警告信-印度太阳制药

一沙一叶

Sun Pharmaceutical Industries Limited - Karkhadi 5/7/14

Warning Letter

警告信



Dear Mr. Subramanian Kalyanasundaram:



During our November 13 through November 16, 2013, inspection of your pharmaceutical manufacturing facility, Sun Pharmaceutical Industries Limited - Karkhadi located at Plot No. 817/A, Village, Karkhadi, Taluka, Padra District, Vadodara, Gujarat, India, investigators from the U.S. Food and Drug Administration (FDA) identified violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211, and deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs). These violations and deviations cause your drug products and APIs to be adulterated within the meaning of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the 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.

检查日期：2013年11月13-16日



We have conducted a detailed review of your firm’s initial response and note that it lacks sufficient corrective actions.  We also acknowledge receipt of your firm's additional correspondence dated January 28, 2014, and March 11, 2014.   

我们对你们公司的首次回复进行了仔细审阅，发现你们的纠正措施不够充分。我们也收到了你们的补充回复，回复日期分别为2014年1月28日和2014年3月11日。



Our investigators observed specific deviations during the inspection of the API manufacturing facility, including, but not limited to, the following:

我们的调查员在对原料药生产场所的检查中发现了一些偏差，包括但不仅限于以下内容：



1.    Failure to ensure that laboratory records included complete data derived from all tests necessary to ensure compliance with established specifications and standards.

未在保证化验室记录包括所有检测中产生的完整数据，无法保证与已有质量标准的符合性。



For example,

例如



a.    Your firm is missing the fundamental raw data and information necessary to document your analyses. For example, these analyses lack the following critical data:

公司缺失分析的基本原始数据和资料。例如，以下关键数据缺失：

identification of the samples tested, including name and source, batch number or other distinctive code, and date of the sample
the complete record of all raw data generated during each test, including graphs and electronic files from laboratory instrumentation
test method used
sample preparation as prescribed by the method, preparation and testing of standards, reagents and standard solutions
records of all calculations performed in connection with the test
test results
the signature of the person who performed each test and the date(s) the tests were performed, and the date and signature of a second person showing that the original records have been reviewed for accuracy, completeness, and compliance with prescribed acceptance criteria
所检样品的识别信息，包括品种、来源、批号或其它可区分的代码，取样日期
在所有检测中产生的所有原始数据的完整记录，包括图谱和化验室仪器产生的电子文件
所用的检验方法
按方法进行样品制备的记录、标准品、试剂和标准溶液的制备和检测
所有与检测相关的计算记录
检验结果
各检验的检验员签名和检测日期，以及对原始记录复核其准确性、完整性和与可接受标准的符合性的第二人签名和日期


This basic analytical information allows for documentation, review, authentication, traceability, quality control and quality assurance at your pharmaceutical firm.

这些基本的分析数据是保证你们制药公司进行记录、审核、确认、追踪、质量控制和质量保证所需的原始资料。



In addition, minimum laboratory control also includes documenting and retaining your system suitability data.   

另外，对化验室进行控制的最低要求也应包括文件记录和对系统适用性数据的保留。



b.    Your firm frequently performs “unofficial testing” of samples, disregards the results, and reports results from additional tests. For example, during stability testing, your firm tested a batch sample six times and subsequently deleted this data.   

你们公司频繁地对样品进行“非正式的检测”，而不管结果如何，也不对额外的检测所得的结果进行报告。例如，在稳定性试验期，你们公司对一个批号的样品检测了6次，随后删除了数据。



