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ParenteralDrugAssociation

Industry Perspective on the Medical Risk of Visible Particles in


Injectable Drug Products

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Industry Perspective on the Medical Risk of Visible Particles in Injectable Drug Products

ExecutiveSummary
Sterileinjectableproductsareusedextensivelyinhealthcare.Patients,caregivers,manufacturers,andregulators
haveaninherentexpectationforsafeandeffectiveinjectabledrugproducts.Thisexpectationrequiresinjectable
pharmaceuticalstobeproducedtostandardsofquality,purity,andsterilitythatincludebeingessentiallyfreeof
extraneousmattersuchasparticles.Despiteguidanceinproducingproductthatisessentiallyfreeofparticles,
manufacturingsuchproductisverychallenging.Inmanyinstances,theobservationofparticlesinpharmaceutical
productshasresultedinproductrecalls.Whilemedicalwarningshaveaccompaniedtheserecallnotices,the
specificsofthesewarningshavevaried.Themedicalliteratureissparsewithrespecttocasereportsand
experimentalstudiesprovidingdatatosupportthesafetyriskofparticles(intrinsicorextrinsic)inhumans.Agap
existsbetweentheobservationofsmallquantitiesofparticlesininjectablepharmaceuticalproductsandpatient
documentedsafetyconcernsresultingfromtheinadvertentadministrationofparticlestopatients.Thus,aneed
existstocreateaframeworktodescribeandassessthepotentialriskofadministeringparticlestopatients.

Thispaperprovidesareviewofcurrentcompendialinspectionrequirementsforvisibleparticlesalongwitha
reviewofthemedicalliteratureassociatedwithanyobservedharmfromsuchparticles.Guidanceisprovidedon
theassessmentofriskinsuchcircumstancesincludingconsiderationofthefollowingkeyattributes;patient
factors,routeofadministrationanduseoffiltrationatthepointofadministration,thevolumeadministered,
particlesizeandtheirfateinbody,particletype,sourceandamount,manufacturingprocessmitigationandthe
frequencyofdetection.

Globally,cliniciansandpatientpopulationsarefacingdrugshortagesinpartduetoinconsistentproductrelease
andrecalldecisionsrelatedtothepresenceofparticlesandalackofunderstandingoftheimpacttopatientrisk.
Thedecisiontorecallproductfromthemarketshouldbebasedoncontextofthemanufacturingtrendhistory,
complaintratetrending,andmedicalriskassessment.Unlesstherearespecificspecialcircumstances,thereshould
benoautomaticrequirementtorecallaproductlotforasingleparticlefoundinasingleunit.Notwithstanding
highriskclinicalcircumstancesandacknowledgingtherearelimitationstoreportingclinicaleventstoparticle
infusion,theexistingdatasuggesttheoverallrisktopatientsisgenerallylowandthebenefitofthesetreatments
isgenerallysignificant.

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Authors:
StanBukofzer,MD,Hospira,Inc(Chair)
JohnAyers,MD,EliLillyandCompany
AnnaChavez,MD,Baxter
MinervaDevera,DBA,QSM,Emergent
JahanviMiller,BS,MBA,ParenteralDrugAssociation
DouglasRoss,MD,Pfizer
JohnShabushnig,PhD,InsightPharmaConsulting,LLC
SusanVargo,MS,PhD,Amgen
HarryWatson,MTSC,CMQ/OE,Hospira,Inc
RickWatson,BS,Merck

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Introduction
Sterileinjectableproductsareusedextensivelyinhealthcare;infact,morethan15billioninjectabledosesare
administeredannuallyworldwide(1).Patients,caregivers,manufacturers,andregulatorshaveaninherent
expectationforsafeandeffectiveinjectabledrugproducts.Thisexpectationrequiresinjectablepharmaceuticals
tobeproducedtostandardsofquality,purity,andsterilitythatincludebeingessentiallyfreeofextraneous
mattersuchasparticles.(Forthepurposesofthispaper,themeaningofthetermparticleincludesparticulateand
particulatematter)Thestandardsofproducingpharmaceuticalproductsaredescribedwithinthevarious
pharmacopeias.Manufacturersstrivetoproduceinjectableproductswiththerequisitequalityoutlinedinthese
standardstoensuretheirsafeandeffectiveuse.

Despiteguidanceinproducingproductthatisessentiallyfreeofparticles,manufacturingsuchproductisvery
challenging(2).Forexample,overtheperiodof20082012,particlerelatedissuesledto22%ofproductrecalls
forinjectableproducts(3).In2007,theEuropeanMedicinesAgency(EMA)performedananalysisofproduct
qualitydefectsreportedin2005andnotedthat6%ofallproductqualitydefectswereattributedtoparticles(4).
ThoseparticledefectsthatresultedinarecallwouldhavebeenclassifiedbyEMAaseitheraclass2(defects,
whichcouldcauseillnessormistreatment,butarenotClass1,e.g.,mislabelingsuchasincorrecttext)orclass3
(defects,whichmaynotposeasignificanthazardtohealthbut,wherearecallhasbeeninitiatedforotherreasons
e.g.,faultypackaging)(EUrecall)(4,5).BetweenJanuary2013andJune2014,theMedicinesandHealthcare
ProductsRegulatoryAgency(MHRA)DrugAlertwebsiteissuedfortytwodrugalerts,withelevenalertsrelatingto
particles(6).Ofthese,alertsreportedin2014wereallclass2andincludedmetalparticles,smallwhiteparticles,
fiberandglassparticles,andsiliconefragments(711).Otheragencies,suchasFDA,havedifferentclassof
recalls:ClassIRecallAsituationinwhichthereisareasonableprobabilitythatuseof,orexposureto,aviolative
productwillcauseseriousadversehealthconsequencesordeath.(21C.F.R.7.3(m)(1));ClassIIRecallA
situationinwhichuseof,orexposureto,aviolativeproductmaycausetemporaryormedicallyreversibleadverse
healthconsequencesorwheretheprobabilityofseriousadversehealthconsequencesisremote.(21C.F.R.
7.3(m)(2));andClassIIIRecallAsituationinwhichuseof,orexposureto,aviolativeproductisnotlikelytocause
adversehealthconsequences(21C.F.R.7.3(m)(3))(12).

Parenteralsolutionswithdrawnfromglassampoulesroutinelyexposepatientstonumerousglassparticlesof
variablesize.Asanexample,a1972studybyTurcoandDavisshowedthatopeningasingle2mLglassampoule
andwithdrawingthemedicineincluded292glassparticlesbetween5mand50mand21particlesthatwere
greaterthan50m(13).Vialpresentationsmaycontainparticlesfromtherubberclosure,ariskthatispresent
witheveryinjection(14).Theseareknownrisksthatmayresultfromthepackaginganduseoftheproductand
arenotmanufacturingrelated.Thetechnologytoproduce,package,andstorecompletelyparticlefreeproducts
onalargescaleisnotcurrentlyavailable.Additionally,Davisetal.identified86to2,200particlesof>5mper
literfollowingfiltrationfromawidevarietyofsterileinfusionsolutionsinglassandplasticcontainers(15).Based
onthestudybyC.M.Backhouseetal.,intensivecarepatientswouldlikelyoftenreceivemorethan107foreign
particles>2mper24hourswiththeirintravenoustherapy(16).

