Ich guidelines for stability testing of biotechnological biological products (1)

Guidelines given by ICH for stability Testing of Biotechnological/Biological Products

1. ICH-GUIDELINES
FOR
STABILITY TESTING
OF
BIOTECHNOLOGICAL /BIOLOGICAL
PRODUCTS
[Q5C]
.

2. PREAMBLE
TheguidancestatedintheICHharmonised tripartite
guideline“StabilityTestingofNewDrugSubstancesand
Products” (27October1993)appliesingeneralto
biotechnological/biological products.
However, biotechnological/biological productsdohave
distinguishing characteristicstowhichconsideration
shouldbegiveninanywell-definedtestingprogram
designedtoconfirmtheirstabilityduringtheintended
storageperiod.
Forsuchproducts,inwhichtheactivecomponents are
typicallyproteinsand/orpolypeptides,maintenance of
molecularconformation and,henceofbiologicalactivity,
isdependentonnon-covalentaswellascovalentforces.
Theproductsareparticularlysensitivetoenvironmental
factorssuchastemperature changes,oxidation,light,
ioniccontent,andshear.
Inordertoensuremaintenance ofbiologicalactivityand
toavoiddegradation, stringentconditionsfortheir
storageareusuallynecessary.

3. PREAMBLE cont’d
•Theevaluationofstabilitymaynecessitate
complex analyticalmethodologies.Assaysfor
biologicalactivity,whereapplicable,shouldbe
partofthepivotalstabilitystudies.
•AppropriatePhysicochemical, Biochemical and
Immunochemical methods fortheanalysisof
themolecular entityandthequantitative
detectionofdegradationproductsshouldalso
bepartofthestabilityprogramwheneverpurity
andmolecularcharacteristicsoftheproduct
permituseofthesemethodologies.

4. Scope
The document covers thegeneration and
submissionofstabilitydataforproductssuchas
cytokines(interferons,interleukins, colony-
stimulating factors,tumour necrosisfactors),
erythropoietins,plasminogen activators,blood
plasma factors,growth hormones andgrowth
factors,insulins,monoclonal antibodies, and
vaccinesconsistingofwell-characterisedproteins
orpolypeptides.
Inaddition,theguidanceoutlinedinthefollowing
sectionsmayapplytoothertypesofproducts,such
asconventionalvaccines,afterconsultationwith
theappropriateregulatoryauthorities.
Thedocumentdoesnotcoverantibiotics,allergenic
extracts,heparins,vitamins,whole blood,or
cellularbloodcomponents.

5. The stability guidelines for Testing of Biological Products
are monitored under the following headings.
1). SELECTION OF BATCHES
A.DugSubstance (Bulk Material)
B.Intermediates
C. Drug Product (Final Container Product)
D.SampleSelection
2). STABILITY INDICATING PROFILE
A.Protocol
B.Potency
C.Purityand Molecular Characterization
D. Other product Characteristics
3). STORAGE CONDITIONS
A.Temperature
B.Humidity
C. Accelerated & Stress Conditions
D. Light
E. container Closure
F. Stability after Reconstitution of Freeze Dried Products
4). TESTING FREQUENCY
5). SPECIFICATIONS
6). LABELLING

6. 1). SELECTION OF BATCHES
a)DrugSubstance(BulkMaterial)
•Wherebulkmaterialistobestoredaftermanufacture but
priortoformulationandfinalmanufacturing, stability
datashouldbeprovidedonatleast3batchesforwhich
manufacture andstoragearerepresentative ofthe
manufacturing scaleofproduction.
•Aminimum of6monthsstabilitydataatthetimeof
submission should besubmitted incasesWHERE
STORAGE PERIODS GREATER THAN 6MONTHS ARE
REQUESTED .
•FordrugsubstancesWITHSTORAGE PERIODS OFLESS
THAN6MONTHS, theminimum amountofstabilitydatain
theinitialsubmissionshouldbedeterminedonacase-by-
casebasis.
•Datafrompilot-plantscalebatchesofdrugsubstance
produced atareduced scaleoffermentation and
purificationmaybeprovidedatthetimethedossieris
submittedtotheregulatoryagencieswithacommitment
toplacethefirst3manufacturing scalebatchesintothe
long-termstabilityprogramafterapproval.

7. 1). SELECTION OF BATCHES
a)DrugSubstance(BulkMaterial)cont’d
Thequalityofthebatchesofdrugsubstanceplacedinto
thestabilityprogram shouldberepresentative ofthe
qualityofthematerialusedinpreclinicalandclinical
studiesandofthequalityofthematerialtobemadeat
manufacturing scale.
Inaddition,thedrugsubstance(bulkmaterial)madeat
pilot-plantscaleshouldbeproducedbyaprocessand
storedunderconditionsrepresentativeofthatusedfor
themanufacturing scale.
Thedrugsubstanceenteredintothestabilityprogram
shouldbestoredincontainerswhichproperlyrepresent
theactualholdingcontainersusedduringmanufacture.
Containersofreducedsizemaybeacceptablefordrug
substance stabilitytestingprovided thattheyare
constructedofthesamematerialandusethesametype
ofcontainer/closure systemthatisintendedtobeused
duringmanufacture.

