FDA 483:诺华AveXis, Inc,原始数据通过口头传递!

实验室资讯网时间:2019-08-09 点击: 百度搜索

【导读】近日,FDA发布了 诺华的子公司AveXis, Inc . 的483缺陷报告,包括如下GMP缺陷: 数据完整性偏差调查不充分,未对其它可能受影响的数据、试验和报告进行审查以确定是否存在数据完整性问题,也没有关于不执行或计划执行此类审查的论证。 偏差调查(数据完整性)在报告后 两个月才发起 ,未就此说明原因......
TAG标签: FDA 诺华 AveXis 原始数据 口头传递

近日,FDA发布了诺华的子公司AveXis, Inc .的483缺陷报告,包括如下GMP缺陷:


  • 数据完整性偏差调查不充分,未对其它可能受影响的数据、试验和报告进行审查以确定是否存在数据完整性问题,也没有关于不执行或计划执行此类审查的论证。

  • 偏差调查(数据完整性)在报告后两个月才发起,未就此说明原因

  • 检验(记录)尚未完成,检验报告已生成且已批准

  • 记录不受控,一共4页的检验记录发现有3页和另外1页打印日期不一致

  • SOP未规定需要对每一页上的日期/时间戳进行确认

  • SOP模棱两可,导致关于小鼠存活天数的记录与实际不一致(有1天的出入)

  • 原始数据通过口头传递,且接收人是质量人员。

  • 天平没有审计追踪,也没有配备打印机

  • 天平本身具备打印功能,但实际未使用

  • 称量记录未记录天平的编号

  • 产品检验人员直接向研发经理报告,且该研发经理自认之前没有GMP实验室的直接工作经验

  • 未对对照品进行检验





Firm name  :AveXis, Inc .

公司名称:AveXis, Inc .

Date Of Inspection:7/24/2019- 8/2/2019 *

检查日期:7/24/2019- 8/2/2019





There is a failure to thoroughly review any unexplained discrepancy whether or not the batch has been already distributed. 



A. Non-conformance Report NCR-1922 (which was open at the time of the current inspection) was opened on 15 May 2019 due to a report that was made to the CQO (Chief Quality Officer) alleging that data derived from the AVXS -101 In-Vivo Relative Potency Assay Studies 1-10 may have been mismanaged or even potentially manipulated. Aside from evaluations of Studies 1-10 and a planned evaluation of toxicological studies under NCR-2018 there is no documentation in this NCR that an audit of all other potentially impacted data, studies, and reports was conducted or is planned to determine if there was evidence of data mismanagement or manipulation or a justification for not conducting or planning such an audit.

A. 2019年5月15日发起了偏差报告NCR-1922(检查期间处于开放状态)调查,原因是有一份报告提交给CQO(首席质量官)的报告表示“AVXS-101体内相对效价测定试验1-10”的数据可能处理不当甚至可能被操纵。除对试验1-10的评估以及根据NCR-2018计划对毒理试验进行评估之外,该NCR中没有文件记录显示对所有其它可能受影响的数据、试验和报告执行了审查或计划进行审查以确定是否存在数据处理不当或数据操纵的证据,也没有关于不执行或计划执行此类审查的论证。


Additionally, there is no documentation in NCR-I922 as to why the NCR was not opened until 15 May 2019 when the initial allegation is documented as having been reported on 14 March 2019.

此外,记录显示该问题报告于2019年3月14日,但是直到2019年5月15日才发起NCR, NCR-1922中未就此说明原因。


B. Non-conformance Report NCR-409 was opened on 31 Jan 2018 and has an "Event Description" of "On 3l Jan2018, during a historical data review of the potency results for Drug Product Lot 600156 per SOP-285, Determination of In Vivo Relative Potency for AVXS-101 Drug Product, it was discovered that the associated assay from (FORM-212) ,was not completed at the time of CoA generation and approval for Lot 600156...." During the inspection, the associated FORM -212 was reviewed and it was observed that the date/time stamps on the 4 page form are discrepant in that 3 of the 4 pages have a "Generated" date/time of "05 Jan 20l8 09:44AM" and 1 page (page 2) has a "Generated" date/time of "04 Jan 20l8 09:39AM". There is no documentation in NCR-409 that this discrepancy was noticed or investigated. Additionally, current SOP-381 Version 2.0 entitled "Control of QC Test Forms" does not specifically require verification of consistent date/time stamps on each page of a test form during reconciliation of the form.

