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PIC/S PI 054-1《如何評估和證實基于風險的變更管理藥品質(zhì)量體系的有效性》指南，指南闡述了藥品變更管理過程中的質(zhì)量體系有效性評估的各個方面，適用于藥品GMP檢查和藥企用于提升其變更管理體系。指南也提出，變更應將產(chǎn)品質(zhì)量風險和/或患者安全危害降低到可接受的水平。至少，變更應保持或改善產(chǎn)品質(zhì)量和/或患者安全，不應增加工藝可變性。
全文翻譯如下：
How to Evaluate andDemonstrate the Effectiveness of a Pharmaceutical Quality System in relation toRisk-based Change Management
如何評估和證實基于風險的變更管理藥品質(zhì)量體系的有效性
1. Document History
文件歷史
|
Adoption by Committee of PI 054-1 |
30June 2021 |
|
Entry into force of PI 054-1 |
15July 2021 |
2. Introduction
介紹
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.
本文件為GMP檢查員評估公司基于風險的變更管理中藥品質(zhì)量體系(PQS)的有效性提供了實用指南。它涵蓋了變更管理過程中的所有相關步驟——變更申請、變更評估、變更計劃和實施、變更審核和有效性檢查。它指出在每個步驟中呈現(xiàn)PQS在該領域中是有效的方面。
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:這些方面與在變更管理過程中已經(jīng)典型和普遍應用的考慮一致;他們沒有引入任何新的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關于質(zhì)量風險管理實施的備忘錄中提供了對GMP檢查員有關變更管理的其他有用指導。
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.
本文件的目的是為評估和論證PIC/S GMP指南中與基于風險的變更管理相關的PQS有效性提供指導。這是認識到PIC/S GMP指南要求公司證明其PQS的有效性，并將質(zhì)量風險管理(QRM)原則應用至變更控制活動中。
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的有效性和計劃的變更闡述了以下內(nèi)容：
Principle: ‘…there must be ‘acomprehensively designed and correctly implemented PQS incorporating GMP andQRM. It should be fully documented and its effectiveness monitored’.
原則：應有一個綜合設計和正確實施的PQS，包括GMP和QRM。它應該被完整地記錄下來，并對其有效性進行監(jiān)測。
Section 1.3 ...’theeffectiveness of the system is normally demonstrated at the site level’.
1.3節(jié)……“系統(tǒng)的有效性通常按工廠進行證實”。
Section 1.5 ‘Seniormanagement has the ultimate responsibility to ensure an effective PQS is inplace...’
第1.5節(jié)“高級管理層有確保PQS有效到位的最終責任……”
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)節(jié)“為對計劃的變更進行預期評估并在實施前獲得批準……”的安排[應]到位。
3.3. In relation to change management, Annex 15of the PIC/S GMP Guide states:
關于變更管理，PIC/S GMP指南附件15規(guī)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節(jié)。“變更控制是知識管理的重要組成部分，應在藥品質(zhì)量體系中進行。”
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節(jié)。應使用質(zhì)量風險管理評估計劃的變更，并為任何必要的工藝驗證、確認或再確認工作制定計劃。
Section 11.7. ‘…an evaluationof the effectiveness of change should be carried out…’
11.7節(jié)。“應該對變更的有效性進行評估……”
3.4. The guidance in Section 5 of this documentaddresses the following points:
本文件第5節(jié)的指南涉及以下幾點:
The key elements that could be included inrisk-based change proposals.
基于風險的變更提議中可能包含的關鍵要素。
The assessment by thepharmaceutical manufacturer of change proposals from a risk perspective, where:
藥品制造商從風險角度對變更申請的評估，其中:
the level of rigor, effort and documentation iscommensurate with the level of risk,
嚴格程度、努力程度和文件編制程度與風險程度相稱，
the risk assessments adequately evaluate thepotential risks and benefits of changes to product quality, safety andefficacy, and
風險評估充分評估變更對產(chǎn)品質(zhì)量、安全性和有效性的潛在風險和收益
those risk assessments consider the potentialrisks and benefits to other products, processes and systems.
