微生物实验室超标的调查

文件编号文 件 名 称页号20/20Microbiology Laboratory Investigations (OOS/OOT Results)微生物实验室超标的调查版本号B/01.0 Purpose目的To provide a standard procedure for the investigation of microbiological results that are Out-of-Specification (OOS), Out-of-Trend (OOT) and questionable, and disposition procedure for finished products Out-of-Specification occurred. 提供微生物实验室发生测试结果超标、超趋势和对测试结果有疑问的实验室调查，以及成品发生微生物超标时的处理程序。2.0 Scope 范围2.1 This sop apples the microbiology laboratory of.本标准操作规程适用于。2.2 This sop applies when suspect or aberrant results are generated during the following activities（but not limited to）:本操作规程适用于在以下（但不限于）实验或操作中出现可以或异常的结果： Raw/auxiliary material testing 原辅料测试 In-process material testing 中间产品测试 Final product release testing 成品放行测试 Stability testing 稳定性测试 Process validation testing 工艺验证测试 Transfer of validated test methods into, within or between quality laboratories 质量实验室之间或内部已验证的实验方法的传递或引入 Microbial limit testing 微生物限度测试 Growth promotion testing 培养基生长支持测试 Environmental monitoring 环境监控 Water testing 水样测试 Microbial identification 微生物鉴定 Biological indicator testing 生物指示剂测试 2.3 Environmental Monitoring investigations are very complex and it may not be possible to investigate the full extent of the excursion through a Laboratory Investigation. However, all excursions shall be investigated to discount an assignable cause of Laboratory Error.环境监控的调查很复杂，很可能不能实验室调查中调查到超标的所有涉及到的因素。但应调查环境监控的因素以排查实验室的错误。A site Environmental Monitoring Plan shall provide the guidance for a consistent investigative process related to excursions. The Environmental Monitoring Plan shall:一个区域环境监控计划应提供与调查一致的指引。环境监控计划应： Provide a clear differentiation between Alert Limits and Action Limits提供清晰的警戒限度和行动限度的区别。 Require identification of all organisms (genus and species if possible) involved in an Action Limit excursion with full tracking and trending of excursion data为超标调查提供微生物鉴定以追溯及分析超标数据的趋势。 Provide guidance on notification to production, resampling requirements and timely closure of the investigation.在向生产部发出的通知中提供指引、重取样要求和几时关闭调查。3.0 Definitions 定义Alert Limit - any statistically based number calculated from historical data that is always lower than the specification action limit.从低于措施限度的历史数据，通过统计学计算得来的数据。Error - a mistake or deviation from specification procedure or standard method. Error may also include calculation errors in which the true value differs from the observed or calculated value.错误-弄错或偏离标准程序或方法,包括真实值和观察值或计算值不同的计算错误。Action Limit - predefined limit or numerical value listed in the applicable corporate testing specification.在相应的测试程序中预先确定的限度或数值。Out of Limit - any data indicating that the tested material or process exceeds a predefined limit.超限度-表明被测试的物料或过程超过预先确定的限度的任何数据。Other definitions refer to ZL-SOP-ZHL-076.其他定义参照ZL-SOP-ZHL-076。4.0 Responsibility 职责Position职位Responsibility 职责Technician or Engineer技术员或工程师4.1Conduct testing according to approved procedures using suitable equipment, materials and reagents.使用合适的仪器设备、物品和试剂并按照已批准的规程进行试验操作。4.2Ensuring that, where applicable, equipment is within calibration and performing to established specifications (e.g. Laminar Flow Unit).确保仪器设备符合试验要求的规格并经过校准。4.3Monitor tests as they are run and immediately notify the laboratory supervisor of any deviations identified and any suspect or aberrant results. In the event that an obvious error occurs, they shall document the event and shall not continue the test for the sole purpose of seeing what results can be obtained.监控测试，当发现明显的可疑或异常结果应马上停止试验并立即通知实验室主管。