FDA:片剂和胶囊仿制药的尺寸和外形设计要求指南译稿

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

　　Tabletsandcapsulesarewidelymanufacturedandprescribedandmayprovideanumberofadvantagesoverotherdosageforms,includingeaseofstorage,portability,easeofadministration,andaccuracyindosing.

　　片剂和胶囊剂是被广泛生产和使用的剂型，相对其它剂型，片剂和胶囊剂具有诸多优势，如存储方便，易于携带，方便服用，剂量精确等。

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

　　我们对仿制药品的要求是在与对照药品列表里的药品（原研药，下同）保持制剂学和疗效学上的一致的同时，还应虑及物理性质的差异（如，胶囊和片的形状和大小）可能影响患者对给药方案的顺应性和可接受性，或者可导致用药差错发生。我们相信这些对患者的安全考虑是至关重要的，而且我们推荐仿制药生产商在候选仿制药品目标质量概况开发时考虑到这些物理属性。

　　Therecommendationsinthisguidanceapplytoabbreviatednewdrugapplications(ANDAs)andtheirsupplementsforadditionalstrengthsthataresubmittedtotheOfficeofGenericDrugs(OGD).

　　本指南中的建议适用于向仿制药办公室提交简化新药申请（仿制药申请，下同）及其新增规格的补充申请。

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

　　本指南不适用于已上市的仿制药申请。然而，如果FDA确定对已批准药品因产品的大小或形状对人民健康表现出风险而需要变更时，我们会通知ANDA持有人。[1]

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

　　本指南不适用于其它口服剂型的申请（如，咀嚼片，口服泡腾片、口腔崩解片、舌下片、含片、胶姆剂）

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

　　总之，FDA的指南文件并非形成法律强制义务，反而，指南描述的内容是我局当前对本议题的考虑，文件只应视为建议进行阅读，除非涉及具体的规章或法定要求。我局在指南中使用“should”一词，代表的是建议或意见，并非强制要求。

　　II.BACKGROUND背景

　　A.DifferencesinSizeandShapeofTabletsandCapsulesbetweenaReferenceListedDrugandaDrugProductSubjecttoanAbbreviatedNewDrugApplication

　　A.仿制药申请中的目标片剂和胶囊剂与原研片剂和胶囊剂之间的大小和形状差异[2]

　　1.Size大小

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

　　对许多人来说，片剂和胶囊剂的吞咽困难可导致各种副反应或患者对治疗方案的不顺应性。公认为美国有1600万人具有一定的吞咽障碍，即吞咽障碍症。对于这些人来说，服用片剂或胶囊剂具有一定的挑战。一项有关成人对片剂和胶囊剂的吞咽障碍的调查表明，可能有40%的美国人受此问题的困扰，远超过视为吞咽障碍症患者的数量。那些经历吞咽困难的人，只有不到四分之一的人与医疗人员讨论过类似的问题，8%接受了跳过处方中某个剂量进行治疗，4%的人因为片剂或胶囊剂的吞咽障碍而放弃了治疗。据那些发现片剂或胶囊剂吞咽困难的人反映，片或胶囊的大小是造成吞咽困难的主要原因。

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

　　片和胶囊的大小和形状影响产品在咽喉和食道的转移，而且可能直接影响患者对某个具体药品的吞咽能力。现已经证实，较大的片或胶囊可延长药品在食道的通过时间。这可能导致药品在食道中崩解，或/和造成适当损伤，进而引起食道局部疼痛和一系列潜在的严重事件，包括溃疡、食道狭窄和穿孔。其它严重事件，如疼痛，作呕，窒息，在口咽阶段，与吞咽困难相关的呼吸问题随胶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.