Our investigators found your practice of performing initial “trial” sample high performance liquid chromatography (HPLC) analyses prior to acquiring the “official” analyses. The “trial” sample results were subsequently discarded. “Trial” HPLC analyses for (b)(4) USP ((b)(4)) were apparently run as part of the 12-month long-term stability studies on batch #(b)(4) for related substances. The inspection revealed that on August 26, 2011, your employee ran an HPLC analysis sequence with the sample names (b)(4) and subsequently deleted the raw data files.  It was noted that the assigned names for the sequence injections indicates that your quality control staff named the samples using the last three digits of the batch numbers to link the "trial" injections for the batches with the official assay analyses. Your Senior Quality Control (QC) Officer confirmed that these were analyses of batch samples. Furthermore, we found that on August 27, 2011, this batch was analyzed for unknown impurities and the results were reported to be within specifications.  However, the chromatographic data showed that the "trial" injection data for this batch failed the unknown impurities specification of (b)(4)% in multiple cases.  

我们的调查员发现你们在对一个样品进行HPLC“正式”分析前，进行了“试验性”检测。该“试验性”样品结果随后被丢弃。对XXX批的“试验性”HPLC分析显然是XXX批有关物质12个月长稳试验的一部分。检查发现，在2011年8月26日，你们的员工运行了一个HPLC分析序列，样品名为XXX，随后删除了原始数据文件夹。还有，你们的QC人员采用了样品批号的最后三位数字对进样序列进行命名，以便将“试验性”进样与正式含量分析进行链接。你们的资深QC主管确认了这些批号样品的分析。另外，我们发现在2011年8月27日，对该批次进行了未知杂质的检测，结果报告符合质量标准。但是，图谱数据显示该批次“试验性”进样数据在多个结果中均不符合未知杂质的质量标准YYY。



Your Senior QC Officer confirmed that QC laboratory employees had frequently practiced the use of “trial” injections at your facility.   Significantly, in addition to the example above, our inspection found 5,301 deleted chromatograms on a computer used to operate two HLPC instruments in your QC laboratory. Many of these files were “trial” injections of batches.   

你们的资深QC主管确认了QC化验室员工经常在你们的仪器上进行“试验性”进样。除上述例子外，我们检查发现了你们QC实验室的1台控制2台HPLC仪器的电脑上，有多达5301个被删除的色谱图。这些文件多是“试验性”批次进样。



c.    Similar unacceptable data handling practices were observed in your laboratory’s conduct of gas chromatography (GC) analyses. The FDA investigators reviewed what appear to be data from “unofficial” injections for GC analyses for recovered (b)(4) raw material batch #(b)(4). On February 11, 2012, your analyst performed testing on recovered (b)(4) raw material batch #(b)(4) and the sample was within specifications. The following day, February 12, 2012, your analyst ran a GC analysis sequence with the sample names (b)(4) and subsequently deleted the raw data files.  Your staff performed calculations during the inspection, at our request, that showed that these samples did not meet the (b)(4) impurity specification for this material. Therefore, it appears that out-of-specification data for batch #(b)(4) was considered to be “unofficial,” while passing data were reported as the "official" results for the batch.

类似的数据处理情况也在化验室里GC分析中发现。FDA检查员对看似XXX回复物料批号YYY的GC“非正式”进样数据进行了审核。在2012年2月11晶，你们的分析人员对回收原料XXX批号YYY进行了检测，样品符合质量标准。在其后日期：2012年2月12日，你们的分析员又运行了一个GC分析序列，样品名称为XXX，之后删除了原始数据文件。在我们的要求下，你们员工在检查期间对数据进行了计算，结果显示这些样品不符合该物料的杂质标准ZZZ。因此，貌似该批OOT数据被作为是“非正式”的，而符合标准的数据被报告为“正式”结果。



In addition, the inspection revealed numerous examples of deleted GC electronic raw data files on the computer controlling the GC instruments that were replaced with identical “official” chromatogram file names.  The identically named GC data files that were deleted had been created at different times and contained disparate data. Also, it appeared that data was not consistently archived to the central server.   

