清洁验证变更控制，如何评估？

翻译：FREDERIC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）》11 Change ontol清洁验证的变更控制Once a validated cleaning program is in place, changesneed to be managed to ensure that the cleaning process remains in a state ofcontrol. Change management is the systematic approach to evaluate, approve, andimplement changes. It includes the oversight of all changes potentiallyaffecting CPPs and/or cleaning effectiveness throughout the cleaning process lifecycle.一旦建立了经过验证的清洁程序，就需要对变更进行管理以确保清洁过程仍然保持在受控状态。变更管理是评估、批准和实施变更的系统性方法。它包括对清洁工艺的整个生命周期中所有可能影响CPP和/或清洁效果变更的监督。Thecompanys quality system should havein place the necessary procedures to define and establish the change management system. Using QRM principles, the changemanagement system categorizes changes according to the risk to the validatedcleaning process.These risks rangefrom high impact to low or no impact on the cleaning process.This section provides principles andguidance regarding actions to take when changing validated cleaning processes.Given the variety of industries, products, and manufacturing processes, theestablished companys quality systemtakes precedence over the principles provided in this section.公司的质量体系应具备必要的程序来规定和建立变更管理系统。采用质量风险管理原则，变更管理系统根据变更对已验证的清洁工艺的风险进行分级。风险范围对清洁过程的影响从高到低或者没有影响。本章提供了变更已验证的清洁工艺时采取措施的原则和指导。考虑到行业、产品和生产工艺的多样性，已经建立的公司质量体系优先于本章提供的原则。111 Elements of alidaed Cleaning Poeses已验证清洁工艺的要素validated cleaning process depends on multiple aspects to ensure consistencyand reproducibilit, with the most critical aspects monitored. Changesto these elements are controlled via change management.The fishbone diagram in Figure 1.1 illustrates the control elements of a validated cleaningprocess.已验证的清洁工艺取决于多方面通过监控最关键的方面来确保一致性和重现性。这些要素的变更通过变更管理进行控制。图11.1所示的鱼骨图说明了已验证的清洁工艺的控制要素。Figure 1.1:Elements of a alidated CleaningProcess图11.1已验证清洁工艺的要素

Modificationsto a cleaning process require an impact assessment and may initiate changemanagement. Changes to cleaning methods, introduction of new products, changes tomanufacturing processes (e.g., parameters, lot size), critical parameters, equipment configurationsor surface area, or analytical methods are potentially high impact changes thattrigger change management.Allchanges to cleaning are evaluated for impact by SMEs and cleaning personnel.清洁工艺的修改应进行影响评估，并可能需要变更管理。清洁方法的变更，引入新产品，生产工艺（如参数，批量）、关键参数、设备结构或表面积或分析方法的变更，可能是触发变更管理的高影响变更。SME和清洁人员应对清洁的所有变更进行影响评估。The following sections provideexamples of possible actions to take when certain changes are executed.The changes illustrated inables1.1 to 1.5 show that there is a relationship between the impact of thechange (lo, medium, high) andactions necessary to keep the cleaning process in control.ypicall, the greater the change impact to acleaning process, the more actions needed to bring it back to a validatedstate.The tables do not cover allpossible examples or conditions.以下各章节提供了执行某项变更时可能需要采取的措施的示例。表11.1至11.5所示的变更表明，变更的影响（低，中，高）与维持清洁工艺处于受控状态所需的措施之间存在某种关系。通常，变更对清洁工艺的影响越大，将其恢复为已验证状态所需的行动就越多。以下表格未涵盖所有可能的示例或条件。Thechange management system ensures that every relevant change is reviewed andassessed for impact to the cleaning validation status.Thus, a determination can be made if revalidation or furtheractions are required.变更管理系统确保审核和评估所有相关变更对清洁验证状态的影响。因此，可以确定是否需要重新验证或进一步的行动。11.2 Eamples of Changeswith oresponding ctions附有相关行动项的变更示例ables 1.1 to 1.5 contain examples for illustrativepurposes onl.The tables do not present all possible changes; howeve, they provide scenarios for changemanagement actions based on the relative risks and impact of the changeto the ability to clean. It is not possible to define the appropriate actionsfor all cases because this depends on the risk profile for each facilit, the degree of knowledge of the cleaningprocess, and the details submitted to the regulatory dossier for the product.