　　一项有关片剂和胶囊的大小对成人吞咽容易程度影响的研究显示，当片剂的尺寸超过直径8mm时，与吞咽困难相关的患者投诉随片剂的增大而增加。在不考虑患者因素和给药技术（如液体的使用和服药的姿势）的前提下，片剂和胶囊剂的大小影响药品在食道的转移。较小的药片在这些研究中一般表现出较短的通过时间。Channer和Virjee专门比较了直径8mm与直径11mm圆片和14mmx9mm椭圆片在食道的通过时间，结果发现，直径8mm的圆片在食道的通过时间显著地少于直径11mm圆片和14mmx9mm椭圆片的通过时间(p<.02和p<.04)。另外，服用较大药片(>8mm)有“卡住”感觉的患者显著性多于服用直径8mm圆片的患者。尽管很少有量化大小对吞咽困难影响的研究，但是增加片剂或胶囊大小将会增大食道转移的难度。

　　2Shape形状

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

　　对于既定的大小，某种形状相对于其它形状可能更容易吞咽。体外研究表明，平片相较囊形片，更容易粘附在食道上。在人上的研究同样说明椭圆形片更容易吞咽，而且相较同样片重的圆片，通过食道的时间更短。患者对给药方案的顺应性可受片剂或胶囊的大小和形状影响。

　　[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.

　　我局意识到其它多种因素也对患者吞咽片剂和胶囊剂的能力构成影响。例如，年龄可能就是一个因素。儿童、少年和老人，更容易对片和胶囊吞咽困难。体位因素，液体摄入和健康状态（如MS、MD、PD）也可能影响到患者对片或胶囊的吞咽能力。

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

　　尽管并非所有的患者因素都能通过药品的设计和生产来解决，但产品的物理性质可以解决。物理特性影响某个患者吞咽产品的能力，尤其是弱势人群。我们相信片剂和胶囊剂能够有效地研发和最小化吞咽困难，这有利于鼓舞患者和提高患者的顺应性。FDA推荐申请人以此为目标进行仿制药品的设计和开发。

　　B.OtherePhysicalAttributeConsiderations其他物理特性的考虑

　　Thepresenceandcompositionofacoatingcanalsopotentiallyaffecttheeaseofswallowingtabletsorcapsules.Thelackofafilmcoatingcandecreaseorpreventtabletmobilitycomparedwithacoatedtabletofthesamesizeandshape.Coatingalsocanaffectotherfactorsthatcontributetopatientacceptance,suchaspalatabilityandsmell.

　　胶囊和片的吞咽难易程度同样受包衣粉和包衣粉的处方的影响，缺乏薄膜包衣能降低或阻止片的流动性，相较同样大小的包衣片。包衣同样能影响其它有利于患者接受因素，如味道和气味。

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

　　片或胶囊的重量同样影响通过时间，同样大小的片或胶囊，较重的通过时间更短。影响食道通过时间和对上市后药品性能具有潜在影响的其它参数包括表面积、崩解时间、吞咽时的肿胀倾向。

　　RECOMMENDATIONS建议

　　TherecommendationsinthisguidancearebasedonpublishedliteratureregardingpatientexperiencesswallowingtabletsandcapsulesandAgencyexperiencewithNDAsandANDAssubmittedfororaltabletsandcapsules.Ifatabletorcapsuleintendedtobeswallowedintactdiffersfromthecriteriarecommendedinthisguidancedocument,thentheapplicantshouldcontactOGDwithsupportiveinformationandjustificationbeforeestablishingtheQTPP.

　　本指南中的意见是基于有关患者所经历的片或胶囊剂吞咽困难方面的公开文献和本局对口服片剂和胶囊剂的NDA和ANDA的审查经验提出的。如果片剂或胶囊需整体服用而不同于本指南文件所推荐的标准，申请人应在确立目标产品质量属性之前联系仿制药办公室，提交支持性资料和理由。

　　Size大小

　　Forcomparableeaseofswallowingaswellaspatientacceptanceandcompliancewithtreatmentregimens,theAgencyrecommendsthatgenericoraltabletsandcapsulesintendedtobeswallowedintactshouldbeofasimilarsizetothecorrespondingRLD.TheAgencyrecommendslimitingsizedifferencesbetweentherapeuticallyequivalenttabletsasfollows:

　　为比较易于吞咽性及患者对治疗方案可接受性和顺应性，我局建议将用于整体吞服的仿制药片剂和胶囊应与相应的原研药品大小相似。我局建议不同等效片剂间的大小限度如下：

　　IftheRLDislessthan17mminitslargestdimension,21thegenericproductshouldbe:

　　如果原研药品最大直径小于17mm，仿制药品应：

　　Nomorethan20percentlargerthantheRLDinanysingledimension(theresultingsingledimensionofthegenericshouldnotexceed17mm).

