[GMP] 最新: FDA给印度药厂'Sri Krishna'的警告信(节译) - 仍然是数据完整性...

Your Preferred Partner to Compliance

April 1, 2016 

Dr. V.V. Subba Reddy

Chairman

Sri Krishna Pharmaceuticals Ltd. - Unit II

A-35, IDA, Nacharam

Hyderabad, Andhra Pradesh

India

 

Dear Dr. Reddy:

 

The U.S. Food and Drug Administration (FDA) inspected your pharmaceutical manufacturing facility, Sri Krishna Pharmaceuticals Ltd. - Unit II, located at A-35, IDA, Nacharam, Hyderabad, Andhra Pradesh, India, from December 1- 4, 2014. Our investigator identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211.

美国FDA于2014年12月1-4日检查了你们公司位于上述地址的工厂。我们的调查员发现你们公司严重违反21CFR210和211部分CGMP要求。

These violations cause your drug products 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.

这些违规行为使得你公司生产的药品根据法规被界定为掺假药品。

We reviewed your firm’s response dated December 24, 2014, in detail and note that it lacks sufficient corrective actions. We also acknowledge receiving additional correspondence from your firm.

我们已详细审核了你们公司于2014年12月24日发出的回复，注意到回复缺乏充分的纠正措施。我们同时通知你们已收到你公司发出的其它回复信函。

Our investigator observed specific violations during the inspection, including, but not limited to, the following:

我们的调查员在检查期间发了的一些具体违规行为包括但不仅限于以下内容：

1. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).

你公司未能确保化验室记录包括所有测试中的完整数据，这些数据是确保产品符合既定质量标准所必须的 (21 CFR 211.194(a))。

Your laboratory records did not contain all raw data generated during each test for finished drug products manufactured at your firm. Your quality unit relied on incomplete records to make batch release decisions in support of regulatory submissions to the Agency.

你们的化验室记录未包括你公司生产的制剂成品各检测中所产生的所有原始数据。你们的质量部门依赖于不完整的记录做出了批放行决定，以此支持给药监当局的法规申报。

During the inspection, your management acknowledged that employees in your QC laboratories conduct trial HPLC injections prior to the injections submitted as the reported test results. These trial injection data files were stored on separate drives from the reported test result data. In some cases original data files were deleted. The results from these trial injections and other original data were not reported. Our investigator found the following examples:

在检查中，你们管理层说你们QC化验室的员工在报告作为申报资料的结果进校之前进行了HPLC试针。这些试针数据文件存贮在一个与所报告的检测结果数据不同的盘内。有些时候原始数据文件被删除了。这些试针以及其它原始数据未被报告。我们调查人员发现了以下例子：

a. A QC analyst injected eleven identically or similarly named samples for impurity and assay analysis approximately one to fifteen seconds apart from one another, according to the HPLC audit trail for (b)(4) DMF submission batches (b)(4) and (b)(4). A second analyst injected eight similarly named impurity and assay samples approximately twelve to sixteen seconds apart, according to the HPLC audit trail for the analysis of(b)(4) batches (b)(4) and (b)(4). Neither analyst reported all results obtained during testing. The laboratory incident reports concluded the first analyst deleted 28 original files due to pressure fluctuations and ghost peaks, while the second analyst deleted original trial injections of working standard and sample testing data due to a problem associated with peak shape. However, your laboratory incident reports provide no evidence to support these conclusions. Both analysts also changed the clock prior to reanalyzing the samples.

根据某DMF申报批次XX和YY的HPLC审计追踪，一个QC化验员进了11针同样或类似命名的含量和杂质样品，相互时间间隔为1-15秒左右。根据某产品批次XX和YY的HPLC审计追踪，另一个化验员进了8针类似命名的杂质和含量样品，时间间隔约为12-16秒。两个化验员都没有报告检测期间获得的所有结果。化验室事件报告结论是第一个化验员删除了28个原始文件，因为压力波动和鬼峰，而第二个化验员删除了工作对照品进样原始试针数据和样品测试数据，因为有一个和峰形有关的问题。但是，你们化验员事件报告没有提供支持这些结论的证据。两个化验员还在重新检验样品之前改了电脑时间。

b. A QC analyst injected sample P140818008.lcd for the assay analysis of (b)(4)(batch (b)(4)) prior to the reported sample injections. The “trails” [sic] folder where the original sample injection file was saved had been deleted. Your response acknowledges that an analyst deleted eight injections, including the blank, six standards, and a sample.

