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译自2020年8月份发布的《ISPE基准指南：清洁验证生命周期–应用，方法和控制（ISPE Baseline Guide: Cleaning Validation Lifecycle: Applications, Methods, and Controls）》 

3 Risk Management

清洁验证风险管理

3.1 RiskManagement Description Overview and Regulatory Expectations

3.1风险管理概览和监管要求

Quality RiskManagement (QRM) is a rational approach to enable good decisions. Cleaningvalidation, like other GMP validation activities, is not exempted from theregulatory expectation of using risk management to control potential hazards,reduce risks, and establish sound cleaning processes. In fact, a risk-basedcleaning validation strategy with justifiable and achievable acceptancecriteria is crucial in attaining a compliant cleaning validation program.

质量风险管理（QRM）是实现良好决策的合理方法。正如其他GMP验证活动一样，清洁验证也需要使用风险管理来控制潜在风险，降低风险，并建立合理的清洁工艺。实际上，基于风险的清洁验证策略以及具有合理且可实现的接受标准，对于获得合规的清洁验证程序至关重要。

Forexample, validation master plans for cleaning should either start with adocumented risk assessment exercise or at least include the risk assessmentprocess in the early stages of developing a new program. In today’s pharmaceuticalregulatory landscape, a retrospective risk assessment is not only a goodpractice, it is expected within cleaning programs, even if that program hasbeen grandfathered as acceptable.

例如，清洁验证主计划应从书面的风险评估活动开始，或者至少在制定新计划的早期阶段就包括风险评估过程。在当今的药品监管环境中，回顾性（倒推式）风险评估不是一种好的做法，而应在清洁计划中采用，尽管历史上它被认为是可以接受的。

3.1.1Regulatory Expectations

监管要求

Quality riskmanagement is a regulatory expectation, as noted in FDA’s Pharmaceutical CGMPsfor the 21th Century [18], which aims to encourage implementation of risk-basedapproaches that focus on critical areas for maintaining or improving productquality.

正如FDA面向21世纪的药品CGMP[18]所指出的那样，质量风险管理是一项监管期望，其目的是鼓励实施基于风险的方法，关注于维持或改善产品质量的关键领域。

Expectationsfor the application of QRM principles to validation are clearly stated inregulatory documents.

法规文件中清楚地说明了QRM原则应用于验证的期望。

For example,EudraLex Annex 15 [4] states applications for QRM in validation:

例如，EudraLex附录15[4]说明了QRM在验证中的应用：

• Todetermine scope and extent of qualification and validation.

• 确定确认和验证的范围和程度。

• To reassessrisks after gaining more knowledge from commercial production.

• 从商业生产中获得更多的知识重新评估风险。

• Todetermine criticality of process parameters.

• 确定关键工艺参数。

• To evaluateplanned changes to determine potential impact.

• 评估计划性变更以确定潜在的影响。

• To justify bracketing approaches.

• 论证括号法的合理性。

• To determine the variable factors which influence cleaningeffectiveness and performance.

• 确定影响清洁效果和性能的可变因素。

• To justifyselected cleaning limits.

• 证明所选择清洁限度的合理性。

• To justifythe number of times the cleaning procedure should be executed (number of runs)for validation.

• 证明清洁程序验证时执行次数的合理性。

• Todetermine the risks presented by microbial and endotoxin contamination duringthe development of cleaning validation protocols.

• 清洁验证方案开发过程中，确定微生物和内毒素污染带来的风险。

Similarly,the FDA Guidance for Industry: Process Validation [5] calls for QRM principlesto be applied:

同样，FDA《行业指南：工艺验证[5]》要求遵循的QRM原则：

• Todetermine the degree of controls needed to control process variation.

• 确定控制工艺变化所需的程度。

• To screenpotential variables for Design of Experiment (DOE) studies to minimize thetotal number of experiments conducted while maximizing knowledge gained.

• 筛选实验设计(DOE)研究的潜在变量，以使实验次数最少，而能最大限度地获得知识。

• To supportthe prioritization of certain equipment qualification activities and toidentify the level of effort needed in both the performance and documentationof qualification activities.

• 支持对某些设备确认活动的优先级，并确定确认活动的性能和文档水平。

• To justifythe sampling location, sampling frequency, and confidence level for samplingplans.

