FDA发布咀嚼片关键质量属性指导原则

**FDA发布咀嚼片关键质量属性指导原则（中英文对照）INTRODUCTIONI.引言ThisguidanceprovidesmanufacturersofchewabletabletsforhumanusewiththeCenterforDrugEvaluationandResearch’s(CDER)currentthinkingonthecriticalqualityattributesthatshouldbeassessedduringthedevelopmentofthesedrugproducts.2Thisguidancealsoprovidesrecommendationsaboutsubmittingdevelopmental,manufacturing,andlabelinginformationforchewabletabletsthatmustbeapprovedbyCDERbeforetheycanbedistributed.Therecommendationsinthisguidanceapplymainlytonewdrugapplications(NDAs),abbreviatednewdrugapplications(ANDAs),3andcertainchemistry,manufacturing,andcontrols(CMC)supplementstotheseapplications.4someoftherecommendationsaboutthesubmissionofdevelopmentalinformationmayalsoapplytoinvestigationalnewdrugapplications(INDs).Therecommendationsaboutassessingcriticalqualityattributesapplytoallchewabletabletsforhumanuse,includingnon-applicationproducts.谢谢阅读本指南向生产者提供了药品审评研究中心（CDER）对人用咀嚼片在研发过程中应评估的关键质量属性的当前想法2。该指南也提供了必须向CDER提交并被其批准的咀嚼片的研发、生产及说明书信息的建议。该指南的这些建议主要针精品文档放心下载**对新药申请（NDAs）、仿制药申请（ANDAs）3和一些化学、生产和质控（CMC）感谢阅读补充申请4。某些建议同样适合于研究性新药申请（即新药临床申请，INDs）。感谢阅读关于评估关键质量属性的建议适用于所有人用咀嚼片，包括非申请产品。精品文档放心下载Ingeneral,FDA’sguidancedocumentsdonotestablishlegallyenforceableresponsibilities.Instead,guidancesdescribetheAgency’scurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutoryrequirementsarecited.TheuseofthewordshouldinAgencyguidancesmeansthatsomethingissuggestedorrecommended,butnotrequired.感谢阅读通常，FDA的指导文件不具有法律强制性，指南中描述的主题仅代表FDA机构目前的看法，只作为建议，除非是引用具体的法规或条例要求。建议或推荐使用该指导原则，但不是必须的。感谢阅读BACKGROUNDII.背景Chewabletabletsareanimmediaterelease(IR)oraldosageformintendedtobechewedandthenswallowedbythepatientratherthanswallowedwhole.Theyshouldbedesignedtohaveapleasanttasteandbeeasilychewedandswallowed.Chewabletabletsshouldbesafeandeasytouseinadiversepatientpopulation,pediatric,adult,orelderlypatients,whoareunableorunwillingtoswallowintacttabletsduetothesizeofthetabletordifficultywithswallowing.Theavailabilityofsafe,easy-to-usedosageformsisimportantinclinicalpractice.Chewable感谢阅读**tabletsareavailableformanyover-the-counter(OTC)andprescriptiondrugproducts.精品文档放心下载咀嚼片是患者经咀嚼后立即释放的口服剂型，而不是整个吞咽。其应被设计为可口的味道且易于咀嚼和吞咽。咀嚼片应是安全的，易于那些因片子大小或吞咽困难导致不能或不愿吞服的特殊人群、儿童、成年、或老年患者服用。能获得安全的、易于服用的剂型在临床实践中非常重要。在许多OTC和处方药中均有咀嚼片。精品文档放心下载TheUnitedStatesPharmacopeia(USP)recognizesanddifferentiatesbetweentwotypesofchewabletablets:(1)thosethatmaybechewedforeaseofadministration,and(2)thosethatmustbechewedorcrushedbeforeswallowingtoavoidchokingand/ortoensurethereleaseoftheactiveingredient.5Theconceptsinthisguidanceareapplicabletobothtypesofchewabletablets.