一个QC化验员在进样所报告的样品之前，进针某样品做含量分析。保存原始样品进样文件的“试针”文件夹被删除了。你们回复说一个化验员删除了8针进样，包括一针空白，6针对照和1针样品。

c. A QC analyst deleted original test method validation data and admitted plans to fabricate sample preparation data. According to the HPLC audit trail, on October 7 and 8, the QC analyst injected two sets of similarly named samples of (b)(4)(#1:P141007001.lcd and #1:P 141007001.lcd) for an impurity analysis method validation study. Your analyst deleted data from the first set of injections and submitted only the second set in the validation documentation. The analyst stated that he planned to back-date the preparation data within the worksheets once all testing was complete. However, aside from balance scale tickets, your firm was unable to provide sample preparation data for either sample. Your response states that you abandoned the method validation study, but you continue to use that method for routine testing. In response to this letter, provide the method validation study that supports your current method for analyzing impurities in (b)(4).

一个QC化验员删除了检验方法验证原始数据，承认本来计划要伪造样品制备数据。根据HPLC审计追踪，10月7日和8日，该QC化验员进了2套命名相似的样品，是同一个杂质分析方法验证的研究。你们化验员将第一套进样数据删除了，在验证文件中只提交了第二套数据。化验员说他计划在所有测试完成后，按原始记录来倒调时间。但是，除了天平打印数据，你们公司没能提供两个样品的样品制备数据。你们的回复说你们废弃了这个方法验证研究，但你们还是使用了该方法用于日常检测。在对此信函的回复中，请提供方法验证研究来支持你们目前对某产品的杂质分析方法。

d. You did not include metadata with audit trails in your (b)(4) data back-up. In November 2014 the system for HPLC #025 crashed and lost all data collected on the instrument, including audit trail information. We acknowledge that you have implemented(b)(4) and (b)(4) system back-ups. In your response to this letter, provide a copy of the associated procedures and details on how the back-ups are performed.

你们没有将元数据和审计追踪包括在你们某产品的数据备份中。在2014年HPLC第025号中，仪器上崩溃，所有数据均丢失，包括审计追踪信息。我们知道你们已实施了某系统的备份，请提供一份相关程序的复印件，详细说明如何实施备份。

e. Prior to October 2014, your gas chromatography instrument sent injection data to PCs without audit trails. The instrument logbook documented analyses that did not appear in the audit trail after your firm said it turned on the audit trail function. Your response does not explain the missing injection data. In response to this letter, compare the logbook and the audit trail and provide an explanation for the discrepancies identified during the inspection.

在2014年10月之前，你们的GC仪器将进样数据发送到没有审计追踪的电脑里。仪器日志文件记录了在审计追踪中未出现的检测，该检测是在你们公司说你们激活审计追踪功能之后 。你们的回复没有解释为什么缺失了进样数据。在对此信函回复时，请将日志与审计追踪进行比较，解释检查中会发现这些的不符合。

f. A QC analyst injected sample (b)(4)141119009 for the assay analysis of (b)(4)batch (b)(4), prior to the reported sample injection. The trial injection was stored in the “trails” [sic] folder located on a personal computer. The release chromatogram identified injection (b)(4)141119009 as the sample. The trial and release chromatograms for (b)(4)141119009 do not match, and they identify different peaks. Your response concluded trial injection (b)(4)141119009 was a blank. However, the chromatogram for(b)(4)141119009, collected during the inspection, shows (b)(4) peaks. You do not explain or provide evidence for how you concluded that this injection was a blank. Furthermore, your response includes a chromatogram for trial injection (b)(4)141119009 that differs from the chromatogram our investigator collected. It appears to have been reintegrated; the y-axis scale was changed, and only two of the original (b)(4) peaks can be seen.

一个QC化验员进了某样品的含量分析样品，而报告的是之后检验结果。试针结果被存贮在“试针”文件夹中，位于一个个人电脑中。放行图谱显示是某批号的样品。试针和放行图谱并不相符合，它们显示出不同的峰。你们回复结论说试针是一针空白。但是，在检查期间收集的该批图谱显示出XX峰。你们没有解释，也没有提供证据说明你们如何得出此针是空白的结论。还有，你们的回复中结论说该批次的试针图谱与我们调查员收集的并不一样。看起来重新进行了积分，Y轴标尺被改了，只能看到2个原始的峰。

When analysts delete nonconforming test results, the quality unit is presented with incomplete and inaccurate information about the quality of the products. None of your explanations justify your failure to maintain complete records, nor do they support your practice of repeating tests or deleting test results.

在化验员删除不合格的检测结果时，质量部门获得的是不完整不准确的产品质量信息。你们的解释都没有论述你们未能维护完整的记录，你们的解释也不能支持你们重复检测和删除检测结果的做法。

2. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).