另外，检查发现在GC电子原始数据文件夹中，有大量数据被删除，然后用了同样的“正式”图谱文件名来替代。被删除的同名GC数据文件是在不同的时间创建的，其中的数据完全不同。还有，这些数据显示并不是连续存档到中央服务器的。



Your response is inadequate in that you did not conduct an adequate investigation into the pervasive practice of deleting files. In the reports provided in your response, you did not identify what criteria you used to designate each type of HPLC and GC data files (e.g. blanks, standards, samples, and system suitability runs). The response does not identify any impurity standards used in your procedures and does not provide the procedures that your firm was using to conduct the “trial” and “unofficial” runs. In addition, your investigation found 47 instances of apparent trial injections of samples for which the results were out-of–specification (OOS), and some of these batches were distributed to the U.S. market. The investigation failed to adequately examine why your analysts hid or deleted these runs. Your response only explains that your firm chose to retest samples from the implicated lots, but does not address the causes of the original OOS results, or justify the basis of your decision to invalidate the original failing result and accept the passing retest result. Such an investigation is necessary for any OOS event. Refer to the FDA’s guidance on OOS investigations Guidance for Industry, Investigating Out-of-Specification (OOS), Test Results for Pharmaceutical Production.

你们的回复不充分。在回复中，你们没有对删除文件这种普遍的作法进行充分的调查。在你们回复所提供的报告中，你们没有识别出准备用什么标准来给每类HPLC和GC数据文件命名（例如，空白、标准、样品和系统适用性运行）。回复中没有识别出用于你们检测程序的所有杂质标准品，没有提供你们公司准备用于实施“试验性”和“非正式”测试的程序。另外，你们的调查发现有47例明显的试验性样品进样，其结果为OOS，其中一些批次已销往美国市场。调查未能充分检查为什么你们的化验员隐藏或删除这些测试。你们的回复只是解释了你们公司选择对相关批次样品进行复测，但没有说明原始OOS结果的原因，或论述你们决定将原始不合格数据认定无效，而接受复测的合格结果的原因。对所有的OOS事件，均需要进行这样的调查。请参见FDA对OOS调查的指南。



The above examples suggest 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 "trial" injections and deletion of both GC and HPLC files to persist without implementation of controls to prevent data manipulation until at least September 2013. Your company’s executive management is responsible for ensuring the quality, safety, and integrity of your products. Implementing adequate controls and systems to prevent manipulation of laboratory data is at the foundation of fulfilling this critical responsibility.

上述例子表明你们公司化验室所生成的数据普遍缺乏可靠性和准确性，这是严重的CGMP缺陷，引起对你们公司所生成数据完整性的质疑。我们关注你们化验室允许“试验性”进样和删除GC和HPLC文件的做法，这表明你们至少到2013年9月止都没有实施控制，防止数据捏造行为发生。你们公司的执行管理人员应负责保证产品的质量、安全和完整性，而实施充分的控制和系统来防止对实验室数据的篡改是履行这个关键职责的根本所在。



2.    Failure to assign and identify raw materials with a distinctive code, batch, or receipt number, and to identify the disposition of materials.

没有对原料给定可以区别的代码、批号或接收编号，未能对原料处理进行识别。



For example, 例如



a.    The investigators observed three partially filled unidentified bags of (b)(4) in your firm's raw material warehouse. Your employees were unable to determine conclusively the identity or status of the material.

检查员在你们公司的原料仓库发现有3个无标识的袋子XXX，均未装满东西。你们员工不能确定这些原料是什么，以及其状态。



b.    The investigators observed numerous unidentified partially filled bags containing what appeared to be (b)(4) in the (b)(4) Room.  The disposition of this unlabeled material was not clear at the time of the inspection.

检查员在XXX房间发现大量未标识的未装满的袋子，看起来像是XXX。检查期间，对这些未标识的物料的所做的处理不清楚。



It is essential that employees adequately label materials as to their identity and status to prevent mix-ups and their unintentional or unauthorized use. In your response, you commit to amend your materials management system to ensure that your employees maintain accurate and adequate labeling of all materials.  In response to this letter, provide evidence that you have implemented these corrective actions. Also, include your training activities for relevant personnel (e.g., staff, managers) to ensure adequate material handling.

