FDA给印度生产商Polydrug的警告信内容很不可思议

1、FDA 给印度生产商 Polydrug 的警告信 (内容很不可思议 )April 14, 2016 Mr. Punit Thakrar, ManagingDirectorPolydrug Laboratories Pvt. Ltd. Corporate OfficeA 201-202, Navbharat Estates, Zakaria Bonder RoadSewri (W)Mumbai -400015Maharashtra, India Dear Mr. Thakrar:From March 16-23, 2015, an investigator from the U.S. Food

2、and Drug Administration (FDA) inspected your drug manufacturing facility, Polydrug Laboratories Pvt. Ltd., PlotN-37, Addl. Ambarnath Industrial Area, MIDC, Anand Nagar,Ambarnath (East), Maharashtra, Mumbai.2015 年 3月 1 6-23日，我们 FDA 的调查员检查了你们位于上述地址的生产工厂。We identified significant deviations from curren

3、t good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (API). 我们发现了严重违反原料药 生产 CGMP 的问题。These deviations cause your drugs to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, andCosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(

4、B), in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP.这些问题导致你们生产的药品根据联邦食品药品化妆品法 案 501(a)(2)(B)部分 21 U.S.C. 351(a)(2)(B)被认定为掺假药。We have reviewed your A

5、pril 9, 2015, response in detail and acknowledge receipt of your subsequent respo nse.我们已经详细审核了你们于 2015年4月 9日的回复，并且告知已收到之后的回复。Our investigator observed specific deviations during the inspection, including, but not limited to, the following. 我们的调 查员在检查期间发现的具体违规情况，包括但不限于以下：1. Failure to record and inv

6、estigate all quality-related customer compi aints according to an established p rocedure.未能根据既定程序记录和调查所有与质量相关的客户投诉。During the inspection our investigator found a torn sheet ofpaper titledProduct Quality Complaints” on the floor of your' s official complaint log' s official complaint log.ware

7、house. We compared it to your firm and discovered that only 2 of the 17 customer complaints on the torn sheet were recorded in your firmFurther, your firm indicated that there may be additional unlogged and/or uninvestigated complaints, but did not provide further explanation. Your firm had not inve

8、stigated the complaints we found on the torn sheet. These uninvestigated complaints reported API that were either sub-potent or containedfilth, including the following problems: 在检查期间，我们的调 查员在你们仓库的地面上发现了一张被撕毁的表，标题是产品质量投诉” 。我们将它与你们公司的正式投诉登记本 进行了比较，发现在被撕毁的表上有 17 个投诉，而在公司rH步正式的客诉登记本上只登记了 2 条。还有，你们公司说可能

9、 还有其它没有登记和 /或没有调查的投诉， 但没有做出进 解释。你们公司没有对我们在被撕毁的表上发现的那些投 诉。这些未经调查的投诉报告了原料药效价不达标以及受到 污染的情况。low assay value for (b)(4) API 某原料药含量低 particles and hairs in (b)(4) API 某原料药发现颗粒和头发 an insect and dirt in (b)(4) API 原料药里发现昆虫和脏物 safety goggles in (b)(4)API 原料药里发现护目镜 (b)(4) scoop in (b)(4) API 原料药里 发现料勺Your res

10、ponse stated that you will initiate a corrective action and preventive action (CAPA) plan to include your quality unit 'sassessment of your current p ractices.你们的回复说你们会启动CAPA 计划，其中会包括你们质量部门对现行做法的评估。Your response is inadequate because it is silent on any retrospective investigations conducted for

11、 the 17 complaints that our investigator found on the sheet of paper on your warehouse floor. Your response also did not specify improvements to your complaint handling procedures and documentation practices or efforts to locate and investigate any other unlogged and/or uninvestigated complaints tha

12、t your firm acknowledged could exist .你们的回复是不充分的，因为你们对于我们调查员在你们仓库地面上发现的表上列出的 17 个投诉的回复性调查保 持沉默。你们的回复也没有说明对你们投诉处理程序和记录规范的改进，也没有努力锁定其它未登记和/未调查的投诉，你们公司已知存在的那些投诉。Although the 17 complaints in the unofficial log were not fromU.S. customers, your firm uses shared equipment, personnel, and materials to man

