 China
Dear Mr. Zou:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Yicheng Goto Pharmaceuticals Co., Ltd. at Group 1 Gaokeng, Xiaohe Town, Yicheng City, Hubei Province, from September 11 to 14, 2017. 美国FDA于2017年9月11-14日检查了你们位于湖北省宜城市小河镇高坑一组的宜城市共同药业有限公司生产场所。
This warning letter summarizes significant deviations ofcurrent 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21U.S.C. 351(a)(2)(B)被认为是掺假药品。
We reviewed your response received on October 13, 2017, indetail and acknowledge receipt of your subsequent correspondence. 我们已详细审核了你公司2017年10月13日的回复，并此告知已收到后续函件。
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 adequately validate the process for cleaning and maintenance of equipment. 未能充分验证设备的清洁工艺和维护。
You have not conducted cleaning validation studies to demonstrate that your cleaning procedures for non-dedicated production equipment are adequate to prevent potential cross-contamination between your API (e.g., (b)(4)), which include (b)(4) drugs. Your firm also processes intermediates on this equipment. 你们没有执行清洁验证以证实非专用设备的清洁程序足以防止不同API间潜在的交叉污染。贵公司还在该设备上加工中间体。
More specifically, you failed to conduct cleaning validation for the majority of the critical non-dedicated production equipment you use to manufacture (b)(4) intermediates and API. 更具体的说，你们未能对用于生产XX中间体和API的大多数关键非专用设备进行清洁验证。
Reactors, (b)(4) are examples of critical multi-use equipment used by your firm. 反应器，XX就是你们使用的关键共用设备例子。
During the inspection, your staff alsostated that it was not required to document equipment cleaning between manufacturing runs. For example, for (b)(4) batch (b)(4), your firm was able to provide a cleaning record for only one piece of equipment (a (b)(4)) to demonstrate that cleaning was performed prior to batch manufacture. 在检查期间，你们的员工还表示不需要记录设备在不同生产阶段之间的清洁。例如，对于XX批次XX产品，贵公司仅提供了一台设备的生产前清洁记录。
In your response, you state that you will conduct cleaning validation for your non-dedicated equipment. However, you failed to provide your plan to ensure that your equipment is adequately cleaned in the interim. 在你们的回复中，你们说你们将会对非专用设备进行清洁验证。然而，你们未能确保在过渡期间设备得到充分清洁的计划。
In response to this letter, provide: 回复此函，请提供
Your updated cleaning validationprotocol and report for all equipment you use to manufacture drugs including all results and established acceptance criteria. Also, include updated procedures for equipment cleaning and maintenance, with provisions including but not limited to documentation of all cleaning operations. 你们更新的所有药品生产设备的清洁验证方案和报告，包括所有结果和建立的接受标准。同时，包括更新的设备清洁和维护规程，提供包括但不限于清洁操作的记录。
A risk assessment to determine the effect of inadequate cleaning practices on all potentially affected lots of intermediates and API distributed to the U.S. market. This assessment should include but not be limited to an analysis of retains of all lots at risk for potential cross-contamination. 风险评估以确定不充分清洁操作对所有潜在受影响批次中间体和原料药影响。这些评估应包括但不限于分析所有风险批次存在交叉污染的可能。
Your proposed market action plan including customer notifications, retain testing protocol, enhanced complaint monitoring, and recalls, if appropriate, to address all potentially affected lots of intermediates and API in the U.S. supply chain at risk for potential cross-contamination. 你们用以解决所有可能受潜在交叉污染风险影响的中间体和API批次的市场行动计划，包括客户通知，残留检测方案，强化的投诉监测，和召回（适当时），以解决所有可能受影响的美国供应链中处于潜在交叉污染风险中的中间体和API批次。
Provide your interim action plan to ensure adequate cleaning before you complete your validation studies, including but not limited to performing cleaning verification testing before change-over to a different API or intermediate to ensure cleaning effectiveness. Also include your acceptance criteria for each API and intermediate. 提供你们的过渡行动计划以在完成清洁验证研究之前确保设备得到充分的清洁，包括但不限于在切换不同API或中间体之前执行清洁确认测试以确保清洁的有效性。同时，提供每个API和中间体的接受标准。
A comprehensive, independent review to identify risks of cross-contamination between drugs (API and intermediates) manufactured at your facility. Assess the suitability of your facility and process design to prevent cross-contamination, and include an evaluation of your equipment, material, personnel, and waste flows. Include a detailed corrective action and preventive action (CAPA) plan with systemic remediation and timelines. 全面独立的回顾以确定不同药品间交叉污染的风险。评估设施和工艺设计防止交叉污染的适当性，并包括一份对设备，物料，人员，和废弃物流向的评价。包括一份详细的纠正预防措施，带有整改措施和时间计划。
2. Failure to ensure that all test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and purity. 未能确保所有检验规程科学合理并足以确保API符合既定质量和纯度标准。
You failed to perform adequate analytical tests for (b)(4) API. For example, you conducted assay, related substance, and residual solvent testing without performing system suitability tests and use of standards. In addition, your analysts performed manual integration on chromatograms without a written procedure. 你们未能对XXAPI执行充分的分析检验。例如，你们进行含量、有关物质和残留溶剂检验没有进行系统适应性测试，也没有使用标准品。另外，你们没有手动积分的书面规程，但是你们的检验员对色谱进行了手动积分。
In your response, you state that you have established procedures that require your analysts to use standards, perform system suitability tests, and employ appropriate practices for chromatographic integration. However, you did not provide your procedures on the use of standards and system suitability. Your response also lacked a retrospective assessment of the effect of manual integration on data generated prior to implementing your new procedure. 在你们的回复中，你们说你们已经建立了规程要求检验员使用标准品和进行系统适应性测试并应具备手动积分的适当经验。然而，你们没有提供关于使用标准品和系统适应性的规程。你们的回复还缺乏回顾性评估手动积分对实施新规程之前说产生的数据的影响。
