T/SHPPA 007-2020 窄治疗指数药物质量评价及标准制订的通用技术要求

ICS03.120.10

CCSC00

SocialOrganizationStandard

T/SHPPA007—2020

窄治疗指数药物质量评价

及标准制订的通用技术要求

GeneralTechnicalGuidelinefortheQualityEvaluationandStandard

DevelopmentofNarrowTherapeuticIndexDrugs

Issuedon：May20,2020Implementedon：July1,2020

IssuedbyShanghaiPharmaceuticalProfessionAssociation

T/SHPPA007—2020

Contents

Foreword..............................................................................Ⅱ

Introduction.........................................................................Ⅲ

1Scope...............................................................................1

2Normativereferences................................................................1

3Termsanddefinitions...............................................................1

4Technicalrequirements..............................................................2

4.1Generalrequirements............................................................2

4.2QualitymanagementofNTIDs.....................................................2

4.3QualityevaluationofNTIDs.....................................................3

4.4StandarddevelopmentofNTIDs...................................................5

AnnexA(normative)Establishmentandvalidationofdissolutionandreleasetestmethodsfor

narrowtherapeuticindexdrugs.....................................7

AnnexB(normative)Settingofcontentandcontentuniformitylimitsfornarrowtherapeutic

indexdrugs.......................................................14

AnnexC(normative)Listofnarrowtherapeuticindexdrugs............................16

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T/SHPPA007—2020

Foreword

Thistechnicalspecification(TS)isdraftedasinstructedinGB/T1.1-2020Directives

forstandardization-Part1:Rulesforthestructureanddraftingofstandardizingdocuments.

ThisisTSforthequalityevaluationandstandarddevelopmentofnarrowtherapeuticindex

drugs.

ThisTSisproposedbyShanghaiPharmaceuticalProfessionAssociation.

ThisTSisunderthejurisdictionofShanghaiPharmaceuticalProfessionAssociation.

ThisTSisdraftedby:ShanghaiPharmaceuticalProfessionAssociation,ShanghaiCenter

forDrugEvaluationandInspection,theSixthPeople'sHospitalofShanghai,andSanofi

(Hangzhou)PharmaceuticalCo.,Ltd.

Maindrafters:ChenGuiliang,ZhangJingchen,ChenLili,LiuPeng,ChenZhidong,WangZitao,

RuanKeping,LinYinan,HuangYifan,YiZhengyu,ZhaoHui,WuYaoweiandZhuBeifen.

TheparticipatingentitiesinthefirstwaveofimplementingthisTSinclude:Sanofi

(Hangzhou)PharmaceuticalCo.,Ltd,ShanghaiFudanForwardS&TCo.,Ltd,ShanghaiHarvest

PharmaceuticalCo.,Ltd,SPHNo.1Biochemical&PharmaceuticalCo.,Ltd,SPHZhongxi

PharmaceuticalCo.,Ltd,SPHSinePharmaceuticalLaboratoriesCo.,Ltd,ShanghaiXinya

PharmaceuticalMinhangCo.,Ltd,andMerckSeronoCo.,Ltd.

ThisisthefirstissueofthisTS.

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Introduction

Anarrowtherapeuticindexdrug(NTID)referstoadrugthatmayleadtoserioustreatment

failuresand/oradversedrugreactions(i.e.,maythreatenlifeorresultinpersistentor

significantdisability)incaseofaminordifferenceinthedoseorplasmaconcentration.

Sofar,regulationsortechnicalstandardsforlife-cyclemanagementofNTIDsinChina

havenotbeensystematicallyestablished.Inviewofthis,thissocialTSwasproposedtobe

developedbyShanghaiPharmaceuticalProfessionAssociationtostrengthenthemanagementof

NTIDsandensuresafetyuseofmedicine.

ConsideringtheparticularityofNTIDs,section4.3“QualityevaluationofNTIDs”in

thisTSmainlyprescribesrequirementsonhumanbioequivalencestudiesandstabilitystudies

forNTIDs.

TheproductsincludedinAnnexC“ListofNarrowTherapeuticIndexDrugs”tothisTS

areproductsofthefirstwaveofapprovedimplementersselectedbyreferencetorelevant

domesticandforeigncataloguesandliteratureinformation.

