起始物料定义.docx
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起始物料定义.docx
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起始物料定义
DrugSubstanceStartingMaterialSelection
Theauthorsreviewthecurrentregulatoryframeworkfortheselectionofdrugsubstancestartingmaterials.
Dec2,2008
By:
GrahamT.Illing, RobertJ.Timko, LindaBillett
PharmaceuticalTechnology
Volume32,Issue12,pp.52-57
(IMAGESOURCE/GETTYIMAGES)
Theterm startingmaterial hasbeenadoptedtoindicatethepointwhereregulatorychangecontrolandcurrentgoodmanufacturingpractices(CGMPs)areintroducedintothesynthesisofadrugsubstance.AtypicalexampleofadrugsubstancesynthesisisshowninFigure1.Thisgenericschemedepictsfourregulatorystepsandvariousqualitycontrolpoints(specifications).
Figure1:
Schematicofregulatorydrugsubstancesynthesis.Steps1–4involveacovalentbondformation.TheregulatorystepsaredisclosedintheMarketingAuthorizationApplicationandrequireregulatoryapprovalforchanges.Boxesinredhavethegreatestregulatorysignificance.Materialsinboldtextareusuallygivenacomprehensiveandrobustspecification.Boxesinorangearesyntheticintermediates,whichcanbeisolatedorremaininsitubutarecontrolledusingamorelimitedspecification.(IMAGESOURCE/GETTYIMAGES)
Usingascience-andrisk-basedframework,thisarticlereviewstheregulatoryguidelinesintheUnitedStates(USFoodandDrugAdministration),EuropeanUnion(EuropeanMedicinesAgency,EMEA),andJapan(MinistryofHealth,Labour,andWelfare,MHLW).Inaddition,theauthorsaddresstheInternationalConferenceonHarmonization(ICH)guidelinesthatcurrentlyimpacttheselectionofstartingmaterialsfornewdrugsubstancesforglobalregistration.ThediscussiontakesintoaccounttherecentguidancechangessincetheinitialpublicationwiththeintroductionofICHQ8 PharmaceuticalDevelopment andICHQ9 QualityRiskManagement andthewithdrawalofFDA'sBACPACIanddrugsubstanceICHguidances(1–5).
Guidancereview
ICHguidances. Thedefinitionofastartingmaterial,aspresentedinICHQ7 GoodManufacturingPracticeGuideforActivePharmaceuticalIngredients, reflectsthediversesourceofpotentialstartingmaterialsandnotesthatchemicalpropertiesandstructurearenormallydefined(6).Thefocusisforfieldinspectoruse(CGMP)ratherthanmarketingauthorizationapplication(MAA)ornewdrugapplication(NDA)review.Itdefineswhatmaybeconsideredastartingmaterial,ratherthanhowtoselectthestartingmaterialsforasynthesisfrom,forexample,therawmaterialsandtheintermediates.
Astartingmaterialcanbedefinedasarawmaterial,intermediate,oradrugsubstancethatisusedintheproductionofadrugsubstanceandthatisincorporatedasasignificantstructuralfragmentintothestructureofthedrugsubstance.Astartingmaterialcanbeanarticleofcommerce,amaterialpurchasedfromoneormoresuppliersundercontractorcommercialagreement,orproducedin-houseandisnormallyofdefinedchemicalpropertiesandstructure.
ICHQ8 PharmaceuticalDevelopment introducestheconceptofdesignspaceandamorescience-basedapproachtotheregulatorycontrolofthemanufactureofpharmaceuticalproductswithpotentialbenefitsofreducedregulatoryoversightforpostapprovalchanges
(2).TheconceptsofICHQ8applytodrugsubstancesanddrugproducts.
ICHQ9 QualityRiskManagement providesguidanceonasystematicapproachtoqualityriskmanagementforpharmaceuticalproducts(3).Theevaluationoftherisktoqualityshouldultimatelylinkbacktotheprotectionofthepatient,andthequalityrisk-managementprocessshouldbecommensuratewiththelevelofriskandbasedonscientificknowledge.
FDAguidance. FDA's GuidanceforSubmittingSupportingDocumentationinDrugApplicationsfortheManufactureofDrugSubstances notedthatwhatconstitutesastartingmaterialmaynotalwaysbeobvious.Thefollowingcriteriamaybehelpful(7):
∙Itisincorporatedintothenewdrugsubstanceasanimportantstructuralelement
∙Itiscommerciallyavailable
∙Itisacompoundwhosename,chemicalstructure,chemicalandphysicalcharacteristicsandproperties,andimpurityprofilearewelldefinedinthechemicalliterature
∙Itisobtainedbycommonlyknownprocedures(thisappliesprincipallytostartingmaterialsextractedfromplantsandanimals,andtosemi-syntheticantibiotics).
ThefinalintermediatecaninfluencetheselectionofthestartingmaterialsandisdefinedbyFDAasfollows(7,8):
Thelastcompoundsynthesizedbeforethereactionthatproducesthedrugsubstance.Thefinalstep,formingthenewdrugsubstance,mustinvolvecovalentbonds.Theformationofsimpleestersorionicbondsdoesnotqualifyasthefinalsyntheticstep.Whenthedrugsubstanceisasalt,theprecursorstotheorganicacidorbaseshouldbeconsideredthefinalintermediate.Theremaybemorethanonefinalintermediatedependingonthenatureofthesynthesis.
