FDA警告信：浙江华海 20181129

翻江鼠

Warning Letter: 320-19-04

November 29, 2018

Mr. Jun Du

Executive Vice President, Zhejiang Huahai Pharmaceutical Co., Ltd.

Coastal Industrial Zone, Chuannan No. 1 Branch No.9, Donghai Fifth Avenue, Linhai, Taizhou Zhejiang 317016, CHINA

Dear Mr. Du:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Zhejiang Huahai Pharmaceutical Co.,Ltd., located at Coastal Industrial Zone, Chuannan No. 1 Branch No. 9, Donghai Fifth Avenue, Linhai, Taizhou Zhejiang, from July 23 to August 3, 2018.

美国FDA于2018年7月23日至8月3日检查了你们位于中国浙江台州临海东海第五大道9号的浙江华海药业川南分厂。

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（API）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 August 26, 2018, response in detail and acknowledge receipt of your subsequent correspondence.  

我们详细审核了你们2018年8月26日的回复，并此告知已收悉你公司后续回复。

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 of your quality unit to ensure that quality-related complaints are investigated and resolved. 你们质量部门未能确保调查和解决与质量有关的投诉

Valsartan API 缬沙坦原料药

Your firm received a complaint from a customer on June 6, 2018, after an unknown peak was detected during residual solvents testing for valsartan API manufactured at your facility. The unknown peak was identified as the probable human carcinogen N-nitrosodimethylamine (NDMA). Your investigation (DCE-18001) determined that the presence of NDMA was caused by the convergence of three process-related factors, one factor being the use ofthe solvent (b)(4)). Your investigation concluded that only one valsartan manufacturing process (referred to as the (b)(4) process in your investigation) was impacted by the presence of NDMA.

你公司于2018年6月6日收到一份客户投诉，该投诉是对你们工厂生产的缬沙坦API的残留溶剂检测中发现一个未知峰。该未知峰被识别为可能的人体致癌物质NDMA。你们的调查（DCE-18001）认为NDMA的出现是3个与工艺有关的因素的叠加引起的，其中一个因素是使用了溶剂XX。你们的调查结论是只有一个缬沙坦生产工艺（在调查中称为XX工艺）受到NDMA的影响。

However, FDA analyses of samples of your API, and finished drug product manufactured with your API, identified NDMA in multiple batches manufactured with a different process, namely the (b)(4) process, which did not use the solvent (b)(4). These data demonstrate that your investigation was inadequate and failed to resolve the control and presence of NDMA in valsartan API distributed to customers. Your investigation also failed:

但是，FDA对你们API和使用你们API生产的制剂样品的检测发现采用不同工艺生产的多批产品中均存在NDMA，也就是说未使用溶剂XX的XX工艺中也有NDMA。这些数据证明你们的调查是不充分的，未能解决销售给客户的缬沙坦API中出现NDMA的问题并进行控制。你们的调查在以下方面也存在问题：

•      To include other factors that may have contributed to the presence of NDMA. For example, your investigation lacked a comprehensive evaluation of all raw materials used during manufacturing, including(b)(4).

•      未包括可能对出现NDMA有影响的其它因素，例如，你们的调查缺乏对生产中所用全部原料的全面评估，包括XX

•      To assess factors that could put your API at risk for NDMA cross-contamination, including batch blending, solvent recovery and re-use, shared production lines, and cleaning procedures.

•      未评估可能使得你们的API受NDMA交叉污染风险的因素，包括批混合、溶剂回收和重复使用、共用生产线和清洁程序

•      To evaluate the potential for other mutagenic impurities to form in your products.  

•      未评估在你们产品中形成其它诱变性杂质的可能性

Our investigators also noted other examples of your firm’s inadequate investigation of unknown peaks observed in chromatograms. For example, valsartan intermediates (b)(4) and (b)(4) failed testing for an unknown impurity (specification ≤ (b)(4)%) with results of (b)(4)% for both batches. Your action plan indicated that the impurity would be identified as part of the investigation; however, you failed to do this. In addition, no root cause was determined for the presence of the unknown impurity. You stated that you reprocessed the batches and released them for further production.

我们的调查人员还注意到你公司对色谱图中发现的未知峰调查不充分的其它例子。例如，缬沙坦中间体XX和XX未知杂质有2批不合格（标准为≤XX%，结果为XX%）。你们的行动计划显示该杂质会作为调查的一部分进行鉴别，但是你们并未照做。另外，亦未确定出现未知杂质的根本原因。你们声称你们返工了该批次并放行用于下一步生产。

Your response states that NDMA was difficult to detect. However, if you had investigated further, you may have found indicators in your residual solvent chromatograms alerting you to the presence of NDMA. For example, you told our investigators you were aware of a peak that eluted after the (b)(4) peak in valsartan API residual solvent chromatograms where the presence of NDMA was suspected to elute. At the time of testing, you considered this unidentified peak to be noise and investigated no further. Additionally, residual solvent chromatograms for valsartan API validation batches manufactured using your (b)(4) process, with(b)(4) in 2012 ((b)(4), and (b)(4)) show at least one unidentified peak eluting after the (b)(4) peak in the area where the presence of NDMA was suspected to elute.