這些風險評估考慮了對其他產(chǎn)品、工藝和系統(tǒng)的潛在風險和收益
The classification by thepharmaceutical manufacturer of changes based on the level of risk.
藥品制造商根據(jù)風險級別對變更進行分類。
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.)
變更計劃和實施的角色，其中風險評估的結(jié)果和所分配的風險級別驅(qū)動變更計劃、優(yōu)先級、實施及其時間表。(注意:本節(jié)也涉及所提議的變更沒有實施的情況。)
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.
藥品制造商的變更審查和有效性評估，根據(jù)變更是否符合預期目標和預先定義的有效性標準，其中剩余風險被評估并管理至可接受水平，通過持續(xù)監(jiān)測系統(tǒng)監(jiān)測變更，以確保受控狀態(tài)的維護。
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.
我們認為，制藥企業(yè)(包括質(zhì)量控制實驗室)對下文第5節(jié)中所列指南的應用，將提供其PQS在基于風險的變更管理方面的有效性的證據(jù)。如果這種基于風險的變更管理體系在PQS中到位，它應導致及時管理產(chǎn)品質(zhì)量和患者安全的風險，以及更好的質(zhì)量和生產(chǎn)性能，持續(xù)改進和創(chuàng)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.
有效的變更管理不僅在上述PIC/S GMP要求的背景下很重要，在ICH Q10的背景下也很重要，它陳述了對經(jīng)證實PQS已有效到位的公司進行基于風險的監(jiān)管的可能性(見附錄1)。該指南在支持ICH Q12指南中的原則和概念的實施方面也可能有用，在ICH Q12指南中，有效PQS中的成熟的基于風險的變更管理被認為是實現(xiàn)批準后變更報告的更大的法規(guī)靈活性的基礎。
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
關于本建議的背景和本指南的預期收益的進一步信息，請參閱PIC/S概念說明PS/INF 88/2019，可在https://picscheme.org/en/publications上獲取。
4. Scope
范圍
4.1. This document applies toGMP inspections of manufacturers of medicinal products and activepharmaceutical ingredients.
本文件適用于藥品和原料藥生產(chǎn)企業(yè)的GMP檢查。
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.
評估和/或證明基于風險的變更管理中PQS有效性的指南——下列檢查表是可用于此評估的工具。
It may be useful formanufacturers to use the checklist as a guide to help define their internalchange management procedures and practices.
制造商可使用該清單作為指南，幫助定義其內(nèi)部變更管理程序和實踐。
5.1. Change Proposals - Determination of when a change is needed:
變更提議——確定何時需要變更
The following are key points to consider:
關鍵考慮點如下：
The trigger(s) for changesand the related evidence are clearly documented. Common lifecycle factors thattrigger change include, but are not limited to:
變更的觸發(fā)因素和相關證據(jù)都有明確的文件記錄。觸發(fā)變更的常見生命周期因素包括，但不限于:
newproduct introductions
新產(chǎn)品引入
upgrades to equipment or facilities, includingcomputerised systems, or changes intended to enhance upstream detectability(e.g. integrated monitoring/testing)
設備或設施的升級，包括計算機化系統(tǒng)，或用以提高上游檢測能力的變更(例如集成監(jiān)控/測試)
changes in raw materials/packaging materials orin their suppliers
原輔料/包裝材料或其供應商的變更
changes in analytical test methods
分析方法變更
changes to improve manufacturing performance andconsistency (to reduce variability, etc.)
改善性能和一致性的變更(減少可變性等)
changes to enhance manufacturing capacity
提高生產(chǎn)能力的變更
corrections ofquality issues
糾正質(zhì)量問題
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,
處理來自PQS的信號，如來自偏差、投訴/不良事件、符合性差距、糾正和預防措施(CAPAs)、產(chǎn)品質(zhì)量回顧、績效指標、管理評審、
new or updated regulations, guidance documents,policies, procedures, etc.
新的或更新的法規(guī)、指導文件、政策、程序等
implementing innovation or continual improvementinitiatives (including lean initiatives to eliminate waste).
實施創(chuàng)新或持續(xù)改進措施(包括減少浪費的精益措施)。
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.
