Guidances (Drugs) - Drug Master Files - Guidelines

12/9/2015
Guidances(Drugs)>DrugMasterFiles:Guidelines
GUIDELINEFORDRUGMASTERFILES
I.INTRODUCTION
ADrugMasterFile(DMF)isasubmissiontotheFoodandDrugAdministration(FDA)thatmaybe
usedtoprovideconfidentialdetailedinformationaboutfacilities,processes,orarticlesusedinthe
manufacturing,processing,packaging,andstoringofoneormorehumandrugs.Thesubmissionof
aDMFisnotrequiredbylaworFDAregulation.ADMFissubmittedsolelyatthediscretionofthe
holder.TheinformationcontainedintheDMFmaybeusedtosupportanInvestigationalNewDrug
Application(IND),aNewDrugApplication(NDA),anAbbreviatedNewDrugApplication(ANDA),
anotherDMF,anExportApplication,oramendmentsandsupplementstoanyofthese.
ADMFisNOTasubstituteforanIND,NDA,ANDA,orExportApplication.Itisnotapprovedor
disapproved.TechnicalcontentsofaDMFarereviewedonlyinconnectionwiththereviewofan
IND,NDA,ANDA,oranExportApplication.
Thisguidelinedoesnotimposemandatoryrequirements(21CFR10.90(b)).Itdoes,however,offer
guidanceonacceptableapproachestomeetingregulatoryrequirements.Differentapproachesmay
befollowed,buttheapplicantisencouragedtodiscusssignificantvariationsinadvancewithFDA
reviewerstoprecludespendingtimeandeffortinpreparingasubmissionthatFDAmaylater
determinetobeunacceptable.
DrugMasterFilesareprovidedforin21CFR314.420.ThisguidelineisintendedtoprovideDMF
holderswithproceduresacceptabletotheagencyforpreparingandsubmittingaDMF.Theguideline
discussestypesofDMF's,theinformationneededineachtype,theformatofsubmissionstoaDMF,
theadministrativeproceduresgoverningreviewofDMF's,andtheobligationsoftheDMFholder.
DMF'saregenerallycreatedtoallowapartyotherthantheholderoftheDMFtoreferencematerial
withoutdisclosingtothatpartythecontentsofthefile.Whenanapplicantreferencesitsown
material,theapplicantshouldreferencetheinformationcontainedinitsownIND,NDA,orANDA
directlyratherthanestablishinganewDMF.
II.DEFINITIONS
Forthepurposesofthisguideline,thefollowingdefinitionsapply:
II.1.AgencymeanstheFoodandDrugAdministration.
II.2AgentorrepresentativemeansanypersonwhoisappointedbyaDMFholdertoserveasthe
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122886.htm
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contactfortheholder.
II.3.Applicantmeansanypersonwhosubmitsanapplicationorabbreviatedapplicationoran
amendmentorsupplementtothemtoobtainFDAapprovalofanewdrugoranantibioticdrugand
anyotherpersonwhoownsanapprovedapplication(21CFR314.3(b)).
II.4.Drugproductmeansafinisheddosageform,forexample,tablet,capsule,orsolution,that
containsadrugsubstance,generally,butnotnecessarily,inassociationwithoneormoreother
ingredients(21CFR314.3(b)).
II.5.Drugsubstancemeansanactiveingredientthatisintendedtofurnishpharmacologicalactivity
orotherdirecteffectinthediagnosis,cure,mitigation,treatment,orpreventionofdiseaseortoaffect
thestructureoranyfunctionofthehumanbody,butdoesnotincludeintermediatesusedinthe
synthesisofsuchingredient(21CFR314.3(b)).
II.6.Exportapplicationmeansanapplicationsubmittedundersection802oftheFederalFood,Drug,
andCosmeticActtoexportadrugthatisnotapprovedformarketingintheUnitedStates.
II.7.HoldermeansapersonwhoownsaDMF.
II.8.Letterofauthorizationmeansawrittenstatementbytheholderordesignatedagentor
representativepermittingFDAtorefertoinformationintheDMFinsupportofanotherperson's
submission.
