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1. Your firm failed to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity (21 CFR 211.160(b)).
未建立科学适宜的质量标准、取样程序和检测规程,来确保物料包材、中间体、标签和产品质量
For example, during inspection of the QC microbiology testing laboratory, our investigators observed:
例如在微生物实验室发现:
A. No growth on the positive control plate for media used to test microbiological (b)(4) samples. When a positive control fails to yield growth, test results cannot be considered valid due to the potential for false negatives.
**阳性对照未长菌,有假阴性的风险。
B. Desiccation of a contact media plate used during environmental monitoring of the sterility testing area. Desiccated, cracked, or otherwise damaged (b)(4) compromises microbial growth promotion and accurate enumeration, and can lead to artificially low microbiological counts and false negatives. Using deficient media compromises the validity of your microbiological test results.
Also, you did not appear to routinely identify (i.e., to species level) bacterial and fungal isolates recovered during environmental monitoring of your aseptic processing room.
用于无菌检查区域的环境监控平皿干了。使用干的、破碎的或其他损坏的平皿会导致促生长性和计数的精确度变差,是计数偏低或假阴性,影响微生物测试结果的有效性。
C. Air bubbles between filtration (b)(4) and (b)(4) plates in 13 out of (b)(4) microbiological (b)(4) system sampling plates. Inadequate contact between the filter (b)(4) and the (b)(4) plate may compromise recovery.
Your response indicates that you evaluated the impact of these laboratory deviations and believe they pose a low risk. The response lacks a commitment to perform a comprehensive evaluation of your microbiology laboratory controls and practices.
微生物采样系统的膜与平皿间有气泡,有气泡的地方会影响回收率,你们回复中反映你们评估了这种偏差,导致的风险很低,回复总未承诺要综合的评估你们微生物实验室的控制和管理规范。
2. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes (21 CFR 211.113(b)).
未建立书面程序来预防产品受微生物污染,包括所有的误解工艺
During review of your 2014 smoke studies, our investigators observed turbulent air flow in the ISO 5 area on the (b)(4) vial filling and capping production line at approximately 09:53 and 10:39 minutes.
In your response, you state that you have performed new smoke studies and that these new studies demonstrate unidirectional airflow during manual interventions. However, your response is inadequate because you did not assess past occurrences of deficient airflow in smoke studies or provide corrective actions to your process design to resolve these issues. You also did not provide copies of the recent dynamic smoke studies.
In response to this letter, include a thorough retrospective review of smoke studies and a CAPA plan to address all deficiencies.
2014年进行的烟雾测试,检察人员发现灌装和压盖的ISO5在大概09:53 -10:39期间有湍流。
在你们的回复中你们声称你们进行了新的烟雾测试,并且新的测试证明在人为干预下气流为层流,然而你们的回复是不充分的,你们并没有评估之前失败的测试或采取整改措施来解决这个问题。你们也没有提供最近的动态烟雾测试的拷贝件。
See FDA's guidance document, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice, to help you meet the CGMP requirements when manufacturing sterile drugs using aseptic processing, athttp://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070342.pdf.
可以学习一下上面这个指南。
3. Your firm failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records (21 CFR 211.68(b)).
未对计算机系统采取适当的控制来确保只有经授权的人才能更改生产和控制记录或其他记录。
For example, during inspection of the sterile manufacturing and QC microbiology areas, our investigators observed:
例如,检查过程中发现微生物室:
A. Deletion of at least six (b)(4) and (b)(4) tests in the audit trails for two instruments used to test sterile (b)(4). Your systems allowed operators to delete files. You had no procedure to control this practice or to ensure a backup file was maintained. When you reviewed the audit trail data further, you identified a total of 25 deleted (b)(4) test results. In your response, you state that the production staff now only have “view and print” privileges. However, your response is inadequate because it lacks details of how appropriate oversight will be exercised over data backup to ensure it is appropriately retained.
删除了两台测试无菌产品的仪器的至少六批测试的审计追踪,你们的系统允许操作员删除文件,没有规定来控制这种行为或确保保留了备份。之后你们审核审计追踪时,你们发现了总共25次删除数据的情况。在你们的回复总你们声称生产人员现在只有浏览和打印权限。然而,你们的回复是不充分的,因为缺少如何合理的监督数据备份来确保数据被合理的保存的细节。
B. No restricted access to the microbial identification instrument. Further, you lacked restricted access to the external hard drive used for backup of this instrument. All users could delete or modify files. In your response, you commit to limit access to the system and external hard drive. However, your response is inadequate because you did not provide a retrospective risk assessment of the impact and scope of inadequate system controls at your firm.
微生物鉴定仪器没有权限管理。你们缺少对外部硬盘用于该仪器的备份的控制,所有人员都可以删除或修改文件。你们回复中承诺限制人员进入和限制外来硬盘,然后你们的回复总并没有回顾之前受该问题影响的风险。
4. Your firm failed to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21 CFR 211.194(a)).
未能确保实验室记录包括所有测试数据。
(b)(4) failed identity testing. You accepted a passing retest result without any investigation of the failed result.
**鉴定失败,你们在为进行调查的情况下接受了复测结果
In your response, you state that you attempted to conduct a retrospective investigation of the analysis which occurred more than a year earlier, and tentatively concluded that the out-of-specification (OOS) result might have been caused by analyst error. Also, your investigation recommends replacement of the polarimeter on which the OOS result was obtained.
你们回复中声称你们试图对一年多以前的事情开展一个回顾调查,并且暂时确定OOS的原因可能是人员错误,同时,你们调查中建议替换产生OOS结果的旋光仪。
Your response did not include a commitment to revisit the adequacy of your OOS procedures. When an OOS result is obtained, initiation of a prompt laboratory investigation is critical. In addition, you must provide all data obtained during testing to the quality unit for batch record review. If the laboratory invalidates an OOS result, it is essential that the batch record include the relevant investigation. Only a scientifically sound and conclusive investigation can justify the exclusion of an OOS result from the final certificate of analysis.
你们的回复中没有包括重新审核你们的OOS程序,但OOS结果出现时,迅速展开实验室调查很关键。另外,你们必须提供所有的检测数据给批记录审核的质量管理人员,如果实验室确认OOS结果无效,批记录中包含调查过程是基本要求,只有一个科学合理的最终调查才可以证明排除一个OOS结果是合理的。
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