翻译：熊
校对：流浪的沙子
GMP办公室翻译组组织翻译，欢迎加入GMP办公室翻译组QQ群参与更多指南翻译！
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 data is usedas an input to a comprehensive risk management process to identify risks,determine controls necessary to address the risks, and evaluate if existing technicaland organizational controls are adequate, or need to be supplemented withadditional controls.
另外，一旦完成基于健康的评估，该数据将用作全面风险管理流程的输入，以识别风险，确定应对风险所需的控制措施，并评估现有的技术和组织控制措施是否足够，或者需要补充其他控制措施。
“It isexpected that for products which present a higher potential harm topatients/animals, more elaborate organisational and technical control measureswill be required. Using a structured Quality Risk Management process,manufacturers should consider the risks of cross contamination down to theestablished level from the HBEL. During the QRM study manufacturers shouldconsider how easily such a quantity of contamination could occur, withoutdetection, at batch and unit dose level.” [7]
“对患者/动物具有较高潜在危害的产品，需要采用更加详细的组织和技术控制措施。使用既定的质量风险管理流程，制造商应考虑将交叉污染风险降到所建立的HBEL水平之下。在QRM研究期间，制造商应考虑在一批和一个单位剂量水平上，不进行检测的情况下，这样的污染量如何容易发生。 [7]
Thecleaning validation element of cross contamination control should be guidedfirst by the HBEL and then consider the impact or contribution from otherfactors that influence the cleaning and requirements to ensure consistency and robustnessin validation.
交叉污染控制的清洁验证要素首先应遵循HBEL指南，然后考虑影响清洁和要求的其他因素的影响或贡献，以确保验证的一致性和耐用性。
Theseexpectations clearly demonstrate that risk management should be an integralpart of cleaning validation efforts.
这些期望清晰地表明了风险管理是清洁验证工作的一个组成部分。
The premisethat a company’s quality system should include a formal risk management programfurther drives the need for cleaning validation to be approved by QualityAssurance (QA). It should have a foundation in observing, remediating, andcontrolling the risks inherent to any equipment that has been cleaned and readyfor release for GMP use.
一个公司的质量体系应包括一个正式的风险管理程序为前提，这进一步推动了清洗验证需要得到质量保证(QA)的批准。它应该有一个观察、纠正和控制任何已清洗和放行用于GMP生产使用设备的固有风险的基础。
3.1.2 RiskManagement Models
风险管理模型
ICH Q9[22] outlines a risk management process that is iterative and consists of theidentification of hazards, and the analysis and evaluation of risks associatedwith exposure to those hazards, as well as control strategies to manage therisks. It has three distinct phases for the application of risk management:Risk Assessment, Risk Control, and Risk Review.
ICH Q9 [22]概述了一个持续迭代的风险管理过程，包括危害的识别，分析和评估，以及管理这些风险的控制策略。风险管理的应用分为三个不同的阶段：风险评估，风险控制和风险审核。
Risk assessment involves the identification of risks(hazards and their impact), the analysis of the risks, and the evaluation andprioritization of risks.
风险评估涉及风险（危害及其影响）的识别，风险分析以及风险的评估和优先级划分。
Risk control includes decision making to reduce/accept risks,create a control strategy, and communicate to stakeholders.
风险控制包括制定决策以降低/接受风险，制定控制策略并与利益相关者进行沟通。
Risk review monitors the results of system performance andchanges on a periodic basis, initiating additional risks assessments if needed.
风险审核将定期监测系统性能和变更的结果，并在需要时启动额外的风险评估。
Duringall phases, the output of each phase is communicated to stakeholders forappropriate knowledge management and decision making, especially aftercompleting the Risk Control phase, where a control strategy is defined [22].
在所有阶段中，每个阶段的输出都将传达给利益相关者，以进行适当的知识管理和决策，尤其是在完成风险控制阶段之后，该阶段已定义了控制策略[22]。
Therisk management system should always be driven with a focus on the patient first,yet should not exclude potential impacts to the business, as the process mustbe considered sustainable with empirical data to support its claims.
风险管理体系应始终以关注患者为中心，但不应排除对业务的潜在影响，因为必须通过经验数据来证明该过程具有可持续性，以支持其主张。
Figure3.1 adapts the ICH Q9 [22] model to cleaning risk management, linking cleaningvalidation activities with risk management principles.
图3.1使ICH Q9 [22]模型适用清洁风险管理，将清洁验证活动与风险管理原则关联起来。
Risk Identification: Hazards from the environment,equipment, methods, chemical and microbial entities, and personnel areidentified. The hazards may have an impact on the final residues after cleaningand therefore are considered risks.
风险识别：识别来自环境，设备，方法，化学和微生物实体以及人员的危害。危害可能会影响清洁后的最终残留物，因此被视为风险。
Risk Analysis: These risks are furtheranalyzed to achieve a better understanding of the process and to prioritizetheir impact to cleaning. During this phase, process knowledge is increased bydesign reviews, data review, and studies to understand interactions betweenprocess parameters, equipment, environment, and personnel.