II.9.Personincludesindividual,partnership,corporation,andassociation.(Section201(e)ofthe
FederalFood,Drug,andCosmeticAct.)
II.10.Sponsormeansapersonwhotakesresponsibilityforandinitiatesaclinicalinvestigation.The
sponsormaybeanindividualorpharmaceuticalcompany,governmentalagency,academic
institution,privateorganization,orotherorganization(21CFR312.3(b)).
III.TYPESOFDRUGMASTERFILES
TherearefivetypesofDMF's:
TypeIManufacturingSite,Facilities,OperatingProcedures,andPersonnel
TypeIIDrugSubstance,DrugSubstanceIntermediate,andMaterialUsedinTheirPreparation,or
DrugProduct
TypeIIIPackagingMaterial
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TypeIVExcipient,Colorant,Flavor,Essence,orMaterialUsedinTheirPreparation
TypeVFDAAcceptedReferenceInformation
EachDMFshouldcontainonlyonetypeofinformationandallsupportingdata.SeeSectionIV.Cof
theguidelineformoredetaileddescriptionsofthekindofinformationdesiredineachtype.
SupportinginformationanddatainaDMFcanbecrossreferencedtoanyotherDMF(seePartV).
IV.SUBMISSIONSTODRUGMASTERFILES
EachDMFsubmissionshouldcontainatransmittalletter,administrativeinformationaboutthe
submission,andthespecificinformationtobeincludedintheDMFasdescribedinthissection.
TheDMFmustbeintheEnglishlanguage.Wheneverasubmissioncontainsinformationinanother
language,anaccuratecertifiedEnglishtranslationmustalsobeincluded.
EachpageofeachcopyoftheDMFshouldbedatedandconsecutivelynumbered.Anupdatedtable
ofcontentsshouldbeincludedwitheachsubmission.
IV.A.TransmittalLetters
Thefollowingshouldbeincluded:
IV.A.1.OriginalSubmissions
a.Identificationofsubmission:Original,thetypeofDMFasclassifiedinSectionIII,anditssubject.
b.Identificationoftheapplications,ifknown,thattheDMFisintendedtosupport,includingthename
andaddressofeachsponsor,applicant,orholder,andallrelevantdocumentnumbers.
c.Signatureoftheholderortheauthorizedrepresentative.
d.Typewrittennameandtitleofthesigner.
IV.A.2.Amendments
a.Identificationofsubmission:Amendment,theDMFnumber,typeofDMF,andthesubjectofthe
amendment.
b.Adescriptionofthepurposeofsubmission,e.g.,update,revisedformula,orrevisedprocess.
c.Signatureoftheholderortheauthorizedrepresentative.
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d.Typewrittennameandtitleofthesigner.
IV.B.AdministrativeInformation
Administrativeinformationshouldincludethefollowing:
IV.B.1.OriginalSubmissions
a.Namesandaddressesofthefollowing:
(1)DMFholder.
(2)Corporateheadquarters.
(3)Manufacturing/processingfacility.
(4)ContactforFDAcorrespondence.
(5)Agent(s),ifany.
b.ThespecificresponsibilitiesofeachpersonlistedinanyofthecategoriesinSectiona.
c.Statementofcommitment.
AsignedstatementbytheholdercertifyingthattheDMFiscurrentandthattheDMFholderwill
complywiththestatementsmadeinit.
IV.B2.Amendments
a.NameofDMFholder.
b.DMFnumber.
c.Nameandaddressforcorrespondence.
d.Affectedsectionand/orpagenumbersoftheDMF.
e.ThenameandaddressofeachpersonwhoseIND,NDA,ANDA,DMF,orExportApplicationrelies
onthesubjectoftheamendmentforsupport.
f.ThenumberofeachIND,NDA,ANDA,DMF,andExportApplicationthatreliesonthesubjectof
theamendmentforsupport,ifknown.
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g.ParticularitemswithintheIND,NDA,ANDA,DMF,andExportApplicationthatareaffected,if
known.