精品文档放心下载USP药典中识别和区分两种类型的咀嚼片：（1）可以咀嚼以方便服用的咀嚼片；（2）必须咀嚼或压碎以避免吞咽窒息和/或确保活性成分充分释放的咀嚼片5。本指南中的概念适用于这两种类型的咀嚼片。谢谢阅读Adverseeventsforchewabletabletscanincludegastrointestinal(GI)obstructionresultingfrompatientsswallowingwholeorincompletelychewedtablets,aswellastoothdamageanddenturebreakageresultingfromexcessivetablethardness.6Arelatedpotentialadverseevent谢谢阅读thatsponsorsshouldalsoconsiderisesophagealirritationfromchewabletablets.Areviewofnumerousapproveddrugproduct感谢阅读**applicationsforchewabletabletsrevealedthatincertaincasescriticalqualityattributessuchashardness,disintegration,anddissolutionwerenotgivenasmuchconsiderationasmayhavebeenwarranted.Thiswasevidencedbyinstancesofincompletemonitoringofallrelevantcriticalqualityattributesortheuseofwidelyrangingvaluesthatwerenotjustifiedasacceptancecriteria.Inaddition,awidevariationinanalyticalprocedureshasbeenreported.7,8,9谢谢阅读咀嚼片的不良反应包括患者整片吞咽或不完全咀嚼导致的胃肠道（GI）阻塞，感谢阅读以及片剂过硬导致牙齿损伤和假牙破损6。也应考虑咀嚼片引起的食道刺激这一潜在不良事件。从过去批准的很多咀嚼片来看，许多产品对硬度、崩解时限、溶出度等关键质量属性的考察仍不充分，例如，对所有相关的关键质量属性监管不完全，或质量指标范围很宽泛但未证明其在可接受的标准之内。此外，据报道，分析方法也存在很大差异7,8,9。感谢阅读Thisguidancedescribesthecriticalqualityattributesthatshouldbeconsideredwhendevelopingchewabletabletsandrecommendsthattheselectedacceptancecriteriabeappropriateandmeaningfulindicatorsofproductperformancethroughouttheshelflifeoftheproduct.精品文档放心下载本指南建议了开发咀嚼片时应考虑的关键质量属性、可选择的合适的可接受标准、产品有效期内的有意义的产品性能指标。精品文档放心下载III.DISCUSSIONIII.讨论**Avarietyofphysicalcharacteristicsshouldbeconsideredinthemanufacturingprocessforchewabletablets.Anidealchewabletabletshouldbe:精品文档放心下载•Easytochew•Palatable(tastemaskedorofacceptabletaste)感谢阅读•Ofappropriatesizeandshape10精品文档放心下载•Abletodisintegratereadilytominimizeaspirationandfacilitatedissolution.感谢阅读在咀嚼片剂生产工艺中，应考虑各种物理特性。理想的咀嚼片应为：感谢阅读•易于咀嚼•味道可口（掩味或可接受的味道）•尺寸及形状适中10•易崩解，以方便吞咽和活性成分溶出Criticalqualityattributesforchewabletabletsshouldincludehardness,disintegration,anddissolution,aswellasallfactorsthatmayinfluencedrugbioavailabilityandbioequivalence.Inaddition,carefulattentionshouldbegiventotabletsize,thickness,andfriability,aswellastaste,whichmayimpacttheabilityorwillingnessofapatienttochewthechewabletablet(i.e.,apatientmayswallowwhole,ratherthanchew,abadtastingtablet).Nosinglequalitycharacteristicshouldbeconsideredsufficienttocontroltheperformanceofachewabletablet.Instead,the谢谢阅读**goalshouldbetodevelopthepropercombinationoftheseattributestoensuretheperformanceofthechewabletabletforitsintendeduse.谢谢阅读咀嚼片的关键质量属性包括硬度、崩解时限、溶出度以及其他影响生物利用度和生物等效性的因素。另外，应重视片剂的形状、厚度、脆碎度和味道，这些会影响患者服用咀嚼片的能力和意愿（即：患者因味道不好可能整个吞咽，而不是咀嚼）。充分控制咀嚼片的性能，不能只考虑单一的质量属性，而应考虑质量属性的合适组合，从而确保咀嚼片达到预期的用途。谢谢阅读HardnessA.