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[FDA药事] FDA警告信——华海 缬沙坦

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药士
发表于 2018-12-12 15:50:54 | 显示全部楼层 |阅读模式

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本帖最后由 红茶. 于 2018-12-12 16:08 编辑

10903 New Hampshire Avenue
Silver Spring, MD 20993

Via UPS                                                                                 Warning Letter: 320-19-04
Return Receipt Requested

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.

This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).

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).

We reviewed your August 26, 2018, response in detail and acknowledge receipt of your subsequent correspondence.  

During our inspection, our investigators observed specific deviations including, but not limited to, the following.

1.      Failure of your quality unit to ensure that quality-related complaints are investigated and resolved.

Valsartan 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.

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:

• 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).

• 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.

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

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.

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.
   
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.
      
In response to this letter:


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


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

• 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.

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

(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 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.   

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.

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 updated method.

In response to this letter, provide:

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

• 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.

• Procedures for accepting and reprocessing returned drugs.

• 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.

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

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.

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.

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.

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.

In response to this letter, provide:


• 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.

• 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.


• 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.  
     

CGMP consultant recommended

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.

Quality Systems Guidance

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.

Additional API CGMP guidance

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.

Conclusion

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.

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 depend on your products.

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

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.

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).

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.

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or 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

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药徒
发表于 2018-12-12 16:14:22 | 显示全部楼层
怎么有种。。想重新划分格局失败后,然后被美国人严查了一波导致自己证据不足,被迫停产整顿的感觉

点评

停产那是NMPA的权限范围内,FDA还管不着  详情 回复 发表于 2018-12-12 16:46
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药士
 楼主| 发表于 2018-12-12 15:55:11 | 显示全部楼层
谷歌机翻




通过UPS                                                                                  警告信: 320-19-04
要求退货收据

2018年11月29日
           

杜军先生
执行副总裁
浙江华海药业有限公司
川南沿海工业区1号分行9号
浙江省台州市临海市东海第五大道317016
中国

亲爱的杜先生:

美国食品药品监督管理局(FDA)从7月开始视察位于浙江省台州市临海市东海第五大道9号川南1号沿海工业区的药品生产厂浙江华海药业有限公司2018年8月3日至201日。

该警告信总结了当前良好生产规范(CGMP)对活性药物成分(API)的重大偏差。

由于您的制造,加工,包装或保存的方法,设施或控制措施不符合CGMP,因此您的API在联邦食品,药品部分501(a)(2)(B)的含义内掺假,化妆品法案(FD&C法案),21 USC 351(a)(2)(B)。

我们详细审核了您对2018年8月26日的回复,并确认收到了您随后的信件。  

在我们的检查过程中,我们的研究人员观察到了具体的偏差,包括但不限于以下情况。

1.      质量部门未能确保调查和解决与质量相关的投诉。

缬沙坦API

在您的工厂生产的缬沙坦API的残留溶剂测试中检测到未知峰值后,贵公司于2018年6月6日收到了客户的投诉。未知峰被鉴定为可能的人类致癌物N-亚硝基二甲胺(NDMA)。您的调查(DCE-18001)确定NDMA的存在是由三个与过程相关的因素的收敛引起的,一个因素是使用溶剂(b)(4)。您的调查得出结论,只有一个缬沙坦制造过程(在您的调查中称为(b)(4)过程)受NDMA的影响。

然而,FDA对您的API样品和使用您的API生产的成品药品进行分析,确定了使用不同工艺生产的多批次NDMA,即(b)(4)工艺,该工艺不使用溶剂(b)( 4)。这些数据表明您的调查不充分,无法解决分发给客户的缬沙坦API中NDMA的控制和存在问题。你的调查也失败了:

•包括可能导致NDMA存在的其他因素。例如,您的调查缺乏对制造过程中使用的所有原材料的综合评估,包括(b)(4)

•评估可能使您的API面临NDMA交叉污染风险的因素,包括批量混合,溶剂回收和再利用,共享生产线和清洁程序。

•评估产品中可能形成的其他诱变杂质的可能性。  

我们的研究人员还注意到贵公司对色谱图中观察到的未知峰的调查不充分的其他例子。例如,缬沙坦中间体(b)(4)(b)(4)未能测试未知杂质(规格≤ (b)(4)%),两个批次的结果为(b)(4)%。您的行动计划表明,杂质将被确定为调查的一部分; 但是,你没有这样做。此外,没有确定未知杂质存在的根本原因。您声明您对这些批次进行了再加工并将其发布以供进一步生产。

