分享 | 药物研发过程中偏差调查的常见8个错误

创业 2025-01-16 16:01 北京

偏差调查是任何GMP组织中最重要的质量活动之一。在FDA和其他监管机构发布的缺陷、警告信和同意令中，它们也一直处于最常被引用的问题列表的首位。(“未能彻底审核[任何无法解释的差异][批次或其任何组分不符合质量，无论批次是否已经销售]。”)

Deviation investigations are one of the most important quality activities in any GMP(good manufacturing practice) organization. They are also perennially near the top of the list of most frequently cited issues in observations, warning letters, and consent decrees from the U.S. Food and Drug Administration (FDA)and other regulatory authorities. (“There is a failure to thoroughly review [any unexplained discrepancy][the failure of a batch or any of its components to meet any of its specifications] whether or not the batch has been already distributed.”)

显然，许多组织在偏差调查的编写和管理方面仍有改进的余地。以下几节列出了公司在进行偏差调查时所犯的常见错误以及如何避免这些错误。

Clearly,many organizations have room to improve in the writing and managing of deviation investigations. The following sections identify common missteps companies make when conducting deviation investigations — and how you can avoid them.

未利用历史数据进行持续改进

Not leveraging historical data for continuous improvement

随着时间的推移，通过调查收集到的信息包含了大量的数据，可用于不断改进、提高生产力和减少调查的再次发生。不幸的是，许多组织每年只审查这一数据一次，而且有些敷衍了事。一个良好的趋势过程是监测和积极应对发展中问题的一个重要因素。跟踪调查数据(根本原因、功能组、单元操作)将有助于持续监控设备中按产品、流程区域和功能组等发生的事件类型和根本原因。制定标准事件类别和可采取行动的根本原因清单，以便趋势偏差和调查数据。这份清单可以超过200或更多数据，可以帮助调查人员以可操作的方式写出他们的根本原因。

The information gathered over time through investigations contains a wealth of data that can be used for continuous improvement, increasing productivity, and reducing the recurrence of investigations. Unfortunately, many organizations only review this data once a year and in a somewhat perfunctory manner. A good trending process is an important element in monitoring and proactively responding to developing issues. Tracking investigation data (root cause, functional group, unit operation) will aid in continuous monitoring of the types of events and root causes occurring in your facility by product, process area, and functional group, among others. Develop a list of standard event categories and actionable root causes in order to trend deviation and investigation data. This list can be upwards of 200 or more and can aid investigators in writing their root cause in actionable terms.

把人为错误作为根本原因

Relying on human error as a root cause

这是监管当局在其缺陷中经常引用的缺陷。重复把人为错误作为根本原因是一个迹象，表明您的组织没有权力和/或资源来找出真正的根本原因，并纠正重复出现的潜在问题。

This is a common finding that regulatory authorities will cite in their observations. Repeatedly stating human error as a root cause is a sign that your organization is not interested and/or resourced to find true root causes and to correct the underlying issues behind recurrence.

人的错误可以是一个根本原因类别，但它本身很少是真正的和可采取行动的根本原因。真正的根本原因通常是在其他领域，如程序(“步骤x.x不明确”)、培训(“由于SOP没有列入培训课程而没有被安排关于程序的培训”)、环境（由于火灾报警引起的注意力分散）或机器(“设备设计和布局不当”)。

Human error can be a root cause category, but rarely is it the true and actionable root cause, in and of itself. The true root cause is usually in other areas,such as procedures (“step x.x unclear”), training (“wasn’t assigned training on procedure since SOP was not on training curriculum”), environment (“distraction due to false fire alarm”), or machine (“improper equipment design and layout”).