• 证明取样点，取样频次和取样计划置信水平的合理性。

• Todetermine criteria for process performance indicators.

• 确定工艺性能指标的标准。

Furthermore,EMA in its guidance for industry to set HBELs recognizes that cleaning is arisk reducing measure.

“A more scientific case by case approach iswarranted for risk identification and to support risk reduction measures forall classes of pharmaceutical substances.” [11]

此外，EMA在其HBEL行业指南中亦指出清洁是降低风险的措施。“对于所有级别的药用物质，有必要采取更科学的个案分析方法来识别风险，并支持风险降低措施。” [11]

Inaddition, once a health-based assessment has been completed, the _width="-30px" src="https://st.yunmeow.com/20251202/5143bcf2-2185-47c2-8c2b-6db186ac96f5.png">

There are many tools available to support theapplication of QRM principles. The most common are:

有许多工具可以用来支持质量风险管理原则的应用。最常见的有：

• Failure Mode Effects Analysis (FMEA)

• 失效模式影响分析（FMEA）

• Fault Tree Analysis (FTA)

• 故障树分析

• Hazzard Analysis and Critical Control Points(HACCP)

• 危害分析和关键控制点（HACCP）

• Fishbone/Ishikawa

• 鱼骨图/石川图

One hint to secure support between Subject Matter Experts (SMEs) andcolleagues during risk assessments is to simplify (when possible) the logicalpath from supporting _width="-30px" src="https://st.yunmeow.com/20251202/d3548b0a-6784-4487-a2d6-360110d9ae76.png">

Adapted fromISPE Training Slides [40]

改自ISPE 培训PPT[40]

3.2 Risk ManagementApplied to the Cleaning Validation Program

风险管理在清洁验证程序中的应用

Riskmanagement for cleaning processes focuses on the hazard represented by theactive and chemical residues on product contact surfaces, the impact orseverity represented by such residues, the likelihood of these residues being present,and the ability to detect them.

清洁工艺的风险管理重点在于产品接触表面上的活性残留物和化学残留物所带来的危害，此类残留物所带来的影响或严重性，存在这些残留物的可能性以及对其进行检测的能力。

Manycleaning regimens originally focused on visual cleanliness as a measure of success.However, there are multiple sources of hazards in a cleaning process that needto be well understood in order to guide the planning and decision making fordeveloping effective and compliant cleaning processes.

许多清洁方案最初都将目视清洁作为成功的标准。但是，清洁过程中存在多种危害源，需要充分了解这些危害，以指导制定计划和决策来开发有效且合规的清洁工艺。

One ofthe most important hazards in a cleaning program comes from the type of soilsto be cleaned. Some chemicals and actives present low risks to patients andothers higher risks, as represented in Figure 3.3.

在清洁程序中最重要的危害之一是待清洁的污染类型。如图3.3所示，某些化学药品和活性物质对患者的风险较低，而有些则较高。

Figure3.3: Hazard Continuum [3]

图3.3：危害轴[3]

Therecommended approach for protecting patients from chemical and active residueis to use toxicological cellpadding="0">

Cleaning Validation  Milestone

清洁验证里程碑

Tasks

任务

Considerations

考虑点

Validation Master Plan

验证主计划

Matrix approach or testing  all products (multiproduct facility)

矩阵方式或测试所有的产品（多产品共用设施）

Define “worst-case” approach  for validating products and API

定义清洁验证“最差条件”产品和API

Define sampling plan

定义取样计划

Sampling methods, locations,  frequency, and confidence levels

取样方法，取样点，频次和置信水平

Selection of analytical  methods

分析方法选择

HPLC versus Total Organic  Carbon (TOC) along with appropriate microbial testing techniques, LOD, method  variability

HPLC与总有机碳（TOC）以及适当的微生物检测技术，检测限（LOD），方法变异性

Design and Development

设计和开发

Determine target HBEL and  perform risk assessment to evaluate cleaning

limits

确定目标HBEL、进行风险评估以评估清洁限度

Availability of PDE/ADE or  clinical>

Determine parameters for the  cleaning process

确定清洁工艺参数

Justify bracketing and  grouping approaches

论证括号法和分组法

Determine interactions  between parameters and justify best ranges for effectiveness and performance

