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[FDA药事] 「翻译」「FDA警告信」上海泰亨实业因数据完整性问题被FDA警告

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药徒
发表于 2016-5-26 09:08:22 | 显示全部楼层 |阅读模式

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本帖最后由 超乎想象 于 2016-5-26 09:14 编辑

本文来源:http://mp.weixin.qq.com/s?__biz=MzA4NDA1MDEzNA==&mid=2247483811&idx=1&sn=56c2d300283fa6ed8a64b04b7224eeec&scene=1&srcid=0526s5gSHxVqLdbvBpRzMmuy#wechat_redirect


Public Health Service
Food and Drug Administration
Silver Spring, MD  20963

Via UPS                                                                                   Warning Letter: 320-16-11
Return Receipt Requested

May 12, 2016
Mr. Yusheng Fang, CEO & President
Tai Heng Industry Co., Ltd.
2715 Long Wu Road, Building 2
Shanghai Juke Biotech Park
Shanghai, China, 200231
Dear Mr. Fang:
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Tai Heng Industry Co., Ltd., 2715 Long Wu Road, Building 2, Shanghai Juke Biotech Park, Shanghai, China from May 4–11, 2015.
This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).
Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API are 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).
We reviewed your firm’s May 28, 2015, response in detail and acknowledge receipt of your subsequent responses.
Our investigator observed specific deviations during the inspection, including, but not limited to, the following.
1. Failure to adequately investigate out-of-specification results and implement appropriate corrective actions.
未能充分的调查OOS结果并且实施适当的纠正措施。
The investigator found that batch samples were routinely retested following failing or atypical results until acceptable results were obtained. Failing or atypical results were not investigated or included in official laboratory control records.
检查员发现工厂在日常生产中,对出现失败或非正常结果的批样品进行重复测试直到结果符合要求。失败或者非正常的结果没有经过调查,也没有将其纳入到正式的实验室控制记录中。

2. Failure to prevent unauthorized access or changes to data, and to provide adequate controls to prevent manipulation and omission of data.
不能防止未经授权的数据访问和数据更改,也不能提供足够的控制防止伪造和遗漏数据。

During the inspection, an FDA investigator discovered a lack of basic laboratory controls to prevent changes to your firm’s electronically stored data and paper records. 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检查员发现,缺少基本的实验室控制以防止更改公司电子储存的数据和文件记录。你们公司依靠不完整的记录评价药品质量,并且判定药品是否符合既定的接受标准。
Our investigator 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 and on multiple pieces of testing equipment.
我们的检查员发现,你们公司经常无正当理由的重新检测样品并删除分析数据。在你们的设备中,我们发现了系统的数据伪造,涉及到多个分析人员和多个分析设备。

