英国药监局OOS翻译

1、* MHRA4nd MfrdiCdl D?vieiOut Of Specification In vestigations.| Medicines and He白IthcmneI Products Regulatory AgencyMHRA-英国医药与保健食品管理局Laboratory AnalysisInvestigations of Out of Specification (OOS) / Out of Trend (OOT)/ Atypical -results have to be done in cases of: 在如下情况下应开展 OOS /OOT / 异常结果结果调查 Batc

2、h release testi ng and testi ng of starti ng 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 ph

3、armaceutical 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 a

4、nd 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 analys es of specific tests (i.e. dissolution level specification for S1, S2 & S3 testin

5、g; 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

6、 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

7、for studies conducted at variable parameters to check the impact of drift (cess 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-determ ined ac

8、cepta nee 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 do

9、cumentation (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 tr

10、end, 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 neces

11、sarily 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

12、 / 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

13、察中的非期望结果。Phase la InvestigationDefinition 定义 :? Phase la investigation is to determine whether there has been a clear obviouserrors due to external circumstances such as power failure or those that theanalyst has detected prior to generating data such as spilling sample that willnegate the requireme

14、nt of a Phase Ib investigation.? For microbiological analysis this may be after the analysis has been completedand reviewed during reading of the samples.? It is expected that these issues are trended even if a laboratory investigation lb orll was not raised.步骤 1a 的调查时确定是否有明显的错误来源于外部环境比如停电或 者生成数据之前检

15、测者发现的那些失误如撒样品， 这样就可以否定开 展 1b 调查步骤。对于微生物分析，这一点可能需要在分析完成后回顾样品的操作。 期望这些问题是有趋势可循的，即使实验室调查步骤 1b 或者 ll 没有开展。Phase la Investigation - Obvious Error步骤 1a 调查 -明显错误Examples 样品? Calculation error -计算错误analyst and supervisor to review, both initial and date correction.分析人员及主管回顾，修正后签名及日期。? Power outageH断电analyst

16、 and supervisor document the event, annotate“power failure; analysisto be repeated ”on all associated analytical documentation.分析人及主管记录这一事件， 并注明“断电，需复检”在所有关联的分析记录中。? Equipment failure仪器错误analyst and supervisor document the event, annotate“equipment failure;analysis to be repeated ”cross reference th

17、e maintenance record.分析人及主管记录这一事件，注明 “仪器错误，需复检 ”并索引至仪器维护记录。? Testi ng errors-试验错误for example, spilling of the sample solution, incomplete transfer of a sample;the analyst must document immediately.for microbiology it could be growth on a plate not in the test sample area, negative or positive contro

18、ls failing.例如，样品溶液倾洒，样品转移不完全；分析人应立即记录。 对于微生物分析， 可能出现微生物生长在非样品区域的平皿中， 阴性或阳性对照 失败。? In correct In strume nt Parameters昔误的仪器参数设置for example setting the detector at the wrong wavelength, analyst and supervisor document the event, annotate“incorrect instrument parameter ”;analysis to be repeated ”on all

19、associated analytical documentation .例如，检测器波长设置错误，分析人及主管记录这一事件，注明“错误的仪器参 数，需复检”在所有关联的分析记录中。? If no error was noted, and none of the above conditions were metPhase Ib investigation must take place. 如果没有错误被记录，上述条件都没有发生，应开展步骤1b 调查Assignable Cause (Root cause identified)Test DataInvalidatedRepeat Analys

20、isGenerate CAPANo Assignable Cause or Evidenee of Error Remains UnclearCon tact: Production/ QA/Contract Giver/MAH/QPPhase II InvestigationRecord ResultsClose InvestigatioiPhase lb Investigation Definitions 定义Specificati on标准A specification is defined as a list of tests, references to analytical pro

21、cedures, and appropriate acceptance criteria which are numerical limits, ranges, or other criteria for the tests described. It establishes the set of criteria to which a drug substance, drug product or materials at other stages of its manufacture should conform to be considered acceptable for its in