表11.1到11.5只包括用于说明目的的示例。表格中未列出所有可能的变更；但是，基于相关风险和变更对清洁能力的影响，这些示例提供了变更管理行动的方案。无法针对所有情况规定适当的行动，因为这取决于各个设施的风险状况、对清洁过程的知识程度，以及为该产品提交给监管机构的申报资料的详细程度。11.21echnicaltems and Equipment Design技术系统和设备设计Technicalsystems include all equipment, facilities, utilities, and unit operations usedto execute the cleaning process.  Systemshave a combination of design features (MOC, gaskets, hold volume, etc.),instruments (temperature, flow, pressure, conductivity, etc.), and proceduresthat make them unique. Changes to technical systems require assessment forimpact. See Table 11.1.技术系统包括所有用于执行清洁工艺的设备，厂房，设施和单元操作。系统的设计特点（结构材料（MOC），垫圈，容积等），仪器参数（温度，流速，压力，电导率等）以及程序的结合使它成为一个独立的整体。对技术系统的变更需要评估影响。见表11.1。Other aspects to consider whenevaluating changes to equipment and technical systems are:评估设备和技术系统变更时考虑的其他方面有：Coverage of cleaning agents in equipmentand pipes (riboflavin tests, flooding cycles)清洁剂在设备和管道中的覆盖情况（核黄素测试，水浸周期）The use of spray balls (pressure, angleof operation, flow rates)喷淋球的使用（压力，操作角度，流速）System holdvolumes (pipes, tanks, valves)系统容积 (管道，罐体，阀门)Level ofdryness after cleaning cycles (dried for storage, drained, no stagnant liquids)清洁后的干燥程度（干燥保存，沥干水分，无积液）Maintenance procedures (post maintenance cleaningcycles, like-for-like replacements, gaskets and other product contactcomponents)维护程序（维护后的清洁周期，同类替换，垫圈和其他产品接触组件）able 1.1:Example Change EvaluationAssessment表11.1变更评定的评估示例CleaningArea清洁区域Changes to…变更May Impact…可能影响Impact to Validated Status对验证状态的影响Possible Actions可能的措施1 = Documentation  Update文件更新2 = Verification 确认3 = Validation 验证4 = Regulatory  Submission注册申报LMH1234Technical  Systems (Facilities, Equipment, Systems)技术系统（厂房，设备，系统）New  Material of Construction新的结构材料Compatibility相容性Cleanability可清洁能力XXXXXExtending  Elastomer Changeover Frequency延长弹性材料的更换频率Cleaning  Effectiveness清洁效果XXXMaximum  Area to be Cleaned变更需要清洁的最大面积Cleaning  Effectiveness清洁效果XXXCleaning  Parameters within Design Space设计空间内的清洁参数Cleaning  Effectiveness清洁效果XXXCleaning  Parameter beyond Design Space设计空间外的清洁参数Cleaning  Effectiveness清洁效果XXXXIncrease  in Level of Automation提高自动化水平Cleaning  Effectiveness清洁效果XXXManual  Cleaning to Automated Cleaning手动清洁变为自动清洁Cleaning  Effectiveness清洁效果XXXImpact  to validated status: L = Low Impact, M = Medium Impact, H = High Impact对验证状态的影响；L=低影响， M=中影响， H=高影响Possible Actions可能的措施:1. Documentation Update means revising existing documents,  plans, or procedures to add new information or conditions.文件更新指修订现有文件，计划或程序以增加新的信息或条件2. Verification means verifying aspects of a cleaning  procedure or extending a parameter without executing a full cleaning  revalidation.确认是指在不执行全面重新清洁验证的情况下确认清洁程序的某些方面或扩展参数。3. Validation means executing a full cleaning validation.验证指执行全面清洁验证4. Regulatory Submission means submitting changes to  regulatory agencies for review and/or approval.注册申报指向监管机构提交变更以进行审核和/或批准11.2.2Cleaning Methods清洁方法The cleaningmethod affects the degree of action on the surface to be cleaned. Changes tocleaning methods (manual brush, wipe downs, chemical cleaning, automatedcleaning, etc.) can have an effect on the cleaning effectiveness andconditions. When evaluating cleaning method changes, it is useful to understandwhat constitutes worst-case conditions and if the proposed changes will stilloperate within those conditions. If a change introduces parameters outside theknown design space, an impact assessment is required to evaluate the potentialimpact to the cleaning process. Actions to maintain the cleaning process in avalidated state range between documenting the change to full revalidation ofthe new parameters. See Table 11.2.清洁方法会影响待清洁表面的行动水平。变更清洁方法（手动刷洗，擦拭，化学清洁，自动清洁等）可能会影响清洁效果和条件。在评估清洁方法的变更时，了解是什么构成最差条件以及拟定的变更是否仍将继续在该条件下运行是非常有用的。如果变更是在已知设计空间外引入参数，那么需要进行影响评估以评估对清洁工艺的潜在影响。用以确保清洁过程维持在验证状态的措施包括文件记录变更到完全重新验证新参数。见表11.2。