ThisguidancerepresentsthecurrentthinkingoftheFoodandDrugAdministration(FDAorAgency)onthistopic.ItdoesnotcreateanyrightsforanypersonandisnotbindingonFDAorthepublic.Youcanuseanalternativeapproachifitsatisfiestherequirementsoftheapplicablestatutesandregulations.Todiscussanalternativeapproach,contacttheFDAstaffresponsibleforthisguidanceaslistedonthetitlepage.

　　Tabletsandcapsulesarewidelymanufacturedandprescribedandmayprovideanumberofadvantagesoverotherdosageforms,includingeaseofstorage,portability,easeofadministration,andaccuracyindosing.

　　片劑和膠囊劑是被廣泛生產(chǎn)和使用的劑型，相對其它劑型，片劑和膠囊劑具有諸多優(yōu)勢，如存儲方便，易于攜帶，方便服用，劑量精確等。

　　Whilegenericformulationsofthesedrugproductsarerequiredtobebothpharmaceuticallyandtherapeuticallyequivalenttoareferencelisteddrug(RLD),2weareconcernedthatdifferencesinphysicalcharacteristics(e.g.,sizeandshapeofthetabletorcapsule)mayaffectpatientcomplianceandacceptabilityofmedicationregimensorcouldleadtomedicationerrors.Webelievethesepatientsafetyconcernsareimportant,andwearerecommendingthatgenericdrugmanufacturersconsiderphysicalattributeswhentheydevelopqualitytargetproductprofiles(QTPPs)fortheirgenericproductcandidates.

　　我們對仿制藥品的要求是在與對照藥品列表里的藥品（原研藥，下同）保持制劑學和療效學上的一致的同時，還應慮及物理性質(zhì)的差異（如，膠囊和片的形狀和大?。┛赡苡绊懟颊邔o藥方案的順應性和可接受性，或者可導致用藥差錯發(fā)生。我們相信這些對患者的安全考慮是至關(guān)重要的，而且我們推薦仿制藥生產(chǎn)商在候選仿制藥品目標質(zhì)量概況開發(fā)時考慮到這些物理屬性。

　　Therecommendationsinthisguidanceapplytoabbreviatednewdrugapplications(ANDAs)andtheirsupplementsforadditionalstrengthsthataresubmittedtotheOfficeofGenericDrugs(OGD).

　　本指南中的建議適用于向仿制藥辦公室提交簡化新藥申請（仿制藥申請，下同）及其新增規(guī)格的補充申請。

　　ThisguidancedoesnotapplytoapprovedANDAs(genericdrugs)alreadyonthemarket.3However,iftheAgencydeterminesthatanapprovedproductshouldbemodifiedbecausethesizeorshapeofaproductposesarisktopublichealth,wewillnotifytheholderoftheANDA.

　　本指南不適用于已上市的仿制藥申請。然而，如果FDA確定對已批準藥品因產(chǎn)品的大小或形狀對人民健康表現(xiàn)出風險而需要變更時，我們會通知ANDA持有人。[1]

　　Thisguidanceisnotintendedtoapplytootheroraldosageforms(e.g.,chewabletablets,oraltabletsforsuspension/solution,orallydisintegratingtablets,sublingualtablets,troches,gums).

　　本指南不適用于其它口服劑型的申請（如，咀嚼片，口服泡騰片、口腔崩解片、舌下片、含片、膠姆劑）

　　Ingeneral,FDA’sguidancedocumentsdonotestablishlegallyenforceableresponsibilities.Instead,guidancesdescribetheAgency’scurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutoryrequirementsarecited.TheuseofthewordshouldinAgencyguidancesmeansthatsomethingissuggestedorrecommended,butnotrequired.