硬度Thehardnessofchewabletabletsshouldbesuchthattheywithstandtherigorsofmanufacturing,packaging,shipping,anddistribution,aswellasbeeasilychewedbytheintendedpatientpopulation.Hardnessisgenerallymeasuredastheforceneededtobreakthetabletinaspecificplane.Tablethardnessmaybemeasuredandexpressedinavarietyofunits.ApplicationssubmittedtoFDAshouldusethesameunitofmeasureinreportingresultsandspecifications.including:kilopond(kp),kilogram-force(kgf),Newton(N),andStrong-CobbUnits(scu).1kp=1kgf=9.8N=1.4scu.Publicstandardsalsoexisttoensureconsistentmeasurementofthetablethardness(TabletBreakingForce11).Tablethardnessmaybeusedtodeterminethechewingdifficultyindex(seeAppendixI).精品文档放心下载**咀嚼片的硬度要求既能承受生产、包装、运输、分发过程中的外力冲击，又要求便于目标患者人群的咀嚼。硬度通常是测定在特定平面上使药片破裂所需力的大小。硬度可以用多种单位表示。向FDA提交申请时，在报告结果和说明中，应使用相同的度量单位。包括：千克磅(kp),千克力(kgf),牛顿(N)和Strong-Cobb单位(scu)。换算关系为1kp=1kgf=9.8N=1.4scu。有公共标准（据参考文献是USP药典标准）来确保片剂硬度测量的一致性（片剂脆碎度11），片剂硬度可用于确定咀嚼难度指数（见附录Ⅰ）。谢谢阅读DisintegrationB．崩解时限Thetimerequiredforatablettobreakupintosmallparticlesis感谢阅读itsdisintegrationtime.Forchewabletablets,disintegrationtimeshouldbeshortenoughtopreventGIobstructionintheeventatabletisnotcompletelychewedbythepatient.Usually,thepresenceofthecorrecttypeandamountofadisintegrantfacilitatesrapiddisintegrationofthetablet.12Invitrodisintegrationtestingshouldbeconductedusingintacttabletsinsuitablemediumusingestablisheddisintegrationequipment(suchasUSPDisintegrationApparatus)andmethods.13精品文档放心下载崩解时限是指药片从整片破碎成细小微粒的时间。对于咀嚼片，崩解时间应足够短，以免患者没有充分咀嚼发生胃肠道阻塞。通常，选用正确类型及使用量的崩解剂有利于片剂迅速崩解12。体外崩解试验应使用完整片剂、在适当的介质、用已确立的崩解装置（例如USP崩解仪）和方法进行13。感谢阅读Dissolution**C.溶出度Drugabsorptionfromchewabletabletsdependsonthereleaseofthedrugsubstance(s)fromtheintactorthechewedtablets;therefore,invitrodissolutiontestingofchewabletabletsshouldfollowtheprinciplesofdissolutiontestingofconventionalIRtablets.14Thatis,theactive谢谢阅读pharmaceuticalingredient(s)ofthechewabletabletsshouldadequatelydissolveoutofthetabletwithorwithoutchewing.感谢阅读咀嚼片的吸收取决于整片或咀嚼后的药物释放。因此，咀嚼片的体外溶出试验应当遵循常规速释片的溶出试验原则14，即：咀嚼片中的活性成分在咀嚼或未咀嚼情况下都应充分溶出。谢谢阅读Forproductcharacterizationduringdevelopmentinvitrodissolutiontestingshouldbeconductedonintacttabletsinatleastfourmedia,suchaswater,aqueousmediaatpH1.2,bufferpH4.5,andbufferpH6.8,withestablisheddissolutionmethodsusingequipmentsuchasUSPApparatus1(basket),USPApparatus2(paddle),orUSPApparatus3(reciprocatingcylinder).15感谢阅读开发过程中的体外溶出试验应当使用完整片剂在至少4种介质中进行，例如水、pH1.2、pH4.5、pH6.8缓冲液；采用USP药典公认的溶出方法试验，例如方法1（转篮法）、方法2（桨法）或方法3（往复筒法）15。精品文档放心下载D.PerformanceinSimulatedPhysiologicalMedia谢谢阅读D.