B. 2018年1月31日发起了偏差报告NCR-409,其“事件描述”为“2018年1月31日,按照SOP-285《AVXS-101药品体内相对效价确定》对药品600156批的效价结果进行历史数据审核时,发现生成和批准600156批CoA时,相关的检验记录(FORM-212)尚未完成……”检查员在检查期间对相关的FORM-212进行了审核,发现该4页记录上的日期/时间戳是不一致的,4页中有3页的“生成”日期/时间为“2018年1月5日09:44AM”,而1页(第2页)的“生成”日期/时间为“2018年1月4日 09:39 AM”。NCR-409没有记录显示此差异被发现或被调查。此外,目前SOP-381版本2.0标题为《QC 检验记录的控制》没有具体要求对每个页面上的日期/时间戳一致进行确认。


C. Non-conformance Report NCR-965 was opened on 23 Aug 2018 and has and "Event Description" of "On 23Aug 2018, during the review of 6.7SMA mouse database, it was discovered that there were discrepancies in the data that was used to calculate relative potency for AVXS-101 Drug Product. Lot 816836 had single mouse survival days recorded that were different from the actual value . . .." As documented in the investigation most of the discrepancies noted were discrepant by a single day which was attributed to ambiguity in SOP-285 "Determination of In-Vivo Relative Potency for AVXS-101 Drug Product" however in 4 cases discrepancies of greater than I day were noted (ranging from 2-19 days). There is no documentation in NCR-965 that these 4 cases were investigated further to determine a potential root cause.

C. 2018年8月23日发起偏差报告NCR-965,其“事件描述”为“2018年8月23日,在对Δ7SMA小鼠数据库进行审查时,发现用于计算AVXS-101药品相对效价的数据存在差异。816836批所记录的单个小鼠存活天数与实际值不同……”正如调查所记录的那样,大多数差异是一天的差异,这是由于SOP-285《AVXS-101 药品体内相对效价确定》的描述模棱两可而导致,但有4个差异的大于1天的(2-19天不等)。NCR-965中未对这四个差异开展进一步调查来确定可能的根本原因。


D. Non-conformance Report NCR-1116 was opened on 15 Oct 2018 and has "Event Description" of "Inconsistencies were identified during the review and approval of the data previously reported within REC -1606 v 1.0 'Mouse Survival Data: Results for In-vivo Relative Potency for AVXS-101 Drug Product' . . .." As documented in the investigation " ...During investigational review of the Quality Employee's process, it was determined that some of the early raw data results were initially communicated verbally from the . .to the AveXis Quality Employee. ..." There is no documentation in NCR- 1116 explaining why the Quality Employee accepted verbal communication of raw data without corresponding written documentation.

D. 2018年10月15日发起偏差报告NCR-1116,其“事件描述”为“在审核和批准之前在REC-1606 v1.0《小鼠存活数据:AVXS-101药品体内相对效价结果》内报告的数据时发现了不一致…”。如调查中所记录,“......在对质量人员的流程进行调查审查期间,发现了一些早期原始数据结果最初是通过……口头传达给AveXis质量人员……的。”NCR-1116没有记录解释为什么质量人员在没有相应书面记录的情况下,接受原始数据口头传达。





Laboratory records do not include complete data derived from all tests, examinations and assay necessary to assure compliance with established specifications and standards.



A. Analytical Balance ID #: (b) (4), which is used to weigh mice handled under SOP-268 Version 2.0 entitled ''Observation and Handling of Study Mice for AVXS-101 Potency Assay" does not have audit trail capability. These mice are used for SOP-346 Version 3.0 entitled "In-vivo Functionality Test using a Single Dose AVXS-101 in SMN△7 Mouse Model."



B. Printouts for the weighing of mice are not made and included in the logbook where the weights are currently manually recorded. Analytical Balance #: (b) (4) which is used to weigh the mice is capable of producing printouts of weighings; however printouts of mouse weights are not made and included with the data that is manually recorded in the logbook, that as an example can be seen in Logbook ID Number 000139 "AVXS-101 In-vivo Functionality" on FORM-339 "Weight and Survival Data for AVXS-101 Functionality Test". These mice are used for SOP-346 Version 3.0 entitled "In-vivo Functionality Test using a Single Dose AVXS-101 in SMN△7 Mouse Model".

