FDA口服制剂检查指南

GUIDETOINSPECTIONSOFORALSOLIDDOSAGEFORMSPRE/POSTAPPROVALISSUESFORDEVELOPMENTANDVALIDATION

January,1994

Note:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s).

IINTRODUCTION

Thisinspectionguideprovidesinformationregardingtheinspectionandevaluationofthemanufacturingandcontrolprocessesusedtomanufacturesolidoraldosageformpharmaceuticalproducts.ThisdocumentprovidesguidancefortheFDAinvestigatorandpromotesuniformityandconsistencyduringtheinspectionandevaluationofthevalidationofthesolidoraldosageformmanufacturingandcontrolprocesses.Itcoversthreephasesofthevalidationprocess;productdevelopment,designofthevalidationprotocol,anddemonstrationruns(validation)oftheequipmentandprocessinthemanufactureoffullscalecommercialproductionbatches.

Althoughthisdocumentitisnotallinclusive,itaddressesmanyoftheissuesandexamplesofvalidationproblemsoforalsoliddosageformswhichinvestigatorsandanalystsmayencounter.Theinspectionteamisexpectedtoreviewotheragencydocumentsinpreparationfortheseinspections

TheValidationGuidelineissuedbytheagencyin1987definesprocess

validationasestablishingdocumentedevidencewhichprovidesahighdegree

ofassurancethataspecificprocesswillconsistentlyproduceaproduct

meetingitspredeterminedspecificationsandqualityattributes.

Thethreecomponentsofthisdefinitionincludedocumentedevidence,

consistency,andpredeterminedspecifications.Documentedevidenceincludes

theexperiments,dataandanalyticalresultsthatsupportthemaster

formula,thein-processandfinishedproductspecifications,andthefiled

manufacturingprocess.

Withregardtoconsistency,severalbatcheswouldhavetobemanufactured,

usingthefullscalebatchsize,todemonstratethataprocessmeetsthe

consistencytest.Atleastthreebatchesareneededtodemonstrate

consistency.

Thedevelopmentofaproductanditsmanufacturingprocessand

specifications,thedesignofthevalidationprotocol,andthedemonstration

(validation)runsofthefullscalemanufacturingprocessrequires

scientificjudgementbasedongoodscientificdata.Weexpectthat

in-processcontrolandproductspecificationswillbeestablishedduringthe

productdevelopmentprocess,withthetestbatchservingasthecritical

batchusedfortheestablishmentofspecifications.

Specifications,suchashardnessandparticlesize,shouldbeestablished

priortovalidationoftheprocess;thesespecificationsshouldbeincluded

inthevalidationprotocol.Theuseofproductdevelopmentrunsofthe

processtoestablishbothspecificationsanddemonstratethatthesystemis

validatedoftencausesproblems.Inthesecases,morein-depthinspection

andevaluationwillberequired;someoftheseprocessrunsoftenproduce

failingproductbecausetheproductspecificationshavenotbeenfully

establishedandtested.

Theinspectionteamshouldobservefacilities,equipmentandprocessesto

putdatareviewinpropercontext.Itisalsoimportantthatrawdata,

includingvalidationandlaboratorylogbooksbeauditedorreviewedto

verifyaccuracyandauthenticity.

IIBACKGROUND

Twocommoncomplaintsregardingvalidationissuesfrequentlyhavebeen

raised.Thefirstconcernsthemisconceptionthatthe1987validationguide

representsanewrequirement.Thesecondconcernsthelackofspecificityin

theagency'sguides.In1978,theCurrentGoodManufacturingPractice

Regulationswererevisedandprovidedforprocessvalidation.Thereforethis

guidelinedoesnotrepresentanewrequirement.Theregulationisnearly15

yearsold.

