FDA发布对IPCA的警告信

julia朱玉姣

2014年，FDA检查了IPCA三个印度工厂，近期FDA发布了对其警告信。以下为节选翻译。

A.    Ratlam facility (FEI: 3002807297)第一个工厂（FEI号3002807297）

1.    Failure to have computerized systems with sufficient controls to prevent unauthorized access or changes to data.

计算机化系统没有充分的控制来防止未经授权的进入或数据更改

During the inspection, FDA investigators discovered a lack of basic laboratory controls to prevent changes to your firm’s electronically stored data. Your firm relied on incomplete records to evaluate the quality of your drugs and to determine whether your drugs conformed with established specifications and standards.

在检查期间，FDA调查员发现缺乏基本的化验室控制来防止你公司电子存贮数据被更改。你公司依赖于不完整的记录来评估你们药品的质量，决定你们的药品是否符合既有质量标准。

Our investigators found that your firm routinely re-tested samples without justification, and deleted analytical data. We observed systemic data manipulation across your facility, including actions taken by multiple analysts, on multiple pieces of testing equipment, and for multiple drugs. You are responsible for determining the causes of these deviations, for preventing recurrence, and for preventing other deviations from CGMP.

我们的调查员发现你公司常规性复测样品，而没有论证，并删除分析数据。我们在你们整个工厂均观察到系统性的数据做假，包括多个化验员在多个检测设备上对多个药品数据进行篡改。你们有责任找到这些偏差的原因，防止这些偏差的重复发生，防止其它CGMP偏差的发生。

During the inspection, our investigators examined the computerized instrumentation and systems you used to conduct chromatographic analyses of your drugs and found that laboratory analysts had PC administrator access that they utilized to manipulate raw data and test results. We found that controls on your computerized chromatographic instrumentation were not adequate to prevent analysts from manipulating processing parameters in order to obtain passing results. We also found that your computerized systems lacked controls to prevent the back-dating of test data.

在检查中，我们调查员检查了你们用来对你们药品进行色谱分析的计算机化仪器和系统，发现化验员具有PC管理权限，他们可以篡改原始数据和检测结果。我们发现你们对计算机化色谱仪器的控制不够充分，不能防止化验员篡改处理参数来获取合格结果。我们还发现你们的计算机化系统缺乏控制，不能防止将测试数据的日期倒签。

For example, we reviewed the (b)(4) API 12-month (b)(4) Commercial Stability assay test for residual solvent by gas chromatography (GC). For batch #(b)(4) US-DMF ((b)(4)), you reported an (b)(4)% result for (b)(4) residual solvent (specification (b)(4)-(b)(4)%) obtained on July 18, 2013.

例如，我们审核了某个原料药第12个月的商业批稳定性测试中气相残留溶剂测试。某批为US-DMF批，你们报告残留溶剂结果为XXX，是在2013年7月18日获得的。

We documented that the original peak had been integrated inconsistently. Standards and samples had been processed using different integration parameters with no documented reason; there were no controls in the software to prevent analysts from manipulating integration settings in order to obtain passing results that you relied on to evaluate the quality of this product. When our investigator asked you to reprocess the chromatograms using appropriate integration parameters, an out-of-specification (OOS) value of (b)(4)% was obtained.

我们记录了积分不一致的原始峰：标准和样品使用了不同的积分参数，并没有记录下原因。这里对软件没有控制，不能防止分析员篡改积分设定来获取合格的结果，而这些结果正是你们赖以评估此药品质量的数据。当我们的调查员要求你们对色谱数据使用适当的积分参数重新处理时，得到的是一个不合格（OOS）结果，计算值为XX%。

In the (b)(4) stability interval assay test of the same API, batch #(b)(4) US-DMF ((b)(4)), you reported an (b)(4)% result for (b)(4) residual solvent (specification: (b)(4)-(b)(4)%) obtained on June 12, 2013. We again found that the original sample peaks had been re-reintegrated inconsistently. There were no controls in the software to prevent the inappropriate manipulation of integration parameters. When our investigator asked you to reprocess the chromatograms using appropriate integration parameters, the result was an OOS value of (b)(4)%.