最基本的要求，员工应对物料的分成和状态进行充分地标识，以防止混淆，和被不恰当或未经授权地使用。在你们的回复中，你们承诺修订你们的物料管理体系，保证你们的员工坚持准确和充分地标识所有的物料。在对本信的回复中，请提供你们已经实施这些纠正措施的证据。还有，需要包括你们对相关人员进行培训（例如，员工、管理人员）以保证对物料的操作符合要求。



Our investigators also observed significant violations regarding the finished drug product manufacturing operations at your facility, including, but not limited to, the following:

我们的检查员还在你们工厂发现关于成品生产操作若干违规情况，包括但不限于以下内容：



1.    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)).

你们公司未能对电脑及相关系统进行有效适当的控制来保证只有经过授权的人员才能对主生产和控制文件，以及其它记录进行更改。



The investigator identified numerous deleted raw data files on computers used for your GC instruments in your quality control laboratory.  The software (“GC Solutions”) on the computers used to control the GC instruments allowed your analysts to delete files from the computer’s hard drive with no audit trail or other adequate form of traceability in the operating system to document the deletion activity. The software as configured assigned sequential, numerical names to raw data files within the same folder.  When a raw data file was deleted or moved out of the designated folder, the next file recorded into the folder would be saved with an identical name as the deleted file. As a result, data can be manipulated so that saved files appear to be in sequence even if they were not generated sequentially. Due to the basic lack of audit trail and data security, an analyst could delete analytical files without traceability of this unacceptable practice.  

检查员在你们QC实验员，GC所用电脑上发现大量被删除的原始数据文件。用于控制GC的电脑软件（GC Solutions）允许你们的分析人员从电脑硬盘删除文件，且不能对文件删除操作进行审计追踪或其它对操作系统所进行的相似的追踪。当一个原始数据文件从指定的文件夹删除时，存入文件夹的下一个文件可以采用同被删除的文件相同的名称进行保存。这样，数据可能被篡改，即使文件产生并不是顺时序的，但所保存的文件看起来是时序的。由于缺乏基本的审计追踪和数据安全功能，一个分析员可以对分析文件进行不被允许的删除，而不被追踪。

                       

The inspection revealed that you stored GC raw data files in multiple folders on the hard drives in the QC laboratory. Your Senior QC Officer stated you had no written procedure describing the management of GC raw data file storage. According to your firm's electronic data archival SOP IT-001, each QC analyst manually transferred individual raw data files to the central server at (b)(4). Your procedure did not address how this data transfer by QC analysts could be reliably verified, and whether proper computerized system controls will be implemented by your company.

检查发现，你们QC实验硬盘上多个文件夹中所存贮的GC原始文件。你们资深QC主管说，你们没有关于GC原始文件存贮管理的书面程序。根据你们公司的电子数据存档SOP IT-001，每个QC化验室手动将各原始数据转移至XXX中央服务器。你们的程序未说明如何确认QC分析员转移的这些数据是可靠的，你们公司是否准备对计算机系统进行适当的控制。



We acknowledge your firm’s commitment to amend the data handling system of your GC instruments to implement controls that ensure that analyses performed by employees are maintained as accurate, with data integrity and traceability. In your response to this letter, describe your detailed systemic improvements, training activities, and other actions implemented to provide evidence of the effectiveness and sustainability of these changes.

我们收到你们公司的承诺，将会对你们GC仪器的数据处理系统进行补充，以实施控制来保证员工所实施的分析能保持准确、数据完整以及可以追踪。在你的对本信的回复中，要详细描述系统性改进、培训措施，以及其它所实施的行动，提供证据证明这些变更的有效性和持续性。



2.    Your firm failed to maintain written production, control, or distribution records specifically associated with a batch of a drug product for at least one year after the expiration date of the batch (21 CFR 211.180(a)).

