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本帖最后由 山顶洞人 于 2019-10-24 09:59 编辑
警告信翻译如下：
Warning Letter 320-19-42
September 10, 2019
Dear Mr. Sun Jia Quan:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Jiangsu NHWA Pharmaceutical Co., Ltd. (Jiawang site), FEI 3005619485, at No. 6 Tianyong Road, Industrial Park, Xuzhou, Jiangsu, from April 1 to 5, 2019. 2019年4月1日至5日，美国食品药品监督管理局（FDA）在江苏徐州工业园区天永路6号检查了你们的药品生产工厂，江苏恩华制药有限公司（贾汪基地）。
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API). 此警告信总结了与活性药物成分 （API） 的违反CGMP的重大偏差。
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). 由于你们的方法、设施或生产、加工、包装或保存的控制不符合 CGMP，你们的API 根据FD&C Act, 21 U.S.C. 351(a)(2)(B)被认定为掺假。
Additionally, your drug products, (b)(4) are adulterated under section 501(b) of the FD&C Act, 21 U.S.C. 351(b), for failure to conform to compendial standards for strength, quality, or purity. 此外，由于你们的药品不符合含量、质量、或纯度的药典标准，你们的药品根据FD&C Act, 21 U.S.C. 351(b) 第501（b）节被认定为掺假。
We reviewed your April 26, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence. 我们详细审阅了你们于2019年4月26日对我们的FDA 483表的回复，并在之后收到你们的回函。
During our inspection, our investigator observed specific deviations including, but not limited to, the following. 在我们期间，我们的检查人员发现的具体的偏差，包括但不限于以下：
1. Failure to ensure that all sampling plans and test procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and purity. 未能确保所有取样计划和测试程序科学合理且适于确保你们的 API 符合既定的质量和纯度标准。
You manufacture multiple API listed in the United States Pharmacopeia (USP) that were imported into the United States and supplied to compounding pharmacies. For (b)(4) API, the laboratory stability protocols used to support expiration dating of these API are based on methods and specifications in the 2015 Chinese Pharmacopeia. You were not able to demonstrate that the tests used are equivalent to or better than the current USP 42 compendial methods. FDA compared your test methods, based on the Chinese Pharmacopeia, to the current standard in the USP. We found multiple differences in specifications and test methods. We also found that required tests for quality attributes in the USP were not part of the Chinese Pharmacopeia or your stability protocols. Beyond a deviation from CGMP, this also causes your drugs to be adulterated within the meaning of 501(b) of the FD&C Act, 21 U.S.C. 351(b), in that their strength, quality, or purity falls below the standards set forth in an official compendium recognized in the FD&C Act. 你们生产多个进口到美国并供应给药房的美国药典 （USP） 级 API，但用于支持这些 API 有效期的实验室稳定性方案是基于 2015 版中国药典中的方法和规范制定的。你们无法证明所使用的测试等效或优于当前的 USP 42 药典方法。FDA将中国药典的测试方法与USP中的现行标准进行了比较。我们发现标准和测试方法存在多个差异。我们还发现，USP 中必需测试的质量属性不包括在中国药典或你们的稳定性方案中。除了偏离CGMP之外，这也会导致你们的药物根据FD&C法案，21 U.S.C. 351（b）被认定为掺假，因为药物的强度、质量或纯度低于官方规定的标准。
Additionally, forced degradation studies were not validated for your USP-grade- (b)(4). 此外，强制降解试验没有针对你们的USP级（b）（4）进行验证。
In your response, you stated that you would cease distribution until you have updated your methods, conducted a comparison of your test methods versus the current USP compendial methods, and tested reserve samples against the current USP standards. You stated that you would take appropriate action if you found quality issues with U.S. distributed product within expiry. 在你们的回复中，你们声明在更新你们的方法、对测试方法与当前 USP 药典方法进行比较、根据当前 USP 标准测试留样样品之前，你们将停止销售。你们表示，如果发现销往美国的产品在效期内存在质量问题，你们将采取适当的措施。
In response to this letter, provide: 回复此函，请提供：
Your commitment to using current USP compendial methods until any alternative methods have been demonstrated to be equivalent or better than the USP methods. 你们的承诺：使用现行 USP药典方法，直到任何替代方法已被证明等效的或优于 USP 方法。 A comprehensive study that determines whether your test methods for your API are equivalent to, or better than, the USP method, if you are not using current USP compendial methods. Include all findings and deviations encountered in assessing whether your alternative method is equivalent or superior to the USP compendial method. For FDA’s current thinking regarding analytical test method validation, seeAnalytical Procedures and Methods Validation for Drugs and Biologics athttps://www.fda.gov/media/87801/download. 一份全面的研究以确定你们的 API 测试方法是否等效或优于 USP 方法，如不使用现行 USP 药典方法。包括在评估你们的替代方法是否等效或优于 USP 药典方法过程中遇到的所有发现和偏差。有关 FDA 目前对分析方法验证的考虑，请参阅药品和生物制品分析程序和方法验证[url=]https://www.fda.gov/media/87801/download。[/url] Updated test results using a validated test method (e.g., USP method) of all reserve samples for all drugs released to the U.S. market within expiry to ensure that your drug products conform to appropriate standards of identity, strength, quality, and purity. 对所有已销往美国市场的效期内药品的留样样品，使用验证后的测试方法（例如 USP 方法）获得的测试结果，以确保你们的药品符合适当的鉴定、含量、质量和纯度标准。 Your action plan to address any product quality or patient safety risks for your drug products in U.S. distribution, including potential customer notifications, recalls, or market withdrawals. 你们用以解决销往美国的药品的任何产品质量或患者安全风险的行动计划，包括可能的客户通知、召回或退市。 Your procedure for documenting and investigating any deviations from laboratory control procedures. 你们用以记录和调查任何偏离实验室控制程序的程序