Boththeagencyandtheindustryhaverecognizedtheneedtoestablish

generalguidanceforthevalidationofmanufacturingprocesses,andthe

agencypublishedadraftguidelineinMarch,1983.Howeverthisdraft

guidelinewasaverygeneraldocumentaddressinggeneralprinciplesandwas

applicabletosterileandnon-steriledrugsanddevices.InMarch,1984,it

wasreissuedasadraftguideline,andwasfinalizedinMay,1987.

The1987validationguidelinemerelypointsouttheneedtoadequately

developandcontrolmanufacturingprocesses.Itdiscussesmicrobiological

issuesandprovidesfewspecificanpracticalapplicationsforthe

validationofmanufacturingprocessesforamarketedsolidoraldosageform.

Theissueofretrospectivevalidation,anditsapplicationtomarketed

products,isfrequentlyencountered.Thisconceptofusinghistoricaldata

(testresults),alongwithprocesscontrolandprocessspecificitywasof

valueuntilmorescientificmethodsfordemonstratingprocessvalidation

evolved.Itshouldbepointedoutthatretrospectivevalidationisnot

merelythereviewoftestresults.Italsorequiresthatthemanufacturing

processbespecificandthesameeachtimeabatchismanufactured.Thus,

specificrawmaterialspecifications(includingparticlesizewhen

necessary),in-processspecifications(tablethardness,etc.),andspecific

manufacturingdirectionsarerequired.Obviously,anyfailingbatches

attributedtotheprocesswouldnecessitatetheconclusionthattheprocess

isnotvalidatedandisinadequate.

Prospectiveprocessvalidationisrequired,particularlyforthoseproducts

introducedinthelast7to8years,orthoseforwhichmanufacturing

changeshavebeenmade.However,insomecaseswhereolderproductshave

beenonthemarketwithoutsufficientpre-marketprocessvalidation,itmay

bepossibletovalidate,insomemeasure,theadequacyoftheprocessby

examinationofaccumulatedtestdataontheproductandrecordsofthe

manufacturingproceduresused.

IIIPRODUCTDEVELOPMENT

A.PRODUCTDEVELOPMENTREPORTS

Thereisnostatuteorregulationthatspecificallyrequiresaproduct

developmentreport,althoughcompaniesarerequiredtoproducescientific

datawhichjustifiestheformulationandthemanufacturingandcontrol

processes.Mostcompanieshaveusedproductdevelopmentreports,technology

transferreports,andotherstosummarizethescientificdatathatjustifies

theproductandprocess.Theproductdevelopmentreportshouldsatisfythe

needsofthecompany.Therefore,thereisnospecificformatforthe

contentsofthereport.

ItissuggestedthatthecompanydevelopaproductdevelopmentSOPwhich

describesthedevelopmentprocess,thedocumentationrequirements,andthe

individualsresponsibleforapprovingthefiledprocess.ThisSOPcanbe

briefandagainthereisnolegalrequirementthatcompaniesproducesuchan

SOP.

Investigatorsmustnotlisttheabsenceandorthepoorqualityofaproduct

developmentreportontheFDA483.Theinvestigatorsshouldlistorinclude

theinadequacyofdatatosupportthefiledprocessandspecificMaster

Formulafiled.ItisnotaGMPdeficiencynorisitafilingrequirementto

haveaformalDevelopmentReport.Investigatorsshouldreviewproduct

developmentreportssincetheywillreducethetimerequiredtoinspectthe

process.

Thedevelopmentdatafoundinthesereportsshouldincludethefollowing:

1.DrugSubstanceCharacterization

Characterizationofthechemicalandphysicalpropertiesofthedrug

substanceisoneofthemostimportantstepsinthedevelopmentofasolid

dosageform.Chemicalpropertiesespeciallytheidentificationofimpurities

areveryimportant.Inaddition,thephysicalpropertiesoftheBPCsuchas

solubility,polymorphism,hygroscopicity,particlesize,density,etc.must

beaddressed.