你们公司未能维护书面的生产、控制或销售记录，特别是某药品一个批次在有效期后至少1 年有关的记录。



During the inspection, the investigators found approximately 10 waste bags containing torn or partially destroyed raw data CGMP records related to a variety of manufacturing activities. Some of the records found in these waste bags included the following:

在检查中，检查员发现约10个废物袋，其中装有撕烂的或部分损毁的与大量生产活动相关的原始数据CGMP记录，这些记录包括以下内容：



a.    A calibration check record for balance #FI-002 was torn and partially destroyed. Your associate stated that he used the wrong weights when conducting the calibration. He said that he recalibrated the balance and prepared new documentation, and subsequently discarded the original record. Furthermore, we learned that additional original calibration records of other balances had similarly been discarded.

天平#FI-002校正检查记录，被撕烂，部分损毁。你们助理说他采用了错的砝码来校正。他说，他对天平进行了重新校正，准备了新的记录，因此将原来的记录丢弃了。另外，我们发现还有其它天平的原始校正记录也是同样被丢弃了。



b.    Six corrective action and preventive action (CAPA) records (form F03-QA-076/01) were torn. Your Senior Quality Assurance (QA) Officer stated that this form is used for extending the due date of an ongoing CAPA. Our inspection team compared the discarded records to the official records and identified corresponding official copies of only three of the records. The three other discarded records did not have an official corresponding copy.  During the inspection, your firm could not produce official records of the corrective actions described in these three partially destroyed documents.  

6份纠正措施和预防措施记录被撕毁了。你们的资深QA管理员说这个表格是用于延期CAPA的。我们检查团将被丢弃的记录与正式记录进行了比较，发现只有3份记录是与正式记录对应的。另3份丢弃的记录并没有对应的正式记录。在检查期间，你们公司未能做出这3份部分销毁文件中所记录的纠正措施的正式记录。



c.    Five completed preventive maintenance forms were torn. A staff member stated that he mistakenly tore and destroyed these original records.

有5份完整的维保记录被撕毁了，一个员工说他撕错了。



The destruction of CGMP records produced by your firm's manufacturing facility is a serious deficiency that raises concerns about the integrity of all records generated by your firm. There was a lack of basic oversight by operations, quality unit, and site managers, as rewriting and destruction of original CGMP records was allowed to persist over a significant period without implementation of systems and controls to prevent data manipulation.

对你们公司生产场所生成的CGMP文件的销毁是一个非常严重的缺陷，它引起对你们公司产生的所有记录完整性的质疑。在相当长的时间内，一直允许对原始CGMP记录进行销毁和重写，不能防止数据捏造，说明你们缺乏由生产、质量和现场管理人员执行的基本监控。



Your response is inadequate in that your investigation was primarily limited to the discarded CGMP records cited in the Form FDA-483. The investigation did not include a comprehensive review of all records in the waste area or a thorough review of your firm’s practice of destroying CGMP records.  In response to this letter, submit your third party auditor’s report of the investigation of the data integrity practices associated with your CGMP records. This report should include a list of all records that your employees rewrote, destroyed, or altered in any way. In addition, address the root cause of your firm’s failure to control and detect the manipulation, alteration, or premature destruction of CGMP records and describe systemic actions to prevent recurrence. Provide your procedures to manage and retain all CGMP records.

你们的回复是不充分的。在其中，你们的调查只是局限于FDA的483表格上写的所丢弃的CGMP记录上。该调查没有包括对废品区的所有记录的综合审核，或对你们公司的CGMP记录销毁行为的彻底审核。在回复本信时，要提交你们的第三方审计人员与CGMP记录相关的数据完整性调查的报告。该报告应包括你们员工重写、销毁或以其它方式处理的所有记录清单。另外，说明你们公司未能控制和发现捏造、篡改和草率销毁CGMP记录的根本原因，描述系统性防止重复发生的措施。提供你们将用于管理和保留所有CGMP记录的程序。



Also provide a list of all the batches of drug products shipped to the U.S. market and APIs intended for use in drugs to be distributed within the U.S. that relied upon missing, inaccurate, or unreliable records.

