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以下为部分翻译的FDA对印度UNIMARK REMEDIES公司的警告信。警告信签发时间为2015年9月28日，检查时间为2014年3月18-21日。
缺陷主要看点还是数据完整性，笑点是没上班的人签字了，以及发现鸟窝、鸟粪和蜥蜴。
Warning Letter
WL: 320-15-17
September 28, 2015
Mr. Mehul J. Parekh
Managing Director
Unimark Remedies Ltd.
Enterprise Centre, 1st Floor
Off. Nehru Road
以下省略一千字。。。
Dear Mr. Parekh:
During our March 18-21, 2014 inspection of your pharmaceutical manufacturing facility, Unimark Remedies Ltd., located at 337 Kerala Nalsarovar Road, Kerala Village, Bavla, Ahmedabad District, India, an investigator 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 (FD&C Act), 21 U.S.C. 351(a)(2)(B). 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.
We acknowledge receipt of your responses dated April 8, 2014, June 5, 2014, September 16, 2014, and November 28, 2014. We note that they lack sufficient corrective actions.
Our investigator observed specific CGMP deviations during the inspection, including, but not limited to, the following.
1. | Failure to document production and analytical testing activities at the time they are performed.
在生产和分析检测当时没有做文件记录。
During our inspection, we found that test results and other entries in the production records were not entered while batches were in production. For example,
在检查中，发现检验结果和其它生产记录的录入并不是在批生产当时做的。例如：
a. The investigator observed (b)(4) batch (b)(4) production on March 18, 2014. The start and stop times and (b)(4) for Step #(b)(4) were not recorded or signed in the batch record contemporaneously.
检查员发现某批次在2014年3月18日生产。某步骤的开始和结束时间没有同步在批生产记录上记录和签字。
b. For your (b)(4) products returned due to the presence of extraneous threads, the investigator found many inconsistencies in your reprocessing batch records. Specifically, operators signed batch records for periods when they were not in your facility, indicating these activities were documented by personnel who did not perform them. During the inspection, and in your written responses, your managers admitted that the batch records were created after the manufacturing process.
你们某批产品由于外源物威胁被退回，检查员发现你们的返工生产记录很多的不一致。尤其是操作人员在批记录上签字，但那个时间他们根本不在工厂里，说明这些活动不是由执行的人员记录的。在检查期间，在你们书面回复中，你们的经理承认批记录是在生产工艺结束后制作的。
c. Water testing records for sampling point (b)(4) on March 19, 2014, were incomplete. Specifically, the analyst did not record observations at the time they were made on March 18, 2014. Your microbiology records did not identify who prepared the samples, when they began incubation, who read the samples, or when the samples were read.
2014年3月19日在某取样点抽取的水样检验结果不完整。尤其是分析员并没有在2014年3月18日检验时记录其观察情况。你们的微生物检测记录没有写明是谁制备了样品，什么时候开始培养，谁给样品计数，什么时候计数。
According to your responses to these FDA 483 observations, your manufacturing staff did not exhibit acceptable documentation practices, and your chemist or microbiologist each neglected his work. However, your management is responsible for routine oversight of manufacturing and testing operations, including the activities of operators and other personnel, and your responses do not address the failure of management and the flaws in your overall quality system.
根据你们对FDA483缺陷的回复，你们的生产员工没有遵守可接受的文件记录规范要求，你们的化学分析员和微生物分析员均对他们的工作很不上心。不管怎么样，你们的管理层有责任对生产和检测操作进行日常监管，包括操作人员和其它人员的活动，但你们的回复里并没有提到管理失败的问题，也没有提到整体质量体系的瑕疵。
In response to this letter, conduct and provide the results of a comprehensive investigation into your poor documentation practices. Your investigation should address the flaws in your quality systems and management oversight that led to these serious deficiencies. Provide your plans to revise your procedures so that all CGMP operations are documented at the time they occur. Also provide your plans to revise your procedures so that you preserve original or true copies of data in the batch records. Also provide your procedures for addressing deviations from acceptable documentation practices, including training and oversight of personnel whose duties require preparation and review of API records.