确定参数之间的相互作用，并证明有效性和性能的最佳范围

Qualification (PPQ)

确认（PPQ）

Test equipment hard to clean  areas to confirm CV

测试设备难以清洁区域以证实清洁验证

Confirm equipment is  sufficiently clean to complete CV through appropriate testing and sampling  locations

通过适当的测试和取样位置确认设备得到充分清洁以完成清洁验证

Determine number of runs for  cleaning qualification

确定清洁确认执行的次数

Optimum number of times cleaning  procedures must be executed to cover the scope of cleaning validation

清洁程序应被执行，且能覆盖清洁验证范围

Verification (CPV)

确证（CPV）

Find areas where the  processes can be improved

寻找可以改进的过程

CHT studies or reduced  testing strategies during campaigning production, evaluation of current  hazards to update controls

在生产活动期间进行洁净保持时间（CHT）研究或减少测试策略，评估当前危害以更新控制措施

Ongoing Monitoring

持续监测

Ensure that cleaning limits remain appropriate and  that periodic testing satisfies requirements

确保清洁限度保持适当，并且定期测试结果满足要求

Additional process knowledge could change initial PDE/ADE calculations;  verification via spot checking the current hazards can reduce risk

额外的工艺知识可能会改变初始的PDE /ADE计算；通过对当前危害的抽查确认风险可以降低

Evaluate opportunities for  reduced testing

评估减少测试的机会

Level of controls (testing)  should be commensurate to current level of risks

控制（测试）的水平应与当前的风险水平相适应。

Periodic Review

定期审查

Assemble a cross-functional  team for assessment to evaluate and report on the cleaning validation program  effectiveness

组件一个跨职能团队以评估和报告清洁验证计划的有效性

This report should be  available for regulatory review to highlight updates in cleaning validation control  strategies

此报告应在法规检查期间可用，应突出清洁验证控制策略的更新

Change Management

变更管理

Evaluate planned changes to determine  potential impact

评估计划性变更以决定潜在的影响

Consider impact to  validation control plan.

考虑对验证控制计划的影响

Consider accumulative impact  of changes.

考虑变更累计的影响

Additional risk evaluation applications are discussed inSections 3.2.1 to 3.2.4 using the cleaning validation lifecycle.

使用清洁验证生命周期在3.2.1至3.2.4节中讨论了其他风险评估应用。

3.2.1Initial Cleaning Validation Assessments

3.2.1初始清洁验证评估

Validation assessments at this stage help determine the scopeand extent of qualification and validation efforts from a perspective of risk.

此阶段的验证评估有助于从风险的角度确定验证工作的范围和程度。

The assessment conclusion should recommend validation,verification (i.e., dedicated indirect equipment), or no validation (i.e.,waste collection vessels) requirements. The assessment should also identify theextent of the effort (number of runs or products involved, studies anticipatedto be needed, special training considerations, etc.). Table 3.2 provides a listof areas to consider during assessments for validation.

评估结论应建议验证，确认（例如，专用的非直接接触设备）或不需验证（如废弃物收集容器）的要求。评估还应确定工作的程度（涉及的运行次数或产品数量，预期需要的研究，特殊的培训等）。表3.2列出了评估中需要考虑的领域。

Table 3.2: Validation Assessment Elements for Cleaning

表3.2：清洁验证评估要素

3.2.2 Introduction of New ProductsRisk Assessments

3.2.2新产品引入的风险评估

Introducing new products into afacility requires in-depth knowledge of the new hazards this may imply. When assessingthe validation effort for legacy cleaning processes, the assessment shouldconsider factors such as:

将新产品引入工厂需要深入了解新的未知危害。在评估已有清洁过程的验证工作时，应考虑以下因素：

• Historical knowledge of current processes

• 当前工艺的历史知识

• Process and equipment similarities

• 工艺和设备的相似性

• Cleaning methods used

• 使用的清洁方法

• Cleaning agents used

• 使用的清洁剂

• Equivalent or worst-caseexcipients/formulations

• 等效或最差情况的辅料/制剂

If the new product to be introduced does not represent a newworst-case chemical or active to clean, then the existing cleaning process maybe considered sufficient. A comprehensive risk assessment is completed toevaluate any changes to the existing control plans, including updatingjustification reports for HBEL, sampling, and all other elements of thecleaning program. Conversely, if the new product introduces new chemicals oractives that exceed the capability of the current cleaning process, then acomprehensive evaluation of the cleaning program is required.

