【GMP缺陷】g008 FDA2014年警告信-印度太阳制药 （下）

【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）

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：

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

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

楼主好强大啊，佩服

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：

楼主太强大了  整理得好仔细啊。佩服。。。。