FDA發(fā)布咀嚼片關(guān)鍵質(zhì)量屬性指導(dǎo)原則

**FDA發(fā)布咀嚼片關(guān)鍵質(zhì)量屬性指導(dǎo)原則（中英文對照）INTRODUCTIONI.引言ThisguidanceprovidesmanufacturersofchewabletabletsforhumanusewiththeCenterforDrugEvaluationandResearch’s(CDER)currentthinkingonthecriticalqualityattributesthatshouldbeassessedduringthedevelopmentofthesedrugproducts.2Thisguidancealsoprovidesrecommendationsaboutsubmittingdevelopmental,manufacturing,andlabelinginformationforchewabletabletsthatmustbeapprovedbyCDERbeforetheycanbedistributed.Therecommendationsinthisguidanceapplymainlytonewdrugapplications(NDAs),abbreviatednewdrugapplications(ANDAs),3andcertainchemistry,manufacturing,andcontrols(CMC)supplementstotheseapplications.4someoftherecommendationsaboutthesubmissionofdevelopmentalinformationmayalsoapplytoinvestigationalnewdrugapplications(INDs).Therecommendationsaboutassessingcriticalqualityattributesapplytoallchewabletabletsforhumanuse,includingnon-applicationproducts.謝謝閱讀本指南向生產(chǎn)者提供了藥品審評研究中心（CDER）對人用咀嚼片在研發(fā)過程中應(yīng)評估的關(guān)鍵質(zhì)量屬性的當(dāng)前想法2。該指南也提供了必須向CDER提交并被其批準(zhǔn)的咀嚼片的研發(fā)、生產(chǎn)及說明書信息的建議。該指南的這些建議主要針精品文檔放心下載**對新藥申請（NDAs）、仿制藥申請（ANDAs）3和一些化學(xué)、生產(chǎn)和質(zhì)控（CMC）感謝閱讀補(bǔ)充申請4。某些建議同樣適合于研究性新藥申請（即新藥臨床申請，INDs）。感謝閱讀關(guān)于評估關(guān)鍵質(zhì)量屬性的建議適用于所有人用咀嚼片，包括非申請產(chǎn)品。精品文檔放心下載Ingeneral,FDA’sguidancedocumentsdonotestablishlegallyenforceableresponsibilities.Instead,guidancesdescribetheAgency’scurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutoryrequirementsarecited.TheuseofthewordshouldinAgencyguidancesmeansthatsomethingissuggestedorrecommended,butnotrequired.感謝閱讀通常，F(xiàn)DA的指導(dǎo)文件不具有法律強(qiáng)制性，指南中描述的主題僅代表FDA機(jī)構(gòu)目前的看法，只作為建議，除非是引用具體的法規(guī)或條例要求。建議或推薦使用該指導(dǎo)原則，但不是必須的。感謝閱讀BACKGROUNDII.背景Chewabletabletsareanimmediaterelease(IR)oraldosageformintendedtobechewedandthenswallowedbythepatientratherthanswallowedwhole.Theyshouldbedesignedtohaveapleasanttasteandbeeasilychewedandswallowed.Chewabletabletsshouldbesafeandeasytouseinadiversepatientpopulation,pediatric,adult,orelderlypatients,whoareunableorunwillingtoswallowintacttabletsduetothesizeofthetabletordifficultywithswallowing.Theavailabilityofsafe,easy-to-usedosageformsisimportantinclinicalpractice.Chewable感謝閱讀**tabletsareavailableformanyover-the-counter(OTC)andprescriptiondrugproducts.