Investigations are an inevitableaspect of any manufacturer’s or wholesaler’s operations; whilst every company strives to put in place perfect systems and processes it is impossible to predict every potential failure mode and totally prevent incidents from happening.
調(diào)查是任何生產(chǎn)商或批發(fā)商運(yùn)營(yíng)中不可避免的事情；盡管每個(gè)公司都在努力建立完善的系統(tǒng)和流程，但仍無(wú)法預(yù)測(cè)每種潛在的故障模式并完全防止事件發(fā)生。
In this post, I will share some common issues that the inspectorate often sees whilst out on inspection at companies of all sizes and of all operating models, so you can consider your own company’s systems and practices and improve investigation outcomes. The concepts outlined in this post are equally applicable to deviations, customer complaints and several other Pharmaceutical Quality System (PQS) activities.
在這篇文章中，我將分享在所有規(guī)模和所有運(yùn)營(yíng)模式的公司進(jìn)行檢查時(shí)檢查員經(jīng)?？吹降囊恍﹩?wèn)題，因此您可以考慮自己公司的系統(tǒng)和做法并改善調(diào)查結(jié)果。此文章所述的概念同樣適用于偏差、客戶(hù)投訴和其他幾個(gè)藥品質(zhì)量體系（PQS）活動(dòng)。
The strength of investigations, and the subcomponents that together make them effective, has been an ongoing area of challenge in deficiency data published since 2010. The most recently published dataset from 2018 shows that roughly 10% of deficiencies raised in that period were directly attributable to poor investigations, though it is important to consider whether they could also bethe root cause of other deficiencies too.
自2010年以來(lái)，調(diào)查的力量以及使它們有效的環(huán)節(jié)在缺陷數(shù)據(jù)挑戰(zhàn)中一直受到挑戰(zhàn)。2018年以來(lái)最新發(fā)布的數(shù)據(jù)集顯示，在此期間提出的缺陷中大約有10％直接源于調(diào)查不良，盡管考慮它們是否也可能是其他缺陷的根本原因也很重要。
It is also worthy of note that some of those deficiencies have been classified by the inspector as Critical. When things do not go to plan or systems do not work as intended, a state of controlis not maintained and the risk of product that is not of the right quality, efficacy or is not safe being produced increases. If such products reach the market this may have a significant impact on public health.
還值得注意的是，檢查員將其中一些缺陷分類(lèi)為“嚴(yán)重”。如果事情沒(méi)有按計(jì)劃進(jìn)行或系統(tǒng)無(wú)法按預(yù)期運(yùn)轉(zhuǎn)，則無(wú)法保持受控狀態(tài)，并且生產(chǎn)質(zhì)量、有效性或安全性不佳的產(chǎn)品的風(fēng)險(xiǎn)也會(huì)增加。如果此類(lèi)產(chǎn)品進(jìn)入市場(chǎng)，則可能對(duì)公眾健康產(chǎn)生重大影響。
Problems we see during inspection
檢查期間看到的問(wèn)題
With the system
系統(tǒng)方面
A strong principle of GMP is operating in a state of control. The PQS is the foundation which helps companies achieve this state. During inspection, we will look for evidence that the investigation and Corrective and Preventive Action (CAPA) system is operating in a state of control. There are some symptoms if it is not, these can include:
GMP的一個(gè)強(qiáng)大原則是要在受控狀態(tài)下運(yùn)行。PQS是幫助公司實(shí)現(xiàn)此狀態(tài)的基礎(chǔ)。在檢查過(guò)程中，我們將尋找證據(jù)證明調(diào)查、糾正和預(yù)防措施（CAPA）系統(tǒng)處于受控狀態(tài)。如果不是，則會(huì)出現(xiàn)問(wèn)題，包括：
investigations being raised long after the event occurred or taking an unreasonable time to complete
事件發(fā)生后很長(zhǎng)一段時(shí)間后才進(jìn)行調(diào)查，或者花費(fèi)了不合理的時(shí)間來(lái)完成調(diào)查
root cause analysis being raised as a CAPA to enable premature deviation closeout
提出某項(xiàng)根本原因只是為了讓CAPA可以早點(diǎn)關(guān)閉偏差
a large proportion of CAPAs being overdue or being extended
大面積CAPA已過(guò)期或被延期
human error being listed as a frequent root cause.
