Filter validation

Filter validation- An Pharmaceutical Overview

1. Validation Of Membrane
Filtration
1
VINOTH R
2061010003
M.Pharm (IP) –1
st
Semester

2. Content
Introduction
Objectives
Why validation needed
Pre-requisites for validation
Validation Study Element
References
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3. Introduction
Unitoperationoffiltrationistheseparationofsolidsfroma
liquidbypassagethroughafiltermedium
Membranefiltrationisusedforsterilizationofdrugproduct
andusedinsterilizationprocess
Therearetwotypesoffilterusedinfiltrationprocess
(1)Depthfilters:Consistoffibrousorgranularmaterialsso
packedastoformtwistedchannelsofminutedimensionsand
theyaremadeofdiatomaceousearth,unglazedporcelain
filter,sinteredglassorasbestos.
(2)Membranefilters:Theseareporousmembraneabout0.1
mmthick,madeofcelluloseacetate,cellulosenitrate,
polycarbonate,andpolyvinylidenefluoride,orsomeother
syntheticmaterial.
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4. Methods of Sterilization of
Products
1.Heat
Moistheat(Autoclave)
Dryheatovenandtunnel
2.Gas
Ethyleneoxide
Peraceticacid
Vaporphasehydrogenperoxide
Chlorinedioxide
3.Radiation
Gamma
Beta
Ultraviolet
4.Membranefiltration
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5. ValidationmaybedefinedasEstablishingdocumented
evidencewhichprovidesahighdegreeofassurancethat
aspecificprocesswillconsistentlyproduceaproduct
meetingitspre-determinedspecificationsandquality
attributes
Ithasbeenmademandatorybytheregulatorybodiesto
provethesafety,efficacy,Purity&effectivenessofthe
drugproduct,medicaldevices&biologicsinthe
marketplace&healthsystem
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6. Objectives
Toestablishdocumentedevidencethattheprocess
employedforvalidationofmembranefiltration
methodwillproducethedesiredresultsconsistently
whenperformedasperthesop
Forgoodbusinesspracticeinwhichoutofcontrol
processincreasetheamountofcost
Toestablishquality,safety,andconsistencyof
product
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7. Why Validation is needed?
Validationisvitalfor
Safety
Fewerinterruptionsofwork
Lowercosts
Eliminationofprematurereplacement
Identificationofhighmaintenancecost
Reductionofvariationinresults
Greaterconfidenceinthereliabilityof
results
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8. Responsibilities
Sr. No. Responsibility Name of the
Department
1Development ofValidation
protocol
QC
2Executionofthisprotocol QC
3Approvalofprotocolandofthe
finalreport
QA
4FinaldeterminationofSystem
Acceptability
QA/QC
5Reviewandassemblingofdatainto
afinalreport
QC
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9. Pre-requisites
Inordertoefficientlyconductvalidationofthe
membranefiltrationmethod,ensurethatthe
followingrequirementsarefulfilled
Validatedasepticfacilitytocarryoutthe
validation
Allequipmentstobeusedforvalidationare
qualifiedandoperationalSOP’sestablished
andfollowed.
Alltheequipmentsandculturemediarequired
forthevalidationshouldbesterile.