精品文檔放心下載咀嚼片是患者經(jīng)咀嚼后立即釋放的口服劑型，而不是整個吞咽。其應(yīng)被設(shè)計為可口的味道且易于咀嚼和吞咽。咀嚼片應(yīng)是安全的，易于那些因片子大小或吞咽困難導(dǎo)致不能或不愿吞服的特殊人群、兒童、成年、或老年患者服用。能獲得安全的、易于服用的劑型在臨床實(shí)踐中非常重要。在許多OTC和處方藥中均有咀嚼片。精品文檔放心下載TheUnitedStatesPharmacopeia(USP)recognizesanddifferentiatesbetweentwotypesofchewabletablets:(1)thosethatmaybechewedforeaseofadministration,and(2)thosethatmustbechewedorcrushedbeforeswallowingtoavoidchokingand/ortoensurethereleaseoftheactiveingredient.5Theconceptsinthisguidanceareapplicabletobothtypesofchewabletablets.精品文檔放心下載USP藥典中識別和區(qū)分兩種類型的咀嚼片：（1）可以咀嚼以方便服用的咀嚼片；（2）必須咀嚼或壓碎以避免吞咽窒息和/或確保活性成分充分釋放的咀嚼片5。本指南中的概念適用于這兩種類型的咀嚼片。謝謝閱讀Adverseeventsforchewabletabletscanincludegastrointestinal(GI)obstructionresultingfrompatientsswallowingwholeorincompletelychewedtablets,aswellastoothdamageanddenturebreakageresultingfromexcessivetablethardness.6Arelatedpotentialadverseevent謝謝閱讀thatsponsorsshouldalsoconsiderisesophagealirritationfromchewabletablets.Areviewofnumerousapproveddrugproduct感謝閱讀**applicationsforchewabletabletsrevealedthatincertaincasescriticalqualityattributessuchashardness,disintegration,anddissolutionwerenotgivenasmuchconsiderationasmayhavebeenwarranted.Thiswasevidencedbyinstancesofincompletemonitoringofallrelevantcriticalqualityattributesortheuseofwidelyrangingvaluesthatwerenotjustifiedasacceptancecriteria.Inaddition,awidevariationinanalyticalprocedureshasbeenreported.7,8,9謝謝閱讀咀嚼片的不良反應(yīng)包括患者整片吞咽或不完全咀嚼導(dǎo)致的胃腸道（GI）阻塞，感謝閱讀以及片劑過硬導(dǎo)致牙齒損傷和假牙破損6。也應(yīng)考慮咀嚼片引起的食道刺激這一潛在不良事件。從過去批準(zhǔn)的很多咀嚼片來看，許多產(chǎn)品對硬度、崩解時限、溶出度等關(guān)鍵質(zhì)量屬性的考察仍不充分，例如，對所有相關(guān)的關(guān)鍵質(zhì)量屬性監(jiān)管不完全，或質(zhì)量指標(biāo)范圍很寬泛但未證明其在可接受的標(biāo)準(zhǔn)之內(nèi)。此外，據(jù)報道，分析方法也存在很大差異7,8,9。感謝閱讀Thisguidancedescribesthecriticalqualityattributesthatshouldbeconsideredwhendevelopingchewabletabletsandrecommendsthattheselectedacceptancecriteriabeappropriateandmeaningfulindicatorsofproductperformancethroughouttheshelflifeoftheproduct.精品文檔放心下載本指南建議了開發(fā)咀嚼片時應(yīng)考慮的關(guān)鍵質(zhì)量屬性、可選擇的合適的可接受標(biāo)準(zhǔn)、產(chǎn)品有效期內(nèi)的有意義的產(chǎn)品性能指標(biāo)。精品文檔放心下載III.DISCUSSIONIII.討論**Avarietyofphysicalcharacteristicsshouldbeconsideredinthemanufacturingprocessforchewabletablets.Anidealchewabletabletshouldbe:精品文檔放心下載?Easytochew?Palatable(tastemaskedorofacceptabletaste)感謝閱讀?Ofappropriatesizeandshape10精品文檔放心下載?Abletodisintegratereadilytominimizeaspirationandfacilitatedissolution.