2. Failure to adequately investigate and document out-of-specification results according to a procedure and implement appropriate corrective actions. 未能按照程序充分调查和记录OOS结果，并采取适当的纠正措施。
Our investigator discovered that (b)(4) batches of (b)(4) API failed finished release testing due to the discovery of foreign particles during color/clarity solution testing. The investigations, OOS-201607109 and OOS-201608130, failed to identify the root cause and source of the foreign materials. 我们的检查人员发现，（b）（4）批次的（b）（4）API放行检验不合格，因在溶液颜色/澄明度检验期间发现颗粒异物。调查OOS-201607109和OOS-201608130未能查明异物的根本原因和来源。
Additionally, in October 2016, (b)(4) of (b)(4) API (b)(4) were returned to your firm due to the presence of (b)(4) of foreign particles ((b)(4) and (b)(4)). 此外，2016年10月，由于存在（b）（4）异物（b）（4）和（b）（4）），（b）（4）API（b）（4））被退回贵公司。
In your response, you stated that you would reexamine your procedures for evaluating laboratory investigations, customer complaints, and deviations. You also committed to review all out-of-specification (OOS) results. Your response was inadequate in that you did not review the analytical test results you used to release drugs to the U.S. supply chain, using non-USP methods, to determine if any passing test results were, in fact, out of specification when compared to the USP standards. 在你们的回复中，你们表示将重新审查用以评估实验室调查、客户投诉和偏差的程序。你们还承诺将回顾所有OOS结果。你们的回复是不充分的，因为你们没有回顾使用非 USP 方法检验销往美国市场的药物的分析测试结果，以确定与 USP 标准相比，原来合格的测试结果实际上是否也是OOS.
In response to this letter, provide: 回复此函，请提供：
A comparison of the test methods used to release API to the U.S. market versus the USP compendial standards. For any tests with differing specifications, investigate whether you released OOS material. 对销往美国市场的API 的测试方法与 USP 药典标准的比较。对于任何具有不同标准的测试，请调查你们是否发布了 OOS 。 A retrospective, independent review of all invalidated OOS (in-process and finished testing) results for products currently on the U.S. market within expiry. Assess whether the scientific justification and evidence for each invalidated OOS result was conclusive. For investigations that establish laboratory root cause, ensure that other laboratory methods vulnerable to the same root cause are identified for remediation. 对目前在美国市场上效期内产品相关的所有无效 OOS（在中控和成品的测试）结果进行回顾性、独立审查。评估每个无效的OOS结果的科学理由和证据是否具有决定性。对于确定实验室根本原因的调查，请确保已对其他易受相同根本原因影响的实验室方法进行补救。 A thorough review of production (e.g., batch manufacturing records, adequacy of manufacturing steps, raw materials, process capability, deviation history, batch failure history) for any OOS results with inconclusive or no root cause identified. 对于任何不确定或未确定根本原因 OOS 结果进行生产系统的彻底审查（例如，批次生产记录、生产步骤的充分性、原辅料、工艺能力、偏差历史、批次故障历史）。 A corrective actions and preventive actions (CAPA) plan that identifies manufacturing root causes and specifies meaningful improvements. 一份针对生产根本原因的纠正措施和预防措施（CAPA）计划，并指定有效的改善。 A review and remediation of your system for investigating OOS results. Provide a CAPA plan to improve OOS handling. Your CAPA plan should ensure that your revised OOS investigations procedure includes: 对你们的OOS调查系统进行审查和补救。提供用以改善 OOS 处理CAPA 计划。你们的 CAPA 计划应确保修订OOS 调查程序以包括： o Enhanced quality unit oversight of laboratory investigations o 加强质量部门对实验室调查的监督 o Identification of adverse laboratory control trends o 识别不良的实验室控制趋势 o Resolution of causes of laboratory variation o 实验室偏差原因的解决方法 o Investigations of potential manufacturing causes when a laboratory cause cannot be conclusively identified o 在无法最终确定实验室原因时调查潜在的生产原因
Drug Distribution Ceased Until Corrective Actions Implemented 停止药品销售，直到纠正行动实施
We acknowledge your commitment to cease distribution of drugs manufactured at the Jiawang site to the U.S. market until you have completed your CAPA plan and confirmed its effectiveness. 我们感谢你们承诺停止向美国市场分销在嘉旺工厂生产的药品，直到完成 CAPA 计划并确认其有效性。
In response to this letter, please confirm that you will not resume manufacturing drugs for the U.S. market until the FDA has verified the adequacy of your CAPA. When you have completed your corrective actions, notify this office in writing. 在回复此函时，请核实在FDA确认你们的CAPA是否足够之前，你们不会恢复为美国市场生产药品。完成纠正措施后，以书面形式通知本办公室。
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. 本信中引用的偏差并非穷尽列表。你们有责任调查和确定这些偏差的原因，并防止其再次发生或其他偏差的发生。
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. 在你们完全纠正所有偏差，并且我们确认符合 CGMP 之前，FDA 可能会拒绝批准任何将贵公司列为药品生产商的药物申请或补充申请。
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. 收到此函后，请在 15 个工作日内以书面形式回复本办公室。详细说明自我们检查以来你们纠正偏差并防止其再次发生行动。如果无法在 15 个工作日内完成纠正措施，请说明延迟原因和完成时间表。
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发表于 2019-10-24 06:20:44
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