【GMP缺陷】g015 FDA对Apotex, Inc.的警告信 （上）（ 2014年6月 ）

2014-07-02 julia翻译 蒲公英

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【GMP缺陷】是国内外GMP认证缺陷或解读集合，前车之鉴是宝贵的财富，但我们也要审慎的接受和学习。（PS：查询GMP缺陷系列文章请在微信回复 g+编号 例如：g001；如需查看全部缺陷文章目录，请在微信回复:g）

CERTIFIED MAIL      

RETURN RECEIPT REQUESTED

June 16, 2014

Jeremy B. Desai, PhD
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President and Chief Operating Officer
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Apotex, Inc.

150 Signet Drive

Toronto, ON, Canada M9L 1 T9

Dear Dr. Desai:

During our January 27, 2014 through January 31, 2014 inspection of your pharmaceutical manufacturing facility, Apotex Pharmachem India Pvt. Ltd. located at Plot # 1A Bommasandra Ind. Area, 4th Phase, Jigani Link Road, Bangalore, India, investigators from the U.S. Food and Drug Administration (FDA) identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs). These deviations cause your APIs to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 USC § 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.

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We have conducted a detailed review of your firm’s response dated February 20, 2014 and note that it lacks sufficient corrective actions. We also acknowledge receipt of your firm's additional correspondence dated April 4, 2014, and May 27, 2014.

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我们审核了你公司签署日期为2014年2月20日的回复，注意到你们的纠正措施不够充分。我们在此也通知你们，我们已收到你公司签署日期为2014年4月4日和5月27日的补充邮件。

Our investigators observed specific deviations during the inspection, including, but not limited to, the following:
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我们的检查人员在检查过程中发现了一些偏差，包括但不仅限于以下：

1.    Failure to maintain complete data derived from all laboratory tests conducted to ensure compliance with established specifications and standards.

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未能维护所有化验室检测所产生的完整数据，因而无法保证与既定规格和标准的符合性。

Your firm lacked accurate raw laboratory data records for API batches shipped by your firm. The inspection revealed that batch samples were retested until acceptable results were obtained. In addition, your quality control (QC) laboratory failed to include complete data on QC testing sheets.  Failing or otherwise atypical results were not included in the official laboratory control records, not reported, and not investigated. For example,
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你公司缺乏你们公司发运的原料药批次的准确的原始检验数据记录。检查显示多批样品被“反复检测直至得到合格结果”。另外，你们QC化验室的检测记录中数据不完整，不合格结果或非正常结果没有包括在正式的化验室检测记录中，没有进行报告，没有进行调查。例如：

·A review of the Gas Chromatograph (GC) electronic records from July 13, 2013, for (b)(4) USP batch #(b)(4)revealed an out-of-specification (OOS) result for the limit of residual solvents that was not reported.  However, the QC test data sheet included passing results obtained from samples tested on July 14, 2013 and July 15, 2013. The inspection documented that your firm discarded sample preparation raw data related to the OOS results. In your response you indicate that the electronic chromatographic data and the weighing log books were available and reviewed during the inspection. However, the raw data and sample preparation information used for the calculation of the test results that were found OOS or disregarded were not in fact available for review.

· 对2013年7月13日XXUSP批次气相色谱的电子记录审核中发现，一个残留溶剂OOS结果没有报告。但是，QC检测数据表中包括了该样品在2013年7月14日和15日检测得到的一个合格结果。检查记录了你们公司丢弃了与OOS结果有关的样品制备原始数据，在你们的回复中，你们说电子色谱数据和称重记录本是有的，并在检查中提供了。但是事实上，在检查过程中，你们并未能提供用于计算OOS检测结果的原始数据和样品制备信息。

·A review of the High Performance Liquid Chromatograph (HPLC) electronic records from July 3, 2013, for(b)(4) batch #(b)(4) revealed an Out-of-Trend (OOT) result. The sample preparation raw data was discarded and not reported. A QC analyst indicated that these results were discarded due to some small extra peaks identified in the chromatogram fingerprint and an unexpected high assay result.  The QC test data sheet reported two new results that were obtained from samples tested on July 4, 2013 and July 5, 2013, using a different HPLC instrument.
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· 对2013年7月3日XX批次的HPLC检测审核发现一个OOT结果。样品制备原始数据被丢弃了，结果没有报告。一个QC化验员说，这些结果之所以被丢弃，是因为在色谱图的指纹区发现一些额外的峰，导致非预期的高含量结果。QC检测数据表报告了2个新的结果，是在2013年7月4日和5日采用另一台HPLC检测得到的。

·A review of the Karl Fischer electronic records from November 21, 2013, for (b)(4) EP batch #(b)(4) revealed an OOS result that was not reported. The passing results reported on the data sheets were generated from another sample tested an hour after the initial OOS results were obtained on the same day, November 21, 2013.