你们公司未能对计算机和相关系统实施适当的控制，以确保只有经过授权的人员才能对主生产和检验记录及其它记录进行更改 (21 CFR 211.68(b))。

During the inspection, our investigator reviewed data from your high performance liquid chromatography (HPLC) analysis for release testing, including assay and impurity testing. Your quality control analysts used administrator privileges to change the controls for the time and date settings and manipulate file names to overwrite injections and delete original HPLC test data. Analysts also routinely turned HPLC audit trails on and off. Your response acknowledges these practices.

在检查期间，我们调查员审核了你们用于分析检测的HPLC分析的数据，包括含量和杂质检测。你们的质量控制化验员使用了管理员权限更改日期和时间，以及改变文件名覆盖进样文件，删除原始HPLC检测数据。分析员还在常规性地打开和关闭HPLC审计追踪。你们的回复承认了这些做法。

During the inspection the investigator also noted the following examples of uncontrolled access to electronic systems used to generate data:

在检查期间，调查员还注意到以下未受控登录产生数据的电子系统的例子：

a. None of the (b)(4) HPLC instruments in your QC laboratory required user-specific log-in names and passwords. Analysts routinely logged in as “Admin” without a password. Your response failed to provide a detailed description of the user roles and responsibilities associated with each instrument in your QC laboratory. In your response to this letter, provide procedures that address user roles and associated privileges for your laboratory instruments.

你们QC化验室里所有HPLC仪器均不需要用户使用各自登录名和密码。化验员日常以管理员名称登录，不需要密码。你们的回复未能提供一份详细你们化验室中每台仪器的用户身份和职责描述。在你们对本信函的回复中，请提供你们说明化验室仪器用户身份和相关权限设置的程序。

b. Laboratory data generated by the Karl Fischer autotitrator was not restricted. The program used to run your autotitrator, Tiamo? 2.3 Light, is unable to record audit trails and cannot support accounts with unique user names and passwords for individual users. We acknowledge your commitment to upgrade to a compliant software package. However, your response is inadequate because you failed to provide an interim solution prior to its installation. In your response to this letter, provide a copy of the performance qualification and training activities associated with the newly purchased software.

KF自动滴定仪产生的化验室数据不受限制。用于运行你们的自动滴定仪的程序，TIAMO2.3，不能记录审计追踪，不能支持各用户使用唯一用户名称和密码账号登录。我们知道你们承诺升级至符合要求的软件包。但是，你们的回复是不充分的，你们未能提供在该软件安装之前的临时解决方案。在你们对此信函的回复中，请提供一份新采购的软件的性能确认复印件以及相关培训活动的复印件。

c. Your analysts created separate folders on personal computers to store data from trial HPLC injections. For example, during the inspection, our investigator found a data folder labeled “trails” [sic]. In response to this letter, provide an assessment of the content of these folders and an evaluation of results that may not have been investigated.

你们化验员在个人电脑上创建了单独的文件夹，用来存贮HPLC试针数据。例如，在检查期间，我们调查员发现一个数据文件夹标识为“试针”。在对此信函的回复中，请提供一份对此文件夹内容的评估，一份可能没有被调查的结果的评估。

We acknowledge your commitment to set up user access restrictions, discontinue the practice of trial injections, and to institute audit trails for computerized systems. Simply activating audit trail functions and instituting user controls are insufficient to correct the broad data manipulation and deletion problems observed at your facility and to prevent their recurrence. Your response is inadequate because the functions and administrative privileges of the IT Head, QC Head, and other personnel remain unclear.  In your response, clarify the specific user roles and associated privileges for each laboratory system, and provide an assessment of the effectiveness of these newly implemented system controls. Also provide a comprehensive assessment of other updates made to your computerized systems.

我们知晓你们承诺要设立起用户登录限制，不再延续试针的做法，对计算机化系统实施审计追踪。仅是激活审计追踪功能和设置用户控制是不充分的，不足以控制在你们公司发现的广泛的数据修改和删除问题，无法防止其再次发生。你们的回复是不充分的，因为IT负责人、QC负责人和其它人员的职责和管理权限仍不清楚。在你们的回复中，请说明每个化验室系统中具体的用户身份以及相关的权限，并提供一份这些新实施的系统控制的有效性评估。还要提供一份对你们的计算机化系统进行的其它更新的全面评估。

3. Your firm failed to follow written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess, and to document same at the time of performance (21 CFR 211.100(b)).

你们公司未能遵守生产和工艺控制的书面程序，这些控制是设计来确保你们生产的药品具有其应有的鉴别、剂量、质量和纯度，未能在实施工艺时即行记录 (21 CFR 211.100(b))。

Our investigator discovered that your firm was destroying original batch records and backdating revised replacement pages. For example, our investigator found original pages from five (b)(4) batch records (batches (b)(4) to (b)(4)) discarded outside your facility. Your quality control unit approved revised and backdated master batch record pages that your firm created to replace the discarded pages. The original data were subsequently transcribed and backdated to the time of production. Quality and production managers allowed this practice.