able 1.2:Example Cleaning MethodsAssessment表11.2清洁方法评估示例Cleaning  Area清洁区域Changes to…变更May Impact…可能影响Impact to Validated Status对验证状态的影响Possible Actions可能的行动1 = Documentation Update文件更新2 = Verification 确认3 = Validation 验证4 = Regulatory  Submission注册申报LMH1234Cleaning  Methodologies清洁方法Critical  Cleaning Parameters关键清洁参数Cleaning  Effectiveness清洁效果xxxxNon-Critical  Parameters非关键参数Cleaning  Consistency清洁一致性xxxCleaning  Solutions清洁溶液Cleaning  Effectiveness清洁效果xxxxCleaning  Procedures清洁程序Cleaning  Effectiveness清洁效果xxxWorst-Case  products最差条件产品Cleaning  Limits清洁限度xxxxDirty  Hold Time Change变更脏的保持时间Cleaning  Effectiveness清洁效果xxxxClean  Hold Time Change变更清洁保持时间Product  Quality产品质量xxxxIncreasing  Campaign Length增加阶段性生产长度Worst-Case  Conditions最差条件xxxxImpact  to validated status: L = Low Impact, M = Medium Impact, H = High Impact对验证状态的影响；L=低影响， M=中影响， H=高影响Possible Actions可能的行动:1. Documentation Update means revising existing documents,  plans, or procedures to add new information or conditions.文件更新指修订现有文件，计划或程序以增加新的信息或条件2. Verification means verifying aspects of a cleaning  procedure or extending a parameter without executing a full cleaning  revalidation.确认是指在不执行全面重新清洁验证的情况下确认清洁程序的某些方面或扩展参数。3. Validation means executing a full cleaning validation.验证指执行全面清洁验证4. Regulatory Submission means submitting changes to  regulatory agencies for review and/or approval.注册申报指向监管机构提交变更以进行审核和/或批准11.2.3 Sampling取样Changes tosampling methods (swabs, wipes, instrument scanning, rinse samples) areassessed for impact to recovery studies and cleaning processes. Sampling locationsare justified prior to validation; therefore, changes to sampling locations areassessed for impact to the cleaning process. See Table 11.3.取样方法（拭子，擦拭，仪器扫描，淋洗样品）的变更应评估对回收率研究和清洁工艺的影响。取样位置在验证之前已进行论证；因此，取样位置的变更应评估对清洁工艺的影响。见表11.3。able 1.3:Example Sampling ChangesAssessment表11.3取样变更评估示例CleaningArea清洁区域Changes to…变更May Impact…可能影响Impact to Validated  Status对验证状态的影响Possible Actions可能的行动1 = Documentation Update文件更新2 = Verification 确认3 = Validation 验证4 = Regulatory Submission注册申报LMH1234Sampling取样Sampling Location取样位置Worst-Case Assumptions最差条件假设xxSample Recovery Technique (Rinse  versus Swab, etc.)样品回收技术（淋洗改擦拭，等）% Recovery回收率xxxStorage样品存放Sample Stability样品稳定性xxSwab Area擦拭区域% Recovery, Location,回收率，位置xxxCoupon Material of Construction结构材料% Recovery回收率xxxResidue Spike Level残留涂布水平% Recovery回收率xxNumber of Spike Levels and  Replicates涂布数量和重复次数% Recovery, CV Program回收率， CV程序xxxRecovery Factor Determination回收因子测定% Recovery, CV Program回收率， CV程序xxxType of Swab擦拭类型% Recovery, CV Program回收率， CV程序xxxNumber of Swabs擦拭次数% Recovery, CV Program回收率， CV程序xxSwab Solvent擦拭溶剂% Recovery, CV Program回收率， CV程序xxxSample Container样品容器% Recovery, Test method回收率，测试方法xxExtraction Solvent提取溶剂% Recovery回收率xxxExtraction Technique提取技术% Recovery回收率xxxExtraction Time提取时间% Recovery回收率xxxTest Method测试方法Data数据xxx*Sampling  Method取样方法% Recovery回收率xxxImpact to validated status: L = Low Impact, M = Medium  Impact, H = High Impact对验证状态的影响；L=低影响， M=中影响， H=高影响CV = Cleaning Validation 清洁验证Possible  Actions可能的行动:1. Documentation Update means revising existing documents,  plans, or procedures to add new information or conditions.文件更新指修订现有文件，计划或程序以增加新的信息或条件2. Verification means verifying aspects of a cleaning  procedure or extending a parameter without executing a full cleaning  revalidation.确认是指在不执行全面重新清洁验证的情况下确认清洁程序的某些方面或扩展参数。3. Validation means executing a full cleaning validation.验证指执行全面清洁验证4. Regulatory Submission means submitting changes to  regulatory agencies for review and/or approval.注册申报指向监管机构提交变更以进行审核和/或批准*Method validation and equivalence  determination to assess impact to cleaning process进行方法学验证并确定等效性以评估对清洁工艺的影响11.2.4 Analytical Methods and eting分析方法和测试Analyticalmethods are validated to ensure accuracy, precision, specificity (asapplicable), robustness, and linearity.  