FDA 483表：浙江华海/川南一分厂

受检公司：Zhejiang Huahai Pharmaceutical Co., Ltd. 浙江华海药业

受检地址：Coastal Industrial Zone, Chuannan No.1 Branch, Duqiao, Linhai Zhejiang 317016 China 中国浙江临海杜桥沿江工业园，川南一分厂

受检身份：原料药生产商

FEI号：3003885745

检查员：Massoud Motamed, Investigator

检查日期：2017-05-15 至 2017-05-19

签发日期：2017-05-19

发布日期：2018-08-09

This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations. And do not represent a final agency determination regarding your compliance if you have an objection regarding an observation, or have implemented, or plan to implement corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA to address above. If you have any questions, please contact FDA at the phone number and address above.

本文件列出了FDA代表在对你工厂检查期间所发现的问题。这些只是检查发现，并不代表FDA对你公司合规性的最终结论。如你们对某一缺陷有异议，或已实施或计划实施纠正措施来纠正某个缺陷，你们在检查期间与FDA代表讨论你们的异议与措施，或通过上述地址向FDA提交资料。如有问题，请通过上述地址电话与FDA取得联系。

DURING AN INSPECTION OF YOUR FIRM WE OBSERVED: 检查你公司期间我们发现

OBSERVATION 1 缺陷1

Appropriate controls are not implemented over Quality Control instruments to ensure the integrity of analytical testing. Furthermore, anomalies in analytical testing are not investigated.  未对QC仪器执行适当的控制以确保分析检测的完整性。另外，分析测试中的异常现象未进行调查。

1.    During a review of API testing assay testingis repeated in order to obtain satisfactory/within specification results: 在对原料药检测的审核期间重复了含量测试以获取满意结果/合格结果。

Standard Operating Procedure (SOP) QC-024-5 requires that replicate samples subject to analysis for assay to exhibit no more than (b)(4)% difference in result. This SOP was utilized to engage in repeat analysis of API in instances of out-of-specification and out-of-trend results without a corresponding investigation. Examples may be found below: 标准操作规程（SOP）QC-024-5要求含量检测采用双样分析，双样结果差异应不得过XX%。该SOP被利用来在OOS或OOT结果时重复API的分析，却不进行相应的调查。发现的例子如下：

(a)  (b)(4) batch (b)(4) exhibited a large differential between replicate sample results, such that one injection yielded an out-of-specification. The initial failing injections were not processed. Dueto this large differential, this batch of (b)(4) was retested without conducting an investigation and passing results were reported. XX品种XX批次显示双样结果有较大差异，一针结果为OOS。开始不合格的这针并未进行数据处理。基于此较大差异，对该批次进行了复测，而未执行调查，然后报告了合格结果。

(b)  (b)(4) batch (b)(4) exhibited failing assay result for one of the replicate injections ((b)(4)% against a specification of (b)(4)%). Due to a large differential in test results between replicate injections for (b)(4) this batch was retested without conducting an investigation and passing results were reported. XX产品XX批次两次进样中有一针得到含量结果不合格（结果为XX%，标准为XX%）。由于两次平行进针检测结果差异较大，该批次进行了复测，而未进行调查，然后报告了合格结果。

(c)  The following batches exhibited out-of-trendresults, which were retested without an investigation due to a greater than (b)(4)% differential in replicate assay injections: 以下批次得到结果为OOT结果，均未进行调查即以两次含量进样之间差异超过XX%为由进行复测：

