风云舍2018-06-12 16:25:38




相关链接:EU GMP不合格报告:济南金达药化








1.    Failure of your quality unit to exercise its responsibility to ensure the API manufactured at your facility are in compliance with CGMP, and meet established specifications for quality and purity.


 Your quality control laboratory disregarded multiple out-of-specification (OOS) impurity results without justification. For example, on September 22, 2015, you encountered an OOS unknown impurity peak during high performance liquid chromatography (HPLC) testing of (b)(4) 36-month stability batch (b)(4). You terminated the analysis. Testing of a new sample also showed the OOS impurity peak. The chromatogram was then manually rescaled, which hid the presence of this peak. Your laboratory set the integration parameters to omit this peak from integration. Because the peak was omitted, the quality unit was not provided with full information to evaluate whether the stability batch, and potentially other marketed batches, continued to meet quality standards.


 In addition, your audit trail showed that from July 1 to 2, 2015, you performed seven sample injections of (b)(4) 60-month stability batch (b)(4) to test for impurities using HPLC. You permanently deleted the first five sample injections. You then renamed the last two injections and reported that they met specifications. Your quality unit failed to identify and address these serious data manipulations.


2.    Failure to adequately investigate out-of-specification results.


 Your firm did not initiate investigations into failing results as required by your standard operating procedure (SOP) ZL/SOP/ZK/00405. On October 5, 2015, when you encountered an OOS value for an unknown impurity peak through HPLC testing of (b)(4) API 12-month stability batch (b)(4), you prepared and tested new aliquots. You did not investigate the failing result.

贵公司没有按照你们编号为ZL/SOP/ZK/00405的SOP 要求对不合格结果发起调查。2015年10月5日,当你们用HPLC分析某API 某批次第12个月稳定性样品时发现一个未知杂质峰超过限度时,你们制备并分析了新的样品你们没有调查该不合格结果。

We acknowledge your commitment to hire a third-party consultant to identify and evaluate all batches compromised by data integrity lapses. However, you failed to perform a comprehensive retrospective evaluation to determine whether appropriate corrective actions and preventive actions were identified and implemented for each OOS result obtained. Also, your retrospective review does not appear to address whether data integrity breaches occurred when using laboratory methods and systems that do not generate electronic data.


For more information about handling OOS results and documentation of your investigations, please refer to the FDA guidance for industry publication Investigating Out-of-Specification (OOS) Test Results for Pharmaceutical Production available online athttp://www.fda.gov/downloads/Drugs/.../Guidances/ucm070287.pdf.


 3.    Failure to prevent unauthorized access or changes to data, and failure to provide adequate controls to prevent omission of data.


 Our investigator observed that your laboratory systems lacked controls to prevent your staff from altering or deleting electronic data. Analysts manipulated and deleted audit trails. You lacked adequate controls for all HPLC, gas chromatography, and ultra-violet systems.


 For example, an analyst deleted audit trails in your gas chromatography equipment #YQ-07-10 from September 15, 2015, through April 24, 2016, and permanently deleted audit trails from November 6 to 13, 2015. In addition, our investigator observed that your quality control manager and quality control deputy manager had full administrative rights on all of your computerized systems, which allows them to manipulate data and turn off audit trails.


 We acknowledge that you commit to upgrading your analytical systems to be compliant with CGMP requirements. However, procuring new instruments, installing new and upgraded data acquisition software, and enabling various software features are insufficient to achieve CGMP compliance. These steps will be effective only if you implement appropriate procedures and systems to ensure that your quality unit reviews all production and control data and associated audit trails as part of the batch release process.


 Your response states that your SOP for electronic data management specifies that only information technology staff will have full administrator rights. However, you did not specify which information technology personnel will have these administrator rights. In addition, this SOP became effective on May 9, 2016, prior to the FDA inspection. However, your quality control management still had full administrative rights to all computerized systems during our inspection from May 30 to June 1, 2016.

你们的回复说你们的电子数据管理SOP规定了只有IT人员才能有最高管理权限。然而,你们没有指定哪个IT人员才有这种管理权限。另外,该SOP在FDA检查之前,2016年5月9日就生效了。然而你们的QC经理在2016年5月30到6月1日我们检查期间仍然对所有计算机化系统拥有最高管理权限 。