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(duì)其它劑型，片劑和膠囊劑具有諸多優(yōu)勢(shì)，如存儲(chǔ)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(duì)仿制藥品的要求是在與對(duì)照藥品列表里的藥品（原研藥，下同）保持制劑學(xué)和療效學(xué)上的一致的同時(shí)，還應(yīng)慮及物理性質(zhì)的差異（如，膠囊和片的形狀和大小）可能影響患者對(duì)給藥方案的順應(yīng)性和可接受性，或者可導(dǎo)致用藥差錯(cuò)發(fā)生。我們相信這些對(duì)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(biāo)質(zhì)量概況開(kāi)發(fā)時(shí)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(jiǎn)化新藥申請(qǐng)（仿制藥申請(qǐng)，下同）及其新增規(guī)格的補(bǔ)充申請(qǐng)。

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

　　本指南不適用于已上市的仿制藥申請(qǐng)。然而，如果FDA確定對(duì)已批準(zhǔn)藥品因產(chǎn)品的大小或形狀對(duì)人民健康表現(xiàn)出風(fēng)險(xiǎn)而需要變更時(shí)，我們會(huì)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(qǐng)（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(qiáng)制義務(wù)，反而，指南描述的內(nèi)容是我局當(dāng)前對(duì)本議題的考慮，文件只應(yīng)視為建議進(jìn)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(jiàn)，并非強(qiáng)制要求。

　　II.BACKGROUND背景

　　A.DifferencesinSizeandShapeofTabletsandCapsulesbetweenaReferenceListedDrugandaDrugProductSubjecttoanAbbreviatedNewDrugApplication

　　A.仿制藥申請(qǐng)中的目標(biāo)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(duì)許多人來(lái)說(shuō)，片劑和膠囊劑的吞咽困難可導(dǎo)致各種副反應(yīng)或患者對(duì)治療方案的不順應(yīng)性。公認(rèn)為美國(guó)有1600萬(wàn)人具有一定的吞咽障礙，即吞咽障礙癥。對(duì)于這些人來(lái)說(shuō)，服用片劑或膠囊劑具有一定的挑戰(zhàn)。一項(xiàng)有關(guān)成人對(duì)片劑和膠囊劑的吞咽障礙的調(diào)查表明，可能有40%的美國(guó)人受此問(wèn)題的困擾，遠(yuǎn)超過(guò)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(guò)類似的問(wèn)題，8%接受了跳過(guò)處方中某個(gè)劑量進(jìn)行治療，4%的人因?yàn)槠瑒┗蚰z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(duì)某個(gè)具體藥品的吞咽能力?，F(xiàn)已經(jīng)證實(shí)，較大的片或膠囊可延長(zhǎng)藥品在食道的通過(guò)時(shí)間。這可能導(dǎo)致藥品在食道中崩解，或/和造成適當(dāng)損傷，進(jìn)而引起食道局部疼痛和一系列潛在的嚴(yán)重事件，包括潰瘍、食道狹窄和穿孔。其它嚴(yán)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(wèn)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(xiàng)有關(guān)片劑和膠囊的大小對(duì)成人吞咽容易程度影響的研究顯示，當(dāng)片劑的尺寸超過(guò)直徑8mm時(shí)，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(shì)）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(guò)時(shí)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(guò)時(shí)間，結(jié)果發(fā)現(xiàn)，直徑8mm的圓片在食道的通過(guò)時(shí)間顯著地少于直徑11mm圓片和14mmx9mm橢圓片的通過(guò)時(shí)間(p<.02和p<.04)。另外，服用較大藥片(>8mm)有“卡住”感覺(jué)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(duì)吞咽困難影響的研究，但是增加片劑或膠囊大小將會(huì)增大食道轉(zhuǎn)移的難度。