Inmanyinstances,theobservationofparticlesinpharmaceuticalproductshasresultedinproductrecalls(3).
Whilemedicalwarningshaveaccompaniedtheserecallnotices,thespecificsofthesewarningshavevaried(17
22).Typically,thesewarningsaredescribedaspotentialandarenotaccompaniedbypublishedreportsof
patientharm.Themedicalliteratureissparsewithrespecttocasereportsandexperimentalstudiesproviding
datatosupportthesafetyriskofparticles(intrinsicorextrinsic)inhumans.Turcoandothershavedemonstrated
mechanismsfortheinadvertentintroductionofparticles,sometimesinlargequantities,toparenteralfluidsprior
toadministration(13).Theinlinefilterarticlessuggestapotentialrelationshipofthereductionofparticlesand
decreaseinrateoninfusionsitephlebitiswhenfiltersareused(16).Theolderliteratureonlargevolumeinfusion
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andparenteralnutritionandtheliteratureonintravenousdrugsaddicts(IVDA),whichhaveverylimitedgeneral
useforcurrentmedicalpracticeshowthatmass,chronicityanduniquecharacteristicsoftheparticlemayhavea
roleinthesespecialsituations(23,24).Thepaucityofcurrentmedicalliteraturedetailingharmsfromparticulate,
inpharmaceuticalproductsmightinpartreflectthehighstandardsofthecurrentmanufacturingprocesses.

Arecentlyobservedexceptionisthereactionofsubvisible(<10m)proteinaggregatestoformantidrug
antibodies.Suchantibodieshavebeenobservedinbothpreclinicalandclinicalstudieswithproteinbaseddrug
products(2528).Theseparticlesaretypicallybelowthevisualthreshold,unlesspresentinlargequantitytobe
observedasahazeinthesolution.Withthisexception,agapexistsbetweentheobservationofsmallquantities
ofparticlesininjectablepharmaceuticalproductsandpatientdocumentedsafetyconcernsresultingfromthe
administrationofparticlestopatients.Thus,aneedexiststocreateaframeworktodescribeandassessthe
potentialriskofadministeringparticlestopatients.

Currentwrittenexpectationsforlimitsonparticlesininjectableproductscanbefoundinthenationalorregional
pharmacopeias.TheserequirementsaremorefullydescribedinthesectionCurrentDefinedRulesthatfollows.
Historically,theseexpectationshaverequiredsignificantinterpretationtotranslateintoausablenumericallimit
forproductreleaseandongoingcomplianceconsiderations.Thishasledtoabroadrangeofdifferingpractices
anddecisionsbyindividualpharmaceuticalmanufacturersandregulatoryauthorities.Theevolvingstandardsand
abetterunderstandingofpatientriskwillhelptodeliverconsistentandsafeproductsacrossthepharmaceutical
industry.

Withtheseconsiderationsinmind,themedicalofficersandindustryexpertsauthoringthispaperreached
consensusonconsiderationstobeusedwhenassessinghealthhazardsofparticlesininjectablesolutions.The
purposeofthispaper,whichpurposelylimitsscopetofocusonnonproductparticles(e.g.,fibers,glass,rubber,
metal),istoprovideascientific,medicalriskbasedapproachforevaluatingpatientsafetyifaparticlecontained
withininjectabledrugproductsisinadvertentlyadministeredtoapatient.Thepaperissupplementedbya
literaturereviewofdescribedharmstopatientsaswellasanumberofanimalstudiesthathavetriedtoevaluate
thephysiologicaleffect;ingeneralthesestudieshavebeenhighlyexperimentalandusedexcessivequantitiesof
particles(2931).Specificapproachestoriskmitigationarenotaddressedinthispaper.

Toassessrisktohealth,considerationneedstoincludeproductsterility,patientfactorsaswellasthevariabilityin
routeofproductadministrationandvariabilityinparticletype,size,andvolumeofanyproductwithinwhichthe
particleexists.Theclinicalimpactcanthenbeadequatelyassessedbyunderstandingthelikelihoodandseverity
ofthepathophysiologicalconsequencesifparticlesareadministeredtopatients.Byunderstandingthehealth
risks,regulatorsandmanufacturerswillbebetterabletodevelopstandardsthatsupportdeliveringhighquality
drugproducts.Theseperspectivesunderliethecreationofariskbasedapproachwhenassessinghealthhazards
associatedwithparticles.

Despitevaryingsourcesandtypesofinertparticles,onlyfourbasicpathogenicmechanismsforpotentialharm
exist:1.Infectionandinflammationduetolocalorsystemicinfectionscausedbythepresenceofmicroagentsor
endotoxins.2.Physicalpresenceofaparticlemaycauseinflammatoryresponsedirectlyorthroughassociated
leachatesthatcausedirecttissueinjury.3.Particlesmightalsostimulateuntowardimmuneresponsessuchas
allergicreactionsoranaphylaxis.4.Tissuedamagecanarisefromtheocclusionoftheaffectedvasculature
(thromboembolism).Symptomsandsignscanmanifestlocallyorsystemically(e.g.,temperature,feelingweak).As
partofthebaserequirementsforaqualitysystem,themanufacturingenvironmentismonitoredforpotential
sourcesofmicrobialagentsorendotoxincontamination.Productisroutinelytestedatfinalreleasetoensure
productrequirements(e.g.,sterility)aremet.Althoughmicrobialagentsandendotoxinsrepresentapotential
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concern,theserisksareaddressedthroughothercommonlyusedcompendialtests.However,thispaperfocuses
ontheconcernssurroundingirritatinginflammationorreaction,localtissuedamage,andthromboembolism.

Theroutesofadministrationconsideredforthepurposeofthispaperarelimitedtodrugsadministeredthrough
directinjectionorinfusion.AsdefinedinTable1laterinthispaper,theexamplesofthetypesofinjections
consideredwithinscopeincludesubcutaneous,intramuscular,intravenous,highvolume/pressureinfusions,
intrathecal,intraarticular,intraocular,intraarterial,andintraperitoneal.Examplesofproducttypesincludedare
antibiotics,antitoxins,antivenums,blood,bloodderivatives,immuneserums,immunologicdiagnosticaids,
therapeuticproteins,toxoids,IVsolutions,andvaccines.Outofscopeofthisdocumentaredrugreleaseproducts
thatareimplanted,evenifimplantationoccursthroughinjection,aswellasallroutesofadministrationother
thaninjection,includinginhalation,topical,andophthalmic.Furthermore,thepaperdoesnotincludegross
contamination,wherebyparticlesmaybeincludedacrossasignificantproportionofvialsofaproductlotorlots
orasinglevialwithalargequantityofparticles,andtheproductdoesnotmeettheexpectationforessentially
free.