感謝閱讀在咀嚼片劑生產(chǎn)工藝中，應(yīng)考慮各種物理特性。理想的咀嚼片應(yīng)為：感謝閱讀?易于咀嚼?味道可口（掩味或可接受的味道）?尺寸及形狀適中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謝謝閱讀**goalshouldbetodevelopthepropercombinationoftheseattributestoensuretheperformanceofthechewabletabletforitsintendeduse.謝謝閱讀咀嚼片的關(guān)鍵質(zhì)量屬性包括硬度、崩解時限、溶出度以及其他影響生物利用度和生物等效性的因素。另外，應(yīng)重視片劑的形狀、厚度、脆碎度和味道，這些會影響患者服用咀嚼片的能力和意愿（即：患者因味道不好可能整個吞咽，而不是咀嚼）。充分控制咀嚼片的性能，不能只考慮單一的質(zhì)量屬性，而應(yīng)考慮質(zhì)量屬性的合適組合，從而確保咀嚼片達(dá)到預(yù)期的用途。謝謝閱讀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).精品文檔放心下載**咀嚼片的硬度要求既能承受生產(chǎn)、包裝、運(yùn)輸、分發(fā)過程中的外力沖擊，又要求便于目標(biāo)患者人群的咀嚼。硬度通常是測定在特定平面上使藥片破裂所需力的大小。硬度可以用多種單位表示。向FDA提交申請時，在報告結(jié)果和說明中，應(yīng)使用相同的度量單位。包括：千克磅(kp),千克力(kgf),牛頓(N)和Strong-Cobb單位(scu)。換算關(guān)系為1kp=1kgf=9.8N=1.4scu。有公共標(biāo)準(zhǔn)（據(jù)參考文獻(xiàn)是USP藥典標(biāo)準(zhǔn)）來確保片劑硬度測量的一致性（片劑脆碎度11），片劑硬度可用于確定咀嚼難度指數(shù)（見附錄Ⅰ）。謝謝閱讀DisintegrationB．崩解時限Thetimerequiredforatablettobreakupintosmallparticlesis感謝閱讀itsdisintegrationtime.Forchewabletablets,disintegrationtimeshouldbeshortenoughtopreventGIobstructionintheeventatabletisnotcompletelychewedbythepatient.Usually,thepresenceofthecorrecttypeandamountofadisintegrantfacilitatesrapiddisintegrationofthetablet.12Invitrodisintegrationtestingshouldbeconductedusingintacttabletsinsuitablemediumusingestablisheddisintegrationequipment(suchasUSPDisintegrationApparatus)andmethods.13精品文檔放心下載崩解時限是指藥片從整片破碎成細(xì)小微粒的時間。對于咀嚼片，崩解時間應(yīng)足夠短，以免患者沒有充分咀嚼發(fā)生胃腸道阻塞。通常，選用正確類型及使用量的崩解劑有利于片劑迅速崩解12。體外崩解試驗(yàn)應(yīng)使用完整片劑、在適當(dāng)?shù)慕橘|(zhì)、用已確立的崩解裝置（例如USP崩解儀）和方法進(jìn)行13。感謝閱讀Dissolution**C.溶出度Drugabsorptionfromchewabletabletsdependsonthereleaseofthedrugsubstance(s)fromtheintactorthechewedtablets;therefore,invitrodissolutiontestingofchewabletabletsshouldfollowtheprinciplesofdissolutiontestingofconventionalIRtablets.14Thatis,theactive謝謝閱讀pharmaceuticalingredient(s)ofthechewabletabletsshouldadequatelydissolveoutofthetabletwithorwithoutchewing.感謝閱讀咀嚼片的吸收取決于整片或咀嚼后的藥物釋放。因此，咀嚼片的體外溶出試驗(yàn)應(yīng)當(dāng)遵循常規(guī)速釋片的溶出試驗(yàn)原則14，即：咀嚼片中的活性成分在咀嚼或未咀嚼情況下都應(yīng)充分溶出。