頻繁將人為錯(cuò)誤被列為根本原因
In view of the requirement to continually improve and perform appropriate root cause analysis, regularly recurring issues are an indicator that the system is ineffective.
從不斷改進(jìn)和執(zhí)行適當(dāng)?shù)母驹蚍治鲆髞?lái)說(shuō)，經(jīng)常出現(xiàn)的問(wèn)題是系統(tǒng)無(wú)效的一個(gè)指標(biāo)。
With the investigation
調(diào)查方面
Professionals in industry have a lot of experience and knowledge, however this can sometimes mean that a theoretical root cause can be concluded based on previous experience - this is especially true if investigators are not given freedom to apply relevant challenge to all relevant processes and systems. This can lead to conclusions being reached based on assumption rather than an evidence-based investigation.
業(yè)內(nèi)的專(zhuān)業(yè)人員具有豐富的經(jīng)驗(yàn)和知識(shí)，但是，這有時(shí)可能意味著其實(shí)是基于先前的經(jīng)驗(yàn)得出理論上的根本原因——尤其是當(dāng)調(diào)查人員不能自主挑戰(zhàn)所有相關(guān)工藝和系統(tǒng)時(shí)。這可能導(dǎo)致結(jié)論是基于假設(shè)而不是基于證據(jù)的調(diào)查得出的。
A common manifestation of this iswhere companies take the view that long-standing procedures and methods work perfectly and cannot be improved, with errors associated with the task attributed to individuals not following instructions accurately. When the same or a related problem has occurred on several occasions and with different people this is a clear indicator that human error is unlikely to be the true root cause.
普遍情況是，公司麻木認(rèn)為已經(jīng)長(zhǎng)期存在的程序和方法可以完美地工作并且無(wú)法改進(jìn)，與任務(wù)相關(guān)的錯(cuò)誤歸因于個(gè)人未正確遵循指令。如果相同或相關(guān)的問(wèn)題在不同的人身上多次發(fā)生，就清楚地表明人為錯(cuò)誤不太可能是真正的根本原因。
Human error should only be cited as root cause when all other system and process related variables have been ruledout. It is plausible that, where human error is a potential root cause, the true root cause could be deficiencies in the training system, an overly complex or difficult to follow procedure, or perhaps other factors such as inappropriate multi-tasking and distraction. It is unlikely that 'remind/re-train the operator' will ever be an effective CAPA in such circumstances.
只有排除了所有其他與系統(tǒng)和過(guò)程相關(guān)的變量后，才可以將人為錯(cuò)誤作為根本原因。如果人為錯(cuò)誤是潛在的根本原因，則真正的根本原因可能是培訓(xùn)系統(tǒng)中的缺陷、程序過(guò)于復(fù)雜或難以遵循，或者其他因素，例如不適當(dāng)?shù)亩嗳蝿?wù)狀態(tài)和注意力分散。在這種情況下，“提醒/重新培訓(xùn)操作員”不太可能成為有效的CAPA。
Risk assessments that from the outsetare used to justify taking - or not taking - certain actions are usually flawed.This is because there is a natural tendency to only include information and arguments that support the outcome the author has set out to conclude. This means that the assessment is not a true reflection of the risk level.