我们调查员发现你们公司销毁了原始批记录，倒签日期在修订后的替换页上。例如，我们调查员发现某批记录的原始页XX至YY批被弃于你们工厂外。你们的质量控制部门批准了修改过的倒签日期的主批记录页，你们公司用这些页来替代被丢弃的页。原始数据誊写过了，倒签日期至生产的时间。质量和生产经理允许了此种做法。

Your response indicated that your firm would not permit backdating in the future and that you would revise procedures to ensure reissued batch record pages are documented in the incident report register and a change control would be initiated for any minor editorial changes. In response to this letter, provide copies of the revised procedures and an assessment of how widespread the practice of revising and backdating batch records is.

你们的回复说你们公司将来不再允许倒签日期了，你们会修订程序来确保如果必要，会重新签发批记录页，报告登记簿，并针对所有小的编辑性更改都启动变更控制。在对本信函的回复中，请提供修订后程序的复印件，以及一份评估说明修订和倒签批记录的做法有多普遍。

4. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

你们公司未能为生产和工艺控制建立充分的书面程序，这些控制是设计来确保你们生产的药品具有其既定或理应具备的鉴别、剂量、质量和纯度的 (21 CFR 211.100(a))。

Your firm said that it initiated a “prospective” process performance qualification protocol to establish the suitability of alternate manufacturing equipment for the manufacture of (b)(4). However, the process qualification protocol was not approved or implemented, and the samples needed to demonstrate batch uniformity were never collected and tested.  As a result, you shipped to the United States (b)(4) batches ((b)(4) to(b)(4)) that were manufactured using the unvalidated process with new equipment.

你们公司说你们启动了一个工艺“前”验证方案来证明替代的某产品生产设备的适用性。但是，工艺验证方案并没有经过批准和实施，用来证明批均一性的样品都没有被采集和检测。因此说，你们发往美国的XX批次YY产品是采用新的设备使用未经验证的工艺生产的。

Your firm responded that it will perform a “retrospective” validation using process step-monitoring data and finished product results for (b)(4) batches. Your response is inadequate. Process validation, including process qualification, is necessary beforecommercial distribution. You have not explained why manufacturing steps and critical process parameters listed in the validation report do not always match those in your protocol. Your firm failed to plan, design, and execute adequate process validation, and was not in accord with sound pharmaceutical development or quality risk management principles. In response to this letter, provide the prospective process performance qualification protocol and report, if completed.

你们公司回复说你们 使用工艺步骤监测数据和成品检测结果实施了一个“回顾性”验证。你们的回复是不充分的。工艺验证，包括工艺确认，必须是在商业批销售之前进行。你们没有解释为什么列在验证报告中的生产步骤和关键工艺参数不能保持与你们方案中所列的相符合。你们公司未能计划、设计和实施充分的工艺验证，不符合合理的药品研发 和质量风险管理原则。在对此信函回复时，请提供前验证工艺性能确认方案，如果已完成的话，还要提供报告。

FDA’s guidance document on Process Validation: General Principles and Practices may help you understand our current thinking on approaches to process validation. The guidance is available at http://www.fda.gov/downloads/Drugs/Guidances/UCM070336.pdf.

FDA关于工艺验证的指南文件可能会有助于你们们理解FDA目前的关于工艺验证的考虑。在上述网址可以下载。

Your firm acts as a contract manufacturer for various drug products. FDA considers contractors as extensions of the manufacturer’s own facility. Your failure to comply with CGMP may affect the quality, safety, and efficacy of the products you manufacture for your clients. There was no evidence that you notified your customers of the manufacturing changes discussed above so that your clients could respond accordingly by, for example, assessing the need to perform stability studies or submit regulatory filings. It is important that you notify your customers of significant problems or discrepancies you encounter during the testing and/or manufacturing of their products. This includes, for example, promptly notifying customers of a significant production problem that could interrupt supply or potentially pose a hazard to the consumer.

你们公司是多个药品的合同生产商。FDA认为合同商是生产商自身工厂的延伸。你们未能符合CGMP，这可能会影响为你 们客户生产的药品的质量、安全性和有效性。没有证据表明你们已通知了你们的客户关于上述所讨论的生产变更，因此你们的客户可能需要相应地，例如，评估是否需要实施稳定性研究，以及是否需要提交法规申报资料。非常重要的一点，你们要通知你们客户你们在生产和/或检测客户药品期间所面临的严重问题和差异。这包括，例如，主动通知客户严重的生产问题，可能会中断供应或对消费者具有潜在危险。