In response to this letter, provide: 回复此函，请提供：
An assessment of all test methods used by your firm to ensure they have appropriate instructions, method suitability criteria, and have been appropriately validated to determine whether they are fit for purpose. 对所有检验方法的评估以确保其有适当的使用，方法适用性标准，并经过适当的验证以确定其是否符合其用途。
A reanalysis plan for all batches within retest date that were analyzed using methods lacking system suitability or standards. 一份对使用缺乏系统适应性或标准品检验的复验期内的所有批次重复检验的计划。
A comprehensive review of all instances of chromatographic manual integration. Provide scientific justification for the manual integration parameters you used for analysis. For integrations that lacked scientific justification, provide your plan for reintegration with appropriate reintegration parameters. Assess whether reintegration results comply with your established API acceptance criteria. If you identify out-of-specification (OOS) results, describe actions, such as customer notification and recalls, you have taken or will take to ensure the quality of marketed products and to protect patients. 全面回顾所有色谱手动积分的事件。对这些手动积分参数提供科学论证。对于那些缺乏科学论证的手动积分，提供使用适当的积分参数重新积分的计划。评估重新积分的结果是否符合你们制定的API接受标准。如果你们确定了OOS结果，描述你们已经采取或将要采取以确保市售产品质量和保护病人的措施，如客户通知和召回。
Provide a comprehensive, independent review of your laboratory practices, methods, equipment, and analyst competencies. Based on this review, provide a detailed CAPA plan to fully remediate your laboratory system. Elements of your CAPA should include, but not be limited to, measures you will take to strengthen quality assurance oversight of review and approval of method validation and test results. Your plan should also include your process for evaluating the effectiveness of the implemented CAPA. 提供一份全面独立的实验室操作，方法，设备，和分析员素质的审核。根据该审核，提供详细的CAPA计划以全面整改实验室体系。你们的CAPA应包括但不限于将要采取的加强方法验证和检验数据审核和批准的质量保证监督措施。你们的计划还应包括你们用以评价CAPA有效性的程序。
3. Failure to design a documented stability program to monitor the stability characteristics of API and to use the results to confirm appropriate storage conditions and retest or expiry dates. 未能设计一个书面的稳定性方案来监测API的稳定性特性并使用其结果确定适当的储存条件和复验或有效期。
For example, you do not have stability data to support the (b)(4) retest date assigned to your (b)(4) API. You also have not performed ongoing annual stability monitoring of API. 例如，你们没有稳定性数据支持XX的复验期。你们也没有执行API年度持续稳定性监测。
In your response, you state that you plan to initiate stability monitoring of (b)(4) API during their next manufacturing campaign.You failed to provide justification for the (b)(4) retest date in the interim. 在你们的回复中，你们说你们计划对XX API在其下一生产阶段期间开始稳定性监测。你们未能提供在过渡期间XX复验期的论证。
In response to this letter, provide your plan of action with timelines to develop and implement a complete drug stability program for API manufactured for the U.S. market. Your program should be designed to support all assigned retest dates and process hold times for each API. Assess the stability of all API currently distributed to the U.S. market. 回复比函， 提供行动计划制定和实施一个完整的药品稳定性试验方案，并有时间计划。你们的方案应设计支持每一个API所有给定的复验期和工艺持续时间。评估所有发运至美国市场的API。
4. Failure to demonstrate that your manufacturing process can reproducibly manufacture an API meeting its predetermined quality attributes. 未能证实你们的生产工艺可以重现的生产出符合其既定质量属性的API。
Your firm failed to conduct process performance qualification for several API. For other API, you conducted partial process performance qualification as you did not adequately evaluate significant variables (e.g., parameters) in your manufacturing processes for those API. In addition, you do not have an on-going program for monitoring process control to ensure stable manufacturing operations and consistent drug quality. See FDA’s guidance document, Process Validation: General Principles and Practices, for approaches that FDA considers appropriate elements of process validation, at http://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf.
In your response, you state that you will complete process validation for your API. However, your response is inadequate because you failed to specify how you will ensure that your API are manufactured reproducibly. You also did not provide a retrospective review of your manufacturing processes to identify whether drug quality was adversely affected. 在你们的回复中，你们表示你们将会完成API的工艺验证。然而，你们的回复不充分。因为你们未能详细阐述你们讲如何确保你们API的生产可重现。你们还未能对生产工艺进行回顾性审核以确定是否对药品质量产生不良影响。
In response to this letter, provide your validation protocols and reports. Also provide an update on the status of process performance qualification for your manufacturing processes for all API distributed to the U.S. market and your program for ensuring an ongoing state of control of your manufacturing processes. 回复此函，请提供你们的工艺验证方案和报告，同时提供所有销往美国市场的API的生产工艺性能确认状态的更新信息 。并提供用以确保生产工艺持续控制状态的计划。
Repeat Observations at Facility 工厂重复缺陷
FDA cited similar CGMP observations during inspections we conducted from September 12 to 15, 2011; and September 1 to 4, 2014. You proposed specific remediation for these observations in your responses. These repeated failures demonstrate that your management’s oversight and control over the manufacture of intermediates and API is inadequate. FDA在2011年9月12-15日和2014年9月1-4日检查中发现了类似缺陷。你们在你们的回复中对这些缺陷提出了具体的补救措施。这些重复问题证明你们的管理层对中间体和API生产的监管和控制是不充分的。
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发表于 2018-8-16 09:22:49
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发表于 2018-8-16 09:53:21