Changesto validated analytical methods require appropriate assessments for impact tothe analytical controls. See Table 11.4.验证分析方法以确保准确性，精密度，专属性（如适用），耐用性和线性。对已验证分析方法的变更需要评估对分析控制的影响。见表11.4。。able 1.4:Example Methods ChangesAssessment表11.4分析方法变更评估示例CleaningArea清洁区域Changes to…变更May Impact…可能影响Impact to Validated Status对验证状态的影响Possible Actions可能的行动1 = Documentation  Update文件更新2 = Verification 确认3 = Validation 验证4 = Regulatory  Submission注册申报LMH1234Testing  Methods检测方法Chemical  Testing Methods化学检测方法LOD  or LOQ检测限或定量限xxWorst-Case  Product Requiring New Analytical Methods最差条件产品需要新的分析方法LOD,  AcceptanceCriteria检测限，接受标准xxxChemical  Testing Going from a Titration Method or TLC to HPLC化学检测方法从滴定方法或TLC改为HPLCLOD  or LOQ检测限或定量限xxxxMicrobial  Methods Going from Traditional Microbiology to Rapid Microbiology Method微生物检测方法从传统微生物方法改为快速微生物方法Microbial  Test Results微生物检测结果xxxxVisual  Inspection Method and Training Personnel (using spiked  coupons)目视检查方法和培训人员（使用涂布样品）Ability  to Detect Residues检测残留物的能力xxxImpact  to validated status: L = Low Impact, M = Medium Impact, H = High Impact对验证状态的影响；L=低影响， M=中影响， H=高影响LOD =  Limit of Detection, LOQ = Limit of QuantitationLOD =检测限, LOQ = 定量限Possible Actions可能的措施:1. Documentation Update means revising existing documents,  plans, or procedures to add new information or conditions.文件更新指修订现有文件，计划或程序以增加新的信息或条件2. Verification means verifying aspects of a cleaning  procedure or extending a parameter without executing a full cleaning  revalidation.确认是指在不执行全面重新清洁验证的情况下确认清洁程序的某些方面或扩展参数。3. Validation means executing a full cleaning validation.验证指执行全面清洁验证4. Regulatory Submission means submitting changes to  regulatory agencies for review and/or approval.注册申报指向监管机构提交变更以进行审核和/或批准11.2.5Residue Limits, eptane Criteria, and Specifictions残留限度，接受标准和质量标准Residuelimits are established to ensure residues or contaminants from previousproducts do not impact the quality attributes of the next productsmanufactured. As a minimum, cleaning processes should render surfaces visuallycleaned. Additional criteria are established for active ingredients andcleaning agents. Changes to these limits require assessment for impact to thecleaning validation. See Table 11.5. See also Appendix 8 for a case study tointroduce a new product into a multiproduct facility.建立残留限度是为了确保上一个产品的残留或污染物不会影响所生产的下一个产品的质量属性。至少清洁工艺应使表面目视清洁。另外，应建立活性成分和清洁剂的标准。这些限度的变更应评估对清洁验证的影响。见表11.5。另参见附录8，多产品工厂引入新产品的案例研究。able 1.5:Example Residue LimitsAssessment表11.5：残留限度评估示例CleaningArea清洁区域Changes to…变更May Impact…可能影响Impact to Validated Status对验证状态的影响Possible Actions可能的行动1 = Documentation  Update文件更新2 = Verification 确认3 = Validation 验证4 = Regulatory Submission注册申报LMH1234Acceptance  Criteria接受标准New  Product Introduction not Representing a Worst Case  for Cleaning引入新产品，但该新产品不是清洁的最差条件Worst-Case  Calculation最差情况计算xxxNew  Product Introduction Representing a Worst Case for Cleaning引入新产品，并且该产品代表清洁的最差条件Cleaning  Effectiveness清洁效果Cleaning  Limits清洁限度xxxxNew  Regulatory Requirement Beyond Current Cleaning Program新的法规要求高于当前的清洁程序Cleaning  Effectiveness清洁效果xxxImpact  to validated status: L = Low Impact, M = Medium Impact, H = High Impact对验证状态的影响；L=低影响， M=中影响， H=高影响Possible Actions可能的行动:1. Documentation Update means revising existing documents,  plans, or procedures to add new information or conditions.文件更新指修订现有文件，计划或程序以增加新的信息或条件2. Verification means verifying aspects of a cleaning  procedure or extending a parameter without executing a full cleaning  revalidation.确认是指在不执行全面重新清洁验证的情况下确认清洁程序的某些方面或扩展参数。3. Validation means executing a full cleaning validation.验证指执行全面清洁验证4. Regulatory Submission means submitting changes to  regulatory agencies for review and/or approval.注册申报指向监管机构提交变更以进行审核和/或批准

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