Figure2:
Exampleofanegotiatedstartingmaterialforanewdrugsubstancesynthesis.(IMAGESOURCE/GETTYIMAGES)
Recently,FDAusedtheconceptofa"negotiatedstartingmaterial"toallowsponsorsthe"option"ofreducedGMPdemandsforearlysyntheticstepswhileretainingregulatoryoversightoveranextendedsynthesis(seeFigure2).Theconceptallowsforan"intermediate"asdefinedbycurrentguidelinestobeconsideredastartingmaterial.Generally,thisresultsinreducedregulatoryflexibilityforstartingmaterialchangesbecauselongersynthesesaredisclosed.However,theremaybealternativeeconomicadvantagestothesponsorcompany.
EMEAguidance. TheCommitteeforMedicinalProductsforHumanUse(CHMP) GuidanceontheChemistryofNewActiveSubstances notesthatastartingmaterialisincorporatedasasignificantstructuralfragmentintothestructureofadrugsubstanceandmarksthebeginningofthedetaileddescriptionofthedrugsubstancesynthesis(9).StartingmaterialswithaCertificateoftheEuropeanPharmacopoeia(CEP)orsubjectofanapprovedMAAareacceptable.AnMAArequiresthefollowing:
∙Fullycharacterizedstartingmaterialswithcompletespecifications,includinganimpurityprofile
∙Nameandaddressofsupplier(s)
∙Thestartingmaterialjustification(giveninCommonTechnicalDocument[CTD]module3.2.S2.3"ControlofMaterials")
∙Aflowchartindicatingthesyntheticprocessbeforetheintroductionoftheproposedstartingmaterial(seeFigure1)
∙DemonstratedcontrolofAdventitiousAgentsandTransmissibleSpongiformEncephalopathy(TSE)ifderivedfromanimalsources.
TheEUGMPAnnex18adoptedtheICHQ7definitionofastartingmaterial(10).TableIofthisdocumentprovidesguidanceonwhereCGMPisappliedtoasyntheticprocess.
TheEuropeanDirectoratefortheQualityofMedicines(EDQM)PublicDocument,innotingthetop10deficienciesinCertificateoftheEuropeanPharmacopoeia(CEP)applications,identifiesthelackofdetailedinformationaboutthesynthesisofstartingmaterials,andimpuritycarryoverhasbeenhighlightedasthenumberonedeficiency(11).
MHLWguidance. TheJapaneseMHLWNotificationPFSB/ELD020001indicatesstartingmaterialsshouldbebasedontheICHQ7definition(PABnotificationnumber1200,Nov.2,2001)(12).ThestartingmaterialjustificationshouldbedescribedinCTDSection3.2.S2.6andincludethecriteriaforthestartingmaterialsandthename,principle,andoutlineoftestingmethods.
Theapplicantshouldstartthedescriptionofthemanufacturingprocessfromastepthatisnecessaryforensuringdrug-substancequality.Theguidancedefinesafinalintermediateandnotesthataregisteredsynthesisshouldincludemorestagesthanthefinalstage.
Fromthestandpointofriskcontrol,themanufacturingprocessstatedintheapplicationshouldincludeprocessesthatareessentialforensuringdrug-substancequality.Manufacturingparametersorchargedquantitiesshouldbeidentifiedaccordingtowhethertheycanbesubsequentlychangedbypriorapproval(partialchangeapplication,PCA)orbyaminoramendment(Notification).Changestothereactionprocess,includingstartingmaterials,orachangeofspecificationortestmethodiflikelytoimpactonqualityofdrugsubstancerequirespriorapproval(i.e.,PCA).
Selectionofstartingmaterials
Designspace. ICHQ8andQ9enablealternativeapproachestotheselectionandjustificationofstartingmaterials(2,9).ICHQ8definesdesignspaceas"themultidimensionalcombinationandinteractionofinputvariables(e.g.,materialsattributes)andprocessparametersthathavebeendemonstratedtoprovideassuranceofquality."Workingwithinthedesignspaceisnotconsideredachange.Movementoutofthedesignspaceisconsideredtobeachangeandwouldnormallyinitiatearegulatorypostapprovalchangeprocess.Designspaceisproposedbytheapplicantandissubjecttoregulatoryassessmentandapproval.Knowledgeofthedesignspacegainedthroughtheapplicationofscientificapproachesandqualityriskmanagement(ICHQ9)tothedevelopmentofaproductanditsmanufacturingprocessissharedwithregulatoryagenciestoestablishrisk-andscience-basedcontrolsthatwillbeapplicablethroughoutaproduct'slifecycle.
ThedegreeofregulatoryflexibilitygainedthroughICHQ8andICHQ9ispredicatedonthelevelofrelevantscientificknowledgeprovided.Theimpactcanbeseenwhencontrastingthetraditionalversusthedesignspaceapproachestoselectingstartingmaterials.
Thetraditionalapproachtostartingmaterialidentificationanddevelopmenthasinvolvedonlytwosteps:
∙Provideminimalstartingmaterialinformationaboutthelevelandfateofimpurities
∙Defineandmaintaintightspecificationsforstartingmaterialanddrugsubstancestocompensateforlimitedsynthet
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