近日，PIC/S发布了PI 054-1《如何评估和证实基于风险的变更管理药品质量体系的有效性》指南，指南阐述了药品变更管理过程中的质量体系有效性评估的各个方面，适用于药品GMP检查和药企用于提升其变更管理体系。指南也提出，变更应将产品质量风险和/或患者安全危害降低到可接受的水平。至少，变更应保持或改善产品质量和/或患者安全，不应增加工艺可变性。
全文翻译如下：
How to Evaluate andDemonstrate the Effectiveness of a Pharmaceutical Quality System in relation toRisk-based Change Management
如何评估和证实基于风险的变更管理药品质量体系的有效性
1. Document History
文件历史
Adoption by Committee of PI 054-1 | 30June 2021 |
Entry into force of PI 054-1 | 15July 2021 |
2. Introduction
介绍
2.1. This documentprovides practical guidance for GMP inspectors when seeking to evaluate theeffectiveness of a company’s pharmaceutical quality system (PQS) in relation torisk-based change management. It covers all relevant steps in the changemanagement process – change proposal, change assessment, change planning andimplementation, change review and effectiveness checks. It indicates withineach step the aspects that render the PQS to be effective in that area.
本文件为GMP检查员评估公司基于风险的变更管理中药品质量体系(PQS)的有效性提供了实用指南。它涵盖了变更管理过程中的所有相关步骤——变更申请、变更评估、变更计划和实施、变更审核和有效性检查。它指出在每个步骤中呈现PQS在该领域中是有效的方面。
2.2. Note: These aspects are in accordance withthe considerations that are already typical and commonly applied in a changemanagement process; they do not introduce any new GMP requirement.
注:这些方面与在变更管理过程中已经典型和普遍应用的考虑一致;他们没有引入任何新的GMP要求。
2.3. Other useful guidance for GMP Inspectors inrelation to change management is provided in the PIC/S Aide Memoire on QRMImplementation.
PIC/S关于质量风险管理实施的备忘录中提供了对GMP检查员有关变更管理的其他有用指导。
3. Purpose
目的
3.1. The purpose of this document is to provideguidance on evaluating and demonstrating the effectiveness of a PQS in relationto risk-based change management as are governed by the PIC/S GMP Guide. This isin recognition of the fact that the PIC/S GMP Guide requires companies todemonstrate the effectiveness of their PQS and to apply quality risk management(QRM) principles to change control activities.
本文件的目的是为评估和论证PIC/S GMP指南中与基于风险的变更管理相关的PQS有效性提供指导。这是认识到PIC/S GMP指南要求公司证明其PQS的有效性，并将质量风险管理(QRM)原则应用至变更控制活动中。
3.2. Itis useful to note that Chapter 1 of the PIC/S GMP Guide states the following inrelation to PQS effectiveness and planned changes:
值得注意的是，PIC/S GMP指南的第1章就PQS的有效性和计划的变更阐述了以下内容：
Principle: '…there must be 'acomprehensively designed and correctly implemented PQS incorporating GMP andQRM. It should be fully documented and its effectiveness monitored’.
原则：应有一个综合设计和正确实施的PQS，包括GMP和QRM。它应该被完整地记录下来，并对其有效性进行监测。
Section 1.3 ...’theeffectiveness of the system is normally demonstrated at the site level’.
1.3节……“系统的有效性通常按工厂进行证实”。
Section 1.5 'Seniormanagement has the ultimate responsibility to ensure an effective PQS is inplace...’
第1.5节“高级管理层有确保PQS有效到位的最终责任……”
Section 1.4 (xii)Arrangements [should be] in place 'for the prospective evaluation of plannedchanges and their approval prior to implementation…’
第1.4(xii)节“为对计划的变更进行预期评估并在实施前获得批准……”的安排[应]到位。
3.3. In relation to change management, Annex 15of the PIC/S GMP Guide states:
关于变更管理，PIC/S GMP指南附件15规定:
Section 11.1. 'The control of change is an important part of knowledge management and should be handledwithin the pharmaceutical quality system.’
11.1节。“变更控制是知识管理的重要组成部分，应在药品质量体系中进行。”
Section 11.4. 'Quality riskmanagement should be used to evaluate planned changes… and to plan for anynecessary process validation, verification or requalification efforts.’
