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May2010年5月
TABLEOFCONTENTS
I.INTRODUCTION
(1)4
II.QUESTIONSANDANSWERS6
A.ForGeneralClarification(1.1)6
B.QualitybyDesign(QbD)Topics
(2)6
1.DesignSpace(2.1)6
2.Real-TimeReleaseTesting(2.2)9
3.ControlStrategy(2.3)11
C.PharmaceuticalQualitySystem(3)12
D.ImpactofNewICHQualityGuidanceonGMPInspectionPractices(4)14
E.KnowledgeManagement(5)15
F.SoftwareSolutions(6)17
GuidanceforIndustry1
工业指南Q8,Q9和Q10问答
ThisguidancerepresentstheFoodandDrugAdministration’s(FDA’s)currentthinkingonthistopic.ItdoesnotcreateorconferanyrightsfororonanypersonanddoesnotoperatetobindFDAorthepublic.Youcanuseanalternativeapproachiftheapproachsatisfiestherequirementsoftheapplicablestatutesandregulations.Ifyouwanttodiscussanalternativeapproach,contacttheFDAstaffresponsibleforimplementingthisguidance.IfyoucannotidentifytheappropriateFDAstaff,calltheappropriatenumberlistedonthetitlepageofthisguidance.
I.INTRODUCTION
(1)概述
SincetheQ8,Q9,andQ10guidancesweremadefinal,experiencesimplementingtheguidancesintheICHregionshavegivenrisetorequestsforclarification.Thisquestionandanswer(Q&
A)documentisintendedtoclarifykeyissues.TheguidancereflectsthecurrentworkingprocedureoftheICHQualityImplementationWorkingGroup(Q-IWG)forimplementingtheQ8,Q9,andQ10guidances.
ThebenefitsofharmonizingtechnicalrequirementsacrosstheICHregionscanberealizedonlyifthevariousqualityICHguidancesareimplementedandinterpretedinaconsistentwayacrossthethreeregions.TheQ-IWGistaskedtodevelopQ&
Astofacilitateimplementationofexistingqualityguidance.
TheQ&
AsreferencethefollowingICHguidancesavailableontheInternetathttp:
//www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htmunderInternationalConferenceonHarmonisation—Quality:
Q8(R2)PharmaceuticalDevelopment(includestheQ8parentguidance(PartI)andtheannex(PartII),whichprovidesfurtherclarificationoftheQ8parentguidanceanddescribestheprinciplesofqualitybydesign)
Q9QualityRiskManagement质量风险管理
Q10PharmaceuticalQualitySystems药品质量体系
FDA’sguidancedocuments,includingthisguidance,donotestablishlegallyenforceableresponsibilities.Instead,guidancesdescribetheAgency’scurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutoryrequirementsarecited.TheuseofthewordshouldinAgencyguidancesmeansthatsomethingissuggestedorrecommended,butnotrequired.
II.QUESTIONSANDANSWERS问答
A.ForGeneralClarification(1.1)一般问题
Q1:
Istheminimalapproachacceptedbyregulators?
A1:
Yes.TheminimalapproachasdefinedinQ8(R2)(sometimealsocalled“baseline”or“traditional”approach)istheexpectationthatistobeachievedforafullyacceptablesubmission.However,the“enhanced”approachasdescribedinICHQ8(R2)isencouraged(Ref.Q8(R2)Annex,appendix1).(ApprovedJune2009)
Q2:
WhatisanappropriateapproachforprocessvalidationusingICHQ8,Q9,andQ10?
A2:
TheobjectivesofprocessvalidationareunchangedwhenusingICHQ8,Q9,andQ10.Themainobjectiveofprocessvalidationremainsthataprocessdesignyieldsaproductmeetingitspredefinedqualitycriteria.ICHQ8,Q9,andQ10provideastructuredwaytodefineproductcriticalqualityattributes,designspace,themanufacturingprocess,andthecontrolstrategy.Thisinformationcanbeusedtoidentifythetypeandfocusofstudiestobeperformedpriortoandoninitialcommercialproductionbatches.Asanalternativetothetraditionalprocessvalidation,continuousprocessverification(seedefinitioninICHQ8R
(2)glossary)canbeutilizedinprocessvalidationprotocolsfortheinitialcommercialproductionandformanufacturingprocesschangesforthecontinualimprovementthroughouttheremainderoftheproductlifecycle.(ApprovedOctober2009)
Q3:
HowcaninformationfromriskmanagementandcontinuousprocessverificationprovideforarobustcontinualimprovementapproachunderICHQ8,Q9andQ10?