CurrentDefinedRules
Thecurrentinspectionmethodsandacceptancecriteriaforparticlematterininjectableproductsmaybefoundin
thenationalorregionalpharmacopeias.FortheU.S.market,theU.S.Pharmacopeia(USP)GeneralChapter<788>
ParticulateMatterinInjectionshasbeenofficialformanyyears.Itdefinestwomethodsforcountingsubvisible
particlesandsetslimitsof6,000and600particlespercontainerfor10mand25mparticles,respectively.
Theselimitsapplytocontainers100mL.Forcontainerslargerthan100mL,limitsaresetonapermilliliterbasis.
Asthisisaharmonizedchapter,thesamemethodsandlimitsarefoundintheEuropeanPharmacopeia(EP)and
theJapanesePharmacopeia(JP).

RequirementsforvisibleparticlesarefoundinUSPGeneralChapter<1>Injections.Therequirementsetinthis
chapteristhateveryfinalcontainerisinspectedforparticlestotheextentpossible,andanyshowingthepresence
ofobservableforeignandparticulatematterarerejected.Itfurtherrequiresthattheinspectionprocessshallbe
designedandqualifiedtoensurethateverylotofparenteralpreparationsisessentiallyfreefromvisible
particulates(32).GeneralChapter<790>VisibleParticulatesinInjectionswaspublishedinthefirstsupplement
toUSP37andbecameofficialAugust1,2014(2).Thischapterestablishesreferenceinspectionconditionsand
providesquantitativelimitsbasedonacceptancesamplingtomeettheexpectationforeverylottobeessentially
freefromvisibleparticles.TheinspectionconditionsareharmonizedwiththosefoundintheEP(33).

AdditionalrequirementsforproductsmarketedinEuropecanbefoundintheFinishingofSterileProductssection
oftheEuropeanMedicinesAgencyAnnex1.Thissectionsetstherequirementthatfilledcontainersofparenteral
productsshouldbeinspectedindividuallyforextraneouscontaminationorotherdefects.Italsosetsan
expectationthatinspectorspassregularvisiontestsandthatfrequentbreaksbegiventoavoidfatigue.TheEP,in
ParenteralPreparationsInjections(0520),specifiessolutionsforinjection,examinedundersuitableconditionsof
visibility,areclearandpracticallyfreefromparticles.Itfollowswithaninspectionmethoddescribedin2.9.20
ParticulateContamination:VisibleParticles.Thissectionspecifiesilluminationintensity,background,andpacefor
theconditionssuitableforinspection.TheEPmonographMonoclonalAntibodiesforHumanUse(2013)aligns
withtheEPmonographParenteralPreparationsforInjections,allowingforanappearancespecificationof
practicallyfreefromparticles.Thespecificationmustbejustifiedandauthorized(34).

TherequirementsforproductmarketedinJapanarecontainedwithintheJP.Itspecifiesinspectionwiththe
unaidedeyewithlightcomingfromanincandescentsourcewithintensitybelowthatstatedintheEPandUSP.

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Theacceptancecriterionforthisinspectionisinjectionsorvehiclesmustbeclearandfreefromreadily
detectableforeigninsolublematters(35).

Allofthepharmacopeiasestablishtheneedtoperform100%inspectionofunitsinabatchorlotofproductunder
controlledcondition,buttheyrecognizetheprobabilisticnatureoftheinspectionprocessintheacceptance
criteria.

EvolvingStancesandDrivers
Particlesrepresentanongoingchallengeindrugproductmanufacturing.Theuseofclearandcolorlessinjectable
liquidsandcontainerspermitscontinuous,nondestructiveinspectionthroughoutthedrugproductlifecyclefor
mostproducts.Whereproductformulation(e.g.,powders,suspensionsandstronglycoloredsolutions)and/orthe
container(e.g.,amberglassortranslucentplastic)limitvisualinspection,supplementaldestructivetestingofa
smallsampleisrecommendedtofurtherassesstheriskofparticlesinthebatch(2).Pointsoffailure,basedon
particlepresence,includeinprocesswaste(rejects)andcustomercomplaints.Asseeninarecentbenchmarking
study,themostcommoncauseforrejectionswasthepresenceofparticles(28).Sourcesofparticlesincludethe
manufacturingenvironment,primarypackagingcomponents,processingequipment,andthedrugproductitself.
Togetherwithcosmeticandotherappearancedefects,particlescontinuetoimpactproductqualityand
availability.

Thepresenceofvisibleparticlesininjectabledrugproductshasbeenamatterofintensediscussion,bothfroma
regulatoryandacomplianceperspective,withinglobalregulatoryagenciesaswellasindustryoverrecentyears
(35).Thereisanexpectationtonotonlyreduceparticlesbutalsocontrolthem,includingthoseinthesubvisible
range.Tobetterunderstandtheparticlessource,andthusaidintheirreduction,particledetectionand
identificationareimportantpartsofregulatorycomplianceandproductqualityassurance.Lotreleaseacceptance
criteriasuchasfreefrom,without,ornovisibleparticlesrisktherejectionofentirebatchesofdrugproduct
shouldasingleparticlebedetectedinasinglecontainerofproduct.Further,currentinspectionmethodsand
technologies,includinghumanmanualinspectionandfullyautomatedinspectionsystems,cannotprovidethis
levelofabsoluteassurance.Visualinspectionisaprobabilisticprocess(36,37),withdetectionprobabilitiesless
than100%,especiallyforparticleslessthan200mindiameter(27,28,38).This100%inspectionissupportedby
acceptancesamplingmethodology(AQLinspection),whichagaindoesnotsupportabsoluteassuranceofthe
absenceofallparticles.Thesepracticallimitationsshouldbeconsideredwhenestablishinganyvisualinspection
limit.

Industryhasbeenworkingwithregulatoryagenciesworldwidetoupdateguidelinesandmonographstoreflect
thesepharmaceuticaldevelopmentsandtogainimprovementsincontrolandmethodsforidentificationofvisible
particles.Industryhasbeguntoadvocateforregulatorydistinctionbetweenparticlesintroducedintoaproductas
anintrinsicorextrinsiccontaminantversustheformationofinherentparticlesfromthedrugproduct,recognizing
thatInherentparticlesshouldhavebeenfullycharacterizedbytheapplicationholderduringproduct
developmentanddescribedintheproductapplication.

Despitetheseefforts,thepublishedguidancefromregulatorybodieshaslimitedspecificityonallowableparticle
size,numbers,andtypesofvisibleparticles(2,29,32,34,40),oronvisibleparticleinvestigations(41).Thereisno
publishedguidanceonthepotentialimpactofsmallnumbersofvisibleparticlestopatientsafety.Inageneral
sense,thisisthemostcommonissuefacingmanufacturers.Whilethepublishedliteraturecontainsanumberof
anecdotalreportsdescribingexposuretolargenumbersofparticles,noneofthesereportsreflectthepotential
hazardsofmoretypicalparticleadministrationvialargeorsmallvolumeparenteralpharmaceutical

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administrationtopatients.Therecontinuestobeemotionalstanceslackingdataaroundthesubject;aclear
understandingofthefactstobenefitallisrequired.

ParticleMatterConsideration
TheEuropean,Japanese,andUSPharmacopeiassharethefollowingharmonizeddefinitionforparticulatematter
ininjectableproducts:

Particulatematterininjectionsandparenteralinfusionsconsistsofextraneousmobileundissolvedparticles,
otherthangasbubbles,unintentionallypresentinthesolutions.