11.4节。应使用质量风险管理评估计划的变更，并为任何必要的工艺验证、确认或再确认工作制定计划。
Section 11.7. '…an evaluationof the effectiveness of change should be carried out…’
11.7节。“应该对变更的有效性进行评估……”
3.4. The guidance in Section 5 of this documentaddresses the following points:
本文件第5节的指南涉及以下几点:
The key elements that could be included inrisk-based change proposals.
基于风险的变更提议中可能包含的关键要素。
The assessment by thepharmaceutical manufacturer of change proposals from a risk perspective, where:
药品制造商从风险角度对变更申请的评估，其中:
the level of rigor, effort and documentation iscommensurate with the level of risk,
严格程度、努力程度和文件编制程度与风险程度相称，
the risk assessments adequately evaluate thepotential risks and benefits of changes to product quality, safety andefficacy, and
风险评估充分评估变更对产品质量、安全性和有效性的潜在风险和收益
those risk assessments consider the potentialrisks and benefits to other products, processes and systems.
这些风险评估考虑了对其他产品、工艺和系统的潜在风险和收益
The classification by thepharmaceutical manufacturer of changes based on the level of risk.
药品制造商根据风险级别对变更进行分类。
The role of change planningand implementation, where the outcomes of risk assessments and the assignedrisk levels drive change planning, prioritisation, implementation, and theirtimelines. (Note: this section also addresses situations where proposed changesare not implemented.)
变更计划和实施的角色，其中风险评估的结果和所分配的风险级别驱动变更计划、优先级、实施及其时间表。(注意:本节也涉及所提议的变更没有实施的情况。)
Change review andeffectiveness assessments at the pharmaceutical manufacturer, in terms ofwhether changes meet their intended objectives and pre-defined effectivenesscriteria, where residual risks are assessed and managed to acceptable levels,and where changes are monitored via ongoing monitoring systems to ensuremaintenance of a state of control.
药品制造商的变更审查和有效性评估，根据变更是否符合预期目标和预先定义的有效性标准，其中剩余风险被评估并管理至可接受水平，通过持续监测系统监测变更，以确保受控状态的维护。
3.5. It is considered thatapplication by a pharmaceutical manufacturer (including quality controllaboratories) of the guidance set out in Section 5 below will provide evidenceof the effectiveness of their PQS in relation to risk-based change management.If such a risk-based change management system were in place within the PQS, itshould lead to the timely management of risks to product quality and patientsafety, as well as better quality and manufacturing performance, continualimprovement and innovation.
我们认为，制药企业(包括质量控制实验室)对下文第5节中所列指南的应用，将提供其PQS在基于风险的变更管理方面的有效性的证据。如果这种基于风险的变更管理体系在PQS中到位，它应导致及时管理产品质量和患者安全的风险，以及更好的质量和生产性能，持续改进和创新。
3.6. Effective change management is important notonly in the context of the aforementioned PIC/S GMP requirements, but also inthe context of ICH Q10, which sets out the potential for risk-based regulatoryoversight for companies that demonstrate an effective PQS is in place (seeAppendix 1). This guidance may also be useful in supporting implementation ofthe principles and concepts in the ICH Q12 guideline where mature risk-basedchange management within an effective PQS is considered foundational to enablegreater regulatory flexibility in reporting of post-approval changes.
有效的变更管理不仅在上述PIC/S GMP要求的背景下很重要，在ICH Q10的背景下也很重要，它陈述了对经证实PQS已有效到位的公司进行基于风险的监管的可能性(见附录1)。该指南在支持ICH Q12指南中的原则和概念的实施方面也可能有用，在ICH Q12指南中，有效PQS中的成熟的基于风险的变更管理被认为是实现批准后变更报告的更大的法规灵活性的基础。
3.7. Further information on the background tothis Recommendation and the anticipated benefits of this guidance are providedin PIC/S Concept Note PS/INF 88/2019, which is available athttps://picscheme.org/en/publications
关于本建议的背景和本指南的预期收益的进一步信息，请参阅PIC/S概念说明PS/INF 88/2019，可在https://picscheme.org/en/publications上获取。
4. Scope
范围
4.1. This document applies toGMP inspections of manufacturers of medicinal products and activepharmaceutical ingredients.
