innovator

ORALTABLETSDEVELOPMENTCHAPTER2

HandbookofPPharmaceuticalSect:22.15GenericDDevelopment

PRODUCTDEVELOPMENTGUIDE

PRE-FORMULATION-TABLETS

Introduction

GuidelinesforthedevelopmentofaANDAproductfortheUSmarket,Note:sometestsor

erofperformingthevariousstagesmaychange

uidelinesmaybemodifiedforother

geographiczones.

DevelopmentStage

ScopeofProductDevelopment

Stage1LiteratureSearch

,PDR,Martindale,Merck,Florey,Vidal

FDA-FOISummaryBasisofApproval

On-linecomputerized

arch

FDACDER

ElectronicDataBa(articlesandpublicationontestmethods,

Dissolutionsynthesisprocedures,drugimpurities,

pharmacokineticsanddynamics)

EvaluationofBiostudyparameters,Dissolutionmethods.

PatentevaluationOrangeGuide+FDACDERWWWPatentConsultant

Stage2ActiveSourcing

SourcingforActive

RawMaterial

InternationalSuppliersUS,European,Asian,e.g.(ACIC-Canada)

(AllChem-UK)(Lek-Czech),(Esteves;Moehs;Uquifa-Spain);

(Biopharma,S.I.M,Midy-Italy)(Chemcaps,Reddy;Tricon-India);

(Federa-Brusls)-Reviewsupplierscatalogues&datacritically.

PotentialSuppliersListRequestsamplesandCofAandSpecifications

Evaluateatleasttwosuppliersfully.

Stage3ActiveEvaluation

EvaluatePotential

Actives

Evaluateatleasttwotothreepotentialactivesuppliers

•DMFavailability

•CompliancewithUSPmonograph

•Impurityprofileandstability

•PotentialPolymorphicforms

•Commitmentforphysicalspecifications

•Statementofnon-patentinfringement

Stage4ActivePurchasing

Purcha(Potential)

ActiveMaterial

Evaluateatleasttwopotentialactivematerialsuppliersfor

approvedsupplierstatus

Stage5ActiveTesting

TestingofActive

Materialsample

ChemicaltestingbytheR&Danalyticallabasper

copoeiamonograph(ifprent)

copoeiaForum(ifavailable)

-houmethod(badonmanufacturer)

er'stestmethodsandspecifications

ORALTABLETSDEVELOPMENTCHAPTER2

HandbookofPPharmaceuticalSect:22.16GenericDDevelopment

PRE-FORMULATION

Development

Stage

ScopeofProductDevelopment

Stage6Innovator'sProductPurchasing

DRUGPRODUCT

InnovatorSamples

Purchaatleast3differentlotsinsmallestandlargestpacksize

foreachproductstrength

Stage7Innovator'sProductTesting

InnovatorTestingEvaluatephysicalparameters:-

tabletshape,tabletcolor,codeforpunchembossing,packsizes

containersmaterials,closuretypes;cottonanddesiccants.

InnovatorPhysical

Testing

Physicaltesting

Weight;Thickness;Hardness;LOD;Friability;Disintegration:

Evaluationoftabletpunch;size;score;embossingandshape

EvaluationofInnovator

formulaingredients

SummaryFormulainPDR;InternationalPDRs(Italian,French,

Swiss)andInnovatorsproduct'sinrt(obtainlatestFOI-FDA)

Performactualanalyticaltestingoninnovator'sproduct.

Microscopic

obrvation

Particle/crystalinformationon

Particlesize

Crystalshape,habit,

Differentiationontheprenceofspecificexcipientscanbe

verifiedfrommicroscopicobrvation.E.g.,Cross-linked

cellulo'sStarchandAvicelhaveaspecificshapesand

morphologyandmaybeeasilydetected.

EvaluationofBiostudy

parameters

ReviewFDACDERHomepageforlistingandBiostudy

parameters

DissolutionprofileUSPmonographandFDAmethod-(whereprent)

Dissolution;12unitDissolutionProfile.

Stage8BulkActiveTesting

FIRSTBATCHFROM

APPROVEDSUPPLIER

FullPhysical

characterization

Physicalcharacterizationofbulkbatch

•Polymorphism

•B.E.T.