风险分析：将对这些风险进行进一步分析，以更好地了解过程并确定其对清洁的影响。在此阶段，通过设计审核，数据审核和研究来了解过程参数，设备，环境和人员之间的相互作用，从而增加过程知识。
Risk Evaluation: Risks are evaluated, andadditional controls are identified to mitigate the risks (risk reduction) oraccept the risk (risk acceptance).
风险评估：评估风险，并确定其他控制措施以减轻风险（风险降低）或接受风险（风险接受）。
Risk Control: During risk control, finaldecisions are made regarding acceptable risks, and a control strategy is completedto ensure mitigating design, procedural, and technical controls are applied andremain in place. This control strategy is communicated formally tostakeholders.
风险控制：在风险控制过程中，将就可接受的风险做出最终决策，并制定控制策略以确保减轻影响的设计，程序和技术控制得到应用并保持有效。该控制策略正式传达给利益相关者。
Risk Review: Risks are reviewedperiodically or when significant or new hazards are introduced, such as the introductionof new products and after major incidents or events.
风险审核：定期审核风险，或在引入重大或新的危害（例如引入新产品以及重大事件或事故之后）时进行审核。
Thereis a relationship between QRM principles and the different phases of thevalidation lifecycle. As illustrated in Chapter 1, Figure 1.3, risk managementis present throughout the validation lifecycle.
质量风险管理原则与验证生命周期的不同阶段之间存在关联。如第一章图1.3所示，在整个验证生命周期中都存在风险管理。
Figure 3.1:Cleaning Risk Management Process
图3.1：清洁风险管理过程
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 data to the outcome of the impact assessment. In-depth informationon other risk assessment tools can be found in focused guidance from ISPE [3]or other reputable sources that give a full view of the tools for QRM use [39].
在风险评估期间，确保主题专家（SME）和同事之间获得支持的一个技巧是，在可能的情况下简化从支持数据到影响评估结果的逻辑路径。有关其他风险评估工具的详细信息，请参见ISPE的专门指南[3]或其他知名资源，其提供了QRM使用工具的详细说明[39]。
3.1.3 Sources of Variation
变异来源
Unsuccessfulcleaning of manufacturing equipment, including major and minor/ancillaryequipment and change parts, as well as utensils, presents a risk to productquality and could ultimately impact patient safety if not adequately addressed.
生产设备（包括主要和次要/辅助设备，零部件以及器皿）未能成功清洁会给产品质量带来风险，如果处理不当，最终可能会影响患者的安全。
Oneapproach to take when determining causes of unsuccessful cleaning during orpost cleaning validation is to start with an outline of the characteristicswithin the cleaning practices for risk assessment. The outline should identify theequipment, cleaning agents, Active Pharmaceutical Ingredients (APIs), types ofproducts produced, microbial particulates/bioburden, lubricants, and proceduresallocated to control the operational and cleaning processes. The cleaningprocedures themselves can be a source of risk, especially manual proceduresthat have not been assessed in this manner; thus, a formal discussion on thesematerials and practices should be thoroughly documented.
在确定清洁验证期间或后续清洁失败的原因时，可采取一种方法是，首先概述清洁操作的特征，以进行风险评估。概述应识别设备，清洁剂，活性药物成分（API），生产的产品类型，微生物数量/生物负荷，润滑剂以及用于控制操作和清洁过程的程序。清洁程序本身可能会带来风险，尤其是未经这种方式评估的手动程序；因此，应该对这些材料和操作进行正式地讨论，并完整记录。
Thefishbone/Ishikawa diagram in Figure 3.2 provides an example3 of thesources of variation that could result in unsuccessful cleaning. From thefishbone outline, various impact assessment challenges can be derivedusing risk-based scenarios where failure could occur.
图3.2中的鱼骨/石川图提供了一个例子3，说明可能导致清洁失败的变异来源。根据该鱼骨图，可以使用基于风险可能发生失败的场景来得出各种影响评估挑战。
【3 The example providedherein is for illustrative purposes and is in no way meant to imply that thisis the only way to perform the risk assessment process or risk identificationtask. Additionally, it is not intended to be an exhaustive, all-inclusive example.】注3：本文提供的示例仅用于说明目的，绝不意味着这是执行风险评估过程或风险识别任务的唯一方法。此外，它也不是一份详尽无遗的示例。
Figure 3.2:Potential Sources of Variation Related to Cleaning
图3.2：与清洁相关的各种潜在变异源
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 data to determine the residue HBELs, and then use theresults to set cleaning limits. This approach is strongly encouraged by theEMA: Questions and answers on implementation of risk-based prevention ofcross-contamination in production and ‘Guideline on setting health-based exposurelimits for use in risk identification in the manufacture of different medicinalproducts in shared facilities’ [7], Question 3:
保护患者免受化学和活性残留物侵害的推荐方法是使用毒理学数据确定残留物的HBEL，然后设定清洁限度。EMA强烈鼓励采用这种方法：关于在生产中实施基于风险的交叉污染预防措施的问答，以及“设定基于健康的接触限值以识别多产品共用设施的风险” '[7]，问题3：
“Oncethe health-based assessment has been completed and the HBEL confirmed, thesedata should be used via a Quality Risk Management process to determine whatcontrols need to be put in place and to assess if existing organisational andtechnical control measures are adequate or if they need to be supplemented.This Quality Risk Management process should be carried out prospectively in thecase of new equipment/facility to determine what control measures arerequired.”