III

T/SHPPA007—2020

Generaltechnicalspecificationforthequalityevaluation

andstandarddevelopmentofnarrowtherapeuticindexdrugs

1Scope

ThisTSisapplicabletothequalityevaluationandstandarddevelopmentofnarrow

therapeuticindexdrugs(NTIDs).

2Normativereferences

Thefollowingdocumentsarenormativelyreferencedinthisdocumentandinsuchawaythat

theircontentconstitutesprovisionsofthisTS.Fordatedreferences,onlytheeditioncited

applies.Forundatedreferences,thelatesteditionofthereferenceddocument(includingany

amendment)applies.

DrugAdministrationLawofthePeople'sRepublicofChinaStandingCommitteeofthe

ThirteenthNationalPeople'sCongressofthePeople'sRepublicofChina

GoodManufacturingPracticeMinistryofHealthofthePeople'sRepublicofChina

PharmacopoeiaofthePeople'sRepublicofChinaChinesePharmacopoeiaCommission

InternationalCouncilforHarmonizationguidelinesQ1E,Q6,Q10,Q12

USPharmacopoeiaUSPharmacopoeiaCommission

BritishPharmacopoeiaBritishPharmacopoeiaCommission

3Termsanddefinitions

Thefollowingtermsanddefinitionsapply.

3.1

medianlethaldose(LD50)

Thedrugdosethatkill50%ofexperimentalanimals.

3.2

medianeffectivedose(ED50)

Thedrugdosethatproducespositiveresponsesin50%ofexperimentalanimals.

3.3

therapeuticindex(TI)

TheLD50/ED50ratio,usedforexpressingthesafetyofadrug.

3.4

narrowtherapeuticIndex(NTI)

TI＜2,ortheminimumpoisoningplasmaconcentration/minimumeffectiveplasma

concentration＜2.

3.5

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narrowtherapeuticindexdrugs(NTIDs)

Drugsthatmayleadtoserioustreatmentfailuresand/oradversedrugreactions(i.e.,may

threatenlifeorresultinpersistentorsignificantdisability)incaseofaminordifference

inthedoseorplasmaconcentration.Ingeneral,NTIDsrefertodrugswithTI＜2.

3.6

Life-CycleManagement

Lifecyclecoveringdrugdevelopment,technologytransfer,commercialmanufacture,

distributionanduseuntilproducttermination.

4Technicalrequirements

4.1Generalrequirements

4.1.1ThisTSisformulatedbyreferencetorelevantlaws,regulationsandtechnical

requirementspertinenttoNTIDsandbasedoncurrentlyavailableNTIDsstudydataregarding

development,manufacture,distribution,anduseandclinicalmonitoringdata.

4.1.2BasedoncharacteristicsofNTIDsandrisksinclinicaluse,thisTSwithquality

managementasthecore,prescribestechnicalrequirementsonqualityevaluationand

specificationdevelopment.

4.2QualitymanagementofNTIDs

4.2.1NTIDsshallbesubjectedtostrictqualitymanagementthroughoutthelifecycleto

ensurecriticalqualityattributesofthedrugscanbeeffectivelymaintainedandtransferred

ateachstageofthelifecycle.

4.2.2Thecoreoflife-cyclemanagementofNTIDsistoestablishaqualityassurancesystem

forensuringthesafety,efficacyandqualitycontrollabilityofdrugs.

4.2.2.1Thedesign,establishmentanddocumentationofthequalityassurancesystemshall

beexecutableandcleartoensureconsistencybetweenunderstandingandimplementation.

4.2.2.2Thequalityassurancesystemshouldeffectivelyleveragelife-cycleknowledge

managementandqualityriskmanagementtoprovidescientificstrategytomitigaterisks.The

qualityassurancesystemshouldbecontinuallyimprovedtoreducedrugqualityfluctuations

andpromotecontinuousimprovementofproductquality.