在回复本警告信时，要对你们这么差的文件管理行为进行全面调查，提交调查结果。你们的调查应说明你们质量体系的瑕疵，以及导致这些严重缺陷的管理层监管问题。提供你们审计程序的计划，要保证所有CGMP操作均在发生时被及时记录。还要提交你们修订程序的计划，这样你们能保存原始或真实批记录数据副本。还要提交你们未遵守可接受的文件记录规范的偏差调查的情况，包括对那些需要准备和审核API记录的人员的培训和监管情况。
2. | Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data.
未能防止未经授权的进入或更改数据，未能提供足够的控制来防止对数据的忽略。
Your laboratory systems lacked access controls to prevent raw data from being deleted or altered. For example:
你们化验室系统缺陷登录控制，不能防止原始数据被删除或更改。例如：
a. During the inspection, we noted that you had no unique usernames, passwords, or user access levels for analysts on multiple laboratory systems. All laboratory employees were granted full privileges to the computer systems. They could delete or alter chromatograms, methods, integration parameters, and data acquisition date and time stamps. You used data generated by these unprotected and uncontrolled systems to evaluate API quality.
在检查中，我们注意到你们多个化验室系统上均没有唯一的用户名、密码，或化验员用户登录分级。所有化验室员工均使用全权限登录至计算机系统。他们可以删除或改变色谱图、方法、积分参数、和数据获取日期和时间戳。你们使用了由这些未受保护未受控制的系统所产生的数据来评估API质量。
b. Multiple instruments had no audit trail functions to record data changes.
多个仪器没有审计追踪功能来记录数据变更。
We acknowledge your commitment to take corrective actions and preventive actions to ensure that your laboratory instruments and systems are fully compliant by January 15, 2015. In response to this letter, provide a copy of your system qualification to demonstrate that your electronic data systems prevent deletion and alteration of electronic data. Describe steps you will take (e.g., installing better systems or software) if your qualification efforts determine that the current system infrastructure does not assure adequate data integrity. Explain the archival process your firm has implemented to address these issues and how you will evaluate the effectiveness of these corrections. Provide a detailed summary of the steps taken to train your personnel on the proper use of computerized systems.
你们告诉我们你们承诺要采取CAPA来确保你们的化验室仪器和系统在2015年1月15日会全面符合要求。在对此警告信的回复中，请提交一份你们系统确认的复印件，证明你们的电子数据系统可以防止对电子数据的删除和篡改。如果你们的确认发现现行系统基础不能确保充分的数据完整性的话，描述你们要采取的步骤（例如，安装更好的系统或软件）。解释你们公司已实施的存档程序，对这些问题进行说明，为你们准备如何来评估这些纠正措施的有效性。提交详细的汇总，说明你们培训你们员工适当使用计算机化系统的步骤。
3. | Failure to maintain complete data derived from all testing, and to ensure compliance with established specifications and standards.
未给维护所有测试中产生的完整数据，未能保证符合已有的质量标准。
Because you discarded necessary chromatographic information such as integration parameters and injection sequences from test records, you relied on incomplete records to evaluate the quality of your APIs and to determine whether your APIs conformed with established specifications and standards. For example:
由于你们丢弃了必要的图谱信息，例如，测试记录里的积分参数和进样序列，你们依赖于不完整的记录来评估你们API的质量，决定你们的API是否符合已建立的质量标准。例如：
a. During the inspection, the investigator found no procedures for manual integration or review of electronic and printed analytical data for (b)(4) stability samples. Electronic integration parameters were not saved or recorded manually. When the next samples were analyzed, the previous parameters were overwritten during the subsequent analyses.
在检查中，检查官发现没有手动积分的程序，也没有对某稳定性样品的电子和打印数据的审核程序。电子积分参数没有保存或人工记录。当进行下一样品的分析时，之前的参数在后续分析时被改写。
b. We found that some analytical testing data was inadequately maintained and reviewed.