你们的回复说NDMA很难检出。但是，如果你们曾进行了深入调查，你们可能会在残留溶剂色谱中发现指征，警示你们可能有NDMA出现。例如，你们告诉我们调查人员说你们了解缬沙坦API残留溶剂色谱中在XX峰之后有一个洗脱峰，那个地方就是疑似NDMA流出点。在检测时，你们认为该未鉴别的峰是噪声，未进行深入调查。另外，采用你们XX工艺生产的缬沙坦API验证批次残留溶剂色谱图中，2012年XX批和XX批显示在XX峰后NDMA疑似流出时间段处至少有一个未鉴别峰流出。

Your response also states that you were not the only firm to identify NDMA in valsartan API. In your case, FDA analyses of samples identified amounts of NDMA in valsartan API manufactured at your firm that were significantly higher than the NDMA levels in valsartan API manufactured by other firms. FDA has grave concerns about the potential presence of mutagenic impurities in all intermediates and API manufactured atyour facility, both because of the data indicating the presence of impuritiesin API manufactured by multiple processes, and because of the significant inadequacies in your investigation.

你们的回复还声称你们并不是唯一一个在缬沙坦API中发现NDMA的公司。在你们的案例中，FDA分析了你公司生产的缬沙坦API样品，发现其中的NDMA数量远远高于其它公司生产的缬沙坦API中的NDMA水平。FDA严重关切你公司生产出的所有中间体和API中出现诱变杂质的可能性，一方面是因为数据显示你们使用多个工艺生产出的API均出现了该杂质，另一方面因为你们调查中出现的严重不足。

In response to this letter:  在回复此函时，请

•      Submit risk assessments for all APIs and intermediates manufactured at your facility for the potential presence of mutagenic impurities.

•      提交一份对你们工厂生产的所有API和中间体出现诱变性杂质可能性的风险评估

•      Provide an updateon investigations and CAPA plans initiated to address the presence of NDMA and other potential mutagenic impurities in all APIs manufactured at your firm.

•      提交一份更新后的调查和CAPA计划，启动解决你公司生产的所有API中出现NDMA和其它潜在诱变性杂质的问题

•      Provide a thorough, independent assessment of your overall system for investigating deviations, discrepancies, out-of-specification (OOS) results, complaints, and other failures. In addition, provide a retrospective review of all distributed batches within expiry to determine if your firm released batches that did not conform to established specifications or appropriate manufacturing standards.

•      提交一份对你们偏差、不符合、OOS结果、投诉和其它失败情形整体调查系统的全面彻底评估。另外，提交一份对所有已销售且仍在效期内批次的回顾审核，确定你公司是否有放行不符合既定质量标准或适当生产标准的批次

•      Provide test results for all (b)(4) and intermediates for the presence of NDMA,N-Nitrosodiethylamine (NDEA), and other potentially mutagenic impurities.  

•      提交所有含有NDMA、NEMA和其它潜在诱变性杂质的XX和中间体的检测结果

(b)(4) API XX原料药

Your firm received a customer complaint on September 13, 2016, concerning (b)(4) API batches ((b)(4) and(b)(4)) that exceeded the specification for (b)(4) (≤ (b)(4) ppm). (b)(4)has been classified as a probable human carcinogen. Your customer's test results conflicted with your (b)(4) test results, which showed the two batches meeting the specification upon release. Your complaint investigation (CC-16008) identified no clear laboratory error, and no anomalies were detected during the production of the batches. Your investigation failed to evaluate other (b)(4) API batches to determine if the presence of excess (b)(4) was an adverse trend. For example, (b)(4) batches (b)(4), and(b)(4) were OOS for (b)(4) because of production errors; however, they were not discussed in your complaint investigation.   

你公司于2016年9月13日收到一份客户投诉，是关于XX原料药批次XX和XX超出XX标准（标准为≤XXppm）。XX被归类为可能的人类致癌物质。你们客户的检测结果与你们的XX检测结果有冲突，你们的结果显示2批均符合放行标准。你们的投诉调查（CC-16008）未识别出明显实验室错误，在这些批次生产中未发现异常。你们的调查未能评估其它XX原料药批次，以确定是否XX超出是不良趋势。例如，XX批次XX和XX为XX的OOS，原因是生产错误，但在你们的投诉调查中并未进行讨论。

Your response states that (b)(4) API batches (b)(4) and (b)(4) were returned, reprocessed, and released to customers in non-U.S. markets.

你们的回复声称XX原料药批次XX和XX被退货、返工并放行到非美国市场的客户。

Your response also states that in August 2017 you implemented a new (b)(4) test method that uses a (b)(4) LC-MS/MS method, to replace the (b)(4) LC-MS method that was prone to erroneous OOS results. You failed to verify the reliability of the (b)(4) resultsfor all (b)(4) API batches (including (b)(4) batch (b)(4)) originally released using your (b)(4) LC-MS method, which you indicated was inferior to your updated method.

你们的回复亦声称2017年8月，你们实施了新的XX检测方法，使用了XXLC-MS/MS方法，取代了易于发生错误OOS结果的XXLC-MS方法。你们未能核查所有XX原料药批次（包括XX批次XX）XX结果的可靠性，这些批次原来是使用你们的XX LC-MS方法放行的，而你们说该方法劣于你们更新后的方法。

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

•      A risk assessment for all (b)(4) API batches manufactured within expiry.