變更管理系統(tǒng)確保及時提出變更，正式評估所提出的變更，并記錄接受或拒絕該變更的決定。對于被拒絕/無效的變更提議，特別是那些與降低質(zhì)量/安全/有效性/合規(guī)性危害有關的變更提議，系統(tǒng)確保這些決定的理由被記錄下來并得到充分論證，持續(xù)的風險得到充分管理。
The objectives, scope,expected outcomes and anticipated benefits of the proposed change aredocumented.
所提議的變更的目標、范圍、預期結(jié)果和預期收益都得到記錄。
The potential impacts of theproposed change on other products, processes, systems or sites are objectivelyassessed and adequately documented.
對擬議變更對其他產(chǎn)品、工藝、系統(tǒng)或場所的潛在影響進行客觀評估并充分記錄。
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.
評估擬議變更對可能同時正在進行的其他變更提議的潛在影響，并對由于多個變更的集體影響而產(chǎn)生的風險進行適當管理。
Relevant subject matterexperts and appropriate internal/external stakeholders (e.g. contract givers,quality assurance, other relevant departments) are involved in change proposaldevelopment and approval.
相關主題專家和適當?shù)膬?nèi)部/外部利益相關方(例如委托方、QA、其他相關部門)參與變更提議的制定和批準。
The potential impacts topending/approved filings and regulatory commitments are addressed.
解決了懸而未決/已批準的文件和監(jiān)管承諾的潛在影響。
5.2. Change Risk Assessments:
變更風險評估
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.
變更管理程序通常要求對擬議的變更進行基于風險的分類(如關鍵、主要、一般)，并進行影響評估。后者常規(guī)地確定擬議變更對各種項目的潛在影響，如產(chǎn)品質(zhì)量、文件、清潔、維護、法規(guī)符合性等。在某些情況下，特別是對于簡單的、較小的/低風險的變更，影響評估足以記錄變更的基于風險的論證，而無需使用更正式的風險評估工具或方法。
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.
應將更正式的風險評估應用于代表更復雜或重大(如重大、關鍵)變更的變更提議。這種風險評估應更實質(zhì)性地解決擬議的變更可能出現(xiàn)的問題，以及變更在當前工藝知識和產(chǎn)品/設施生命周期的背景下的潛在影響。
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.
在可能情況下，變更應將產(chǎn)品質(zhì)量風險和/或患者安全危害降低到可接受的水平。至少，變更應保持或改善產(chǎn)品質(zhì)量和/或患者安全，不應增加工藝可變性。
The Change Management system ensures thatappropriate science and knowledge-based risk assessments are performed anddocumented for changes, considering the points below:
考慮到以下幾點，變更管理體系確保對變更進行適當?shù)目茖W和以知識為基礎的風險評估并形成文件:
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(例如測試、驗證、審核)和文件程度與風險程度相稱
Risk assessments adequatelyassess the potential risks and benefits of changes to product quality, safetyand efficacy.
風險評估充分評估變更對產(chǎn)品質(zhì)量、安全性和有效性的潛在風險和收益
Risk assessments adequatelyassess potential risks and benefits to other products, processes, and systems.
風險評估充分地評估對其他產(chǎn)品、工藝和系統(tǒng)的潛在風險和收益
Risk assessments identify anddocument both current and needed risk controls.
風險評估識別并記錄當前和需要的風險控制。
Changes and their risks areassessed using current product and process knowledge. Appropriate data andinformation are used (or generated, if needed) to support such riskassessments.
使用現(xiàn)有的產(chǎn)品和工藝知識評估變更及其風險。使用(或根據(jù)需要生成)適當?shù)臄?shù)據(jù)和信息來支持此風險評估。
Classifications (and anypre-defined approaches that are used for assigning such classifications) areappropriate and based on the level of risk.
分類(以及用于分配此分類的任何預定方法)是適當?shù)?，并基于風險級別。
5.3. Change Planning and Implementation:
變更計劃和實施
The outcomes of riskassessments and the assigned risk levels drive change planning, prioritisation,implementation, and their timelines.
風險評估的結(jié)果和分配的風險級別驅(qū)動變更計劃、優(yōu)先級、實施和它們的時間線。
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.