还要提供一份依赖于失踪的、不准确的或不可信记录的，所有发运往美国市场的制剂批次清单，以及销往美国的制剂生产用的原料药批次清单。



3.    Your firm failed to ensure that each person engaged in the manufacture, processing, packing, or holding of a drug product has the education, training, and experience, or any combination thereof, to enable that person to perform his or her assigned functions (21 CFR 211.25(a)).

你们公司未能保证每个从事药品生产、处理、包装或保存的人员都经过教育、培训，以及具备经验，或上述要求的综合，以使员工可以从事他或她所被赋予的任务。



For example, you did not train your contract employees in CGMP or in job-specific procedures. In addition, CGMP documents, including procedures and batch records,  apparently could not be fully comprehended by many of the contract employees. Your contract employees conducted critical CGMP operations for your finished drug products such as visual inspection of filled capsules, (b)(4) sealing, 100% verification of sealed bottles, final label quality inspection, outsert pasting on bottle caps, and the final packing in boxes. CGMP training is essential to ensure employees are qualified to perform all operations in compliance with good manufacturing practice.

例如，你们没有对合同制员工进行CGMP培训，或与岗位相关的程序的培训。另外，很明显许多合同员工都不能完全理解CGMP文件，包括程序和批记录。你们的合同员工进行了很多成品的关键CGMP操作，例如目视检查已充填胶囊、XXX封装、已封装瓶的100%确认、最终标签质量检查、瓶盖外贴和最后装箱。CGMP培训的基本要求是保证员工具有相应的资质，可以按GMP要求实施所有操作。



We acknowledge your commitment to amend training procedures for your contract employees to ensure that you adequately train all of them. In response to this letter, provide an update on the implementation of these actions. Also, provide the final investigation report described in your initial response that assesses the deficiencies and their root causes in your training system.  Note that only qualified individuals must conduct training.  Such training must occur on a continuing basis and with sufficient frequency to ensure that employees remain familiar with CGMP requirements applicable to their assigned functions.

我们收到你们承诺对合同员工培训程序进行补充，以保证对他们进行充分的培训。在对本信进行回复时，要提供对实施这些措施的更新情况。还有，提供你的初始回复中提到的最终的调查报告，对培训系统中的缺陷及根本原因进行评估。注意，只有有资质的人员才能对其它人进行培训。培训必须要持续进行，其频次要能保证员工对其工作相关的CGMP要求保持熟悉。



The items listed above, as well as other cited deficiencies, indicate that you have not implemented a robust quality system at your firm. Your corporate management should immediately undertake a comprehensive evaluation of global manufacturing operations to ensure compliance with CGMP regulations. We strongly recommend that you hire a qualified third party auditor with experience in detecting data integrity problems to assist you with this comprehensive evaluation.

上述所列各项，以及其它所引用的缺陷，说明你们没有在公司里实施稳固的质量体系。你们公司管理层应立即对全球生产操作进行综合评估，以保证符合CGMP法规。我们强烈建议你们雇佣一位有资质，具备检查数据完整性问题经验的第三方审计人员，协助你们进行上述综合评估。



You are responsible for the accuracy and integrity of the data generated by your firm. A firm must maintain all raw data generated during each testing and manufacturing operation, including graphs, charts, and spectra from laboratory instrumentation. You must properly identify these records to demonstrate that each released batch was manufactured in accordance with validated parameters, was tested appropriately, and met release specifications.  