生理介质模拟实验**Chewabletabletsshouldalsobeevaluatedusingdissolutionmediasuchassimulatedfastedandfedstategastricandintestinalfluidswithenzymes(biorelevantdissolutionmedia).Hardnessshouldalsobetestedafterbrief(30-120s)exposurestosmallquantities(1-2mL)ofhumanorsimulatedsaliva.Suchstudiesmayprovideabetterunderstandingofinvivoperformanceofthechewabletablets16.Invitrotestingin感谢阅读physiologicalmedia,consistentwiththetargetedpatientpopulationcharacteristicsmaysupportfurthercharacterizationofthedrugproductanditscriticalqualityattributes.谢谢阅读咀嚼片剂应当使用模拟空腹和餐后胃肠生理环境的溶出介质（生物相关介质）进行评价。硬度测试，应短时（30-120S）暴露于少量（1-2ml）人类或模拟唾液后进行。这些研究可以更好的了解咀嚼片的体内性能。16在体外生理介质模拟感谢阅读实验中，采用与目标患者人群一致的生理介质可能会对该药品进一步的鉴定和关感谢阅读键质量属性提供数据支持。E.BiowaiverandPostapprovalConsiderations谢谢阅读E.生物等效性豁免及上市后的注意事项ThesolubilityandpermeabilitycharacteristicsofthedrugsubstancemaybeusedtodeterminewherethedrugfitswithintheBiopharmaceuticsClassificationSystem(BCS).DependingontheBCSclassificationofthedrugsubstance,proposalsforwaiverofbioequivalence(BE)studiesmaybeconsideredforchewabletablets17.Changesinthechemistry,manufacturingandcontrolsafterapprovalof谢谢阅读**thechewabletabletsshouldbemadeinconformancewiththeprinciplesoutlinedintheScale-upandPost-ApprovalChangesImmediateRelease(SUPACIR)guidancedocument18.感谢阅读药物的溶解度和渗透性可以用来确定药物的生物药剂学分类系统（BCS）。根据感谢阅读药物的BCS分类，咀嚼片可提出生物等效性（BE）研究豁免的申请17。咀嚼片谢谢阅读上市后发生化学、生产及质控工艺变更时，应遵从《速释口服固体制剂：放大生精品文档放心下载产和批准后变更》（SUPACIR）指南18。IV.RECOMMENDATIONSIV.建议Thefollowinggeneralandspecificrecommendationsshouldbeconsideredduringthedevelopmentphaseofachewabletablet.精品文档放心下载下面的一般和具体建议，应在咀嚼片的开发阶段考虑。Potentialproductdesignanddevelopmentconsiderationsshould精品文档放心下载include:disintegrant(s)tofacilitatereleaseoftheactiveingredient,andsweetenersandflavoringagentsfortaste-masking19.Thepossibilityof精品文档放心下载theinteractionofexcipientswitheachotherand/orthedrugsubstance(s),andtheirlikelyimpactonthemanufacturingprocess,shouldbeexplored.谢谢阅读产品设计和开发阶段应考虑的方面包括：促进活性成分释放的崩解剂，增甜剂和用于掩味的调味剂19。应研究可能出现的辅料之间的相互作用和/或辅料与药物之间的相互作用，及这些相互作用可能对生产工艺的影响。精品文档放心下载Thefollowinginformationshouldbecollectedeitherduringthe谢谢阅读conductofpivotalclinicalstudiesandreportedinthesubsequentNDA:谢谢阅读**1.Werethechewabletabletsswallowedintact(i.e.,withoutbreaking)orafterbeingthoroughlychewed?感谢阅读2.Ifswallowedintact,doestheshapeandsizeofchewabletabletposeachokingorbowelobstructionrisk?20精品文档放心下载3.Ifwaterwasusedtoaidswallowing,whatwasthevolume?精品文档放心下载4.Whatwasthesubject’ssensoryexperience(e.g.,taste,mouthfeel,andaftertaste)?21,22精品文档放心下载下面的信息应该在临床研究期间收集并在随后的NDA申请资料中报告：感谢阅读1.该咀嚼片可以完整吞服（不破坏）还是应该彻底咀嚼后吞服？精品文档放心下载2.如果完整吞服，该咀嚼片的形状和大小是否有造成窒息或肠梗阻的风险？谢谢阅读203.如果患者可以用水帮助吞咽，水的用量是多少？4.患者用药的感官体验如何（例如，味觉、口感、余味）？