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2017621 AnADEDerivedScaleForAssessingProductCrossContaminationRiskInSharedFacilities

GuestColumn|May22,2017

An ADE-Derived Scale For Assessing Product Cross-Contamination Risk In Shared


Facilities
PartoftheCleaningValidationforthe21stCenturyseries

ByAndrewWalshEsterLovsinBarle,Ph.D.MichelCrevoisier,Ph.D.DavidG.Dolan,
Ph.D.AndreasFlueckiger,MDMohammadOvaisOsamuShirokizawaandKellyWaldron

Beginningin2004,aglobalteamofpharmaceuticaltoxicologists,industrialhygienists,quality
assuranceprofessionals,acleaningvalidationprofessional,andarepresentativefromtheUS
FDAparticipatedinthedevelopmentoftheInternationalSocietyforPharmaceutical
Engineering's(ISPE)RiskBasedManufacturingofPharmaceuticalProducts(RiskMaPP)
BaselineGuide.1ThepurposeoftheRiskMaPPGuidewastoprovidea"scientific,riskbased
approachtomanagetheriskofcrosscontamination."1TheRiskMaPPGuidewasbasedonthe
InternationalConferenceonHarmonisation'sQualityRiskManagementGuideline(ICHQ9)2
andencouragedthe"selectionoftheappropriateriskcontrolstrategiestobeimplementedonacasebycasebasistomaintainpatientsafetyand
assureproductquality."1

GuidanceOnManagingRiskInSharedFacilities

FromacGMP(quality)perspective,RiskMaPPprovidedguidanceonhowtomanagetheriskofproductcrosscontaminationinsharedfacilities,
fromthefourmainsourcestheRiskMaPPguideidentified:

1.Mixup(wrongmaterialbeingused)
2.Retention(residuesleftinequipmentaftercleaning)
3.Mechanicaltransfer(transferofmaterialoncontaminatednonproductcontactsurfaces)
4.Airbornetransfer(materialmovementthroughair)

DuringtheplanningmeetingsfortheRiskMaPPGuide,theFDAspecificallyrequestedthatthisguide:1

provideanapproachtoquantifythetoxicityofdrugs
provideariskmanagement/assessmentmodelthatgivesaclearviewonhowtoaddressthecontrolstocomplywith21CFR211.42(c)for
separation/dedicationinfacilities,etc.
discusshowtheapproachfitsintocleaningvalidation.

ADEAsAMetricForAssessingRisk

In2010,theRiskMaPPGuidewaspublishedandintroducedtheacceptabledailyexposure(ADE)asanappropriatemetricforassessing
pharmaceuticalmanufacturingrisksforworkerexposure,andforpatientsafety(e.g.,incleaningvalidation),asitisavaluebasedonallthe
availablepreclinicalandclinicaldataforacompound.InaccordancewiththeprinciplesofICHQ9,thelevelofcontrolsrequiredandthelevelof
effort,formality,anddocumentationneeded(includingvalidation)arecommensuratewiththelevelofrisk.Consequently,itiscriticaltohavea
meansofmeasuringthelevelofrisk.Itshouldbeunderstoodfromthisarticlethatsimplydividingcompoundsintotwoclasses(highlyhazardous
andnonhazardous)isfallacious,andthatthehazardsthatdrugspresenttopatientsshouldbeviewedonacontinuum,asenvisionedbyRisk
MaPP.ThisarticlepresentsanewhazardratingscaleapproachderivedfromtheADEconceptthatcanbeusedasavisualtooltoquicklyevaluate
andprioritizetherelativehazardsposedbydrugsmanufacturedinasharedfacilityorequipmenttrain.

ICHQ9AndApplyingRiskInTheManufacturingEnvironment

TheprinciplesbehindapplyingriskinpharmaceuticalandbiopharmaceuticalmanufacturingwereintroducedinICHQ9,whichwasformally
adoptedbyUSFDAin2006.ICHQ9mentioneditsapplicabilitytocleaning(includingacceptancelimits)inAnnexII.4andtovalidationinAnnex
II.6.AccordingtoICHQ9,riskisdefinedasthecombinationoftheprobabilityofoccurrenceofharmandtheseverityofthatharm.Thiscanbe
expressedas:

Risk=f(SeverityofHarm,ProbabilityofOccurrenceofThatHarm)

Risk,intermsofahazard(i.e.,thepotentialsourceofharm),canalsobeexpressedas:

Risk=f(SeverityofaHazard,LevelofExposuretoThatHazard)

Ifthehazardisintrinsictoanactivepharmaceuticalingredient(API),thenthisgeneralequationcanbefurtherrefinedto:

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2017621 AnADEDerivedScaleForAssessingProductCrossContaminationRiskInSharedFacilities
Risk=f(ToxicityAPI,LevelofExposureAPI)