A:
Liketheproductitself,processvalidationalsohasalifecycle(processdesign,processqualificationandongoingprocessverification).Ariskassessmentconductedpriortoinitialcommercialvalidationbatchescanhighlighttheareaswhereparticularfocusanddatacollectioncoulddemonstratethedesiredhighlevelofassuranceofcommercialprocessrobustness.Continualmonitoring(e.g.,viacontinuousprocessverification)canfurtherdemonstratetheactuallevelofassuranceofprocessconsistencyandprovidethebasisforcontinualimprovementoftheproduct.QualityRiskManagementmethodologiesofICHQ9canbeappliedthroughouttheproductlifecycletomaintainastateofprocesscontrol.(ApprovedOctober2009)
B.QualitybyDesign(QbD)Topics
(2)
Isitalwaysnecessarytohaveadesignspace(DS)orreal-timerelease(RTR)testingtoimplementQbD?
UnderQualitybyDesign,establishingadesignspaceorusingreal-timereleasetestingisnotnecessarilyexpected(ICHQ8(R2)).(ApprovedApril2009)
1.DesignSpace(2.1)
Isitnecessarytostudymultivariateinteractionsofallparameterstodevelopadesignspace?
No,theapplicantshouldjustifythechoiceofmaterialattributesandparametersformultivariateexperimentationbasedonriskassessmentanddesiredoperationalflexibility.(ApprovedApril2009)
Canadesignspacebeapplicabletoscale-up?
Yes,whenappropriatelyjustified(foradditionaldetails,seeQ8(R2)AnnexsectionII.D.4(2.4.4)).Anexampleofascale-independentdesignspaceisprovidedintheEuropeanFederationofPharmaceuticalIndustriesandAssociations(EFPIA)MockP2document(EFPIAMockP2submissionon“Examplain”:
ChrisPotter,RafaelBeerbohm,AlastairCoupe,FritzErni,GerdFischer,StaffanFolestad,GordonMuirhead,StephanRoenninger,AlistairSwanson,AguidetoEFPIA’s“MockP.2”Document,Pharm.Tech.(Europe),18,December2006,39-44).
Thisexamplemaynotreflectthefullregulatoryrequirementsforascale-up.(ApprovedApril2009)
Canadesignspacebeapplicabletoasitechange?
A3:
Yes,itispossibletojustifyasitechangeusingasiteindependentdesignspacebasedonademonstratedunderstandingoftherobustnessoftheprocessandanindepthconsiderationofsitespecificfactors(e.g.,equipment,personnel,utilities,manufacturingenvironment,andequipment).Thereareregionspecificregulatoryrequirementsassociatedwithsitechangesthatneedtobefollowed.(ApprovedApril2009)
Q4:
Canadesignspacebedevelopedforsingleand/ormultipleunitoperations?
A4:
Yes,itispossibletodevelopadesignspaceforsingleunitoperationsoracrossaseriesofunitoperations(seeQ8(R2)Annex,sectionII.D.3(2.4.3)).(ApprovedApril2009)
Q5Isitpossibletodevelopadesignspaceforexistingproducts?
A5:
Yes,itispossible.Manufacturingdataandprocessknowledgecanbeusedtosupportadesignspaceforexistingproducts.Relevantinformationshouldbeutilizedfrome.g.,commercialscalemanufacturing,processimprovement,correctiveandpreventiveaction(CAPA),anddevelopmentdata.
Formanufacturingoperationsrunundernarrowoperationalrangesinfixedequipment,anexpandedregionofoperationandanunderstandingofmulti-parameterinteractionsmaynotbeachievablefromexistingmanufacturingdataaloneandadditionalstudiesmayprovidetheinformationtodevelopadesignspace.Sufficientknowledgeshouldbedemonstrated,andthedesignspaceshouldbesupportedexperimentallytoinvestigateinteractionsandestablishparameter/attributeranges.(ApprovedApril2009)
Q6:
Istherearegulatoryexpectationtodevelopadesignspaceforanexistingproduct?
A6:
No,developmentofdesignspaceforexistingproductsisnotnecessaryunlesstheapplicanthasaspecificneedanddesirestouseadesignspaceasameanstoachieveahigherdegreeofproductandprocessunderstanding.Thismayincreasemanufacturingflexibilityand/orrobustness.(ApprovedApril2009)
Q7:
Canadesignspacebeapplicabletoformulation?
A7:
Yes,itmaybepossibletodevelopformulation(notcomponentbutrathercomposition)designspaceconsistingoftherangesofexcipientamountanditsphysicochemicalproperties(e.g.,particlesizedistribution,substitutionde