IV.C.DrugMasterFileContents
IV.C.1.TypesofDrugMasterFiles
IV.C.1.a.TypeI:ManufacturingSite,Facilities,OperatingProcedures,
andPersonnel
ATypeIDMFisrecommendedforapersonoutsideoftheUnitedStatestoassistFDAinconducting
onsiteinspectionsoftheirmanufacturingfacilities.TheDMFshoulddescribethemanufacturingsite,
equipmentcapabilities,andoperationallayout.
ATypeIDMFisnormallynotneededtodescribedomesticfacilities,exceptinspecialcases,suchas
whenapersonisnotregisteredandnotroutinelyinspected.
Thedescriptionofthesiteshouldincludeacreage,actualsiteaddress,andamapshowingits
locationwithrespecttothenearestcity.Anaerialphotographandadiagramofthesitemaybe
helpful.
Adiagramofmajorproductionandprocessingareasishelpfulforunderstandingtheoperational
layout.Majorequipmentshouldbedescribedintermsofcapabilities,application,andlocation.Make
andmodelwouldnotnormallybeneededunlesstheequipmentisneworunique.
Adiagramofmajorcorporateorganizationalelements,withkeymanufacturing,qualitycontrol,and
qualityassurancepositionshighlighted,atboththemanufacturingsiteandcorporateheadquarters,
isalsohelpful.
IV.C.1.b.TypeII:DrugSubstance,DrugSubstanceIntermediate,and
MaterialUsedinTheirPreparation,orDrugProduct
ATypeIIDMFshould,ingeneral,belimitedtoasingledrugintermediate,drugsubstance,drug
product,ortypeofmaterialusedintheirpreparation.
IV.C.1.b.(1)DrugSubstanceIntermediates,DrugSubstances,and
MaterialUsedinTheirPreparation
Summarizeallsignificantstepsinthemanufacturingandcontrolsofthedrugintermediateor
substance.DetailedguidanceonwhatshouldbeincludedinaTypeIIDMFfordrugsubstancesand
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intermediatesmaybefoundinthefollowingguidelines:
GuidelineforSubmittingSupportingDocumentationinDrugApplicationsfortheManufactureofDrug
Substances.
GuidelinefortheFormatandContentoftheChemistry,Manufacturing,andControlsSectionofan
Application.
IV.C.1.b.(2)DrugProduct
Manufacturingproceduresandcontrolsforfinisheddosageformsshouldordinarilybesubmittedin
anIND,NDA,ANDA,orExportApplication.IfthisinformationcannotbesubmittedinanIND,NDA,
ANDA,orExportApplication,itshouldbesubmittedinaDMF.WhenaTypeIIDMFissubmittedfor
adrugproduct,theapplicant/sponsorshouldfollowtheguidanceprovidedinthefollowingguidelines:
GuidelinefortheFormatandContentoftheChemistry,Manufacturing,andControlsSectionofan
Application.
GuidelineforSubmittingDocumentationfortheManufactureofandControlsforDrugProducts
GuidelineforSubmittingSamplesandAnalyticalDataforMethodsValidation
IV.C.1.c.TypeIII:PackagingMaterial
Eachpackagingmaterialshouldbeidentifiedbytheintendeduse,components,composition,and
controlsforitsrelease.Thenamesofthesuppliersorfabricatorsofthecomponentsusedin
preparingthepackagingmaterialandtheacceptancespecificationsshouldalsobegiven.Data
supportingtheacceptabilityofthepackagingmaterialforitsintendeduseshouldalsobesubmitted
asoutlinedinthe"GuidelineforSubmittingDocumentationforPackagingforHumanDrugsand
Biologics."
ToxicologicaldataonthesematerialswouldbeincludedunderthistypeofDMF,ifnototherwise
availablebycrossreferencetoanotherdocument.
IV.C.1.d.TypeIVExcipient,Colorant,Flavor,Essence,orMaterialUsed
inTheirPreparation
Eachadditiveshouldbeidentifiedandcharacterizedbyitsmethodofmanufacture,release
specifications,andtestingmethods.
ToxicologicaldataonthesematerialswouldbeincludedunderthistypeofDMF,ifnototherwise
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availablebycrossreferencetoanotherdocument.