Theliterature,andactualexperiencedemonstrates,thatthephysical

quality,e.g.,particlesizeofrawmaterials,cansometimesproducea

significantimpactontheavailabilityandclinicaleffectofadosageform

drug.Therefore,itisappropriatethatthephysicalcharacteristicsofa

drugsubstancebecharacterized,thattheimpactofthephysical

characteristicsbedeterminedandthataspecificationforthebulkdrug

productbeestablishedifnecessary.

Developmentdatawillvarybetweennewdrugsandgenerics.Characterization

andestablishmentofspecificationsforthedrugsubstanceisoneexample.

Inmostcasesthemanufacturingprocessforanewdrugsubstance(new

chemicalentity)isdevelopedandscaled-upbeforethedosageform.Inearly

developmentstagesverylittleinformationisavailableregarding

polymorphicforms,solubility,etc.Consequently,changestothe

manufacturingprocessforthedrugsubstancemaychangethepurityprofile

orphysicalcharacteristicsandthuscauseproblemswiththefinisheddosage

form.Althoughthesetypesofproblemsareexpected,thefirmmust

investigateanddocumentbatchfailuresfortheBPCanddosageformproduct.

Ontheotherhandthegenericmanufacturerusuallypurchasesthedrug

substancefromaBPCmanufacturerwhomaynotbewillingtosupply

informationregardingthesynthesisoranalysisofthedrugsubstance.

Therefore,thefinisheddosageformmanufacturermustperformthe

appropriatetesttocharacterizethedrugsubstancechemicallyand

physicallyandestablishappropriatespecifications.Thismayrequire

developinganalyticalmethodstoidentifyimpurities.Insomecasesthis

informationcanbeobtainedfromliteraturesearches.

Ineithercaseitisimportantthatthefirmcomparethedrugsubstanceused

tomanufacturerthebio-batchorclinicalbatch(es)andthedrugsubstance

usedforthecommercialbatches.Therefore,reviewthespecifications,

analyticalmethods,andtestresultsforthelotsofthedrugsubstanceused

tomanufacturethesebatches.Rememberthatthesafetyofthedrugmaybe

baseduponthetypeandlevelofimpuritiesanddifferentphysical

characteristicsmayaffectdissolutionorcontentuniformity.

Inspectionalcoverageshouldbegiventothephysicalcharacteristicsofraw

materials,especiallybulkdrugsubstances,sincetheyfrequentlyaffectthe

performanceofthedosageforminwhichtheyareincorporated.Thisis

particularlyimportantforthosedrugsubstancesthatarepoorlysolublein

water.

Forthoseproductsonwhichbiostudieswereconducted,thephysical

characteristicsofthedrugsubstanceusedforthestudyshouldserveasthe

basisforthephysicalspecifications.

Itiswidelyrecognizedthatwhendiscussingin-vivoreleaseratesanddrug

absorptionrates,fast,immediatereleaseisnotalwaysbest.Forsome

"immediate"releasedrugproducts,suchascarbamazepinetablets,aslower

releaseisdesired.Therefore,itisfrequentlydesirabletohaveminimum

andmaximumparticlesizespecificationstocontrolthereleaserate.For

example,micronizingormillingadrugsubstanceandprovidinggreater

surfaceareaofthesubstancemayalsoresultinfasterdissolutionand

possiblyfasterabsorptionandhigherbloodlevels.Suchchangesto

"improve"thedissolutionmaynotalwaysbedesired.

Inadditiontoreleaseordissolution,variationinparticlesize,particle

shape,and/orbulkdensitycanalsohaveaneffectontheuniformityof

dosageforms,particularlythosemanufacturedbydirectcompressionor

directencapsulation.

Particulatesolids,oncemixed,haveatendencytosegregatebyvirtueofdifferencesintheshape,sizeanddensity(othervariablesarealsoimportant)oftheparticlesofwhichtheyarecomposed.Thisprocessofseparationoccursduringmixing,aswellasduringsubsequenthandlingofthecompletedmix.Generally,largedifferencesinparticlesize,densityorshapewithinthemixtureresultininstabilityinthemixture.Thesegregationprocessnormallyrequiresenergyinputandcanbereducedfollowingmixingbycarefulhandling.