　　2Shape形狀

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

　　對(duì)于既定的大小，某種形狀相對(duì)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(shuō)明橢圓形片更容易吞咽，而且相較同樣片重的圓片，通過(guò)食道的時(shí)間更短?；颊邔?duì)給藥方案的順應(yīng)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(shí)到其它多種因素也對(duì)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(gè)因素。兒童、少年和老人，更容易對(duì)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(duì)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(guò)藥品的設(shè)計(jì)和生產(chǎn)來(lái)解決，但產(chǎn)品的物理性質(zhì)可以解決。物理特性影響某個(gè)患者吞咽產(chǎn)品的能力，尤其是弱勢(shì)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(yīng)性。FDA推薦申請(qǐng)人以此為目標(biāo)進(jìn)行仿制藥品的設(shè)計(jì)和開(kāi)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(dòng)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(guò)時(shí)間，同樣大小的片或膠囊，較重的通過(guò)時(shí)間更短。影響食道通過(guò)時(shí)間和對(duì)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(shí)間、吞咽時(shí)的腫脹傾向。

　　RECOMMENDATIONS建議

　　TherecommendationsinthisguidancearebasedonpublishedliteratureregardingpatientexperiencesswallowingtabletsandcapsulesandAgencyexperiencewithNDAsandANDAssubmittedfororaltabletsandcapsules.Ifatabletorcapsuleintendedtobeswallowedintactdiffersfromthecriteriarecommendedinthisguidancedocument,thentheapplicantshouldcontactOGDwithsupportiveinformationandjustificationbeforeestablishingtheQTPP.

　　本指南中的意見(jiàn)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(kāi)文獻(xiàn)和本局對(duì)口服片劑和膠囊劑的NDA和ANDA的審查經(jīng)驗(yàn)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(biāo)準(zhǔn)，申請(qǐng)人應(yīng)在確立目標(biāo)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(duì)治療方案可接受性和順應(yīng)性，我局建議將用于整體吞服的仿制藥片劑和膠囊應(yīng)與相應(yīng)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(yīng)：

　　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(guò)17mm）

　　Nomorethan40percentlargerthanthevolumeoftheRLD

　　體積不得超過(guò)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(yīng)：

　　NolargerthantheRLDinanysingledimension.

　　任何單一方向直徑不得比原研品大。

　　NolargerthanthevolumeoftheRLD.

　　體積不得超過(guò)原研品。

　　Werecommendthatthelargestdimensionofatabletorcapsuleshouldnotexceed22mmandthatcapsulesshouldnotexceedastandard00size.23

　　我們建議片劑或膠囊劑的最大直徑不要超過(guò)22mm，所對(duì)應(yīng)的膠囊不要超過(guò)0號(hào)標(biāo)準(zhǔn)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(yīng)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(dāng)原研藥品是3號(hào)或更小號(hào)的膠囊時(shí)，在標(biāo)準(zhǔn)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(dāng)原研藥品是2號(hào)膠囊或更大時(shí)，增大膠囊的尺寸只有在具有充分理由的條件下進(jìn)行考慮。當(dāng)膠囊尺寸小于0號(hào)膠囊的尺寸時(shí)，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(rèn)識(shí)，兩種藥品可能具有不同的推薦最大尺寸限度，但尺寸應(yīng)被視為單一產(chǎn)品效益/風(fēng)險(xiǎn)特征的一部分。在確立治療等效性時(shí)，申請(qǐng)人應(yīng)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(shí)，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(píng)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(huì)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(xiàng)技術(shù)可用于片劑或膠囊劑的體積檢測(cè)，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(jì)算。對(duì)于本指南的建議是推薦使用空間成像或使用計(jì)算機(jī)模型，因?yàn)檫@手段更精確，且適用于各種形狀的檢測(cè)，當(dāng)然如有正當(dāng)?shù)睦碛?，可以使用其他有效的手段?/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(yīng)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(yīng)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(píng)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(kāi)發(fā)仿制藥目標(biāo)產(chǎn)品質(zhì)量概況時(shí)，文中提及的其它片劑和膠囊的物理特性對(duì)吞咽困難的影響也應(yīng)該關(guān)注，如片劑包衣，重量，表面積，崩解時(shí)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(yīng)在CTD文件的3.2.P.1，DescriptionandCompositionoftheDrugProduct部分進(jìn)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(yīng)體現(xiàn)在在3.2.P.2，藥品開(kāi)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(duì)于新增規(guī)格的口服固體制劑常常批準(zhǔn)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(dāng)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(jìn)行生物等效性研究時(shí)，組成比例可能是尤為重要的。