謝謝閱讀Forproductcharacterizationduringdevelopmentinvitrodissolutiontestingshouldbeconductedonintacttabletsinatleastfourmedia,suchaswater,aqueousmediaatpH1.2,bufferpH4.5,andbufferpH6.8,withestablisheddissolutionmethodsusingequipmentsuchasUSPApparatus1(basket),USPApparatus2(paddle),orUSPApparatus3(reciprocatingcylinder).15感謝閱讀開發(fā)過程中的體外溶出試驗(yàn)應(yīng)當(dāng)使用完整片劑在至少4種介質(zhì)中進(jìn)行，例如水、pH1.2、pH4.5、pH6.8緩沖液；采用USP藥典公認(rèn)的溶出方法試驗(yàn)，例如方法1（轉(zhuǎn)籃法）、方法2（槳法）或方法3（往復(fù)筒法）15。精品文檔放心下載D.PerformanceinSimulatedPhysiologicalMedia謝謝閱讀D.生理介質(zhì)模擬實(shí)驗(yàn)**Chewabletabletsshouldalsobeevaluatedusingdissolutionmediasuchassimulatedfastedandfedstategastricandintestinalfluidswithenzymes(biorelevantdissolutionmedia).Hardnessshouldalsobetestedafterbrief(30-120s)exposurestosmallquantities(1-2mL)ofhumanorsimulatedsaliva.Suchstudiesmayprovideabetterunderstandingofinvivoperformanceofthechewabletablets16.Invitrotestingin感謝閱讀physiologicalmedia,consistentwiththetargetedpatientpopulationcharacteristicsmaysupportfurthercharacterizationofthedrugproductanditscriticalqualityattributes.謝謝閱讀咀嚼片劑應(yīng)當(dāng)使用模擬空腹和餐后胃腸生理環(huán)境的溶出介質(zhì)（生物相關(guān)介質(zhì)）進(jìn)行評價。硬度測試，應(yīng)短時（30-120S）暴露于少量（1-2ml）人類或模擬唾液后進(jìn)行。這些研究可以更好的了解咀嚼片的體內(nèi)性能。16在體外生理介質(zhì)模擬感謝閱讀實(shí)驗(yàn)中，采用與目標(biāo)患者人群一致的生理介質(zhì)可能會對該藥品進(jìn)一步的鑒定和關(guān)感謝閱讀鍵質(zhì)量屬性提供數(shù)據(jù)支持。E.BiowaiverandPostapprovalConsiderations謝謝閱讀E.生物等效性豁免及上市后的注意事項(xiàng)ThesolubilityandpermeabilitycharacteristicsofthedrugsubstancemaybeusedtodeterminewherethedrugfitswithintheBiopharmaceuticsClassificationSystem(BCS).DependingontheBCSclassificationofthedrugsubstance,proposalsforwaiverofbioequivalence(BE)studiesmaybeconsideredforchewabletablets17.Changesinthechemistry,manufacturingandcontrolsafterapprovalof謝謝閱讀**thechewabletabletsshouldbemadeinconformancewiththeprinciplesoutlinedintheScale-upandPost-ApprovalChangesImmediateRelease(SUPACIR)guidancedocument18.感謝閱讀藥物的溶解度和滲透性可以用來確定藥物的生物藥劑學(xué)分類系統(tǒng)（BCS）。根據(jù)感謝閱讀藥物的BCS分類，咀嚼片可提出生物等效性（BE）研究豁免的申請17。咀嚼片謝謝閱讀上市后發(fā)生化學(xué)、生產(chǎn)及質(zhì)控工藝變更時，應(yīng)遵從《速釋口服固體制劑：放大生精品文檔放心下載產(chǎn)和批準(zhǔn)后變更》（SUPACIR）指南18。IV.RECOMMENDATIONSIV.建議Thefollowinggeneralandspecificrecommendationsshouldbeconsideredduringthedevelopmentphaseofachewabletablet.精品文檔放心下載下面的一般和具體建議，應(yīng)在咀嚼片的開發(fā)階段考慮。