FDA 警告信 [重庆莱美药业股份有限公司] 2016年6月21日

kslam

FDA于2016年6月21日对重庆莱美药业股份有限公司(重庆市长寿区经济技术开发区化南四支路 2 号)发警告信。

1. Failure to prevent unauthorized access or changes to data and failure to provide adequate controls
to prevent manipulation and omission of data. 未能防止不经授权获取或更改数据，未能提供充分的控制以防止数据被篡改及数据遗失。

2. Failure to document manufacturing operations at the time they are performed. 未能在执行生产操作时就对其进行记录。

__________________________________________________________________________________

2016年4月19日, FDA发进口警报。

syhorchid

言下之意，重庆莱美药业有数据被篡改之嫌。

kc1711422001

Thanks for sharing

fangyuan5

缺陷项怎么整改啊？

北重楼

这种是不是到时候也会被国家局飞检呀

kslam

关于媒体报道情况说明的公告 2016年6月20 日

2016 年4月，公司长寿原料药厂和茶园老厂被 FDA 列入了进口警报名单，受上述进口警报影响的品种仅为原料药替莫唑胺。替莫唑胺原生产地址为公司茶园老厂（重庆南岸区月季路 8 号），在接受 FDA 检查时该厂区由于搬迁的缘故已停产较长时间，因此，未能通过 FDA 检查。由于公司此时原料药的生产许可证已变更为长寿原料药厂地址（重庆市长寿区经济技术开发区化南四支路 2 号），因此在进口警报名单中，FDA 也增加了长寿原料药厂（实际上 FDA 并未对长寿原料药厂整体进行检查）。

说明不符合事实

"实际上 FDA 并未对长寿原料药厂整体进行检查" 这一点需要澄清。

因为在2016年6月21日发出的警告信明确列出FDA于2016年3月14日至16日检查工厂在 "Changshou at No. 2 the 4th Branch Road Hua’nan Road, Chongqing, from March 14–16, 2016." (重庆市长寿区经济技术开发区化南四支路 2 号), 也包括另一家工厂在8号,南岸区重庆市 No. 8 Rose Road, Nan’an District Chongqing。

sallawu

篡改就是造假

Doitasyoulike

1.        Failure to prevent unauthorized access or changes to data and failure to provide adequate controls to prevent manipulation and omission of data. 未能防止对数据进行未授权的访问或更改以及未能提供充分的措施防止数据的操纵和丢失。

During the inspection, FDA’s investigator discovered a lack of basic laboratory controls to prevent changes to and deletions from your firm’s electronically-stored data. Your firm relied on incomplete and falsified 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调查员发现实验室缺乏一些基本的措施以防止电子存储数据的更改和删除。贵公司是在不完整和受到篡改的数据基础上对药品的质量进行评价并决定药品是否符合既定的质量标准。

Our investigator found that your firm failed to prevent data manipulation on multiple computerized analytical systems. Your firm re-tested samples without justification and deleted raw analytical data from computerized systems. You are responsible for determining the causes of these deviations, for preventing their recurrence, and for preventing other deviations from CGMP. FDA调查员发现贵公司无法防止多用户计算机系统的数据受到篡改。贵公司复测样品但并无合理的理由，而且还删除了计算机系统上的原始分析数据。你们有责任确定这些偏差的发生的原因，并需要防止它们再次发生以及防止其他cGMP偏差。

a.        Our investigator’s review of the audit trail for the residual solvent stability testing indicated that an analyst manipulated your computerized gas chromatography (GC) system to falsify residual solvent stability results for multiple batches of (b)(4) API distributed to the U.S. FDA调查员查看了稳定性测试的残留溶剂分析的审计追踪，结果表明分析员对气相色谱系统（GC）进行了操纵以篡改多个发往美国的原料药批次的稳定性测试的残留溶剂分析结果。

For example, on March 4, 2016, your analyst set the GC personal computer (PC) clock back to make it appear as if testing had been done seven months earlier – on August 3, 2015. The analyst then performed five different injections to produce falsified results for long term stability 25C/65% RH 12 month time-point residual solvent testing for finished API lot (b)(4). The analyst deleted the first four backdated results and reported only the results of the fifth and final injection as passing in the quality control data package. Your quality unit relied on this incomplete data package to evaluate the quality of this lot of API and determine whether it was within specification.
例如，在2016年3月4日，你们分析员将GC电脑的时钟回调，使检测看起来完成在7个月前，即2015年8月3日。分析员随后进了5针，以作为成品API（b）（4）长期稳定性试验（25℃/65%RH）第12个月的残留溶剂检测数据。分析员又删除了前4针的数据，并只报告了第5针即最后一针的检测结果，作为通过质量控制的结果。质量部门根据此结果对该批次的原料药的质量进行评估，并作出了是否符合书面质量标准的结论。

