Defining an OOS Event

定义OOS事件

An investigation should occur every time an OOS result isreceived for a grab sample from the utility system, or when the specificationis exceeded during the use of online monitoring to show compliance to thespecification. Systems should be in place to notify the appropriate personnelin the event of an OOS result. For grab samples, the LIMS should be set to testthe sample result against the specification and notify the user of any failure.When online monitoring instrumentation is used, the associated automationsystem can be configured to alarm at the appropriate value.

对于公用系统，无论是离线样品，还是在线监测，当出现OOS时，应进行调查。应有系统在出现OOS结果时通知适当的人员。对于离线取样的样品，应设置LIMS，根据质量标准对样品结果进行检验，并将任何失败通知用户。使用在线监测仪器时，可配置与之关联的自动化系统，以适当的值进行报警。

USP <1231> Section 9.4 [36] contains suggestions for howto properly implement alert and action levels, and how to respond if thoselevels are exceeded.

USP <1231>第9.4节[36]包含有关如何正确实施警戒限和行动限，以及在超出这些水平时如何响应的建议。

Trends

趋势

Trends such as repeated alert-level excursions or warning alarmsmay also be encountered. These types of trends should be investigated similarlyto OOS events, although it is typically not necessary to assess product impact becauseno specification or critical alarm limit has been exceeded.

系统在运行的过程，可能会有一些趋势，如重复超警戒限或报警。与OOS事件类似，应对这种趋势进行调查，尽管通常没有必要评估产品影响，因为没有超出质量标准或关键报警。

Investigations

如何调查

EU GMP Chapter 1 Section 1.8 (vii) [37] requires that:

欧盟GMP第1章第1.8节（vii） [37]要求：

“Any significant deviations are fully recorded, investigatedwith the objective of determining the root cause and appropriate corrective andpreventive action implemented.”

 “任何重大偏差都应得到充分记录，并进行调查以确定根本原因并采取适当的纠正和预防措施。”

An investigation should identify the cause of the issue andprovide the rationale for CAPAs. It should be comprehensible, traceable, andwell documented to ensure that the circumstances can be well communicated upon request.It should be clear what was included in the scope of the investigation, and ifany items were specifically excluded and why. Root-cause tools, for example, 5Whys/Kepner-Trego Analysis (KTA)/Cause and Effect Analysis (5M+, Fishbone, orIshikawa Diagram)/FMEA, etc., should be used, particularly for more complicatedinvestigations. The investigation should include a review of pastinvestigations for recurrence over a relevant period of time, typically 12months unless, for example, if the issue is seasonal, in which case the timeperiod may be longer.

调查应确定问题的原因，并提供CAPA的理由。它应易于理解，可追溯，并应良好记录以确保在要求时能够很好地沟通情况。应明确调查的范围，是否有任何项目被明确地排除以及为什么排除。应使用根本原因工具，例如5个为什么/ KT分析（KTA）/因果分析（5M +，鱼骨或石川图） / FMEA等，尤其是对于复杂程度较大的调查。调查应包括对过去一段时间内重复发生的调查的回顾，例如通常12个月，但如果问题是季节性的，则这种情况下的时间可能会更长。

Investigations should be science-based, meaning that they shouldstart with a problem statement (defining also the boundaries of theinvestigation) and one or more hypotheses that should be proved or disproved.

调查应以科学为基础，这意味着调查应由问题陈述（同时定义了调查的范围）和一个或多个应进行证明或排除的假设开始。

Factors to consider during the investigation are listed below(not a comprehensive list). Not all of these factors will need to be consideredfor every investigation, but the appropriate ones should be applied based onthe issue.

下面列出了调查期间需要考虑的因素（不是完整列表）。并非每次调查都需要考虑所有这些因素，但应根据问题的具体情况选择适当的因素。

Environment: 

环境

Was nonroutine work occurring in the area?

该区域是否发生非常规工作？

Equipment:

设备

Is instrument failure or calibration drift related to the issue?Power related?

仪器故障或校准漂移是否与此问题有关？电源相关？

Was nonroutine work being performed on the system?

是否在系统上执行非常规工作？

Were maintenance interventions and recovery carried outcorrectly (even if routine)?

设备维护（包括日常维护）和恢复是否得到正确执行？

Have there been changes, such as idling of an area or piece ofequipment, that may contribute to usage patterns or the sampling environment?

是否存在可能导致使用模式或取样环境变化的变更，例如某个区域或设备的闲置？

Is the use point or sampling outlet retaining water due toimproperly sloped piping, surface tension in a narrow tube, or improperly sizedgaskets being installed?

使用点或取样点是否由于管道倾斜不当，细管中的表面张力或安装的垫圈尺寸不当而积水？

If hoses are used at the outlet, are they treated correctly(disconnected after use, sanitized/drained/dried if reusable)?

如果在出口使用了软管，是否正确处理了它们（使用后断开连接；如果可重复使用，则进行消毒/排水/干燥）？

Is product impacted? Product made since the last passing sampleshould be evaluated. The product-impact assessment is generally limited toproduct made using the specific outlet involved with a microbial failure, butis generally expanded to assess all products supplied by a loop or system forchemical failures.