本文件适用于药品和原料药生产企业的GMP检查。
5. Guidance onevaluating and/or demonstrating the effectiveness of a PQS in relation torisk-based change management – the checklist below is a tool that can be usedfor this evaluation.
评估和/或证明基于风险的变更管理中PQS有效性的指南——下列检查表是可用于此评估的工具。
It may be useful formanufacturers to use the checklist as a guide to help define their internalchange management procedures and practices.
制造商可使用该清单作为指南，帮助定义其内部变更管理程序和实践。
5.1. Change Proposals - Determination of when a change is needed:
变更提议——确定何时需要变更
The following are key points to consider:
关键考虑点如下：
The trigger(s) for changesand the related evidence are clearly documented. Common lifecycle factors thattrigger change include, but are not limited to:
变更的触发因素和相关证据都有明确的文件记录。触发变更的常见生命周期因素包括，但不限于:
newproduct introductions
新产品引入
upgrades to equipment or facilities, includingcomputerised systems, or changes intended to enhance upstream detectability(e.g. integrated monitoring/testing)
设备或设施的升级，包括计算机化系统，或用以提高上游检测能力的变更(例如集成监控/测试)
changes in raw materials/packaging materials orin their suppliers
原辅料/包装材料或其供应商的变更
changes in analytical test methods
分析方法变更
changes to improve manufacturing performance andconsistency (to reduce variability, etc.)
改善性能和一致性的变更(减少可变性等)
changes to enhance manufacturing capacity
提高生产能力的变更
corrections ofquality issues
纠正质量问题
addressing signals from the PQS such as those fromdeviations, complaints/adverse events, compliance gaps, corrective actions andpreventative actions (CAPAs), product quality reviews, performance indicators,management reviews,
处理来自PQS的信号，如来自偏差、投诉/不良事件、符合性差距、纠正和预防措施(CAPAs)、产品质量回顾、绩效指标、管理评审、
new or updated regulations, guidance documents,policies, procedures, etc.
新的或更新的法规、指导文件、政策、程序等
implementing innovation or continual improvementinitiatives (including lean initiatives to eliminate waste).
实施创新或持续改进措施(包括减少浪费的精益措施)。
The change management systemensures that changes are proposed in a timely manner, proposed changes areformally evaluated, and a decision to accept or reject the proposal isdocumented. For rejected/voided change proposals, particularly those thatrelate to mitigation of a quality/safety/efficacy/compliance hazard, the systemensures that the rationales for those decisions are documented and welljustified, and that continued risks are adequately managed.
变更管理系统确保及时提出变更，正式评估所提出的变更，并记录接受或拒绝该变更的决定。对于被拒绝/无效的变更提议，特别是那些与降低质量/安全/有效性/合规性危害有关的变更提议，系统确保这些决定的理由被记录下来并得到充分论证，持续的风险得到充分管理。
The objectives, scope,expected outcomes and anticipated benefits of the proposed change aredocumented.
所提议的变更的目标、范围、预期结果和预期收益都得到记录。
The potential impacts of theproposed change on other products, processes, systems or sites are objectivelyassessed and adequately documented.
对拟议变更对其他产品、工艺、系统或场所的潜在影响进行客观评估并充分记录。
The potentialimpacts of the proposed change on other change proposals that may be ongoing atthe same time are assessed, and there is appropriate management of risks due tothe collective effect of multiple change proposals.
评估拟议变更对可能同时正在进行的其他变更提议的潜在影响，并对由于多个变更的集体影响而产生的风险进行适当管理。
Relevant subject matterexperts and appropriate internal/external stakeholders (e.g. contract givers,quality assurance, other relevant departments) are involved in change proposaldevelopment and approval.
相关主题专家和适当的内部/外部利益相关方(例如委托方、QA、其他相关部门)参与变更提议的制定和批准。
The potential impacts topending/approved filings and regulatory commitments are addressed.