CalculatingCleaningRisk

PatientriskforadverseeffectsincreasesasexposuretoagivenAPIorothercompoundrisesabovetheADE(whichissynonymouswiththe
permissibledailyexposure[PDE]andhealthbasedexposurelimits[HBEL],asusedintheEU3).Thisriskisafunctionoftheuniquedose
responsedurationrelationshipforeachcompoundandthelevelofexposuretothecompoundfrom,forexample,residualAPIcarryoverafter
cleaning.Notethatthismethodologycanbeappliedtoanyagentorcompound,andisthereforenotexclusivetoAPIs.Consequently,theADE
providesavaluethatcanbeusedasasurrogateforseveritytocalculatethepotentialcleaningrisk,asshowninthefollowingequation:

CleaningRisk=f(ADEAPI,LevelofExposureAPI)

Thisequationtellsusthattherisktoapatientfromcleaningisafunctionofthetoxicityofthedrugandthelevelofexposure(residues)foundafter
cleaning.

IntroducingTheToxicityScaleandToxicityScores

SinceADEvaluesvaryoverseveralordersofmagnitude,theyarehardtocomparedirectly.However,tofacilitatesuchacomparison,thevaluescan
beconvertedintoalogarithmicscaleinamannersimilartothatusedtocreatethepHscale.ByconvertingtheADEvaluesintounitsofgramsper
dayandtakingtheirnegativelogarithms,acontinuoustoxicityscalecanbegenerated,asshowninTable1.Theresultingtoxicityscoresareshown
rangingfrom0to10.However,itshouldbeunderstoodthattoxicityscorevaluesabove10andbelow0canstillbelegitimatelyobtained.

SimilartohowthepHscaleprovidesaconvenientmeansofquicklyassessingandcomparingtheacidityoralkalinityofsolutions,thistoxicityscale
canbeusedasameansofcomparingthetoxicitiesorhazardlevelsofpharmaceuticalcompounds.

PracticalExamplesAndInsights

Forexample,inFigure1,theADEvaluesforfourwellknowncompoundswereconvertedtothistoxicityscale.Thefirstcompoundisdioxin(i.e.,
2,3,7,8Tetrachlorodibenzopdioxin),awellknownandveryhazardouscompoundwithanADEof35picograms/day(toxicityscore=10.5).The
secondcompoundisarsenictrioxide,arelativelyhazardouscompoundusedtotreatacutepromyelocyticleukemia,withanADEof13g/day
(toxicityscore=4.9).TheAPIsalsoincludetwolowhazardcompounds:aspirin,withanADEof5mg/day(toxicityscore=2.3),andsodium
chloride,withanADEof26mg/day(toxicityscore=1.6).

Figure1:ComparisonofpHandtoxicityscales

Whileitisnotunexpectedtoseeaspirinandsodiumchlorideoccupyingthelowendofthetoxicityscaleanddioxinatthehighend,readersmay
finditsurprisingtoseearsenictrioxide,acompoundmostpeoplewouldconsidertobequitehazardous,occupyingaplaceatthemidpointofthe
scale.ThisillustratestheADEconceptatwork:Thetoxicityofacompoundisdosedependent,sowhilehigherdosesofacompoundmaygenerate
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2017621 AnADEDerivedScaleForAssessingProductCrossContaminationRiskInSharedFacilities
extremeadverseeffects,somewhatlowerdosesmaybeharmless.Thetoxicityscalehelpstorevealthisinrelationtoothercompounds/APIs.It
shouldalsobeunderstoodthatexceedingtheADEbyasmallamountdoesnotnecessarilyputpatientsatrisk.Forexample,aswabresultexceeding
theADEderivedlimitbyasmallamountduringacleaningvalidationstudyisnotanimmediatecauseforalarm.

ALargeScaleStudyDemonstratingTheToxicityScaleConcept

Inourpreviousarticle3,theADEsof304APIswerecomparedtotheir0.001dosebasedlimitsasademonstrationofhowinaccurateandoverly
conservativethe0.001dosebasedapproachisinestimatingsafelevelsforexposureinpatients,whichcouldleadtoimpracticalandunachievable
limits.ThedistributionoftheseADEvaluesfitswellwithinthepresentedscale,withanaveragetoxicityscoreof3.7amedianof3.6amode(16
compounds)of3.3andaslightlypositiveskewnessof0.42,indicatingafairlynormaldistributionforthesevalues(Figure2).Whiletheanalysisdid
notincludeallknownpharmaceuticalcompounds,asignificantsampleofthesecompoundswasrepresented,withtheresultsindicatingthatthere
wasnotabiastowardhighlytoxicorrelativelynontoxiccompoundsinthedataset.Theanalysisalsodemonstratesthatthetoxicityscale
encompassesthetypicalrangeofADEsquitewell.