4.4Check test results for compliance with specifications before discarding samples, sample plates and extraction fluids (where still available).在丢弃样品、培养皿和样品提取液（若还有效）前检查它们是否与要求一致。4.5Track and trend all microbiological results.对微生物结果进行追溯和趋势分析。4.6In the event of an OOS/OOT result being obtained, work with the Laboratory Supervisor to review testing and to determine if any deviations took place during testing that may have contributed to the OOS/OOT result.在OOS/OOT事件出现时，与实验室主管一起回顾测试和确认是否有实验室偏差出现以致造成OOS/OOT。4.7Contributes to the completion of the Laboratory Investigation.协助完成实验室调查。4.8Performs required reanalysis and/or retests following proper authorization.在授权情况下进行再分析和/或重测。Laboratory Supervisor or Designee实验室主管或授权人员4.9Works with the technician or engineer to investigate the OOS/OOT result in an objective, timely and thoroughly documented investigation.与技术员或工程师一起调查OOS/OOT结果，及时并完整记录（包括收集证明文件）整个调查。4.10Works with the technician or engineer to review the testing, determine the cause of the problem and complete the laboratory investigation record.与技术员或工程师一起回顾实验过程，找到原因并完成实验室调查记录。4.11Ensures that the investigation is registered in the appropriate system.确保调查在合适的系统中已被登记。4.12Escalates the outcome of the laboratory investigation and informs the affected functions as appropriate e.g. QA, Manufacturing, and Planning etc.对实验室调查结果进行进一步的措施并通知相关部门如QA和生产部等。4.13When an OOS/OOT is confirmed as being valid, supports the manufacturing investigation (if required).当OOS/OOT已被确认有效，为生产部调查提供支持（若被要求）。4.14Notifies Laboratory Management of all aberrant or suspect results, and provides data for the trending of Laboratory Investigations (e.g. frequency of occurrence, assignable cause etc.)通知经理所有的可疑或异常结果，以及实验室调查的数据和趋势（如出现的频率和已确认的原因）。Laboratory Management / QA or designee 经理/QA或授权人员4.15Approves in advance resampling or further testing during phase II of the investigation.审批在调查第二阶段的重取样和进一步的重测。4.16Approves Laboratory Investigation Records审核实验室调查记录。4.17Maintains awareness and oversight of Laboratory Investigations for tracking purposes, and provides the link to CAPA management and Management Review. 监督实验室调查，连接CAPA管理部门。4.18Ensures investigation closure within 30 calendar days. Provides written authorization for any investigation that will extend beyond 30 calendar days.确保调查在30个日历日内完成并关闭，若需延期应经经理审批和授权。4.19Ensures proper and timely alert notification确保及时发出内容完整的警告通知。5.0 STANDARD REQUIREMENTS 标准要求5.1 Phase I: Initial Laboratory Investigation 阶段1：初步实验室调查5.1.1 In the event that an aberrant or suspect result (OOS or OOT) has been identified, the technician or engineer shall immediately inform the laboratory supervisor and initiate a Laboratory Investigation within one (1) business day. 在确定发生可疑或异常结果（OOS/OOT）时，技术员或工程师应立即通知实验室主管和在1个工作日内开启实验室调查。5.1.2 The Technician or engineer with the equivalent of a Laboratory Supervisor, shall document an investigation of the items listed in the following table using an appropriate Laboratory Investigation Record. The investigation shall be thorough, timely, unbiased, well-documented, and scientifically sound. Failure investigation tools such as cause and effect analysis can aid the investigation. Appendix 2 shows an example of a cause and effect analysis.技术员或工程师与实验室主管或其授权人员应按以下表格中的事项进行调查。调查应是完整彻底的、及时的、公正的、科学并系统的和良好地进行记录的。关于失败（错误）调查的工具如因果分析可有助于调查。附录2列举了一个因果分析的例子。Area of Investigation调查方面Items to be Investigated 调查事项Technician or engineer (Manpower) 技术员或工程师（人） Confirm the technician or engineers knowledge and correct performance of the procedure (including revision).