解决了悬而未决/已批准的文件和监管承诺的潜在影响。
5.2. Change Risk Assessments:
变更风险评估
Change Management procedures often require arisk-based classification (e.g. critical, major, minor) to be assigned toproposed changes as well as an impact assessment to be performed. The latterroutinely determines the potential impacts of the proposed change on variousitems, such as product quality, documentation, cleaning, maintenance,regulatory compliance, etc. In some cases, especially for simple and minor/lowrisk changes, an impact assessment is sufficient to document the risk-basedrationale for a change without the use of more formal risk-assessment tools orapproaches.
变更管理程序通常要求对拟议的变更进行基于风险的分类(如关键、主要、一般)，并进行影响评估。后者常规地确定拟议变更对各种项目的潜在影响，如产品质量、文件、清洁、维护、法规符合性等。在某些情况下，特别是对于简单的、较小的/低风险的变更，影响评估足以记录变更的基于风险的论证，而无需使用更正式的风险评估工具或方法。
More formal risk assessments should be appliedto change proposals, which represent more complex or significant (e.g. major,critical) changes. Such risk assessments should more substantially address whatmight go wrong with theproposed change, as well as the potential impactof the change in the context of current process knowledge and theproduct/facility lifecycle.
应将更正式的风险评估应用于代表更复杂或重大(如重大、关键)变更的变更提议。这种风险评估应更实质性地解决拟议的变更可能出现的问题，以及变更在当前工艺知识和产品/设施生命周期的背景下的潜在影响。
Where possible, changes should reduce productquality risks and/or patient safety hazards to an acceptable level. At aminimum, changes should maintain or improve product quality and/or patientsafety, and should not increase process variability.
在可能情况下，变更应将产品质量风险和/或患者安全危害降低到可接受的水平。至少，变更应保持或改善产品质量和/或患者安全，不应增加工艺可变性。
The Change Management system ensures thatappropriate science and knowledge-based risk assessments are performed anddocumented for changes, considering the points below:
考虑到以下几点，变更管理体系确保对变更进行适当的科学和以知识为基础的风险评估并形成文件:
The level of formality,effort (e.g. testing, validation, review) and documentation is commensuratewith the level of risk.
正式程度、努力程度(例如测试、验证、审核)和文件程度与风险程度相称
Risk assessments adequatelyassess the potential risks and benefits of changes to product quality, safetyand efficacy.
风险评估充分评估变更对产品质量、安全性和有效性的潜在风险和收益
Risk assessments adequatelyassess potential risks and benefits to other products, processes, and systems.
风险评估充分地评估对其他产品、工艺和系统的潜在风险和收益
Risk assessments identify anddocument both current and needed risk controls.
风险评估识别并记录当前和需要的风险控制。
Changes and their risks areassessed using current product and process knowledge. Appropriate data andinformation are used (or generated, if needed) to support such riskassessments.
使用现有的产品和工艺知识评估变更及其风险。使用(或根据需要生成)适当的数据和信息来支持此风险评估。
Classifications (and anypre-defined approaches that are used for assigning such classifications) areappropriate and based on the level of risk.
分类(以及用于分配此分类的任何预定方法)是适当的，并基于风险级别。
5.3. Change Planning and Implementation:
变更计划和实施
The outcomes of riskassessments and the assigned risk levels drive change planning, prioritisation,implementation, and their timelines.
风险评估的结果和分配的风险级别驱动变更计划、优先级、实施和它们的时间线。
The data neededto demonstrate effective implementation of the change, as well as theacceptance criteria and change effectiveness criteria, are pre-defined inchange planning. These may include provisions such as intensified sampling,continuous process verification (CPV) and statistical assessments (e.g.CpK/PpK) to aid with the quantitative assessment of risk control.
证实变更有效实施所需的数据，以及接受标准和变更有效性标准，都在变更计划中预先定义。这可能包括加强取样、持续工艺确认(CPV)和统计评估(如CpK/PpK)等，以帮助对风险控制进行定量评估。
Potential risks with thecurrent state (until changes are implemented) and any risks that might betemporarily introduced during the change process are adequately assessed.
充分评估当前状态(直至变更实施前)的潜在风险，以及在变更过程中可能临时引入的任何风险。
Interim controls (short-termmeasures), as needed, are identified and implemented in a timely manner tomonitor/mitigate risks associated with the current situation (until changeimplementation).
