发布时间 : 星期三 文章英国药监局OOS翻译 - 图文更新完毕开始阅读2d35954710661ed9ad51f388
-使用合适的根因分析法，以头脑风暴寻找所有可能 - It is likely that there may be more than one root cause -很可能不止一个根本原因。
- Review decisions and actions taken in light of any new information. - 根据任何新的信息回顾决定及行动。
- Due to the variability of microbiological results don‘t limit the investigation to the specific batch it should be broader to review historical results and trends -由于微生物监测结果的可变性，不能将调查局限于特定批，应扩展至回顾历史数据及趋势。 - Unusual events should be included to understand potential impacts. -异常事件应利于理解潜在影响
- What is the justification to perform a repeat analysis (is sample left); re-test or Resample -开展再分析（样品丢失）；复检或再取样的理由是什么
- Any identifications may need to be at DNA/RNA level (bioburden failures) -一些鉴定可能需要在DNA/RNA水平（生物负荷失败）
- All potential sources of contamination need to be considered – process flow the issue from sample storage to the test environment. -所有潜在污染源需要确认-程序应遵循从样品贮存到实验环境。
- Use scientific decisions/justifications and risk based analysis. - 应用系统决策，并风险分析。
- The investigation may include working closely with the manufacturing team -调查应包括与生产团队紧密相关的工作。
- During the investigation it is an advantage to go and look at where the contamination occurred. -调查过程中，去看污染发生在哪里是有利的。
- Ask how relevant plant is cleaned, tested for integrity, checked for wear, checked for material suitability and maintained at the occurrence site may reveal possible causes. -在发生地询问相关厂房如何清洁、完整性试验、着装检查、原料稳定性检查及维护，可能揭示可能的原因。
- Where possible talk directly to the staff involved as some information may be missed if not looked at from the chemist/ microbiologist point of view. -哪里有可能直接告诉相关的员工，如果不是从一个化学家/微生物学家的视角去看，有些信息可能被忽视。
- Look for other documentation such as deviations and engineering notifications around the area of concern (this is applicable to the laboratory as well as manufacturing). - 翻阅其他文件例如相关区域的偏差及工程报告（这适用于化验室及生产部门）
- Trending can have species drift which may also be worthy of an action limit style investigation. -物种变异的趋势可能也是值得开展一个有限的调查活动
- Statistical analysis for microbiology can include lots of zero results so recovery rates or similar may have to be used. -微生物实验统计分析包括一些0结果，所以回收率或类似方法可能不得不使用。
- If a sample is invalidated the remaining level of assurance needs to be carefully considered, is their sufficient residual information? -如果一个样品宣告无效，应认真考虑其残留的保证水平，其是否残留有足够的信息？ - Corrective actions may be appropriate for more than one root cause. -纠正措施应适合一个以上的根本原因。
Stability – OOS/OOT:稳定性-OOS/OOT
Stability OOS/OOT situations should be escalated as soon as the
suspect result is found. Follow the investigation as above for Phase I and Phase II. For OOS Situations Regulatory agencies will require notification within a short time point of discovery due to recall potential. 一旦可疑的结果被发现，稳定性OOS/OOT状态应被升级。按照上述步骤l及步骤ll调查程序开展。OOS管理部门要求在发现后最短时间通知，因为有潜在的召回工作。
If abnormal results are found at any stability interval which predicts that the test results may be OOS before the next testing interval, schedule additional testing before the next scheduled testing interval. This will help better determine appropriate actions to be taken. The stability OOS should link to the Product Recall procedures. 在下一个检测时间段之前的任何稳定性考察时间段如果发现异常结果表明试验结果为OOS，应在下一个时间点检测之前计划增加试验。这将有助于采取更合适的行动。稳定性OOS应与产品召回程序关联。
OOT
To facilitate the prompt identification of potential issues, and to ensure data quality, it is advantageous to use objective (often statistical) methods that detect potential out-of-trend (OOT) stability data quickly. OOT alerts can be classified into three categories to help identify the appropriate depth for an investigation. OOT stability alerts can be referred to as: 为有利于潜在问题的快速识别及确保数据的质量，使用客观方法（经常为统计方法）快速确定潜在的OOT是有益的。OOT警报可分为三类以帮助识别调查的合适深度。OOT稳定性警报可被称为： ? analytical,分析的
? process control, and 过程控制，和 ? compliance alerts, 合规性 警报
As the alert level increases from analytical to process control to compliance alert, the depth of investigation should increase. 警报水平从分析警报、过程控制警报到合规性警报逐渐增加，调查深度也逐步增加。
Stability:
– A compliance alert defines a case in which an OOT result suggests the
potential or likelihood for OOS results to occur before the expiration date within the same stability study (or for other studies) on the same product. - 合规性警报定义为此种情况：OOT结果暗示在有效期之前该产品用该稳定性考察方法会有潜在的或
可能的OOS结果。
– The stability OOS should link to the Product Recall procedures. -稳定性OOS应与产品召回程序关联。
– Historical data are needed to identify OOT alerts. -需要用历史数据来识别OOT警报
– An analytical alert is observed when a single result is aberrant but within specification limits (i.e., outside normal analytical or sampling variation and normal change over time). - 分析警报触发：当单个结果异常但是在标准范围内（即 超出正常分析结果或取样差异及随时间的正常变化。
Phase III Investigation
The phase 3 investigation should review the completed manufacturing
investigation and combined laboratory investigation into the suspect analytical results, and/or method validation for possible causes into the results obtained. 步骤lll调查应当检查完成的生产调查，及与可疑结果关联的实验室调查，和/或与结果关联的为寻找可能原因而开展的方法验证。
? To conclude the investigation all of the results must be evaluated. 所有的结果必须得到评估后才能结束调查，
? The investigation report should contain a summary of the investigations performed; and a detailed conclusion. 调查报告应包含调查执行过程的概要，以及详细的结论。
? For microbiological investigations ,where appropriate, use risk analysis tools to support the decisions taken and conclusions drawn. It may not have been possible to determine the actual root cause therefore a robust most probable root cause may have to be given. 对于微生物实验调查，应适当的使用风险分析工具以支持做决定和下结论。可能不会找到真正的原因，因此最可能的根本原因应找到。
? The batch quality must be determined and disposition decision taken. 该批产品质量必须给予确定，并制定处理措施。
? Once a batch has been rejected there is no limit to further testing to determine the cause of failure, so that corrective action can be taken. 一旦该批产品判定不合格，没有限制开展进一步的试验以确定失败原因，以便执行纠正措施
? The decision to reject cannot be reversed as a result of further testing. 不合格的决定不能因为进一步的试验结果而得到逆转。
? The impact of OOS result on other batches, on going stability studies, validated processes and testing procedures should be determined by Quality Control and Quality Assurance and be documented in the
conclusion, along with appropriate corrective and preventive actions. OOS结果对其他批次、进行中的稳定性研究的影响，应有QC和QA确定验证过程和试验程序，并在结论中书面说明，并附适当的CAPA活动。
Conclusion:
– If no laboratory or calculation errors are identified in the Phase I and Phase II there is no scientific basis for invalidating initial OOS results in favour of passing retest results. All test results, both passing and suspect, should be reported (in all QC documents and any Certificates of Analysis) and all data has to be considered in batch release decisions. -如果在步骤l及步骤ll中未发现实验室或者计算错误，那么就没有科学的根据使原OOS结果无效而支持过去的复检结果。所有试验结果，包括以往的和此怀疑结果应报告（在所有QC记录中及任何的检验报告中），所有数据应在批放行决定时予以考虑。
– If the investigation determines that the initial sampling method was inherently