确认技术员或工程师的知识和是否按照规程操作。 Confirm the technician or engineers training, aseptic technique and experience in the procedure确认技术员或工程师在测试中的消毒操作及其培训。 Confirm the correct gowning of the Technician or engineer during testing.确认技术员或工程师在测试中使用的洁净服。 Confirm that controls, samples and solutions were prepared and stored according to the procedures. Investigate the possibility of mislabeling, testing out of sequence and cross contamination.确认是否根据规程准备、保存对照品、样品和溶剂。调查贴错标签、没有按顺序进行测试和交叉污染的可能性。 Confirm that control samples met with acceptance criteria确认对照样品是否符合接收标准。 Verify calculations 检查计算是否正确。 Confirm that sampling (where applicable) was performed correctly.确认取样操作是否正确。 Examine any sampling ports for evidence of contamination调查取样点有无污染的证据。Instruments (Machine)仪器设备 Confirm the performance of instruments & equipment 确认仪器设备的性能。 Confirm that instruments and equipment were within their calibration dates.确认仪器设备在校准有效期内。 Confirm that instrument & equipment settings were correct 确认仪器设备是否正确设置。Materials物料 Confirm that samples were in an acceptable condition确认样品是否在合适的环境内。 Confirm that appropriate media and reagents were used, and that they were within their expiry dates. 确认是否使用了合规的、在有效期内的培养基和试剂。 Confirm that glassware of the appropriate type, grade, size and preparation (e.g. sterile, depyrogenated, etc. was used.确认使用的器皿是否合规（如型号、等级、大小，是否已灭菌、去热源、已使用等） Confirm that any consumables and other materials used to perform the method were of the appropriate type, grade and size.确认使用的消耗品和其他物品是否合规。Environment环境 Examine testing environment, bench, Laminar Airflow Cabinet etc.检查测试的环境、实验台和层流橱等。 Verify cleaning and sanitization performed as required检查清洁和消毒操作。 Verify appropriate controls are in place (e.g. High Efficiency Particulate Air filter, etc.)检查适当的监控、设备等是否已经到位（如高效空气过滤器等）。Test Method and Samples (Method)测试方法和样品（方法） Confirm that the test method was performed as per procedure. Additional tests of the original samples (where available) can be used to investigate method performance. 确认是否按照规程进行操作。原样（若还有效）可用于调查方法的测试操作。 Evaluate the original samples for damage, deviation in storage conditions, contamination or other factors that may have contributed to the aberrant result.评估原样的损坏、储存环境的偏差、污染或其他等导致异常结果的因素。 Review for trends in the data within the analysis and for samples tested immediately before and after or over a defined time period 在一定时间内回顾、分析数据。5.1.3 If a laboratory error is identified as being the assignable root cause (e.g. a verifiable error is identified for the OOS/OOT results), perform the following actions: 若实验室错误被确定为OOS/OOT的根本原因，按以下步骤进行操作：i) Invalidate the original result, but retain all original data. 原结果无效，但保留原始数据。ii) If the error occurred during calculation, only the calculations are invalidated; recalculate the results. 若只是计算错误，原计算结果无效，重新进行计算。iii) If the error occurred during the test, perform a reanalysis/retest from the point at which the original result was invalidated. In situations where a reanalysis/retest cannot be performed (e.g. destructive test) perform a resample of the relevant sample type. The number of reanalyses/retests shall be defined in the site procedure.若错误是在测试过程中，在错误出现的地方进行重新分析/测试。若不能进行重新分析/测试（如破坏性测试），则对相关的样品重新取样。在相应的规程中应规定重新分析/测试的次数。5.1.4 If no laboratory error is identified during the lab assessment, a reanalysis will be performed. In situations where a reanalysis cannot be performed on the original test samples (e.g. bioburden testing where the extraction fluid would have been discarded prior to receipt of results) request additional test samples from the same lot/batch/product type where possible for testing. The number of measurements used during the reanalysis shall exceed the number made routinely and must be defined in an approved site procedure. 