13、ufacture products for multiple markets,' s poor complaintincluding the Un ited States. Your firm handling practices and your inability to prevent and detect product quality defects, such as filth, indicate significant lapsesin your firm's quality system. You are responsible for ensuring that

14、 prior to release your API meet quality and safety requirements and for assuring that any subsequent quality defects are thoroughly investigated. You are also responsible for taking appropriate corrective actions and preventive actions. 虽 然在非正式的登记本上的 17 个投诉并不是来自美国客户， 但你们公司使用了相同的设备、人员和物料来生产药品供给 多个市场，

15、其中包括美国市场。你们公司差劲的客户投诉处理做法，对防止和发现产品质量缺陷如污染的无能为力，显 示出你们公司质量体系的严重失策。你们有责任在放行原料药之前确保其符合质量和安全要求，确保随后的质量缺陷受到彻底调查。你们还有责任采取适当的CAPA。In response to this letter, provide the following: 在回复此信函 时，请提供以下内容： a summary of your investigations of all complaints received since 2012, noting whether each complaint is logg

16、ed in your official complaint log and including root cause determinations and CAPA 你们对所有自 2012 年以来收到的投 诉的调查总结，注意是否每个投诉都登记在你们的正式投诉登记本上，并且包括了对根本原因的确定以及CAPAyourimproved complaint handling procedure and details of any further controls implemented to ensure that all complaints are logged, documented, and

17、 promptly investigated 你们改善过的 客户投诉处理程序，你们为了确保所有投诉都会登记、记录 和尽快调查所实施的所有进一步控制方法2. Failure to review and investigate all production deviations. 未 能审核和调查所有生产偏差Our investigator found a torn page from a batch production record for lot (b)(4) of API(b)(4) in the trash. He noted discrepancies between the disc

18、arded page and the complete batch production record that your firm represented as the official record for that lot. Your firm did not investigate this deviation or the unacceptable practice of discarding a manufacturing record.You did not determine the root cause or assess its effect on drug quality

19、 prior to releasing lot (b)(4). 我们的调查员在垃圾中发 现某原料药某批号批生产记录上撕下来的一页。他注意到被 丢弃的页和你们提供的作为该批次正式记录的完整批生产 记录之间有差异。你们公司没有调查此偏差，也没有调查将 生产记录丢弃这样的不可接受的做法。你们在放行该批次之 前，没有确定根本原因，也没有评估其对药品质量的影响。Your response states that your quality unit is working on a system to record original data at the time it is generated.Howe

20、ver, your response is inadequate because you failed to indicate whether you intend to retrospectively investigate theextent to which your firm's manufacturing records are unreliable,determine root causes, and take necessary corrective actions.Further, you did not note whether your quality unit w

21、ill conduct a thorough review of all batch production records for accuracy and investigate any discre pancies.你们的回复中声称你们质量部门有一个体系可以在数据产生时记录原始数据。但是，你 们的回复是不充分的，因为你们没有说明你们是否准备进行 回顾性调查，延伸至你们公司生产记录不可靠的情况，确定 根本原因，采取必要的纠正措施。还有，你们没有说明你们质量部门是否准备对所有批生产记录进行准确性审核，调查 所有差异。回复中，请提供以下内容：In response to this letter,

22、 provide the following: 在对此信函的a summary of your retrospective investigation of the duplicate batch production records for lot (b)(4) 你们对某批次双份批生记录的回顾性调查总结retrospective review of all batch production records for lots within expiry, including an evaluation of the effect of any discrepancies on API batc

23、h quality 你们对尚在有效期内的所 有批次的生产记录进行回顾性审核，包括所有差异对原料药 批质量影响评估 your CAPA plan describing actions and controls to ensure accuracy and retention of all records including original batch production records 你们的 CAPA 计划， 其中说明为了确保所有记录，包括原始批生产记录，的准确 性和保存所采取的措施和控制方式 documentation that your employees are adequately

24、 trained to complete batch production records contemporaneously and accurately, to investigate production record discrepancies, and to understand the connection between accurate recordkeeping and product quality你们员工受到充分培训，在生产同时同步并准确完成批生产 记录，调查生产记录差异，以及理解准确记录保存和产品质 量之间关联的培训文件记录3. Failure of computeri