Figure2:HistogramofADEderivedtoxicityscoresfor304APIs

PracticalUsesOfTheToxicityScale

Thetoxicityscalecanbeusedtovisualizeand,quitequickly,understandtherelativehazardofdifferentcompoundsthataremanufacturedina
commonfacility.ThescalecanalsosatisfytheUSFDA'sdesireforatoolthatbothidentifythehazardofadrugfromamaximumsafecarryover
(MSC)perspectiveandprovidesalinkagetocleaningvalidation.Figure3providesexamplesofhowthetoxicityscalecanbeusedtovisualizethe
hazardsofdrugproducts(asexpressedbytheirtoxicityscoresand,thus,theirADEAPIvalues)manufacturedinfacilitieswherethehazardsarelow,
moderate,andhighandonewherethehazardsaremixed.

Figure3:Comparisonoffourfacilitieswithfiveproductseach,usingthetoxicityscale

Intheaboveexampleswecanclearlyseethat,inFacilityA,theproductsareofverylowhazard.Tomanagetherisksofoperatorandpatient
exposure,thisfacilitywouldnotneedtoemploythesamelevelofcontrolsasafacilitywithhighhazardproducts.Conversely,FacilityChandles
highlyhazardousproductsandwouldneedtohavesignificantcontrolsinplace.Itshouldbeunderstoodthat,allotherfactorsbeingrelativelyequal,
lowerhazardproductsmeanlowermanufacturingriskandhigherhazardproductsmeanhighermanufacturingrisk.Usingthismodel,acompany
canquicklyassesswhetheronefacilityrequiresagreaterdegreeofcontrolsthananotherfacility,or,assuggestedbytheRiskMaPPGuide,whether
agivenproductisappropriateforintroductionandmanufactureinanexistingfacilitywithitsequipmentandcleaningpractices,orwhether
adaptationofoneortheotherisnecessary.

ApplicationsToCleaningValidation

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Fromacleaningperspective,itshouldalsobeclearthatFacilityAhasverylowhazardsassociatedwithitsproducts,andthereforeshouldnothave
toputthesamecleaningvalidationprograminplacethatFacilityCmayrequire.FacilityAmayactuallybeabletouse"visuallyclean"asitssole
acceptancecriterionforcleaningvalidationifthemaximumsafesurfaceresidues(MSSRs)calculatedfromtheseADEsarewellabovethelevelthat
isvisibleandallsurfacesarecapableofbeinginspected.Theremayalsobelimitedneed,ornoneed,foranycontinuedmonitoringbasedonrisk
managementcriteriaofanindividualfacility.Ontheotherhand,theMSSRsforFacilityCwouldmostlikelybewellbelowthelevelthatisvisiblefor
theseAPIs,soswab/rinsesamplingwouldberequiredandspecificanalyticalmethodsmayevenbeneeded.Continuedmonitoringmaybe
necessary.FacilityDpresentsauniquemixtureoflow,medium,andhighhazards.Inacasesuchasthis,comprehensivemanufacturingcontrols,
swab/rinse,sampling,andcontinuedmonitoringmaybenecessaryafterDrug1(toxicityscore=9.6).Decontaminationandothercross
contaminationmitigationstepsmayevenbenecessary.ButDrug4(toxicityscore=2.7)andDrug5(toxicityscore=2.5)mayonlyrequire"visually
clean"astheirsoleacceptancecriterionforcleaningvalidation,especiallyiftheyarefollowedbyproductswithlowmaximumdailydoses.

BenefitsToRegulators

Thetoxicityscalecanbenefitregulators,aswell,sinceaninspectorseeinganAPItoxicityscalinggraphicwithinafacilityriskassessmentmay
choosetofocuslessinspectioneffortonthecrosscontaminationcontrolsforFacilityA,andmoveontoFacilityC,whichpresentshighercross
contaminationrisk.BasedontherelativelyhazardousproductsmanufacturedinFacilityC,itwouldbeappropriateforaninspectortospendmore
energyexploringthecrosscontaminationcontrolsforsuchafacility.FacilityDhasamixoflow,moderate,andhighhazardproducts,andmay
havedifferentlevelsofcontrolsinplaceforhandlingthem.Assuch,inspectorsmightelecttoinvestigatehowthisfacilityhandlestheseproducts
andmaywanttofocustheirinspectionontheriskreductionandcrosscontaminationcontrolsduetoDrug1andhowtheseproductsinteractwith
theotherproducts(e.g.,mixup,retention,mechanicaltransfer,andairbornetransfer).