Usually,theofficialcompendiaandFDAregulationsforcoloradditives(21CFRParts70through
82),directfoodadditives(21CFRParts170through173),indirectfoodadditives(21CFRParts174
through178),andfoodsubstances(21CFRParts181through186)maybeusedassourcesfor
releasetests,specifications,andsafety.GuidelinessuggestedforaTypeIIDMFmaybehelpfulfor
preparingaTypeIVDMF.TheDMFshouldincludeanyothersupportinginformationanddatathat
arenotavailablebycrossreferencetoanotherdocument.
IV.C.1.e.TypeV:FDAAcceptedReferenceInformation
FDAdiscouragestheuseofTypeVDMF'sformiscellaneousinformation,duplicateinformation,or
informationthatshouldbeincludedinoneoftheothertypesofDMF's.Ifanyholderwishestosubmit
informationandsupportingdatainaDMFthatisnotcoveredbyTypesIthroughIV,aholdermust
firstsubmitaletterofintenttotheDrugMasterFileStaff(foraddress,seeD.5.a.ofthissection).
FDAwillthencontacttheholdertodiscusstheproposedsubmission.
IV.C.2.GeneralInformationandSuggestions
IV.C.2.a.EnvironmentalAssessment
TypeII,TypeIII,andTypeIVDMF'sshouldcontainacommitmentbythefirmthatitsfacilitieswillbe
operatedincompliancewithapplicableenvironmentallaws.Ifacompletedenvironmental
assessmentisneeded,see21CFRPart25.
IV.C.2.b.Stability
Stabilitystudydesign,data,interpretation,andotherinformationshouldbesubmitted,when
applicable,asoutlinedinthe"GuidelineforSubmittingDocumentationfortheStabilityofHuman
DrugsandBiologics."
IV.D.Format,Assembly,andDelivery
IV.D.1.
AnoriginalandduplicatearetobesubmittedforallDMFsubmissions.
DrugMasterFileholdersandtheiragents/representativesshouldretainacompletereferencecopy
thatisidenticalto,andmaintainedinthesamechronologicalorderas,theirsubmissionstoFDA.
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IV.D.2.
Theoriginalandduplicatecopiesmustbecollated,fullyassembled,
andindividuallyjacketed.
EachvolumeofaDMFshould,ingeneral,benomorethan2inchesthick.Formultivolume
submissions,numbereachvolume.Forexample,fora3volumesubmission,thevolumeswouldbe
numbered1of3,2of3,and3of3.
IV.D.3.
U.S.standardpapersize(81/2by11inches)ispreferred.
Paperlengthshouldnotbelessthan10inchesnormorethan12inches.However,itmay
occasionallybenecessarytouseindividualpageslargerthanstandardpapersizetopresentafloor
plan,synthesisdiagram,batchformula,ormanufacturinginstructions.Thosepagesshouldbefolded
andmountedtoallowthepagetobeopenedforreviewwithoutdisassemblingthejacketand
refoldedwithoutdamagewhenthevolumeisshelved.
IV.D.4.
Theagency'ssystemforfilingDMF'sprovidesforassemblyontheleftsideofthepage.Theleft
marginshouldbeatleastthreefourthsofaninchtoassurethattextisnotobscuredinthefastened
area.Therightmarginshouldbeatleastonehalfofaninch.Thesubmittershouldpunchholes81/2
inchesapartineachpage.Seethepagemeasurementsshowninthefollowingfigure:
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IV.D.5.DeliverytoFDA
IV.D.5.a.
DrugMasterFilesubmissionsandcorrespondenceshouldbe
addressedasfollows:
DrugMasterFileStaff
FoodandDrugAdministration
5901BAmmendaleRd.
Beltsville,MD207051266
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IV.D.5.b.Deliverychargestotheaboveaddressmustbeprepaid.