Identificationofthecompositionoftheparticulatematteristhefirststepincharacterizingparticulatematterrisk.
Basedonthisinformation,particlescanbefurtherclassifiedintooneofthreesubcategories:extrinsic,intrinsic,
andinherent.Bothextrinsicandintrinsicparticlesareconsideredwithinthescopeofthispaper,whileinherent
particlesarenot.Thefollowingdiscussionprovidesdefinitionsandexamplesofextrinsic,intrinsic,andinherent
particles.

Extrinsicparticlesaredefinedasthosethatarenotpartoftheformulation,package,orassemblyprocess,but
ratherareforeignandunexpected.Examplesofextrinsicparticlesincludefibers(e.g.,cellulous),clothing
fragments,hair,rubber,metal,plastic,andpaint.Materialssuchasrubber,metal,andplasticaredefinedas
extrinsicincaseswherethespecificmaterialidentifiedisnotaproductcontactmaterialandthereforenot
consideredpartoftheformulation,package,orassemblyprocess.Extrinsicparticlespresentagreaterriskto
sterilityassurance,especiallyforasepticallyfilledproducts,astheirbioburdenisunknownanduncontrolled.

Intrinsicparticlesaredefinedasthosethatarisefromsourcesrelatedtotheformulation,packaging,orassembly
processes.Examplesofintrinsicparticlematerialsincludeglass,stainlesssteel,rubberfromstoppers,andgasket
material.Ineachofthesecases,theparticlematerialshouldbeaknownproductcontactmaterialtobe
consideredintrinsic.Suchmaterialsarechosenbecausetheyareinertandunreactivetothedrugproduct.
Intrinsicparticlescanalsoberelatedtochangesintheproductovertimeorduetophysicalandchemical
reactionsbetweentheproductandthecomponents(e.g.,oxidation,incompatibilitybetweenadmixturedrugand
thecarriersolution).Suchreactionsmayformavisibleprecipitateorglasslamellae.Whiletheseareformedin
partfromthedrugformulation,theyarenotconsideredinherentparticles,asdiscussedbelow,becausetheyare
indicativeofanunexpectedreactionandalackofproductstability.

Inherentparticlesaredefinedasmaterialsthatareexpectedfromthedrugformulation,andthusrepresenta
generallyacceptedcharacteristicoftheproduct.Examplesofinherentmatterincludethefollowing:adjuvant
materialinsuspensionproducts,certainexcipientssuchashumanserumalbumin,proteinaceousaggregatesin
therapeuticproteins,andmannitolcrystallization(38).Inherentparticles,althoughanticipated,shouldbehandled
asaparticledefectwhenfoundtoexceedexpectedlevels.Becauseinherentparticlebyitsnatureisproduct
specific,assessingitssafetyisconsideredoutofthescopeofthisdocument.Importantly,productswithinherent
particlesshouldbecharacterizedfullyandboththeproductqualityandthepatientsafetyimpactsshouldbe
analyzedwithsimilarriskassessmentconsiderationsaslaidoutinthisdocument.

ParticleSize
Whileparticlesofvaryingsizehavebeenobservedininjectabledrugproducts,theyaregenerallyclassifiedinto
oneoftwocategories;visibleandsubvisible.Visibleparticlesaredefinedasthosethatcanbedetectedunder
controlledconditionsbytheunaidedhumaneye(i.e.,withoutsupplementalmagnification)(2,33,35).Asa
reference,studieshavedemonstratedthatunderidealizedconditions,trainedinspectorsperformingthe
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pharmacopeiainspectionmethodwillbegintohavereliabledetectionofnear70%efficiencywhenparticlesizes
reach150m(38).The150mthresholdshouldbeconsideredabestcasethresholdforhumanvisual
identificationofparticleininjectabledrugproductsgiventhatitrepresentsidealizedinspectionconditions.Any
changesinproduct,container,orparticlematerialfromthoseidealizedconditionswillcausethevisibledetection
thresholdtoshiftabove150m.Therearespecificnonzerolimitsinthepharmacopeiasforsubvisibleparticles
10mand25m.Thesubvisibleparticlecategorycoversmaterialsranginginsizefromsubmicronuptothe
visiblethreshold.ThelimitsareharmonizedintheUSP,EP,andJPandare6,000and600percontainer,
respectively,forcontainers100mL.

PathophysiologicalConsiderationsandClinicalImplications
Theeffectsofparticlesininjectabledrugproductshavebeendiscussedinthemedicalliteraturefordecades(42
47),andarebasedoninvitrostudies,someanimaldata,humancasereports,andsmallobservationalstudies.
Humandataislimitedbecauseitisethicallyimpossibletoprospectivelytesttheimpactofparticlesininjections.
Further,evenifparticulatematterisadministeredtopatient,theclinicalimpacttoapatientcanbehardtoassess
orevenmaybeunnoticedorasymptomatic.Potentialclinicalsequellacould,insomecircumstances,be
indistinguishablefromanunderlyingdiseaseorothertreatmentimpact.Theliteratureoftencontainsthemost
extremeexamplesfromintravenousdrugabuseandhyperalimentation.Giventheselimitations,itsbestto
understandpotentialharmtopatientsbasedonanunderstandingofthepathophysiologyofparticleinfusion.

Thetypeanddegreeofclinicalimpactisdependentonmultiplefactors,includingtherouteofadministration,the
sizeandamountoftheparticle(s)injected,andpatientfactorssuchasunderlyinghealthstatus.Althoughthere
arelimiteddataonhumanexposuretoinfusedparticles,itisestimatedthatpatientsinintensivecareunitsmay
receivemorethanamillioninjectedparticles>2mdaily(48).Assuch,particlescouldtheoreticallyhave
meaningfulclinicalimpactifhighlyexperimentalanimalstudiesareconsideredappropriatesurrogates(49,50,51).
Asanexample,ICUpatientsareatgreaterriskofconsequencesofparticleinfusion,duetotheirneedfor
continuousinfusionofparenteralsolution,includingthatforhyperalimentation.

Manyinjectabledrugsareadministeredintramuscularlyandsubcutaneously.Intramuscularlyandsubcutaneously
administereddrugscontainingparticlesgenerallyhaveminimalimpactonpatienthealth.Complicationsfrom
subcutaneousandintramuscularmedicationsgenerallyarisefromtheirritatingpropertiesofthedrugproduct
andareoftendrugspecific(52).Forparticlesthatareprimarilymechanicalobstructionsandinert(e.g.,cellulose,
metal,orglass),thecompositionofaparticleisnotcriticaltoclinicalimpactexceptforimpactonsterility,which
isdiscussedbelow.Subcutaneousadministrationofsmall,inert,sterileparticleswouldnotbeexpectedtoinduce
aclinicallysignificantreactionbeyondminorirritationorperhapsasmallgranuloma(53).Likewisefor
intramuscularinjections,GreenblattandAllenlookedat26,294hospitalizedmedicalpatients,46%ofwhom
receivedatleastoneintramuscularinjection,findingthatclinicallyapparentlocalcomplicationsareuncommonly
(lessthan0.4%)associatedwithIMinjections(54).Inconsiderationofglassparticlesinparticular,glassfragments
fromtubularandmoldedglasscangenerallybeconsideredinert,andinsmallquantitiestheyarenotlikelyto
causesignificantinjuries.However,thespecialcaseofglasslamellaewhichcanbeeithervisibleorsubvisiblecan
bepresentinlargenumbersandcanincreaseinnumberwithtime,canhaveahigherclinicalimpactif
administeredinlargevolumes.