Our investigator observed that long-term stability results for at least five other lots of (b)(4) API were falsified using this technique of setting back the clock on the GC personal computer and then performing multiple injections until favorable results were obtained. Your firm failed to prevent analysts’ access to manipulate and delete laboratory data. In addition, your laboratory equipment lacked software controls to assure data integrity. FDA调查员发现还有至少其他5个批次的（b）（4）原料药的长期稳定性检测数据同样用此改GC电脑时间的方法进行了篡改，并且同样是多次进针，直至得到有利的结果。贵公司未能防止分析员对实验室数据进行操纵和删除。另外实验室设备也缺乏软件控制以保证数据完整性。

b.        Our investigator’s review of the audit trails for the high performance liquid chromatography (HPLC) system indicated that, just prior to the completion of certain stability analyses for (b)(4) API, analysts routinely aborted the ongoing tests to prevent your HPLC system from recording some assay and impurities test data. FDA调查员查看了高效液相色谱（HPLC）系统的审计追踪，并发现在某些产品稳定性分析完成前，分析员即中止了进行中的测试以防止HPLC系统记录到一些含量和杂质的检测数据。

Your HPLC system, controlled by Chemstation software, was configured to automatically delete the results if a test was aborted prior to completion. Our investigator’s review of the system’s limited audit trails indicated that when an analyst aborted assay and impurities tests, the partial results from the aborted tests were automatically deleted from your computerized HPLC system’s records.
贵公司的HPLC系统采用Chemstation软件控制，并设置了如果某项测试在完成前被中止即会自动删除检测结果。我们调查员查看了系统有限的审计追踪，并发现当分析员中止含量和杂质检测，被中止测试的部分结果会自动从HPLC计算机系统记录上删除。
For example, our investigator reviewed a data file audit trail that showed that during impurities analysis of an 18-month stability sample of (b)(4) crude batch (b)(4), your analyst aborted the injection before the test was complete, set the HPLC PC clock back, and then repeated the injection. Your analyst only reported the results of the second injection in the quality control data package. This test, for which your computerized system did not retain original data about the quality of your (b)(4) crude, had been performed as part of a stability study your firm executed in response to FDA’s previous inspection in July, 2013. Our investigator observed the same technique for data manipulation and deletion in multiple other impurities analyses for (b)(4). 例如，FDA调查员审核了数据的审计追踪，结果显示在第18个月的粗品批次（b）（4）的稳定性样品（b）（4）的杂质分析期间，分析员在检测完成前中止了进样，然后将HPLC电脑时钟回调，并重新进针。该分析员只报告了第2针的检测结果作为质量控制检测数据。该次检测并没有保留该批粗品（b）（4）的原始检测数据，而且是作为贵公司针对FDA2013年7月检查回复中承诺进行的稳定性测试中的一项检测。FDA调查员观察到在其他多个杂质分析中（b）（4），同样采用了该方法以对数据进行操纵和删除。

When our investigator asked your staff about these instances of falsification and manipulation, your quality control manager stated that your firm “forgot” to perform stability testing and therefore created falsified results for each missed time point by manipulating the controlling PC clock.
当FDA调查员要求贵公司员工对这些发现的篡改和操作问题进行解释时，贵公司质量控制部经理说是“忘记”了进行稳定性检测，因此操作控制电脑的时钟，创建了这些漏掉的稳定性批次检测的篡改结果。
In your response to the FDA-483, you stated that you would upgrade your GC and HPLC software, and revise standard operating procedures (SOPs) for handling analytical data and train your staff on these revised SOPs. You also indicated that you would retrospectively review analytical data, and if data manipulation was identified, conduct a risk assessment to determine whether “re-testing actions are required.”
在贵公司对FDA483回复中，你们声明会对GC和HPLC的软件进行升级，并且会修订处理分析数据的相关标准操作规程（SOP）并对员工进行培训。贵公司还表示会对分析数据进行回顾性审查，且如果发现数据受到操纵，则进行风险评估以决定是否“有必要进行复测”。