•      一份对所有生产的仍在效期内的XX原料药批次的风险评估

•      A revised complaint handling procedure and details of any further controls your facility has implemented to ensure that all complaints are adequately documented and thoroughly investigated.

•      一份修订后的客户投诉程序，其中详细说明对你们工厂实施用以确保所有投诉均会全部记录并彻底调查的所有进一步控制措施

•      Procedures for accepting and reprocessing returned drugs.

•      接受和返工退回药品的程序

•      Results of (b)(4) testing of all (b)(4) API batches released to the U.S. market using your updated (b)(4)LC-MS/MS (b)(4) test method.

•      所有采用你们更新后的XXLC-MS/MS检测方法检测后放行至美国市场的XX原料药批次的XX检测结果

2. Failure to evaluate the potential effect that changes in the manufacturing process may have on the quality of your API. 未能评估生产工艺中变更对你们API质量的潜在影响

In November 2011 you approved a valsartan API process change (PCRC - 11025) that included the use of the solvent (b)(4). Your intention was to improve the manufacturing process, increase product yield, and lower production costs. However, you failed to adequately assess the potential formation of mutagenic impurities when you implemented the new process. Specifically, you did not consider the potential for mutagenic or other toxic impurities to form from (b)(4) degradants, including the primary (b)(4) degradant,(b)(4). According to your ongoing investigation, (b)(4) is required for the probable human carcinogen NDMA to form during the valsartan API manufacturing process. NDMA was identified in valsartan API manufactured at your facility.

2011年11月，你们批准了一个缬沙坦API工艺变更（PCRC-11025），其中包括使用XX溶剂。你们意图改进该生产工艺，提高产品收率以及降低生产成本。但是，你们在实施新工艺时未充分评估诱变性杂质形成的可能性。具体来说，你们并未考虑XX降解物形成诱变性或其它毒性杂质的可能性，包括初期XX降解物XX。根据你们仍在进行中的调查，在缬沙坦API生产工艺中要形成可能的人体致癌性NDMA需要有XX，而在你们工厂生产的缬沙坦API中检出了NDMA。

You also failed to evaluate the need for additional analytical methods to ensure that unanticipated impurities were appropriately detected and controlled in your valsartan API before you approved the process change. You are responsible for developing and using suitable methods to detect impurities when developing, and making changes to, your manufacturing processes. If new or higher levels of impurities are detected, you should fully evaluate the impurities and take action to ensure the drug is safe for patients.

在批准工艺变更之前，你们亦未评估是否需要有其它分析方法来确保恰当检出和控制你们缬沙坦API中的非预期杂质。在开发生产工艺并对其做出变更时，你们有义务开发和使用适当的方法来检出杂质。如果检出更高水平杂质或新杂质，你们应对杂质进行全面评估，并采取措施确保药品对于患者来说是安全的。

Your response states that predicting NDMA formation during the valsartan manufacturing process required an extra dimension over current industry practice, and that that your process development study was adequate. We disagree. We remind you that common industry practice may not always be consistent with CGMP requirements and that you are responsible for the quality of drugs you produce.

你们的回复声称预测缬沙坦生产工艺中形成NDMA需要有超出当前行业规范的额外维度，你们的工艺开发研究是充分的。我们不同意此观点。我们提醒你们，通用行业规范可能并不总与CGMP要求保持一致，你们对你们生产的药品质量负有义务。

Your response does not describe sufficient corrective actions to ensure that your firm has adequate change management procedures in place: (1) to thoroughly evaluate your API manufacturing processes, including changes to those processes; and (2) to detect any unsafe impurities, including potentially mutagenic impurities. For FDA’s current thinking on control of potentially mutagenic impurities, see FDA’s guidance document M7(R1) Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk for approaches that FDA considers appropriate for evaluating mutagenic impurities, athttps://www.fda.gov/downloads/Dr ... nces/UCM347725.pdf.

你们的回复并未描述足够的纠正措施，用以确保你们公司具备足够的变更管理程序：（1）彻底评估你们的API生产工艺，包括对这些工艺的变更，以及（2）检出所有不安全杂质，包括潜在诱变性杂质。关于FDA当前对潜在诱变性杂质的控制观点，参见FDA指南文件M7(R1)“评估和控制药品中DNA活性（诱变性）杂质以限制潜在致癌风险”。

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

•      Detailed revised change management procedures describing how your firm will assess and control all impurities, including mutagenic impurities, in API and intermediates manufactured at your facility.

•      修订后的详细的变更管理程序，在其中描述你公司将如何评估和控制在你工厂生产的API和中间体中的所有杂质，包括诱变性杂质

•      Detailed procedures describing how your firm establishes impurity profiles for products manufactured at your firm. These procedures should contain instructions for comparing at appropriate intervals against the impurity profile in the regulatory submission, or for comparing against historical data, to detect changes to the API resulting from modifications in raw materials, equipment operating parameters, or the production process.