您的回答表明NDMA很难被发现。但是,如果您进一步调查,可能会在残留溶剂色谱图中找到指示器,提醒您存在NDMA。例如,您告诉我们的研究人员您知道在缬沙坦API残留溶剂色谱图中(b)(4)峰后洗脱的峰,其中怀疑存在NDMA洗脱。在测试时,您认为这个未识别的峰值是噪音,并且不再进行调查。此外,使用您的(b)(4)工艺制造的缬沙坦API验证批次的残留溶剂色谱图,以及(b)(4)在2012年((b)(4)(b)(4)))显示在怀疑存在NDMA的区域中(b)(4)峰之后洗脱至少一个未鉴定的峰。
   
您的回复还指出,您并不是唯一一家在缬沙坦API中识别NDMA的公司。在您的情况下,FDA对样品的分析确定贵公司生产的缬沙坦API中的NDMA含量显着高于其他公司生产的缬沙坦API中的NDMA含量。FDA严重关注您工厂生产的所有中间体和API中可能存在的诱变杂质,这是因为数据表明多种工艺生产的API中存在杂质,并且由于您的调查存在严重不足。
      
回应这封信:


•提交您工厂生产的所有API和中间体的风险评估,以确定是否存在诱变杂质。


•提供调查和CAPA计划的最新信息,以解决贵公司生产的所有API中NDMA和其他潜在诱变杂质的存在。

•对整个系统进行全面,独立的评估,以调查偏差,差异,不合规格(OOS)结果,投诉和其他故障。此外,对到期内的所有分布式批次进行回顾性审查,以确定贵公司是否发布了不符合既定规格或适当制造标准的批次。

•为所有(b)(4)和中间体提供NDMA,N-亚硝基二乙胺(NDEA)和其他潜在诱变杂质的测试结果。  

(b)(4) API

贵公司于2016年9月13日收到客户投诉,涉及(b)(4) API批次((b)(4)(b)(4))超出(b)(4)的规格(≤ ( b)(4) ppm)。(b)(4)已被列为可能的人类致癌物。您的客户的测试结果与您的(b)(4)测试结果相冲突,这表明两批产品在发布时符合规范。您的投诉调查(CC-16008)未发现明确的实验室错误,并且在批次生产过程中未发现任何异常情况。您的调查未能评估其他(b)(4) API批次以确定是否存在过量(b)(4)是一个不利的趋势。例如,(b)(4)批次(b)(4)(b)(4)由于生产错误而成为(b)(4)的OOS ; 但是,在您的投诉调查中没有讨论过它们。   

您的回复表明(b)(4) API批次(b)(4)(b)(4)被退回,重新处理并发布给非美国市场的客户。

您的回复还指出,在2017年8月,您实施了一种新的(b)(4)测试方法,该方法使用(b)(4) LC-MS / MS方法,以取代(b)(4) LC-MS方法,很容易出现错误的OOS结果。您未能验证最初使用您的(b)发布的所有(b)(4) API批次(包括(b)(4)批次(b)(4))的(b)(4)结果的可靠性(4)您指出的LC-MS方法不如您更新的方法。

在回复这封信时,请提供:

•对到期内生产的所有(b)(4) API批次的风险评估。

•修订后的投诉处理程序和您的工厂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。

•接受和再加工退回药物的程序。

• (b)(4)使用您更新的(b)(4) LC-MS / MS (b)(4)测试方法测试发布到美国市场的所有(b)(4) API批次的结果。

2.未能评估制造过程中的变化可能对API的质量产生的潜在影响。

2011年11月,您批准了缬沙坦API工艺变更(PCRC - 11025),其中包括使用溶剂(b)(4)。您的目的是改善制造工艺,提高产品产量并降低生产成本。但是,当您实施新工艺时,未能充分评估诱变杂质的潜在形成。具体而言,您没有考虑到(b)(4)降解物形成诱变或其他有毒杂质的可能性,包括初级(b)(4)降解物,(b)(4)。根据你正在进行的调查,(b)(4)在缬沙坦API制造过程中可能形成可能的人类致癌物质NDMA。NDMA在您工厂生产的缬沙坦API中确定。

