A RiskManagement Approach to CleaningAssay ValidationWord文件下载.docx
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Jun2,2010
By:
BrianW.Pack,
JeffreyD.Hofer
PharmaceuticalTechnology
Volume6,Issue34,pp.48-55
Cleaningvalidationandverificationarebasedonthepremiseofriskmanagement.Severalregulatoryandguidancedocumentsmakethisclear.TheInternationalConferenceonHarmonization'
s(ICH)guidelineonriskmanagementoutlinesseveralapproachestomakinganddocumentingrisk-baseddecisions
(1).Itclearlystatesthatriskmanagementshouldbebasedonscientificknowledgeandthatpersonnelshouldevaluatetheeffectofpotentialfailuresonthepatient.Inaddition,itnotesthatthelevelsofeffort,formality(e.g.,useoftools),anddocumentationofthequalityrisk-managementprocessshouldbecommensuratewiththelevelofrisk.
TheUSCodeofFederalRegulationsstatesthatequipmentandutensilsshallbecleaned,maintained,andsanitizedatappropriateintervalstopreventmalfunctionsorcontaminationthatwouldalterthesafety,identity,strength,quality,orpurityofthedrugproduct
(2).Inaccordancewith21CFR211.67,ICHissuedrecommendationsonequipmentmaintenanceandcleaning(Q7A,Sections5.20–5.26)forcomplianceandsafetythatincludesimilar,butmoredetailedrequirements(3).
TheUSFoodandDrugAdministration'
s1993guidanceoncleaninginspectionsstatesthatforaswabmethod,recoveryshouldbeestablishedfromthesurface(4).Theguidancecontainsnospecificrequirementsabouthowtoestablishtheserecoveryestimates,ortheacceptancelimits.Itisuptothemanufacturertodocumentthecleaningrationale(i.e.,processandacceptancelimits)formaintainingthequalityandpurityofthedrugproductbeingmanufactured.
Cleaningvalidationandverification
Cleaningverificationconsistsofroutinemonitoring(e.g.,swabanalysis)ofequipment-cleaningprocesses.Cleaningvalidationconfirmstheeffectivenessandconsistencyofacleaningprocedureandeliminatestheneedforroutinetesting(5).Forexample,cleaninglimitsareestablishedtodeterminethemaximumallowanceofProductAthatcancarryovertoProductB.Thecalculationoftheselimitsiswelldocumentedandincludesfactorsthatincreasethemarginofsafetytoprotectthepatient(6,7).Becauseitisnotfeasibletoswabeverysquareinchoftheequipment,swabbinglocationsarechosenbaseduponfactorssuchashowdifficulttheareaistoclean,thesizeoftheequipment,andtheareaswhereproductbuildupislikely.Allproduct-contactsurfacesmustbeconsideredduringcleaningverificationtodemonstratethatequipmentisclean,andarecoveryvalueisexpectedtobeestablishedforeachproduct-contactsurfaceduringmethodvalidation.Therecoveryisusedtocorrectthesubmittedswabresultforincompleteremovalfromthesurfaceandtocompareitwiththeacceptancelimit.Thislastaspectofriskmanagement(i.e.,establishingthesurfacerecovery)isthefocusofthisarticle.
Analystshavemanywaystoestablishtheswab-recoveryvalueforaparticularproduct-contactsurface.Stainlesssteelisthemostcommonmaterialinamanufacturingenvironment(seeFigure1).Somecompaniesthereforeestablisharecoveryvalueforstainlesssteelandapplythatstandardtoallswabsubmissions.Othercompaniesattempttoestablisharecoveryvalueforeachproduct-contactsurfaceforeverycompound.Fromananalyticalstandpoint,supportingthisactivitybecomesarduous,ifnotimpossibletosustain.Forexample,equipmentinaclinical-trialmaterials(CTM)manufacturingareaisusedformanycompoundsinthecompany'
sportfolio.Newequipmentmighthavedifferentproduct-contactsurfaces.Eachcompoundintheportfoliomanufacturedonanewpieceofequipmentwouldrequireamethodrevalidationtoaddarecoveryfactorforthenewproduct-contactsurface.Asthenumberofmaterialsofconstructionincreases,thedifficultyofsustainingthatapproachalsoincreases.Groupingmaterialsofconstructionforanalytical-methoddevelopmentinsupportofcleaningverificationandvalidationactivitiesisanexcellentopportunitytoapplyaqualityrisk-managementapproach,especiallywhenthetotalproduct-contactsurfaceareaisconsidered.Stainlesssteelaccountsforapproximately95%ofthesurfaceareainaCTMmanufacturingandpackagingenvironment.Otherproduct-contactsurfacesaccountforonly5%ofthetotalsurfacearea.WhenpolymersurfacesareconsideredinaCTMpackagingenvironment,thenumberofminorproduct-contactsurfacescangrowsignificantly.Arisk-managementapproachallowsthemajorityofthetimeandefforttobespentonactivitiesthatensurethecleanlinessofthestainless-steelareawhileidentifying,analyzing,evaluating,andcommunicatingtherisksassociatedwiththesmallfractionofremainingsurfaces.Thisstrategydoesnotignorethesurfacesotherthanstainlesssteel,butdividesthemintothreerecoverygroupstosupportanalytical-methodvalidation.Bychoosingrepresentativerecoverysurfacesforthosenonstainless-steelmaterials,theeffortproportionallyaddressestherisk.