· 对XX EP批号在2013年11月21日的KF电子记录审核发现一个OOS结果没有被报告。在数据表上报告了一个合格的结果，是在首次OOS结果一个小时后同一天（2013年11月21日）对另一份样品检测得到的。

According to laboratory analysts interviewed during the inspection, the common practice was to complete the analysis and to record the sample preparation data only if the results were acceptable. If the results obtained were atypical, a fresh sample was to be prepared and analyzed. The original sample testing was not recorded.  

检查期间化验室的化验员说，他们一般是先完成分析操作，只有结果可以接受时，才记录样品制备数据。如果结果不正常，就会制备另一份样品重新检测，初始的检测就不记录了。

Your firm’s response states that the observations listed in the Form FDA 483 refer to work performed by analysts who did not follow the established procedures found in standard operating procedure (SOP) QC027 “Out of Specification Test Results and Investigation,” SOP QC098 “Laboratory Incidents Investigation and Resolution,” and SOP QA006 “Deviations.” In addition, your response states “[t]he examples cited in this and other observations where additional testing was conducted by the analyst resulted from a number of factors ranging from system suitability parameters not being met to equipment malfunction to available in-process test data results that were inconsistent with release results.”
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你公司的回复声称在FDA483上所列的缺陷是化验员的个人行为，他们没有遵守公司所建立的标准操作程序（SOP）QC027“超标结果调查”、SOP QC098“化验室事件调查和处理”和SOP QA006“偏差”。另外，你们的回复声称“在这个缺陷和其它缺陷中所引用的例子中，化验员进行额外检测是因为很多原因，这些原因从系统适用性参数不符合到设备故障到中控检测结果与放行结果不符合”。

In addition, your response to the FDA Form-483 indicates that your firm identified similar variances from established procedures that occurred in September 2013.  Your response goes on to indicate that, following this discovery, you reviewed data from the month of August 2013, and identified nine additional incidents in which extra testing was performed without maintaining appropriate laboratory records.  You fail to explain why, given these troubling findings, you did not then expand your investigation to discover the full scope of such variances from established procedures. Based on findings from these two months, it would be reasonable to believe that improper variances occurred in prior months as well.
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另外，你们对FDA-483表的回复说，你公司已在2013年9月对已有程序进行了类似变更。你们的回复继续指出，在发现这些之后，你们审核了2013年8月的所有数据，又找到9个进行了额外测试但没有进行适当记录的事件。你们没有解释这是什么原因，对于这些发现的问题，你们没有将调查延伸以发现偏离已有程序的所有情况。基于对这2个月的调查发现，有理由相信在更早的时间段内也有类似情况发生。

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The above examples demonstrate a general lack of reliability and accuracy of data generated by your firm's laboratory, which is a serious CGMP deficiency that raises concerns about the integrity of all data generated by your firm. We are concerned that your laboratory allowed the practice of retesting for GC, HPLC, and Karl Fischer methods without appropriate documentation, justification, and investigation. It is critical that you investigate these data integrity issues and identify the extent of these practices in your laboratory and manufacturing operations as part of a comprehensive data integrity audit. In your response, please also provide copies of the procedures in place that set forth the requirements to review and preserve complete data generated from your operations.

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上述例子说明，你公司化验室所产生的数据普通缺乏可靠性和准确性，这是一个很严重的CGMP问题，使得我们对你公司所产生的所有数据的完整性均有担忧。我们担心你们化验室允许进行GC、HPLC和KF检测项目的复测，且没有适当的记录、判定和调查。你们很有必要对这些数据完整性问题进行调查，找出你们化验室里和生产操作中这些行为的所涉及的范围，作为数据完整性审计的一部分。在你们的回复中，请提供已有程序的复印件，设定审核的要求，保存你们公司操作中所产生的完整数据。

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The failure to create and maintain accurate documentation is a repeat observation reported to your facility during the 2006 and 2010 inspections.

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未能创建和维护准确的记录是2006年和2010年检查中发现的重复缺陷。

2.    Failure to investigate and document out-of-specification results.  

未能对OOS结果进行调查和记录

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For example,

例如

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· Your firm failed to investigate unknown peaks found during the HPLC testing for related compounds of API(b)(4) USP batch #(b)(4).  A reviewer of the raw data reported on the “finished product report review data” worksheet that unknown peaks were observed due to vial contamination. The electronic records indicate that the first analysis performed on August 20, 2013, failed the specification ((b)(4)) limit for both any single unknown impurity ((b)(4)% vs. NMT (b)(4)%) and total impurities ((b)(4)% vs. NMT (b)(4)%).  These OOS results were not reported or adequately investigated, and the raw data was discarded. The sample was re-analyzed on August 21, 2013, at which time it met specifications and the results were recorded. According to a laboratory analyst, the sample preparation printout corresponding to the initial testing (on August 20, 2013) was destroyed.