Somemanufacturershaveestablishedwiderangesforspecifications.

InvestigatorsshouldreviewthesespecificationsfromaGMPandvalidation

perspective.Eventhoughawiderangeforaphysicalspecification,suchas

particlesizeorsurfaceareamaybeestablishedinafiling,itisexpected

thatsuchrangesbeverifiedinthevalidationoftheprocess.Inarecent

courtdecisionthejudgeruledthatcompaniescannothidebehindthe

approvalofprocesseslistedinanapplicationwhentheseprocessesdonot

work.Inotherwordstheapprovalofthefilinghasnoimpactonprocesses

thatdonotperformconsistently.

Forexample,inafiledprocessitwasdeterminedthatparticlesizewould

havenoeffectondrugabsorptionanddissolutionandawiderangeparticle

sizespecificationwasestablished.However,intheGMPreview,itwasfound

thatvariationinparticlesizehadamajoreffectoncontentuniformity.

Therefore,atighterparticlesizespecificationhadtobeestablished.

Controlofthephysicalcharacteristicsoftheexcipientisalsoimportant

becausevariationsinsuchcharacteristicsmayalsoaffecttheperformance

ofthedosageform.Changesinparticlesizeofsomeexcipients,for

example,mayaffectcontentuniformity.Inothercases,achangeinthe

supplierofanexcipientorlubricantmayaffectdissolutionor

bioavailability.Infact,thereleaseoftheactiveingredientsinsome

productsis"timed"byvaryinglubricantblendingtimeandconcentration.

Theliteraturecontainsmanyexamplesoflubricantprocessingcausingmajor

changes.Suchchangesinexcipientsillustratethedeficiencieswiththe

utilizationofretrospectivevalidationbecause,forsuchvalidationtobe

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satisfactory,controlofallparametersandkeystepsintheprocessare

necessary.

Thecontrolofmixingtimesandphysicalcharacteristicsofallingredients

iscriticaltosuccessfulvalidationofallformulationsandprocesses.A

majorquestionthatmustbeaddressedistheneedfortestingphysical

characteristics(particlesize)foreachbatchofexcipient.Formanysingle

sourceexcipients,particlesizeisasupplierspecificationandisusually

tightlycontrolled.Havingestablishedaspecificationandnottestingeach

lotofexcipientuponreceiptmaybesatisfactoryinsuchcases.However,

forsomemulti-sourceexcipientsandwherethedosageformulatorexpectsto

shiftsourcesofsupply,theremaybedifferencesinphysical

characteristics(particlesize)thatmayhaveaneffectondoseuniformity

anddissolution.Examinethepracticeswithrespecttothesourceofsupply

ofthekeyexcipientsanddetermineifthereisjustificationforthelack

oftestinglotsofexcipientforphysicalcharacteristics.

2.ManufacturingProcedures

Proceduresusedtomanufacturedevelopmentbatchesmustbespecificandwell

documented.Thisisnecessaryforscale-upandsubsequentcomparisontothe

commercialprocess.

ThisisanotherareawhereyouwillseedifferencesbetweenNDA/NADAand

ANDA/ANADAproducts.InthecaseoftheNDA/NADAyouwillseeseveral

clinicaland/ortestbatchesmanufacturedoveraperiodoftimeandyou

wouldexpecttoseechangesintheprocessasmoreislearnedaboutthedrug

andtheprocess.Thelevelofdocumentationshouldincreaseastheprocess

becomesmoredefinedandthefirmbeginsphaseIIandIIIstudies.

Thegenericproductfocusisonthebiobatch.Againtheprocessusedto

manufacturerthebiobatchmustbewelldefinedandwelldocumented.Alsothe

firmshouldhaveworkedwiththeprocessbymeansoftestbatchessothey

canreproducethebiobatch.Thereforeyouwouldexpecttoseemorethanone

batchmadeatthisstageofthedevelopmentprocess.