•      详细描述你公司如何建立你公司所生产的产品杂质概况的程序。这些程序应包括有按适当的时间间隔将杂质概况与注册资料相比较，或与历史数据进行比较的要求，从而发现由于原料、设备操作参数或生产工艺修改而导致的API变更

•      A retrospective analysis of other API and intermediates manufactured at your firm to determine if they were adequately evaluated for anticipated and unanticipated impurities, including potentially mutagenic impurities.

•      对你公司生产的其它API和中间体的回顾性分析，确定是否这些产品中的预期和非预期杂质有经过充分评估，包括潜在的诱变性杂质  

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 operations and assist your firm in meeting CGMP requirements.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.

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资质的顾问来协助你们公司符合CGMP要求。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。

Quality Systems Guidance 质量体系指南

Your firm’s quality systems are inadequate. For guidance on establishing and following CGMP compliant quality systems, see FDA’s guidances: Q8(R2) Pharmaceutical Development, athttps://www.fda.gov/downloads/drugs/guidances/ucm073507.pdf; Q9 Quality Risk Management, athttps://www.fda.gov/downloads/Drugs/Guidances/ucm073511.pdf; and Q10 Pharmaceutical Quality System, at https://www.fda.gov/downloads/drugs/guidances/ucm073517.pdf.

你公司的质量体系是不充分的。关于建立和遵守CGMP合规质量体系的指南，参见FDA指南Q8（R2）“药物开发”、Q9“质量风险管理”以及Q10“药物质量体系”。

Additional API CGMP guidance 其它API CGMP指南

FDA considers the expectations outlined in ICH Q7 in 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 manufacture of API, athttps://www.fda.gov/downloads/Drugs/.../Guidances/ucm073497.pdf.

FDA在决定API生产是否符合CGMP要求时参考的是ICH Q7中所列要求，参见FDA指南文件Q7“原料药优良生产规范指南”。

Conclusion 结论

Deviations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these deviations, for determining 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。

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) and 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 dependon 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。

FDA placed your firm on Import Alert 66-40 on September 28, 2018.

FDA已于2018年9月28日将你公司放入进口禁令清单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 Zhejiang Huahai Pharmaceutical Co., Ltd., located at Coastal Industrial Zone, Chuannan No. 1 Branch No. 9, Donghai Fifth Avenue, Linhai, Taizhou Zhejiang, 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 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.govor mail your reply to:

Rory K. Geyer

Compliance Officer

U.S. Food and Drug Administration

White Oak Building 51, Room 4235

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Please identify your response with FEI 3003885745.

Sincerely,

/S/

Francis Godwin

Acting Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research

本文摘自 Julia法规翻译

知足123

哦  哦 问题很严重啊

北极的熊猫

这个问题越发酵越严重了

lhd000000

发过了

syhorchid

FDA对浙江华海，应该认真整改！

kakalzx

两次客户投诉，说不得都是美国的客户，然后华海就这样被FDA顺藤摸瓜了

gmy0061

不断学习，失败中成长

ocxen

明摆着老美挖坑让你跳

gdg661837

闹大了吧，全面评估所有预期和非预期的杂质，真是逗，永远都有你现有水平检测不出的东西，既然检测不出你怎么全面评估，而且不排除有检测不出的其他基因毒性，严谨的讲，基因毒性无论含量多少，有一点就有问题，华海这次真的自己有点作死了，人家欧美大企都不敢这样挺身而出。现在就算你有充分的证据证明现有的工艺使得现有产品不存在这个东西，但是人家很明显，现在就是说深挖你之前的产品啊，这不就麻烦大了？

ravenhigh

FDA的职责就是以技术门槛保证大药厂的垄断，俺们的“你妈怕啊”NMPA也在学这个，过了门槛就是美滋滋，过不了就死

hdz0750

过了这一关，华海的质量体系应该会得到较大提高。

懒虫9527

美国FDA是针对华海这点一直不放，反映出华海的产品对美国市场的技术冲击不小。看来老美很怕自己的技术垄断被打破啊。

xqliu

积极应对，不断提高。

快活王

hdz0750 发表于 2018-12-13 09:35
过了这一关，华海的质量体系应该会得到较大提高。

体系估计现在就很好了，主要还是观念要变了，要谨慎了。

时光里的繁星

如果药监部门是以技术门槛确保大企业的垄断，那我是支持的，有了技术门槛才不会有稀奇古怪的玩意和牛鬼蛇神都来插一脚

翻江鼠

lhd000000 发表于 2018-12-12 23:22
发过了

在这个板块吗？

来自安卓APP客户端

天啦噜

质量人在一念之间，千差万别。一个是代表法律监管高高在上，一个是背道而驰，低到尘埃里。

罗伊鲱

The U.S. Foodand Drug Administration (FDA) inspected your drug manufacturing facility,Zhejiang Huahai Pharmaceutical Co.,Ltd., located at Coastal Industrial Zone,Chuannan No. 1 Branch No. 9, Donghai Fifth Avenue, Linhai, Taizhou Zhejiang,from July 23 to August 3, 2018.

美国FDA于2018年7月23日至8月3日检查了你们位于中国浙江省台州市临海市东海第五大道9号的药物制造设施：浙江华海药业川南一分厂。

This warningletter summarizes significant deviations from current good manufacturingpractice (CGMP) for active pharmaceutical ingredients (API).