22、tended use.“Conformance tospecification ”means that the drug substance and drug product, when tested according to the listed analytical procedures, will meet the acceptance criteria. Specifications are critical quality standards that are proposed and justified by the manufacturer and approved by reg

23、ulatory authorities as conditions of approval .标准被定义为一组测试，参照分析程序，及适当的接受条件，这些标准应为数 字限度、范围或这一组测试描述的其他条件。建立的这套在生产过程各阶段的 药物、药品或材料的标准，如果达到，应当被认为就符合其预定用途。“符合 标准”意味着药物以及药品，当按照这套分析程序检验，达到了可接受条件。 标准是判定性的质量标准，它是有生产厂家提出并证实，由法规机构作为批准 条件颁发的。? Regulatory Approved Specification 法定标准Specifications for release testi

24、ng. If no release specifications have been established then the internal specification becomes the release specification. 放行试验标准。如果没有放行标准被建立，那么中间控制标准即为放行标准。? Acceptance Criteria 可接受标准 Numerical limits, ranges, or other suitable measures for acceptance of the results of analytical procedures which th

25、e drug substance or drug product or materials at other stages of their manufacture should meet. 生产各过程的药物、 药品或物料应当符合限度、 范围或者分析过程结果的其他合 适的可接受方式。? Internal Specification 中间标准Are also action limits within regulatory specifications.法定限度内的行动线。Assignable Cause 明确原因An identified reason for obtaining an OOS

26、or berrant/anomalous result.出现oos或者异常结果的被确定的原因? No Assignable Cause 非明确原因When no reason could be identified. 无法确定的原因? Invalidated test 无效实验A test is considered invalid when the investigation has determined the assignable cause.经调查确定可指明原因，试验被认为无效。? Reportable result 可报告结果Is the final analytical resul

27、t. This result is appropriately defined in the writtenapproved test method and derived from one full execution of that method, starting from the original sample.为最终分析结果。使用书面的批准方法适当的明确并且从这一方法完整执行后得 到的结果，此结果从原始样品的检测结果。? Warni ng Level or Trend excursio ns-警戒水平或者趋势偏离If two or more consecutive samples e

28、xceed warning (alert), or if an increasing level of counts, or same organisms identified, over a short period was identified consideration should be given to treat the results as action level excursions. 如果两个或者更多的连续取样样品超出警戒，或者如果出现数量水平的持续增 加，或者相同的微生物被鉴定出来， 极短时间得到鉴定， 应该被认作行动水平偏 离导致的结果。Hypothesis/I nve

29、stigative Testi ng-假设 / 调查试验Is testing performed to help confirm or discount a possible root cause i.e what might have happened that can be tested:- for example it may include further testing regarding sample filtration, sonication /extraction; and potential equipment failures etc. Multiple hypothes

30、is can be explored.开展的试验能够帮助证实或者缩小根本原因的可能范围， 也就是说， 可能发生的 事情能够被试验得出： 例如 可能包括更多的试验关于样品过滤、超声、提取； 和潜在的设备故障等等。可以进行多个假设。Investigation by Analyst and Supervisor分析人及主管调查Phase lb In vestigati on In itial Inv estigati on con ducted by the an alyst and supervisor using the Laboratory Investigation Checklist1b步

31、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, dilut

32、ions, ampoules/vials of product, temperature data, autopipettes, reage nts growth media. No implicated test en vir onmen talplates shouldbe 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

33、。? 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 te

34、sting.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 sh

35、ould 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 f

36、rom 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 follow

37、ed 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.

38、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

39、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)

40、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

41、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/humidi

42、ty 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

43、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 ddimples 滤膜等。-Was the sample media integral- i.e. no cracks in plates.- Was there contamination p

44、resent 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

45、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 photog

46、raphs 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假:殳试皱Unknown CauseNo Assig nwble CauseI Hypothesis Testing f?.： ivinixA 惊因不知逍 无明确的原因4 Stability 4稳定性JMicrobiology微生捞学Phase III Investigation 步骤 lll 调查? If the batch

