英国药监局OOS翻译

MHRA-英国医药与保健食品管理局

Laboratory Analysis

Investigations of \-results\

在如下情况下应开展OOS /OOT /异常结果结果调查

– Batch release testing and testing of starting materials. 批放行检验及原物料检验

– In-Process Control testing: if data is used for batch alculations /decisions and if in a dossier and on Certificates of Analysis.

过程控制检验：如果数据用作在记录或者检验报告作为批计算/决定

– Stability studies on marketed batches of finished products and or active pharmaceutical ingredients, on-going / follow up stability (no stress tests)

成品和/或原料药市售批次的稳定性研究，用作持续跟踪稳定性（非破坏性试验） – Previous released batch used as reference sample in an OOS investigation showing OOS or suspect results.

产品放行批之前在OOS调查中的参考品显示OOS或者非预期结果。 – Batches for clinical trials.临床试验批

? All solutions and reagents must be retained until all data has been second person verified as being within the defined acceptance criteria.

所有溶液和实际必须保留，直到数据被第二个人证实在规定的可接受标准内。 ? Pharmacopoeia have specific criteria for additional analyses of specific tests (i.e. dissolution level specification for S1, S2 & S3 testing; Uniformity of dosage units specification for testing of 20 additional units; Sterility Testing).

药典明确规定需要增加额外的特定实验分析（例如：分散水平规范S1, S2 & S3试验；含量均匀度规范要求增加20个样品；无菌试验）

However if the sample test criteria is usually the first level of testing and a sample has to be tested to the next level this should be investigated as it is not following the normal trend.

然而，如果样品试验标准通常在第一实验水平，样品的检测却在下一个水平，这种情况需要调查，因为它不是正常趋势。

? The OOS process is not applicable for In-process testing while trying to achieve a manufacturing process end-point i.e. adjustment of the

manufacturing process. (e.g. pH, viscosity), and for studies conducted at variable parameters to check the impact of drift (e.g. process validation at variable parameters).

OOS程序不适用于为了达到生产过程重点而开展的中间过程检测。即判定生产过程（如PH、粘度），及为了研究可变参数以检查漂移的影响（如可变参数的过程验证）

Out-of-Specification (OOS) Result –OOS结果

– Test result that does not comply with the pre-determined acceptance criteria (i.e. for example, filed applications, drug master files, approved marketing submissions, or official compendia or internal acceptance criteria).

– Test results that fall outside of established acceptance criteria which have been established in official compendia and/or by company documentation (i.e., Raw Material Specifications, In-Process/Final Product Testing, etc.).

-试验结果不符合已制定接受标准（即: 例如 申请材料、药品主文件、批准的销售合同、官方通则、内控标准） - 试验结果超出已建立的接受标准，这些标准在官方通则或者公司文件中规定了（即：原料标准、中间产品/成品检验标准等） ? Out of Trend (OOT) Result –

– Is generally a stability result that does not follow the expected trend, either in comparison with other stability batches or with respect to previous results collected during a stability study.

通常是一个稳定性考察结果不符合预期的趋势，包括其他批次稳定性数据趋势或者同以往稳定性研究结果数据趋势。

However the trends of starting materials and in-process samples may also yield out of trend data. The result is not necessarily OOS but does not look like a typical data point.Should be considered for environmental trend analysis such as for viable and non viable data (action limit or warning limit trends) 然而，原物料的趋势以及中控样品也会产生趋势数据。这些结果不需要OOS，但是不能看做为典型数据点，应当被看做环境趋势分析，例如可接受的或者不可接受的数据（行动线或者警戒线趋势）

? Atypical / Aberrant / Anomalous Result –

– Results that are still within specification but are unexpected, questionable, irregular, deviant or abnormal. Examples would be chromatograms that show unexpected peaks, unexpected results for stability test point, etc. 非典型/异常结果-

虽然在标准范围内但是非期望的、可疑的、不正常的数据。例如色谱图中的出现异常的峰、稳定性考察中的非期望结果。

Investigation by Analyst and Supervisor

分析人及主管调查

Phase Ib Investigation – Initial Investigation conducted by the analyst and supervisor using the Laboratory Investigation Checklist 1b步骤调查-由分析人及主管使用实验室调查清单开展的最初调差。

? Contact Production/Contract Giver/QP/MAH as appropriate 视情况联系生产、供应商、质量受权人、药品批准文号持有者。

? For microbiological analysis where possible once a suspect result has been identified ensure all items related to the test failure are retained such as other environmental plates, dilutions, ampoules/vials of product, temperature data, autopipettes, reagents – growth media. No implicated test environmental plates should

be destroyed until the investigation has been completed. 对于微生物分析实验，一旦发现可以结果，应确保与本失败实验相关的所有物品得到保存，例如环境监测平皿、稀释液、产品安瓿或西林瓶、温度数据、自动吸样器、试剂-培养基。试验相关的环境监测平皿不得销毁，直到调查完成。

? The Analyst and Supervisor investigation should be restricted to data / equipment / analysis review only 分析人及主管调查应仅限于数据、仪器、分析过程回顾。

? On completion of the Analyst and Supervisor investigation

re-measurement can start once the hypothesis plan is documented and is only to support the investigation testing. 分析人及主管调查完成，一旦假设方案记录下来并且只支持调查试验，那么就可以再开始试验。

? This initial hypothesis testing can include the original working stock

solutions but should not include another preparation from the original sample (see: re-testing) 这个最初的假设试验从原始工作储备溶液开始，但是不包括从原始样品开始。

The checklist may not be all-inclusive, but should be a good guideline to cover the pertinent areas that need to be covered in any laboratory investigation:- 检查清单不可能非常详尽，但是应该是一个良好的指导，包括了在任何实验室调查中覆盖的相关方面。 - Correct test methodology followed e.g.. Version number.