Wheneveradrugisinjectedintoacontainedspace,forexample,intraocularorintrathecaluse,theremaybe
moreriskforinflammationfromparticlesoraparticlemayserveasanidusforinfection,causingharm(55).There
arelimiteddata,butthepresenceofparticlesinsolutionsforintrathecalusehasbeenreportedfromuseofdrugs
withinglassampoules(56).Theaveragenumberofparticleswas17(738)witharangeinsizefrom15mto80
m.Atthetimeofthestudy,theincidenceofcentralnervoussystemcomplicationfollowingsubarachnoid
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anesthesiawaslow.Theauthorsnotethataforeignbodyreactionmayhaveresultedandmayaccountforthe
reportedeventsofchemicalmeningitis.

Intravenousinfusionofparticlesmightresultinphlebitisduetoparticlescausingdirecttraumaticdamagetothe
vein,orchemicaldamagefromundissolvedparticles,orinfectioniftheparticleisnonsterile.Nondissolvable
particlematterwillbecometrappedinsmallvesselsorcapillarybeds,whentheintroducedparticleislargerthan
thevessel.Thediameterofthesmallestcapillaryorbloodvesselisabout7minanadult(57)andthediameter
ofapulmonarycapillary,whichisapproximately1015m,justlargerthanthesizeofredbloodcellswhichare
responsibleforoxygenationofbloodastheytravelthroughthepulmonaryvasculature.Thereforeany
intravenouslyadministeredparticlesgreaterthan7mbutlessthan10mmayoccludesomecapillaries.If
pulmonarycapillariesarecompromisedinthepresenceofmicroemboli(pulmonaryembolism),theclinical
consequenceisimpairedoxygentransferandcompromisedrespiratoryfunction(58).Smallerparticles(<7m)
willgenerallybephagoctisedbymacrophagesandultimatelydepositedinspleenorliver.Massiveamountsof
subvisibleparticlesmightnotbephagocystosedandmightthenbedepositedinotherorgans,especiallythe
kidney.Ingeneraltheclinicalconsequencesarenegligiblebecausemostorgansystemshavesignificantreserve
capacity(30,31).

Theclinicalimpactfromanoccludedvesselisdependentonmanyvariables,includingthesizeofthevessel
affectedaswellasthenumberofvesselssupplyingaparticularorgan.Inmanyinstances,theremaybenoclinical
impactassometissuesororganshaveextensivebloodvasculaturesothatnumerousvesselsmaybefeedingthe
sametissue.Therefore,oneornumerousoccludedsmallvesselsmayhavenoclinicalsignificanceorpatient
symptoms.Infact,solidparticlemicroemboliarearecognizedcomplicationofextracorporealcirculationinopen
heartsurgery(5962).Microsphereinfusionduringbypassinlaboratoryanimalsshowedpulmonaryultrastructure
damagewasproportionallyrelatedtoparticlesincreasinginsizefrom20mto75m.Aftersimpleperfusionof
theextracorporealcircuit,Liureportedthatthe15to80mparticlecountreached19969permL(63).Despite
theserisks,theclinicalbenefitsoutweightherisks,justifyingwhyextracorporealcirculationhascontinuedtobe
usedinopenheartsurgery.Thishighlightsthatriskaloneisbutoneconsiderationwhenassessingtheuseof
productsandshouldnotbetheonlyconsiderationwhenassessingimpact.

Numerousanimalstudieshavebeenconductedtodeterminethefateofintravenousparticlesofdifferingsizeand
composition(29,51,64,65).Moststudieshavefocusedonsubvisibleparticles,withadiameteroflessthan50m.
Inthesestudies,theinfusionofmassivequantitiesofparticleshasbeenaccompaniedbyhistologicevidenceof
injurytopulmonarycapillaryendothelialcells(63),microscopicthrombiinthepulmonarycapillaries(66),
microscopicpulmonarygranulomata(67),andhepaticinflammatoryeffects(68).Inahamstermodelusing
antibioticswithsubvisibleandvisibleparticles,capillaryperfusionwasjeopardizedinposthypoxictissuebutnotin
normallyperfusedtissue(24).Whileusefulinunderstandingthepathophysiologicresponsetointravenous
particleexposures,thelargemassofparticlesemployedintheseanimalstudiesprovideslittleguidanceonthe
riskofsmallnumbersofmacroscopicparticlestohumanpatients.

Therearelimiteddataonhumanexposuretoinfusedparticles.Clinicallydetectablepatientharmsfromparticle
injectionaredifficulttodetectevenifsuspected,suggestingminimalshorttermimpact.GarvinandGunnerwere
amongthefirsttoreportaconcernabouttheeffectsofparticlesinhumanpatients,findingpostmortem
pulmonaryvasculaturegranulomas(cellulosefiber)inthelungsofpatientswhohadreceivedlargevolumesofIV
fluids(69,70).Forobviousethicalreasons,thereisalackofcontrolledhumanstudiesontheeffectofparticlesin
humanpatients.However,clinicaleventsfromtotalparenteralnutrition(TPN)complications,intravenousdrug
use,andcardiopulmonarybypassproviderelevantinformationontheeffectsofhigh(andprolonged)particle
exposure(thesearespecificandnotnecessarilygeneralizablecircumstances).
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TheAmericanSocietyofParenteralandEnteralNutrition(ASPEN)Guidelinesnoteparticlesof5to20mand
largerarecapableofobstructingbloodflowthroughthepulmonarycapillaries,whichcouldleadtocomplications
suchaspulmonaryembolism(42).Areviewoftheliteraturerevealsacasereportofadyspneicpatientreceiving
TPNwhohaddiffuse<1mmmicronodulesoncomputerizedtomographyexamination,elevatedpulmonaryartery
pressures,and,onpostmortem,amorphousmaterialmicroemboliinthepulmonaryvasculature(71).Thisfinding
highlightsthatparticlesmayhaveaclinicalimpactwhenadministeredoveranextendedperiodoftimewith
multipleexposures(72).Hyperalimentationassociatedwithinherentparticles(calciumandphosphate)
administeredtopigshasbeenshowntocauserespiratorydistressandsuddendeathwithamorphouscalcium
phosphateprecipitantdebris(71).