B. 小鼠称重未配备打印输出并且贴在同步的手写记录中。小鼠称重所用分析天平ID#:(b)(4),是具备打印功能的;但是没有使用并附在手写记录中,可以在记录# 000139《AVXS-101 体内功能检验》表-339《AVXS-101 体内功能检验的重量和存活数据》中可以看到这样的例子。这些小鼠被用于SOP-346版本3.0《在SMN△7小鼠模型中使用单剂量AVXS-101进行体内功能检测》。


The equipment number of the analytical balance which is used to weigh mice handled under SOP-268 Version 2.0 entitled "Observation and Handling of Study Mice for AVXS-101 Potency Assay" is not recorded in the logbook which, as an example can be seen in Logbook Number 000139 "AVXS-101 In-vivo Functionality". These mice are used for SOP-346 Version 3.0 entitled "In-vivo Functionality Test using a Single Dose AVXS-101 in SMN~7 Mouse Model".

C.被用于按照SOP-268版本2.0《用于AVXS-101效价测定的试验小鼠的观察和处理》处理的小鼠称重的分析天平设备编号没有记录在记录中,例如,记录# 000139《AVXIS-101体内功能检验》。这些小鼠被用于SOP-346版本3.0《在SMN△7小鼠模型中使用单剂量AVXS-101进行体内功能检测》。






The responsibilities and procedures applicable to the quality control unit are not fully followed.



Specifically, vivarium employees who have responsibilities for GMP functions such as animal dosing, tail snips for genotyping, weighing, death determination, and contemporaneous documentation report directly to an R&D manager. This is not in accordance with the "Quality Manual" version 3. There are (b){4 employees that perform these functions for commercial product testing (SOP-346 - In-vivo Functionality Test using a Single Dose AVSX-101 in SMN.6.7 Mouse Model) who directly report and are supervised by a "Senior Scientist" in the Research and Development team. This Senior Scientist has

self-described no direct prior experience in GMP controlled lab work.







Laboratory records do not include complete records of any testing and standardization of laboratory reference standards.



Specifically, reference standard lots have not been tested and shown to meet initial release criteria in applicable versions of SOP-285 (Determination of In Vivo Relative Potency for AVXS-101 Drug Product) such as minimum slope of increasing doses, minimum mouse cohort sizes, and minimum survivability medians at the test dose.



This is applicable to reference standard lots #AAV9SMN0613 and #600443 tested in March 2017 and February 2018 respectively winch serve as reference standards for potency and in-vivo functionality methods performed for the AVXS-101 product over the past three years. These lots have potency values reported in BLA 125694.

这适用于分别在2017年3月和2018年2月检测的参照标准批#AAV9SMN0613和#600443 , 这两批产品作为AVXS-101产品在过去3年中执行的效价和体内功能性方法的参照标准。这些批次在BLA 125694中报告了效价值。






Established test procedures are not followed.



Specifically, as per SOP-346 Version 3.0 "In-vivo Functionality Test using a Single Dose AVXS-101 in SMN△7 Mouse Model" the mouse date of death is in part defined as the " ...date the animal first lost (b)(4)% of its body weight...". As per SOP-268 Version 2.0 "Observation and Handling of Study Mice for AVXS-101 Potency Assay" study animals are weighed"...(b) (4) (separated by at least (b) (4))until end of study .. ." AveXis has interpreted the date the animal first lost (b)(4)% of its body weight as the date this loss Is first documented. Since mice are not weighed daily there is no documentationS owing the exact date the mouse lost (b)(4) %of its body weight.

具体而言,按照SOP-346版本3.0《在SMN△7小鼠模型中使用单剂量AVXS-101进行体内功能检测》 , 鼠死亡日期部分被定义为“……动物首次减少其体重(b)(4)%的日期……”。根据SOP-268版本2.0《用于AVXS-101效价测定的试验小鼠的观察和处理》,对试验动物进行称重“...... (b)(4)(至少间隔(b)(4) )直至试验结束……”AveXis将动物首次减少其体重的(b)(4) %的日期解释为该体重损失首次被记录的日期。由于未每天对小鼠进行称重,因此没有文件记录显示小鼠体重减少(b)(4)%的确切日期。






7/24/2019(Wed), 7/25/2019(Thu), 7/26/2019(Fri), 7/29/2019(Mon), 7/30/2019(Tue), 7/31/2019(Wed), 8/01/2019(Thu), 8/02/2019(Fri)


(本文来源:公众号 GMP办公室)



TAG标签: FDA 诺华 AveXis 原始数据 口头传递
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