APIC颁布原料药工厂清洁验证指南

APIC颁布原料药工厂清洁验证指南AnAPICmultinationalworkinggrouphascompiledanewguidanceoncleaningvalidationwiththetitleAPICGuidanceonAspectsofCleaningValidationinActivePharmaceuticalIngredientsPlants.PublicationdateisMay2014andthedocumentcanbedownloadedfromtheAPICwebsite.Thefollowingisasummarydescriptionofthedocument.Thedocumentcontains55pagesandissubdividedinto13chapters.APIC多国工作组汇编了新的清洁验证指南，题为“APIC原料药工厂清洁验证指南面面观”。颁布日期为2014年5月，文件可以从APIC官网下载。以下是该文件的摘要。文件包括55页，分为13章。Foreword前言Objective目的Scope范围AcceptanceCriteria可接受标准LevelsofCleaning清洁水平ControlofCleaningProcess清洁工艺控制BracketingandWorstCaseRating括号法和最差情况分类法DeterminationoftheAmountofResidue残留量的检测CleaningValidationProtocol清洁验证方案ValidationQuestions验证问题References参考文献Glossary术语CopyrightandDisclaimer版权和声明ThetopiccleaningvalidationgainednewimportanceintheEUwiththepublicationoftheEMAGuidelineGuidelineonsettinghealthbasedexposurelimitsforuseinriskidentificationinthemanufactureofdifferentmedicinalproductsinsharedfacilitiesandwiththechapterCleaningValidationinthedraftoftherevisionofAnnex15.Theforewordreferstotheintegrationofcleaningvalidationwithinaqualitysystemsupportedbyqualityriskmanagementprocessesinordertoprotectthepatients.AccordingtotheauthorsthedocumentisalignedwithISPERisk-MaPPanditrecommendstherevisedPDATechnicalReport29asavaluableguidancedocument.Thedocumentissupposedtoassistcompaniesincleaningvalidationandtoserveasastartingpointforinternaldiscussions.Itshouldinnowaybeconsideredasatechnicalstandard.Thedocumentaddressessixtopics:清洁验证主题在欧盟EMA指南前言指出了清洁验证应与质量体系结合，由质量风险管理过程支持，以保护患者利益。根据文件作者们所言，该文件与ISPE的药品风险管理是一致的，并推荐将修订后的PDA第29号技术报告作为参考文件。该文件意在清洁验证方面给公司提供帮助，作为内部讨论的基础，而不应作为一个技术标准。文件阐述了以下6个主题：Acceptancecriteria可接受标准Levelsofcleaning清洁水平Controlofthecleaningprocess清洁工艺的控制Bracketingandworstcaserating括号法和最差情况分类法Determinationoftheamountofresidue残留量的检测Cleaningvalidationprotocol清洁验证方案AcceptanceCriteria(Chapter4)可接受标准（第4章）Theacceptancecriteriapreferablyshouldbebasedontheacceptabledailyexposure(ADE)calculationswheneverthisdataisavailable.Alternatively,occupationalexposurelimits(OEL)arerecommendedasacceptancecriteria.Thedocumentthenpresentsexamplesforthecalculationofacceptancecriteria.BasedupontheADEthemaximumallowablecarryover(MACO)iscalculatedbywayofexample.如果可以得到可接受日暴露（ADE）值，则可接受标准应优先采用ADE进行计算。另外，也推荐采用职业暴露限度（OEL）值作为可接受标准。文件举出了可接受标准的计算实例，例中采了ADE计算允许最大残留（MACO）值。As(further)examplesforacceptancecriteriaandtheircalculationthedocumentlists:文件中给出了可接受标准及其计算样例：Acceptancecriteriausinghealth-baseddata(ADE,MACO)采用健康的数据（ADE、MACO）计算可接受标准Acceptancecriteriabasedonthetherapeuticdailydose(TDD)采用日治疗剂量（TDD）计算可接受标准AcceptancecriteriabasedonLD50采用半数致死量计算可接受标准Acceptancecriteriabasedonagenerallimit(ppmvalue)采用通用限度（ppm值）计算可接受标准Thesamechapteraddressesthecalculationofacceptancecriteriabymeansofswabandrinsetests.Thechaptercloseswitharationalefortheuseofdifferentlimitsinpharmaceuticalandchemicalproductionofactivepharmaceuticalingredients.Acompetentchemistshouldaccompanythefindingofarationale.Itismentionedexpresslythatintheproductionofactivepharmaceuticalingredientstheriskofcarry-overofcontaminantsbecauseofmanufacturingprocesses(suchasextractionorfiltration...)canbemuchlowerthaninthemanufactureofmedicinalproducts.Basedonthisconsiderationlimitscouldbesethigher.Naturally,theseconsiderationsdonotapplytophysicalmanufacturingprocesses(drying,milling).Inthiscase,themethodsappliedshouldbethosenormallyusedinpharmaceuticalproduction.Annex1containsfiveexamplesofMACOcalculationsaccordingtotheacceptancecriteriamentionedabove.在同一章中，还说明了采用擦拭和淋洗取样方式如何计算可接受标准。该章结尾阐述了在原料药生产中，采用与药品生产所不同的限度的合理性。需要有一名具备资质的化学家审核限度的合理性。文件中提到，在原料药生产中，由于生产工艺的特点（例如萃取或过滤），污染物被带入下一产品的风险比起制剂生产过程来，要低的多。基于该考虑，可以将限度设定在较高数值。当然，这些考虑并不适用于物理生产过程（干燥、磨粉），这些步骤中应使用制剂生产中的常规方法。附录1包括了5个根据上述可接受标准计算MACO的实例。LevelsofCleaning(chapter5)清洁水平（第5章）Dependingonthestepofmanufactureand/ortheuseofmulti-purposeequipmentthecleaningintensityvaries.Thedocumentrecommendsthatatleastthreelevelsofcleaning(level0-2)areimplementedaccordingtothedifficultyofcleaning.Dependingontheleveldifferentactivitiesarerequiredasconcernsvisualinspection,analyticalverificationandcleaningvalidation.Anexamplepresentsdifferentproductchangeoverscenarios.Inthatcasethenumberofcleaningvalidationactivitiesisdefinedwithatleastthreeconsecutiveruns.Incasesinwhichittakessometimetofinalizethecleaningvalidationcleaningverificationhastobeperformedinthemeantime.Inthecourseofcleaningvalidationthedirtyholdtimeshouldalsobedetermined.根据生产步骤和/或设备是否为多用途情况，清洁的程度会有很大差异。文中推荐根据清洁的难度，至少将清洁分为3级（0-2）。在不同水平，要求实施不同的操作，如目视检查、检测验收和清洁验证。文中给出一个更换产品的例子。在这种情况下，清洁验证活动的次数被界定为至少3个连续轮次。如果需要较长时间来对清洁验证做出结论，则在同时要进行清洁验收。在清洁验证中，还要确定未清洁前状态保持时长。Thewholeprocessisdividedinto:整个过程分为Cleaningprocessdesign(understandingthecleaningprocessresiduesandestablishingastrategyforthecleaningprocesscontrol;清洁工艺设计（对工艺残留清洁的了解，建立清洁工艺控制的策略）Cleaningprocessqualification(demonstratesthatthecleaningprocedureworksasexpected.Thisincludesqualificationofspecificequipment,cleaningoperationalparameters,trainingofoperators,identificationofcriticalcleaninglocations);清洁工艺确认（证明清洁方法能达到预期目标。这包括对特殊设备确认