21,22感谢阅读ForANDAapplications,generalinformationsuchassubject’ssensoryexperience(acceptabilityoftaste,mouthfeel,andaftertaste)andeaseofswallowing–incaseoftabletsswallowedintact–canbecollectedduringtheconductofbioequivalencestudiesandreportedinthesubsequentANDAsubmissions.精品文档放心下载对于ANDA申请，一般要求，在生物等效性研究期间收集患者的用药体验（味道可接受性、口感和余味）和在片剂整个吞服时的吞咽改善，在后续ANDA申报资料中报告。感谢阅读**ThepotentialforbuccalabsorptionofthedrugsubstanceshouldbeevaluatedanddescribedintheNDA.Theimportanceofanybuccalabsorptionmaydependonthesolubilityandpermeabilitycharacteristicsofthedrugsubstance,itsstabilityinsaliva(overapHrange6.0to7.5),andwhetheritundergoesextensivefirst-passmetabolism.感谢阅读对于药物潜在的口腔吸收应评估并在NDA申请中说明。药物口腔吸收的重要性主要取决于药物的溶解性和渗透性，药物在唾液中的稳定性（pH6.0~7.5），以及药物是否有首过代谢。感谢阅读Stabilityinthebuccalenvironmentcanusuallybeassessedinvitro.Forexample,studiesattheapplicablepHrangeoverashortperiodoftime(e.g.,<5min)showingminimaldrugsubstancereleaseorlackofdegradationofthedrugsubstancemaybeadequatetodemonstrateshort-termstabilityinthebuccalenvironment.精品文档放心下载通常，可以采用体外研究评估药物在口腔环境中的稳定性。例如，在合适的pH值范围内，研究短时间内（例如，<5分钟）药物的最小释放或降解可得出口腔环境的短期稳定性。感谢阅读A.CriticalQualityAttributes感谢阅读A．关键质量属性Thehardness,dissolution,anddisintegrationofthechewabletabletshouldbeestablishedearlyindevelopment.FDArecommendsthatmultipleattributesbestudiedtoaddresstheperformanceofthe感谢阅读**chewabletabletandincorporatedintheproductspecification.Relianceononlyoneattributeshouldbeavoided.精品文档放心下载咀嚼片研发早期应该研究硬度、溶解度、崩解时限。FDA建议研究多个属性，来了解咀嚼片的质量，并在质量标准中制订。应避免只依赖一个属性。精品文档放心下载FordrugproductsthatrequirefilingofanapplicationwiththeAgency,thedevelopmentinformationshouldbeprovidedinsection谢谢阅读3.2.P.2(PharmaceuticalDevelopment)ofacommontechnicaldocument(CTD)formattedsubmission.Theinformationontablethardnessandchewingdifficultyindex(seeAppendixI)shouldbeprovidedinsection3.2.P.3.4(ControlofCriticalStepsandIntermediates)orsection3.2.P.5.1(Specification)ofaCTDformattedapplication23.谢谢阅读对于需要在FDA申请的药品，应在CTD文件3.2.P.2（药品开发）中提供研发信息。在CTD文件3.2.P.3.4（关键步骤和中间体的控制）或3.2.P.5.1（质量标准）中提供片剂硬度和咀嚼难度指数的信息（见附录Ⅰ）23。感谢阅读TheAgencyencouragesmanufacturersofcurrentlyapprovedchewabletabletsandnonapplicationchewabletabletstoreevaluatethecriticalqualityattributesandensureappropriatespecificationsareinplace.ShouldtheAgencyhavereasontodeterminethatamarketedchewabletabletposesaparticularrisktopublichealthbecauseitisdifficulttochew(e.g.,causesdamagetotheteethordentalprosthetics,orGIobstruction),appropriateactionwillbetakentoalleviatetherisktopublichealth.感谢阅读**FDA鼓励目前已批准的咀嚼片和非申请的咀嚼片的生产商重新评价其关键精品文档放心下载质量属性，并确保适当的质量标准。FDA须确定市售咀嚼片是否因咀嚼困难带精品文档放心下载来公共健康风险（例如，对牙齿或假牙的损伤，或胃肠阻塞），并采取适当的措感谢阅读施来降低公共健康风险。Hardness硬度oBasedonthereviewofapplicationsandliteraturesources,theAgencyrecommendsthathardnessforchewabletabletsbekeptlow(e.g.,<12kp).