你们要对你们公司所产生的数据准确完整性负责。一个公司必须维护在每次检测和生产操作期间产生的所有原始数据，包括化验室仪器生成的图表、图谱、光谱图。你们必须采用合适的方式，识别出这些记录，以证明每个放行批次均是根据验证过的参数生产，经过适当的检测，并符合放行标准。



Appropriate record retention policies should also be in place. Our inspection revealed that your firm destroyed CGMP records directly related to the testing and manufacturing of your products. Your firm should reevaluate your record retention policy for all of your CGMP records. Should product quality or safety concerns arise over the lifecycle of an application, the original records pertaining to batches listed in an application may be integral in providing reasonable assurances to the Agency regarding a product and integrity of data submitted to support it. When destruction of documents is appropriate, you should follow a documented destruction procedure that ensures documents are destroyed in a controlled manner. This would include, at a minimum, identification of the appropriate documents and retention timelines, documentation of what was destroyed, and the names and signatures of those who witnessed the destruction.

还要有适当的记录保存方针。我们的检查揭示你们公司销毁与你们产品生产和检测直接相关的CGMP记录。你们公司应重新评估你们的所有CGMP记录的保存方针。如果在申报的生命周期中发生产品质量或安全问题，申报中列出的批次的原始记录可以给官方提供合理的保证。如果对文件的销毁是恰当的，你们应该遵守书面的销售程序，保证文件在受控情况下销毁。这至少要包括：文件性质和保存时限有识别的识别、销毁的文件内容，监督销毁的人员姓名和签名。



Your data integrity consultant should: 你们的数据完整性顾问应



1.    Identify any historical period(s) during which inaccurate data reporting occurred at your facilities.

要识别出你们工厂报告不准确数据的时间段。



2.    Identify and interview your current employees who were employed prior to, during, or immediately after the relevant period(s) to identify activities, systems, procedures, and management behaviors that may have resulted in or contributed to inaccurate data reporting.

要找你们现有的，在相关时段之间、期间或之后被雇佣的员工，与他们面谈，找出可能导致或对不准确数据报告有影响的活动、系统、程序和管理行为。



3.    Identify former employees who departed prior to, during, or after the relevant periods and make diligent efforts to interview them to determine whether they possess any relevant information regarding any inaccurate data reporting.

要找出在相关时段之前、期间或之后离职的员工，尽力与他们面谈，以确定他们是否知道与不做准确数据报告相关的信息。



4.    Determine whether other evidence supports the information gathered during the interviews, and determine whether additional facilities were involved in or affected by inaccurate data reporting.

要决定是否有其它证据来支持审核期间收集的资料，要决定是否有其它工厂卷入不准确数据报告或受其影响。



5.    Use organizational charts and SOPs to identify the specific managers in place when the inaccurate data reporting was occurring and determine the extent of top and middle management involvement in, or awareness of, data manipulation.

要使用组织机构图和SOP来界定当不准确的数据报告发生时，哪些管理人员是责任人员，并决定到哪一层次的高层和中层管理人员要插手，或知晓数据捏造的问题。



6.    Determine whether any individual managers are still in a position to influence data integrity with respect to CGMP requirements or data submitted to the agency.

要决定是否所有管理人员都有权限对与CGMP有关的或提交官方的数据完整性产生影响。



7.    Expand your internal review to any other facilities determined to be involved in, or affected by, inaccurate data reporting.

要将你们的内部审核延伸到所有涉及不准确数据报告的，或受其影响的工厂。



8.    Include a report that describes in detail the criteria used to determine the identity of the data files generated from the testing of batch, standard, or system suitability samples. The report should include examples of the use of these criteria, as well as identify which data files are standards and samples. In addition, include the procedures followed to prepare samples for system suitability runs (i.e., procedures followed to spike impurities into samples), and to handle product samples and the data files. This assessment should be conducted for both GC and HPLC data.