8. 1). SELECTION OF BATCHES
b)Intermediates
•During manufacture of
biotechnological/biological products,thequality
andcontrolofcertainintermediates maybe
criticaltotheproductionofthefinalproduct.
•Ingeneral,themanufacturer shouldidentify
intermediatesandgeneratein-housedataand
processlimitsthatassuretheirstabilitywithin
theboundsofthedevelopedprocess.
•Whiletheuseofpilot-plantscaledatais
permissible,themanufacturer shouldestablish
thesuitabilityofsuch data using the
manufacturing scaleprocess.

9. 1). SELECTION OF BATCHES
c)DrugProduct(FinalContainerProduct)
•Stabilityinformationshouldbeprovidedonatleast3
batchesoffinalcontainerproductrepresentativeofthat
whichwillbeusedatmanufacturing scale.Where
possible,batchesoffinalcontainerproductincludedin
stabilitytestingshouldbederivedfromdifferentbatches
ofbulkmaterial.
•Aminimum of6monthsdataatthetimeofsubmission
shouldbesubmitted incaseswherestorageperiods
greaterthan6monthsarerequested.Fordrugproducts
withstorageperiodsoflessthan6months,theminimum
amountofstabilitydataintheinitialsubmissionshould
bedeterminedonacase-by-casebasis.
•Productexpirationdatingwillbebasedupontheactual
datasubmittedinsupportoftheapplication.Sincedating
isbaseduponthereal-time/real-temperature data
submitted forreview,continuing updates ofinitial
stabilitydatashouldoccurduringthereviewand
evaluationprocess.
•

10. 1). SELECTION OF BATCHES
c)DrugProduct(FinalContainerProduct)cont’d
•Thequalityofthefinalcontainerproductplacedon
stabilitystudiesshouldberepresentativeofthequalityof
thematerialusedinthepreclinicalandclinicalstudies.
•Datafrompilot-plantscalebatchesofdrugproductmay
beprovidedatthetimethedossierissubmittedtothe
regulatoryagencieswithacommitment toplacethefirst
3manufacturing scalebatchesintothelongtermstability
programafterapproval.
•Where pilot-plantscalebatchesweresubmitted to
establishthedatingforaproductand,intheeventthat
productproducedatmanufacturing scaledoesnotmeet
thoselong-termstabilityspecificationsthroughout the
datingperiodorisnotrepresentativeofthematerialused
inpreclinicalandclinicalstudies,theapplicantshould
notifytheappropriateregulatoryauthoritiestodetermine
asuitablecourseofaction.

11. 1). SELECTION OF BATCHES
d)Sample Selection
•Whereoneproductisdistributedinbatchesdiffering
infillvolume(e.g.,1ml,2ml,or10ml),unitage
(e.g.,10units,20units,or50units),ormass(e.g.,
1mg,2mg,or5mg)samplestobeenteredintothe
stabilityprogrammaybeselectedonthebasisofa
matrixsystemand/orbybracketing.
•Matrixing,i.e.,thestatisticaldesignofastability
studyinwhichdifferentfractionsofsamplesare
testedatdifferentsamplingpoints,shouldonlybe
appliedwhenappropriatedocumentation isprovided
thatconfirmsthatthestabilityofthesamplestested
representsthestabilityofallsamples.
•Thedifferencesinthesamplesforthesamedrug
productshouldbeidentifiedas,forexample,
covering differentbatches,differentstrengths,
differentsizesofthesameclosureandpossibly,in
somecases,differentcontainer/closuresystems.

12. 1). SELECTION OF BATCHES
d)Sample Selection cont’d
•[Matrixingshouldnotbeappliedtosamples with
differencesthatmayaffectstability,suchasdifferent
strengthsanddifferentcontainers/closures, whereit
cannotbeconfirmedthattheproductsrespondsimilarly
understorageconditions.]
•Where the same strength and exact
container/closure systemisusedfor3ormore
fillcontents,themanufacturer mayelectto
placeonlythesmallestandlargestcontainer
sizeintothestabilityprogram,i.e.,bracketing.
•TheBracketingdesignassumesthatthestability
oftheintermediate conditionsamples are
representedbythoseattheextremes.Incertain
cases,datamaybeneededtodemonstrate that
allsamplesareproperlyrepresented bydata
collectedfortheextremes.