V.AUTHORIZATIONTOREFERTOADRUGMASTERFILE
V.A.LetterofAuthorizationtoFDA
BeforeFDAcanreviewDMFinformationinsupportofanapplication,theDMFholdermustsubmitin
duplicatetotheDMFaletterofauthorizationpermittingFDAtoreferencetheDMF.Iftheholder
crossreferencesitsownDMF,theholdershouldsupplyinaletterofauthorizationtheinformation
designatedbyitems3,5,6,7,and8ofthissection.Theholderdoesnotneedtosendatransmittal
letterwithitsletterofauthorization.
Theletterofauthorizationshouldincludethefollowing:
1.
2.
3.
4.
5.
6.
7.
8.
Thedate.
NameofDMFholder.
DMFnumber.
Nameofperson(s)authorizedtoincorporateinformationintheDMFbyreference.
Specificproduct(s)coveredbytheDMF.
Submissiondate(s)of5,above.
Sectionnumbersand/orpagenumberstobereferenced.
StatementofcommitmentthattheDMFiscurrentandthattheDMFholderwillcomplywiththe
statementsmadeinit.
9. Signatureofauthorizingofficial.
10. TypednameandtitleofofficialauthorizingreferencetotheDMF.
V.B.CopytoApplicant,Sponsor,orOtherHolder
Theholdershouldalsosendacopyoftheletterofauthorizationtotheaffectedapplicant,sponsor,or
otherholderwhoisauthorizedtoincorporatebyreferencethespecificinformationcontainedinthe
DMF.Theapplicant,sponsor,orotherholderreferencingaDMFisrequiredtoincludeacopyofthe
DMFholder'sletterofauthorizationintheapplication.
VI.PROCESSINGANDREVIEWINGPOLICIES
VI.A.PoliciesRelatedtoProcessingDrugMasterFiles
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VI.A.1.
PublicavailabilityoftheinformationanddatainaDMFisdetermined
under21CFRPart20,21CFR314.420(e),and21CFR314.430.
VI.A.2.
AnoriginalDMFsubmissionwillbeexaminedonreceipttodetermine
whetheritmeetsminimumrequirementsforformatandcontent.Ifthe
submissionisadministrativelyacceptable,FDAwillacknowledgeits
receiptandassignitaDMFnumber.
Ifthesubmissionisadministrativelyincompleteorinadequate,itwillbereturnedtothesubmitterwith
aletterofexplanationfromtheDrugMasterFileStaff,anditwillnotbeassignedaDMFnumber.
VI.B.DrugMasterFileReview
ADMFISNEVERAPPROVEDORDISAPPROVED.
TheagencywillreviewinformationinaDMFonlywhenanINDsponsor,anapplicantforanNDA,
ANDA,orExportApplication,oranotherDMFholderincorporatesmaterialintheDMFbyreference.
Asnoted,theincorporationbyreferencemustbeaccompaniedbyacopyoftheDMFholder'sletter
ofauthorization.
IfFDAreviewersfinddeficienciesintheinformationprovidedinaDMF,aletterdescribingthe
deficienciesissenttotheDMFholder.Atthesametime,FDAwillnotifythepersonwhoreliesonthe
informationinthedeficientDMFthatadditionalinformationisneededinthesupportingDMF.The
generalsubjectofthedeficiencyisidentified,butdetailsofthedeficiencyaredisclosedonlytothe
DMFholder.WhentheholdersubmitstherequestedinformationtotheDMFinresponsetothe
agency'sdeficiencyletter,theholdershouldalsosendacopyoftheaccompanyingtransmittalletter
totheaffectedpersonsrelyingontheDMFandtotheFDAreviewingdivisionthatidentifiedthe
deficiencies.Thetransmittalletterwillprovidenoticethatthedeficiencieshavebeenaddressed.
VII.HOLDEROBLIGATIONS
Anychangeoraddition,includingachangeinauthorizationrelatedtospecificcustomers,shouldbe
submittedinduplicateandadequatelycrossreferencedtoprevioussubmission(s).Thereference
shouldincludethedate(s),volume(s),section(s),and/orpagenumber(s)affected.