本警告信总结了原料药（API）生产严重违反CGMP的行为。

Because yourmethods, facilities, or controls for manufacturing, processing, packing, orholding do not conform to CGMP, your API are adulterated within the meaning ofsection 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API根据FDCA第501(a)(2)(B)款21 U.S.C.351(a)(2)(B)被认为是假药。

We reviewed yourAugust 26, 2018, response in detail and acknowledge receipt of your subsequentcorrespondence.

我们详细审核了你们2018年8月26日的回复，并承认收到你的后续信件。

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 of your quality unit to ensure thatquality-related complaints are investigated and resolved.

你的质量部门未能确保质量相关投诉得到调查和解决。

Valsartan API  缬沙坦原料药

Your firmreceived a complaint from a customer on June 6, 2018, after an unknown peak wasdetected during residual solvents testing for valsartan API manufactured atyour facility. The unknown peak was identified as the probable human carcinogenN-nitrosodimethylamine (NDMA). Your investigation (DCE-18001) determined thatthe presence of NDMA was caused by the convergence of three process-relatedfactors, one factor being the use of the solvent (b)(4)). Yourinvestigation concluded that only one valsartan manufacturing process (referredto as the (b)(4) process in your investigation) was impacted bythe presence of NDMA.

在对你工厂生产的缬沙坦API的残留溶剂测试中检测到一个未知峰后，你公司于2018年6月6日收到了客户的投诉。该未知峰被识别为可能的人体致癌物NDMA。你们的调查（DCE-18001）确定，NDMA的存在是3个与工艺有关的因素叠加引起的，其中一个因素是使用了溶剂XX。你的调查结论是，只有一个缬沙坦生产工艺（在调查中称为XX工艺）受NDMA存在的影响。

However, FDAanalyses of samples of your API, and finished drug product manufactured withyour API, identified NDMA in multiple batches manufactured with a differentprocess, namely the (b)(4) process, which did not use the solvent (b)(4). These datademonstrate that your investigation was inadequate and failed to resolve thecontrol and presence of NDMA in valsartan API distributed to customers. Yourinvestigation also failed:

然而，FDA对你的API样品和用你的API生产的制剂样品的检测发现采用不同工艺（即XX工艺，该工艺不使用溶剂XX）生产的多批产品中均存在NDMA。这些数据证明你们的调查是不充分的，未能解决分销给客户的缬沙坦API中NDMA的控制和存在的问题。你们的调查也未能：

·        To include other factors that may have contributed tothe presence of NDMA. For example, your investigation lacked a comprehensiveevaluation of all raw materials used during manufacturing, including(b)(4).

·        包括可能对NDMA的存在有贡献的其它因素。例如，你的调查缺乏对生产中使用的所有原材料的全面评估，包括XX。

·        To assess factors that could put your API at risk forNDMA cross-contamination, including batch blending, solvent recovery andre-use, shared production lines, and cleaning procedures.

·        评估可能使你的API受NDMA交叉污染风险的因素，包括批混合、溶剂回收和重复使用、共用生产线和清洁程序。

·        To evaluate the potential for other mutagenicimpurities to form in your products.  

·        评估在你的产品中形成其它诱变性杂质的可能性。

Ourinvestigators also noted other examples of your firm’s inadequate investigationof unknown peaks observed in chromatograms. For example, valsartanintermediates (b)(4) and (b)(4) failed testing for an unknown impurity (specification≤ (b)(4)%) with resultsof (b)(4)% for both batches. Your action plan indicated that theimpurity would be identified as part of the investigation; however, you failedto do this. In addition, no root cause was determined for the presence of theunknown impurity. You stated that you reprocessed the batches and released themfor further production.

我们的调查人员还注意到你公司对色谱图中发现的未知峰调查不充分的其它例子。例如，缬沙坦中间体XX和XX有2批未知杂质不合格（标准≤XX%），结果为XX%。你的行动计划显示该杂质会作为调查的一部分进行鉴别，但是你没有这样做。此外，亦未确定未知杂质存在的根本原因。你声称你返工了这些批次并放行用于下一步生产。

Your responsestates that NDMA was difficult to detect. However, if you had investigatedfurther, you may have found indicators in your residual solvent chromatogramsalerting you to the presence of NDMA. For example, you told our investigatorsyou were aware of a peak that eluted after the (b)(4) peak invalsartan API residual solvent chromatograms where the presence of NDMA wassuspected to elute. At the time of testing, you considered this unidentifiedpeak to be noise and investigated no further. Additionally, residual solventchromatograms for valsartan API validation batches manufactured using your (b)(4) process, with (b)(4) in 2012 ((b)(4), and (b)(4)) show at leastone unidentified peak eluting after the (b)(4) peak inthe area where the presence of NDMA was suspected to elute.