若在实验室评估中确定不是实验室错误，应进行再分析。若不能对原样进行再分析（如生物负荷测试中测试的提取液在得到结果前已丢弃），按原样的规格或条件进行附加测试。在相应的规程中应规定在再分析中的测试数应大于一般测试数。5.1.5 If reanalysis confirms the original result as being OOS, then the original result may either be valid or the entire sample preparation could be in question. In either case, a full-scale investigation shall be performed according to 5.2 若在再分析中确认原结果是OOS，则原结果为有效或整个样品处理过程为可疑。无论哪种情况，都应按照5.2进行全面的调查。5.1.6 If reanalysis is inconclusive (due to the nature of the test or the availability/integrity of original solutions), or the investigation does not identify a laboratory error as being the assignable cause, then the original result is still suspect and a full-scale investigation shall be conducted according to 5.2 若再分析的结果是不确定的（由于测试的性质或原始溶液的有效性/完整性），或调查不能确定实验室错误为根本原因，则原结果仍为可疑并应按照5.2进行全面的调查。5.2 Phase IIA: Full Scale OOS/OOT Investigation (Production Review)阶段2A：全面的OOS/OOT调查（产品回顾）5.2.1 The full scale investigation should be led by both QA and Microbiology and supported by other functions as appropriate to the issue, e.g. manufacturing, supply chain, engineering, R&D etc. In cases where manufacturing occurs off-site (e.g. performed by a contract manufacturer or at multiple manufacturing sites), all sites potentially involved should be included in the investigation. 全方面的调查应由QA和微生物实验室主持，并得到相关部门如生产部、供应链、工程部、研发部等的支持。若有非本厂内的生产（如供应商或合作厂商等），应对所有生产现场进行调查。5.2.2 The full-scale investigation shall be conducted following a pre-defined site procedure. The investigation will include additional laboratory testing, which is described in further detail in 5.3应根据预定义的现场程序进行调查。调查包括在5.3中有详细规定的附加实验室测试。5.2.3 The degree of investigation should be commensurate with the severity of the issue. For example, a pre defined procedure should outline the level of investigation required for both OOT and OOS (e.g. one OOT may require a lesser investigation than three consecutive OOT results or an OOS result).调查的程度应与问题的严重性相配。例如，已有的标准操作规程应规定了OOS和OOT的调查要求（如连续出现3个OOT或1个OOS的情况应比只出现1个OOT调查得更细致和深入）。5.3 Phase IIB: Full Scale OOS/OOT Investigation (Additional Laboratory Testing)阶段2B：全方面的OOS/OOT调查（附加实验室测试）5.3.1 The full-scale OOS investigation will include additional laboratory testing including retesting a portion of the original sample or resampling of the same lot where possible. However, additional testing may only be done according to a predefined, preapproved retesting/resampling plan defined in the applicable site procedure. The plan shall: 全方面的OOS调查包括附加实验室测试（包括一部分原样的重测或相同批次样品重取样）。特定的规程应对附加测试、重测、重取样等计划进行规定。计划应：a. Be scientifically justified; on no account shall the practice of “testing into compliance” be used. 科学系统地进行判断：决不能出现测试到合格为止的情况。b. Define the number of tests allowed, and at which point the retesting ends and the batch is evaluated. The number of retests shall not be adjusted depending on the results obtained. However, once a batch is rejected, unlimited further tests can be made to further the search for a root cause.规定允许测试量，并规定重测在何处结束和需评估的产品。不能根据获得的结果来设定重测次数或量。然而一旦有产品被拒，应进行无限量的进一步的测试指导直到找到根本原因为止。c. Define how data obtained during the investigation shall be handled. 规定如何处理在调查中获得的数据。d. Define how outliers are handled. Outlier tests shall be used with caution and it should never be assumed that an outlier is due to an error in the testing procedure. Procedures for outlier tests shall specify the minimum number of results required to obtain statistical significance. 