　　總之，F(xiàn)DA的指南文件并非形成法律強制義務，反而，指南描述的內(nèi)容是我局當前對本議題的考慮，文件只應視為建議進行閱讀，除非涉及具體的規(guī)章或法定要求。我局在指南中使用“should”一詞，代表的是建議或意見，并非強制要求。

　　II.BACKGROUND背景

　　A.DifferencesinSizeandShapeofTabletsandCapsulesbetweenaReferenceListedDrugandaDrugProductSubjecttoanAbbreviatedNewDrugApplication

　　A.仿制藥申請中的目標片劑和膠囊劑與原研片劑和膠囊劑之間的大小和形狀差異[2]

　　1.Size大小

　　Difficultyswallowingtabletsandcapsulescanbeaproblemformanyindividualsandcanleadtoavarietyofadverseeventsandpatientnoncompliancewithtreatmentregimens.Itisestimatedthatover16millionpeopleintheUnitedStateshavesomedifficultyswallowing,alsoknownasdysphagia.4,5Fortheseindividuals,swallowingatabletoracapsulecanbeparticularlychallenging.Asurveyofadultsondifficultiesswallowingtabletsandcapsulessuggeststhatthisproblemgoeswellbeyondthepatientpopulationwithclinicallyrecognizeddysphagiaandmayaffectasmanyas40percentofAmericans.Ofthosewhoexperiencedifficultyswallowingmedications,lessthanaquarterdiscusstheproblemwithahealthcareprofessional,8percentadmittoskippingadoseofprescribedmedication,and4percenthavediscontinuedtherapybecausethetabletsand/orcapsulesweredifficulttoswallow.6Individualswhofinditdifficulttoswallowtabletsandcapsulesfrequentlycitethesizeasthemainreasonforthedifficultyinswallowing.7,8

　　對許多人來說，片劑和膠囊劑的吞咽困難可導致各種副反應或患者對治療方案的不順應性。公認為美國有1600萬人具有一定的吞咽障礙，即吞咽障礙癥。對于這些人來說，服用片劑或膠囊劑具有一定的挑戰(zhàn)。一項有關(guān)成人對片劑和膠囊劑的吞咽障礙的調(diào)查表明，可能有40%的美國人受此問題的困擾，遠超過視為吞咽障礙癥患者的數(shù)量。那些經(jīng)歷吞咽困難的人，只有不到四分之一的人與醫(yī)療人員討論過類似的問題，8%接受了跳過處方中某個劑量進行治療，4%的人因為片劑或膠囊劑的吞咽障礙而放棄了治療。據(jù)那些發(fā)現(xiàn)片劑或膠囊劑吞咽困難的人反映，片或膠囊的大小是造成吞咽困難的主要原因。

　　Sizeandshapeoftabletsandcapsulesaffectthetransitoftheproductthroughthepharynxandesophagusandmaydirectlyaffectapatient’sabilitytoswallowaparticulardrugproduct.Largertabletsandcapsuleshavebeenshowntohaveaprolongedesophagealtransittime.Thiscanleadtodisintegrationoftheproductintheesophagusand/orcauseinjurytotheesophagus,resultinginpainandlocalizedesophagitisandthepotentialforserioussequelaeincludingulceration,stricture,andperforation.9,10Otheradverseeventssuchaspain,gagging,choking,andaspirationarerelatedtoswallowingdifficultiesintheoropharyngealphaseofswallowingandincreasinglyoccuratlargertabletandcapsulesizes.11,12

　　片和膠囊的大小和形狀影響產(chǎn)品在咽喉和食道的轉(zhuǎn)移，而且可能直接影響患者對某個具體藥品的吞咽能力?，F(xiàn)已經(jīng)證實，較大的片或膠囊可延長藥品在食道的通過時間。這可能導致藥品在食道中崩解，或/和造成適當損傷，進而引起食道局部疼痛和一系列潛在的嚴重事件，包括潰瘍、食道狹窄和穿孔。其它嚴重事件，如疼痛，作嘔，窒息，在口咽階段，與吞咽困難相關(guān)的呼吸問題隨膠囊和片的增大而增加。

　　Studiesinadultsevaluatingtheeffectoftabletandcapsulesizeoneaseofswallowingsuggestthatincreasesinsizeareassociatedwithincreasesinpatientcomplaintsrelatedtoswallowingdifficultiesattabletsizesgreaterthanapproximately8mmindiameter.13,14,15Thesizeofthetabletorcapsuleinfluencesesophagealtransit,irrespectiveofpatientfactorsandadministrationtechniques(i.e.,useoffluids,patientposition).Smallertabletsgenerallyhavebeenshowntohavesignificantlyfastertransittimesinthesestudies.ChannerandVirjeespecificallycomparedthetransittimeof8mmdiameterroundtabletsto11mmdiameterroundtabletsand14mmx9mmovaltabletsandfoundthetransittimesforthe8mmroundtablettobesignificantlyshorterthanfor11mmroundand14mmx9mmovaltablets(p<.02andp<.04,respectively).16Inaddition,significantlymorepatientswereawareofthelargerroundtablets(>8mm)stickingintheesophaguscomparedwiththe8mmroundtablets.17Althoughtherehasbeenlessresearchquantifyingtheeffectsofsizedifferenceontheoropharyngealphaseofswallowing,increasingtabletorcapsulesizeisbelievedtocorrelatewithincreasingdifficultywithoropharyngealtransfer.