在XX稳定性时间点，相同原料药的测试中，批号XX的US-DMF规格，你们报告2013年6月12日获得的残留溶剂结果为XX%（质量标准为YY%）。我们再次发现原始样品峰被重新积分，积分参数不同。这里对软件没有控制，无法防止对积分参数的不当修改。当我们的调查员要求你们使用适当的积分参数重新处理色谱图时，结果为ZZ%，是OOS结果。

For the same test, we found that on and after June 18, 2013, the date and time of the chromatographic injections for the (b)(4) stability test appear to have been set back to June 12, 2013. The data was reprocessed to obtain a passing result, upon which you relied to evaluate the quality of this drug.

相同检测中，我们发现在2013年6月18日及之后，XX稳定性测试显示色谱图进样时间被调至2013年6月12日。数据被重新处理以获得合格结果，而你们依赖此结果来评估此药品的质量。

In addition to these examples of computerized systems that permitted inappropriate manipulation of integration parameters and backdating, our investigators also found several instances of computerized data systems that failed to prevent the deletion of original injections. For example, our investigators reviewed the GC audit trail for(b)(4) (finished API batch #(b)(4)) and found that the original sample injection for related substance was on June 4, 2013 at (b)(4). This injection was aborted with no justification and the computerized system that your laboratory used to capture raw data did not retain the original results. The sample was re-injected at (b)(4)., which automatically deleted the original sample result. Passing results from the re-injection were reported for individual and total impurities. You used these incomplete results to evaluate the quality of this drug.

除了这些计算机化系统允许不当的积分参数修订和修改日期的例子外，我们的调查员还发现几个计算机化数据系统未能防止原始进样数据被删除的例子。例如，我们的调查员审核GC审计追踪时（原料药XX批号YY），发现有关物质原始进样时间为2013年6月4日。此进样被中断，并无任何论述，你们化验室用来捕获原始数据的计算机化系统并未保留原始结果。样品在XX重新进样，它自动删除了原始样品结果。根据重新进样所获得的合格结果报告了单杂和总杂。你们使用这些不完整的结果来评估此药品的质量。

The High Performance Liquid Chromatography (HPLC) audit trail for (b)(4) (finished API batch #(b)(4)) shows that the first sample injection for aliquot #2 assay test was on May 28, 2013 at (b)(4). This injection result was deleted without justification. The sample was re-injected at (b)(4). A passing assay result was reported from the re-injection. As with the GC system discussed above, the electronic system your laboratory used to capture HPLC results lacked sufficient controls to prevent the deletion of data without justification, and failed to retain the original data. You relied on these incomplete results to evaluate the quality of this drug.

HPLC审计追踪（XX原料药成品批次YY）显示第2次含量测试首次进样是在2013年5月28日。此次进样结果被删除，没有任何论证。样品被重新进样。重新进样所获得的合格结果被报告。与上述对GC系统的讨论相同，你们化验室用来捕获HPLC结果的电子系统缺乏充分的控制，不能防止没有论证前提下对数据的删除，并且还未能保留原始数据。你们依赖这些不完整的结果来评估此药品的质量。

These practices appear to be commonplace in your analytical laboratory. During the inspection, our investigators spoke with an analyst who reported that “…if we find a failure, we set back the date/time setting and re-integrate to achieve passing results…” The analyst explained that deleting, overwriting, changing integration parameters, and altering PC date and time settings were done for raw materials, in-process testing, and finished API drugs.

这些做法似乎在你们分析化验室里很常见。在检查中，我们的调查员与一位化验员谈话，这位化验员说“……如果我们发现检验不合格，我们就把日期/时间改回去，重新积分，获得合格结果……”。分析解释说，删除、覆盖、改变积分参数、改动电脑日期和时间设定的有原料、中控测试和成品原料药测试。

In your response you stated that the stand-alone chromatographic instruments in the Quality Control and Stability laboratories are no longer under full control of individual analysts and have been connected to a network-based laboratory system. You also acknowledged that you did not identify all instances of data manipulation that may have led to inaccurate conclusions regarding product quality. However, your response still lacks a comprehensive assessment and retrospective review of data generated from all of your computerized laboratory systems. This includes but is not limited to a risk assessment that evaluates all potentially-affected test data.