3.In-processTesting

Specificspecificationsrequiredtocontrolthemanufacturingprocessmust

beestablishedandjustified.Thiswillrequiregranulationstudieswhich

wouldincludeblenduniformity,sieveanalysis,andmoisture.Readthe

sectionunder,"DemonstrationRunsoftheProcess(ValidationofProcess)"

formoreinformation.

4.FinishedProductTesting

Testingforthemonographstandardssuchascontentuniformity(whena

specificationapplies),assay,hardness,friability,dissolution,andothers

areessential.

5.DissolutionProfile

Thedissolutionprofilesforthebiobatchorpivotalclinicalbatchesshould

beevaluatedintheproductdevelopmentreport.Thereshouldbegood

correlationtothedissolutionspecificationsandtestresultsforthe

biobatch/clinicaltestbatchesandthefullscalecommercialprocess.

6.Stability

TheCenterforDrugsconductsanevaluationofthestabilitydataand

approvestheexpirationdate.Theproductdevelopmentreportshouldcontain

anevaluationofthestabilitydatathathasbeenobtained.

Duringpost-approvalinspectionsstabilitydataisreviewedbythefield.

Therefore,theinvestigatormustauditunderlyingrawdataandanalytical

worksheetstoassuretheaccuracyandauthenticityofstabilitydata

containedinsummaryreports.

B.PRE-APPROVALINSPECTIONS

Validationofthreefullsizecommerciallotsisnotrequiredforapproval

oftheapplication,howeverthefirmmusthavedatathatjustifiesthefull

scalecommercialprocessfiledintheNDA/ANDAorNADA/ANADAapplication.In

otherwords,thefirmshouldhavesufficientresearchonthetestbatchesto

establishspecificationsforthemanufacturingandcontrolprocedureslisted

intheapplication.Thesedataandspecificationsformthebasisforthe

validationprotocolwhichmaybedevelopedfollowingapprovalofthe

application.Thefinalstepintheprocessisthedemonstration(validation)

runsprovingthattheprocesswillperformconsistently.Firmsshould

validatetheprocessusingthespecificationslistedinthefiling.

Toevaluatetheproposedmanufacturingprocessthefollowingareasmustbe

coveredduringthepre-approvalinspection:

1.MasterFormula

Thisdocumentmustincludespecificmanufacturingdirectionsforthefull

scalecommercialprocessincludingin-processandfinishedproduct

specifications.

Comparetheprocessfiledintheapplicationtotheprocessusedto

manufacturerthebio/clinicalbatch.Insomecasestheprocessmaybe

differentafterscale-up.Thisisacceptableifthefirmhasdatashowing

theproductproducedbythisprocesswillbeequivalent.Datasuchas

granulationstudies,finishedproducttestresults,anddissolutionprofiles

areusedtodocumentthatthetwoprocessesareequivalent.

2.HistorySectionoftheApplication

Thissectionoftheapplicationisusedtoidentifythebiobatchorbatches

usedforpivotalclinicalstudies.Itisalsousefulforreviewofthe

correspondencebetweenthefirmandCDER/CVM.Oneofthebasicobjectivesof

ourreviewistoidentifythebiobatch.Also,anybatchesinwhichin-vivo

studieswerecarriedout,andparticularlythosewhichin-vivostudies

showedinequivalencyshouldbereviewed.

3.DevelopmentData(ProductDevelopmentReport)

Thefirmcannotlogicallyproceedtothevalidationstepwithoutsomeprior

evaluationoftheprocess.Duringthedevelopmentphasethecriticalprocess

parametersmustbeidentifiedandspecificationsestablished.These

predeterminedspecificationsmustbeestablishedduringthedevelopmentof

theprocess,withthebiobatchorpivotalclinicalbatchservingasthe

referencebatch.