Additionalanecdotalinformationforhumanpatientriskmaybeobtainedfromtheexaminationofcasereports
involvingintravenousdrugabusers(68,73,74).Inthesecases,apowderorpulverizedtabletissuspendedina
vehicle,thenvariablyfilteredthroughcotton(75).Thesepatientsmaydevelopdyspneaandshowreduced
pulmonaryfunctiontesting(72).Cuttingagentsorexcipientssuchasmicrocrystallinecellulose,talc,andstarch
havebeenidentifiedinpulmonary,foreignbodyemboliandgranulomasintheseindividuals(7577).Inone
instance,theparticleslodgedinthepulmonaryarteriole,causinginflammationandthrombosis,subsequently
erodingthroughthearteriolarwallandbecomingagiantcellgranuloma(77).Talcgranulomasinorgansother
thanthelungswerefoundtobeofnegligibleclinicalsignificance(78).NidenandAviado(1956)foundthat
experimentalintravenousinjectionofagivenmassofglassbeadsproducedgreaterpulmonarydysfunctionwith
smallerparticlesizessuggestingsystemiceffectsmightberelatedtosurfacearearatherthansizeofparticles(58).
Importantly,themeaningfulclinicalriskstohumanpatientsaredifficulttoinferfromtheseobservationsof
extremecasesofparticleinfusionthatresultinchronicexposure,extremesinmass,number,anddiversityof
foreignparticles,aswellastheuncontrolledconditionsinwhichtheywereadministered.

Inanotherpaperwhereembolizationeventsresultedinalessextremecaseinregardstonumberofevents,
Bayduretal.demonstratedthatprolongedindwellingcentralvenouscatheterusemaydegradeandleadto
embolizationofcathetermaterial(79).Thisoccurredinapatientwherethecatheterparticlesenteredthe
pulmonarycirculation.Thispatientrequiredacentralvenouscatheterformorethanfiveyears,andnumerous
catheterswereutilizedinthistimeperiod.Thepatientwasclinicallyasymptomaticthroughoutthattimeandfour
yearslaterdevelopedsymptomsofsarcoidosisthatincludedgranulomaformationoftheskin.Thepatient
requiredfurtherevaluation,includinganopenlungbiopsy,whichrevealedpulmonarygranulomasoftwodistinct
types,thatfromsarcoidosisandtheotherofcathetermaterial.Theauthorreportsthetwogranulomatous
processeswereunrelated.ThispaperandcasereportsofIVdrugabusershighlightthatalocalizedpulmonary
inflammatoryresponsemaybemorelikelytoresultfromparticlesthanpulmonaryembolismorclinically
symptomatictissuedamage.

Perhapsmorerelevantareclinicalresultsofarterialembolizationproceduresperformedusingmaterialssuchas
polyvinylalcoholembolicagents(80),collagencoatedacrylicmicrospheres,andgelatinspheres(81).These
proceduresprovideussomeinsightonthepotentialhumanpathophysiologicoutcomesduetonontarget
embolizationwithinintravenousinfusions(82).Theseproceduralreportedcasesinvolvedmassive,300500m
particleloadsmovingfromthearterialinjectionsiteintothevenouscirculation.Whiletheseembolization
proceduresdidresultintheintendedthromboembolicevent,theyhavenotresultedinsignificantlongterm
consequencesfrommaterialthatwouldbeconsideredextrinsicparticlesformost,ifnotall,drugproducts(27,83
87).

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Inthepresenceofanabnormalcommunicationbetweenthevenousandarterialsystems,intravenously
administeredparticlescanbypassthelunganditsvasculature.Aberrantanatomymightbeknown,forexample
fistulaeforrenaldialysis,orunknownforexample,upto30%oftheadultpopulationhasapatentforamenovale
thatallowsforarighttoleftshiftofthebloodcirculationwithintheheartandbypassesthelungs(38).Thisallows
forthepossibilityofparticlestoenterdirectlyintothecentralvascularsystem,withpotentialcomplicationsto
includeischemicstrokeandmyocardialischemia,orintotheperipheralvascularsystem,whereperipheral
vascularischemiamayresult.Inaddition,endorgandamagecanoccurthroughdepositionorembolismofparticle
intotheorganvasculature.Further,evenwithanintactnormalvascularanatomy,particleslessthan10mmay
passthroughthelungscirculation,intotheperipheralcirculation,anddepositinotherorgans,suchastheliver,
kidney,andspleen.Patientswithexistingendorgandiseaseandsmallvesseldiseasemaybeconsideredat
greaterrisk.

Insummary,particleadministrationhasalowprobabilityofclinicallysignificantinjuryonthevascularsystem,and
currenthypotheticalassessmentsareoverestimated.Clearlysomeimpactcanexist,butcasesareinfrequentand
oftenassociatedwithextremerisksituations.Datasuggestadministrationofalargevolumeofparticlesover
time,theuseofhyperalimentationandlargevolumesofsmallsizeparticlesmaycauseclinicaldamage.Small
amountsofinertparticlesareunlikelytocauseclinicallymeaningfulpatientharm.Inaddition,intramuscularand
subcutaneousinjectionsofsterileinertparticlesareveryunlikelytocausemeaningfulpatientinjury.Further
considerationshouldhoweverbegiventopatientswithendorgandisease,immunecompromised,orneonates
andinfants,aswellaswhenparticlesareinjectedintoclosedspaces(e.g.,intrathecal,intraocular,intraarticular)
asthesesituationsmayhaveagreaterpotentialforharm.

RiskAssessment
Toassessthepotentialimpactoftheparticletothepatient,ariskassessmentshouldbeperformedinaccordance
withrecognizedguidancedocumentsandstandards(88).IntheInternationalConferenceonHarmonisation
QualityGuidelineQ9:QualityRiskManagement,riskisdefinedasthecombinationoftheprobabilityof
occurrenceofharmandtheseverityofthatharm(89).Inrelationtoparticles,whenassessingtherisktothe
patientpopulation,theassessmentcanbereducedintothelikelihoodforthehazardtooccurandtheseverityof
theharmorclinicallysignificantoutcomethatmightoccurtothepatientduetothehazard.Theriskisderived
afterassessingthelikelihoodoftheharmagainsttheseverityoftheharmunderspecificcircumstances.
Differentiationshouldbemadebetweenthelikelygeneralpopulationandasubsetofpatientswhomightbemost
atrisk.

Notingthatposthocprocesscontrolsshouldnotbeusedasasafetynetforpoormanufacturingmethods,the
riskassessmentneedstoconsiderthepossibletypesofclinicalimpactthepatientmightexperienceandassess
whethertheharmwouldbelikelytooccurgiventhespecificcircumstances.Someproductsareknowntohavea
riskforprecipitant,andlabelingandstandardusereflectthisunderstandingandtheimportanceforproduct
inspectionpriortousewithinthepharmacyaswellasatpatientbedside.Theassessmentshouldaccountfor
standardclinicalpracticetoreflectrealworlduse.