13. 2).STABILITY-INDICATING PROFILE
•Onthewhole,thereisnosinglestability-indicating
assayorparameter thatprofilesthestability
characteristics ofabiotechnological/biological
product.Consequently, themanufacturer should
proposeastability-indicatingprofilethatprovides
assurancethatchangesintheidentity,purityand
potencyoftheproductwillbedetected.
•Atthetimeofsubmission,applicantsshouldhave
validatedthemethods thatcomprisethestability-
indicatingprofileandthedatashouldbeavailablefor
review.
•Thedeterminationofwhichtestsshouldbeincluded
willbeproduct-specific.Theitemsemphasized inthe
followingsubsectionsarenotintendedtobeall-
inclusive,butrepresentproductcharacteristicsthat
shouldtypicallybedocumented toadequately
demonstrate productstability.

14. 2).STABILITY-INDICATING PROFILE
a)Protocol
•Thedossier(Document ofReports)accompanying the
application formarketing authorization should
includeadetailedprotocolfortheassessmentofthe
stabilityofbothdrugsubstanceanddrugproductin
supportoftheproposed storageconditionsand
expirationdatingperiods.
•The protocol should include allnecessary
informationwhichdemonstrates thestabilityofthe
biotechnological/biological productthroughout the
proposed expirationdatingperiodincluding,for
example, well-defined specifications and test
intervals.
•Thestatisticalmethods thatshouldbeusedare
describedinthetripartiteguidelineonstability.
•.

15. 2).STABILITY-INDICATING PROFILE
b)Potency
•Whentheintendeduseofaproductislinkedto
adefinableandmeasurable biologicalactivity,
testingforpotencyshouldbepartofthe
stabilitystudies.Forthepurposeofstability
testingoftheproducts described inthis
guideline,potencyisthespecificabilityor
capacityofaproducttoachieveitsintended
effect.
•Itisbasedonthemeasurement ofsome
attributeoftheproductandisdeterminedbya
suitablequantitative method.Ingeneral,
potencies of biotechnological/biological
productstestedbydifferentlaboratoriescanbe
comparedinameaningfulwayonlyifexpressed
inrelationtothatofanappropriatereference
material.

16. 2).STABILITY-INDICATING PROFILE
b)Potencycont’d
•Forthatpurpose,areferencematerialcalibrated
directlyorindirectlyagainstthecorresponding
nationalorinternationalreferencematerial
shouldbeincludedintheassay.
•Potency studiesshould beperformed at
appropriateintervalsasdefinedinthestability
protocolandtheresultsshouldbereportedin
unitsofbiologicalactivitycalibrated,whenever
possible,againstnationallyorinternationally
recognised standard.Where nonationalor
internationalreferencestandards exist,the
assayresultsmaybereportedinin-house
derivedunitsusingacharacterisedreference
material.

17. 2).STABILITY-INDICATING PROFILE
b)Potencycont’d
•Insome biotechnological/biological products,
potencyisdependent upontheconjugationofthe
activeingredient(s)toasecondmoietyorbindingto
anadjuvant.
•Dissociationoftheactiveingredient(s)fromthe
carrierusedinconjugatesoradjuvantsshouldbe
examined inreal-time/real-temperature studies
(includingconditionsencounteredduringshipment).
•Theassessmentofthestabilityofsuchproductsmay
bedifficultsince,insomecases,invitrotestsfor
biological activity and physicochemical
characterisation are impractical or provide
inaccurateresults.
•Appropriate strategies(e.g.,testingtheproduct
priortoconjugation/binding, assessingtherelease
oftheactivecompound fromthesecondmoiety,in
vivoassays)ortheuseofanappropriatesurrogate
testshould beconsidered toovercome the
inadequaciesofinvitrotesting.

18. 2).STABILITY-INDICATING PROFILE
c)PurityandMolecularCharacterisation
•Forthepurposeofstabilitytestingoftheproducts
describedinthisguideline,purityisarelativeterm.Due
totheeffectofglycosylation,deamidation,orother
heterogeneities, the absolute purity of a
biotechnological/biological productisextremelydifficult
todetermine.
•Thus,thepurityofabiotechnological/biological product
shouldbetypicallyassessedbymorethanonemethod
andthepurityvaluederivedismethod-dependent.Forthe
purposeofstabilitytesting,testsforpurityshouldfocus
onmethodsfordeterminationofdegradationproducts.
•Thedegreeofpurity,aswellasindividualandtotal
amounts of degradation products of the
biotechnological/biological product entered intothe
stabilitystudies,shouldbereportedanddocumented
wheneverpossible.
•Limitsofacceptabledegradationshouldbederivedfrom
theanalyticalprofilesofbatchesofthedrugsubstance
anddrugproductusedinthepreclinicalandclinical
studies.