要包括一份报告，其中详细描述用于决定批检测、标准或系统适用性样品产生的数据文件识别的标准。报告要包括这些标准的使用实例，并识别哪些数据文件是标准和样品。另外，要包括在系统适用性样品制备后的操作程序（即，在样品中加杂质后的操作程序），对产品样品的处理程序以及对数据文件的处理程序。GC和HPLC数据都要进行上述评估。



9.    As part of this comprehensive data integrity audit of your laboratory, your audit report also should include any discrepancies between data or information identified in approved applications, and the actual results, methods, or testing conditions submitted to the Agency. Include an explanation of the impact of all discrepancies. Provide a corrective action plan describing the specific procedures, actions, and controls that your firm will implement to ensure integrity of the data in the future. This should cover method validation and any test data (e.g., stability tests, release tests) you have obtained.

作为对你们化验室综合性数据完整性审计的一部分，你们的审计报告还应包括数据或已批准的申报资料与提交给官方的实际结果、方法或检验条件之间的差异。要包括这些差异所产生影响的解释。要提供一份纠正措施计划，其中包含你们公司将要实施的特定程序、措施和控制，用以保证将来数据的完整性。要覆盖方法验证和所有你们所得到的检验数据（例如，稳定性测试、放行测试）。



The violations and deviations cited in this letter are not intended to be an all-inclusive list of violations and deviations that exist at your facility. You are responsible for investigating and determining the causes of the violations and deviations identified above and for preventing their recurrence and the occurrence of other violations and deviations.

上面所说违规和偏差并不代表你们工厂所有的，你们有责任进行调查并确认原因，并且要组织它们再次发生或其它违规和偏差发生。

If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of finished drug products or active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Program immediately, as you begin your internal discussions, at drugshortages@fda.hhs.gov so that we can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Program also allows you to meet any obligations you may have to report discontinuances in the manufacture of your drug under 21 U.S.C. 356C(a)(1), and allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products. In appropriate cases, you may be able to take corrective action without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.

接到警告信或由于其它原因，如果你们哟考虑决定减少该工厂生产的成品和原料药，那么FDA要求你们联系CDER的药品短缺部门，只有这样我们才能配合你们尽快使你们的操作符合法规要求。同时，你们也是履行了告知21 U.S.C. 356C(a)中药物生产中断的义务，同时允许FDA考虑，他们是否需要尽快采取行动来避免药物短缺，并保护依赖此药物的病人的健康。在一定情况下，你们也许可以不必中断供应或减少中断时间。



Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct and prevent the recurrence of violations, and deviations, and provide copies of supporting documentation. If you cannot complete corrective actions within fifteen working days, state the reason for the delay and the date by which you will have completed the corrections. Additionally, if you no longer manufacture or distribute the drug products and the APIs at issue, provide the dates and reasons you ceased production. Please identify your response with FEI # 3005409363.

收到这封信的15个工作日内，你们要通知办公室，写明为了改正预防违规行为和偏差重复发生而采取的步骤，并提供支持文件。如果无法再15个工作日完成，那么要说明理由和将会完成的日期。另外，如果不再生产和发运产品，那么要提供中止日期和原因。




Please send your reply to:

Joseph Duran

Compliance Officer

转载Julia博客

了了.

希望转载更多的FDA警告信。
蒲公英微信专门开设了GMP缺陷专题，收集国内外GMP缺陷。

幻影

，死不承认作假的节奏。

土豆王

学习了，谢谢楼主的分享！FDA对QC的电子数据查的这么仔细！

wangjin1023

FDA很重视电子数据的保管

一沙一叶

wangjin1023 发表于 2014-6-10 20:51
FDA很重视电子数据的保管

QC数据非常重要。         

冰封世界

电子数据很重要哦

彩虹

收藏学习

zdj1219

检查的很细啊

一沙一叶

zdj1219 发表于 2014-6-11 08:38
检查的很细啊

现在是打假专业队的

北方的狼

这是打假的节奏。

大葱一根

妥妥的造价，跑不了啊

三万英尺

FDA比较重视QC的电子数据保存

lindaqueen

为什么重新写过的就记录还在现场出现，QC数据大量造假

pczzq

电子数据很重要,要作假还得需要计算机技术