在你们回复中，你们声称化验员现在不能再全面控制化验室里单独的色谱仪器，这些仪器都被接入了网络化验室系统。你们还说你们没有发现可能会导致关于产品质量的不准确结论的任何数据篡改案例。但是，你们的回复仍缺乏全面评估，和对你们所有计算机化实验室系统中生成的数据的回顾性审核。其中包括但不仅限于对所有可能会受到影响的检测数据的风险评估。

2.    Failure to adequately investigate and resolve critical deviations.

未能对关键偏差进行充分调查和解决

Our inspection documented that your firm’s quality unit was aware of the lack of controls in your computerized systems to prevent the manipulation and deletion of quality-related data. Your site’s senior management failed to take sufficient corrective action and prevent the recurrence of these problems. For example, an anonymous email dated August 5, 2013 notified your quality management about data falsification and manipulation in your laboratory. This email stated: “…[t]here is no control of data in the department…Falsification is going on…Take action as early as possible..." Although you investigated your GC and HPLC equipment, the multi-part investigation that you opened on August 10, 2013 (CD/RTM/QA/001/2013) was incomplete and did not resolve the underlying problems of data falsification and manipulation.

我们的检查文件记录了你们公司质量部分明白你们的计算机化系统缺乏控制，无法防止质量相关数据的篡改和删除。你们工厂的资深管理未能采取足够的纠正措施，未能预防这些问题的再次发生。例如，一份匿名邮件，日期为2013年8月5日提醒你们关于化验室数据篡改和伪造的质量管理问题。该电子邮件说“……在部门里对数据没有控制……在做假……尽快采取措施……”。尽管你们调查了你们的GC和HPLC仪器，你们在2013年8月10日启动的多部门调查（CD/RTM/QA/001/2013）并不完整，没有解决暗藏的数据伪造和篡改的问题。

Phase I: GC Investigation 第一阶段：GC 调查

Your GC Investigation was limited to review of audit trails for batches analyzed on GCs #052 and #202 between January and August, 2013. Although your investigation found multiple examples of deficient data management and retention practices, you concluded that none of the deviations were considered critical. You also concluded that there was no product or patient risk associated with these deviations. You closed this phase of the investigation on November 27, 2013, without implementing effective corrective actions and preventive actions.

你们的GC调查仅限于对GC#052和#202上从2013年1月至8月分析的批号的审计追踪。尽管你们的调查发现多个缺陷数据管理和保存做法的例子，但你们结论说没有偏差是关键的。你们还得出结论说这些偏差没有产品或患者风险。你们于2013年11月27日半面妆了该调查阶段，没有实施有效的纠正和预防措施。

Our investigator reviewed the same data and audit trail records that you included in your own investigation. In the limited time available during the inspection, our investigator found serious deficiencies and questionable data management practices that your own four-month investigation did not identify, including:

我们的调查者审核了你们自己调查中记录的相同数据和审计追踪记录。在检查有限的时间内，我们的调查员发现严重缺陷和值得质疑的数据管理做法，而你们自己在4个月的调查中都没有发现。其中包括：

·         altering time and date settings of computerized equipment using the software administrator’s access privilege

·         使用软件管理者权限更改计算机化设备的日期和时间设置

·         manipulating test integration parameters to obtain passing or desirable results;

·         修改测试积分参数来获得合格或想要的结果

·         aborting on-going sample analyses

·         中断正在进行的样品分析

·         over-writing and deleting raw data files containing original results

·         覆盖和删除含有原始结果的原始数据文件

When presented with the results of our review of these records during the inspection, your QA manager agreed that that these examples, which you had not documented or addressed in your own investigation, were serious deviations from CGMP. Specifically, the manager concurred that these examples would be categorized as “critical” under your own system for assessing deviations.

在检查中，当我们把我们审核这些记录的结果告诉你们时，你们的QA经理认同这些例子，而这些你们都没有记录，也没有在你们自己的调查中进行说明，这是对CGMP的严重违背。尤其是经理同意这些例子根据你们自己的偏差评估系统应该归为“关键”。

julia朱玉姣

Phase II: HPLC Investigation 第二阶段：HPLC调查

Your investigation also considered HPLC data from July to December, 2013. On May 3, 2014, your investigation concluded that good documentation practices were not being followed, and your staff was insufficiently aware of requirements set forth in 21 CFR Part 11.