Notes：Knowledgemanagementreferstothemanagementofproductandprocessknowledgefromproduct

developmenttotheproduct’scommerciallifecycleuntilproductiondiscontinuation.Forexample,

developmentactivitiesguidedbyscientificmethodsprovideknowledgeforunderstandingproducts

anddevelopmentprocesses.Knowledgemanagementisasystematicmethodtoacquire,analyze,store

anddisseminateinformationrelatedtoproducts,manufacturingprocessesandcomponents.

Knowledgesourcesincludebutarenotlimitedtopriorknowledge(publicorinternaldocuments),

drugdevelopmentstudies,technologytransferactivities,productlife-cycleprocessvalidation

studies,manufacturingexperience,innovation,continuousimprovement,andchangemanagement

activities.

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4.2.2.3Thequalityassurancesystemshallfocusonqualityevaluationandinspectionof

processperformance,dosageformanddosage,pharmacokineticsandbioavailabilityevaluation

aswellasmanagementofproductqualitymonitoringsystem,correctiveandpreventiveactions

system,changemanagementsystem,processperformanceandproductqualitymanagementand

evaluation,pharmacovigilance,clinicalrationaluse,medicationsafetysurveillance,

information-baseddrugtraceability,etc.

4.2.2.4Thesuitability,adequacyandeffectivenessofthequalitysystemshallbereviewed

andevaluatedregularlytoensurecontinuousimprovementofthequalitysystem.

4.2.3NTIDsmarketingauthorizationholdersshouldestablishgoodqualityevaluationsystems

andriskpreventionandcontrolsystemstoensureeffectivemonitoring,evaluationandcontrol

throughoutthelifecycle.

4.2.3.1Post-marketingriskmanagementplansshallbedevelopedandpost-marketingstudies

shouldbeactivelyconductedtofurtherverifythesafety,efficacyandqualitycontrollability

ofdrugs.

4.2.3.2Ongoingmanagementofmarketeddrugsshallbestrengthenedandinformationabout

suspectedadversedrugreactionsshouldbevoluntarilycollected,followedandanalyzedso

that,incaseofspecialsituations,effectivemeasurescanbetakentoensuredrugquality

andminimizerisks.

4.2.4InthedevelopmentofNTIDs,criticalconsiderationshouldbegiventoinformation

aboutadministereddosesandplasmaconcentrationmeasurement(includingpharmacy,

pharmacology,toxicology,andbioequivalencestudydata);drugdosages,drugreleasebehaviors

andcontentcontrolrangesshouldbefullyjustified.

4.2.5InthemanufactureofNTIDs,agoodqualityassurancesystemshouldbeestablishedto

ensurecontinuousproductionofdrugsthatstrictlymeetintendedquality.

4.2.6Procurement,storageandallocationshouldbestrictlymanagedinNTIDdistribution.

Agoodqualityassurancesystemshouldbeestablishedtoensurethedrugpersistentlymeets

qualityrequirementsthroughoutdistributionandthewholeprocessistraceable.

4.2.7ManagementofclinicaluseofNTIDsshallbestrengthenedtoensureclinicalusesafety.

4.2.7.1InclinicaluseofNTIDs,medicalinstitutionsshallestablishstandardized

managementregulations,clearpharmacovigilancereportregulationsanddrugsafetymonitoring

plansandstrengtheneducationandtrainingofrelatedresponsiblepersons.

4.2.7.2DoctorsprescribingNTIDsshouldstrictlyfollowinstructionsindrugpackageinserts.

Off-labeluseinspecialcircumstancesmustmeetrelevantregulations.Cautionshouldbe

exercisedinselectingandchangingNTIDsfromdifferentmanufacturers.

4.2.7.3InprovidingpharmaceuticalservicesrelatingtoNTIDsforpatients,pharmacists

shouldclearlyinformthedosagesandadministration,adversereactionrisksaswellas

requiredmedicationsafetymonitoringandstrengthenprescriptionreview,dispensingandother

technicalservices.

4.3QualityevaluationofNTIDs

4.3.1HumanbioequivalencestudiesforNTIDs

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4.3.1.1HumanbioequivalencestudiesforNTIDstypicallyincludeearlyphasestudydesign,

subjectselection,referenceproductselection,single-dosestudy,steady-statestudy,fed

bioequivalencestudy,analysisofbiologicalsamples,pharmacokineticparametersfor

evaluatingbioequ