你的回复声称NDMA很难检出。但是，如果你进行了深入调查，你们可能已经在残留溶剂色谱图中发现指标，提醒你NDMA的存在。例如，你告诉我们的调查人员，你知道缬沙坦API残留溶剂色谱图中XX峰后的一个洗脱峰，那里疑似NDMA洗脱处。在检测时，你们认为这个未识别峰是噪声，未进行深入调查。此外，使用你的XX工艺生产的缬沙坦API验证批的残留溶剂色谱图，以及2012年XX（XX批和XX批）显示在XX峰后NDMA疑似洗脱处至少有一个未识别峰洗脱。

Your responsealso states that you were not the only firm to identify NDMA in valsartan API.In your case, FDA analyses of samples identified amounts of NDMA in valsartanAPI manufactured at your firm that were significantly higher than the NDMAlevels in valsartan API manufactured by other firms. FDA has grave concernsabout the potential presence of mutagenic impurities in all intermediates andAPI manufactured at your facility, both because of the data indicating thepresence of impurities in API manufactured by multiple processes, and becauseof the significant inadequacies in your investigation.

你的回复还声称，你并不是唯一一个在缬沙坦API中发现NDMA的公司。在你的案例中，FDA对样品的分析确定你公司生产的缬沙坦API中的NDMA量显著高于其它公司生产的缬沙坦API中的NDMA水平。FDA严重关注你公司生产的所有中间体和API中可能存在的诱变性杂质，一方面是因为数据显示多种工艺生产的API中存在杂质，另一方面因为你的调查存在严重不足。

In response tothis letter:

在回复此函时：

·        Submit risk assessments for all APIs and intermediatesmanufactured at your facility for the potential presence of mutagenicimpurities.

·        提交一份对你们工厂生产的所有API和中间体出现诱变性杂质可能性的风险评估

·        Provide an update on investigations and CAPA plansinitiated to address the presence of NDMA and other potential mutagenic impuritiesin all APIs manufactured at your firm.

·        提交一份更新后的调查和CAPA计划，启动解决你公司生产的所有API中存在NDMA和其它潜在诱变性杂质的问题。

·        Provide a thorough, independent assessment of youroverall system for investigating deviations, discrepancies,out-of-specification (OOS) results, complaints, and other failures. Inaddition, provide a retrospective review of all distributed batches withinexpiry to determine if your firm released batches that did not conform toestablished specifications or appropriate manufacturing standards.

·        提交一份对你们调查偏差、不符合、OOS结果、投诉和其它失败的整体系统的全面彻底评估。另外，提交一份对所有已销售且仍在有效期内批次的回顾审核，以确定你公司是否有放行不符合既定质量标准或适当生产标准的批次。

·        Provide test results for all (b)(4) andintermediates for the presence of NDMA,N-Nitrosodiethylamine (NDEA), and otherpotentially mutagenic impurities.

·        提交所有存在NDMA、NDEA和其它潜在诱变性杂质的XX和中间体的检测结果。

(b)(4) API  XX原料药

Your firmreceived a customer complaint on September 13, 2016, concerning (b)(4) API batches ((b)(4) and (b)(4)) that exceededthe specification for (b)(4) (≤ (b)(4) ppm). (b)(4) has beenclassified as a probable human carcinogen. Your customer's test resultsconflicted with your (b)(4) test results, which showed the two batches meeting thespecification upon release. Your complaint investigation (CC-16008) identifiedno clear laboratory error, and no anomalies were detected during the productionof the batches. Your investigation failed to evaluate other (b)(4) API batches todetermine if the presence of excess (b)(4) was anadverse trend. For example, (b)(4) batches (b)(4), and (b)(4) were OOSfor (b)(4) because of production errors; however, they were notdiscussed in your complaint investigation.

你公司于2016年9月13日收到一份客户投诉，是关于XX原料药批次XX和XX超出XX标准（≤ XX ppm）。XX被归类为可能的人体致癌物。你客户的检测结果与你的XX检测结果有冲突，你的结果显示2批均符合放行标准。你的投诉调查（CC-16008）确认无明显的实验室错误，也未在批次生产中发现异常。你的调查未能评估其它XX原料药批次，以确定是否过量XX是不良趋势。例如，因为生产错误，XX批次XX和XX是XX的OOS；然而，它们在你们的投诉调查中未被讨论。

Your responsestates that (b)(4) API batches (b)(4) and (b)(4) were returned, reprocessed, and released to customersin non-U.S. markets.

你们的回复声称XX原料药批次XX和XX被退货、返工并放行到非美国市场的客户。

Your response alsostates that in August 2017 you implemented a new (b)(4) test method thatuses a (b)(4)LC-MS/MSmethod, to replace the (b)(4) LC-MS method that was prone to erroneous OOS results.You failed to verify the reliability of the (b)(4) results for all (b)(4) API batches(including (b)(4) batch (b)(4)) originally released using your (b)(4) LC-MS method,which you indicated was inferior to your updated method.

你的回复还声称，在2017年8月你实施了一个使用XX LC-MS/MS方法的新XX检测方法，以代替易于产生错误OOS结果的XX LC-MS方法。你未能确认所有XX API批次（包括XX批次XX）XX结果的可靠性，这些批次最初使用你的XX LC-MS方法放行，你指出该方法不如你更新后的方法。

In response tothis letter, provide:

在回复此函时，请提交

·        A risk assessment for all (b)(4) API batchesmanufactured within expiry.

·        一份对所有生产的仍在有效期内的XX原料药批次的风险评估。

·        A revised complaint handling procedure and details ofany further controls your facility has implemented to ensure that allcomplaints are adequately documented and thoroughly investigated.