Designofexperiments
Severalvariables(i.e.,roughnessaverage,materialofconstruction,activeingredient,andspikedamount)wereevaluatedinarandomizedfashiontopreventsystematicbiasthatcouldbeintroducedbygoingfromthelowesttothehighestacceptancelimit,fromthesmoothesttotheroughestsurface,orfromonematerialofconstructiontothenext.Theinitialdesignofexperimentsincludedtwoactivepharmaceuticalingredients(APIs),threespikedacceptance-limitlevels(i.e.,0.5,5.0,and50μg/swab),sevensurfacetypes,fourtargetroughnessaverages(Ra<
25,75,125,and150μin.),andsixreplicatespersurface.TheseRasweretargetedtoevaluatewhethersurfacerecoverydependedonthesurfaceRa.Couponsweredividedintoagroupofpolymers[i.e.,Lexan(polycarbonate),acetal(Polyoxymethylene),andPTFE]andagroupofmetals(i.e.,stainlesssteel316L,bronze,TypeIIIhard-anodizedaluminum,andcastiron).ThesesurfaceswerechosentorepresentacrosssectionofsurfacesfoundintheCTMmanufacturingandpackagingareasandrequired1008swabdeterminationstocompletethestudy.Theremainingproduct-contactsurfacesfoundintheclinical-trialmanufacturingandpackagingareaswereevaluatedaccordingtotheinitialdesignofexperiments.Thesesurfacesincludednickel,anodizedaluminum,Rilsan(polyamide),Oilon(blended-oilnylon),andstainlesssteel316Lwitha4×
4-in.area.
TheauthorschosetwoAPIsforthisevaluationonthebasisoftheirsolubilityprofilestorepresentthemost-andleast-solublecompoundsacompanywouldlikelymanufacture.CompoundA,thelesssoluble,isslightlysolubleinmethanolandinsolubleacrossthepHrange,butCompoundBissolubleinallsolvents.Inaddition,EliLilly(Indianapolis,IN)identifiedCompoundAasoneofthemostdifficultcompoundstocleanfromequipment,basedonitslowsolubilityandstainingproperties.Acontrol(i.e.,stainlesssteel316L,0.5μg/swab,CompoundA)wasruneachdaythatdataweregenerated.
Equipmentandoperatingconditions
TheauthorsusedanAgilent1100high-performanceliquidchromatography(HPLC)analyzer(Agilent,SantaClara,CA)forallexperiments.TheHPLCoperatingconditionswerevalidatedaccordingtoICHstandardsforprecision,linearity,limitofdetection(LOD),limitofquantitation(LOQ)andspecificity(seeTableI)(8).Precisionwas1.85%and3.13%forCompoundsAandB,respectively,andwasdeterminedat0.025μg/mL(i.e.,25%ofthelowestspike).Themethodwaslinearacrosstheequivalentrangeof0.5μg/swabto5μg/swab(R=0.999).TheLOQwascalculatedtobe0.005μg/mLforCompoundAand0.008μg/mLforCompoundB.TheLODwascalculatedtobe0.001μg/mLforCompoundAand0.0024μg/mLforCompoundB.Swabsandsolventsdidnotresultininterferingpeaks.TheauthorsperformedswabbingconsistentlyusingTexwipeAlphalargeswabs(ITWTexwipe,Kernersville,NC).First,10verticalswipes,then10horizontalswipeswereperformedforthe2×
2-in.surfaces.Forthe4×
4-in.surfaces,20swipeswereexecutedineachdirection.Methanolwasusedastheswabbingsolvent.Spikeamountswere0.5,5,and50μgpersurfaceandwereextractedinto5mLofmobilephase,whichcorrespondedto0.1-,1.0-,and10-μg/mLstandardconcentrations,respectively.TheauthorsusedaQuantaFEG200Ffield-emissionscanningelectronmicroscope(SEM,FEI,Hillsboro,OR)togeneratethesurfaceimages.
Resultsanddiscussion
Inthisstudy,asingleanalystevaluatedtheanalyticalswabrecoveryfromarepresentativesetofsurfacesfoundintheCTMmanufacturingandpackagingareas.ThesurfacesweremanufacturedspecificallyforthisstudytohaveabroadrangeofRas.InadditiontoRa,theeffectofthematerialofconstruction,acceptancelimit,compound,andmethodvariabilityalsowereevaluated.Baseduponthesedatasets,theauthorsusedastrategyinvolvingthreegroupsofmaterialstorepresentallofthesurfacesinCTMoperations.MerckandCo.usedasimilarstrategytoestablishfiverecoverygroups(9).TheauthorsexpandedonMerck'
sstrategybyaddingadetailedstudysupportingthegroupsandanapproachfordeterminingtheappropriateplacementofnewsurfacesintopre-establishedgroups.
Roughnessaverage(Ra).TheRatargetslistedaboveweredifficulttoachieve.TheintermediateRavaluesweresignificantlylowerthanthetargetvaluesgiveninthedesignofexperimentssectionabove.Bothintermedia
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