Specifically, your Quality Control (QC) analysts used administrator privileges and passwords to manipulate your high performance liquid chromatography (HPLC) computer clock to alter the recorded chronology of laboratory testing events.
具体来讲,你们的QC分析员对你们的HPLC计算机时钟进行了篡改,以此来改变所记录的实验室测试事件的发生顺序。
3. Failure to record activities at the time they are performed, and destruction of raw data.
未能在活动执行时就对其进行记录,并且破坏原始数据。
Your employees did not complete batch production and control records immediately after activities were performed. Your operators used “mock” sheets (copies of the uncontrolled copy of the master production records) to capture critical manufacturing data. Your employees then completed and backdated batch production records days after operations ended.
你们的员工没有在活动执行后立即完成批生产和批检验记录。你们的操作人员使用“模拟”表格(主生产记录的非受控复印件)来记录关键的生产数据。然后在操作结束数天后,你们的员工再完成批生产记录并将日期修改为之前的日期。
Our investigator noted discrepancies between the “mock” sheets and the complete batch production record that your firm represented as the official record for that lot. Because of your uncontrolled documentation practices, you could not produce evidence that your batch production records were accurate.
我们的检查员注意到“模拟”表格和你们公司作为正式的批生产记录的表格有不一致的地方。因为你们文件不受控的做法,导致你们并不能提供证据来证明你们的批生产记录是准确的。
Batch production records must be generated contemporaneously and include complete and accurate information on the production and control of each batch. The practice of using unbound, uncontrolled loose paper, in conjunction with backdating records, raises additional concerns about the integrity, authenticity, and reliability of all your data, and the quality of your API.
批生产记录必须要在生产和操作发生的同时进行记录,并包含每个批次生产和控制的完整及准确的信息。使用未装订的,非受控的散装纸来记录,并且将记录日期修改为之前的日期,这些都让我们对你们数据的完整性,真实性和可靠性,以及对你们原料药的质量产生了忧虑。
Conclusion
Deviations cited in this letter are not intended as an all-inclusive list. You are responsible for investigating these deviations, for determining the causes, for preventing their recurrence, and for preventing other deviations from CGMP.
If, as a result of receiving this warning letter or for other reasons, you are considering a decision that could reduce the number of drugs 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 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 actions without interrupting supply, or to shorten any interruption, thereby avoiding or limiting drug shortages.
After you receive this letter, you have 15 working days to respond to this office in writing. Specify what you have done since our inspection to correct your deviations and to prevent their recurrence.
Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. We acknowledge your commitment to hire a third party to perform (b)(4) audits of your quality system, but we feel that an (b)(4) audit is inadequate. We recommend more frequent reviews of your quality system for more timely oversight and compliance with CGMP. We also recommend your third party audit include appropriate evaluation of sophisticated electronic systems and the possibility of data integrity manipulation of such systems.
In your response to this letter, provide the following.
在您回复这封信时,请提供以下内容

1. A comprehensive investigation into the extent of the inaccuracies in data records and reporting. Your investigation should include:
对数据记录和报告的不准确的程度进行全面调查。你的调查应该包括:

  • A detailed investigation protocol and methodology; a summary of all laboratories, manufacturing operations, and systems to be covered by the assessment; and a justification for any part of your operation that you propose to exclude.
    一份详细的调查方案和方法;总结所有的实验室,生产操作,和根据评估结果涵盖的系统;并说明为何你们要将操作中的某一部分排除在评估外的理由。
  • Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies. We recommend that these interviews be conducted by a qualified third party.
    与现任和前任员工进行访谈,以确定数据不准确性的性质,范围和根源。我们建议这些访谈由有资格的第三方执行。
  • An assessment of the extent of data integrity deficiencies at your facility. Identify omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies. Describe all parts of your facility’s operations in which you discovered data integrity lapses.
    一份对你们工厂中的数据完整性缺陷的程度和范围所进行的评估。确定和找出遗漏,改动,删除,记录的销毁,非同时完成的记录,及其他的缺陷。描述你们发现的数据完整性的疏漏所进行的所有操作和行为。


  • A comprehensive retrospective evaluation of the nature of all data integrity deficiencies. We recommend that a qualified third party with specific expertise in the area where potential batches were identified should evaluate all data integrity lapses.  
    全面的回顾性评价所有数据的完整性缺陷的性质。我们建议,一个合格的有特定专长的第三方应该评估潜在批次所有数据完整性问题。

2. A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses  of the risks to patients caused by the release of drugs affected by a lapse of data integrity, and risks posed by ongoing operations.
一份对你们工厂中的数据完整性缺陷的程度和范围所进行的评估。确定和找出遗漏,改动,删除,记录的销毁,非同时和按时完成记录,及其他的缺陷。将你们发现数据完整性的疏漏所进行的所有操作和行为都描述下来。


3. A management strategy for your firm that includes the details of your global corrective action and preventive action plan. Your strategy should include:
公司的管理策略,包括全面的CAPA措施的详细情况。你们的策略应该包括:

  • A detailed corrective action plan that describes how you intend to ensure the reliability and completeness of all of the data you generate, including analytical data, manufacturing records, and all data submitted to FDA.
    一个详细的纠正行动计划,说明你们是如何保证所产生的所有数据的可靠性和完整性,包括数据分析、生产记录以及提交FDA的所有数据。
  • A comprehensive description of the root causes of your data integrity lapses, including evidence that the scope and depth of the current action plan is commensurate with the findings of the investigation and risk assessment. Indicate whether individuals responsible for data integrity lapses remain able to influence CGMP-related or drug application data at your firm.
    对你们的数据完整性疏漏的根源进行全面的分析描述,包括证据来证明当前的改正计划的范围和深度是与调查发现和风险评估所相称的。说明造成这些数据完整性疏漏的人员是否还能够对你们公司CGMP相关的数据或药品申请数据产生影响。
  • Interim measures describing the actions you have taken or will take to protect patients and to ensure the quality of your drugs, such as notifying your customers, recalling product, conducting additional testing, adding lots to your stability programs to assure stability, drug application actions, and enhanced complaint monitoring.
    临时措施,描述你们已经采取或者计划采取的措施以保护患者并确保药品的质量,比如通知客户、召回产品、进行额外的测试、增加稳定性测试的批次以确保药品的稳定、药物申请行动并加强投诉监控。
  • Long-term measures describing any remediation efforts and enhancements to procedures, processes, methods, controls, systems, management oversight, and human resources (e.g., training, staffing improvements) designed to ensure the integrity of your company’s data.
    长期措施,描述所有对程序,工艺,方法,控制,系统,管理监督和人力资源(例如,培训,人员配备改进)进行的任何补救或者改善性的措施,以确保贵公司数据的完整性。
  • A status report for any of the above activities that are already underway or completed.
    对上述已经完成或正在进行的行动的状态报告。


If you cannot complete corrective actions within 15 working days, state your completion date and reasons for delay.
如果你不能在15个工作日内完成纠正措施,那么需要说明完成日期和延迟的原因。

Until you completely correct all deviations and we confirm your compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as an API manufacturer. Failure to correct these deviations may also result in FDA refusing admission of articles manufactured at Tai Heng Industry Co., Ltd., 2715 Long Wu Road, Building 2, Shanghai Juke Biotech Park, Shanghai, China into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Under the same authority, articles may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).
Send your reply to:
            Kevin Maguire
            Compliance Officer
            U.S. Food and Drug Administration
            White Oak, Building 51, Room 4359
            10903 New Hampshire Avenue
            Silver Spring, MD 20993
            USA
Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov
Please identify your response with FEI 3006986091.

Sincerely,
/S/
Francis Godwin
Acting Director
Office of Manufacturing Quality
Office of Compliance
Center for Drug Evaluation and Research


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药徒
发表于 2016-5-26 09:13:22 | 显示全部楼层
看看,吸取经验,要准备欧盟的了
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药徒
发表于 2016-5-26 10:13:19 | 显示全部楼层
学习了  要发给领导看
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药徒
发表于 2016-5-26 10:17:38 | 显示全部楼层
涨知识了!多谢楼主!
请问楼主是哪里人?
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发表于 2016-5-26 10:53:15 | 显示全部楼层
学习了,很受用,谢谢分享!
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发表于 2016-5-27 15:49:44 | 显示全部楼层
学习了,谢谢
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发表于 2016-6-14 09:13:42 | 显示全部楼层
谢谢,我有英文的,省的自己翻译了
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发表于 2017-2-24 16:10:48 | 显示全部楼层
这样啊!可怜啊。
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发表于 2017-2-24 16:22:02 | 显示全部楼层
谢谢分享,可以做为例子培训了。
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发表于 2017-5-1 12:45:28 | 显示全部楼层
才发现,泰亨已经的WR已经被closeout了,算了下时间大概只用了10个月,这应该是因为DI问题被警告后,最短时间被Close out的吧。

https://www.fda.gov/iceci/enforc ... /2016/ucm549074.htm
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发表于 2017-5-3 20:53:49 | 显示全部楼层
山外青山 发表于 2017-2-24 16:22
谢谢分享,可以做为例子培训了。

警告信已经解除,可以继续当培训的例子了
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