你们的调查还考虑了2013年7月至12月的HPLC数据。在2014年5月3日，你们的调查得出结论说违背了优良记录规范，你们员工不够明白21CFR第11部分中设定的要求。

Our investigators confirmed these same deficiencies. When reviewing the same HPLC audit trails that you considered in your own investigation, our investigators also found that standard injections were manipulated without scientific justification. Your analyst admitted to us that he had manipulated the standard sequence injections.

我们的调查员确认了这些相同的缺陷。在审核你们调查中所考虑的相同的HPLC审计追踪时，我们的调查员也发现对照品进样被篡改了，而没有科学论证。你们的化验员向我们承认他篡改了对照序列进样。

Our investigator reviewed data from the same July–December 2013 time frame for (b)(4) finished API batch #(b)(4) commercial batch release assay via HPLC. As with the GC data discussed above, although your own lengthy investigation did not capture critical deviations, our investigator’s limited review of this data during the inspection identified data manipulation, including deleted injections, re-injections, and missing injections.

我们调查员审核了在相同时间段时，2013年7月到12月，使用HPLC进行测试的成品原料药XX批号YY商业批次。与上面已讨论的GC数据相同，尽管你们自己冗长的调查并没有发现关键偏差，但我们的调查员在检查期间对这些数据进行有限的审核即发现了数据篡改，包括删除进样、重新进样以及进样缺失。

The investigators also reviewed HPLC data for May, 2013, which was not covered in your investigation. The information reviewed during the inspection identified data manipulation in batches (b)(4) for (b)(4) finished API assay determination, including deleted injections. Again, these deviations and their potential effects on product quality were not covered in your own investigation.

调查员还审核了2013年5月的HPLC数据，这些数据不在你们的调查范围内。检查期间审核的资料说明XX批YY成品原料药含量检测数据伪造，包括删除进样。这些偏差和其对药品质量可能的影响同样也没有被包括在你们自己的调查中。

Your investigation concluded that some chromatograms were manipulated, but it failed to identify the scope or extent of such practices. It lacked sufficient rigor to demonstrate that other laboratory data were not compromised, including data supporting drug applications or stability.

你们的调查得到结论说有些色谱图是篡改过的，但并没有识别出这样做法的范围和深度。它缺乏充分的严谨来证明其它化验室数据没有问题，包括支持药品申报或稳定性的数据。

In your response to this letter, provide the phase 2 investigation into the HPLC systems. Include an assessment of all API batches tested. Also indicate whether senior management is taking appropriate actions in response to critical deviations, such as supporting investigations into possible reported data falsification and manipulation. Provide a status report on these efforts and any actions taken so far.

你们在对此信的回复中，包括了第二阶段对HPLC系统的调查。包括了对所有受测原料药批次的评估。还指出了高级管理人员正采取措施对关键偏差进行回复，例如对可能的被报告数据的伪造和篡改的支持性调查。提供到目前为止所采取的所有措施的这些努力的状态。

Your firm lacks a robust corrective action and preventive action (CAPA) program. Without strong investigation procedures and management support for activities of the quality unit, you cannot consistently identify root causes of product quality failures, rendering it impossible to make adequate corrections. These failures can expose patients to unnecessary risk.

你们公司缺乏强有力的纠正和预防措施程序。没有健全的调查程序，对质量部门的活动没有有力的管理支持，你们不能坚持找出产品质量不合格的根本原因，使得不可能进行充分纠正。这些失败使患者暴露于不必要的风险。

3.   Failure to follow and document laboratory controls at the time of performance; failure to document and explain any departures from laboratory procedures.

在进行检验时未能遵守和记录化验室控制要求，未能记录和解释所有偏离化验室程序的情况。

During the inspection of your microbiology laboratory, our investigators observed multiple examples of your firm’s practice of back-dating and falsifying laboratory data. This laboratory monitors the quality of (b)(4) used in the manufacture of APIs for total plate count as well as the absence of objectionable organisms. Without contemporaneous and accurate data, there is no way for you to ensure that your APIs meet specifications for the absence of objectionable microorganisms.

