PDA TR54 中英对照-质量风险管理在制药和生物制品生产中的实施

Technical Report No. 54

Implementation of QualityRisk Management For Pharmaceutical and Biotechnology Manufacturing Operations

PDA技术报告No.54

质量风险管理在制药和生物制品生产中的实施

Process Maturation

过程改善

1.0Purpose and Scope

1.1目的和范围

The task force that developed this report was comprised of experiencedprofessionals from risk management，manufacturing,technology, quality, and regulatory authorities. The broad diversity inexperience and expertise in the task force enabled rich, balanced discussionsfrom industry and regulatory perspectives; therefore, the content in thisreport does not represent the QRM practices of any one particular organization.

这本报告的作者由来自具有专业经验的风险管理、制造、技术、质量以及法规的权威人士组成。作者广泛的经验和意见能够有见解平衡地在业界和法规观点进行讨论：因此，本报告的内容不代表任何特定组织的质量风险管理实践。

The task force recognizes that there are many approaches that can be usedfor implementation of the ICH Q9 guideline. This report is intended to alignwith ICH Q9 and presents information that can be helpful to the reader on howto implement QRM. .The objective is not to represent or replace regulatoryrequirements and guidance; nor does it establish legally enforceablerequirements.

工作组认识到有许多种途径能够用来贯彻执行ICH Q9的指导方针。报告的目的是与ICHQ9保持一致以及介绍信息帮助读者如何去贯彻质量风险管理。

This technical report was distributed for public review and comment priorto publication to ensure its suitability as a valuable guide for QRMimplementation.

这本技术报告在出版之前分发给公众以便检查和解释，确保他能够成为贯彻质量风险管理有价值的指南。

3.0 General Principles On Quality Risk Management Application

质量风险管理应用的基本原则

A combinedapplication of ICH Q8[R2] (Pharmaceutical Development), Q9 (Quality RiskManagement) and QI0 (Pharmaceutical Quality System) results in an enhancedknowledge of product performance over a range of material attributes,manufacturing process options, and process parameters to further support thescience and risk-based management of the product lifecycle.

ICH Q8 (药物开发），Q9 (质量风险管理）和Q10 (制药质量体系）的共同应用在一定程度上提高了对包括物料属性、生产工艺的选择和工艺参数方面的产品性能的认识，以进一步支持依据科学和风险管理的产品生命周期的管理。

3.1 When, Where, and How to ApplyQuality Risk Management 何时、何地和怎样

应用质量风险管理

One of thecharacteristics of a mature PQS is the effective integration of QRM intorelevant processes throughout the product and process lifecycles. At each phasein the lifecycle, QRM should be applied at a level that is commensurate withthe knowledge available during that phase, and complexity of the process. QRMshould start with product design and progress to process design as the productadvances to clinical and commercial production. Risk assessments should berevisited throughout the product lifecycle (Figure 3.1-1) as additional processand product knowledge become available. Additionally, QRM can be useful inidentifying and managing similar risks for other products to facilitatecontinual improvement.

成熟的PQS的特征之一是在贯穿整个产品和工艺的生命周期中，将质量风险管理有效地整合到相关的过程管理中。在生命周期的各个阶段，质量风险管理应用的程度应该与该阶段的可获得的工艺知识和工艺的复杂程度相适应。质量风险管理应该开始于药物研发阶段，当产品用于临床研究和商业生产时，应将质量风险管理并入工艺设计中。当获得额外的工艺和产品知识时，应将风险评估重新应用到整个生命周期（图表3.1-1)中。除此之外，质量风险管理在鉴别和管理其他产品的相似风险时很有用，并可以帮助其获得持续的改进。

3.1.1Quality Risk Management Application During Pharmaceutical Development

药物开发阶段的质量风险管理应用

Per ICH QI0,the intent of the Pharmaceutical Development phase is to "design a productand its manufacturing process to consistently deliver the intended
performance and meet the needs of patients, healthcare professionals,regulatory authorities, and internal customers."(1) This phase providesthe basis for scientific knowledge and understanding of the product.

