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2017-11-30 18:42 卓远天成
【工作资料】 FDA警告信之10大微生物发现项精选案例分析,你的实验室中招了吗?


“合规”是每一个质量人经常挂在嘴边的词。那么如何才能算合规?有没有统一的标准?要回答这个问题,很多人都会把审计有没有严重的缺陷项作为一项重要的指标。而在众多的审计中,FDA的审计似乎是“严厉”的代名词。一旦FDA审计出现问题、拿到警告信,企业立即声名扫地。今天,笔者精选了FDA警告信中与微生物实验室相关的缺陷项,聊聊微生物实验室的合规问题。

  案例一
On August 22, 2012, an FDA investigator observed your microbiologist reading an environmental monitoring (personnel) plate. The microbiologist reported the result for that plate as zero; however, our FDA investigator observed one (1) colony forming unit (CFU) on the plate.  Your microbiologist corrected this observation on the form WI-MI-150-108-J Microbiology Laboratory after the FDA investigator pointed it out to him. Your firm did not take further action to investigate and determine the impact of inaccurate reporting of your microbiological plate readings on the release of your batches.


2012年8月22日,检查员观察了贵公司的微生物分析员读取环境监测(人员监控)平板。该分析员报告了所读取的平板长菌数为零。然而,我们的检察员注意到该平板上有1cfu的菌。在我们的检察员指出之后,贵公司的分析员在表格“WI-MI-150-108-J微生物实验室”上纠正了这一错误。你们没有采取更多的措施去调查你们的分析员报告结果不准确对放行批次的影响。
  点评:这个是最基本的合规问题,也是最低级的造假。在FDA检查官眼皮底下谎报结果,真不知道这位分析员心里怎么想的。


  案例二
On June 23, 2014, during the inspection of the QC Microbiology Laboratory, our investigators observed missing in-progress microbiological test plates for various finished drug products, in-process products, water, and media growth promotion samples. For example….


2014年6月23日,在QC微生物实验室检查过程中,我们的检查官发现正在培养中的成品、中控产品、水和培养基促生长的平板数量缺少。例如:…...
  点评:正在培养中的平板数量与实际数量对不上,这已经成为了不少公司的发现项。据说核对平板数量已经成为部分检查员的固定套路,真实性有待考证。


  案例三:
Poor aseptic techniques were observed of Microbiology Technician performing sterility testing on 9/19/2012.


2012年9月19日,检查员观察微生物技术进行无菌检查时,发现无菌操作技术不当。
  点评:对于无菌生产企业,FDA检查员非常关注无菌操作技术。因此,在微生物实验室检查时,很多检查员会全程观察无菌检测试验,过硬的无菌操作技术才是硬道理。


  案例四
Your environmental monitoring data is not reliable. This is a serious deviation, as your ability to detect microbial contamination in the manufacturing environment during aseptic processing is fundamentally compromised. This information is critical to monitor the acceptability of the environment that the sterile drug and its container-closure components are exposed to during processing, and assure that these conditions consistently safeguard product sterility.
你们的环境监控数据是不可靠的。这是一个非常严重的偏离,因为你们无法探测到无菌生产过程中生产环境的微生物污染。这一信息(环境监控结果)对于监控无菌药品及其容器-密封组件在无菌生产过程中所暴露的环境、以及对于确保这些条件能够持续保护产品的无菌性是极为重要的。


a) Your firm used dried/desiccated media agar plates for environmental monitoring testing used to support the release of batches. On November 15, 2011, you documented that 155 of a total of 247 media plates evaluated (more than 50%) were dried. The use of dried agar plates, which do not reliably support microbial growth, to recover microbial contamination is inadequate.
贵公司使用干燥/失水的琼脂培养基进行环境监控,并用于批次的放行。2011年11月15日,你们记录中评估的247个平板中有155个平板干燥失水(超过50%)。干燥的平板不能可靠的支持微生物的生长,使用其检测微生物污染是不合适的。