•Particlesizedistribution(&methoddevelopment)

•Bulkdensity;

•Microscopicobrvation

FULLCHEMICAL

CHARACTERIZATION

Chemicalcharacterization

•Assay

•StresdAnalysis

•Degradants(Expected)

•Impurityprofile

•Opticalrotation

•Enantiomericpurity

•g

ORALTABLETSDEVELOPMENTCHAPTER2

HandbookofPPharmaceuticalSect:22.17GenericDDevelopment

DEVELOPMENTBATCHES

DevelopmentStage

ScopeofProductDevelopment

Stage9Excipients

Evaluationofformu-

lationwithsuitable

excipients

ExcipientcompatibilityusingDSCmethodsandstability

asssment

Stage10ContainerClosureSystem

Evaluationofsuitable

Container-Closure

System

Choiceofcontainer-closure-linersystemincluding:

•materialcomposition,

•typeofthermoplasticresinandresinpigments,

•manufacturersandsuppliers,

•linersandalsudbyclosuremanufacturer,

•cottonanddesiccants.

•manufacturer'sDMFnumbersforallcomponentparts

•LettersofAccessforregulatoryauthoritiestoviewDMFdossiers

Stage11ManufacturingProcess

EVALUATION

SUITABLE

MANUFACTURING

PROCESSES

WetGranulation

DryGranulation

SluggingandDry

Granulation

•Wetgranulation(aqueousornonaqueous)

highshearmixing/lowshearmixing

•FBDsprayprocedure),or

•Drymixing,drygranulationand/'orSlugging

•Determinationoforderofmixing

•Determinationofpre-mixing(inGranulator)

•Determinationoffluidaddition(ifrelevant)

•Determinationofgranulationtime(chopperI&II)

•Determinationoftorqueend-pointvalue

•DeterminationofDryingparameters

•DeterminationofLODlimits

•DeterminationoftestingtemperatureforcheckingLODlimits

(r™,Computrac™).

GRANULATION

PhysicalPropertiesof

Granulate

•Flowproperties,

•Density,

•Particle-sizedistribution

•Compressibility

Compression

PhysicalPropertiesof

CompresdTablets

•Weight,•Hardness,

•Thickness,•Friability

•Disintegration•Dissolution

FinalFormula

Established

AsssmentofFinalMasterFormulaandaccelerated1-3month

stabilityprofile.

Stage12BulkActivePurchad

Activematerial

Bulkpurcha

OrderingofActivematerialforProcessQualification(PQ)and

PivotalBatch(es).

Onapprovaloffinalformula,ordersufficientmaterialforthePQ

(2)andPivotalLots(sufficientforallstrengthsandbatchsizes).

NB:NevermixbatchnumbersinPQandPivotalLots.

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HandbookofPPharmaceuticalSect:22.18GenericDDevelopment

FULLLABORATORYEVALUATION

DevelopmentScopeofProductDevelopment

Stage13AnalyticalEvaluation

Analyticaltestingof

tablets/Caplets

•Dissolution-inUSPmedium(Multipointprofiles)andother

relevantmediaversusInnovator'sproduct

•oUSPrequirements

mityofdosageunits.

•;Dissolution;Content

UniformitycompletedpriortoProcessQualification

PROCESSOPTIMIZATION

DevelopmentScopeofProductDevelopment

Stage14ProcessOptimization

GRANULATION

OPTIMIZATION

•Effectofgranulationparameters

•Granulationtime

•Speedofchoppers(I&II)ormixerblades

•Solventadditionrateandoverallamount

•Ratioofintra-granulateDisintegrantandbindersagents

•Screensizeformilling(e.g.0.6or0.8mm)

•Adjustingmillscreensizeupordowntofinetunehardness

•Evaluationofoptimizedgranulateandtabletattributes

DRYING•FBDryingtemperatureversustargetLODandrangelimitsand

theeffectongranulateandtabletproperties(flow,capping,

sticking).

BLENDING◊Blendingtimes

◊LubricantSplitintotwoparts(pre-blendingandfinalblending)

◊TheeffectonContentUniformity,Granulelubricationand

Dissolutionprofile.