根据ICH Q10，药物开发阶段的目的是“设计出一种产品，其生产工艺可以按照其本身的性质持续地生产出符合病人，卫生保健专业人员，监管机构和国内客户的药品”。（1)这一阶段提供科学知识的基础和对产品的理解。

Duringdevelopment, the application of QRM can support the development of systematicunderstanding of products and processes beginning early in the lifecycle. Theappropriate use of QRM principles can serve the following objectives:

在开发阶段，质量风险管理的应用可以支持对产品系统的认识和对生产周期早期工艺的开发。质量风险管理原则的合理应用可以实现以下目标：

•Design the product and processto reduce risk to product quality and to the patient.

根据减少对产品的质量和对病人的风险来设计产品和工艺。

•rioritizethe pharmaceutical development studies needed to collect and enhance productknowledge.

优先进行必要的药物开发以收集并提高产品知识。

•Establish arobust control strategy to adequately manage risks to Critical QualityAttributes (CQA) (per ICH Q8[R2]).

建立稳定的控制策略以实现对关键质量属性（CQA)的充分风险管理。（根据ICH Q8[R2])

Examples of how to apply QRMprinciples during the development phase include:

如何在药物开发阶段应用质量风险管理原则的例子如下：

•Developing a process thatroutinely meets critical quality attributes (CQA).

开发一个通常能实现关键质量属性（CQA)的工艺。

•Developing a suitable drugdelivery system.

•开发一种合适的药品给药系统。

•Identifying critical processparameters (CPP) and material attributes.

•鉴别关键工艺参数(CPP)和物料属性

•Identifying appropriateranges for CPP, material attributes and manufacturing controls.

•鉴别关键工艺参数，物料属性和过程控制的合理范围

•Supporting the selection andsubsequent qualification of suppliers.

•支持接下来的合格供应商选择

Riskmanagement tools such as Risk Ranking and Filtering or Ishikawa diagram (alsoknown as a Fishbone diagram) may be used to identify variables that may have animpact on a critical quality attribute. These identified variables can then befurther analyzed using a qualitative/ semi-quantitative risk management toolsuch as a Preliminary Hazard Analysis (PHA). Failure Mode and Effects Analysis(FMEA) may also be useful, particular1y during the later stages of development.

风险管理工具如风险定级和筛选或是石川图（也被称为鱼骨图）可以用于鉴别可能会影响到关键质量属性的变量。这些鉴别出来的变量可以使用定量或半定量的风险管理工具如初步危害分析（PHA)来进行进一步的分析。失效模式和影响分析(FMEA)也可能是有用的，特别是在药物开发的后阶段。

3.1.2 Quality Risk Management Application during Technology Transfer 技术转

移阶段的质量风险管理应用

Per ICH QI0，the goal of Technology Transferis to "trasfer knowledge between development and manufacturing or betweenmanufacturing sites to achieve product realization . "(1) QRM applicationduring thetechnology transfer phase can serve the following objectives:

根据ICH Q10，技术转移的目的是“在药物开发部门与生产部门或在不同的生产岗位中进行知识转移，以实现药物的最终生产”。（1)质量风险管理在技术转移阶段的应用可以达到以下目的：

•Assess andmanage risks to process and product quality as a result of the transfer ormanufacturing scale-up.

•评估和管理工艺和产品质量的风险以达到技术转移和扩大生产的结果。

•Facilitateknowledge transfer.

•帮助知识的转移。

•Drive decisions for control strategies to reduce risk during commercialmanufacturing.

