首页 > 资讯 > Janssen连续制造线批准前检查曾收到FDA483

出自识林

2016-06-14

4月8日FDA批准Janssen公司用于治疗HIV-1感染的Prezista（darunavir，地瑞那韦）将生产方式从“批制造”变更为连续制造。两个月前，FDA于2月22日到26日对Janssen公司位于波多黎各Gurabo市的工厂就NDA 21-976/Supp-42 Prezista（地瑞那韦）600mg薄膜包衣片新的连续制造工艺开展批准前检查（PAI），检查之后发布483缺陷表。

Janssen公司表示，已制定整改计划回复483发现项以解决检查员的担忧，FDA在批准生产变更之前也已接受该整改计划。FDA发言人Kristofer Baumgartner证实，鉴于观察项的性质和公司的书面回复，FDA决定Janssen的申请可以获得批准。

公司于今年4月正式将生产线从批生产转向连续生产，成为第一家做出生产中转变的公司。

483观察项中文翻译

观察项 1

没有按照设计用于确保正常性能的书面程序执行自动化控制系统的日常维护。具体来说，

a. 用于负责确保Prezista600mg的制造质量的■■和相关联的自动化控制没有预防维护计划，包括频率和维护活动说明。

b. 根据近红外（NIR）模型维护方法■■，维护依赖于对模型性能的追踪、■■和监测。然而，未建立书面程序对NIR模型性能结果进行追踪和趋势分析。

观察项 2

计算机或相关系统没有适当的控制，无法确保主生产和控制记录或其它记录的修改仅由授权人员执行。具体来说，■■的普通用户帐号具有维护、主管和管理员权限。

观察项3

设备维护和清洗记录未保存。具体来说：

1. 2015年3月IQ/OQ方案按照验证文件计划■■中的描述执行，而2016年2月22日批准的验证报告未按照计划中所规定的实施。例如：

a. 2014年3月19日，■■ ■■的安装和运行确认的■■附录被发布给■■，这一操作的实施未报告偏差。（直至）2014年6月12日，发布方案的差异报告（DR）（才）包括■■范围。要求该活动在同一偏差中记录单独的安装和确认操作，而非通过原始方案附加的附录或独立方案。在差异报告发布后，在2014年7月记录了仅针对附录的执行后批准认定。

b. 2015年10月最新版本■■ ■■的■■功能需求和系统设计规格中描述了拟定的■■。然而，如■■中所报告，新的组件于2014年7月通过差异报告（DR）安装。

2. 用于波多黎各Gurabo市的Janssen供应链的Prezista 600mg连续制造线■■的“■■清洁研发中期报告"于2016年2月22日被批准。报告包括了从为放行■■所执行的清洁操作中获得的结果。报告的所有结果均为可接受，在专用设备的一些清洁次数上建议更新，以及在实际清洁验证期间不增加或减少测试点。

评估Prezista 600mg片剂用■■（设备）清洁工艺和脏设备保留时间的“■■验证方案”于2016年2月23日根据中期报告所记录的清洁研发活动结果被批准执行。

该方案对■■的几件设备中■■，但未能包括可以■■的书面证据。

3. 配方成分供给装置的设备部件组装缺少充分的书面说明。工作辅助（说明）■■不包括将螺丝匹配给正确的成分供给装置的具体说明。

483观察项英文原文

OBSERVATION 1

Routine maintenance of the automated control system is not performed according to a written program designed to assure proper performance. Specifically,

a. There is no preventative maintenance plan including frequency and a description of maintenance activities, available for the ■■ and associated automation controls which are responsible for ensuring the quality manufacture of Prezista 600 mg.

b. As per NIR model maintenance approach ■■ maintenance relies on tracking and ■■ and monitoring of model performance. However, written procedures are not established to track and trend NIR model performance results.

OBSERVATION 2

Appropriate controls are not exercised over computers or related systems to assure that changes in master production and control records or other records are instituted only by authorized personnel. Specifically, general user accounts with Maintenance, Supervisor, and Administrative privileges are available for the ■■.

OBSERVATION 3

Records are not kept for the maintenance and cleaning of equipment. Specifically:

1. IQ/OQ protocols executed on site as described in Validation Document Plan ■■ Mar 2015, and approved report ■■ 22 Feb 2016 are not always executed as defined in the plan. For example:

a. ■■ Addendum to the Installation and Operational Qualification to the ■■ ■■ was issued to ■■ the exercise was executed with no reported deviations as of 3/19/14. In 6/12/14, a Discrepancy Report (DR) to the protocol was issued to include ■■ scope. This activity required separate installation and qualification exercises documented in the same deviation and not via an addendum to the original protocol or with a separate protocol. A post-execution approval certificate to only the addendum was documented in 7/2014, after the discrepancy was issued.

b. ■■ Functional Requirement and System Design Specification for the ■■ ■■ described the proposed ■■ in the most recent version dated Oct 2015. However, as reported in ■■ the new part was installed via discrepancy (DR) in 7/2014.

2. ■■ Interim report of the Cleaning Development for the Continuous Manufacturing Line ■■ used for Prezista 600mg at Janssen Supply Chain, Gurabo, was approved in 22-Feb-2016. The report included results obtained for cleaning exercises conducted in order to release the ■■. All results were reported as acceptable, with recommended updates in some of the cleaning times for identified equipment and no additional or reduced testing sites to be executed during the actual cleaning validation.

■■ Validation Protocol to Evaluate the Cleaning Process and Dirty Holding Times for the ■■ used for Prezista 600mg Tablets, was approved on 23-Feb-2016 for execution based on outcome of Cleaning Development exercise documented with Interim report ■■

This protocol ■■ in several pieces of equipment for the ■■ but failed to include documented evidence that would ■■ ■■.

3. Adequate written instructions are not in place for assembling the equipment parts of the formulation component feeders. Job Aid ■■ does not include specific instructions for matching the screws with the correct component feeder.

编译：识林-椒
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