◊tUniformity

COMPRESSION∗Effectofhardnessontabletproperties(aging,dissolution,

friability).

∗EvaluationofHardnessRangeLimits

∗s

PROCESS

OPTIMIZATION

REPORT

∗ocessOptimizationReportforms

partoftheproductDevelopmentReport

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HandbookofPPharmaceuticalSect:22.19GenericDDevelopment

ESTABLISHINGANDINVITROINVIVOCORRELATION

DevelopmentScopeofProductDevelopment

Stage15AnalyticalEvaluation

IVIVCorrelation•Dissolution-inUSPmedium(Multipointprofiles)andother

relevantmediaversusInnovator'sproduct.

•PerformIVIVBioavailabilityStudy(whererelevant)

EstablishaLevelAorCcorrelationwithoutadjustingdissolution

parametersandtimescale

•Adjustthedissolutionparametersortimescaletoachievea

LevelAorCcorrelation(adjustonlyifnecessary)

SCALEUP

DevelopmentScopeofProductDevelopment

Stage16SCALEUP

Scale-up

Scale-uplotpreparediflargerbatchsizescaleupproblems

anticipated.

ProcessQualificationbatchandScale-upbatchmaybe

evaluatedasasinglebatch.

le-upreportforms

partoftheoverallDevelopmentReport

PROCESSQUALIFICATION

Development

Stage

ScopeofProductDevelopment

Stage17ProcessQualification

Theprocessqualificationbatchismanufacturedinordertodetectanyproblemsthatmayariduring

themanufactureofproductionsizebatches,allowingasolutionpriorthemanufactureofthepivotal

-uptothepivotalbatchsizeor70%ofthepivotalbatchmaybecombined

withqualifyingthemanufacturingprocessAtthisstagefullmanufacturingdocumentationisprepared

alonestandardprocedures.

PRODUCTION

FACILITIES

ProcessQualificationbatchshouldbecompresdinaproduction

(orproductiontypewithsameprincipleandoperation)tabletting

machine

Sizeofpivotalandmarketingbatchconfirmed(NLT100000net/

packedattargetparametersor10%ofpropodmarketbatch).

BATCH

DOCUMENTATION

PreparationofMasterFormulaandProcessingInstructions

Discussionofformula,manufacturingprocessandcontrol

parameterswithproductionpersonnelandQAStaff

ORALTABLETSDEVELOPMENTCHAPTER2

HandbookofPPharmaceuticalSect:22.20GenericDDevelopment

PROCESSQUALIFICATION

DevelopmentStage

ScopeofProductDevelopment

Stage17(Cont)ProcessQualification

FINALREVIEWand

AUTHORIZATION

Reviewofpropodformula,manufacturingprocessandcontrol

parameterswithproductionpersonnelandQAStaffwith

authorizationsignatures(RD;QA-QC;RA;andProduction)

olprepared

KEYSTEPSCriticalmanufacturingstepsdesignatedandsamplingandtesting

parametersspecified.

OPERATING

CONDITIONS

PrenceofproductionandcontrolpersonnelduringPQ

manufacture

-Q

reportformspartoftheoverallDevelopmentReport

PIVOTALBATCH

DevelopmentScopeofProductDevelopment

Stage18PivotalProduction

PRODUCTION

FACILITIES

PivotalbatchMUSTbecompresdinaproductiontabletting

machine(orproductiontypewithsameprincipleandoperation)

BATCH

DOCUMENTATION

PreparationofFINALMasterFormulaandProcessingInstructions

REVIEWand

AUTHORIZATION

ReviewofFINALformula,manufacturingprocessandcontrol

l

authorizationsignatures(RD;QA-QC;RA;andProduction)

attached.

OPERATING

CONDITIONS

OperationofproductionandcontrolpersonnelduringPivotal

manufacture,aidedbydevelopmentteam.

votalreportformspart

oftheoverallDevelopmentReport.