在商业化生产的过程中驱动控制策略的决策以降低风险。

The outcomes of the QRM process can be used to implement corrective andpreventive actions to appropriately manage identified risks and provide timelymanagement of process controls during the technology transfer process. QRM can be used to develop a riskbased validation master plan to determine the extent of the qualification andvalidation activities. During the technology transfer phase，detailed risk management tools such as anFMEA or Hazard and Operability Analysis (HAZOP) are Often used.

在技术转移过程中，质量风险管理过程的结果可以用来实施纠正和预防措施，以妥善管理确定的风险并提供及时的过程控制的管理。质量风险管理可以用于开发一个基于风险的验证主计划以确定确认和验证活动的程度。在技术转移的阶段，详细的风险管理工具如FMEA或危险和可操作性分析(HAZOP)会被经常用到。

Per ICH Q10,the goal during Commercial Manufacturing is to "achieve productrealization with suitable processperformance， establish and maintain a state ofcontrol, faciliitate continual improvement and expand the body ofknowledge."(3) QRM application during the Commercial Manufacturing phasecan serve the following objectives:

根据ICHQ10，商业化生产阶段的目的是“用合适的工艺性能实现产品的生产，建立和维护控制状态，帮助持续改善和扩大知识容量。”在商业化阶段应用质量风险管理可以达到以下目标：

•roactivelyassess and manage risks to process and product quality during commercialoperations.

•在商业化运营的过程中可以主动地评估和管理工艺和产品质量风险。

•Establishrobust control strategies and adjust (as needed) through continual improvement， to ensure consistent process performanceand product quality as intended.

•通过持续的改善以建立稳定的控制策略和调整（如果需要），以确保达到预期的持续工艺性能和产品质量。

Duringcommercial manufacturing, QRM can be a useful process for effectivedecision-making as-sociated with change control, discrepancies, failures, orinvestigations related to product quality or patient safety events. QRM is alsouseful in the selection and management of suppliers and vendors, and managingrisks related to internal and contract manufacturing operations, to ensure astate of control is maintained at all times.

在商业化生产阶段，质量风险管理在有关产品质量或病人安全事件方面的变更控制，偏差，失败或调查的有效决策时是很有用的过程。质量风险管理在供应商或供货商选择与管理方面也很有用，通过管理相关内部或委托生产操作的风险，以确保整个阶段保持在控制状态。

QRM may also be applied to effectivelymanage risks in the supply chain. Risks to product availability throughout theproduct lifecycle relate to product storage, distribution, transportation,chain of custody, counterfeiting, diversion, theft，geopolitical issues, compliance, anddisaster recovery activities， amongst others. (See Section 5.4, QRM Application in MaterialsManagement.)

质量风险管理也可以有效地应用在供应链风险管理方面。在整个产品生命周期内保持产品的有效性的风险包括产品的储存，分发，运输，产销监管链，造假，转移，偷盗，区域政治问题，合规，灾难恢复活动等等其他方面。（具体见5.4部分，物料管理方面的质量风险管理）

Per ICHQlO,the goal of Product Discontinuation activities is to "manage the terminalstage of the product lifecycleeffectively."(1) QRM application duringproduct discontinuation activities can serve the following objectives:

根据ICH Q10，产品退市活动的目的是“有效地管理产品生命周期的最后阶段”。在产品退市活动阶段应用质量风险管理可以达到以下目标：

• Ensure risks to patients and product quality continue to be managed whileproduct remains on the market.

•当产品仍然在市场上销售时，确保病人和产品质量的风险持续可控。

• Identify and manage risks related to transitioning patients to alternatetherapies.

•转移患者至替代疗法时，识别和管理相关的风险。

3.2 Proactive and Reactive Application of Quality Risk Management 质量风险管理的主动和被动应用

QRM shouldideally be proactive because its greatest value is in early identification andmanagement of risks. Retrospective or reactive application of QRM may also beappropriate and add value.

