FDA 483表：Cook Pharmica 美国

翻译：JULIA 来源：Julia法规翻译

受检公司：Cook Pharmica LLC

受检地址：1300 S. Patterson Drive Bloomington, IN 47403

受检身份：原料药生产场所

FEI号：3005949964

检查员：

检查日期：2018-04-23至 2018-04-27，2018-04-30 至2018-05-01

签发日期：2018-05-01

发布日期：2018-09-10

This document lists observations made by the FDA representative(s) during the inspection of your facility. They are inspectional observations. And do not represent a final agency determination regarding your compliance if you have an objection regarding an observation, or have implemented, or plan to implement corrective action in response to an observation, you may discuss the objection or action with the FDA representative(s) during the inspection or submit this information to FDA to address above. If you have any questions, please contact FDA at the phone number and address above.

本文件列出了FDA代表在对你工厂检查期间所发现的问题。这些只是检查发现，并不代表FDA对你公司合规性的最终结论。如你们对某一缺陷有异议，或已实施或计划实施纠正措施来纠正某个缺陷，你们在检查期间与FDA代表讨论你们的异议与措施，或通过上述地址向FDA提交资料。如有问题，请通过上述地址电话与FDA取得联系。

DURING AN INSPECTIONOF YOUR FIRM WE OBSERVED: 

检查你公司期间我们发现

Observation1. There is an unacceptably high number of mold recoveries in the classified rooms used for manufacture of (b)(4) bulk drug substance. Specifically, mold recoveries in ISO-8 classified rooms ranged from 6 to 46 during 2017, and one mold was recovered in the ISO-7 manufacturing area during 2017. The mold recoveries have been trending upward since 2015.

缺陷1：用于生产XX散装原料药的洁净区内霉菌回收数字高得不可接受。具体来说，ISO-8洁净级别房间在2017年霉菌回收在6-46，2017年在ISO-7级生产区回收到一个霉菌。自2015年以来霉菌回收持续趋高。

Observation 2. Written procedures to prevent contamination of (b)(4) drug substance are not followed. Specifically, deviation PR 104369 was opened due to a bioburden excursion of the (b)(4) of (b)(4)lot (b)(4) on 12 July 2014. 190 CFU/mL were recovered (action limit: ≤(b)(4)CFU/mL).The root cause investigation showed that equipment ((b)(4)-160-01) was improperly setup: the (b)(4) connector was incorrectly (b)(4) during (b)(4) resulting in an ineffective cleaning cycle.

缺陷2：未遵守防止XX原料药污染的书面程序。具体来说，2014年7月12日XX批号XX产品的生物负载超标，偏差PR104369启动，其中发现回收值高达190CFU/ML（行动限≤XXCFU/mL）。根本原因调查显示设备（XX-160-01）安装不当：XX连接器在XX期间XX不正确，导致清洁循环无效。

Observation3. There is a lack of quality oversight in the review of records and proceduresfollowed in drug substance manufacture. Specifically, after deviation PR 176620(due to a bioburden excursion of the (b)(4) on 2 March 2017) was opened, an unacceptably high level of bioburden ((b)(4) CFU/100mL) was (b)(4) detected on1 May 2017 (LIMS sample #974194) , on the same process equipment (X-165-01) used to manufacture (b)(4) drug substance. The result (LIMS sample #974194) did not automatically trigger a root cause investigation because the associated bioburden limit was “report result”.

缺陷3：对记录和原料药生产所遵守程序的审核中质量监管缺乏。具体来说，在偏差PR176620（由于20170302生物负载超标）启动之后，20170501发现用于生产XX原料药的同一工艺设备（X-165-01）的生物负载水平高至不可接受（XXCFU/100ML）。该结果（LIMS样品#974194）未自动激活根本原因调查，因为相关的生物负载限度为“报告结果”。

Observation4. Corrective actions do not include implementation of adequate procedures to prevent similar deviations from recurring. Specifically, deviations PR 188727 and PR 189163 were opened because (b)(4) μm (b)(4) filter, item Master (IM) number 403350 (lot (b)(4)) failed to pass the (b)(4) integrity test. the root cause was determined to be a defect in the filter’s manufacturing process. The filter vendor implemented corrective actions to the filter manufacturing process inAugust 2017. The corrective actions implemented after deviations PR 188727 and PR 189163 did not include establishing appropriate procedures to prevent use of defective filters in the (b)(4) manufacturing process.

缺陷4：纠正措施未包括实施足够的程序来防止类似偏差的重复发生。具体来说，偏差PR188727和偏差PR189163由于XXμmXX过滤器，材料编号403350（批号XX）未通过XX完整性测试而启动。根本原因确定为过滤器生产工艺有缺陷。该过滤器供应商于2017年8月对过滤器的生产工艺实施了纠正措施。在偏差PR188727和PR189163之后实施的纠正措施不包括建立适当的程序防止在XX生产工艺中使用有缺陷的过滤器。

Observation 5. Sufficient controls to prevent unauthorized changes to data stored on your firm’s HPLC and GC computer systems are inadequate. Specifically, on 25 April 2018, a Senior Scientist demonstrated that the time zone setting could be changed and saved on the HPLC and GCsystems. No requirement of administrative privileges was required to change the time zone of your firm’s (b)(4) HPLCs and (b)(4) GC system, thereby allowing for the alteration of real-time records and data collection.

缺陷5：防止未经授权修改你们公司的HPLC和GC计算机系统上所存贮的数据的控制是不充分的。具体来说，20180425，一位高级实验员演示了可修改时区并保存在HPLC和GC系统上。修改你们公司的XXHPLC和XXGC系统的时区不需要有管理员权限，从而可以修改实时记录和数据集。