Potentialproductdesignanddevelopmentconsiderationsshould精品文檔放心下載include:disintegrant(s)tofacilitatereleaseoftheactiveingredient,andsweetenersandflavoringagentsfortaste-masking19.Thepossibilityof精品文檔放心下載theinteractionofexcipientswitheachotherand/orthedrugsubstance(s),andtheirlikelyimpactonthemanufacturingprocess,shouldbeexplored.謝謝閱讀產(chǎn)品設(shè)計和開發(fā)階段應(yīng)考慮的方面包括：促進(jìn)活性成分釋放的崩解劑，增甜劑和用于掩味的調(diào)味劑19。應(yīng)研究可能出現(xiàn)的輔料之間的相互作用和/或輔料與藥物之間的相互作用，及這些相互作用可能對生產(chǎn)工藝的影響。精品文檔放心下載Thefollowinginformationshouldbecollectedeitherduringthe謝謝閱讀conductofpivotalclinicalstudiesandreportedinthesubsequentNDA:謝謝閱讀**1.Werethechewabletabletsswallowedintact(i.e.,withoutbreaking)orafterbeingthoroughlychewed?感謝閱讀2.Ifswallowedintact,doestheshapeandsizeofchewabletabletposeachokingorbowelobstructionrisk?20精品文檔放心下載3.Ifwaterwasusedtoaidswallowing,whatwasthevolume?精品文檔放心下載4.Whatwasthesubject’ssensoryexperience(e.g.,taste,mouthfeel,andaftertaste)?21,22精品文檔放心下載下面的信息應(yīng)該在臨床研究期間收集并在隨后的NDA申請資料中報告：感謝閱讀1.該咀嚼片可以完整吞服（不破壞）還是應(yīng)該徹底咀嚼后吞服？精品文檔放心下載2.如果完整吞服，該咀嚼片的形狀和大小是否有造成窒息或腸梗阻的風(fēng)險？謝謝閱讀203.如果患者可以用水幫助吞咽，水的用量是多少？4.患者用藥的感官體驗(yàn)如何（例如，味覺、口感、余味）？21,22感謝閱讀ForANDAapplications,generalinformationsuchassubject’ssensoryexperience(acceptabilityoftaste,mouthfeel,andaftertaste)andeaseofswallowing–incaseoftabletsswallowedintact–canbecollectedduringtheconductofbioequivalencestudiesandreportedinthesubsequentANDAsubmissions.精品文檔放心下載對于ANDA申請，一般要求，在生物等效性研究期間收集患者的用藥體驗(yàn)（味道可接受性、口感和余味）和在片劑整個吞服時的吞咽改善，在后續(xù)ANDA申報資料中報告。感謝閱讀**ThepotentialforbuccalabsorptionofthedrugsubstanceshouldbeevaluatedanddescribedintheNDA.Theimportanceofanybuccalabsorptionmaydependonthesolubilityandpermeabilitycharacteristicsofthedrugsubstance,itsstabilityinsaliva(overapHrange6.0to7.5),andwhetheritundergoesextensivefirst-passmetabolism.感謝閱讀對于藥物潛在的口腔吸收應(yīng)評估并在NDA申請中說明。藥物口腔吸收的重要性主要取決于藥物的溶解性和滲透性，藥物在唾液中的穩(wěn)定性（pH6.0~7.5），以及藥物是否有首過代謝。感謝閱讀Stabilityinthebuccalenvironmentcanusuallybeassessedinvitro.Forexample,studiesattheapplicablepHrangeoverashortperiodoftime(e.g.,<5min)showingminimaldrugsubstancereleaseorlackofdegradationofthedrugsubstancemaybeadequatetodemonstrateshort-termstabilityinthebuccalenvironment.精品文檔放心下載通常，可以采用體外研究評估藥物在口腔環(huán)境中的穩(wěn)定性。例如，在合適的pH值范圍內(nèi)，研究短時間內(nèi)（例如，<5分鐘）藥物的最小釋放或降解可得出口腔環(huán)境的短期穩(wěn)定性。感謝閱讀A.CriticalQualityAttributes感謝閱讀A．