b) On November 14, 2011, the FDA investigator observed desiccated environmental monitoring plates in your incubators. However, your analysts only recorded the results as dried media but not the counts from the plates (if any). On this same day, the FDA investigator observed plate “(b)(4),” sampled on November 9, 2011, to have growth of 1 Colony Forming Unit (CFU). However, your firm documented the result of this plate’s reading as "SAUSEN MEDIUM", dry medium, and failed to report the microbial growth.
2011年11月4日,FDA检查员观察到你们的培养箱中有失水的环境监控平板。然而,你们的分析员只记录为平板干燥,而不记录平板上的微生物数量(如有)。同一天,FDA检查员观察到平板xxx(取样日期2011年11月9日)上有1cfu的微生物。然而,贵公司记录这个平板的读数结果仅为“SAUSEN MEDIUM”,干燥的培养基,但没有报告培养基上有微生物生长。


c) Your environmental monitoring data for January 2009 through October 2011 contains documentation of only two action limit excursions in the Grade A manufacturing areas. In apparent contradiction, during an FDA visit to your microbiology laboratory on November 14, 2011, nine plates, collected as part of the environmental monitoring program from the Grade A manufacturing area were found inside an incubator in the microbiology laboratory with visible growth of microorganisms.
2009年10月至2011年,在A级区生产区,你们的环境监控数据仅有2次超出行动限。与之矛盾的是,2011年11月14日,一位FDA检查员检查你们的微生物实验室的时候,收集了部分在微生物实验室培养箱中正在培养的A级生产区的环境监控平板时,9块平板被观察到有微生物生长。


d) Your environmental sampling and testing program procedure is inadequate because it fails to adequately identify (e.g., with diagrams) the locations from which the surface samples are collected. In addition, you do not collect sufficient active viable air samples and dynamic non-viable particulate air samples from the critical area during manufacturing.
你们的环境监控程序是不充分的,因其不能识别(如:使用图表)表面微生物的取样位置。此外,在生产区的关键区域,你们没有采集足够的浮游菌样品和动态的粒子监控样品。


e) The agar level on surface contact plates (used for surface environmental and personnel monitoring sample testing) was below the rim of the plates creating the possibility that the agar would not have contact with the surface intended to be sampled.
接触平板(用于环境表面和人员监控)的琼脂高度低于平板的边缘,这使得琼脂在采样时可能没有接触到被取样位置的表面。


f) Your bioburden testing of the (b)(4) components is inadequate. Your firm lacks adequate controls to assure that the melted agar is sufficiently cool to prevent cell death of viable microorganisms. Specifically, your analyst determines by hand touch, without any instruments, the adequacy of the temperature of the melted agar medium used for the bioburden testing of the API, (b)(4) and (b)(4), before pouring the agar into the plates and mixing it with the samples.
你们对xxx组件的微生物负载的测试是不充分的。你们没有合适的控制措施确保融化的培养基充分冷却以防止微生物细胞的死亡。尤其,在把琼脂倒入到平板与样品混合前,你们的分析员靠手的接触而不是仪器确定融化的培养基的温度。
  点评:平板干燥、取样点位置不清晰、记录不准确、取样点数量不足、数据造假、检验过程培养基温度控制不当,这个环境监控体系的警告信够全面的。对于微生物的控制,每一个细节都是很重要的。


  案例五
For example: 例如b.   Sterility testing records for Anascorp® Bulk lots (b)(4) and Anascorp® Final Filled lots (b)(4) all show negative results for each day of the (b)(4) day incubation period. However, no analysts work on weekends and plates are only read Monday – Friday. An investigation revealed that microbiology personnel are instructed to record Saturday and Sunday results as negative if Monday’s results are negative as well. Anascorp®
半成品批次xxx和Anascorp®灌装批次xxx的无菌检查记录显示每一天的无菌培养结果均为阴性。然而,周末并没有分析员工作,平板仅在周一至周五观察。调查表明微生物人员被要求如果周一的结果也为阴性,则周六和周日的结果记录为阴性。


c.   Four different company personnel performed a secondary signoff on environmental monitoring records that had no documented results.
贵公司4个不同的人员在环境监控的二级复核上签了名,然而记录上结果记录部分却没有填写完整。
点评:这个有点尴尬,也是很多实验室面临的问题,即周末是否需要观察无菌检查结果。其实USP并没有规定无菌检查必须逐日观察(中国药典有此规定),因此只需真实记录观察日期的结果即可。然而,周六周日没有观察却记录为阴性,这就是数据完整性的问题了。记录复核部分,复核人员是检测结果放行的一道关键防线,不可掉以轻心,草率的签字,换来的是FDA对整个质量控制体系的质疑。

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