检查员:Justin A, Boyd、Peter E.Baker

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.

你们的质量部门未能确保质量相关的投诉得到调查和解决。

Valsartan API

缬沙坦API

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 of the 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.

贵公司于2018年6月6日收到客户投诉, 此前在你们工厂生产的缬沙坦原料药的残留溶剂检验中检测到未知峰。未知峰被确定为可能的人类致癌物N-硝基二甲胺 (NDMA)。你们的调查 (DCE-18001) 确定NDMA的存在是由三个与工艺相关的因素造成的, 其中一个因素是(b)(4)溶剂的使用)。你们的调查得出的结论是, NMDA的存在只影响了一个缬沙坦制造工艺 (在你们的调查中称为 (b)(4) 过程)。 

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对你们的原料药样品和使用你们的原料药生产的成品进行分析, 确定了使用其他工艺 (即(b)(4) 工艺生产的多个批次中也存在NDMA, 该工艺不使用溶剂(b)(4)。这些数据表明, 你们的调查不充分, 未能解决分发给客户的缬沙坦API中NDMA的控制和存在问题。你们的调查还未能:

• 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).

  包括可能导致NDMA存在的其他因素。例如, 你们的调查缺乏对生产过程中使用的所有原料的全面评估, 包括 (b)(4)。 

• 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.

  评估可能导致原料药面临NDMA交叉污染风险的因素, 包括批混合、溶剂回收和再使用、共线生产和清洁程序。 

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

  评估产品中其他诱变杂质形成的可能性

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.

我们的检查人员还发现贵公司对色谱图中发现的未知峰的调查不足的其他例子。例如, 缬沙坦中间体 (b)(4) 和 (b)(4) 未知杂质的检验不合格(结果:(b)(4)%,标准≤(b)(4)%)。你们的行动计划表示杂质将被确定为调查的一部分;然而, 你们并没有这么做。此外, 没有确定存在该未知杂质的根本原因。你们表示, 你们对该批次进行了重新处理, 并将其放行以进行下一步生产。

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.

你们的回复提到 ndma 很难检测。然而, 如果你们有进一步调查, 也许就可以发现在你们的残留溶剂色谱图中已经预警了 ndma 的存在。例如, 你们告诉我们的检查人员, 你们发现在缬沙坦api 残留溶剂色谱图 (b)(4) 峰后出现疑似ndma的峰。在检验的时候, 你们认为这个未知峰是噪音, 没有进一步调查。此外, 你们使用(b)(4)工艺生产的缬沙坦api 验证批次的残留溶剂色谱图中,在 (b)(4) 峰之后出现至少一个未识别的峰,疑似NDMA。

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 at your facility, both because of the data indicating the presence of impurities in API manufactured by multiple processes, and because of the significant inadequacies in your investigation. 

你们的回复还说, 你们并不是唯一一家在缬沙坦 api 中识别 ndma 的公司。在你们的案例中, fda 对样品的分析发现, 贵公司生产的 valsartan 原料药中的 ndma 含量明显高于其他公司生产的 valsartan 原料药。fda 对你们工厂生产的所有中间体和原料药中可能存在诱变杂质表示严重关切, 这既是因为数据表明原料药中存在由多种工艺制造的杂质, 也是因为在你的调查中的显著不足。

In response to this letter:

回复此函:

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

  对你们工厂生产的所有原料药和中间体进行风险评估, 以确定可能存在的诱变杂质。

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

  提供最新的调查和启动的CAPA计划, 以解决贵公司生产的所有原料药中ndma 和其他潜在的诱变杂质的存在 

• 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.

  提供一份对你们的整个偏差、OOS、投诉和其他失败调查体系的全面、独立的评估。此外, 提供一份对所有已销售的效期内批次的回顾性审查, 以确定贵公司是否放行了不符合既定标准或适当的生产标准的批次。

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

  提供所有 (b)(4) 和中间体关于ndma、n-硝基二乙胺 (ndea) 和其他潜在诱变杂质的检测结果。

(b)(4) API

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 customers 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.   

