发布时间 : 星期六 文章英国药监局OOS翻译 - 图文更新完毕开始阅读2d35954710661ed9ad51f388
– Can be a 2nd aliquot from the same sample that was the source of the original failure.
从相同样品得到整数倍的结果，可能是原始错误的来源。
– If insufficient quantity of the original sample remains to perform all further testing then the procedure for obtaining a resample must be discussed and agreed by QA/Contract Giver/QA equivalent. The process of obtaining the resample should be recorded within the laboratory investigation. - 如果原始样品保存不足以开展所有进一步的试验，重新取样程序必须进行讨论并得到QA/合同供应商/具有QA职责的人的批准。重新取样程序应当在实验室调查记录中体现。
– The decision to retest should be based on sound scientific judgement. The test plan must be approved before re testing occurs. - 复检的决定应当给予全面科学的判断。在复检开始前试验计划必须的到批准。 – The minimum number of retests should be documented within the procedure and be based upon scientifically sound principles. Any statistical review with regards to %RSD and repeatability should relate to the values obtained during method validation (accuracy, precision, and intermediate precision). The
number of retests should be statistically valid; papers have suggested 5, 7, or 9. 应给予科学全面的原则制定最少复检次数，并在程序中文件规定。任何关于RSD、重复性的统计回顾分析应符合方法验证中的值（准确性、精密度、及中间精密度）。复检次数应在统计上有效，文件建议5,7或9次。
– The retests should be performed by a different analyst where possible. The second analyst should be at least as experienced and qualified in the method as the original analyst.
-复检应尽可能由不同分析人员开展。第二个检验人对于该方法的经验和资质应至少与原检人一致。
Averaging:求平均
– The validity of averaging depends upon the sample and its purpose. Using averages can provide more accurate results. For example, in the case of
microbiological assays, the use of averages because of the innate variability of the microbiological test system. The kinetic scan of individual wells, or
endotoxin data from a number of consecutive measurements, or with HPLC consecutive replicate injections from the same preparation (the determination is considered one test and one result), however, unexpected variation in replicate determinations should trigger investigation and documentation requirements. -平均值的有效性基于样品及目的。使用平均值能够提供更准确的结果。例如：微生物分析中，因为微生物检验系统固有的可变性而使用平均值。单孔动态扫描，或者一系列测量的内毒素数据，或者HPLC试验对同一试验溶液进行连续重复进样（一个试验或者一个结果的得出），然而，平行测定中异常的数据应进行调查并达到文件要求。 – Averaging cannot be used in cases when testing is intended to measure variability within the product, such as powder blend/mixture uniformity or dosage form content uniformity.
-当检测用作检测生产过程的可变性时，平均值在一些情况下不能使用，如粉末混匀均匀
性，制剂的含量均匀度。
– Reliance on averaging has the disadvantage of hiding variability among
individual test results. For this reason, all individual test results should normally be reported as separate values. Where averaging of separate tests is
appropriately specified by the test method, a single averaged result can be reported as the final test result. In some cases, a statistical treatment of the variability of results is reported. For example, in a test for dosage form content uniformity, the standard deviation (or relative standard deviation) is reported with the individual unit dose test results.
使用平均值具有隐藏个别实验结果差异的缺点。为此，所有独立试验结果应作为独立值常规性报告。各试验结果的平均在试验方法中给予适当的说明，独立的平均值可作为最终实验结果报告。例如，在制剂含量均匀性试验中，应报告标准偏差（或相对标准偏差）及单个单位样品的试验结果。
– In the context of additional testing performed during an OOS investigation, averaging the result (s) of the original test that prompted the investigation and additional retest or resample results obtained during the OOS investigation is not appropriate because it hides variability among the individual results.
Relying on averages of such data can be particularly misleading when some of the results are OOS and others are within specifications. It is critical that the laboratory provide all individual results for evaluation and consideration by Quality Assurance (Contract Giver/QP).
在OOS调查过程中增加额外检验的情况下，对引发调查的原始试验结果的平均及在OOS调查过程中对增加的复检结果或再取样检验结果进行平均是不合适的，因为这样隐藏了单个结果的差异。
– All test results should conform to specifications (Note: a batch must be formulated with the intent to provide not less than 100 percent of the labelled or established amount of the active ingredient. -所有的试验结果应符合标准（注意：一批产品必须按配方配制以达到标示量的100%，或者要求的活性物质的量）
– Averaging must be specified by the test method. 求平均值必须在检验方法中予以明确。
– Consideration of the 95% Confidence Limits (CL 95% ) of the mean would show the variability when averaging is used.