                     i.       (b)(4) batch (b)(4)  产品XX批号XX

                    ii.       (b)(4) batch (b)(4)  产品XX批号XX

                   iii.       (b)(4) batch (b)(4)  产品XX批号XX

                   iv.       (b)(4) batch (b)(4)  产品XX批号XX

Further, due to this repeat testing as aresult of discrepancies in replicate assay values, I reviewed repeat analytical testing for (b)(4) exhibited an increased rate of repeat testing. The replicate samples from repeat testing conducted between September 2016 and March 2017 for(b)(4) exhibited an average differential in assay results of approximately (b)(4)% (with the acceptable range of the specification spanning (b)(4)%). The replicate samples from repeat testing conducted between September 2016 and March 2017 for (b)(4) exhibited an average differential in assay results ofapproximately (b)(4)% (with the acceptable range of the specification spanning (b)(4)%). I asked your firm’s Quality Control Director to explain how such routine, large differences in assay value of replicate samples was consistent with assurance that the analytical method is effective and released API indeed met specification. They did not provide a sustentative explanation. 鉴于两次含量测定值之间差异引发的重复检测情况，我审核了重复检测呈现增加趋势的XX的重复检测。2016年9月至2017年3月之间所执行的重复检测结果双样间XX的含量结果平均差异约为XX%（标准可接受范围为XX%）。2016年9月至2017年3月之间所执行的重复检测结果双样间XX的含量结果平均差异约为XX%（标准可接受范围为XX%）。我询问了你们公司的QC主任要求解释为何如此常见，重复样本含量值的如此大差异能持续确保分析方法的有效性，确保所放行的API实际是符合其质量标准的。他们并未提供强有力的解释。

Note: this repeat testing encompassed subjecting the same API batch to repeat testing without investigating the initial test results and the requirement for re-testing.

注：此重复检测指向相同API批次进行了重复检测，而未对初始检测结果和复测要求进行调查。

2.    Impurities occurring during analytical testing are not consistently documented/quantitated. 在分析中出现的杂质未能全部记录/定量。

(a)  Testing of (b)(4) content of (b)(4) batch(b)(4) by Liquid Chromatography-Mass Spectrometry yielded an unidentified peak at an approximate retention time of (b)(4) minute. Your firm explained this unknown peak as a “ghost peak” that appears from time to time in chromatograms for undetermined reasons. This peak was substantially larger than that of (b)(4) the subject of the testing. No investigation was conducted. XX产品XX批次的XX含量LC-MS检测中在XX分钟保留时间处出现了未知峰。你们公司将此不明原因偶尔出现在色谱图的未知峰解释为“鬼峰”。该峰远远大于检测对象XX。你们未进行调查。

(b)  Testing of (b)(4) content of (b)(4) batches(b)(4) (among others) by Liquid Chromatography-Mass Spectrometry yielded an unidentified peak at an approximate retention time of (b)(4) minute until the end of the chromatogram. This peak was substantially larger than that of (b)(4) the subject of the testing. No investigation was conducted. XX产品XX批次的XX含量LC-MS检测中在XX分钟保留时间处出现了未知峰并持续直到运行结束。该峰远远大于检测对象XX。你们未进行调查。

(c)  Impurity testing of (b)(4) batches (b)(4) yielded a prominent, coalescing peak with that of the primary (b)(4) peak. Nevertheless, the impurity was quantitated along with the (b)(4) peak as desired API and no investigation was initiated. XX产品XX批次的杂质检测发现一个突起的峰与主峰XX重叠，而该杂质是与XX峰一起进行定量计算作为目标API，对此未启动调查。

OBSERVATION 2 缺陷2

Facilities and equipment are not maintained to ensure quality attributes of drug product. 设施设备的维护不能确保药品的质量属性。

a)    On May 15, 2017, (b)(4) V-305 exhibited particulate matter and (b)(4) paint on the inner face of the gasket to the(b)(4). Further, this gasket was fraying, and loose threads were visible (b)(4). The gasket inside the (b)(4) had deteriorated such that the missing portions could not be accounted for. The mass balance of this gasket could not be accounted for. Further, this gasket was discolored brown. Finally, a portion of the interior of this (b)(4) was discolored white. This (b)(4) was utilizedin the manufacture of (b)(4) lot (b)(4) intended for the US market. This equipment was in the clean status. 2017年5月15日，XX设备V-305的XX垫圈内表面发现有颗粒物和XX涂料。另外，此垫圈已磨损，松开的线头在XX处可见。XX内的垫圈已老化，有一部分已缺失无法拼回。该垫圈的质量已无法平衡。另外，此垫圈已变为棕色。最后，此XX的内部有一部分已变为白色。此XX用于生产发往美国市场的XX产品XX批号。此设备为清洁状态。