我们发现有些分析测试数据维护和审核不充分。
i. Your HPLC 14 computer files included raw data for undocumented (b)(4) stability samples analyzed on December 30, 2013, but no indication of where these samples came from and why they were tested.
你们的HPLC14号电脑文件包括有未经过记录的某产品稳定性样品原始数据，分析日期为2013年12月30日，但没有显示这些样品是从哪里来的，为什么要进行检测。
ii. In a data file folder created on May 22, 2013, 23 chromatograms were identified as stability samples for (b)(4) lots (b)(4), and (b)(4). Results were not documented. More importantly, the acquisition date was July 7, 2013, more than six weeks after the samples were run.
在2014年5月22日创建的数据文件夹里，有图谱被标示为某批的稳定性样品，结果并没有记录。更重要的是，数据获取日期为2013年7月7日，在样品运行了6周多之后。
iii. (b)(4) lots (b)(4) and (b)(4) were not in your stability study records at the time of inspection. Additionally, there were no log notes of any samples from the three lots removed from the stability chamber.
某批和某批在检查当时并不在你们的稳定性研究记录里。另外，这三批样品也没有任何从稳定性考察箱中取出的样品登记。
You responded that “the probable reason for this inconsistency in data acquisition was due to some malfunction in the computer system at the time of data acquisition.” Your response is inadequate because you have provided neither evidence to support this conclusion, nor a retrospective review of the effects your incomplete analytical data records may have had on your evaluation of API quality.
你们回复说“数据获取时间不一致的可能原因是因为计算机系统在数据获取时发生故障”。你们的回复不够充分，因为你们没有提供证据来支持这种结论，也没有对你们不完整的数据记录的影响进行回顾性审核，这些可能会对你们的原料药质量评估有影响。
In response to this letter, provide your revised procedures and describe steps you have taken to retrain employees to ensure retention of complete electronic raw data for all laboratory instrumentation and equipment. Also, provide a detailed description of the responsibilities of your quality control laboratory management, and quality assurance unit for performing analytical data review and assuring integrity (including reconcilability) of all data generated by your laboratory.
在对本警告信的回复中，请提交你们修订后的程序，描述你们已采取的重新培训员工的措施，确保所有化验室仪器和设备产生的电子原始数据得到完整保留。还要提交你们质量控制化验室管理的职责的详细描述，实施分析数据审核的质量保证部门的详细职责描述，确保你们化验室产生的所有数据的完整性（包括一致性）。
4. | Failure to properly maintain buildings and facilities used in the manufacture of intermediates and APIs in a clean condition.
未能适当维护用于中间体和原料药所用的建筑和设备，使处于清洁状态。
We saw evidence of pests in your facility. For example, when we inspected your (b)(4) block, the (b)(4) manufacturing building was not sealed against pests. There were significant gaps in the (b)(4) level, where piping entered from outside. The investigator observed what appeared to be a bird’s nest near the ceiling. On March 18, 2014, the investigator saw bird feces on a rack and on a bag of (b)(4) in the general raw material warehouse #2. On the same day, the investigator saw a lizard in the general raw material warehouse #1.
我们看到在你们工厂有许多虫子的证据。例如，当我们检查你们某区时，某生产建筑没有对昆虫的封闭措施。在某楼管道从外进入的地方有很大的缝隙。检查员发现在天花板附近有一个像是鸟巢的东西。在2014年3月18日，检查员看到在2号通用原料库里一个某物料的袋子上和一个货架上有鸟粪。在同一天，检查员看到在1#通用原料库里有蜥蜴。
Your firm did not have written procedures for pest control. According to your responses, you performed corrective actions on the facility. However, you did not include any assessment of potential damage to your products.
你们公司没有书面的防虫控制程序。根据你们的回复，你们已经对工厂实施了纠正措施。但是，其中没有包括对你们产品的潜在损害的评估。
Proper building design and maintenance, including operator training in prescribed cleaning and maintenance procedures are required elements of your facility’s operations. In response to this letter, provide details of your pest prevention and control program and provide the results of your review of the effects of the presence of pests in your facility on API quality.