　　一項有關(guān)片劑和膠囊的大小對成人吞咽容易程度影響的研究顯示，當片劑的尺寸超過直徑8mm時，與吞咽困難相關(guān)的患者投訴隨片劑的增大而增加。在不考慮患者因素和給藥技術(shù)（如液體的使用和服藥的姿勢）的前提下，片劑和膠囊劑的大小影響藥品在食道的轉(zhuǎn)移。較小的藥片在這些研究中一般表現(xiàn)出較短的通過時間。Channer和Virjee專門比較了直徑8mm與直徑11mm圓片和14mmx9mm橢圓片在食道的通過時間，結(jié)果發(fā)現(xiàn)，直徑8mm的圓片在食道的通過時間顯著地少于直徑11mm圓片和14mmx9mm橢圓片的通過時間(p<.02和p<.04)。另外，服用較大藥片(>8mm)有“卡住”感覺的患者顯著性多于服用直徑8mm圓片的患者。盡管很少有量化大小對吞咽困難影響的研究，但是增加片劑或膠囊大小將會增大食道轉(zhuǎn)移的難度。

　　2Shape形狀

　　Foranygivensize,certainshapesmaybeeasiertoswallowthanothers.Invitrostudiessuggestthatflattabletshavegreateradherencetotheesophagusthancapsule-shapedtablets.18Studiesinhumanshavealsosuggestedthatovaltabletsmaybeeasiertoswallowandhavefasteresophagealtransittimesthanroundtabletsofthesameweight.19,20Patientcompliancewithmedicationregimensmaybeinfluencedbythesizeandshapeofatabletorcapsule.

　　對于既定的大小，某種形狀相對于其它形狀可能更容易吞咽。體外研究表明，平片相較囊形片，更容易粘附在食道上。在人上的研究同樣說明橢圓形片更容易吞咽，而且相較同樣片重的圓片，通過食道的時間更短?；颊邔o藥方案的順應性可受片劑或膠囊的大小和形狀影響。

　　[3]3.PatientFactors患者因素

　　TheAgencyrecognizesthatavarietyofotherfactorsmayaffectapatient’sabilitytoswallowatabletoracapsule.Forexample,agecouldbeafactor.Childrenandadolescents,aswellastheelderly,aremorelikelytohavedifficultyswallowingtabletsorcapsules.Bodyposition,fluidintake,andthepresenceofcertainmedicalconditions(e.g.,multiplesclerosis,musculardystrophy,Parkinson'sdisease)mayalsoaffectapatient’sabilitytoswallowtabletsandcapsules.

　　我局意識到其它多種因素也對患者吞咽片劑和膠囊劑的能力構(gòu)成影響。例如，年齡可能就是一個因素。兒童、少年和老人，更容易對片和膠囊吞咽困難。體位因素，液體攝入和健康狀態(tài)（如MS、MD、PD）也可能影響到患者對片或膠囊的吞咽能力。

　　Althoughnotallpatientfactorscanbeaddressedthroughpharmaceuticaldesignandmanufacture,thephysicalcharacteristicsofaproductcanbeaddressed.Thesephysicalcharacteristicsinfluencetheabilityofcertainpatientstoswallowtheproduct,particularlyinvulnerablepopulations.Webelievethattabletsandcapsulescanbeeffectivelydevelopedandmanufacturedtominimizeswallowingdifficulties,whichcanencourageandimprovepatientcompliancewithmedicationregimens.FDArecommendsthatapplicantsdesignanddevelopgenericdrugswiththisinmind.