　　任何单一直径不得大于原研品的20%（所产生的仿制药品单一直径不得超过17mm）

　　Nomorethan40percentlargerthanthevolumeoftheRLD

　　体积不得超过原研品的40%

　　IftheRLDisequaltoorgreaterthan17mminitslargestdimension,thegenericproductshouldbe:

　　如果原研药品最大直径大于等于17mm，仿制药品应：

　　NolargerthantheRLDinanysingledimension.

　　任何单一方向直径不得比原研品大。

　　NolargerthanthevolumeoftheRLD.

　　体积不得超过原研品。

　　Werecommendthatthelargestdimensionofatabletorcapsuleshouldnotexceed22mmandthatcapsulesshouldnotexceedastandard00size.23

　　我们建议片剂或胶囊剂的最大直径不要超过22mm，所对应的胶囊不要超过0号标准胶囊。

　　Additionalflexibilitymaybegivenforproductsthatare8mmorsmallerintheirlargestdimension,buteffortsshouldbemadetodeveloptabletsandcapsulesthatareofasimilarsizeandshapetotheRLD.

　　尽管可以给予8mm或最大尺寸更小的产品额外的灵活性，但也应努力保持仿制片剂或胶囊剂与原研药品尺寸和外形的一致性。

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

　　当原研药品是3号或更小号的胶囊时，在标准尺寸的常规胶囊下，上述条款将普遍允许增大胶囊的尺寸。当原研药品是2号胶囊或更大时，增大胶囊的尺寸只有在具有充分理由的条件下进行考虑。当胶囊尺寸小于0号胶囊的尺寸时，这些建议将允许增加胶囊的尺寸。

　　TheAgencyrecognizesthattwodrugproductsmayhavedifferentrecommendeduppersizelimits,butsizeshouldbeconsideredaspartofasingleproductrisk/benefitprofile.Whenestablishingtherapeuticequivalence,theapplicantshouldcomparetheirgenericproductonlytotheRLD.

　　根据我局认识，两种药品可能具有不同的推荐最大尺寸限度，但尺寸应被视为单一产品效益/风险特征的一部分。在确立治疗等效性时，申请人应只将制药品与原研药品做比较。

　　Shape外形

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

　　除了上述尺寸建议，我们推荐生产仿制药品时，保持药品的形状与原研药品一致或使用相较原研药品更容易吞咽的药品形状。评估和比较仿制药品和原研药品的最大横截面积是一种量化外形改变程度的一种策略。体积相同，相较横截面积更小的片或胶囊，横截面积（如片剂是圆面）更大的片剂或胶囊剂将会产生更多的吞咽困难。[4]

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

　　目前已有多项技术可用于片剂或胶囊剂的体积检测，包括使用比重瓶，或基于片剂或用于生产片剂模具的物理尺寸的计算。对于本指南的建议是推荐使用空间成像或使用计算机模型，因为这手段更精确，且适用于各种形状的检测，当然如有正当的理由，可以使用其他有效的手段。

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

　　片剂或胶囊剂的尺寸应在通用技术文件的3.2.P.1，DescriptionandCompositionoftheDrugProduct中体现。任何研究和/或相关信息应在CTD文件的5.3.1.2部分，ComparativeBioavailabilityandBioequivalenceStudyReports.中提现。我局可能要求样品以评估片剂或胶囊的物理属性。

　　OtherPhysicalAttributes其它物理属性

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

　　在开发仿制药目标产品质量概况时，文中提及的其它片剂和胶囊的物理特性对吞咽困难的影响也应该关注，如片剂包衣，重量，表面积，崩解时间，肿胀倾向。

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

　　这些物理性质的描述应在CTD文件的3.2.P.1，DescriptionandCompositionoftheDrugProduct部分进行体现。各研究总结以支持超出指南推荐尺寸的物理性质应体现在在3.2.P.2，药品开发和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

　　对于新增规格的口服固体制剂常常批准豁免生物等效性（即，豁免体内生物等效性数据），如果符合规章中的相关规定，其中之一就是活性成分和非活性成分间的相似比例。当相同剂型其他规格（包括更小和更大规格）的处方和片子尺寸考虑在内，及其是否视作有必要要进行生物等效性研究时，组成比例可能是尤为重要的。