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VII.A.NoticeRequiredforChangestoaDrugMasterFile
AholdermustnotifyeachaffectedapplicantorsponsorwhohasreferenceditsDMFofanypertinent
changeintheDMF(21CFR314.420(c)).Noticeshouldbeprovidedwellbeforemakingthechange
inordertopermitthesponsor/applicanttosupplementoramendanyaffectedapplication(s)as
needed.
VII.B.ListingofPersonsAuthorizedToRefertoaDrugMasterFile
VII.B.1.
ADMFisrequiredtocontainacompletelistofpersonsauthorizedto
incorporateinformationintheDMFbyreference[21CFR314.420(d)].
Theholdershouldupdatethelistintheannualupdate.Theupdatedlist
shouldcontaintheholder'sname,DMFnumber,andthedateofthe
update.Theupdateshouldidentifybyname(orcode)theinformation
thateachpersonisauthorizedtoincorporateandgivethelocationof
thatinformationbydate,volume,andpagenumber.
VII.B.2.
Anypersonwhoseauthorizationhasbeenwithdrawnduringthe
previousyearshouldbeidentifiedunderasuitablecaption.
VII.B.3.
Ifthelistisunchangedontheanniversarydate,theDMFholdershould
alsosubmitastatementthatthelistiscurrent.
VII.C.AnnualUpdate
Theholdershouldprovideanannualreportontheanniversarydateoftheoriginalsubmission.This
reportshouldcontaintherequiredlistasdescribedinB.1.,andshouldalsoidentifyallchangesand
additionalinformationincorporatedintotheDMFsincethepreviousannualreportonthesubject
matteroftheDMF.IfthesubjectmatteroftheDMFisunchanged,theDMFholdershouldprovidea
statementthatthesubjectmatteroftheDMFiscurrent.
FailuretoupdateortoassureFDAannuallythatpreviouslysubmittedmaterialandlistsintheDMF
remaincurrentcancausedelaysinFDAreviewofapendingIND,NDA,ANDA,ExportApplication,
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oranyamendmentorsupplementtosuchapplicationandFDAcaninitiateproceduresforclosureof
theDMF(seeSectionIX).
VII.D.AppointmentofanAgent
Whenanagentisappointed,theholdershouldsubmitasignedletterofappointmenttotheDMF
givingtheagent'sname,address,andscopeofresponsibility(administrativeand/orscientific).
DomesticDMFholdersdonotneedtoappointanagentorrepresentative,althoughforeignDMF
holdersareencouragedtoengageaU.S.agent.
VII.E.TransferofOwnership
TotransferownershipofaDMFtoanotherparty,theholdershouldsonotifyFDAandauthorized
personsinwriting.Thelettershouldincludethefollowing:
1.
2.
3.
4.
5.
6.
Nameoftransferee
Addressoftransferee
Nameofresponsibleofficialoftransferee
Effectivedateoftransfer
Signatureofthetransferringofficial
Typewrittennameandtitleofthetransferringofficial.
Thenewholdershouldsubmitaletterofacceptanceofthetransferandanupdateoftheinformation
containedintheDMF,whereappropriate.Anychangerelatingtothenewownership(e.g.,plant
locationandmethods)shouldbeincluded.
VIII.MAJORREORGANIZATIONOFADRUGMASTERFILE
AholderwhoplansamajorreorganizationofaDMFisencouragedtosubmitadetailedplanofthe
proposedchangesandrequestitsreviewbytheDrugMasterFileStaff.Thestaffshouldbegiven
sufficienttimetocommentandprovidesuggestionsbeforeamajorreorganizationisundertaken.
IX.CLOSUREOFADRUGMASTERFILE
AholderwhowishestocloseaDMFshouldsubmitarequesttotheDrugMasterFileStaffstating
thereasonfortheclosure.SeeSectionIV.D.5.afortheaddress.
Therequestshouldincludeastatementthattheholder'sobligationsasdetailedinSectionVIIhave
beenfulfilled.
TheAgencymaycloseaDMFthatdoesnotcontainanannualupdateofpersonsauthorizedto
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incorporateinformationintheDMFbyreferenceandalistofchangesmadesincetheprevious
annualreport.TheholderwillbenotifiedofFDA'sintenttoclosetheDMF.
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