20140716 ECA新闻：意大利原料药厂因数据完整性问题收到FDA警告信

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北京-丹丹 发表于 2014-7-21 07:03:06 | 只看该作者回帖奖励

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2014-07-21 julia翻译蒲公英

GMP News
16/07/2014

Italian API Manufacturer Receives FDA Warning Letter for Data Integrity Issues

意大利原料药厂因数据完整性问题收到FDA警告信

On July 7th the US FDA issued a Warning Letter to Trifarma S.p.A. for violating Good Manufacturing Standards at their facility in Rozzano, Italy. The company produces APIs and had been inspected early this year. As a result of the inspection and the response of the company to the GMP findings the FDA decided to issue a Warning Letter.

7月7日，美国FDA向TRIFARMA S.p.A签发了警告信，因其位于意大利ROZZANO的工厂违反GMP标准。该公司生产原料药，在今年早些时候接受了检查。鉴于在检查中发现的缺陷及公司对缺陷所提交的回复，FDA决定签发警告信。

While so far mainly Indian Manufacturers have been blamed by FDA and EU Inspectors for data integrity issues, now also an European API manufacturer has been cited for that problem. According to the Warning Letter the firm deleted all electronic raw data supporting the companies high performance liquid chromatography (HPLC) testing. Moreover, Trifarma failed to retain basic chromatographic information such as injection sequence, instrument method or integration method for the tests.

此前，被FDA和欧盟检查官批评数据不完整的主要是印度公司，这次一个欧洲原料药公司也被发现有此问题。从警告信的内容来看，该公司删除了所有HPLC检测的原始电子数据。另外，TRIFARMA未能保留基本的色谱资料，如进样序列、仪器方法或检验所用的积分方法。

In a response to the FDA the firm explained that it has been researching backup systems since July 2013 and will have a backup system online by the third quarter of 2014. But FDA is not satisfied with this answer. Some interim actions such as storing backup data on each computer, including the integration method as part of that data are not sufficient. The FDA expects to see backups of the injection sequence, the instrument method and audit trails. According to the FDA the firm does not address how it will ensure that electronic files are not deleted prematurely from local computers.

公司在给FDA的回复中解释说，自2013年7月开始已经在研发备份系统，到2014年第三季会有在线备份系统。但FDA对此答复并不满意。仅仅是采取一些临时措施，如在每台电脑上存贮备份数据，包括积分方法是不够的。FDA希望看到对进样序列、仪器方法和审计追踪均有备份。FDA认为公司没有说明将来如何保证电子文件不会在未经批准时被从本地电脑中删除。

In addition further basic GMP provisions are not met in the lab. There are no proper controls in place to prevent the unauthorized manipulation of the raw electronic data. All persons in the lab were able to delete and/or adulterate data because all lab employees were granted full privileges to the computer systems. Some equipment in place in the lab such as the HPLC and the GC lacked active audit trail functions to record changes to data, including information on original results, the identity of the person making the change, and the date of the change.

另外，化验也未能符合一些基本的GMP要求，不能防止未经授权对原始电子数据进行篡改。化验室所有人员都可以删除和/或更改数据，因为化验室所有员工都具有计算机系统的全部权限。化验室里有些设备，如HPLC和GC，审计追踪未激活，不能记录对数据的更改，包括对原始结果修改的内容、修改人以及修改时间。

The FDA also expected to see electronic raw data supporting cleaning, method and process validations but the company was not able to provide these data. Another critical deviation referred to the fact that the company did not document any training of production employees on the production operations they perform. The company did change an SOP on how to perform training at the manufacturing site in July 2013 in order to include on-the-job training but Trifarma is not following it's own procedures.

FDA还希望看到支持清洁、方法和工艺验证的原始电子数据，但公司未能提供这些数据。另一个关键缺陷是公司未记录所有生产部员工的针对其操作内容的培训。2013年7月，公司对一个如何在生产场所进行培训的SOP进行了修订，以包括在岗培训，但TRIFARMA并未遵守自己的程序。

Interestingly the US FDA has used the information gathered in a previous inspection of another production site of the company to check the compliance in the Rozzano site. Trifarma received a 483 form on similar deficiencies for it's Ceriano Laghetto plant but did not take the necessary actions to check if similar problems exist also at other manufacturing sites. From this the FDA concluded that there is not robust quality system is in place. The FDA also references the ICH Q7 Guide GMP for APIs and expects form API manufacturers to meet the requirements stated in that Guide.

有意思的是，美国FDA使用了此前在该公司的另一个生产场所检查中获得的信息，用于对ROZZANO场所的检查。在之前的检查中，TRIFARMA在CERIANO LAGHETTO的工厂收到了类似的483缺陷，但他们并没有采取必要的措施检查是否其它生产场所也存在同样问题。据此，FDA认为该公司质量体系不够好。FDA还引用了原料药GMP的ICH Q7指南，期望原料药生产商符合该指南中所提出的要求。