根本原因调查的良好做法

A fresh look at an old topic: Investigations in the GMDP environment
老话新谈：GM/DP环境下的调查

Posted by:CallumMcLoughlin, 
Posted on:14 September 2020 – 
Categories:Compliance matters, Good distribution practice, Good manufacturing practice
 
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.
调查是任何生产商或批发商运营中不可避免的事情；尽管每个公司都在努力建立完善的系统和流程，但仍无法预测每种潜在的故障模式并完全防止事件发生。

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.
在这篇文章中，我将分享在所有规模和所有运营模式的公司进行检查时检查员经常看到的一些问题，因此您可以考虑自己公司的系统和做法并改善调查结果。此文章所述的概念同样适用于偏差、客户投诉和其他几个药品质量体系（PQS）活动。

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年以来，调查的力量以及使它们有效的环节在缺陷数据挑战中一直受到挑战。2018年以来最新发布的数据集显示，在此期间提出的缺陷中大约有10％直接源于调查不良，尽管考虑它们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.
还值得注意的是，检查员将其中一些缺陷分类为“严重”。如果事情没有按计划进行或系统无法按预期运转，则无法保持受控状态，并且生产质量、有效性或安全性不佳的产品的风险也会增加。如果此类产品进入市场，则可能对公众健康产生重大影响。

Problems we see during inspection 
检查期间看到的问题

Withthe system 
系统方面

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的一个强大原则是要在受控状态下运行。PQS是帮助公司实现此状态的基础。在检查过程中，我们将寻找证据证明调查、纠正和预防措施（CAPA）系统处于受控状态。如果不是，则会出现问题，包括：

· investigations being raised long after the event occurred or taking an unreasonable time to complete
· 事件发生后很长一段时间后才进行调查，或者花费了不合理的时间来完成调查
· root cause analysis being raised as a CAPA to enable premature deviation closeout
· 提出某项根本原因只是为了让CAPA可以早点关闭偏差
· a large proportion of CAPAs being overdue or being extended
· 大面积CAPA已过期或被延期
· human error being listed as a frequent root cause.
· 频繁将人为错误被列为根本原因

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.
从不断改进和执行适当的根本原因分析要求来说，经常出现的问题是系统无效的一个指标。

With the investigation
调查方面

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.
业内的专业人员具有丰富的经验和知识，但是，这有时可能意味着其实是基于先前的经验得出理论上的根本原因——尤其是当调查人员不能自主挑战所有相关工艺和系统时。这可能导致结论是基于假设而不是基于证据的调查得出的。

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.
普遍情况是，公司麻木认为已经长期存在的程序和方法可以完美地工作并且无法改进，与任务相关的错误归因于个人未正确遵循指令。如果相同或相关的问题在不同的人身上多次发生，就清楚地表明人为错误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与系统和过程相关的变量后，才可以将人为错误作为根本原因。如果人为错误是潜在的根本原因，则真正的根本原因可能是培训系统中的缺陷、程序过于复杂或难以遵循，或者其他因素，例如不适当的多任务状态和注意力分散。在这种情况下，“提醒/重新培训操作员”不太可能成为有效的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.
从一开始就使用风险评估来证明采取或不采取某些措施的合理性通常是有问题的，因为事情走向很自然会发展成只写下可以支持作者已预设的结果的信息和推论，而这意味着评估没有反映出真正的风险水平。

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.
在出现问题的地方正确使用风险评估至关重要，必须准确了解其对质量和有效性的影响以及对患者总体安全的影响。应将所有可用的证据一起使用，以准确地建立所有潜在的故障模式、发生的可能性、可检测性或其他因素，这些因素综合起来有助于做出适当的决策。

What good looks like
什么是“良好”的调查？

Effectiveinvestigations
有效调查

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.
应该从一开始就开展调查，目的是查明真正的根本原因并确定适当的CAPA。这不仅是保护患者安全的机制，而且是提高组织运营效率的一种方式。

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.
调查人员应考虑事件的最初可能根本原因之外的其他原因，并确认或排除其他可能的潜在根本原因。调查应该包括与参与该事件的相关同事交谈，最佳做法包括查看相关区域。回顾以前的事件对于确定这是否是该区域、特定设备或工艺中重复出现的问题很重要。

Risk assessments 
风险评估

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、生产周期和之前的生产周期的风险评估应予以适当考虑。ICH Q9中提供了有关风险评估方法的指南。评估应足够详细，涵盖所有合理风险，以证据为导向得出批处置结论和/或召回决策，而不是试图制造案例来支持已做出的决策。

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.
有些问题在表面上看起来并不重要，只有评估后才能知道有更大的风险。应该考虑问题的严重程度和其他批次的影响，有可能问题已经存在一段时间了但没有发现。

Consideration of patient safety
考虑患者安全

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.
在患者情况下的质量、安全性和功效风险应作为所有检查的重点。应该清楚地考虑它，并将其包含在相关文件中。必须考虑可能其它未发现故障的情况以及该风险状况可能是什么。

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.
有几种根本原因分析方法是众所周知的，但是即使这些方法有明显的优势或报告记录说“无法确定真正的根本原因”，我们却很少看到公司使用它们。

Such approaches include:
这些方法包括：
· Ishikawa fishbone diagrams
· 石川鱼骨图
· the 5 whys
· “ 5个为什么”
· thinking wider and considering PQS trend data and any potential links.
· 广泛地思考，并考虑PQS趋势数据和任何潜在的联系。

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，生产设备的密封故障是漏油和设备卡死的直接原因，但根本原因可能是：
· the wrong seals were fitted during planned maintenance
· 在计划性维护期间安装了错误的密封件
· the supplier has changed their specifications
· 供应商已变更密封件规格
· the seal had worn out, indicating the planned maintenance schedule was ineffective, potentially due to an increase of equipment utilisation.
· 密封件已磨损，表明制订的维护计划无效，这可能是由于设备使用率增加所致。

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将有助于确定适当和相关的CAPA。这些应该：

· be clearly defined
· 有明确定义
· directly address the root cause
· 直接解决根本原因
· have realistic and risk-based target dates
· 具有现实的和基于风险的目标日期
· be monitored to conclusion.
· 监测结论

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.
过于乐观的目标日期可能会以其他方式影响PQS，公司应考虑采用任意的完成时间，尤其是在应紧急实施或确定了下一批生产的CAPA的情况下。

A well-managed system 
良好管理的系统

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.
支持调查活动和输出的系统应进行趋势监测，以获得有意义的信息，这些信息可用于推动例行改进并确保达成批准的时间表。这包括在管理评审期间进行检查，并在需要时进行升级，以确保系统保持受控状态，以及在出现问题时采取保护患者的有效手段。

       文章来源：允咨GMP制药技术

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