Developmentofasoliddosageformwillvaryfromfirmtofirmandwillbe

dependentuponthespecificproductandprocess.However,theformula

ranges,physicalandchemicalspecificationsofthedrugsubstanceand

excipients,in-processvariables,interactioneffectsofthedosageform

ingredientsundernormalandstressagingconditions,shouldbeconfirmedby

limitedchallengeinpilot-scaleandproduction-sizebatches.

Thisdevelopmentdataservesasthefoundationforthemanufacturing

procedures,specificationsandvalidationofthecommercialprocess.Insome

cases,manufacturershaveattemptedtoestablishspecificationssuchas

hardnessandparticlesizeduringvalidation.However,asthevalidation

definitionstates,specificationsmustbedeterminedpriortovalidationof

theprocess.

Whenamanufacturerfilesamanufacturingprocessinanapplication,we

expectthattheprocesswillyieldaproductwhichisequivalenttothe

productonwhichthebiostudyorpivotalclinicalstudywasconducted.

Therefore,itisimportantthatthedevelopmentandscale-upoftheprocess

bewelldocumentedsothatalinkbetweenthebio/clinicalbatchesandthe

commercialprocesscanbeestablished.Thefirmshouldhavedatasuchas

granulationstudies,finishedproducttestresults,anddissolutionprofiles

whichmaybeusedtodocumentthatthetwoprocessesareequivalent.

Inmostcasesinvitrodataalonewillnotbesufficienttodocument

equivalency.Determineifanequivalencyevaluationhasbeenmade.This

bioequivalencyevaluationmustbemadebyqualifiedindividuals,andthe

firmshouldhaveasignedstatementdocumentingthattheprocessesare

equivalent.Therefore,inmanycasesyoumayseeanin-vivobioequivalency

studyperformed.Obviously,thefirmcannotprovidethistypeofdataifthe

havenotmanufacturedpilotortestbatchesusingthetypesofequipmentan

controlsspecifiedintheproposedmasterformula.

4.InspectionoftheFacilities

Itisimportantthatyouphysicallyinspectthefacilitytoassurethatthe

areaandtheancillaryequipmentsuchasairhandlingandwatersystemsare

suitablefortheproposedmanufacturingprocess.Constructionofnewwalls,

installationofnewequipment,andothersignificantchangesmustbe

evaluatedfortheirimpactontheoverallcompliancewithGMPrequirements.

Thisincludesfacilitiesusedfordevelopmentbatchesandtobeusedfor

full-scaleproductionbatches.

5.RawMaterials

ReviewtheinformationcontainedintheRawMaterialsectionunderProduct

DevelopmentReportabove.Inventoryrecordsareagoodsourceforthe

identificationofbatchesusedforproductdevelopmentandbiostudies.

6.Laboratory

Theinspectionofalaboratoryrequirestheuseofobservationsofthe

laboratoryinoperationandoftherawlaboratorydatatoevaluate

compliancewithGMP'sandtospecificallycarryoutthecommitmentsinan

applicationorDMF.

Evaluaterawlaboratorydata,laboratoryproceduresandmethods,laboratory

equipment,andmethodsvalidationdatatodeterminetheoverallqualityof

thelaboratoryoperationandtheabilitytocomplywithGMPregulations.

(RefertotheLaboratoryInspectionGuideforadditionaldiscussion).

Manyofourinspectionhaveidentifiedforeignpeaksandimpuritiesnot

filedordiscussedinapplications.Also,manyofourinspectionshaveshown

laboratorytestmethodsnottobevalidated.Thetransferoflaboratory

methodsandtechnologyfromtheResearchandDevelopmentDepartmenttothe

QualityControlDepartmentshouldbereviewed.

7.Equipment

Atthetimeofthepre-approvalinspectionweexpectthattheequipmentis

inplaceandqualified.Newproducts,particularlypotentdrugproducts,can

presentcleaningproblemsinexistingequipment.Manufacturersmustvalidate

theircleaningprocessesforthenewdrug/dosageform.(Refertothe

CleaningValidationInspectionGuideforadditionaldiscussion).