Theseverityofharmisdeterminedbasedonthepotentialclinicalimpactthatthepatientwillexperiencedueto
administeringproductfromtheaffectedlot.Severitycanberatedastemporarydiscomfortallthewaytopatient
death.Potentialharms,asdiscussedinthePathophysiologysection,mayincludephlebitis,granuloma,and
occlusionorthromboembolicevents,eachwithdifferingseveritylevelsofharm.Forexample,anotherwise
healthyindividualreceivingasubcutaneousorintramuscularinjectioncontainingsterileextraneousinertparticle
wouldlikelyexperiencenoadverseeffectoratworstdevelopasmallgranuloma.Theseverityoftheharmmaybe
consideredminorwithnoneedformedicalintervention.Bycomparison,acriticallyillprematureinfantreceiving
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aparticleladeninfusiondirectlythroughanumbilicalcathetermightsufferpermanentorlifethreateninginjury
(47,90).Thisoutcomemaybeconsideredcritical,asalifethreateningsituationarose.Insomesituations,
permanentinjurymayresultandshouldbeconsideredindeterminingthedegreeofseverityoftheharm.

Thescopeofthispaperdoesnotallowthecreationofaspecifictemplatetoconsiderrisk;however,thefactors
presentedinTable1shouldbetakenintoconsiderationinsuchanassessment.

Table1:Factorstobeconsideredinparticleriskassessment
Parameter
PotentialRiskFactor
Patientfactors
Age,gender,weight,diseasebeingtreated,
underlyingillness,immunestatus,other
treatments,physicalactivity
Routeofadministrationanduseoffiltrationat
Subcutaneous,intramuscular,intravenous,high
pointofadministration
volumeinfusions,intrathecal,intraarticular,
intraocular,intraarteriol,other;useoffilter(and
type)atpointofuse
Volumeofadministration
Numberofparticleslikelypresentpervolumeof
administration
Size
Ifvisibleparticlesarepresent,determinethe
likelihoodofadditionalsubvisibleparticlespresent
andthelikelysize.Determineifthesubvisible
particlesarewithinacceptablelimits
Fateinbody
Remainsatsiteofadministration(e.g.,
subcutaneousorclosedcavity),peripheralversus
centralvenousadministration,intrinsicreactivity
(immunogenicity,proinflammatory,
nonreactive/inert)
Particletype
Inherent:intacttherapeuticprotein,denatured
therapeuticprotein,degreeofdegradation,other
proteincomponent(s)
Intrinsic:silicone,glass,rubber,stainlesssteel,
fibers(cellulose,polyester),etc.
Extrinsic/processrelated:autoclavetape,gowning
materials,Tyvekwrap,etc.
Extrinsic/foreign:hair,insectparts,clothing
fragments,metal,paint,etc.
Characterization
Symmetrical,asymmetrical/irregular,rigid,thick,
thin,fragile,flexible,malleable,charged,chemical
composition,metalliccomponents,surface
characteristics,bioreactivity,leachability,
infectivity,sterility,infectionrisk
Source
Processrelated,foreigntoprocess
Amount
Numberpercontainer,numberofcontainersper
lot
Manufacturingprocessmitigation
Pointoffiltration,particlereductionmitigation,
sterilizationprocedures(terminally
sterilized/asepticprocessing),potentialfor
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FrequencyofDetection

detection[100%visualinspection,acceptable
qualitylevel(AQL),alert/actionlimitsbasedon
trendandstatisticalanalysis]
Inspectionprocessandproductandpackage
attributes

Akeyconsiderationistoassessthesourceoftheparticleandtoassesstherisktothesterilityofthedrugproduct
inthisregard.Theimpactmightbemodifiedbyadditionalmanufacturingvariables,suchasterminalsterilization
(ascomparedtoasepticfilling)fordeterminationofpossiblemicrobialcontamination.Thus,understandingthe
manufacturingprocessandwheretheparticleswereintroducedintotheproductisimportantinunderstanding
theoverallrisktothesterilityassuranceoftheproduct.Microbialcontaminationand/orendotoxinintroduction
intotheproductshouldbeconsideredinadditiontopathophysiologicalconsiderationsforparticlesinorderfor
healthcareprofessionalstohaveacomprehensiveunderstandingofpotentialimpacttothepatient.

Aspreviouslystated,theoverallriskisdeterminedbyassessingthelikelihoodofharm,whichmaybedetermined
qualitativelyorquantitatively,occurringagainsttheseverityoftheharm.Basedontheassessment,a
determinationcanbemadeastotheactionsrequiredforaparticle(e.g.,limitusetospecificpatientpopulation,
recallthelot).Forparticles,itmightbepossibletoestablishpredefinedacceptablerisktowhichmanufacturers
canrefer;thisshouldinnowaypreventmanufacturersfromcontinualimprovementofsystemswithagoalto
eliminateallparticles.Forexample,inlinefiltersforintravenousadministrationofparenteralsolutionsatthe
pointofusewouldreduceriskforlargerparticlesbutnotallsubvisibleparticles.Allcuttetal.(1983)showedthat
inlinefiltrationdelayedtheonsetofinfusionphlebitiswhichistheonlywelldocumentedclinicalcomplicationof
particledrugcontaminants(91).Whentherisktopatientsexceedstheseestablishedparameters,fieldaction
shouldbeconsidered.Whennewtypesoffailuresorparticlesarediscovered,anewriskassessmentshouldbe
completedfortheproducttodetermineappropriateactions.Thesecanincludeinternalmanufactureractionsas
wellasexternalfieldactions.Patientpopulationsshouldbedefinedaspartoftheintendeduseoftheproduct.A
determinationofappropriateactionsshouldbebasedonlabelindicationsforproductuseratherthanspeculation
onofflabelpotentialuses.

Inadditiontotheriskassessment,theriskofhavinglimitedproductavailabletothepublicmustbeconsidered
whenassessingthetrueimpactofproductcontainingparticles.Thisriskbenefitanalysisprovidesabroader
perspectivewithanunderstandingofthemarketconditions,includingavailabilityofanalternateproductaswell
aspotentialdrugshortages.

DuringapresentationtotheU.S.SenateCommitteeonHealth,Education,LaborandPensionsonDecember15,
2011,Dr.SandraKweder,thedeputydirectoroftheOfficeofNewDrugDevelopment,FDA,statedthatbetween
January2010andSeptember2011,therewere127episodesofdrugshortages.Ofthese,120oftheproduct
shortagesinvolvedsterileinjectabledrugs(92).Further,54%ofthesehadproductqualityissues(particles,
microbiologiccontaminants,impurities,andstability).Theavailabilityofinjectabledrugproductstopatientsdue
topotentialriskfromasinglevialcontainingaparticlecreatesanadditionalconcernforpatientsafety.An
outcomeofaseriousadverseeventmaybetheexceptionandnottheruleforinjectabledrugproductswith
limitednumbersofparticlespresentinproductreleasedasessentiallyfreeofparticles.

QualityRiskManagement
Thefrequencyorrateatwhichtheparticleislikelytooccurshouldbedeterminedandbasedonobjectivedata.
Thepresenceofparticles,forexample,canoccurasasingleparticleorasmultipleparticlescontainedwithina
singleunit.Onemustconsiderthedistributionoftheseparticles,thatis,whethertheparticleisanisolatedevent
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oritsdetectionmayimplicateotherunitsorbatches.Furtherconsiderationshouldalsobegiventootherproducts
manufacturedonthesameproductionline.