關(guān)鍵質(zhì)量屬性Thehardness,dissolution,anddisintegrationofthechewabletabletshouldbeestablishedearlyindevelopment.FDArecommendsthatmultipleattributesbestudiedtoaddresstheperformanceofthe感謝閱讀**chewabletabletandincorporatedintheproductspecification.Relianceononlyoneattributeshouldbeavoided.精品文檔放心下載咀嚼片研發(fā)早期應(yīng)該研究硬度、溶解度、崩解時限。FDA建議研究多個屬性，來了解咀嚼片的質(zhì)量，并在質(zhì)量標(biāo)準(zhǔn)中制訂。應(yīng)避免只依賴一個屬性。精品文檔放心下載FordrugproductsthatrequirefilingofanapplicationwiththeAgency,thedevelopmentinformationshouldbeprovidedinsection謝謝閱讀3.2.P.2(PharmaceuticalDevelopment)ofacommontechnicaldocument(CTD)formattedsubmission.Theinformationontablethardnessandchewingdifficultyindex(seeAppendixI)shouldbeprovidedinsection3.2.P.3.4(ControlofCriticalStepsandIntermediates)orsection3.2.P.5.1(Specification)ofaCTDformattedapplication23.謝謝閱讀對于需要在FDA申請的藥品，應(yīng)在CTD文件3.2.P.2（藥品開發(fā)）中提供研發(fā)信息。在CTD文件3.2.P.3.4（關(guān)鍵步驟和中間體的控制）或3.2.P.5.1（質(zhì)量標(biāo)準(zhǔn)）中提供片劑硬度和咀嚼難度指數(shù)的信息（見附錄Ⅰ）23。感謝閱讀TheAgencyencouragesmanufacturersofcurrentlyapprovedchewabletabletsandnonapplicationchewabletabletstoreevaluatethecriticalqualityattributesandensureappropriatespecificationsareinplace.ShouldtheAgencyhavereasontodeterminethatamarketedchewabletabletposesaparticularrisktopublichealthbecauseitisdifficulttochew(e.g.,causesdamagetotheteethordentalprosthetics,orGIobstruction),appropriateactionwillbetakentoalleviatetherisktopublichealth.感謝閱讀**FDA鼓勵目前已批準(zhǔn)的咀嚼片和非申請的咀嚼片的生產(chǎn)商重新評價其關(guān)鍵精品文檔放心下載質(zhì)量屬性，并確保適當(dāng)?shù)馁|(zhì)量標(biāo)準(zhǔn)。FDA須確定市售咀嚼片是否因咀嚼困難帶精品文檔放心下載來公共健康風(fēng)險（例如，對牙齒或假牙的損傷，或胃腸阻塞），并采取適當(dāng)?shù)拇敫兄x閱讀施來降低公共健康風(fēng)險。Hardness硬度oBasedonthereviewofapplicationsandliteraturesources,theAgencyrecommendsthathardnessforchewabletabletsbekeptlow(e.g.,<12kp).謝謝閱讀基于申請資料和文獻(xiàn)資料綜述，F(xiàn)DA建議，咀嚼片硬度應(yīng)保持較低（例如，<12KP）。感謝閱讀oAhigherhardnessvalue(e.g.,>12kp)maybeconsideredifbrief(approximately30seconds)exposuretosalivabeforechewingresultsinsignificantdisintegrationand/orreductioninhardnessofthesetablets.Thestudymaybeperformedinvivousinghumanvolunteersorinvitrofor30secondsexposure,using1mLofsimulatedsalivaryfluid(seeAppendixII).精品文檔放心下載如果咀嚼片在短時（約30秒）暴露于唾液中崩解和/或硬度顯著降低，可以考慮較高的硬度值（例如，>12KP）。這項(xiàng)研究可以利用人類志愿者體內(nèi)進(jìn)行或在體外30秒暴露于1ml模擬唾液來進(jìn)行（見附錄II）。