　　盡管并非所有的患者因素都能通過藥品的設(shè)計和生產(chǎn)來解決，但產(chǎn)品的物理性質(zhì)可以解決。物理特性影響某個患者吞咽產(chǎn)品的能力，尤其是弱勢人群。我們相信片劑和膠囊劑能夠有效地研發(fā)和最小化吞咽困難，這有利于鼓舞患者和提高患者的順應性。FDA推薦申請人以此為目標進行仿制藥品的設(shè)計和開發(fā)。

　　B.OtherePhysicalAttributeConsiderations其他物理特性的考慮

　　Thepresenceandcompositionofacoatingcanalsopotentiallyaffecttheeaseofswallowingtabletsorcapsules.Thelackofafilmcoatingcandecreaseorpreventtabletmobilitycomparedwithacoatedtabletofthesamesizeandshape.Coatingalsocanaffectotherfactorsthatcontributetopatientacceptance,suchaspalatabilityandsmell.

　　膠囊和片的吞咽難易程度同樣受包衣粉和包衣粉的處方的影響，缺乏薄膜包衣能降低或阻止片的流動性，相較同樣大小的包衣片。包衣同樣能影響其它有利于患者接受因素，如味道和氣味。

　　Theweightofthetabletorcapsulealsomayaffecttransittime,withheaviertabletsorcapsuleshavingfastertransittimescomparedtosimilarly-sized,lightertabletsorcapsules.Surfacearea,disintegrationtime,andpropensityforswellingwhenswallowedareadditionalparametersthatcaninfluenceesophagealtransittimeandhavethepotentialtoaffecttheperformanceofthedrugproductforitsintendeduse.ThesephysicalattributesshouldalsobeconsideredwhendevelopingaQTPPforgenericdrugproductsintendedtobeswallowedintact.

　　片或膠囊的重量同樣影響通過時間，同樣大小的片或膠囊，較重的通過時間更短。影響食道通過時間和對上市后藥品性能具有潛在影響的其它參數(shù)包括表面積、崩解時間、吞咽時的腫脹傾向。

　　RECOMMENDATIONS建議

　　TherecommendationsinthisguidancearebasedonpublishedliteratureregardingpatientexperiencesswallowingtabletsandcapsulesandAgencyexperiencewithNDAsandANDAssubmittedfororaltabletsandcapsules.Ifatabletorcapsuleintendedtobeswallowedintactdiffersfromthecriteriarecommendedinthisguidancedocument,thentheapplicantshouldcontactOGDwithsupportiveinformationandjustificationbeforeestablishingtheQTPP.

　　本指南中的意見是基于有關(guān)患者所經(jīng)歷的片或膠囊劑吞咽困難方面的公開文獻和本局對口服片劑和膠囊劑的NDA和ANDA的審查經(jīng)驗提出的。如果片劑或膠囊需整體服用而不同于本指南文件所推薦的標準，申請人應在確立目標產(chǎn)品質(zhì)量屬性之前聯(lián)系仿制藥辦公室，提交支持性資料和理由。

　　Size大小

　　Forcomparableeaseofswallowingaswellaspatientacceptanceandcompliancewithtreatmentregimens,theAgencyrecommendsthatgenericoraltabletsandcapsulesintendedtobeswallowedintactshouldbeofasimilarsizetothecorrespondingRLD.TheAgencyrecommendslimitingsizedifferencesbetweentherapeuticallyequivalenttabletsasfollows:

　　為比較易于吞咽性及患者對治療方案可接受性和順應性，我局建議將用于整體吞服的仿制藥片劑和膠囊應與相應的原研藥品大小相似。我局建議不同等效片劑間的大小限度如下：

　　IftheRLDislessthan17mminitslargestdimension,21thegenericproductshouldbe:

　　如果原研藥品最大直徑小于17mm，仿制藥品應：

　　Nomorethan20percentlargerthantheRLDinanysingledimension(theresultingsingledimensionofthegenericshouldnotexceed17mm).

　　任何單一直徑不得大于原研品的20%（所產(chǎn)生的仿制藥品單一直徑不得超過17mm）

　　Nomorethan40percentlargerthanthevolumeoftheRLD

　　體積不得超過原研品的40%

　　IftheRLDisequaltoorgreaterthan17mminitslargestdimension,thegenericproductshouldbe:

　　如果原研藥品最大直徑大于等于17mm，仿制藥品應：

　　NolargerthantheRLDinanysingledimension.