是否遵循的正确的实验方法，例如所用的文件版本号

- Correct sample(s) taken/tested (check labels was it taken from correct place). 是否使用正确的样品或样品处理（检查样品标签，确认从正确的地方得到的样品）

- Sample Integrity maintained, correct container and chain of custody (was there an unusual event or problem). 样品保存的完好性，正确的容器及保管链（是否存在异常事件或问题？） - How were sample containers stored prior to use. 样品使用之前，样品容器如何存放？

- Correct sampling procedure followed e.g. version number. 是否遵循正确的取样程序，例如文件版本号。

- Assessment of the possibility that the sample contamination has occurred during the testing/ re-testing procedure (e.g. sample left open to air or unattended). 评估在实验或复检过程中样品污染的可能性（例如样品非受控开口存放）

- All equipment used in the testing is within calibration date. 所有使用的仪器均在校验期内。

- Review equipment log books. 回顾审核仪器使用维护记录

- Appropriate standards used in the analysis. 分析过程中是否使用合适的标准品。

- Standard(s) and/or control(s) performed as expected. 标准品或内控品的使用是否合规

- System suitability conditions met (those before analysis and during analysis). 是否达到系统适用性（那些分析之前的或者分析过程中的） - Correct and clean glassware used. 是否使用正确的、洁净的玻璃器皿？

- Correct pipette / volumetric flasks volumes used. 是否使用正确量程的吸管量瓶？

- Correct specification applied. 是否使用正确的说明书。

-Media/Reagents prepared according to procedure. 培养基、试剂是否按程序准备。

? Items were within expiry date 各试验物料是否在有效期内。

? A visual examination (solid and solution) reveals normal or abnormal appearance 是否肉眼检查（液体或固体）发现正常或非正常外观？ - Data acceptance criteria met 是否达到验收标准?

- The analyst is trained on the method. 分析人是否接受过该方法培训？

- Interview analyst to assess knowledge of the correct procedure. 与分析人面谈，评估其对正确程序的掌握程度。

- Examination of the raw data, including chromatograms and spectra; any anomalous or suspect peaks or data. 原始数据检查，包括色谱或者光谱分析数据、任何异常的或可以的峰或数据。 - Any previous issues with this assay. 回顾这项分析以前发生的所有问题。

- Other potentially interfering testing/activities occurring at the time of the test. 是否在实验阶段出现潜在的干扰实验或者实验活动的事情发生？

- Any issues with environmental temperature/humidity within the area whilst the test was conducted. 实验过程中是否存在该区域温湿度问题？

- Review of other data for other batches performed within the same analysis set. 回顾分析使用相同分析设置的其他批次数据。

- Consideration of any other OOS results obtained on the batch of material under test. 考虑该批物料检验时发现的其他项目OOS结果。 - Assessment of method validation. 方法验证评估。

Additional considerations for microbiological analysis: 微生物检验的其他附加考虑：

- Are the isolates located as expected – on glove dab marks, SAS ?dimples‘, filter membrane etc. 是否按要求隔离放置-手套印记平皿，SAS ?dimples‘滤膜等。

- Was the sample media integral – i.e. no cracks in plates.

- Was there contamination present in other tests (or related tests) performed at the same time, including environmental controls. 采样培养基是否完整-即平皿未皲裂； 在其他同时间开展的试验中是否也存在同类污染，包括环境控制。 - Were negative and positive controls satisfactory. 是否阳性及阴性控制均合格？

- Were the correct media/reagents used. 是否使用正确的培养基或试剂？

- Were the samples integral (not leaking) 样品是否完整（没有倾洒）

- Were the samples stored correctly (refrigerated) 样品是否正确储存（冷藏的）

- Were the samples held for the correct time before being tested. 实验前，样品是否时间受控？

- Was the media/reagent stored correctly before use

使用之前，培养基/试剂是否正确贮存。

- Were the incubation conditions satisfactory. 培养条件是否适当？

- Take photographs to document the samples at time of reading (include lates, gram stains and any thing else that may be relevant). 将样品的结果以照片的形式附在记录中

– 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

-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。

Out Of Specification Investigation OOS调查

This is a guidance document that details the MHRA expectations

这是一个详述MHRA期望的指导文件

Note: This guidance is complementary to FDA Guidance For Industry Investigating Out-Of-Specification (OOS) Test Results for Pharmaceutical Production October 2006.

注：这个指导原则是“FDA药品OOS试验结果工业调查 2006年十月”的补充。

Updated to include Microbiological expectations 本更新包括微生物学调查期望

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