质量风险管理理想的状态应该是主动的应用，因为早期识别和管理风险是非常有价值的。质量风险管理的回顾和被动应用也可以适应地增加其价值。

ln general,the earlier risks are identified, the more effective their management can be.For example, if a risk is identified during the development of designspecifications for a system, the system can be designed to reduce or eveneliminate the risk. However, if the same risk is not identified until routinecommercial operation of the system, the redesign of the system can bechallenging and likely be more costly than if the system had initially beendesigned to manage the risk appropriately. This would be in addition to thecost of managing potential harm to product quality that might occur due to thatrisk during commercial operation.

一般来讲，越早识别风险，风险管理措施越有效。例如，如果一个系统的设计标准在开发阶段就被识别，那这个系统可以设计成减少或消除风险。然而，如果同样的风险直到系统的常规商业化生产时才被识别，系统的重新设计可能是具有挑战性的，而且极大可能比在系统的设计初期适当的管理风险的造价更昂贵。另外，在商业化运营期间，由于那个风险给产品质量带来潜在危害可能会发生额外的管理成本。

There are ， however, some instances where not all risks can be identified prospectivelyand risk assessments may need to be performed retrospectively.Examples would benew potential risks identified through a deviation or introduced due to achange such that it impacts the validated status of an existing manufacturingprocess. ln these instances， deductive risk management toolslike Fault and Event Tree Analysis (FTA/ ETA), FMEA, or Fishbone Analysis maybe used to determine the contributing cause(s) of the event， and any risks impacting product qualitywill consequently need to be managed retrospectively.

然而，某些情况下，并非所有的风险都可以如预期般识别，这样就需要执行回顾性风险评估。例如，通过偏差识别或由于变更影响现有生产工艺的验证状态引进新的潜在风险。在这些实例中，演绎的风险管理工具如失效和事件树分析(FTA/ ETA)，FMEA,或鱼骨图分析可以用来确定事件的相关因素，接下来任何影响产品质量的风险将需要进行回顾性风险评估。

QRM is not anindependent Quality System element， but should be integrated intoexisting operations and appropriate parts of the PQS. QRM should never be usedto deviate from regulations， justify bad practices， defend practices that need to be corrected， or as a substitute for sound science.Compliance with current Good Manufacturing Practices (cGMPs) is a mandate.

质量风险管理不是独立于质量系统的元素，而应该整合到现存的规程中，作为PQS适宜的一部分。质量风险管理不应该背离法规，维护不好的操作，应该维护必需正确的操作、或是科合理学的代名词。符合现行生产质量管理规范(cGMPs)是强制性的。

3.3Formality of the Quality Risk Management Process

质量风险管理程序的正式流程

One of theprinciples of QRM as per lCH Q9 is that the level of effort， formality and documentation of the QRMprocess should be commensurate with the level of risk. lt is neither alwaysappropriate nor always necessaryto use a formal risk management process (2).The use of informal risk management processes (using empirical tools orinternal procedures) is also considered acceptable， as long as they meet the intentof lCH Q9. Since QRM provides a suitable knowledge management and documentationframework for previously undocumented or historical knowledge， even simple informal risk managementprocesses can support this objective. Therefore， a risk-based approach can rangefrom a documented scientific rationale to a formal risk assessment methodology(See Figure 3.3-1).

根据ICH Q9，质量风险管理的原则之一是质量风险管理程序的评估结果，正式性和文档性应该与其风险级别相适应。合适的或正式的风险管理程序并不是都是必须的。（2)只要能符合ICH Q9的要求，使用非正式的风险管理程序（如使用经验工具或内部程序）也是被认为是可接受的。因为质量风险管理只是给先前的非文档化或历史数据提供了一种合适的知识管理和文档框架，所以简单的非正式的风险管理程序也可以达到此目的。因此，风险管理方法可以从记录科学原理的文档开始到形成正式的风险评估方法（详见图表3.3-1)。

Figure 3.3-1 Rigor and Formality of QRMApproaches 图表3.3-1严谨和正式的质量风险管理方法

来源：齐力佳

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