感謝閱讀oInallothercases,thesponsorshouldprovidejustificationfortheproposedhardness,includingstudiesdemonstratingthatthetabletcan謝謝閱讀**besafelychewedbytheintendedpopulationwithoutdamagetoteeth,dentures,orotheradverseeffectsrelatedtochewingthesetablets.精品文檔放心下載在其他情況下，申請者應(yīng)對所提出的硬度提供理由，包括研究，來表明該片劑可以被預(yù)期人群安全地咀嚼，而對牙齒、假牙無損害，或無其他與咀嚼相關(guān)的不良影響。精品文檔放心下載oInadditiontoevaluatingthehardnessofchewabletablets,thesponsorshouldconsiderevaluatingthetabletsforthechewingdifficultyindex(seeAppendixI)bothbeforeandafterexposuretohumansaliva.精品文檔放心下載除了評估咀嚼片的硬度外，申請者應(yīng)考慮評估咀嚼片暴露于人的唾液前后的咀嚼難度指數(shù)（見附錄Ⅰ）。精品文檔放心下載DisintegrationandDissolution感謝閱讀崩解時限和溶出度oChewabletabletsshouldtypicallymeetthesamedisintegrationanddissolutionspecificationsasIRtablets.精品文檔放心下載咀嚼片的崩解時限和溶解度通常應(yīng)符合相同的速釋片的標(biāo)準(zhǔn)要求。感謝閱讀oInvitrodissolutiontestingshouldbeconductedonintactchewabletabletssinceitispossiblethatsomepatientsmightswallowthetabletswithoutchewing.Crushingofthechewabletabletspriortoconductinginvitrodissolutiontestinggenerallyisnotrecommendedsincethereisnoreportedvalidatedmethodforthisprocesstodate.Furthermore,thisapproachwouldbeunlikelytoresultinexperimentalconditionssimulatingarangeofchewingpatternsthatmightbeobservedin精品文檔放心下載**differentpatientpopulations.However,additionaldissolutionassessmentsmaybeneededonacase-by-casebasis24basedonproduct-specificinformation.感謝閱讀體外溶出度試驗(yàn)應(yīng)該采用完整的咀嚼片進(jìn)行，因?yàn)橐恍┗颊呖赡軙唤?jīng)咀嚼而整個吞服。原來的體外溶出試驗(yàn)通常將咀嚼片破碎后進(jìn)行，不推薦該方式，因?yàn)槠扑檫^程未經(jīng)過驗(yàn)證。此外，這種方法無法模擬多種試驗(yàn)條件，不能考察不同的患者群體中的咀嚼模式。然而，可能需要基于特定產(chǎn)品的信息，根據(jù)具體情況逐一進(jìn)行溶出評估24。感謝閱讀oItispossibletouseothermethods,aslongastheproposedmethodsaredemonstratedtobeequivalentorsuperiortotheexistingapproaches.感謝閱讀可以使用其他方法，只要可以證明該方法等同或優(yōu)于現(xiàn)有的方法。精品文檔放心下載OtherCriticalQualityAttributes謝謝閱讀其他關(guān)鍵質(zhì)量屬性oOthercriticalqualityattributesapplicabletoaparticularchewabletabletshouldbeevaluatedusingAgencyrecommendedmethodsorusingmethodsthataredemonstratedtobeequivalentorsuperiortotheexistingapproaches.精品文檔放心下載咀嚼片的其他關(guān)鍵質(zhì)量屬性應(yīng)使用FDA建議的方法，或使用被證明是等同或優(yōu)于現(xiàn)有方法的方法進(jìn)行評價。精品文檔放心下載B.NomenclatureandLabeling謝謝閱讀命名和標(biāo)識**Aspreviouslystated,theUSPrecognizesanddifferentiatesbetweentwotypesofchewabletablets:(1)thosethatmaybechewedforeaseofadministration,and(2)thosethatmustbechewedand/orcr