根据需要，确定并及时实施临时控制(短期措施)，以监控/减轻对当前状态相关的风险(直到变更实施前)。
Identified risk controlmeasures are adequately implemented in a timely manner.
已识别的风险控制措施及时得到充分实施。
The change management systemensures that approval to proceed with change implementation is documented.
变更管理系统确保对变更实施步骤的批准得到记录。
Relevant riskassessments are reviewed and are updated after the implementation of changes.
对相关风险评估进行审查，并在变更实施后进行更新。
Relevant and timely updatesare made to regulatory filings, when appropriate, in accordance with therelevant requirements.
适当时，根据相关要求对监管备案文件进行关联和及时更新。
The changemanagement system triggers any required communications with MarketingAuthorisation Holders or other parties in relation to changes made.
变更管理系统触发与上市许可持有人或其他相关方的任何必要沟通。
5.4. Change Review and Effectiveness:
变更回顾和有效性
Prior to change closure:
变更关闭前
Changes meet their intendedobjectives and pre-defined acceptance and effectiveness criteria. Anydeviations from those criteria are adequately assessed, managed, and justified,or follow-up measures are identified. Whenever possible, quantitative data areleveraged to objectively determine change effectiveness (e.g. statisticalconfidence and coverage).
变更符合其预期目标和预先定义的接受和有效性标准。任何与这些标准的偏差都得到充分的评估、管理和论证，或确定后续措施。只要有可能，使用定量数据来客观地确定变更的有效性(例如统计置信度和覆盖范围)。
As part of the quality riskmanagement activities, residual risks are assessed and managed to acceptablelevels, and appropriate adaptations of procedures and controls are implemented.
作为质量风险管理活动的一部分，对剩余风险进行评估和管理，使其达到可接受的水平，并对程序和控制实施适当的调整。
Any unintended consequencesor risks introduced as a result of changes are adequately evaluated,documented, mitigated or accepted, and are subject to a pre-defined monitoringtimeframe.
任何因变更而引起的非预期后果或风险都得到充分评估、记录、减轻或接受，并遵循预先定义的监控时间框架。
Prior to or after change closure:
变更关闭前或后
Any post-implementationactions needed (including those for deviations from pre-defined acceptancecriteria and/or CAPAs) are identified and adequately completed.
任何变更实施后所需的措施(包括与既定可接受标准和/或CAPA的偏差)都被识别并充分完成。
Relevant risk assessments areupdated following effectiveness assessments. New product/process knowledgeresulting from those risk assessments and from the related change managementactivity are captured in the appropriate Quality and Operations documents (e.g.SOPs, Reports, Product Control Strategy documents.)
在有效性评估之后更新相关风险评估。从这些风险评估和相关的变更管理活动中产生的新的产品/工艺知识应记录在适当的质量和操作文件(如SOP，报告，产品控制策略文件)中。
Changes are monitored viaongoing monitoring systems to ensure maintenance of a state of control, andlessons learned are captured and shared/communicated. (Note: Activities such asManagement Review, Annual Product Quality Review, Continuous ProcessVerification, Deviation Management and Complaint Monitoring can be useful inthis regard.)
通过持续监测系统对变更进行监测，以确保控制状态的维护，并获得和分享/交流经验教训。(注:管理评审、年度产品质量回顾、持续工艺确认、偏差管理和投诉监测等活动在这方面是有用的。)
5.5. Conclusion
结论
The adherence to the above guidance shouldprovide sufficient evidence of an effective science and risk-based changemanagement system. It should drive risk reduction, where possible, to ensurebetter quality performance, manufacturing performance, continual improvementand innovation, through adequate and timely management of product quality and patientsafety risks. Maturity in change management may support maximal benefits fromthe regulatory flexibilities discussed in ICH Q12.
对上述指南的遵守可为科学有效和基于风险的变更管理系统提供充分的证据。它应通过适当和及时地管理产品质量和患者安全风险，在可能的情况下推动风险降低，以确保更好的质量性能、生产性能、持续改进和创新。变更管理的成熟度可以支持ICH Q12中讨论的法规灵活性带来的最大利益。
Note: The input of industry representatives wasconsidered by the PIC/S Expert Circle on QRM during the development of thisdocument.
注:在制定本文件时，PIC/S专家考虑了行业代表的意见。
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