重要的是找到一个真正的、潜在的根源，并以可操作的方式描述它，以防止再次发生，并减少今后与人员错误相关的事件的数量。这类事件在生产效率损失、合规和劳动力成本以及调查不合格行为所需的人力资源等方面给企业造成了惊人的损失。对于大型制药公司来说，偏差的平均成本高达数万美元。防止人为错误的再次发生不仅节省了组织的资金，而且降低了合规问题的可能性，包括监管缺陷。

It is important to find a true, underlying root cause and to describe it in actionable terms to prevent recurrence and reduce the number of future human error-related events. Such events cost the industry a staggering amount interms of lost productivity, compliance and labor costs, and the human resources needed to investigate nonconformances. The average cost of a deviation runs into tens of thousands of dollars for major pharmaceutical companies.Preventing human error recurrence not only saves organizations money, but it reduces the likelihood of compliance issues, including regulatory findings.

一些质量系统不允许将人为错误用作根本原因，以防止组织无法识别和解决错误背后的真正根源(见下面的错误#3)。例如，在许多(但肯定不是所有)人为错误事件中，所涉及的员工可以在错误变成偏差之前检测到错误。因此，在这种情况下，“发现问题的能力不足”是可采取行动的根本原因。由此产生的CAPA(纠正和预防行动)将是咨询或额外培训，重点是提高个人发现和解决错误的能力，或其他工作辅助或改进人机界面(HMI)，使操作者能够及时更好地发现问题，以防止出现偏差。仅仅建议“注重细节”或“GMP的重要性”，作为一个独立的CAPA来说，是不具体的，也是不够的。如果有人不理解GMP的重要性，他们就不应该在GMP环境下工作，而且他们肯定需要更多的培训。

Some quality systems will not allow human error to be used as a root cause, in order to prevent the organization from stopping short of identifying and addressing the true root cause behind errors (see error #3 below). For example, in many(but definitely not all) human error events, the employee involved could have detected the error prior to it becoming a deviation. Therefore, “in adequate ability to detect the problem” could be the actionable root cause in such situations. The resulting CAPA (corrective and preventive action) would be counseling or additional training that focuses on increasing the person’sability to detect and fix an error, or other job aids or improvements in theHMI (human machine interface) that will allow operators to better detect problems in time to prevent a deviation. Counseling just on “paying attention to detail” or on “the importance of GMPs” is not specific or adequate as a stand alone CAPA. If someone doesn’t understand the importance of GMPs, they shouldn’t be working in a GMP environment — and they definitely need more training.

没有找到可能的根本原因

Not getting to the probable root cause

调查出根本原因的偏差调查所占的百分比是衡量质量体系健康的一个很好的指标-这个百分比越高，越好。没有找出根本原因的原因是多方面的，没有投入足够的时间和资源是其中之一。然而，更普遍的情况是作出了足够的努力，收集所有必要的事实和信息，但仍然找不到根本原因。有时，这是调查人员技能直接导致的，他们可能没有受过充分的培训，或对所涉问题缺乏技术上的掌握。

The percentage of investigations resulting in a root cause is a good metric for the health of your quality system — the higher the percentage, the better. There are many reasons why root causes are not found. Not committing adequate time and resources is one. However, it is all too common for organizations to put in sufficient effort, gather all the necessary facts and information, but still fail to identify a root cause. Sometimes, this is the direct result of the investigator’s skill — they may have been trained insufficiently or lack technical command of the issues involved.

然而，令人惊讶的是，调查得出的结论也令人惊讶，即无法查明“确定的”根本原因，尽管有所有必要的资料，而且结论是显而易见的。对事实的错误解释或不现实的确定性概念可能会使调查无法找到最可能的根本原因。没有任何监管标准要求所有调查结论都是确定的。一个最可能的根本原因是以彻底调查为基础并以现有数据和资料为依据的，这就足够了。

However,it is also surprisingly common for an investigation to conclude that a“definitive” root cause could not be identified, despite the fact that all the necessary information is available and the conclusion is readily discernable. A misguided interpretation of the facts or an unrealistic notion of definitive can prevent the investigation from arriving at a most probable root cause.There is no regulatory standard that requires all investigation conclusions bedefinitive. A most probable root cause based on and justified by a thorough investigation and supported by the available data and information is sufficient.