产品是否受到影响？自上次取样合格以来生产的产品应进行评估。对于微生物失败的产品影响评估，通常限于该使用点生产的产品即可；但对于化学失败，通常会扩展至评估由该回路或系统提供的所有产品。

Should additional samples be collected as part of theinvestigation or to show that the system has returned to normal? Is additionalsampling part of an approved SOP or do the additional samples need to bepreapproved by the quality unit?

在调查过程中，是否应收集更多样品或表明系统已恢复正常？额外取样是否是已批准SOP的一部分，或是额外取样需要质量部门的预先批准？

For microbial failures, was the organism identified? This canhelp determine the root cause of the failure (organisms intrinsic to the watersystem versus external contamination of the sample) and may also be useful for theproduct-impact assessment.

对于微生物失败，是否进行了微生物鉴别？这可以帮助确定失败的根本原因（确定是水系统固有的微生物，还是与样品的外部污染），并且对于产品影响评估也可能有帮助。

Personnel:

人员

Is sampling error a concern? 

是否取样错误？

- Was good aseptic technique used?

- 是否使用了良好的无菌技术？

- Was the correct outlet/utility/system sampled (potable waterversus purified)?

- 是否取样了正确的取样点/公用设施/系统（饮用水，还是纯化水）？

- Is it possible that the sample was contaminated, such as ifthe same hose could be used for both potable and PW in the same area?

- 样品是否可能被污染，例如同一区域的饮用水和纯化水是否使用相同的软管？

- Was the sampling procedure followed correctly (any requiredoutlet flushing, cleanliness of any hoses or accessories)?

- 取样程序是否正确执行（取样点是否需要排水，软管或附件如何清洁）？

Is laboratory error a concern? It is typical for analyticallaboratories to conduct an investigation for each failing result that isgenerated to ensure that there is no obvious laboratory cause for the failure.

是否实验室错误？分析实验室通常会对生成的每个失败结果进行调查，以确保没有明显的实验室失败原因。

If personnel errors become a recurring theme duringinvestigations, is the training program adequate? Are the SOPs clear andaccurate?

如果在调查期间人为错误屡屡发生，培训计划是否足够？SOP是否清晰准确？

A product risk assessment should be conducted as part of theinvestigation. This must assess the impact of specification excursions onproducts associated with the water around the time of the excursion. A productcan be associated with the excursion if the water was used as an ingredient orif the water was used to clean the equipment used to manufacture the product.The assessment should include a discussion of any processing conditions that mayimpact the specific excursion (extremes of pH, toxic ingredients, or low wateractivity in the event of a microbial excursion, for example). The assessmentshould also include the impact of any specific organisms identified from microbialresults. This assessment should conclude with a statement indicating that theproduct is either fit for use or being rejected and whether a product recall iswarranted.

产品风险评估应作为调查的一部分进行。这应评估偏差期间，超出质量标准对与水相关的产品的影响。如将水用作辅料，或使用水清洁用于生产产品的设备，则该产品可能与偏差事件相关。评估应包括可能影响特定偏差的任何加工条件的讨论（例如，极端的pH值、有毒成分，或在发生微生物偏离的情况下水活度低）。对于从微生物结果中鉴别出的任何特定生物，评估还应包括其影响分析。该评估应表明所涉及的产品是否适合使用或应被拒签，以及是否需要召回产品。

The investigation should be completed in a timely manner inaccordance with site procedures and the associated risk. After theinvestigation, consideration should be given to how the issue will be presentedduring an audit. Complicated investigations may benefit from supplementalmaterials such as story boards or concise presentation slides. The visual toolsutilized during formal root-cause analysis activities (e.g., fish bone) arefrequently good additions to these presentations. The subject matter expert whowill discuss the investigation with the auditor should have thorough knowledgeof the investigation, and may benefit from a practice audit with personnel notdirectly involved in the initial investigation during a site self-assessment.

应根据工厂程序和相关风险及时完成调查。调查之后，应考虑在审计过程中会如何提出问题。对于复杂的调查，故事板或简明演示文稿等补充材料可能会有帮助。在正式的根本原因分析活动（例如鱼骨图分析）中，使用视觉工具通常是对这些演示文稿的很好的补充。与检查员讨论调查的主题专家应该对调查有透彻的了解，并可能从模拟性审计中获益：在工厂自查期间，由未直接参与初始调查的人员进行审计。

A complete list of all investigations for the system over aperiod of time (typically 2 years or since the end of the last inspection)should be continuously controlled and ready at the start of the inspection.Some companies may maintain a list of investigations on an ongoing basis, andothers may use their investigation tracking system to generate such a list ondemand. Personnel should refresh themselves on the complicated investigationsprior to the inspection when possible.

在一段时间内（通常为2年或自上次检查结束以来）对系统进行的所有调查的完整清单，应持续控制更新，在检查开始时需要准备就绪。一些公司可能会持续维护调查列表，而其它公司可能会使用其调查跟踪系统按需生成此类列表。在可能的情况下，在检查之前，人员应对复杂的调查有所了解。

摘译自：ISPE 《良好实践指南：关键公用系统GMP符合性》-2020