·        一份修订后的投诉处理程序和你工厂已实施的任何进一步控制的详细信息，以确保所有投诉都得到充分记录和彻底调查。

·        Procedures for accepting and reprocessing returneddrugs.

·        接受和返工退货药物的程序。

·        Results of (b)(4) testing of all (b)(4) API batchesreleased to the U.S. market using your updated (b)(4)LC-MS/MS (b)(4) test method.

·        使用你更新后的XX LC-MS/MS检测方法对所有放行至美国市场的XX原料药批次的XX检测结果。

2.    Failure to evaluate the potential effectthat changes in the manufacturing process may have on the quality of your API.

未能评估生产工艺中的变更可能对API质量的潜在影响。

In November 2011you approved a valsartan API process change (PCRC - 11025) that included theuse of the solvent (b)(4). Your intention was to improve the manufacturingprocess, increase product yield, and lower production costs. However, youfailed to adequately assess the potential formation of mutagenic impuritieswhen you implemented the new process. Specifically, you did not consider thepotential for mutagenic or other toxic impurities to form from (b)(4) degradants,including the primary (b)(4) degradant, (b)(4). According toyour ongoing investigation, (b)(4) is required for the probable human carcinogen NDMA toform during the valsartan API manufacturing process. NDMA was identified invalsartan API manufactured at your facility.

2011年11月，你们批准了一个缬沙坦API工艺变更（PCRC-11025），其中包括使用XX溶剂。你的意图是改进该生产工艺、提高产品收率和降低生产成本。然而，你们在实施新工艺时未充分评估诱变性杂质形成的可能性。具体而言，你未考虑XX降解物形成诱变性或其它毒性杂质的可能性，包括初级XX降解物XX。根据你们仍在进行中的调查，在缬沙坦API生产工艺中形成可能的人体致癌物NDMA需要XX。NDMA在你工厂生产的缬沙坦API中已被检出。

You also failedto evaluate the need for additional analytical methods to ensure thatunanticipated impurities were appropriately detected and controlled in yourvalsartan API before you approved the process change. You are responsible fordeveloping and using suitable methods to detect impurities when developing, andmaking changes to, your manufacturing processes. If new or higher levels ofimpurities are detected, you should fully evaluate the impurities and takeaction to ensure the drug is safe for patients.

在批准工艺变更之前，你也未能评估是否需要其它分析方法以确保适当地检出和控制缬沙坦API中的非预期杂质。在开发（和变更）生产工艺时，你有责任开发和使用合适的方法以检出杂质。如果检测到新的或更高水平的杂质，你应充分评估杂质并采取措施确保药物对患者是安全的。

Your responsestates that predicting NDMA formation during the valsartan manufacturingprocess required an extra dimension over current industry practice, and thatthat your process development study was adequate. We disagree. We remind youthat common industry practice may not always be consistent with CGMPrequirements and that you are responsible for the quality of drugs you produce.

你的回复声称，预测缬沙坦制造过程中NDMA的形成需要超出当前行业规范的额外维度，并且你的工艺开发研究是充分的。我们不同意。我们提醒你，通用行业规范可能并不总是与CGMP要求一致，并且你对所生产的药物质量负责。

Your responsedoes not describe sufficient corrective actions to ensure that your firm hasadequate change management procedures in place: (1) to thoroughly evaluate yourAPI manufacturing processes, including changes to those processes; and (2) todetect any unsafe impurities, including potentially mutagenic impurities. ForFDA’s current thinking on control of potentially mutagenic impurities, seeFDA’s guidance document M7(R1) Assessment and Control of DNA Reactive(Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Riskfor approaches that FDA considers appropriate for evaluating mutagenicimpurities, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM347725.pdf.

你的回复并未描述足够的纠正措施，以确保你公司具备适当的变更管理程序：（1）彻底评估你们的API生产工艺，包括对这些工艺的变更，以及（2）检出所有不安全杂质，包括潜在诱变性杂质。关于FDA当前对潜在诱变性杂质控制的意见，参见FDA指南文件M7(R1)《评估和控制药品中DNA活性（诱变性）杂质以限制潜在致癌风险》。

In response tothis letter, provide:

在回复此函时，请提交：

·        Detailed revised change management proceduresdescribing how your firm will assess and control all impurities, includingmutagenic impurities, in API and intermediates manufactured at your facility.

·        详细的修订后的变更管理程序，描述你公司将如何评估和控制在你工厂生产的API和中间体中的所有杂质，包括诱变性杂质。

·        Detailed procedures describing how your firmestablishes impurity profiles for products manufactured at your firm. Theseprocedures should contain instructions for comparing at appropriate intervalsagainst the impurity profile in the regulatory submission, or for comparingagainst historical data, to detect changes to the API resulting frommodifications in raw materials, equipment operating parameters, or theproduction process.

·        描述你公司如何为所生产的产品建立杂质概况的详细程序。这些程序应包含规定：按适当的时间间隔将杂质概况与注册资料比较，或与历史数据比较，以发现由于原材料、设备操作参数或生产工艺改变而导致的API变化。

·        A retrospective analysis of other API and intermediatesmanufactured at your firm to determine if they were adequately evaluated foranticipated and unanticipated impurities, including potentially mutagenicimpurities.