对于手头的问题，应该选择合适的RCA(根原因分析)工具。对于更困难的调查，Kepner-Tregoe或IS-IS NOT分析通常可以从一系列不一致的事实中找出最具挑战性的最可能的根本原因。

The proper RCA (root cause analysis) tool should be chosen for the problem at hand.For more difficult investigations, a Kepner-Tregoe or IS-IS NOT analysis can often tease out a challenging most probable root cause from an array of discordant facts.

找不到真实的根本原因

Not getting to the true root cause

找到真正的根源是至关重要的。在许多情况下，组织未能找出和纠正一个容易解决的问题的真正根源，结果他们遭受了数百万美元的损失(甚至更糟)。真正的根本原因是一个可采取行动的原因，是最符合现有的事实和彻底调查得出的信息，可以是最可能的根本原因，上述提到。

Finding the true root cause is critically important. There have been many cases where organizations failed to identify and correct the true root cause of a problem that was readily solvable — and they suffered millions of dollars in losses (or worse) as a result. The true root cause is an actionable one that is the most consistent with the available facts and information from a thorough investigation and can be the most probable root cause mentioned above.

真正的根本原因是允许事件发生的潜在原因。了解真正的根本原因需要收集所有相关的事实。有时，这些在事件发生时就被清楚地理解了。其他时候，它需要深入的技术评估，可以跨越几个月。

A true root cause is the underlying reason that allowed the event to occur.Understanding the true root cause requires the collection of all relevant facts. Sometimes, these are clearly understood at the time of the event. Othertimes, it requires in-depth technical assessments that can span several months.

评估是否找到了真正的根本原因一个很好的测试是，看看是否可以用直接采取行动的形式来说明，这意味着它与纠正行动有着明确的联系且在可控制范围内。一个简单而有效的方法，以确定是否找到了真正的，可采取行动的根本原因是在调查结束时使用5 Whys工具，包括应用于更先进的工具，如鱼骨图或Kepner-Tregoe分析（KT法，问题解决技巧-方法）。

One good test for assessing if the true root cause has been found is to see if it can be stated in terms that are directly actionable, meaning it links clearly to a corrective action and is within the organization’s control. A simple and effective way to determine if the true, actionable root cause has been found is to use the 5 Whys tool at the conclusion of an investigation, including application to the outputs from more advanced tools, such as a fishbone diagramor Kepner-Tregoe analysis.

例如，备用电源的故障不是真正的、可采取行动的根本原因。为什么备用电源失灵？飓风马修不能被列为可采取行动的根本原因，因为该组织无法防止飓风。然而，备用电源预防性维护程序不足可能是真正的根本原因，在这种情况下，纠正措施是完善程序。

For example, failure of the backup power supply is not a true, actionable root cause. Why did the back-up power supply fail? Hurricane Matthew cannot be listed as an actionable root cause, because the organization cannot prevent hurricanes. However, an inadequate procedure for preventative maintenance of the backup power supply can be a true root cause, in which case the corrective action is to fix the procedure.

准备一份不明确或难以跟进的调查报告

Preparing an unclear or difficult-to-follow investigation report

许多写调查报告的人忘记了，他们的读者不仅是内部员工，而最终还是外部第三方，比如检查员。因此，调查必须易于理解和清晰，包含所有必要的支持事实和理由，以便在事件发生后几年还能理解。要做到这一点，最困难的挑战是在不显示和重复冗余信息的情况下，以逻辑、清晰和简洁的方式书写。因此，培训是写出有效调查报告的重要内容。有导师协助调查人员可能是提高技能的一个重要因素。

Many investigation writers forget that their audience is not only internal employees, but ultimately an external third-party, such as an inspector. Thus,the investigation needs to be readily understandable and clear, with all the necessary supporting facts and rationale, so that it is comprehensible years after the event. The most difficult challenge in accomplishing this is writing logically, clearly, and succinctly, without presenting and repeating redundant information. Thus, training is an important element of writing effective investigations. Having mentors available to assist investigators can be an important element in advancing skills.