Your response is inadequate because you have not demonstrated how the software upgrades, SOP revisions, and training will correct the broad data manipulation and deletion problems observed at your facility and to prevent their recurrence. Your quality unit must review all pertinent analytical data when making decisions about the quality of your drugs and when evaluating their conformance to established specifications. When your electronic systems permit the falsification and manipulation of data to obscure or delete test results, the quality unit is presented with incomplete and inaccurate information about the quality of your drugs. Your response does not demonstrate how your proposed software upgrades, revised procedures, or training will prevent the deletion of data or how your quality unit ensures that the records relied upon for batch release and other quality review decisions are complete and accurate
贵公司的回复是不充分的，因为你们没有证明软件升级，SOP修订以及培训如何能纠正这些在贵公司发现如此多的数据操纵和删除问题，并如何防止它们再次发生。贵公司质量部门在确定产品质量并对产品是否符合书面的质量标准进行评价时，必须审查所有相关的分析数据。当贵公司电子系统允许对数据进行操纵和篡改以掩盖或删除检测结果时，质量部门得到的将是产品质量不完整和不正确的信息。贵公司回复并没有证明你们提出的软件升级、修订的规程以及进行的培养将如何防止数据的删除或贵公司质量部门如何保证用于批次放行的记录以及其他质量审核决策是完整的和准确的。

scslk0045

关注数据完整性

卢青

我是一直比较郁闷的，如何保证数据不被删除，只有意识上的管理肯定是不被认可的，但要用比如安家的DATE STORE之类的网络服务器一类的又会把人做死，

Doitasyoulike

2.        Failure to document manufacturing operations at the time they are performed.
未能及时记录生产操作。

During the inspection, our investigator reviewed 20 executed batch manufacturing records and found that most of them contained similar or identical entries that could not be adequately explained. For example, our investigator examined batch records for (b)(4) different batches of (b)(4) API manufactured between January and February 2015. All (b)(4) batch records indicated that certain process steps or measurements had transpired at exactly the same time for each different batch. When our investigator asked your production supervisor to explain why the time stamps were identical on these records, the production supervisor stated that the full manufacturing process takes (b)(4) to complete, and that all batch records are kept in the production area until (b)(4) lots are completed. The production supervisor stated that the operators most likely did not record the actions at the time they were performed but rather completed batch records in groups.
在检查期间，FDA调查员审核了20个已生产批次的批记录并发现大部分记录均有相似或完全相同的记录内容，并且无法合理解释。例如，FDA调查员检查了2015年1月至2月多个批次（b）（4）的批记录。所有批记录（b）（4）显示某些工艺步骤或者测量进行的时间在每个批次中恰好一样。当FDA调查员要求贵公司生产主管解释这些记录中的时间为何完全一样时，生产主管声称这些批次的整个生产工艺均完成，并且所有批记录均保存在该生产区域直到这些批次完成。生产主管声称很可能是操作员没有在操作时进行记录而是后面一起完成所有批记录。

In your response to the FDA-483, you indicated that you would not release any new (b)(4) API to the U.S. market until “FDA deems our facility acceptable.” You also indicated that you had reviewed all manufacturing data and found “some batches have the same falsification” and committed to revising your batch manufacturing record template and SOPs, and retraining your staff.
在贵公司给FDA483的回复中，贵公司表示将不会放行任何新的原料药批次（b）（4）销售至美国直至FDA“认可我公司”。贵公司还表示已经审核过所有的生产数据并发现“一些批次有相同的伪造现象”，并承诺会对批生产记录模板和SOP进行升版，并对员工重新培训。

Your response was inadequate. Neither revised templates and procedures nor retraining your staff alone can prevent operators from continuing to falsify batch manufacturing records.
你们的回复是不充分的。仅模板和规程的修订以及员工的重培训均不能防止操作员继续伪造批生产记录。

Doitasyoulike

卢青 发表于 2016-6-30 10:20
我是一直比较郁闷的，如何保证数据不被删除，只有意识上的管理肯定是不被认可的，但要用比如安家的DATE STO ...

看这里有一部分解决方法
https://www.ouryao.com/forum.php? ... p;extra=&page=1

Doitasyoulike

你好，请问下怎么及时查找FDA的WL
例如在http://www.fda.gov/Drugs/Guidanc ... /ucm482462.htm#OPDP
这里好像没找到lummy的信息，只有搜索还能找到

2A2MXnrNlF

kslam 发表于 2016-6-30 09:33
关于媒体报道情况说明的公告 2016年6月20 日

2016 年4月，公司长寿原料药厂和茶园老厂被 FDA 列入了进口 ...

怎会有人去买这公司的股票呢?

zysx01234

严格职责权限管理是一种公司文化，如果平时工作（部门内和部门间）喜欢扯皮、推责任，仅仅要求QC把电脑控制死死的，估计QC检验员都干不长