從一開(kāi)始就使用風(fēng)險(xiǎn)評(píng)估來(lái)證明采取或不采取某些措施的合理性通常是有問(wèn)題的，因?yàn)槭虑樽呦蚝茏匀粫?huì)發(fā)展成只寫(xiě)下可以支持作者已預(yù)設(shè)的結(jié)果的信息和推論，而這意味著評(píng)估沒(méi)有反映出真正的風(fēng)險(xiǎn)水平。
Appropriate use of risk assessment is crucial where things have gone wrong and the impact on quality and efficacy, and the overall patient safety impact, must be accurately understood. Allavailable evidence should be used together to accurately establish all potential failure modes, likelihood of occurrence, detectability, or other factors which when taken together help appropriate decisions be made.
在出現(xiàn)問(wèn)題的地方正確使用風(fēng)險(xiǎn)評(píng)估至關(guān)重要，必須準(zhǔn)確了解其對(duì)質(zhì)量和有效性的影響以及對(duì)患者總體安全的影響。應(yīng)將所有可用的證據(jù)一起使用，以準(zhǔn)確地建立所有潛在的故障模式、發(fā)生的可能性、可檢測(cè)性或其他因素，這些因素綜合起來(lái)有助于做出適當(dāng)?shù)臎Q策。
What 'good' looks like
什么是“良好”的調(diào)查？
Effectiveinvestigations
有效調(diào)查
Investigations should be launched from the outset with the intention of establishing true root cause and identifying appropriate CAPAs. It is not only a mechanism to protect patient safety, but a way to improve the efficiency of an organisation’s operations.
應(yīng)該從一開(kāi)始就開(kāi)展調(diào)查，目的是查明真正的根本原因并確定適當(dāng)?shù)腃APA。這不僅是保護(hù)患者安全的機(jī)制，而且是提高組織運(yùn)營(yíng)效率的一種方式。
Investigators should consider beyond the initial probable root cause of an incident and confirm or rule out other plausible potential root causes. This should include speaking to relevant colleagues involved in the incident and best practice would include visiting the areas involved. A review of previous incidents is important to identify if this is a recurring issue within that area, on a specific piece of equipment, or a process.
調(diào)查人員應(yīng)考慮事件的最初可能根本原因之外的其他原因，并確認(rèn)或排除其他可能的潛在根本原因。調(diào)查應(yīng)該包括與參與該事件的相關(guān)同事交談，最佳做法包括查看相關(guān)區(qū)域。回顧以前的事件對(duì)于確定這是否是該區(qū)域、特定設(shè)備或工藝中重復(fù)出現(xiàn)的問(wèn)題很重要。
Risk assessments
風(fēng)險(xiǎn)評(píng)估
Risk assessment on the batch, campaign and previous campaigns should be considered as appropriate. Guidance on risk assessment methodology is available in ICH Q9. The assessments should be sufficiently detailed to cover all reasonable risks, be evidence-led and drive decisions on batch disposition and/or recalls, rather than building cases to support any decisions already made.
批次、生產(chǎn)周期和之前的生產(chǎn)周期的風(fēng)險(xiǎn)評(píng)估應(yīng)予以適當(dāng)考慮。ICH Q9中提供了有關(guān)風(fēng)險(xiǎn)評(píng)估方法的指南。評(píng)估應(yīng)足夠詳細(xì)，涵蓋所有合理風(fēng)險(xiǎn)，以證據(jù)為導(dǎo)向得出批處置結(jié)論和/或召回決策，而不是試圖制造案例來(lái)支持已做出的決策。
Some issues can appear minor at surface level, only when assessed will more significant risks become known. The extent of the issue and other batches affected should be considered, it may be that the issue has been there but undetected for some time.
有些問(wèn)題在表面上看起來(lái)并不重要，只有評(píng)估后才能知道有更大的風(fēng)險(xiǎn)。應(yīng)該考慮問(wèn)題的嚴(yán)重程度和其他批次的影響，有可能問(wèn)題已經(jīng)存在一段時(shí)間了但沒(méi)有發(fā)現(xiàn)。
Consideration of patient safety
考慮患者安全
The quality, safety and efficacy risk in the context of the patient should be central to all investigations. It should be clearly considered and included in the associated documentation.Thought must be given to other circumstances in which the failure may not have been detected and what that risk profile could be.