Conclusion

Asstatedearlier,theUSFDA,EU,andotherhealthauthoritieshave,duringthedevelopmentoftheRiskMaPPGuideandthroughotherpublished
guidelines,expressedastronginterestinan"approachforidentifyinghighlyhazardousdrugs."Webelievethatdividingpharmaceuticalcompounds
intotwoclasses,highlyhazardousandnonhazardous,cannotbescientificallyjustified,andthatthehazardsthatdrugspresenttopatientsshould
beviewedonacontinuum.Thenewtoxicityscaledescribedinthisarticleprovidessuchanapproach,andpotentiallycouldbeused:

1.tovisuallycomparethehazardlevelsortoxicitiesofpharmaceuticalcompoundsprocessedwithinthesameoracrossdifferentfacilities
2.asameasureofseverityinassessingcrosscontaminationrisksinfacilitiesandidentifyingordeterminingappropriatecontrolstrategies
3.tocommunicaterelativeseveritylevelsofhazardstointernal(e.g.,QA,RA)andexternal(e.g.,customers,regulators)stakeholders
4.bymanufacturersasatooltoquicklyassessifanewproductcanbeintroducedintoanexistingfacility
5.toassistinspectorsinidentifyingfacilitiesandareaswiththegreatestrisktofocusonpriortoorduringtheirinspections,potentially
acceleratinginspectionsabenefittobothregulatorandindustry
6.asahealthbasedseverityscaleforuseincleaningprocessFMEAs/FMECAs(failuremodeandeffectsanalysis/failuremodes,effects,and
criticalityanalysis).

FuturePublications

Thetoxicityscalepresentedinthisarticleprovidesawaytomeasuretherelativetoxicityofcompoundswithregardtocrosscontamination.A
subsequentarticlewilldiscussanewscaleforprobabilitybasedonprocesscapabilityvalues.Anotherarticlewilldiscussanewscalefordetectability
basedonvisualresiduelimits(VRLs)andmaximumsafesurfacelimits.Afinalarticlewilldiscusshowthesethreescalesincombinationcanbe
usedinFMEAs/FMECAsforriskassessmentofcleaningorotherprocesses.

Acknowledgements:

TheauthorswishtothankThomasAltmannJamesBergum,Ph.D.AlfredoCanhoto,Ph.D.ParthDesaiMalloryDeGennaroIgorGorskyMichael
Hyrtzak,Ph.D.RobertKowal,MariannNeverovitchandJoelYoungforreviewingthisarticle,andfortheirinsightfulcommentsandhelpful
suggestions.

References:

1.ISPEBaselineGuide:RiskBasedManufactureofPharmaceuticalProducts:AGuidetoManagingRisksAssociatedwithCross
Contamination.(ISPE,Tampa,FL,FirstEdition,2010),Vol.7,p.186.
2.ICHQ9:QualityRiskManagement(Step4)(InternationalConferenceonHarmonisationofTechnicalRequirementsforRegistrationof
PharmaceuticalsforHumanUse[ICH],London,2005).
3.EMAGuidelineonSettingHealthBasedExposureLimitsforUseinRiskIdentificationintheManufactureofDifferentMedicinalProducts
inSharedFacilities,www.ec.europa.eu/health/files/gmp/2013_gmp_pc_en.pdf.

AboutTheAuthors:

MichelCrevoisierretiredfromNovartisPharmain2015.Inhislastposition,hewasaseniorQAexpertforqualificationandvalidation.

DavidDolan,Ph.D.,isanoccupational,environmental,andqualitytoxicologistatAmgenInc.

AndreasFlueckigerhasbeeninchargeofoccupationalhealthincludingoccupationaltoxicologyintheRocheGroupfor30+years.Hisdepartment
alsoestablishesRoche'shealthbasedlimitsvaluesusedinGMPcleaning.

EsterLovsinBarleisheadofhealthhazardassessmentinNovartisGlobalHSE&BCM,wheresheisresponsiblefordevelopmentofhealthbased
exposurelimits(HBELs),occupationaltoxicology,andpatientsafetyrelatedprocessinsupportofmanufacturinginNovartisglobally.

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2017621 AnADEDerivedScaleForAssessingProductCrossContaminationRiskInSharedFacilities
MohammadOvaisisscientificaffairsmanagerforXepaSoulPattinson(M)SdnBhd,Malaysiaandalongtimestudentofcleaningvalidation.

OsamuShirokizawaisadirectorandseniorconsultantofLifeScientiaLimited,apharmaceuticalengineeringandconsultancyfirm.

KellyWaldronisaseniorconsultantwithValsourceandaregulatoryscienceresearcherwiththePharmaceuticalRegulatoryScienceTeamatthe
DublinInstituteTechnology.

AndrewWalshispresidentoftheCenterforPharmaceuticalCleaningInnovation,anonprofitresearchandeducationalorganization.

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