Sterile70%IPAsolution
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10. Membranefilter:-Sterileindividuallypacked
cellulosenitrateorcelluloseacetateaveragepore
size0.45m
Validationtasksaretobecarriedoutbytrained
personnelusingtechniquesandequipment,which
minimizetheriskofaccidentalmicrobial
contaminationofthetestandofthetesting
environment
Personnelconductingsterilitytestingorassociated
asepticmanipulationsshouldwearsterilized
garments
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11. Identificationofcriticalcontrol/
monitoringparameter
Eachlotofmediausedmustbetestedforits
growthpromotingqualitiesasperSOP
Duringvalidationcarryoutenvironmental
monitoringbysettleplateandpersonnel
monitoringbyandswabmethodasperSOP
IfanyCFUobservedduringmonitoringonswab
method,allCFUmustbeidentifieduptospecies
level
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12. Validation study element
Physical
Reproducibilityoffilter
Sterilization
Integritytest
Operatingcondition
Shedding
Microbialchallengetest
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13. 13
Biological
Endotoxin
Toxicity
Chemical
Inertness
Activity/stability
Test for antimicrobial activities
Consistency and reliability

14. (1)Reproducibilityoffilter
Membranefiltersshouldberoutinelydiscardedafter
processingofsinglelotbecausetherearechancesof
contaminationorcrosscontaminationofproduct
Howeverinthoseinstanceswhenrepeatedusecan
bejustifiedthemembranefiltrationshould
incorporatethemaximumnumberoflotstobe
processed
Factorthatcanaffectinfiltrationprocessinclude
viscosity,surfacetensionofmaterialtobefiltered,
ph,flowrates,time,temperature,osmolarityetc.
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15. (2)Sterilization
Validationofsterilizationmethodoffilteris
necessarybecausefilteritselfcausecontaminationof
theproduct
Tovalidateuseofsterilizinggradefilteritisnotonly
provethatthefilterisadequatelysterilizedbutalso
methoddoesnotdamagethefilter
Mostpreferredmethodismoistheatsterilizing
Variablelikeheatup,cooldown,pressure,
temperature,time,ifitisuncontrolleditleadtofilter
failure
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16. (3)Integritytest
Itshouldbenondestructiveandprovidean
indicationof“fitnessforuse”
Thisincludebubblepointtest,diffusiontest,pressure
holdtest,waterintrusiontest
Thistestoffiltershouldbeperformedpriorto
processingandshouldbeperformedroutinelyand
conductedafterfiltrationtodetectanyfilterleaksor
perforationthatmighthaveoccurredduringthe
filtration
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17. Inbubblepointtestfiltermediumwetted
withaliquidandtestgaspressureisincrease
untilsteadystreamofbubbleappearsfrom
tubewhichisimmersedinwater
Thepressureatwhichthebubblefirstappear
isrecordedasthebubblepoint
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18. Theaimsofthisseriesoftestswereto:
Determinethemicrobialremovalefficiencyoffilters
inliquidchallengetestsusingBrevundimonas
diminuta(ATCC19146)
Determineintegritytestparameters
Waterbubblepointoffiltershouldexceedthegreater
than50psig
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19. (4)Operatingcondition
Thevalidationstudymustensurethatwithin
anticipatedworstcaseoperatingconditionthefilteris
notcompromised
Time:
Longprocessingtimecouldallowbacteriawhich
havebeentrappedbythefilter
Filtermanufacturercanprovidethedataonthe
retentionteststhathavebeenconductedforspecific
membraneandgenerallysuggestthatfiltershould
retainbacteriaexcessof48hr.
Filtermanufacturerdecidethetimebyperforming
test
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20. Temperature:
Manufactureoffilterrecommendedthelimitand
thesenotexceeded
Pressure:
Inletpressuretothefiltermustbemonitoredto
ensurethatthereisnopotentialforstructuredamage
Thedifferentialpressureacrossthemembranemust
complywiththefiltermanufacturesrecommended
limits
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21. (5)Shedding
Itincludesparticulatesandfiber
Particulates:
Itconcernforthefollowingreason
Isthefiltercontributestoparticularloadofthe
solution?
Isthefilterspecifiedasreducingtheparticulateload
ofthesolution?
USPlimitswhentestedbylightobscurationmethod
ForLVPsnotmorethan25particulatesperml≥10
µmandnotmorethan3particulatesperml≥25µm
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22. ForSVPsnotmorethan6000particulate
percontainer≥10µmand600≥25µm
Opticalmicroscopy,lightobscuration,light
microscopicimageanalysis,scanning
electronmicroscopeareusedinparticulates
count
Tomeasureremovalofparticulatesby
filterknownamountandsizedistributionof
particulatesfilteredandamountofretention
ismeasured
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23. Fiber :
It concern for 2 reason
Is the filter shedding fiber into the solution?