你们工厂的操作要求你们的建筑有适当的设计和维护，包括对操作人员进行指定的清洁和维护程序培训。在对本信函的回复中，请提交你们防虫和控制虫鼠程序的详细内容，提交你们对工厂出现虫鼠对原料药质量产生的影响的审核结果。
| Summary 总结 |
The examples in this letter are serious CGMP deviations. Your quality system does not adequately ensure the accuracy and integrity of data generated at your facility to support the safety, effectiveness, and quality of the drug products you manufacture.
本函中的例子都是严重的CGMP偏差。你们的质量体系并不足以保证在你们工厂产生的数据的准确性和完整性，来支持你们生产的药品的安全性、有效性和质量。
We strongly recommend that you hire a qualified third-party auditor/consultant with experience in detecting data integrity problems to help you comply with CGMP requirements. However, it is your responsibility to ensure that any third-party audit evaluates your sophisticated electronic systems and their vulnerability to data integrity manipulation.
我们强烈建议你们聘请一位有资质的具备发现数据完整性问题经验的第三方审计人员/顾问，来帮助你们符合CGMP的要求。但是，确保所有第三方审计评估你们复杂的电子系统和及其数据完整性造假的弱点仍是你们的责任。
In response to this letter, provide:
在回复本函时，请提交：
1. | A complete evaluation of the extent of inaccuracies in your reported data. Include a detailed action plan to investigate the extent of your deficient documentation practices noted above.
你们所报告的数据中不准确性的程序的全面评估。包括对你们上述有缺陷的文件记录规范程度的详细调查计划。
2. | A comprehensive investigation into root causes of the data integrity problems, including but not limited to independent interviews of current and former employees.
对数据完整性问题根本原因的全面调查，包括但不仅限于对现有和之前员工的单独面谈。
3. | A risk assessment of the effects of these deviations on data submitted in any pending drug applications.
这些偏差对所有审核中的药品申报资料的影响的风险评估。
4. | A comprehensive management strategy to address these serious issues, including the details of your corrective action and preventive action plans.
处理这些严重问题的全面管理策略，包括你们CAPA计划的详细内容。
a) As part of your corrective action and preventive action plan, describe the comprehensive actions you have taken or will take to assure product quality. Contacting your customers, recalling product, conducting additional tests, adding lot numbers to your stability programs and monitoring complaints may be among the steps.
作为你们CAPA计划的一部分，描述你们已采取或将要采取的全面措施，以确保产品质量。联系你们的客户，召回产品，实施附加测试，增加批号到你们的稳定性试验计划中，监测这些步骤中可能的客诉。
b) Also include in your corrective action and preventive action plan, a section describing the actions you have taken or will take to prevent the recurrence of CGMP deviations, including breaches of data integrity. Revising procedures, implementing new systems and controls, and training or re-training personnel may be among the steps.
在你们的CAPA计划中，还要包括有一部分来描述你们已采取或将要采取的防止CGMP偏差再次发生的措施，包括数据完整性问题。修订程序，实施新的体系和控制，培训或再次培训员工。
The deviations cited in this letter are not intended to be an all-inclusive list of deviations that exist at your facility. You are responsible for determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations.
If, as a result of receiving this letter or for other reasons, you are considering a decision that could reduce the number or volume of active pharmaceutical ingredients produced by your manufacturing facility, FDA requests that you contact CDER's Drug Shortages Staff immediately 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 Staff also allows you to meet any obligations you may have to report discontinuances in your drug manufacturing under 21 U.S.C. 356C(a)(1). FDA must consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the 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.
Within 15 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 deviations.
If you cannot complete corrective actions within 15 working days, state the reason for the delay and the date by which you will have completed the corrections. If you no longer manufacture or distribute the APIs at issue, provide the dates and reasons you ceased production. Please identify your response with FEI # 3005202703.
来源：Julia的博客。免责声明：编辑对上述内容，对文中陈述、观点判断保持中立，不对所包含内容的准确性、可靠性或完整性提供任何明示或暗示的保证。仅作参考，并请各位自行承担全部责任。
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