IVVALIDATIONPROTOCOLS

Validationprotocolsaredevelopedfromtheinformationobtainedduring

productdevelopmentresearch.Theseprotocolslistthespecific

manufacturingprocessandspecificationsthatwillbetestedduringthe

demonstrationruns.Validationprotocolsarenotrequiredforthe

Pre-ApprovalInspectionbutarerequiredforPost-ApprovalInspections.

Keyprocessesandcontrolspecificationsshouldhavebeenestablishedduring

productdevelopmentresearchandshouldbecarefullylistedinthe

validationprotocol.

VDEMONSTRATIONRUNS(VALIDATIONOFTHEPROCESS)

A.TESTBATCHRELATIONSHIPS

A"validated"processshouldproduceadosageformthatisdirectlyrelated

tothedosageformonwhichequivalencyand/orefficacyansafetywere

determined.Thisisusuallythetestbatch.Therefore,comparetheprocess

usedtomakethetestbatchwiththeprocessthatisusedforroutinefull

scaleproductionbatches.Theseprocessesandspecificationsmustbe

equivalent.Therefore,theimportanceandtheneedforgoodcontrolofthe

manufacturingprocessusedtoproducethetestandclinicalbatchescannot

beoveremphasized.Typicallythecontroloftestbatchesincludes,among

others,drugsubstancecharacterization,granulationanalyses,anddose

uniformityanddissolutionprofiles.

Thevalidationreportshouldcomparethemanufacturingprocessesand

specificationsforthetestbatchestothefullscalebatches.However,such

afindingmaybecontainedinotherdocuments.Requestanyevaluationthat

hasbeenconductedontheequivalencyofthesebatchesandprocessesand

reviewanytabulateddatathatshowstheprocessingequivalencybetweenthe

biobatchandvalidationbatches.

B.Post-ApprovalProspectiveValidationInspections

InspectionteammembersmustrereadthesectionsunderPartIProduct

Developmentwhichwillnotberestatedunderthissection.Thosesections

containinformationthatiskeytotheevaluationofthevalidationprocess.

Inthepost-approval,pre-marketingphase,wereviewtheValidationProtocol

andtheValidationReport.Obviously,aValidationProtocolthatlistsall

ofthevariablesandparametersthatshouldbecontrolledwhentheprocess

isvalidatedcannotbewrittenuntilthevariablesareidentifiedinthe

developmentphase.

Inmanyofourpost-approval,pre-marketinginspections,validation(and

consistency)couldnotbeestablished.Failuresofproductionsizebatches

includeddissolution,contentuniformityandpotency.Validationreportson

batchscale-upsmayalsoreflectselectivereportingofdata.Onlythrough

inspectionandreviewofthefacilitiesandrawdataweretheproblems

identified.

Severalparametersmustbeconsideredwhenevaluatingthevalidationofan

oralsoliddosageformmanufacturingprocess.Forexamplethereareatleast

eightmajorareasthatmustbeincluded:

oBiobatchRelationship

oRawMaterials

oManufacturingProceduresandEquipment

oGranulation/MixAnalysis

oIn-ProcessControls

oTestResultswithValidatedMethods

oInvestigations/ProductFailures

oSiteReview

1.RawMaterials

Physicalcharacteristicsofrawmaterialscanvaryamongmanufacturersof

drugsubstancesand,onoccasion,havevariedfromlottolotfromthesame

manufacturer.Uponexaminationofretainsamplesofthelotsofraw

material,obviousphysicaldifferencesbetweenthetwolotsmaybeobserved.

Reviewtherawmaterialinventoryrecordstoevaluatetheuseofthedrug

substanceinbiobatch,clinical,and/ortestbatches.Payattentiontothe

quantitiesandsourceofmaterialsusedandthetestingperformed.

Inspectionssho