规定如何处理异常值。异常值测试应慎重使用，而且不能假设由于测试程序的错误导致出现异常值。异常值测试程序应规定用于统计数据的最少结果量。5.3.2 Retesting involves additional testing of the original sample/lot/batch/product type from which the OOS result was obtained, and may be used to investigate instrument malfunctions or possible sample handling problems. 重测包括对出现OOS/OOT的原样（同批次的成品等）的附加测试，重测也可用于调查仪器是否失灵或操作是否有问题。i) The number of retests may vary according to the variability of the particular test method, but shall be scientifically justified. 重测的次数可根据特定的测试方法变更而变更，但须先进行科学的判断。5.3.3 Re-sampling may be justified with appropriate rationale, for example: 根据适当的依据进行重取样，例如：i) If the original sample is insufficient to allow for reanalysis due to the test being destructive or the original sample does not exist 若由于原样在测试过程被破坏或原样已不存在导致不能进行再分析。ii) If reanalysis testing is inconclusive and the original sample is insufficient to allow for further confirmation of original results. 若再分析测试结果不确定以及原样不足以对原结果进行确认。iii) If the original sample was found to be unrepresentative of the batch quality due to a problem with the sampling process.若原样被发现在取样过程中出现问题而不能对产品有代表性。iv) If the original sample was compromised during handling or storage in the laboratory or contaminated during preparation or analysis.若原样在操作或在实验室储存时经过处理，或在分析或准备时受到污染。5.3.4 Resampling shall not be used in non-batched processes except if the original sample was compromised during handling or storage in the laboratory or contaminated during preparation or analysis.重取的样品不能用于非正式生产，除非原样在操作或在实验室储存时经过处理，或在分析或准备时受到污染。5.4 Phase III: Investigation Conclusion & Closure 阶段3：调查结论及其关闭5.4.1 A thoroughly documented description of the incident, chronology of all events and investigation findings shall be provided, including supporting documents.提供完整描述事件的记录、所有事件的年表和调查结果，包括支持文件（如辅助文件和证明文件等）。5.4.2 All test results, including those that were originally OOS/OOT (unless invalidated with scientific justification) shall be reported and considered in batch evaluation or release decisions.应向产品评估或放行决策提供所有的测试结果，包括原始的OOS/OOT测试结果（除非经科学判断为无效）。Note: In any case, true OOS results shall never be averaged with the results of additional reanalyses/retests all test results shall be reported for use in deciding product disposition. The original results, reanalysis/retest results, assignable cause and correction(s) applied shall be recorded during the course of the Laboratory Investigation.注意：在任何情况下，真实的OOS结果绝不能用附加的再分析/重测的结果来平均计算，所有测试结果应报告并用于产品配置。原结果、再分析/重测的结果、指明原因和实施的纠正应在实验室调查期间进行记录。5.4.3 Assess the impact of the investigation findings and document appropriate corrective actions and/or preventive actions as applicable. 评估调查结果的影响和对可适用的纠正或预防措施进行记录并形成文件。5.4.4 The Laboratory Investigation shall be completed within 30 calendar days starting from the date of detection of the original event. Extensions to this date shall be limited, and where made they shall be justified and approved by Management. 实验室调查应在OOS/OOT发生的24小时内开始并在30个日历日内关闭。可延期的日期是有限的并应由经理审批。5.4.5 The timeliness of closure of non-conformances/failure investigations that result from Laboratory Investigations should be in accordance with local procedures. 由实验室调查造成的不符合项/失败调查的时效性应与本地规程相一致。5.4.6 Where a non-conformance is confirmed, a decision shall be made as to whether it shall be escalated based on its severity, extent and rate of occurrence. Levels of escalation include:当发生一部符合项，应根据其严重性、程度范围和出现频率进行进一步措施，包括： CAPA 纠正和预防措施 Stab