47、 is rejected there still needs to be an investigation.即便该批产品拒绝放行，仍然需要调查。To determine:-if other batches or products are affected.ide ntificatio n and impleme ntati on of corrective and preve ntative actio n. 决定：- 是否其他批次或产品受到影响？- CAPA 的启动实施Phase II InvestigationConducted when the phase I investigation

48、s did not reveal an assignable laboratory error. Phase II investigations are driven by written and approved instructions against hypothesis. Prior to further testing a manufacturing investigation should be started to determine whether there was a possible manufacturing root cause .如果步骤I调查没有找到明确的实验室差

49、错，需要开展步骤 II调查。步骤II调查应 按根据假设制定的书面批准的方案开展。 在开展进一步实验之前， 生产调查应启 动，以确定是否根本原因在生产上。? If not aIready notified the contract giver/MAH/QP (in accordance with the responsibiIities in the TA) shouId be notified aIong with production and QA if a manufacturing site.在一个生产基地，如果还没有通知合同供应商/药品文号持有者 /质量受权人(遵循TA规定的职责)，应

50、该连同生产及 Q/一并通知。? It is important when considering performing additionaI testing that it is performed using a predefined retesting pIan to incIude retests performed by an anaIyst other than the one who performed the originaI test. A second anaIyst performing a retest shouId be at Ieast as experienced

51、and quaIified in the method as the originaI anaIyst.当考虑开展附加试验时非常重要的一点是， 应由不同于原试验人员的另外的试验 人员运用预先制定的再试验计划开展再试验。 再试验人员的对该试验的经验和资 质至少与原试验人员等同。? If the investigation determines anaIyst error aII anaIysis using the same technique performed by the concerned anaIyst shouId be reviewed. 如果调查确定为分析错误，那么使用同一方法开

52、展的相关分析都应该回顾分析。Phase II Investigation - Definitions? Hypothesis/Investigative Testing-假设/调查试验Is testing performed to help confirm or discount a possible root cause i.e what might have happened that can be tested:- for example it may include further testing regarding sample filtration, sonication /ext

53、raction; and potential equipment failures etc. Multiple hypothesis can be explored.开展的试验能够帮助证实或者缩小根本原因的可能范围， 也就是说， 可能发生的 事情能够被试验得出： 例如 可能包括更多的试验关于样品过滤、超声、提取； 和潜在的设备故障等等。可以进行多个假设。? Re-Test -复检Performing the test over again using material from the original sample composite, if it has not been compromi

54、sed and/or is still available. If not, a new sample will be used.实验应再次使用原样品处理后的样品， 如果它还没有被破坏而且还有效。 不若不 是，应使用新样品。? Re-sample 重新取样A new sample from the original container where possible, required in the event of insufficient material remaining from original sample composite or proven issue with origin

55、al sample integrity.尽可能从原样品容器中取新样品， 当原样品的处理样品不足或者证实使用完整原 始样品有问题时? Most probable cause-最可能原因Scientifically justified determination that the result appears to be laboratory error.应科学系统的合情合理的决定是否因实验室错误导致00结果的出现。Phase II Investigation - Unknown Cause / NoAssignable Cause步骤II调查-未知原因/不确认的原因Hypothesis Test

56、ing (Applicable to Phase Ia and Phase II):假设试验(步骤 la和II都适用)? ShouId be started as part of Phase Ia and continue into Phase II if no assignabIe cause found.如未发现明确的原因，应开始假设试验作为步骤1a的一部分，持续到步骤II o? Description of the testing shouId be written, and then approved by QA/Contract Giver/QA equivaIent prior t

57、o initiating investigationaI testing. The requirements of investigationaI testing Iisted beIow:在初始调查试验开始之前，应书面制定试验方案并经QA/合同供应商/具有QA只责 的人的批准。调查实验要求如下：? The description must fuIIy document-The hypothesis to the test the root cause being investigated.-What samples will be tested.The exact executi on of the test ing.-How the data will be evaluated必须全面记录- 为调查根本原因对试验的假设- 检验什么样品- 试验的准确开展- 数据如何评估? This Hypothesis testing may continue from the re-measurement of the original preparations.假设试验可能从原始准备样品的复检开始。? Investigational testing may