證實變更有效實施所需的數(shù)據(jù)，以及接受標準和變更有效性標準，都在變更計劃中預先定義。這可能包括加強取樣、持續(xù)工藝確認(CPV)和統(tǒng)計評估(如CpK/PpK)等，以幫助對風險控制進行定量評估。
Potential risks with thecurrent state (until changes are implemented) and any risks that might betemporarily introduced during the change process are adequately assessed.
充分評估當前狀態(tài)(直至變更實施前)的潛在風險，以及在變更過程中可能臨時引入的任何風險。
Interim controls (short-termmeasures), as needed, are identified and implemented in a timely manner tomonitor/mitigate risks associated with the current situation (until changeimplementation).
根據(jù)需要，確定并及時實施臨時控制(短期措施)，以監(jiān)控/減輕對當前狀態(tài)相關的風險(直到變更實施前)。
Identified risk controlmeasures are adequately implemented in a timely manner.
已識別的風險控制措施及時得到充分實施。
The change management systemensures that approval to proceed with change implementation is documented.
變更管理系統(tǒng)確保對變更實施步驟的批準得到記錄。
Relevant riskassessments are reviewed and are updated after the implementation of changes.
對相關風險評估進行審查，并在變更實施后進行更新。
Relevant and timely updatesare made to regulatory filings, when appropriate, in accordance with therelevant requirements.
適當時，根據(jù)相關要求對監(jiān)管備案文件進行關聯(lián)和及時更新。
The changemanagement system triggers any required communications with MarketingAuthorisation Holders or other parties in relation to changes made.
變更管理系統(tǒng)觸發(fā)與上市許可持有人或其他相關方的任何必要溝通。
5.4. Change Review and Effectiveness:
變更回顧和有效性
Prior to change closure:
變更關閉前
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).
變更符合其預期目標和預先定義的接受和有效性標準。任何與這些標準的偏差都得到充分的評估、管理和論證，或確定后續(xù)措施。只要有可能，使用定量數(shù)據(jù)來客觀地確定變更的有效性(例如統(tǒng)計置信度和覆蓋范圍)。
As part of the quality riskmanagement activities, residual risks are assessed and managed to acceptablelevels, and appropriate adaptations of procedures and controls are implemented.
作為質(zhì)量風險管理活動的一部分，對剩余風險進行評估和管理，使其達到可接受的水平，并對程序和控制實施適當?shù)恼{(diào)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.
任何因變更而引起的非預期后果或風險都得到充分評估、記錄、減輕或接受，并遵循預先定義的監(jiān)控時間框架。
Prior to or after change closure:
變更關閉前或后
Any post-implementationactions needed (including those for deviations from pre-defined acceptancecriteria and/or CAPAs) are identified and adequately completed.
任何變更實施后所需的措施(包括與既定可接受標準和/或CAPA的偏差)都被識別并充分完成。
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.)
在有效性評估之后更新相關風險評估。從這些風險評估和相關的變更管理活動中產(chǎn)生的新的產(chǎn)品/工藝知識應記錄在適當?shù)馁|(zhì)量和操作文件(如SOP，報告，產(chǎn)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.)
通過持續(xù)監(jiān)測系統(tǒng)對變更進行監(jiān)測，以確?？刂茽顟B(tài)的維護，并獲得和分享/交流經(jīng)驗教訓。(注:管理評審、年度產(chǎn)品質(zhì)量回顧、持續(xù)工藝確認、偏差管理和投訴監(jiān)測等活動在這方面是有用的。)
5.5. Conclusion
結(jié)論
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.
對上述指南的遵守可為科學有效和基于風險的變更管理系統(tǒng)提供充分的證據(jù)。它應通過適當和及時地管理產(chǎn)品質(zhì)量和患者安全風險，在可能的情況下推動風險降低，以確保更好的質(zhì)量性能、生產(chǎn)性能、持續(xù)改進和創(chuàng)新。變更管理的成熟度可以支持ICH Q12中討論的法規(guī)靈活性帶來的最大利益。
Note: The input of industry representatives wasconsidered by the PIC/S Expert Circle on QRM during the development of thisdocument.
注:在制定本文件時，PIC/S專家考慮了行業(yè)代表的意見。
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