如果拟引入的新产品不会引起新的最差情况化学物质或活性物质，则可以认为现有的清洁工艺已足够。应完成一份全面的风险评估报告，以评估对现有控制计划的任何更改，包括更新有关HBEL，取样和清洁计划所有其他要素的论证报告。相反，如果新产品引入的新化学品或活性物质超出了当前清洁工艺的能力，则需要对清洁程序进行全面评估。

Refer to Appendix 8 for a case studyapplying QRM principles to the introduction of new products in an existingfacility.

有关将QRM原理应用于现有工厂中引入新产品的案例研究，请参阅附录8。

3.2.3 Ongoing Monitoring Maintenance Risk Assessments

3.2.3持续监测维护风险评估

The level, type, and frequency of testing during the ongoingmonitoring of a validated cleaning process is evaluated via an initial riskassessment. This ensures the implementation of a monitoring program that isscience and riskbased. Additionally, as risk is reduced, the level ofmonitoring can be reduced.

通过初始风险评估，评估对已验证清洁工艺进行持续监测的测试级别，类型和频率。这样可以确保实施基于科学和风险的监测程序。另外，随着风险的降低，监测级别也可以降低。

The scope of the risk assessment should be determined early inthe process, ideally as part of the Validation Master Plan (VMP) and periodicreview of cleaning processes.

风险评估的范围应在过程的早期确定，理想情况下应作为验证主计划（VMP）和清洁工艺定期审查的一部分。

3.2.4 Routine Operation of Cleaning Process Risk Assessments

3.2.4清洁工艺风险评估的日常操作

As part of the ongoing verificationof cleaning processes, a risk assessment is performed to assess the cleaning processfor changes in hazards and corresponding risks. It assesses changes inprocesses, procedures, activities, and determines points of highest impact. Theassessment should be a living document to be updated on a periodic schedule(i.e., during cleaning periodic reviews) or be part of a control strategy tocapture changes to the process.

作为清洁工艺持续确认的一部分，应执行风险评估，以评估清洁工艺中的危害变化和相应的风险。它评估工艺，程序，活动的变更，并确定影响最大的点。该评估应是一份定期更新的动态文件（例如，在清洁定期审查期间），或作为控制策略的一部分，以捕获过程的变化。

HACCP or modified versions are goodfor assessing the process and determining potential failure points or weak pointswithin the process.

HACCP或其改良版本非常适合评估工艺并确定工艺中潜在的失败点或薄弱点。

Considerations:

考虑点：

• Changes documented as part of thecleaning process periodic review

• 作为清洁工艺定期审查的一部分记录的变更

• In-process sampling methods

• 过程中采样方法

• Process performance

• 工艺性能

• Changes in manufacturing processsteps

• 生产工艺步骤的变更

• Changeover procedures

• 切换程序

• Training program

• 培训计划

• Changes in CIP/COP recipes andalarms

• CIP /COP配方的更改和报警

• New product and equipment grouping

• 新产品和设备分组

• Equipment maintenance

• 设备维护保养

3.2.5 Additional Applications

3.2.5其他应用

For complex processes or scenarios, separate risk assessmentscan be used to evaluate special hazards and identify appropriate controlmeasures to mitigate risks. For example:

对于复杂的过程或场景，可以使用单独的风险评估来评估特定危害并确定适当的控制措施以减轻风险。例如：

• Implementing an aggressive cleaning validation groupingstrategy

• 实施积极的清洁验证分组策略

• Using reduced Material of Construction (MOC) recoverygroupings to represent larger groups of materials

• 使用代表性的结构材质（MOC）回收组来代表大量的材质组

• Optimizing the level of detail for non-critical manualcleaning activities

• 优化非关键手动清洁活动的详细程度

These scenarios require that SMEs understand how to effectivelyanalyze and control potential hazards. The output of these risk assessments isused to support better decisions.

这些情况要求SME了解如何有效分析和控制潜在危害。风险评估的结果用于支持做出更好的决策。