WHO第992号技术报告附录4保存时间研究通用指南

WHO第992号技术报告附录4：保存时间研究通用指南，2015Annex4Generalguidanceonhold?timestudies1.Introductionandbackground概述和背景2.Glossary术语3.Scope范围4.Aspectstobeconsidered要考虑的方面Reference参考文献1.Introductionandbackground概述和背景Manufacturersshouldensurethattheproductsthattheymanufacturearesafe,effectiveandofthequalityrequiredfortheirintendeduse.Systemsshouldbeinplacetoensurethatpharmaceuticalproductsareproducedaccordingtovalidatedprocessesandtodefinedprocedures.Manufacturingprocessesshouldbeshowntobecapableofconsistentlymanufacturingpharmaceuticalproductsthatareoftherequiredqualityandthatcomplywiththeirspecifications.生产商必须保证其生产的产品安全有效，具有其既定用途所需要的质量。应有一个系统来保证药品是根据经过验证的工艺和既定的程序生产的。生产工艺应具备持续生产出具有所需的质量，并符合其质量标准的药品的能力。Goodmanufacturingpractices(GMP)requirethatarrangementsshouldbemadetoensurethatthedispensedrawmaterialsandpackagingmaterials,intermediateproducts,bulkandfinishedproductsarestoredunderappropriateconditions.Storagearrangementsshouldnothavedeleteriouseffectsonthesubsequentprocessing,stability,safety,efficiencyorqualityofstartingmaterials,intermediateproductsandbulkproductspriortofinalpacking.Maximumacceptableholdingperiodsshouldthereforebeestablishedtoensurethatintermediatesandbulkproductcanbeheld,pendingthenextprocessingstep,withoutproducingresultsoutsidetheacceptancecriteriaforthequalityofthematerial.Normally,intermediateandbulkproductsshouldnotbestoredbeyondtheestablishedholdtime.优良生产规范（GMP）要求必须做出适当的安排来保证分好的原料、包材、中间产品、散装产品和包装后的成品存贮在适当的条件下。存贮条件不应对随后的工艺、稳定性、安全性、有效性或起始原料、中间体产品和包装前的散装产品的质量产生不良影响。因此应设定最长的可接受保存时间来保证中间体和散装产品可以在下一工序前的保存不会使得原料质量超出可接受标准。通常，中间体和散装产品存贮时间不应超过设定的保存时间。Thechoiceofmaximumholdingperiodshouldbesupportedbyrelevantdata.Studiesmayextendbeyondthechosenmaximumbutitisnotnecessarytoextendtestingtodeterminetheextremelimitsatwhichfailureoccurs.最长保存时间的选择应有相应的数据来支持。研究可以延长超过所选的最长时间，但没有必要将检测延长直到检验结果超出标准。2.Glossary术语Someimportanttermsusedintheseguidelinesaredefinedbelow.Theymayhavedifferentmeaningsinothercontexts.本指南中所用的一些重要术语定义如下。他们可能在其它语境中有不同含义。Bulkproduct.Anypharmaceuticalproductthathascompletedallprocessingstagesupto,butnotincluding,finalpackaging.散装产品：完成了所有工序直到，但还没有完成最终包装的制剂成品。Intermediate.Partlyprocessedproductthatmustundergofurthermanufacturingstepsbeforeitbecomesabulkproduct.中间体：完成部分工序，必须要经过进一步生产工序才能成为散装成品的部分加工产品。3.Scope范围Theseguidelinesfocusprimarilyonaspectsthatshouldbeconsideredinthedesignofthehold?timestudiesduringthemanufactureofnon?sterilesoliddosageforms.Manyoftheprinciplesdescribedherealsoapplytootherdosageformssuchasliquids,creamsandointments.Theseguidelinesdonotcoveraspectsforholdtimesincleaningvalidation,orthemanufacturingofactivepharmaceuticalingredients(APIs)orbiological.这些指南主要关注非无菌固体制剂保存时间研究设计中要考虑的问题。其中描述的许多原则也适用于其它剂型，例如液体、乳霜和软膏。这些指南不包括清洁验证或原料药或生物制剂的生产中保留时间的问题。TheseguidelinesareintendedasabasicguideforusebymanufacturersofpharmaceuticalsandbyGMPinspectors.Thisdocumentisnotintendedtoprescribeaprocessforestablishingholdtimes,butreflectsaspectsthatshouldbeconsideredinthedesignofthehold?timestudy.这些指南意在作为一个药品生产商和GMP检查员使用的基本指南。本文件无意描述建立保存时间的流程，而只是反映在保存时间研究设计中所需考虑的问题。Manufacturersshouldgatherscientificandjustifiabledatatodemonstratethatthedispensedrawmaterialsandpackagingmaterials,intermediateandbulkproducts:生产商应收集可以论证的科学数据来证明分装后的原料和包材、中间体和散装产品：-remainofappropriatequalitybeforeprocessingtothenextstage;-在加工至下一工序时保持适当的质量-meettheacceptancecriteria.-符合可接受标准Thefinishedproductshouldmeetthereleasespecifications.制剂成品应符合放行标准。4.Aspectstobeconsidered要考虑的问题Holdtimecanbeconsideredastheestablishedtimeperiodforwhichmaterials(dispensedrawmaterials,intermediatesandbulkdosageformawaitingfinalpackaging)maybeheldunderspecifiedconditionsandwillremainwithinthedefiedspecifications.保存时间可以认为是已建立的某种物料（分装后的原料、中间体和散装待包装的制剂）在指定条件下可以保存并能维持其质量在既定质量标准内的时间长度。Hold?timestudiesestablishthetimelimitsforholdingthematerialsatdifferentstagesofproductiontoensurethatthequalityoftheproductdoesnotproduceresultsoutsidetheacceptancecriteriaduringtheholdtime.Thedesignofthestudyshouldreflecttheholdingtimeateachstage.保存时间研究建立不同生产工序物料保存的时间限度，以保证产品的质量不会在保存时间内超出可接受标准。研究设计应反映各工序的保存时间。Holdtimesshouldnormallybedeterminedpriortomarketingofaproduct.Theriskassessmentofchangesinprocesses,equipment,storageconditions,startingorpackagingmaterialsshouldincludeanassessmentofwhetherfurtherhold?timestudiesshouldbeperformed.Hold?timestudiesmaybeincludedduringdevelopmentonpilot?scalebatchesorduringscale?up,andshouldbeconfirmedduringprocessvalidationofcommercial?scaleprocessing(1).Furtherdatacanalsobecollectedaspartofaninvestigationofadeviationthatoccurredduringmanufacture.保存时间通常应在产品上前确定。工艺、设备、存贮条件、起始物料或包材变更的风险评估应包括是否需要进一步进行保存时间研究的评估。保存时间研究可以包括在研发过程中的中试规模中，也可以是在放大生产过程中，还应该包括在商业规模工艺验证中。也可以从生产过程发生的偏差调查中收集更多信息。Manufacturersmayuseaflowcharttoreviewthemanufacturingprocedureforaproductandthenbreakupthecriticalstagesofthemanufacturingprocessonthebasisofthetimeperiodrequiredfortheparticularstorageandprocessingstages,typicalpausesinthemanufacturingcampaign,andthepotentialimpactofstoragewithreferencetoenvironmentalandstorageconditions.AnexampleofaflowchartisgiveninFigureA4.1.生产商可以使用工艺流程图对生产过