在对你们微生物化验室的检查中，我们的调查员发现多个例子中你们公司的做法均倒签日期，伪造实验室数据。该化验室监管用于原料药生产的XX的质量，项目为总碟计数以及致病菌不得检出。没有同步记录和准确的数据，你们无法确保你们的原料药符合不得检出致病菌的质量标准。

"Temperature Record" logbooks in microbiology laboratory

微生物化验室的“温度记录”登记本

On July 14, 2014, our investigator noticed that the daily record in the 2-8°C refrigerator #(b)(4) temperature logbook had only been completed up to July 9, 2014. When the investigator requested the logbook later that day, he observed that the logbook had been completed up to July 13, 2014. The entries for July 10–13, 2014, were not present when the investigator initially reviewed the log. When questioned by the investigator, the laboratory analyst responsible for performing these entries stated three times that she had documented the newly-completed temperature values at the time of performance. The same analyst’s supervisor later admitted to directing the analyst to fill out the logbook after the fact. The investigator also observed another analyst actively backdating/back-filling the “Temperature Record” logbook for refrigerator #(b)(4) during the inspection.

在2014年7月14日，我们的调查员注意到2-8度冰箱XX的温度记录本只填写到2014年7月9日。当调查员在那天迟些时候要看这本记录时，他发现记录本已经被写到了2014年7月13日，而2014年7月10-13日的数据当 调查员初次看到时根本都没有。当调查员询问此事时，负责检查记录该温度的化验室分析员说了三次，说实际上刚刚完成的温度值是她在之前按时填写的。后来，该 化验员的主管承诺其指使该化验员在事后填写的记录本。调查员还发现另一个化验员在检查期间，主动地倒签日期，填写YY冰箱的“温度记录”登记本。

(b)(4) Sample Data 样品数据

During the inspection, investigators visually examined the (b)(4) quality and media growth promotion samples (plates) currently in incubation, and compared them with the QC documentation for those samples purported to be in progress (incubation). Your (b)(4) sampling records showed that 45 (b)(4) quality samples had been prepared and incubated on July 9, 2014 ((b)(4), total viable aerobic count) and were in process. During the inspection, three of these plates were not in the incubator, although your (b)(4) sampling logbook recorded the presence of these three plates. QC worksheets for these three plates showed that documentation for the sample preparation and incubation had been created, even though the plates were not actually tested.

在检查期间，调查员目视检查了XX的质量和在培养中的培养基促生长试验样品（碟），将它们与这些样品的QC记录进行了比较。你们XX取样记录显示45YY质量样品是在2014年7月9日制备并开始培养的（总需氧菌计数），当时正在培养中。在检查期间，这些碟中的三个并不在培养箱中，而你们的YY取样登录本中记录了这三只碟。QC对这三只碟的检验记录显示样品制备和培养已经开始，但实际上这些碟甚至都未被检测。

Your management informed the investigators that one microbial plate had been found. However, upon inspection of this plate, the investigator noted that the handwriting was different from all the other microbial plates. After questioning, your microbiologist admitted that the microbial plate was re-created (falsified) to appear as if the sample was complete.

你们管理人员告诉调查员找到了一个微生物碟。但是，在对此碟的检查中，调查员注意到其形态与所有其它微生碟都不相同。在质询之后，你们微生物化验员承认微生物是重新制备（伪造），让其看起来就象样品制备完成一样。

In the 20-25°C and 30-35°C incubation chambers, our investigator reviewed documentation for 117 growth promotion samples. Only 74 samples were in the chambers; 43 were missing. According to your firm’s response, the plates were missing because, during the inspection, you were moving the microbiology laboratory from the(b)(4) floor to the (b)(4) floor. No one mentioned the laboratory move during the inspection.

针对20-25度和30-35度培养箱，我们调查员审核了117个促生产样品记录。只有74个样品在箱内，而43个找不着。根据你们公司的回复，碟找不到是因为在检查期间，你们将微生物实验室从XX层转移到YY层。而在检查期间，并没有人提到实验室转移。
B.     Pithampur (FEI: 3007574780) 第二个工厂

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

你们公司未能确保化验室记录包括从所有确保符合既定规格和标准所必须的所有测试产生的完整数据（21CFR211.194(a)）。

We found documented instances of analytical test results without original data. For example, your raw data is incomplete for GC analysis performed during the (b)(4) method verification for (b)(4) USP (raw material) and (b)(4) (raw material).