　　任何單一方向直徑不得比原研品大。

　　NolargerthanthevolumeoftheRLD.

　　體積不得超過原研品。

　　Werecommendthatthelargestdimensionofatabletorcapsuleshouldnotexceed22mmandthatcapsulesshouldnotexceedastandard00size.23

　　我們建議片劑或膠囊劑的最大直徑不要超過22mm，所對應的膠囊不要超過0號標準膠囊。

　　Additionalflexibilitymaybegivenforproductsthatare8mmorsmallerintheirlargestdimension,buteffortsshouldbemadetodeveloptabletsandcapsulesthatareofasimilarsizeandshapetotheRLD.

　　盡管可以給予8mm或最大尺寸更小的產(chǎn)品額外的靈活性，但也應努力保持仿制片劑或膠囊劑與原研藥品尺寸和外形的一致性。

　　Underthestandardcapsulesizeconvention,theallowancesdescribedabovewillgenerallyallowanincreaseofonecapsulesize,whentheRLDcapsuleisofsize3orsmaller.WhentheRLDcapsuleisofsize2orlarger,anincreaseofonecapsulesizeshouldonlybeconsideredwhenadequatejustificationcanbeprovidedforthesizeincrease.Theserecommendationswouldallowanincreaseofonecapsulesizewhenthecapsulesizeislessthancapsulesize00.

　　當原研藥品是3號或更小號的膠囊時，在標準尺寸的常規(guī)膠囊下，上述條款將普遍允許增大膠囊的尺寸。當原研藥品是2號膠囊或更大時，增大膠囊的尺寸只有在具有充分理由的條件下進行考慮。當膠囊尺寸小于0號膠囊的尺寸時，這些建議將允許增加膠囊的尺寸。

　　TheAgencyrecognizesthattwodrugproductsmayhavedifferentrecommendeduppersizelimits,butsizeshouldbeconsideredaspartofasingleproductrisk/benefitprofile.Whenestablishingtherapeuticequivalence,theapplicantshouldcomparetheirgenericproductonlytotheRLD.

　　根據(jù)我局認識，兩種藥品可能具有不同的推薦最大尺寸限度，但尺寸應被視為單一產(chǎn)品效益/風險特征的一部分。在確立治療等效性時，申請人應只將制藥品與原研藥品做比較。

　　Shape外形

　　Inadditiontothesizerecommendationsdescribedabove,werecommendmanufacturingtabletsandcapsulesthathaveasimilarshapeorhaveashapethathasbeenfoundtobeeasiertoswallowcomparedwiththeshapeoftheRLD.EvaluatingandcomparingthelargestcrosssectionalareasoftheRLDandgenericproductisonestrategytoquantifychangesinshape.24Tabletsandcapsulesthathavealargercrosssectionalarea(e.g.,tabletsthatarerounder)wouldgenerallybemoredifficulttoswallowthantabletsorcapsulesofthesamevolumebutwithsmallercrosssectionalareas.

　　除了上述尺寸建議，我們推薦生產(chǎn)仿制藥品時，保持藥品的形狀與原研藥品一致或使用相較原研藥品更容易吞咽的藥品形狀。評估和比較仿制藥品和原研藥品的最大橫截面積是一種量化外形改變程度的一種策略。體積相同，相較橫截面積更小的片或膠囊，橫截面積（如片劑是圓面）更大的片劑或膠囊劑將會產(chǎn)生更多的吞咽困難。[4]

　　Thereareavarietyoftechniquesthatmaybeusedtodeterminethevolumemeasurementsofatabletorcapsule,includinguseofpycnometers,orcalculationsbasedonphysicalmeasurementsofthetabletorthedieusedtoproducethetablet.Forthepurposeofthisguidance,spatialimagingand/ortheuseofcomputermodelsisrecommended,becausetheyaremoreaccurateandapplicabletoavarietyofshapes,althoughotherappropriatelyvalidatedmethodsmaybeusedifproperlyjustified.