b)   On May 15 2017, (b)(4) J09-805 contained screws displaying a reddish-brown discoloration consistent with rust (interior of the (b)(4)). This (b)(4) was utilized in the manufacture of (b)(4) lot(b)(4) intended for the US market. This equipment was in the clean status andis used in the (b)(4). 2017年5月15日，XX设备J09-805上的螺丝显出红褐色，与铁锈颜色相似（XX的内部）。该XX用于生产发往美国市场的XX产品XX批号。此设备处于清洁状态。

c)    On May 15 2017, (b)(4) IX-501-2 exhibited particulate matter and blue paint on the inner face of the gasket to the (b)(4). Particulate matter and paint were falling from the (b)(4) upon opening the (b)(4). Further, this gasket was fraying, and loose threads were visible (b)(4). The gasket inside the (b)(4) had deteriorated such that the missingportions could not be accounted for. The mass balance of this gasket could not be accounted for. Further, this gasket was discolored brown. Finally, the interior of this (b)(4) was discolored brown. This (b)(4) was utilized in the manufacture of (b)(4) lot (b)(4) intended for the US market. This equipment was in the clean status. 2017年5月15日，XX设备IX-501-2的XX垫圈内表面发现有颗粒物和蓝色涂料。颗粒物和涂料在打开XX时从XX掉下。此外，该垫圈已磨损，松开的线头在XX处可见。XX内的垫圈已老化，有一部分已缺失无法拼回。该垫圈的质量已无法平衡。另外，此垫圈已变为棕色。最后，此XX的内部有一部分已变为白色。此XX用于生产发往美国市场的XX产品XX批号。此设备处于清洁状态。

d)   On May 15 2017, (b)(4) IX-501-1 exhibited what appeared to flaking of the surface to the (b)(4). The gasket inside the(b)(4) had deteriorated such that portions of the gasket were missing and threads of the gasket were fraying. The mass balance of this gasket could not be accounted for. This (b)(4) was utilized in the manufacture of (b)(4) lot(b)(4) intended for the US market. This equipment was in the clean status.2017年5月15日，XX设备IX-501-1表面貌似正在掉皮掉到XX。XX内的垫圈已老化，有一部分已缺失无法拼回。该垫圈的质量已无法平衡。另外，此垫圈已变为棕色。最后，此XX的内部有一部分已变为白色。此XX用于生产发往美国市场的XX产品XX批号。此设备处于清洁状态。

e)    On May 15 2017, the (b)(4) W02-802-2 exhibited white particulate facing the interior of the (b)(4) that appeared to originate from the gasket to the (b)(4). Further, this (b)(4) appeared heavily scratched. This (b)(4) was utilized in the manufacture (b)(4) lot (b)(4) intended for the US market. This equipment was in the clean status and is used in the (b)(4). 2017年5月15日，XX设备W02-802-2的XX内发现有白色的颗粒，貌似是来自XX的垫圈。另外，此垫圈已严重刮伤。此XX的内部有一部分已变为白色。此XX用于生产发往美国市场的XX产品XX批号。此设备处于清洁状态并用于XX。

f)    On May 16 2017, (b)(4) III-319 exhibited whatappeared to white particulate matter in the interior of the (b)(4). The gaske tinside the (b)(4) had deteriorated such that portions of the gasket were missing and threads of the gasket were fraying. The mass balance of this gasket could not be accounted for. This (b)(4) was utilized in the manufacture of (b)(4) lot (b)(4) intended for the US market. This equipment was in the clean status. 2017年5月16日，XX设备III-319的XX内发现有白色的颗粒物。XX内的垫圈已老化，有一部分已缺失，垫圈线头已松开。该垫圈的质量已无法平衡。此XX用于生产发往美国市场的XX产品XX批号。此设备为清洁状态。