·你公司未能对原料药XXXUSP批号YYY有关物质HPLC检测中未知峰进行调查。对在“成品报告审核数据”工作表进行原始数据审核的人员报告说未知杂质原因是进样瓶被污染。电子记录显示在2013年8月20日进行了第一次分析，单个未知杂质X%和总杂均不符合标准规定。该OOS结果未进行报告或进行充分调查，原始数据被弃置。在2013年8月21日对样品重新进行了检测，这次样品符合标准规定，结果被记录下来。根据化验员所述，第一次（8月20日）样品制备打印记录已被销毁。

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·Your firm’s investigation of the data from the Empower software identified instances where additional testing was performed but not properly documented in laboratory records. This investigation was limited in scope to only a short timeframe, the month of August 2013, and to only one type of laboratory instrumentation, HPLC. During FDA’s inspection, the QC manager explained that the scope of the risk assessment was limited to the month of August 2013 because he was busy with other laboratory responsibilities. According to your response to the Form FDA-483, some of the corrective actions implemented as a result of this investigation include: re-training of QC analysts, revision of the laboratory incident investigations SOP, and enhancements to the documentation and sample handling practices. As failures to investigate and document OOS results have persisted, it is clear that your corrective actions were not sufficient.

·你公司对EMPOWER工作站数据调查显示，你们做了一些额外检测但并没有在化验室记录本上进行适当的记录。该调查仅局限于一个较短的时间段，即2013年8月期间，局限于单一种检测仪器，即HPLC。在FDA检查中，QC经理解释说风险评估的范围局限于2013年8月这一个月是因为他忙于化验室的其它事务。根据你们对FDA483表格的回复，你们根据调查结果实施了一些纠正措施，包括：对QC化验员进行重新培训、修订化验室事故调查SOP、加强记录和样品处理操作管理。但对未调查和记录OOS结果的情况仍在持续，很显然你们的纠正措施并不充分。

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·  An email chain from December 26, 2013 to January 21, 2014, reviewed during the inspection, discussed an unexpected unknown peak observed in the residual solvents release test for (b)(4) batches (b)(4) and (b)(4).  Your firm acknowledged during the inspection that SOP QC 098/01 “Laboratory Incident Investigation and Resolution” was not followed. During the inspection, a Quality Control manager stated that this incident was not investigated and resolved because this was an unknown peak and no failure had been identified.

·在检查中审核了从2013年12月26日至2014年1月21日一系列的电子邮件，其中讨论了在XX批和YY批放行检测残留溶剂项目中发现了意外的未知峰。在检查期间你们公司说你们没有按照SOP QC 098/01“化验室事件调查和处理程序”进行调查。在检查期间，一个QC经理说该事件未经过调查和处理，因为这是一个未知峰，不认为这是一个事件。

Your management failed to prevent the practices of product sample retesting without investigation, and rewriting and/or omission of original CGMP records persisted without implementation of controls to prevent data manipulation.

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你们管理层未能防止未经调查即对产品样品进行复测，以及重新书写和/或忽略原始CGMP记录事件反复发生，未能实施控制以防止对数据篡改。

Your firm’s response to the Form FDA-483 acknowledges the deficiencies regarding data integrity observed during this inspection. Nevertheless, your firm’s health hazard evaluation “Drug Safety Analysis” conducted in response to the Form FDA-483 concluded that there was no effect on product quality or patient safety.  However, this evaluation was based on unreliable and incomplete data, as undesired records appear to be excluded. For instance, your report failed to include all of the batches tested, and did not list all of the customers you notified other than Apotex, Inc.  Your response to the previous 2010 inspectional findings stated that “We are confident that … SOPs covering OOS … and Deviation … will provide the necessary control over the system to ensure consistent application and on-going compliance to this requirement.” However, you clearly failed to detect and investigate the inaccurate data found by our investigators during this recent inspection.

你公司对FDA483表的回复中说明了关于本次检查中发现的数据完整性缺陷，你们公司在回复FDA483表时所做的卫生安全评估“药品安全性分析”做出结论说对产品质量或患者安全没有影响。但是，该评估是基于不可靠不完整的数据所得出的结论，不符合结论的记录显然未被包括在评估中。例如，你们的报告未能包括所有被检测的批次，未能列出除APOTEX公司以外的其它被通知的客户。你们在对2010检查缺陷的回复中声明“我们相信……SOP包括OOS……和偏差……能给系统进行必要的控制，以保证持续应用和符合该要求”，而在此次最近的检查中，显然你们未能发现并调查我们在检查中所发现的不准确数据。

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