　　目前已有多項技術(shù)可用于片劑或膠囊劑的體積檢測，包括使用比重瓶，或基于片劑或用于生產(chǎn)片劑模具的物理尺寸的計算。對于本指南的建議是推薦使用空間成像或使用計算機模型，因為這手段更精確，且適用于各種形狀的檢測，當然如有正當?shù)睦碛桑梢允褂闷渌行У氖侄巍?/p>

　　Thesizeofatabletorcapsuleshouldbeprovidedinthecommontechnicaldocument(CTD)format,25section3.2.P.1,DescriptionandCompositionoftheDrugProductoftheANDA.Anystudiesand/orrelatedinformationshouldbeprovidedintheCTDsection,5.3.1.2,ComparativeBioavailabilityandBioequivalenceStudyReports.TheAgencymayrequestsamplesforevaluationofthephysicalattributesofatabletorcapsule.

　　片劑或膠囊劑的尺寸應在通用技術(shù)文件的3.2.P.1，DescriptionandCompositionoftheDrugProduct中體現(xiàn)。任何研究和/或相關(guān)信息應在CTD文件的5.3.1.2部分，ComparativeBioavailabilityandBioequivalenceStudyReports.中提現(xiàn)。我局可能要求樣品以評估片劑或膠囊的物理屬性。

　　OtherPhysicalAttributes其它物理屬性

　　Otherphysicalattributesoftabletsandcapsulesshouldbeconsideredinthecontextoftheireffectoneaseofswallowing.Forexample,tabletcoating,weight,surfacearea,disintegrationtime,andpropensityforswellingshouldbeconsideredwhendevelopingaQTPPforgenerictablets.

　　在開發(fā)仿制藥目標產(chǎn)品質(zhì)量概況時，文中提及的其它片劑和膠囊的物理特性對吞咽困難的影響也應該關(guān)注，如片劑包衣，重量，表面積，崩解時間，腫脹傾向。

　　DescriptionofthesephysicalcharacteristicsshouldbeprovidedintheCTDsection3.2.P.1,DescriptionandCompositionoftheDrugProductoftheANDA.AsummaryofanystudiestosupportsizesoutsidetherecommendationprovidedinthisguidanceshouldbeprovidedintheCTDsection3.2.P.2,PharmaceuticalDevelopmentorCTDsection3.2.P.5.6,JustificationofSpecifications.

　　這些物理性質(zhì)的描述應在CTD文件的3.2.P.1，DescriptionandCompositionoftheDrugProduct部分進行體現(xiàn)。各研究總結(jié)以支持超出指南推薦尺寸的物理性質(zhì)應體現(xiàn)在在3.2.P.2，藥品開發(fā)和3.2.P.5.6，JustificationofSpecifications中。

　　Biowaivers生物等效性豁免

　　Abiowaiver(i.e.,thewaiverofinvivobioequivalencedata)foradditionalstrengthsofasolidoraldosageformisgenerallygrantedifitmeetsoneofthecriteriasetforthintheregulations,26oneofwhichisproportionalsimilaritybetweenstrengthsinactiveandinactiveingredients.Compositionalproportionalitymaybeparticularlyrelevantwhenconsideringtabletsizeandtabletformulationforotherstrengths(bothlowerandhigher)ofthesamedosageformtobeconsideredforawaiveroftheinvivobioequivalencestudyrequirement.Althoughcompositionalproportionalitymayexistwhenallactiveandinactiveingredientsareinthesameproportionbetweendifferentstrengths,othermethodsofachievingcompositionalproportionalitymaybemoreamenabletomaintainingappropriatetabletsizesforgenericproductswhencomparedwiththeRLD.AdetaileddescriptionofhowtheAgencydefinesproportionalsimilaritycanbefoundintheGuidanceforIndustry:BioavailabilityandBioequivalenceStudiesforOrallyAdministeredDrugProducts-GeneralConsiderations.27

　　對于新增規(guī)格的口服固體制劑常常批準豁免生物等效性（即，豁免體內(nèi)生物等效性數(shù)據(jù)），如果符合規(guī)章中的相關(guān)規(guī)定，其中之一就是活性成分和非活性成分間的相似比例。當相同劑型其他規(guī)格（包括更小和更大規(guī)格）的處方和片子尺寸考慮在內(nèi)，及其是否視作有必要要進行生物等效性研究時，組成比例可能是尤為重要的。