For the aforementioned Observation, the following complaints pertaining to your firm’s API were noted:

对于上述问题，有记录到以下对你们公司API的投诉：

     i.       CC-16006 addressing (b)(4) particles, (b)(4) color, yellow rust in (b)(4) batch (b)(4) 某批次中发现颗粒物、XX颜色、黄色锈

     ii.       CD-15004 reporting “black metallic particles”in (b)(4) batch (b)(4) 某批次报告“黑色金属颗粒物”

    iii.       CD-15003 addressing “mixed fragment (b)(4)”in (b)(4) batch (b)(4) 某批次中发现“混合碎片XX”

    iv.       CD-15006 stating “black particles were foundin (b)(4) batch (b)(4) 某批次中发现“黑色颗粒物”

     v.       CD-15001 reporting “That (b)(4) particles is(b)(4)”. The affected product is (b)(4) 报告XX颗粒物是XX。受影响产品为XX。

OBSERVATION 3 缺陷3

Invalidation of out-of-specification results lacks adequate scientific justification. 宣布OOS结果无效时缺乏充分的科学论证。

a)    Report OOS-CQC15067 relating to (b)(4) batch (b)(4) was reported “Unknown impurity peak is appeared under unknown reason”. Your firm explained this unknown peak as a “ghost peak” that appears from time to time in chromatograms for undetermined reasons. Without an indication of the cause of the out-of-specification, an attribution of “Lab error was made.” 报告OOS-CQC15067是XX产品批次XX，报告“未知杂质峰出现，原因不明”。你们公司将此未知峰解释为“鬼峰”，因未知原因偶尔出现在色谱图中。未指明OOS的原因，归因于“实验室犯错”。

b)   Report OOS-CQA16103 reported out-of-specification of residual solvents in (b)(4). The Phase I laboratory investigation failed to identify a laboratory error. This investigation attributed the failure to “Pollution” from the environment during sample preparation.报告OOS-CQA16103是XX中残留溶剂OOS结果。第一阶段实验室调查未能发现实验室错误。该调查将不合格归因于样品制备过程中来自环境的“污染”。

c)    Report OOS-CQC15103 due to a single impurity in (b)(4) batch (b)(4) ((b)(4)% against a specification of no more than (b)(4)%). This was assigned as a “Lab error” due to “possible” residue in the column. When inquiring about why this impurity specifically eluted in the (b)(4) analytical test of the testing sequence, your firm again referenced a “ghost peak”. 报告OOS-CQC15103是XX产品XX批次单杂（结果为XX%，标准为不得过XX%）。该OOS归因为因柱中“可能”有残留而发生的“实验室错误”。在询问为何在检测序列中的XX分析测试中会有洗出该特定杂质时，你们公司又将其归为“鬼峰”。

FDA警告信：宜城市共同药业

Warning Letter: 320-18-65              July 26, 2018

Mr. Michael Zou, Chief Marketing Officer

Yicheng Goto Pharmaceuticals Co., Ltd.

5^th Floor, East Gate of Building #2, Servo Industrial Park, 1^st Qilin Road, Xiangyang, Hubei Province, 441021, 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和维护过程。

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.

 你们未执行清洁验证研究以证明你们的非专用生产设备所用清洁程序是足以防止你们API（例如XX），其中包括XX药品，之间潜在交叉污染的。你公司在该设备上也生产中间体。

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.

 更具体地说，你们未对用于生产XX中间体和API的关键非专用生产的大部分设备进行清洁验证。

Reactors, (b)(4) are examples of critical multi-use equipment used by your firm.