忽视成因及相关因素

Ignoring contributing factors and associated CAPAs

除了根本原因之外，事件发生的成因是必要的，或者是增加事件的影响的因素。成因也需要根本原因的确定和纠正预防措施。解决这些问题限制了今后再次发生类似事件的可能性或影响。调查往往只关注根本原因，而忘了处理成因。使用5-Whys工具是区分成因和根本原因的有用机制。

Contributing factors are elements that either were necessary — in addition to the root cause — for an event to occur, or that increased the event’s impact. Contributing factors also require root cause determinations and CAPAs. Addressing them limits the likelihood or impact of similar events recurring in the future. Too often, investigations focus only on the root cause and forget to address contributing factors. Use of the 5-Whys tool is a useful mechanism to distinguish contributing factors from root causes.

执行不足的纠正预防措施

Prescribing inadequate CAPAs

太多的调查调查出了适当的根本原因，但从来没有将这一原因与CAPA联系起来。大多数根本原因和促成因素应与一个或多个CAPA相关联；如果没有，则应提供明确的理由。调查的主要目的之一是防止事件再次发生，只有当调查确定了根本原因并将其与适当的、有效的CAPA联系起来时，才能实现这种情况。另一个考虑因素是在将实施“CAPA”时是否需要临时控制，应利用风险评估来确定。

Too many investigations lead to an appropriate root cause but never link that cause to a CAPA. Most root causes and contributing factors should be associated with one or more CAPAs; if not, a clearly justified rationale should be provided. One of the main purposes of an investigation is to prevent recurrence of the event, and this can only happen if the investigation determines a root cause and connects it to an appropriate,effective CAPA. Another consideration is whether or not an interim control is needed while the CAPA(s) is being implemented. A risk assessment should be used to make this determination.

不进行面谈

Not performing interviews

太多的调查没有从员工那里获得与事件相关的见解和信息，要么是因为调查从未进行，要么是在事件发生后太久才进行。

Too many investigations fail to obtain information from the employees with the most relevant insight and information surrounding the event, either because the interviews are never conducted orthey occur too long after the event.

记忆很快就会消失，所以调查应该在事件发生后尽快进行。一些组织在事件发生后立即“蜂拥而至”，由一个团队进行面谈。这就是所谓的“冻结现场”。事件发生后迅速收集高质量的信息将节省你今后的时间和精力，并提高调查的质量。

Memories fade quickly, so interviews should be conducted as soon as possible after an event occurs. Some organizations “swarm” an event immediately after it happens, with a team conducting interviews. This is called “freezing the scene.” Gathering high-quality information soon after the event will save you future time and effort, and improves the quality of the investigation.

在适当的情况下，用事先准备好的面谈问题与关键人员交谈，会使调查更有用、更有洞察力，调查也更有效率。面谈的基本细节应在调查中加以总结。

Talking to key personnel using well thought-out interview questions prepared in advance, when applicable, will make theinterview more useful and insightful and the investigation much more efficient.The essential details of interviews should be summarized in the investigation.

结论

Conclusion

尽管进行彻底的偏差调查是一项艰巨的工作，但如果不这样做，将产生不准确的根本原因和错误的CAPA，以及重复的偏差，并增加监管和经济风险。偏差调查投入的回报来自改善运营绩效，降低成本，提高质量和改善合规性。

While conducting a thorough deviation investigation is hard work, failing to do so will yield inaccurate root causes and misdirected CAPAs, and recurring deviations, along with increased regulatory and financial risk. The payback from investing in deviation investigations comes in the form of improved operational performance, reductionin costs, increased quality, and improved compliance.

撰稿人 | GMP办公室

责任编辑 | 邵丽竹

审核人 | 何发

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