谢谢阅读基于申请资料和文献资料综述，FDA建议，咀嚼片硬度应保持较低（例如，<12KP）。感谢阅读oAhigherhardnessvalue(e.g.,>12kp)maybeconsideredifbrief(approximately30seconds)exposuretosalivabeforechewingresultsinsignificantdisintegrationand/orreductioninhardnessofthesetablets.Thestudymaybeperformedinvivousinghumanvolunteersorinvitrofor30secondsexposure,using1mLofsimulatedsalivaryfluid(seeAppendixII).精品文档放心下载如果咀嚼片在短时（约30秒）暴露于唾液中崩解和/或硬度显著降低，可以考虑较高的硬度值（例如，>12KP）。这项研究可以利用人类志愿者体内进行或在体外30秒暴露于1ml模拟唾液来进行（见附录II）。感谢阅读oInallothercases,thesponsorshouldprovidejustificationfortheproposedhardness,includingstudiesdemonstratingthatthetabletcan谢谢阅读**besafelychewedbytheintendedpopulationwithoutdamagetoteeth,dentures,orotheradverseeffectsrelatedtochewingthesetablets.精品文档放心下载在其他情况下，申请者应对所提出的硬度提供理由，包括研究，来表明该片剂可以被预期人群安全地咀嚼，而对牙齿、假牙无损害，或无其他与咀嚼相关的不良影响。精品文档放心下载oInadditiontoevaluatingthehardnessofchewabletablets,thesponsorshouldconsiderevaluatingthetabletsforthechewingdifficultyindex(seeAppendixI)bothbeforeandafterexposuretohumansaliva.精品文档放心下载除了评估咀嚼片的硬度外，申请者应考虑评估咀嚼片暴露于人的唾液前后的咀嚼难度指数（见附录Ⅰ）。精品文档放心下载DisintegrationandDissolution感谢阅读崩解时限和溶出度oChewabletabletsshouldtypicallymeetthesamedisintegrationanddissolutionspecificationsasIRtablets.精品文档放心下载咀嚼片的崩解时限和溶解度通常应符合相同的速释片的标准要求。感谢阅读oInvitrodissolutiontestingshouldbeconductedonintactchewabletabletssinceitispossiblethatsomepatientsmightswallowthetabletswithoutchewing.Crushingofthechewabletabletspriortoconductinginvitrodissolutiontestinggenerallyisnotrecommendedsincethereisnoreportedvalidatedmethodforthisprocesstodate.Furthermore,thisapproachwouldbeunlikelytoresultinexperimentalconditionssimulatingarangeofchewingpatternsthatmightbeobservedin精品文档放心下载**differentpatientpopulations.However,additionaldissolutionassessmentsmaybeneededonacase-by-casebasis24basedonproduct-specificinformation.感谢阅读体外溶出度试验应该采用完整的咀嚼片进行，因为一些患者可能会不经咀嚼而整个吞服。原来的体外溶出试验通常将咀嚼片破碎后进行，不推荐该方式，因为破碎过程未经过验证。此外，这种方法无法模拟多种试验条件，不能考察不同的患者群体中的咀嚼模式。然而，可能需要基于特定产品的信息，根据具体情况逐一进行溶出评估24。感谢阅读oItispossibletouseothermethods,aslongastheproposedmethodsaredemonstratedtobeequivalentorsuperiortotheexistingapproaches.感谢阅读可以使用其他方法，只要可以证明该方法等同或优于现有的方法。精品文档放心下载OtherCriticalQualityAttributes谢谢阅读其他关键质量属性oOthercriticalqualityattributesapplicabletoaparticularchewabletabletshouldbeevaluatedusingAgencyrecommendedmethodsorusingmethodsthataredemonstratedtobeequivalentorsuperiortotheexistingapproaches.精品文档放心下载咀嚼片的其他关键质量属性应使用FDA建议的方法，或使用被证明是等同或优于现有方法的方法进行评价。精品文档放心下载B.NomenclatureandLabeling谢谢阅读命名和标识**Aspreviouslystated,theUSPrecognizesanddifferentiatesbetweentwotypesofchewabletablets:(1)thosethatmaybechewedforeaseofadministration,and(2)thosethatmustbechewedand/orcr