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Defining an OOS Event

定義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.

對于公用系統(tǒng)，無論是離線樣品，還是在線監(jiān)測，當出現(xiàn)OOS時，應進行調查。應有系統(tǒng)在出現(xiàn)OOS結果時通知適當的人員。對于離線取樣的樣品，應設置LIMS，根據質量標準對樣品結果進行檢驗，并將任何失敗通知用戶。使用在線監(jiān)測儀器時，可配置與之關聯(lián)的自動化系統(tǒng)，以適當的值進行報警。

 

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節(jié)[36]包含有關如何正確實施警戒限和行動限，以及在超出這些水平時如何響應的建議。

 

Trends

趨勢

 

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.

系統(tǒng)在運行的過程，可能會有一些趨勢，如重復超警戒限或報警。與OOS事件類似，應對這種趨勢進行調查，盡管通常沒有必要評估產品影響，因為沒有超出質量標準或關鍵報警。

 

Investigations

如何調查

 

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

歐盟GMP第1章第1.8節(jié)（vii） [37]要求：

 

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

 “任何重大偏差都應得到充分記錄，并進行調查以確定根本原因并采取適當的糾正和預防措施。”

 

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.

調查應確定問題的原因，并提供CAPA的理由。它應易于理解，可追溯，并應良好記錄以確保在要求時能夠很好地溝通情況。應明確調查的范圍，是否有任何項目被明確地排除以及為什么排除。應使用根本原因工具，例如5個為什么/ KT分析（KTA）/因果分析（5M +，魚骨或石川圖） / FMEA等，尤其是對于復雜程度較大的調查。調查應包括對過去一段時間內重復發(fā)生的調查的回顧，例如通常12個月，但如果問題是季節(jié)性的，則這種情況下的時間可能會更長。

 

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.

調查應以科學為基礎，這意味著調查應由問題陳述（同時定義了調查的范圍）和一個或多個應進行證明或排除的假設開始。

 

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.

下面列出了調查期間需要考慮的因素（不是完整列表）。并非每次調查都需要考慮所有這些因素，但應根據問題的具體情況選擇適當的因素。

 

Environment: 

環(huán)境

 

Was nonroutine work occurring in the area?

該區(qū)域是否發(fā)生非常規(guī)工作？

 

Equipment:

設備

 

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

儀器故障或校準漂移是否與此問題有關？電源相關？

Was nonroutine work being performed on the system?

是否在系統(tǒng)上執(zhí)行非常規(guī)工作？

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

設備維護（包括日常維護）和恢復是否得到正確執(zhí)行？

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

是否存在可能導致使用模式或取樣環(huán)境變化的變更，例如某個區(qū)域或設備的閑置？

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

使用點或取樣點是否由于管道傾斜不當，細管中的表面張力或安裝的墊圈尺寸不當而積水？

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

如果在出口使用了軟管，是否正確處理了它們（使用后斷開連接；如果可重復使用，則進行消毒/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.

產品是否受到影響？自上次取樣合格以來生產的產品應進行評估。對于微生物失敗的產品影響評估，通常限于該使用點生產的產品即可；但對于化學失敗，通常會擴展至評估由該回路或系統(tǒng)提供的所有產品。

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?

在調查過程中，是否應收集更多樣品或表明系統(tǒng)已恢復正常？額外取樣是否是已批準SOP的一部分，或是額外取樣需要質量部門的預先批準？

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.

對于微生物失敗，是否進行了微生物鑒別？這可以幫助確定失敗的根本原因（確定是水系統(tǒng)固有的微生物，還是與樣品的外部污染），并且對于產品影響評估也可能有幫助。

 

Personnel:

人員

 

Is sampling error a concern? 

是否取樣錯誤？

- Was good aseptic technique used?

- 是否使用了良好的無菌技術？

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

- 是否取樣了正確的取樣點/公用設施/系統(tǒng)（飲用水，還是純化水）？

- 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?

- 樣品是否可能被污染，例如同一區(qū)域的飲用水和純化水是否使用相同的軟管？

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

- 取樣程序是否正確執(zhí)行（取樣點是否需要排水，軟管或附件如何清潔）？

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.

是否實驗室錯誤？分析實驗室通常會對生成的每個失敗結果進行調查，以確保沒有明顯的實驗室失敗原因。

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

如果在調查期間人為錯誤屢屢發(fā)生，培訓計劃是否足夠？SOP是否清晰準確？

 

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.

產品風險評估應作為調查的一部分進行。這應評估偏差期間，超出質量標準對與水相關的產品的影響。如將水用作輔料，或使用水清潔用于生產產品的設備，則該產品可能與偏差事件相關。評估應包括可能影響特定偏差的任何加工條件的討論（例如，極端的pH值、有毒成分，或在發(fā)生微生物偏離的情況下水活度低）。對于從微生物結果中鑒別出的任何特定生物，評估還應包括其影響分析。該評估應表明所涉及的產品是否適合使用或應被拒簽，以及是否需要召回產品。

 

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.

應根據工廠程序和相關風險及時完成調查。調查之后，應考慮在審計過程中會如何提出問題。對于復雜的調查，故事板或簡明演示文稿等補充材料可能會有幫助。在正式的根本原因分析活動（例如魚骨圖分析）中，使用視覺工具通常是對這些演示文稿的很好的補充。與檢查員討論調查的主題專家應該對調查有透徹的了解，并可能從模擬性審計中獲益：在工廠自查期間，由未直接參與初始調查的人員進行審計。

 

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.

在一段時間內（通常為2年或自上次檢查結束以來）對系統(tǒng)進行的所有調查的完整清單，應持續(xù)控制更新，在檢查開始時需要準備就緒。一些公司可能會持續(xù)維護調查列表，而其它公司可能會使用其調查跟蹤系統(tǒng)按需生成此類列表。在可能的情況下，在檢查之前，人員應對復雜的調查有所了解。

 

摘譯自：ISPE 《良好實踐指南：關鍵公用系統(tǒng)GMP符合性》-2020