Adeterminationneedstobemadeastohowoftenthehazard,particlesinthiscase,islikelytooccurwithinalot
ofproductoracrossproductlots.Thisassessmentneedstotakeintoaccounthowwidespreadtheparticlehazard
mightbe(e.g.,oneparticleinonevialofonebatchofproductortenparticlesintwohundredvialswithintwenty
batchesofproduct).Tomakethisdetermination,amanufacturingsiteneedstoconservativelyassessthe
potentialcausesofthehazardanddeterminehowlongthesepotentialcauseshavebeenoccurring.Ultimately,
eveniftheproductiswithinthespecifiedAQL,itisincumbentonthemanufacturertounderstandleadingand
laggingtrendsovertime.

Manufacturersareencouragedtotakealifecycleapproachtounderstandwhereparticlesmaybegenerated,
detected,andremovedinaproductionprocess.Characterizationofdefectsatthetimeofmanufacturecan
providevaluableinsightsintotheoverallunderstandingofparticlegenerationandsubsequentmitigationto
reducethelevelofparticlesinproducts.Examplesofitemstoreviewtodetermineafailurerateinclude,butare
notlimitedto,thefollowing:complaintdata(trendsorspikes),exceptionreport/CAPArecords,manufacturing
batchrecords,supplierincomingreports/data,andinspectionresultsofinventoryaswellasofretainedsamples.
Fromthisanalysis,themanufacturingsitecanestimateatabaselevelthelikelihoodofoccurrenceforparticles
withintheaffectedlotorlotsofproduct.

Conclusion:OverallMedicalRisk
Advancesinprocesscapabilitytoreducetheparticleburden,andcontinuedvigilanceforparticles,haveresulted
inreportedinjuriesbeingrareandmostappearlimitedtothecasereportsassociatedwiththeinfusionof
significantquantitiesofprecipitatedadmixtures.Additionally,macroscopicparticlesaremorelikelytobe
discoveredpriortoadministrationorcanbetoolargetopassthroughthelumenofaneedle.Further,evenwhen
largerparticlesareusedpurposefullytooccludeAVMs(andtheyhavebeenshowntocrossintothevenous
circulation),thereisrarelysignificantsequelaeobservedforthesepatientswhoareundercloseobservation.
However,clinicaldatasuggeststhatproductconformingtocompendialparticlelimitscancontainsubvisible
particles,which,canresultinpatientsbeingexposedtolowlevelsofparticlesaspartofthepracticeofroutine
healthcare.Theintravenousinfusionofrigidparticlesgreaterthanthe1012mdiameterofapulmonary
capillarywillbeocclusive.Onceinfusedorinjectedanaggregatenumberofsubvisibleparticlesmightimparta
similarpathophysiologicaleffectasamacroscopicparticle,butmoreimportantly,itisincreasinglyrecognizedthat
subvisibleaggregatesmightinduceanuntowardimmuneresponse(27).Thus,theoftenprevailingassumption,
thatlargerparticlesposeagreaterrisktopatientsratherthansmallerparticles,maybeamisconception.

Anestimated15billioninjectabledosesofmedicinesareadministeredworldwideeachyear(1).Theevidencein
thispapersuggeststhattruepatientharmassociatedwithinjectionsisextremelylimitedatthecurrentthelevel
ofparticlemattercontainedtherein.Whilemanufacturingprocesses,recallprocedures,andclinicalpracticesall
contributetothiscurrentstate,currentprocessesandproceduresseemadequate.Smallamountsofinert
particlesareunlikelytocauseclinicallymeaningfulpatientharm.Inaddition,intramuscularandsubcutaneous
injectionsofsterileinertparticlesareveryunlikelytocausemeaningfulpatientinjury.Furtherconsideration
shouldhoweverbegiventopatientswithendorgandisease,immunecompromised,orneonatesandinfants,as
wellaswhenparticlesareinjectedintoclosedspaces(e.g.,intrathecal,intraocular,intraarticular)asthese
situationsmayhaveagreaterpotentialforharm.Thereisinsufficientevidencetoconcludethatintravenous
injectionofinertvisibleparticlesresultsinharmtopatients(47,71,93).

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Asthereislimiteddirectevidenceofpatientriskduetosterile,inertparticles,itisreasonabletoconcludezero
toleranceshouldnotbetherequirement,butinsteadconsideredasthegoalinmanufacturinginjectabledrug
products(72,90,93).Despitemanufacturingprocessimprovementsandanincreasedsurveillancewithimproved
detectionmethodology,themanufactureofparticlefreeinjectableproductisnottechnicallyfeasible,but
continuousprocessimprovementisanexpectation.

ApragmaticapproachensuringhighqualitydrugsareavailabletopatientsisprovidedbyUSP<790>and<1790>.
Thesechaptersrequirearobustqualitymanagementsystemwitha100%inspectionprocess,particle
identificationprocess,andagoodinvestigationandmonitoringprocesstoensuretheoccurrenceandcomposition
ofparticulatesareunderstood.Thecompositionoftheparticulatematterisveryimportantwhenconsideringthe
medicalsignificancewhenperformingariskassessment.Tounderstandthecomposition,afirmwouldneeda
systemtoidentifytheparticulatematterfoundinthedrugproduct.USP<790>and<1790>,togetherwitha
medicalriskbasedapproach,offerapracticalstrategytoensuremanufacturersmeetexpectationsforvisible
particles.Thisstandardwaswrittenconsideringbothcurrentmanufacturingcapabilityandpatientrisk.Following
therecommendationsinUSP<790>and<1790>willprovidetheminimumexpectationsformanufacturing
standards.Forlowriskroutesofadministration,suchasintramuscularandsubcutaneousinjections,the
acceptancecriterionofanAQLof0.65%basedonUSP<790>,ensurestheadequatesafetyoftheproduct.There
maybeclinicalcircumstanceswheretighterAQLvalues(limits)maybeappropriateforhighriskpatientsandfor
otherroutesofadministrationbasedonanevaluationofpatientrisk.

Globally,cliniciansandpatientpopulationsarefacingdrugshortages,inpartduetoinconsistentproductrelease
andrecalldecisionsrelatedtothepresenceofparticlesandalackofunderstandingoftheimpacttopatientrisk.
Safetyconsiderationsrelatedtoparticlesininjectabledrugproductsmustbeassessedonthebasisofthefactors
identifiedinthispaper,whichincludetheintendedpatientpopulationandmethodofadministration.The
decisiontorecallproductfromthemarketshouldbebasedonthecontextofthemanufacturingtrendhistory,
complaintratetrending,andmedicalassessmentofpatientrisk.Unlesstherearespecificspecialcircumstances,
thereshouldbenoautomaticrequirementtorecallaproductlotforasingleparticlefoundinasingleunit.While
manufacturersstrivetoremoveparticlesfrominjectableproducts,thispaperhasoutlinedconsiderations
importanttoassessingtheriskbenefitratioofadministeringproducttoapatient.Ingeneral,notwithstanding
highriskclinicalcircumstancesandacknowledgingtherearelimitationstoreportingclinicaleventstoparticle
infusion,theexistingdatasuggesttheoverallrisktopatientsisgenerallylowandthebenefitofthesetreatments
isgenerallysignificant.

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