-当求平均值时，平均值的95%置信限（CL95%）的应用可以显示数值的差异性。 The confidence interval is calculated from the formula: CL= sample mean ± t 95% sample standard deviation/√n ? Where t is a value obtained from tables ? Where n is the sample size 置信区间按下式计算： CL=样品平均值±t95%样品标准偏差/ ? Table:
n
Re-sampling:重新取样
– Should rarely occur! 应尽量减少其发生！
– If insufficient quantity of the original sample remains to perform all further testing then the procedure for obtaining a resample must be discussed and agreed by QA/Contract Giver/QA equivalent. The process of obtaining the resample should be recorded within the laboratory investigation. 如果原始样品留存数量不足以开展所有进一步的试验，从新取样的程序必须得到讨论并由QA/合同供应商/与QA相同职责的人的批准。重新取样的程序必须在实验室调查中予以记录。
– Re-sampling should be performed by the same qualified methods that were used for the initial sample. However, if the investigation determines that the initial sampling method was in error, a new accurate sampling method shall be developed, qualified and documented. 重新取样应该按照取原样品的批准方法执行。但是，如果调查发现原样品取样方法错误，那么应重新制定正确的取样方法，并经批准、制定成文件。
– It involves the collecting a new sample from the batch. 从本批产品中取新样品。
– Will occur when the original sample was not truly representative of the batch or there was a documented/traceable lab error in its preparation.
当原始样品不能代表该批，或者在样品的准备有记录体现/可追踪的实验室错误才可再取样。
– Evidence indicates that the sample is compromised or invalid. 证据表明样品被污染或者失效。
– Sound scientific justification must be employed if re-sampling is to occur. 如果开展重新取样，必须有全面科学的理由。
Outlier test:离群值试验
– An outlier may result from a deviation from prescribed test methods, or it may be the result of variability in the sample. It should never be assumed that the reason for an outlier is error in the testing procedure, rather than inherent variability in the sample being tested. -离群值出现可能因为偏离了规定试验方法，或者样品差异。不能假定出现离群值的因为检验程序错误，宁可认为是被测样品固有的差异导致。
– Statistical analysis for Outlier test results can be as part of the investigation and analysis. However for validated chemical tests with
relatively small variance and that the sample was considered homogeneous it cannot be used to justify the rejection of data.
对离群值试验结果的统计分析应作为调查和分析的一部分。但是，对于验证证实具有相对很小偏差的化学试验，而且样品也被认为是均匀的，那么这个值的剔除是不可以的。
– While OOS guidance is not directly intended for bioassay analysis, it can be used as a starting point for the investigation. Compendia such as the BP; PhEur and USP, provide guidance on outliers for these types of analysis. -然而，OOS指导原则不能直接用于生物分析实验，可以作为调查起始点。BP、PhEur及USP的概论中提供了这类分析的离群值的指导原则。
? Microbiological investigations:微生物实验调查：
- These are difficult to perform as the result can be 1 to 2 weeks after the
analysis was performed and may be weeks after the batch was manufactured. - 该调查是困难的，因为实验完成后需可能要1-2周才会出结果，也可能该批产品生产完成后数周才会出结果。
- It is important to evaluate the test conditions carefully and determine what the boundary of samples/products/manufacturing area is. It you do not determine the boundary of the suspect results it is difficult to determine if it one or more batches impacted. 仔细的评价实验条件、确定样品/产品/生产区域的范围是很重要的。如果你不能确定怀疑结果的范围，那么就很难确定是否是一批或多批产品受到影响。 - The laboratory and manufacturing investigations need to be in depth. 实验室调查及生产调查需要更加深入。
- The investigations should clearly state the hypothesis and who will be responsible for the identified tasks. -调查应该非常清楚的明确鉴定任务的假设及责任人。
- Are the organisms of an expected type, determine likely source – would it be likely to be found where it was? 为预期类型的微生物、确定有类似的来源-是否可能发现它存在于哪里？
- Review the media – prepared in house or bought in pre-prepared, supplier history, sterilisation history -回顾培养基-是实验室制备或者购买的预制备培养基，供应过程，灭菌过程。
- Equipment/utilities used – validation, maintenance and cleaning status. -设备/公用设施的使用-验证、维护以及清洁状态。
- Evaluate area/environmental trends for test area and support areas. - 评估试验区及维持区的环境趋势。
- Cleaning and maintenance of the test environment 实验环境的清洁及维持 - Disinfectant used 消毒剂的使用
- Use appropriate root cause analysis to help brain storm all possibilities