BIOEQUIVALENTSTUDY

StageScopeofProductDevelopment

Stage19BIOSTUDYEvaluation

BIOSTUDYFastedPerformFasted/FoodEffectBiostudyonPivotalLotSamples

BIOSTUDY

[FoodEffect]

PerformFoodEffectBiostudyonPivotalLotSamples(Seefood

effectguidelines,whereappropriate)

HIGHESTDOSAGEBiostudygenerallyperformedonhigheststrengthofproduct

OneortwostudiesFastedANDFoodEffectStudymayberequired

WAIVER

CONDITIONS

FormultiplestrengthproductsInvitrodissolutiontestingconducted

inthreedifferentpHmediaonlowerdosageforms

SIMILARITYTESTINGPerformSimilarityTest[F

2

Test]ondissolutionresults.

ORALTABLETSDEVELOPMENTCHAPTER2

HandbookofPPharmaceuticalSect:22.21GenericDDevelopment

PRE-SUBMISSIONAUDITING

DevelopmentStageScopeofProductDevelopment

Stage20ANDAPre-SubmissionAuditing

DevelopmentReportAuditallrawdatasupportingDevelopmentReport

ANDARegulatoryFileAuditPlantandLaboratoryDocumentationasperANDA

SOPsReviewSOPSystemandUpdatelevel

cGMPReviewcGMPofManufacturingProcess

BiostudyReportEvaluateanddevelopaIVIVcorrelation(LevelAwherepossible.)

ValidationProtocolProductProcessValidationProtocolcompleteandsigned

ANDASUBMISSION

DevelopmentStage

ScopeofProductDevelopment

Stage21ANDASubmission

ANDASubmissionSubmitANDAstructuredasPartTwoofthisHandbook

(9Copies-asperColorsystem)

(1FieldCopy)

VALIDATIONBATCHES

Development

Stage

ScopeofProductDevelopment

Stage22ProcessValidation

ProtocolProcessValidationProtocolfor3concutivemarketinglots

ExecutevalidationProcessValidationof3concutivemarketinglots

ReportProcessValidationReport

SimilarityShowintra-batchsimilarity

Bio-Validation

Similarity

Showinter-batchsimilaritybetweenBiobatch(Pivotal)andthe

CommercialValidationLots

ORALTABLETSDEVELOPMENTCHAPTER2

HandbookofPPharmaceuticalSect:22.22GenericDDevelopment

COMMERCIALRE-VALIDATION

DUETOMAJORCHANGE

Development

Stage

ScopeofProductDevelopment

Stage23ProcessRe-validation

FormulaChangeRevalidateprocedurewithnewformulaprocessorequipmentwith

ProcessChangeadifferentoperatingprinciple

EquipmentChange

MinorchangeFollowSUPACRulesLevelIIIorIII

IMPORTANTNOTEONDEVELOPMENT

DevelopersareencouragedtodevelopIVIVCforIRdosageforms,whereapplicable

totheBCS,(BiopharmaceuticalClassificationSystem)intheexpectationthatthe

informationwillbeufulinestablishingappropriatedissolutionspecificationsand

thuspermitcertainpostapprovalformulationandmanufacturingchangestobe

effected,-withoutadditionalbioequivalencestudies.

TheobjectiveofdevelopinganIVIVCistoestablishapredictivemathematical

modeldescribingtherelationshipbetweeninvitrodissolutionttingsandtheactual

invivodrug-plasmaparametersfound,(suchasAUC,Cmax,Tmax).

Theinvitrodissolutionttingsareadjusted(viamedia,pHagitation)untilaI:I

correlationisachieved(LevelA)orasingledissolutionpointandaplasma

parameterisshowntocorrelate(LevelC).

WhenmorethanonepointcorrelatesamultipleLevelCisobtained-whichmay

possiblybeupgradedtoaLevelAwithadditionaldevelopmentwork.

Thismatchingofdissolutionttingswithplasmalevels,thatarederivedfroma

specificIRformulaanditscorrespondingmanufacturingprocess,isinfactsimplyan

arbitrarytofvaluesthatestablishthesocalled'predictivemathematicalmodel'.

AnIVIVCshouldbeevaluatedtodemonstratethatpredictabilityoftheinvivo

performanceofthedrugproduct(dfromtheplasmaparameters)fromitsin

vitrodissolutioncharacteristics(entttings/andmanufacturing

changes)ismaintainedovertheproduct'sdissolutionprofile