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 April 14, 2016
Mr. Punit Thakrar, Managing Director
Polydrug Laboratories Pvt. Ltd. Corporate Office
A 201-202, Navbharat Estates, Zakaria Bonder Road
Sewri (W)
Mumbai – 400015
Maharashtra, India
Dear Mr. Thakrar:
From March 16-23, 2015, an investigator from the U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Polydrug Laboratories Pvt. Ltd., Plot N-37, Addl. Ambarnath Industrial Area, MIDC, Anand Nagar, Ambarnath (East), Maharashtra, Mumbai.
2015年3月16-23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 current 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, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(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 April 9, 2015, response in detail and acknowledge receipt of your subsequent response.
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 investigate all quality-related customer complaints according to an established procedure.
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 of paper titled “Product Quality Complaints” on the floor of your warehouse. We compared it to your firm’s official complaint log and discovered that only 2 of the 17 customer complaints on the torn sheet were recorded in your firm’s official complaint log. Further, your firm indicated that there may be additional unlogged and/or uninvestigated complaints, but did not provide further explanation. Your firm had not investigated the complaints we found on the torn sheet. These uninvestigated complaints reported API that were either sub-potent or contained filth, 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，而在公司正式的客诉登记本上只登记了2条。还有，你们公司说可能还有其它没有登记和/或没有调查的投诉，但没有做出进一步解释。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。
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low assay value for (b)(4) API
某原料药含量低
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particles and hairs in (b)(4) API
某原料药发现颗粒和头发
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an insect and dirt in (b)(4) API
原料药里发现昆虫和脏物
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safety goggles in (b)(4) API
原料药里发现护目镜
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(b)(4) scoop in (b)(4) API
原料药里发现料勺
Your response stated that you will initiate a corrective action and preventive action (CAPA) plan to include your quality unit’s assessment of your current practices.
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 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 that 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 from U.S. customers, your firm uses shared equipment, personnel, and materials to manufacture products for multiple markets, including the United States. Your firm’s poor complaint handling practices and your inability to prevent and detect product quality defects, such as filth, indicate significant lapses in your firm’s quality system. You are responsible for ensuring that 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，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：
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a summary of your investigations of all complaints received since 2012, noting whether each complaint is logged 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CAPA
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your improved complaint handling procedure and details of any further controls implemented to ensure that all complaints are logged, documented, and 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 discarded 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 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. However, your response is inadequate because you failed to indicate whether you intend to retrospectively investigate the extent 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 will conduct a thorough review of all batch production records for accuracy and investigate any discrepancies.
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。
In response to this letter, provide the following:
在对此信函的回复中，请提供以下内容：
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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
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a retrospective review of all batch production records for lots within expiry, including an evaluation of the effect of any discrepancies on API batch 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
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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
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documentation that your employees are adequately 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 computerized systems to have sufficient controls to prevent 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 sufficient 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 demonstrated for our investigator how results on an already finalized CoA could be manipulated after the formal quality unit approval. Also, the quality unit’s 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示在正式的质量部门批准之后，如何对已经定稿的COA的结果进行篡改。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。
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 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 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：
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a CAPA plan for controlling access to computer systems for all laboratory and manufacturing records and equipment
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
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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
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a detailed summary of your steps to train personnel on the proper use of computerized systems
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 numerous “invalid” moisture content results while reviewing data from the Karl Fischer 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 as 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 referred to the invalid assay results as “out of specification” (OOS). You say that your staff failed to report the invalid results because they were not aware of the reporting and documentation requirements. You also say that you are revising your OOS procedure.
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（OOS）”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OOS程序。
Your response is inadequate because, although you conducted a failure investigation, you did not provide us with sufficient detail about your investigation or its findings, such as whether your firm retrospectively investigated the “invalid” results or took necessary corrective actions. These problems have persisted for approximately three years without adequate resolution.
你们的回复是不充分的，因为尽管你们实施了失败调查，但你们没有给我们提供关于你们调查的细节和调查所发现的问题，例如，是否你们公司对“无效”结果进行了回顾性调查，以及有没有采取必需的纠正措施。这些问题持续了近三年都没有充分地解决掉。
In response to this letter, provide the following:
在对本信函的回复中，请提供以下内容：
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an evaluation of all laboratory methods to determine their suitabitily and copies of all validation reports for methods you will continue to use
对所有化验室方法的评估，以确定其适用性，提供所有你们将要持续使用的方法的验证报告的副本
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an action plan to replace any method found to be unsuitable for its intended use
一份替换所有发现不适合于其既定用途的方法的行动计划
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all original and retest results for moisture content for all API lots within expiry and distributed since 2012
所有仍在有效期内的以及自2012年开始销售的原料药所有批次水分的原始结果和复测结果
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your actions to ensure all laboratory discrepancies, including any OOS or “invalid” results for any API lot within expiry, have been fully documented, investigated, and resolved
你们确保所有化验室差异，包括所有仍在有效期内的原料药批次的所有OOS或“无效”结果，已经充分记录、调查和解决的措施
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your actions to ensure that any future laboratory discrepancies, including OOS or “invalid” results, will be adequately documented and resolved prior to API release for distribution
你们确保所有未来的化验室差异，包括OOS或“无效”结果，在原料药放行销售之前将被充分记录和解决的措施
Conclusion
Deviations cited in this letter are not intended to be an all-inclusive list. You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations.
Your quality system does not securely and reliably retain your manufacturing data and records. We acknowledge your ongoing work with your own subject matter experts to identify root causes of the deficiencies. In addition, we strongly recommend that you engage a third-party consultant with appropriate CGMP expertise to assess your firm’s facilities, procedures, processes, systems and data integrity to ensure the identity, strength, quality, and purity of the API you manufacture.
 
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