您还未能评估是否需要其他分析方法,以确保在您批准更改过程之前,在缬沙坦API中正确检测和控制了未预料到的杂质。在开发和更改制造过程时,您有责任开发和使用合适的方法来检测杂质。如果检测到新的或更高水平的杂质,您应该充分评估杂质并采取措施确保药物对患者安全。

您的回答指出,在缬沙坦制造过程中预测NDMA的形成需要超出当前行业惯例的额外维度,并且您的过程开发研究已经足够。我们不同意。我们提醒您,通常的行业惯例可能并不总是符合CGMP要求,并且您对所生产的药物质量负责。

您的回复没有描述足够的纠正措施,以确保您的公司有适当的变更管理程序:(1)彻底评估您的API制造流程,包括对这些流程的更改; (2)检测任何不安全的杂质,包括潜在的致突变杂质。对于FDA目前关于控制潜在诱变杂质的思考,请参阅FDA的指导文件M7(R1)评估和控制药物中的DNA反应性(致突变性)杂质以限制FDA认为适合评估诱变杂质的方法的潜在致癌风险,https: //www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM347725.pdf

在回复这封信时,请提供:


•详细的修订变更管理程序,描述贵公司如何评估和控制贵厂生产的API和中间体中的所有杂质,包括诱变杂质。

•描述贵公司如何为贵公司生产的产品建立杂质概况的详细程序。这些程序应包含以适当的时间间隔与监管提交中的杂质概况进行比较,或与历史数据进行比较,以检测原材料,设备操作参数或生产过程中的修改导致的API变化的说明。


•对贵公司生产的其他API和中间体进行回顾性分析,以确定是否对预期和未预料到的杂质(包括潜在的致突变杂质)进行了充分评估。  
     

CGMP顾问推荐

根据我们在贵公司确定的偏差的性质,我们强烈建议聘请有资格评估您的运营的顾问,并协助贵公司满足CGMP要求。您使用顾问并不能免除您公司遵守CGMP的义务。贵公司的执行管理层仍然有责任全面解决所有缺陷并确保持续的CGMP合规性。

质量体系指导

贵公司的质量体系不足。有关建立和遵循CGMP合规质量体系的指导,请参阅FDA的指南:Q8(R2)药物开发网址:https//www.fda.gov/downloads/drugs/guidances/ucm073507.pdf ; Q9质量风险管理网址:https://www.fda.gov/downloads/Drugs/Guidances/ucm073511.pdf ; 和Q10药品质量体系网址:https://www.fda.gov/downloads/drugs/guidances/ucm073517.pdf

额外的API CGMP指南

FDA考虑ICH Q7中概述的预期,以确定API是否符合CGMP。有关制造API的CGMP 指南,请参阅FDA的指导文件Q7活性药物成分良好生产规范指南网址https://www.fda.gov/downloads/Drugs/.../Guidances/ucm073497.pdf

结论

本函中引用的偏差并非旨在列为全包列表。您有责任调查这些偏差,确定原因,防止其再次发生,以及防止其他偏差。

如果您正在考虑可能导致您工厂生产的药物供应中断的行动,FDA要求您立即联系CDER的药物短缺工作人员,在drugshortages@fda.hhs.gov,以便FDA可以与之合作您将以最有效的方式使您的运营符合法律规定。联系药物短缺工作人员还允许您履行根据21 USC 356C(b)报告药品生产中断或中断的任何义务,并允许FDA尽快考虑采取的行动(如果有的话)需要避免短缺并保护依赖于您产品的患者的健康。

FDA于2018年9月28日将您的公司置于进口警报66-40。

在您完全纠正所有偏差并确认您符合CGMP之前,FDA可能会拒绝批准您的公司作为药品制造商列出的任何新申请或补充。

未能纠正这些偏差也可能导致FDA继续拒绝进入位于浙江省台州市临海市东海第五大道川南第一分院沿海工业区浙江华海药业有限公司生产的物品。根据FD&C法案第801(a)(3)条,21 USC 381(a)(3)进入美国。在同一权力下,条款可能会被拒绝承认,因为其制造中使用的方法和控制似乎不符合FD&C法案第501(a)(2)(B)节意义上的CGMP。 ,21 USC 351(a)(2)(B)。