贵公司于2016年9月13日收到客户投诉, 关于XX API批次XX和xx (b)(4)超出标准 (≤(b)(4)ppm)。(b)(4) 已被列为可能的人类致癌物。你们的 (b)(4) 测试结果显示这两个批次在放行时符合标准,与你们的客户的测试结果相矛盾。你们的投诉调查 (cc-16008) 没有发现明显的实验室错误, 在批生产过程中也没有发现异常。你们的调查未能评估其他 (b)(4) api 批次, 以确定(b)(4)的存在是否为一个不良趋势。例如, 由于生产错误, (b)(4)批次 (b)(4) 和 (b)(4) 为(b)(4)oos;然而, 他们没有在你们的投诉调查中进行讨论。

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.

你们的回复指出, (b)(4) api 批次 (b)(4) 和 (b)(4) 已退货、重新处理并放行至非美国市场的客户。

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) 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 d method.

你们的回复还指出, 在 2017年8月, 你们实施了一种新的 (b)(4) 测试方法, 该方法使用 (b)(4) lc-mms-ms 方法来替代容易出现错误 oos 结果的 (b)(4) lc-ms 方法。你们未能确认最初使用 (b)(4) lc-ms 方法放行的所有 (b)(4) api 批次。

In response to this letter, provide:

回复此函,请提供:

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

  对所生产的所有效期内 (b)(4) 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.

  修订后的投诉处理规程和你们工厂实施的任何进一步控制以确保所有投诉都有充分的文件记录和彻底调查的细节。

• Procedures for accepting and reprocessing returned drugs.

  退货的接收和再处理程序。

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

  使用更新的 (b)(4) lc-mmsms (b)(4) 测试方法对所有放行至美国市场的(b)(4) api 批次的 (b)(4) 测试结果。

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

未能评估生产工艺变更对 api 质量产生的潜在影响。

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, 你们批准了缬沙坦原料药工艺变更 (pcrc-111025), 其中包括(b)(4)溶剂的使用。你们的目的是改进生产工艺, 提高产品产量, 降低生产成本。然而, 当你们实施新工艺时, 你们未能充分评估诱变杂质的潜在形成。具体而言, 你们没有考虑 (b)(4) 降解剂中产生诱变或其他有毒杂质的可能性。根据你们的调查,缬沙坦原料药生产过程中形成可能的人类致癌物 ndma需要(b)(4)。ndma 是在你们工厂生产的缬沙坦原料药中确定的。

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. 

在你们批准工艺变更之前,也没能评估是否需要额外的分析方法用以检测和控制缬沙坦 api 中意外的杂质。你们有责任在生产工艺开发和变更过程中使用合适的方法来检测杂质。如果检测到新的或更高的杂质水平, 应该充分评估杂质, 并采取行动确保药物对患者是安全的。

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.

您回复说, 在缬沙坦生产过程中预测 ndma 的形成需要比当前的行业实践有一个额外的维度, 并且你们的工艺开发研究是充分的。我们不同意这种看法。我们提醒你们,行业一般做法可能并不总是符合CGMP的要求, 你们要对你们生产的药品质量负责。

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, at https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM347725.pdf. 

你们的回复没有描述足够的纠正措施来确保贵公司有足够的变更管理程序以:(1) 彻底评估你们的 api 生产工艺, 包括对这些工艺的变更;和 (2) 检测任何不安全的杂质, 包括潜在的诱变杂质。有关 fda 目前对控制潜在诱变杂质的思考, 请参阅https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM347725.pdf

In response to this letter, provide:

回复此函,请提供:

• 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, at https://www.fda.gov/downloads/drugs/guidances/ucm073507.pdf; Q9 Quality Risk Management, at https://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, at https://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。