Is the fiber function to remove fibers
Fiber releasing filter may not be used in filtration
process unless it is not possible to manufacture such
drug product without the use of such filters
If it is not avoidable than use subsequently 0.22 µm
mean porosity and 0.45 µm NFR filter
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24. (6)microbialchallengetest
Toensurefilterisnotundergoingdegradation
deformationorsomechangeunderconditionofuse
Drugproductnotcauseinorganismtoshrink
resultingnonsterilizingcondition
Sterilizingfilteronethatwhenchallengedwith10
7
B.diminutapercm
2
offilterareawillproducesterile
effluent
Careshouldbetakenthatdrugproductshouldnotbe
toxictoorganism
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25. (7)Filterinertness
Theremaybeextractionandadsorptionphenomena
occurs
Varioustechniquefordetermininginertnesslike
compatibility,ph,conductivity,gravimetric
extractable,weightchange,adsorption,USP
oxidizablesubstancetestetc
Stabilityoftheproductshouldnotbeaffectedbythe
filter
Ingravimetricextractabletestweightofthe
extractablearemeasuredwhenfilteredareshocked
inASTMgradewaterfor24hr.
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26. USPoxidizablesubstancetestamountofoxidizable
substancereleasefromthefilterinfiltrateismeasure
(8)Atestforantimicrobialactivity
Objectives
Thetestisperformedtoensurethat,anyresidualof
AntimicrobialActivityissatisfactoryeliminatedby
usingthestepsmentionedinthisprotocol
Aninoculumsofviablecellsofthespecificbacteria
andfungihasbeenpassedthroughthefilter,
inoculatefilterpaperinFTM&incubateat30to
35
0
CorinSCDMandincubateat20to25
0
C
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27. Ifconspicuousgrowthdoesnotoccurwithin3days
forbacteriaand5daysforfungi,thetestprocedure
isnotvalidandmustbemodified
(9)Endotoxin
Validationmustaddressfilterdoesnotaddendotoxin
todrugproduct
Itdependonqualitycontrolprocessofthefilter
manufacturer,waterusedinmanufacturing,choice
offiltervendor,verificationarenotdoneproperly
Millipakfilterunitcontainlessthan0.5unitsof
endotoxinpermlasperUSPbacterialendotoxintest
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28. (10)Toxicity
Avalidationstudyshoulddeterminethatpassageof
thedrugproductthroughafilterdoesnotcauseany
toxicologicaleffects
Constructionmaterialofffiltrationsystemshouldbe
nontoxic
Manufactureproviderelevanttestdatasucha
compendialplastictestsimilartoUSPclass6testfor
plasticsandUSPmousesafetytestforall
constructionmaterials
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29. InUSPclass6testwasperformedtoconformthat
filteraresuitableandnon-toxicwithcontactwith
parenterals
Testingincludessystematicandintracutaneous
injectionaswellasintramuscularimplantation
Ifnotoxicityfoundthenfilterpassesthetest
InUSPmousesafetytestmousewereinjectedwith
filterunitextract,thenmonitoredforsignfortoxicity
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30. Validation Report
Standardformat
1.Executivesummary
2.Discussion
3.Conclusions&recommendation
4.Listofattachment
Topicshouldbepresentedintheorderinwhich
theyappearintheprotocol.
Protocoldeviationarefullyexplained&justified.
Thereportissigned&datedbydesignated
representativesofeachunitinvolvedinwater
systemvalidation.
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31. References
R. A. Nash and A. H. Watcher “Pharmaceutical
process validation”; Third edition
Agalloco James, Carleton J. Fredric “Validation
of Pharmaceutical Processes”; Third edition
Pharmaguideline.blogspot.com
www.milipore.com
www.nsdl.niscair.res.in/bitstream
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THANK YOU