 反应釜，XX是你们公司所用多用途关键设备的例子。

During the inspection, your staff also stated 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，你们员工还声称不需要记录设备在不同生产轮次之间的清洁。例如，对于XX产品XX批次，你公司只提供了一份单个设备（XX）的清洁记录用以证明批生产之前已执行了清洁。

In your response, you state that you will conduct cleaning validation for your non-dedicated equipment. However, you failed to provideyour plan to ensure that your equipment is adequately cleaned in the interim.

 在你们的回复中，你们声称你们会对你们的非专用设备执行清洁验证。但是，你们并未提交你们计划用以确保你们的设备会临时进行充分清洁。

In response to this letter, provide:在回复此函时请提交

• Your updated cleaning validation protocol 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.你们更新后的所有用于生产药品的设备的清洁验证方案和报告，其中包括所有结果和确立的可接受标准。还有请包括更新后的设备清洁与维护程序，以及包括但不仅限于所有清洁操作的文件记录的条款。

• 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.一份风险评估，用以确定不充分的清洁做法对所有可能受影响的销往美国市场所的中间体和API批次的影响。该评估应包括但不仅限于有潜在交叉污染风险的留样的分析。

• 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.你们所拟的市场运行计划包括通知客户、留样检测计划、加强投诉监测和召回（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.提交一份临时计划，以确保在你们完成你们的验证研究之前会进行充分的清洁，包括但不仅限于在更换生产不同的API或中间体之前执行清洁核查检测，以确保清洁效果。还请包括你们对每种API和中间体的可接受标准。

• 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.一份全面独立的审核，识别出在你们设施内所生产的药品（API和中间体）之间的交叉污染风险。评估你们设施和工艺设计防止交叉污染的适用性，包括对你们设备、物料、人员和废料通道的评估。在其中包括一份详细的系统补救CAPA计划和时间。

2.      Failure to ensure that alltest procedures are scientifically sound and appropriate to ensure that your API conform to established standards of quality and purity.  未能确保所有检测方法均科学合理及适当，可确保你们的API符合既定的质量和纯度标准。

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 awritten procedure.

 你们对XX原料药未执行充分的分析方法。例如，你们执行了含量、有关物质和残留溶剂检测，但未执行系统适用性测试且未使用对照品。此外，你们的化验员对色谱图进行了手动积分，但该手动积分并无书面程序规定。

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，你们声称你们已建立了程序要求你们化验员使用对照品，进行系统适用性试验，并规定了适当的色谱图积分规范。但是，你们并未提交你们使用对照品和系统适用性的程序。你们的回复亦缺乏对受影响手动积份对实施新方法之前所生产数据的影响性回顾评估。

In response to this letter, provide:在回复此函时请提交

• 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.对所有你们公司所用检测方法的评估，以确保其具备适当的指导、方法适用性标准，并经过适当的验证以确定其是否符合其目的

• A reanalysis plan for all batches within retest date that were analyzed using methods lacking system suitability or standards.对所有仍在有效期内采用缺乏系统适用性或标准的方法检测的的批次进行重新分析的计划

• 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.一份对所有色谱手动积分案例的全面回顾。提交对你们用于检测的手动积分参数的科学论证。对于缺乏科学论证的积分情况，提交采用适当的重新积分参数重新积分的计划。评估重新积分结果是否符合你们既定的API可接受标准。如果你们发现有OOS结果，请说明你们已采取或将要采取用以确保已销售产品的质量及保护患者的措施，如通知客户和召回。

• 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. 提交一份对化验室做法、方法、设备和化验员资质的全面独立审核。基于此审核，请提交一份详细的CAPA计划以全面补救你们的化验室体系。你们CAPA的要素应包括但不仅限于你们将要采取用以加强QA对方法验证和检测结果审核及批准进行监管的措施。

3.      Failure to design adocumented stability program to monitor the stability characteristics of API and to use the results to confirm appropriate storage conditions and retest or expiry dates. 未能设计书面稳定性计划用以监测API的稳定性特性，并使用这些结果来确认适当的存贮条件和复测或有效期。

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，你们并无稳定性数据来支持你们给定XX原料药的XX复验期。你们亦未对API执行持续的年度稳定性监测。

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，你们声明你们计划在下次生产周期中启动对XX原料药的稳定性监测。你们未提供临时复验期的论证。

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 stabilityof all API currently distributed to the U.S. market.