我们发现没有原始数据的分析检测结果记录的例子。例如，你们的在XXUSP（原料）和YY（原料）ZZ方法确认中GC原始数据不完整。

(b)(4) tablets (b)(4)mg (b)(4) were tested for (b)(4) by GC on October 9, 2013. The first four injections were overwritten and deleted without justification. They were not available for review.

XX片剂YYmg的ZZ产品于2013年10月9日进行了GC检测。第一次进了4针，其结果被覆盖，没有论证即被删除。没有数据可供审核。

(b)(4) USP (raw material) (b)(4) was tested for (b)(4) by GC on January 8, 2014. The first three injections were overwritten using the same sequence and raw data file path.

XXUSP（原料）YY于2014年8月采用GC测试ZZ项目。第一次进了3针，被使用相同的序列和原始数据文件路径所覆盖。

(b)(4) (raw material) was tested for method verification for (b)(4) content by GC on January 2, 2014. The first five injections were overwritten and deleted.

XX（原料）于2014年1月2日进行YY含量方法确认。第一次5针进样被覆盖和删除。

We also found multiple instances of trial injections of samples. The results of additional tests were reported, but the original (trial) results were not. Chromatograms related to these original test results were overwritten by subsequent testing. No investigation related to these injections was initiated. No other documentation or explanation was provided.

我们还发现多个样品试针的例子。所报告的结果是增加测试的结果，但原始（试验）结果并没有报告。与这些原始测试结果相关的色谱图被随后的检测所覆盖。对这些进样并没有启动相关调查。没有提供其它文件记录或解释。

In your response, you focused on reviewing your data print outs and revising your SOP. Because your quality unit did not review the original electronic raw data, you were unable to detect rewritten, deleted, or overwritten files. Without this information, you have no way to ensure that the tests you use to evaluate the quality of incoming raw materials are accurate or reliable.

在你们回复中，你们集中注意了审核你们的打印出的数据，正在修订你们的SOP。由于你们的质量部门并没有审核原始电子原始数据，你们无法发现重写、被删除或被覆盖的文件。没有这些信息，你们无法确保你们用于评估进厂原料的测试是准确可靠的。

C. Piparia Silvassa (FEI 3005977675) 第三个工厂



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. (21CFR 211.194(a))

你们公司未能确保化验室记录包括从所有确保符合既定规格和标准所必须的所有测试产生的完整数据（21CFR211.194(a)）。

During our inspection, we documented that your QC laboratory was conducting trial injections of samples but failed to report all of the data generated. For example, (b)(4) tablets USP (b)(4) mg (batch # (b)(4) & (b)(4)) were tested for assay and dissolution for finished product stability on June 26, 2013. A total of (b)(4) trial standard injections were performed. Only (b)(4) were submitted for your quality unit review. Your quality unit only reviews the data print out and had not detected your laboratory’s practice of failing to submit all of the data for review.

在我们检查期间，我们记录下你们QC化验室正在进行样品试针，但未报告其中产生的所有数据。例如，XX片剂USP版本YYmg（批号XX和YY）在2013年6月26日测试了制剂稳定性溶出含量。总共有进了XX针试验对照液。只有YY针被提交给你们质量部门审核。你们质量部门只是审核了打印出的数据，没有发现你们化验室并不提交所有数据来审核的做法。

For (b)(4) tablet USP (b)(4) mg (batch # (b)(4)), the first injection (trial injection) began at 2:59 p.m. The official run began (b)(4) after the trial injections, at (b)(4). The 2:59 p.m. injection was not reported, instead the (b)(4)result was reported as the official run.

XX片剂USP版本YYmg（批号ZZ），第一针（试针）开始于下午2:59。正式运行在试针之后，开始于XX。下午2:59的那针的结果并没有报告，所报告的是作为正式运行的XX结果。

Your quality unit must review all analytical data when making batch release decisions. Without complete and accurate information about the quality of the products, your quality unit cannot ensure that the products it releases comply with established specifications and standards for quality. Your response does not demonstrate how your laboratory systems and procedures prevent the deletion of data or how the managers at your facility will ensure that all records relied upon for batch release and other quality-related decisions are complete and accurate.