“一旦完成了基于健康的评估并确认了HBEL，则应通过质量风险管理流程使用该数据来确定需要采取哪些控制措施，并评估现有的组织和技术控制措施是否足够，或者是否需要补充。对于新设备/设施，应前瞻性地执行此质量风险管理流程，以确定所需的控制措施。”
Additionally,organizations need to implement appropriate technical and procedural controlscommensurate to the risks for contamination. The QRM process should considercross contamination risks down to the established HBEL and evaluate how therisks may impact a batch or unit dose [7].
此外，组织需要实施与污染风险相适应的适当的技术和程序控制措施。QRM过程应考虑将交叉污染风险降至所建立的HBEL之下，并评估该风险如何影响一批产品或一个剂量单位[7]。
Table3.1 lists a summary of specific applications of QRM to cleaning validation.
表3.1汇总了QRM在清洁验证中的特定应用。
Table 3.1: Examples of QRM Applications in Cleaning Validation
表3.1：清洁验证中QRM应用示例
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 data Impact to existing control plans
PDE/ADE或临床数据的可用性对现有控制计划影响
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
Scope
范围
Evaluation Scope
评估范围
Analytical Methods
分析方法
· Supplies (e.g., containers, swabs)
供应商（如容器，拭子）
· Specificity
专属性
· Robustness
耐用性
· Range
范围
· Sensitivity
灵敏度
· Active degradation
活性物质降解
· Procedure for unknown peaks
处理未知峰的程序
Cleaning Agents
清洁剂
· ADE/PDE levels
ADE/PDE水平
· Cleaning effectiveness
清洁的效果
· Rinsability
漂洗力
· Detectability
可检测性
Cleaning Cycle Development
清洁周期开发
· Number of runs
运行次数
Cleaning Procedure
清洁程序
· TACT* characteristics
TACT（时间，作用，化学和温度）特性
· Reproducibility (e.g., automated, semiautomated, manual)
重现性（自动，半自动，手动）
· Level of training
培训水平
· Level of detail (e.g., manual cleaning)
详细程度（如手动清洁）
Cleaning Qualification Execution
清洁确认执行
· Number of runs
次数
Hold Times
保持时间
· Dirty (e.g., effect on cleanability)
脏的保持时间（如对可清洁性的影响）
· Clean (e.g., length, storage, proliferation)
洁净保持时间（如时长、存放条件，增殖）
Manufacturing Equipment
生产设备
· Equipment and process product contact points
设备和工艺产品的接触点
· Equipment complexity (e.g., components, circuits, shape)
设备的复杂性（如组件、回路、形状等）
· Buildup concerns
累积相关
· Grouping (e.g., products, equipment)
分组（如产品、设备）
Manufacturing Process
制造过程
· Soil cleanability
污染可清洁性
· Process step criticality
工艺步骤的关键性
· Soil load/batch size variation
污染负荷/批量变化
Residue
残留
· ADE/PDE levels of process residues (e.g., APIs, excipients, degradants, process aides, lubricants)
过程残留物（例如，API、辅料、降解产物、工艺助剂、润滑剂）的ADE/PDE水平
· Cleanability
可清洁性
· Detectability
可检测性
Safety Cleaning Limits
清洁限度安全性
· Cleaning limit calculation and justification
清洁限度计算和论证
· Rationale for chosen cleaning limit method
选择清洁限度方法的原理
· HBEL safety limit calculation and justification
HBEL安全限度计算和论证
Sampling Approach
取样方法
· Indirect (e.g., timing, sequence (in-line, grab sample, separate))
间接取样（时间，次序（在线，擦拭，单独））
· Direct (e.g., accessibility, locations)
直接取样（如可及性，取样位置）
· Visual inspection (e.g., accessibility, lighting)
目视检查（如可及性，照明）
Sampling Recovery
取样回收
· Recoverability (cleaning agent, active ingredient, and microbial)
可回收性（清洁剂，活性物质和微生物）
· Materials of construction
结构材质
· Percent recovery
回收百分比
*TACT = Time, Action, Chemical, and Temperature
TACT=时间，作用，化学，温度
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。