收到这封信后,请在15个工作日内以书面形式回复本办公室。指定自检查以来您所做的工作,以纠正您的偏差并防止其再次发生。如果您无法在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。

将您的电子回复发送至CDER-OC-OMQ-Communications@fda.hhs.gov或将您的回复邮寄至:

Rory K. Geyer
合规官
美国食品和药物管理局
白橡树51号楼4235室
10903 New Hampshire Avenue
Silver Spring,MD 20993
美国

请通过FEI 3003885745确认您的回复。

此致
/ S /
弗朗西斯戈德温
代理主任
制造质量办公室
合规办公室
药物评估和研究中心


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药士
发表于 2018-12-12 15:57:46 | 显示全部楼层
吓了一跳,应该停产整改中吧
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药徒
发表于 2018-12-12 16:38:19 | 显示全部楼层
就是随着贸易战开打以来,美国对我们国家的药企检查力度明显加大了,也不用幸灾乐祸,当真正相查你的时候每一家企业都是同一个结局,只看他想不想查死你
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大师
发表于 2018-12-12 16:46:05 | 显示全部楼层
哈里路球球 发表于 2018-12-12 16:14
怎么有种。。想重新划分格局失败后,然后被美国人严查了一波导致自己证据不足,被迫停产整顿的感觉

停产那是NMPA的权限范围内,FDA还管不着
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药师
发表于 2018-12-12 16:48:57 | 显示全部楼层
好像有点回头看的意思
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药徒
发表于 2018-12-12 17:22:12 | 显示全部楼层
山顶洞人 发表于 2018-12-12 16:46
停产那是NMPA的权限范围内,FDA还管不着

谢谢山顶大人指点,又懂了新知识
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药士
发表于 2018-12-12 17:50:06 | 显示全部楼层
您的回答表明NDMA很难被发现。但是,如果您进一步调查,可能会在残留溶剂色谱图中找到指示器,提醒您存在NDMA。例如,您告诉我们的研究人员您知道在缬沙坦API残留溶剂色谱图中(b)(4)峰后洗脱的峰,其中怀疑存在NDMA洗脱。在测试时,您认为这个未识别的峰值是噪音,并且不再进行调查。此外,使用您的(b)(4)工艺制造的缬沙坦API验证批次的残留溶剂色谱图,以及(b)(4)在2012年((b)(4)和(b)(4)))显示在怀疑存在NDMA的区域中(b)(4)峰之后洗脱至少一个未鉴定的峰。
   
您的回复还指出,您并不是唯一一家在缬沙坦API中识别NDMA的公司在您的情况下,FDA对样品的分析确定贵公司生产的缬沙坦API中的NDMA含量显着高于其他公司生产的缬沙坦API中的NDMA含量。FDA严重关注您工厂生产的所有中间体和API中可能存在的诱变杂质,这是因为数据表明多种工艺生产的API中存在杂质,并且由于您的调查存在严重不足。
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药士
发表于 2018-12-12 23:40:21 | 显示全部楼层
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大师
发表于 2018-12-12 23:47:26 | 显示全部楼层
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药徒
发表于 2018-12-13 15:49:44 | 显示全部楼层
这个剧情有点狗血。
重新处理了卖给非美国市场?是投诉后才重视的?
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药徒
发表于 2018-12-18 13:05:54 | 显示全部楼层

你很无聊啊,看到国内的企业被警告,就恨不得别人完蛋吗?为何还要将标题高亮啊,有意思吗

点评

确定这贴是我进行高亮的?确定? 另外,贴警告信就是恨不得别人完蛋?这逻辑谁教的?  详情 回复 发表于 2018-12-18 14:44
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药士
 楼主| 发表于 2018-12-18 14:44:17 | 显示全部楼层
bartonding 发表于 2018-12-18 13:05
你很无聊啊,看到国内的企业被警告,就恨不得别人完蛋吗?为何还要将标题高亮啊,有意思吗

确定这贴是我进行高亮的?确定?

另外,贴警告信就是恨不得别人完蛋?这逻辑谁教的?
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药圣
发表于 2022-8-3 19:06:30 | 显示全部楼层
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