你们质量部门在进行批放行决策的时候必须审核所有分析数 据。没有关于产品质量的完整和准确信息，你们质量部门无法确保药品的放行符合既定的规格和质量标准。你们回复并未说明你们化验室系统和程序如何来防止数据 删除，你们工厂的管理人员如何来确保所有赖以批放行和其它质量相关决策的记录是准确完整的。

2.  Your laboratory controls failed to establish scientifically sound test procedures to assure that your drug products conform to appropriate standards of identity, strength, quality and purity. (21 CFR 211.160 (b))

你们化验室控制未能建立科学合理的检验程序来确保你们的药品符合适当的鉴别、剂量、质量和纯度标准。(21 CFR 211.160 (b))

During our inspection, we found that on November 24, 2014, the in-house (b)(4) was inoculated withStaphylococcus aureus (gram-positive bacteria)and E. Coli (gram-negative bacteria). The medium showedStaphylococcus aureus growth.

在我们检查中，我们发现在2014年11月24日，内控XX进行金葡菌（革兰氏阳性菌）和大肠杆菌（革兰氏阳性菌）接种。培养基显示为金葡菌生产。

On December 7, 2014, the same media was prepared and challenged with the same microorganisms, and again showed Staphylococcus aureus growth.

在2014年12月7日，制备了相同的培养基，挑战相同的微生物，还是显示金葡萄菌生产。

However, (b)(4) is selective for gram-negative bacteria. It contains an inhibitor for gram-positive bacteria. Therefore, gram-positive bacteria should not grow on (b)(4).

但是，XX具有革兰氏阳性菌选择性。它含有一种革兰氏阳性菌抑制剂。因此革兰氏阳性菌在XX上是不应该生长的。

Your QC data confirmed microbial growth for Staphylococcus aureus in a medium that is intended to inhibit its growth. No investigation was initiated. Despite confirmed microbial growth, this media batch was used for (b)(4)samples.

你们化验室数据确认了金葡菌在一种培养基上有生产，而这种培养基是要抑制其生长的。你们没有启动调查。你们没有理会这些，仍将此培养基批次用于XX样品检测。

Your firm’s response is deficient in that it is limited to the retrospective review of the growth promotion test results generated from January 2014 to December 2014. It lacks an evaluation of the acceptability of your media supplier, the adequacy of laboratory controls, and a determination whether laboratory personnel (including supervisors) are appropriately qualified to detect and correct these deviations. In response to this letter, include a copy of your investigation into this matter, including your root cause determination and CAPA.

你们公司回复是有缺陷的。在回复中，仅仅对2014年1月至12月之间的促生长测试结果进行了回顾性审核。没有对你们培养基供应商的可接受程度、化验室控制的充分程度、你们化验室人员（包括主管）是否具备适当资质来发现和纠正这些偏差进行评估。在对此信的回复中，请包括一份你们对此的调查复印件，其中包括你们根本原因确定和CAPA。

syhorchid

坐沙发

syhorchid

检查真够细致啊

bjlidi

感谢分享

晴天悠悠

版主很及时，谢谢分享。好好研读

Doitasyoulike

生长错打成了生产

七天行健

感谢分享,将会好好研读。

尼采

好好学习

一沙一叶

检查缺陷内容很细。  

曹小芬爱疯叮

学习了，感谢楼主的分享。

孙艳红

全部是实验室问题

zysx01234

天下乌鸦一般黑，国内国外都一样

海阳山山

an anonymous email dated August 5, 2013 notified your quality management about data falsification and manipulation in your laboratory. This email stated: “…[t]here is no control of data in the department…Falsification is going on…Take action as early as possible..."
这一条很匪夷所思，inspector怎么会看到内部的Email呢？

北重楼

说到底还是不想暴露检验结果超标，所以也就隐瞒了数据或者删除数据、选择数据等等，如果检验结果都是杠杠的，谁还会重复测试、删除数据……

xhf123456

很详细，谢谢分享。

cgc717

海阳山山 发表于 2016-2-14 13:35
an anonymous email dated August 5, 2013 notified your quality management about data falsification an ...

是的，怎么会检到Email？内部举报？

冬生傲梅

谢谢楼主分享

fqxiaopei

这种明显是专项检查，有人举报。