EUGDMP数据：无锡积大欧盟检查失败 - 药群论坛

检查方：意大利

检查日期：2015-6-11

产品：无菌冻干谷胱甘肽钠

检查区域：一厂和3号生产车间

不符合情况：检查发现28个缺陷，15个缺陷为重大缺陷。

重大缺陷：多个生产步骤有关于无菌保证的偏差，产品有污染风险：

a）取样间（念头14-15-16）：更衣间设计不适当，不能将污染风险降至最小；不同洁净级别之间的压差没有监测；更衣程序不符合洁净区的要求。

b)生产区域（偏差19-20-21-24）：不同洁净级别相邻区域的压差不符合欧洲

指南要求的值，有些生产房间的清洁状况很差，处理不充分，B级区粒子计数（即冻干机和压盖间）位置不适合既定用途，原料药从混合机转移到铝听时不能排除原料药污染风险。

c)验证（偏差7从a到j）：不同活动的验证方法没有根据GMP要求正确实施，验证报告不够详细（仓库温度分布研究、工具无菌状态保存时间、UV传递窗内物品放置时间、胶塞灭菌用温热灭菌柜的灭菌时过滤器最大数量验证、铝听灭菌用的干热灭菌验证、称重间的称量罩验证、取样间HVAC验证、预冻间级别验证、工艺模拟即将散装产品装入冻干机的最大灌装时间以及将原料药从混合机转移至铝听和压盖的最大时间验证报告。

d）包装和标签（偏差5-10-11-13）：有些测试中发现没有对无菌谷胱甘肽钠冻干粉的容器密闭系统进行管理，不能保证产品的无菌状态；一个“错误” 和未更新的标签用作标准来确认原料药的发运标签；在原料药仓库里，无菌原料药的铝听没有密封；铝盖没有批号标识无法追溯。

e）化验室测试（偏差28）：发现一些IR仪器的偏差，特别是红外没有通过ID和密码的受控权限，不能禁止拷贝和重命名文件。

f）人员行为（偏差2-7i(ii)18-19）：在检查期间，检查团对同一个问题从工人和管理人员得到的回答不一致，相互冲突；有时这些答案看起来是根据检查官的要求进行修正。文件展示不清楚，例如：有些平面图被替换了，有些文件与主题无关。最后，管理人员在现场检查过程中未能遵守更衣程序。

The inspection was performed by GMP inspectors in relation to the manufacture of sterile glutathione sodium lyophilised object of a variation. The inspection was focused on site 1 and production workshop number 3. During the inspection 28 deficiencies were found, 15 of which were rated as major deficiencies. Major Deficiencies: In many production steps deviations were found regarding the sterility assurance and a risk of contamination of the product: a) Sampling room (deviations 14-15-16): the changing room was not designed in a suitable way to minimize the risk of contamination; the differential pressure between the areas maintained at different cleanliness grade was not monitored; the garments procedure was not in accordance to the principle of classified areas; b) Production areas (deviations 19-20-21-24): the pressure differential between adjacent areas at different cleanliness grade was not in compliance with the guidance value of the European good manufacturing practices; the maintenance and cleaning conditions of some production rooms were poor and not adequately handled; the particle counters in B class grade (i.e. freeze-dryers and capping room) were unsuitable located for the intended use; the API transfer from the mixer to aluminum tin did not exclude a risk of API contamination. c) Validation (deviation 7 from letter a to j): the validation approach for different activities was not correctly performed according to the GMP requirements and validation reports were not detailed (warehouse temperature mapping; holding time for sterilization of tools; stay-time in UV-pass box; maximum number of filters sterlisation (20) validation for the moist heat sterilizer used for the rubber stopper sterilization; validation for the dry heat steriliser used for the aluminium tin sterilisation; validation for LAF in weighing room; validation for the HVAC of the sampling room; validation for front-freezing room classification; validation report for the process simulation namely maximum filling time of loading the bulk product in freeze-dryers and maximum time of transferring API from mixer to aluminum tins and capping. d) Packaging and labeling (deviations 5-10-11-13): the management for the container closure system for sterile glutathione sodium freeze-dried was found lacking in some tests to guarantee the sterility assurance of the product; a “wrong“ and not-updated label was used as a standard to verify the shipping labels of API; in the API warehouse, the aluminum tins of sterile API were not sealed; the aluminum caps were not identified with a batch number loosing traceability. e) Laboratory testing (deviation 28): some deviations were found for the IR instrument, in particular the IR software had not a controlled access via ID and password and it was not forbidden to copy and rename a file. f) Personnel behavior (deviations 2-7i(ii)-18-19): during the inspection, the inspectors’ team received inconsistent and conflicting answers on the same topic from both personnel and management; sometimes the answers seemed to be modified according to the inspectors’ requests. The documentation was showed in an ambiguous way as the examples: some layouts were replaced; some documentation was unrelated to the topic. Finally management did not comply with the clothing procedure during the inspection tour.