在回复此函时，请提交你们为美国市场所生产的API建立和执行完整的药品稳定性计划的行动计划，以及时间表。你们的计划设计应能支持所有给定的复验期，以及每种API的工艺保存时间。评估已销售至美国的所有API的稳定性。

4.      Failure to demonstrate that your manufacturing process can reproducibly manufacture an API meeting its predetermined quality attributes. 未能证明你们的生产工艺能重复地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 donot 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, forapproaches that FDA considers appropriate elements of process validation, athttp://www.fda.gov/downloads/Drugs/…/Guidances/UCM070336.pdf.

 你们公司未能为几个API执行工艺性能确认。对于其它API，你们执行了一部分工艺性能确认，但你们未充分评估你们这几个API生产工艺中的重要变更（例如参数）。此外，你们对工艺控制并无持续监测计划，以确保稳定的生产操作和持续的药品质量。参见FDA工艺验证指南。

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，你们声称你们将完成你们API的工艺验证。但是，你们的回复是不充分的，因为你们未能说明你们将如何确保你们的API可重复生产。你们亦未提交一份对生产工艺的回顾性审核以识别是否药品受到不良影响。

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.

 在回复此函时，请提交你们的验证方案和报告。还有请提交一份对所有销售至美国市声的API工艺性能确认状态的更新，以及确保对你们工艺处于持续受控状态的计划。

Repeat Observations at Facility工厂重复缺陷

FDA cited similar CGMP observations during inspections weconducted 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 overthe 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。

CGMP Consultant Recommended 顾问建议

Based upon the nature of the deviations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluateyour operations and to assist your firm in meeting CGMP requirements. We also recommend that the third party perform a comprehensive audit of your entire operation for CGMP compliance and, and evaluate the completion and effectiveness of any corrective actions and preventive actions you have implemented before you pursue resolution of your firm’s compliance status with FDA.

依据我们在你们工厂发现的违规情况，我们强烈建议你们使用一位有21 CFR211.34所述资质的顾问来协助你们公司符合CGMP要求。我们还建议具备资质的第三方对你们全面操作的CGMP合规情况进行综合审计，并在你们寻求公司符合FDA要求的解决方案之前评估所有已实施的CAPA的完整性和有效性。

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 ensuring ongoing CGMP compliance.

你们使用顾问并不解除你们公司符合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

Deviations cited in this letter are not intended as anall-inclusive list. You are responsible for investigating these deviations, fordetermining the causes, for preventing their recurrence, and for preventing 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，防止其它偏差的发生。

FDA placed your firm on Import Alert 66-40 on January 10,2018.

 FDA已于2018年1月10日将你公司置于进口禁令66-40项下。

Until you correct all deviations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new 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的新申报和增补申报的批准。

Failure to correct these deviations may also result in FDA continuing to refuse admission of articles manufactured at Yicheng Goto Pharmaceuticals Co., Ltd., Group 1 Gaokeng, Xiaohe Town, Yicheng City, Hubei Province, into the United States under section 801(a)(3) of the FD&C Act,21 U.S.C. 381(a)(3). Under the same authority, articles 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 section501(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 inwriting 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 or mail your reply to:

Ms. Christina Alemu-Cruickshank

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4212

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Please identify your response with FEI 3004459466.

Sincerely,

/S/ 

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research