在患者情況下的質(zhì)量、安全性和功效風(fēng)險(xiǎn)應(yīng)作為所有檢查的重點(diǎn)。應(yīng)該清楚地考慮它，并將其包含在相關(guān)文件中。必須考慮可能其它未發(fā)現(xiàn)故障的情況以及該風(fēng)險(xiǎn)狀況可能是什么。
Root cause analysis
根本原因分析
There are several approaches to root cause analysis that are well known and recommended, however we do not always see them used even when there are clear advantages or 'true root cause could not be identified' has been recorded in the report.
有幾種根本原因分析方法是眾所周知的，但是即使這些方法有明顯的優(yōu)勢(shì)或報(bào)告記錄說(shuō)“無(wú)法確定真正的根本原因”，我們卻很少看到公司使用它們。
Such approaches include:
這些方法包括：
Ishikawa fishbone diagrams
石川魚(yú)骨圖
the '5 whys'
“ 5個(gè)為什么”
thinking wider and considering PQS trend data and any potential links.
廣泛地思考，并考慮PQS趨勢(shì)數(shù)據(jù)和任何潛在的聯(lián)系。
For example, while a seal failure on manufacturing equipment is the direct cause of oil leakage and equipment seizing, the root cause could be that:
例如，生產(chǎn)設(shè)備的密封故障是漏油和設(shè)備卡死的直接原因，但根本原因可能是：
the wrong seals were fitted during planned maintenance
在計(jì)劃性維護(hù)期間安裝了錯(cuò)誤的密封件
the supplier has changed their specifications
供應(yīng)商已變更密封件規(guī)格
the seal had worn out, indicating the planned maintenance schedule was ineffective, potentially due to an increase of equipment utilisation.
密封件已磨損，表明制訂的維護(hù)計(jì)劃無(wú)效，這可能是由于設(shè)備使用率增加所致。
Targeted CAPAs
CAPA有的放矢
Effective root cause analysis willlead to the identification of appropriate and relevant CAPAs. These should:
有效的根本原因分析將有助于確定適當(dāng)和相關(guān)的CAPA。這些應(yīng)該：
be clearly defined
有明確定義
directly address the root cause
直接解決根本原因
have realistic and risk-based target dates
具有現(xiàn)實(shí)的和基于風(fēng)險(xiǎn)的目標(biāo)日期
be monitored to conclusion.
監(jiān)測(cè)結(jié)論
Target dates that are too optimistic can impact the PQS in other ways and companies should think about the application of arbitrary completion times, especially where CAPAs that should be implemented urgently or before manufacture of the next batch have been identified.
過(guò)于樂(lè)觀(guān)的目標(biāo)日期可能會(huì)以其他方式影響PQS，公司應(yīng)考慮采用任意的完成時(shí)間，尤其是在應(yīng)緊急實(shí)施或確定了下一批生產(chǎn)的CAPA的情況下。
A well-managed system
良好管理的系統(tǒng)
The systems supporting investigation activities and outputs should be monitored with trending to obtain meaningful information that can be used to drive routine improvements and ensure that approved timescales are met. This includes scrutiny during management review and escalation where needed to ensure the system remains in control and an effective means of protecting patients when things have gone wrong.
支持調(diào)查活動(dòng)和輸出的系統(tǒng)應(yīng)進(jìn)行趨勢(shì)監(jiān)測(cè)，以獲得有意義的信息，這些信息可用于推動(dòng)例行改進(jìn)并確保達(dá)成批準(zhǔn)的時(shí)間表。這包括在管理評(píng)審期間進(jìn)行檢查，并在需要時(shí)進(jìn)行升級(jí)，以確保系統(tǒng)保持受控狀態(tài)，以及在出現(xiàn)問(wèn)題時(shí)采取保護(hù)患者的有效手段。
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