25、zed systems to have sufficient controls to p revent unauthorized access or changes to data 计算机化系统 没有充分的控制，无法防止未经授权的进入以及更改数据Your firm 's computer system for entering test results and storing certificates of analysis (CoA), which document whether a drug meets specifications, does not have sufficie

26、nt controls to prevent unauthorized changes to a CoA after quality unit approval. 你们 公司用于输入检测结果和存贮 COA 的计算机系统，其中记录了药品是否符合质量标准，没有充分的控制来防止在质量部门批准之后，未经授权对COA 的改动。During the inspection, our investigator reviewed (b)(4) CoA stored on computer #16, all of which were approved by the quality unit. A manager

27、 demonstrated for our investigator how results on an already finalized CoA could be manipulated after the formal quality unit approval. Also, the quality unit electronic signatures on these CoA were uncontrolled images of signatures rather than certificate-based electronic signatures.在检查期间，我们调查员审核存贮

28、于 16 号计算机的某 COA 时，所有 COA 均经过质量部门批准。一个经理向我们调查员演 结果进行篡改。还有，质量部门在这些 COA 上的电子签名 是非受控的签字图形，而不是经过认证的电子签名。示在正式的质量部门批准之后，如何对已经定稿的COA 的Your response states that your firm plans to implement an enterprise resource planning system. Your response is inadequate because you did not provide sufficient detail about

29、 how this system will prevent unauthorized access or data manipulation, nor did you indicate your timeframe for installing and validating the system. In addition, you failed to review and confirm authenticity of CoA data for products you have already released under the deficient conditions described

30、 above.你们的回复中说， 你们公司计划实施一个 ERP 系统。你们的回复是 不充分的，因为你们没有提供足够细节说明此系统如何防止 非法进入和数据篡改，也没有说明你们安装和验证此系统的 时间框架。另外，你们没有审核和确认你们已经在上述有缺 陷的条件下放行的 COA 数据的权威性。In response to this letter, provide the following: 在回复此信函 时，请提供以下内容： a CAPA plan for controlling access to computer systems for all laboratory and manufacturi

31、ng records and equi pm ent 一份CAPA计划，说明如何控制所有化验室、 生产记录和设备用计算机系统的权限 your firm 's plan to establish, issue, and strictly control access to your manufacturing and laboratory systems 你们的公司建立、签发 和严格控制你们生产和实验室系统权限的计划 a detailed summary of your steps to train personnel on the proper use ofcomputerized s

32、ystems 一份详细的总结， 说明你们培训员工正 确使用计算机化系统的步骤4. Failure to have appropriate test procedures to ensure that API conform to established standards of quality and/or purity. 没有适当的测试程序来确保原料药符合既定的质量和/或纯度标准。Our investigator found numerousinvalid ” moisture contentresults while reviewing data from the Karl Fischer

33、Potentiometer (Tiamo 2.3 software). These results, generated from July 2012 to March 2015, indicate either a quality problem or an inadequate moisture content test method. Correctly measuring water content is especially important because excess moisture in your API can lead to quality defects such a

34、s chemical degradation and/or microbial growth. 我们的调查员在 审核 KF 滴定仪（ TIAMO2.3 软件）的数据时发现大量“无效”水份含量结果。这些结果产生于2012 年 7 月至 2015 年3 月期间，要是显示是质量有问题，要么是水分测试方法不 充分。正确测定的水分结果尤其重要，因为你们原料药中超 量的水份可能会导致质量缺陷，如化学降解和 /或微生物滋生。During the inspection and in your written response, you referredto the invalid assay results

35、asout of specification” (OOsay that your staff failed to report the invalid results becausethey were not aware of the reporting and documentation requirements. You also say that you are revising your OOSP rocedure.在检查期间以及在你们书面回复中，你们将无效的 含量结果称为“超标（00S）”结果。你们说你们员工没有 将无效结果报告上来，因为他们不明白报告和记录的要求。你们还说你们正在修订你们的 00S 程序。Your response is inadequate because, although you conducted a failure investigation, you did not provide us with sufficientinvalid ” resultdetail about your investigation or its findings, such as whether your firm retrospectively investigated the took necessary corrective actions. These