·        对你公司生产的其它API和中间体的回顾性分析，以确定是否对预期和非预期的杂质（包括潜在的诱变性杂质）进行了充分评估。

CGMP consultantrecommended  CGMP顾问建议

Based upon thenature of the deviations we identified at your firm, we strongly recommendengaging a consultant qualified to evaluate your operations and assist yourfirm in meeting CGMP requirements. Your use of a consultant does not relieveyour firm’s obligation to comply with CGMP. Your firm’s executive managementremains responsible for fully resolving all deficiencies and ensuring ongoingCGMP compliance.

基于发现的违规行为性质，我们强烈建议你们聘请一位符合21 CFR 211.34要求的顾问来协助你公司达到CGMP要求。使用顾问并不能免除你公司符合CGMP的义务。你公司的高级管理层有责任全面解决所有缺陷，确保持续的CGMP合规性。

Quality SystemsGuidance  质量系统指南

Your firm’s quality systems are inadequate. For guidance onestablishing and following CGMP compliant quality systems, see FDA’s guidances:Q8(R2) Pharmaceutical Development, at https://www.fda.gov/downloads/drugs/guidances/ucm073507.pdf; Q9 QualityRisk Management, at https://www.fda.gov/downloads/Drugs/Guidances/ucm073511.pdf; and Q10Pharmaceutical Quality System, at https://www.fda.gov/downloads/drugs/guidances/ucm073517.pdf.

你公司的质量体系是不充分的。关于建立和遵守符合CGMP标准的质量体系的指南，参见FDA指南Q8（R2）《制药开发》、Q9《质量风险管理》以及Q10《制药质量体系》。

Additional API CGMPguidance  其它API CGMP指南

FDA considers the expectations outlined in ICH Q7 indetermining whether API are manufactured in conformance with CGMP. See FDA’sguidance document Q7 Good Manufacturing Practice Guidance for ActivePharmaceutical Ingredients for guidance regarding CGMP for the manufactureof API, at https://www.fda.gov/downloads/Drugs/.../Guidances/ucm073497.pdf.

FDA在确定API生产是否符合CGMP时考虑ICH Q7中所列的期望。参见FDA指南文件《Q7原料药GMP指南》。

Conclusion  结论

Deviations citedin this letter are not intended as an all-inclusive list. You are responsiblefor investigating these deviations, for determining the causes, for preventingtheir recurrence, and for preventing other deviations.

此函中引用的偏差并不是全部。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，并防止其它偏差的发生。

If you areconsidering an action that is likely to lead to a disruption in the supply ofdrugs produced at your facility, FDA requests that you contact CDER’s DrugShortages Staff immediately, at drugshortages@fda.hhs.gov,so that FDA can work with you on the most effective way to bring youroperations into compliance with the law. Contacting the Drug Shortages Staffalso allows you to meet any obligations you may have to report discontinuancesor interruptions in your drug manufacture under 21 U.S.C.356C(b) and allows FDAto consider, as soon as possible, what actions, if any, may be needed to avoidshortages and protect the health of patients who depend on your products.

如果你们考虑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要求你们立即通过邮箱联系CDER药品短缺办公室，以便FDA可以与你们一起以最有效的方式工作，引导你们的运作符合法律。联系药物短缺办公室还能让你们履行21 U.S.C.356C(b)规定的可能必须报告你们药品生产中断的义务，并让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。

FDA placed yourfirm on Import Alert 66-40 on September 28, 2018.

FDA已于2018年9月28日将你公司列入进口禁令清单66-40中。

Until youcorrect all deviations completely and we confirm your compliance with CGMP, FDAmay withhold approval of any new applications or supplements listing your firmas a drug manufacturer.

在你公司未能完成所有偏差纠正并由我们确认你符合CGMP之前，FDA可以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 tocorrect these deviations may also result in FDA continuing to refuse admissionof articles manufactured at Zhejiang Huahai Pharmaceutical Co., Ltd., locatedat Coastal Industrial Zone, Chuannan No. 1 Branch No. 9, Donghai Fifth Avenue,Linhai, Taizhou Zhejiang, into the United States under section 801(a)(3) of theFD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may besubject to refusal of admission, in that the methods and controls used in theirmanufacture 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根据FDCA第801(a)(3)款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。在同一权力下，产品可能会被拒绝接受，因为在其制造过程中使用的方法和控制措施不符合FDCA第501(a)(2)(B)款21 U.S.C. 351(a)(2)(B)规定意义上的CGMP。

After youreceive this letter, respond to this office in writing within 15 working days.Specify what you have done since our inspection to correct your deviations andto prevent their recurrence. If you cannot complete corrective actions within15 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。

bartonding

gdg661837 发表于 2018-12-13 08:55
闹大了吧，全面评估所有预期和非预期的杂质，真是逗，永远都有你现有水平检测不出的东西，既然检测不出你怎 ...

你这话缺乏一个专业人士应有的公正性，带有明显的个人倾向

gdg661837

bartonding 发表于 2018-12-17 10:15
你这话缺乏一个专业人士应有的公正性，带有明显的个人倾向

那你认为应该如何呢。