19. 2).STABILITY-INDICATING PROFILE
c)PurityandMolecularCharacterisationcont’d
•Theuseofrelevantphysicochemical, biochemical
and immunochemical analytical methodologies
shouldpermitacomprehensive characterisationof
thedrugsubstance and/ordrugproduct(e.g.,
molecular size,charge,hydrophobicity)andthe
accuratedetectionofdegradationchangesthatmay
resultfromdeamidation,oxidation,sulfoxidation,
aggregationorfragmentationduringstorage.
•Asexamples,methodsthatmaycontributetothis
include electrophoresis (SDS-PAGE,
immunoelectrophoresis , Western blot,
isoelectrofocusing),high-resolutionchromatography
(e.g.,reversed-phasechromatography, gelfiltration,
ionexchange,affinitychromatography), andpeptide
mapping.

20. 2).STABILITY-INDICATING PROFILE
c)PurityandMolecularCharacterisationcont’d
•Wherever significantqualitativeorquantitative
changesindicativeofdegradationproductformation
aredetectedduringlong-term,acceleratedand/or
stressstabilitystudies,consideration shouldbe
giventopotentialhazardsandtotheneedfor
characterisationandquantificationofdegradation
productswithinthelong-termstabilityprogram.
•
•Acceptablelimitsshouldbeproposedandjustified,
takingintoaccountthelevelsobservedinmaterial
usedinpreclinicalandclinicalstudies.
•Forsubstancesthatcannotbeproperlycharacterised
orproductsforwhichanexactanalysisofthepurity
cannotbedetermined throughroutineanalytical
methods,theapplicantshouldproposeandjustify
alternativetestingprocedures.

21. 2).STABILITY-INDICATING PROFILE
d) Other Product Characteristics
•Thefollowing product characteristics,though not
specifically relating to biotechnological/biological
products,shouldbemonitoredandreportedforthedrug
productinitsfinalcontainer:
•Visualappearanceoftheproduct(colourandopacityfor
solutions/suspensions ;colour,textureanddissolution
timeforpowders),visibleparticulatesinsolutionsor
afterthereconstitutionofpowdersorlyophilisedcakes,
pH,andmoisture levelofpowders andlyophilised
products.
•Sterilitytestingoralternatives(e.g.,container/closure
integritytesting)shouldbeperformed ataminimum
initiallyandattheendoftheproposedshelf-life.
•Additives(e.g.,stabilisers,preservatives)orexcipients
maydegradeduringthedatingperiodofthedrugproduct.
Ifthereisanyindicationduringpreliminarystability
studiesthatreactionordegradation ofsuchmaterials
adverselyaffectthequalityofthedrugproduct,these
itemsmayneedtobemonitored duringthestability
program.
•Thecontainer/closure hasthepotentialtoadversely
affecttheproductandshouldbecarefullyevaluated.

22. 3).STORAGE CONDITIONS
a)Temperature
•Sincemostfinishedbiotechnological/biological
products need precisely defined storage
temperatures, thestorageconditionsforthe
real-time/real-temperature stabilitystudies
maybeconfinedtotheproposed storage
temperature.
•

23. 3).STORAGE CONDITIONS
b) Humidity
•Biotechnological/biological products are
generallydistributedincontainersprotecting
themagainsthumidity.
•Therefore,whereitcanbedemonstrated that
theproposed containers(andconditionsof
storage)affordsufficientprotectionagainst
highandlowhumidity,stabilitytestsat
differentrelativehumiditiescanusuallybe
omitted.
•Wherehumidity-protectingcontainersarenot
used,appropriate stabilitydatashouldbe
provided.

24. 3).STORAGE CONDITIONS
c) Accelerated and Stress Conditions
•Aspreviouslynoted,theexpirationdating
shouldbebasedonreal-time/real-temperature
data.
•However,itisstronglysuggestedthatstudies
beconductedonthedrugsubstanceanddrug
product under accelerated and stress
conditions.
•Studiesunder accelerated conditions may
provideusefulsupportdataforestablishingthe
expiration date,provide product stability
information forfutureproductdevelopment
(e.g.,preliminary assessment ofproposed
manufacturing changes suchaschange in
formulation,scale-up),assistinvalidationof
analyticalmethodsforthestabilityprogram,or
generateinformationwhichmayhelpelucidate
thedegradationprofileofthedrugsubstanceor
drugproduct.

25. 3).STORAGE CONDITIONS
c) Accelerated and Stress Conditions cont’d
•Studiesunderstressconditionsmay beusefulin
determiningwhetheraccidentalexposurestoconditions
otherthanthoseproposed(e.g.,duringtransportation)
aredeleterioustotheproductandalsoforevaluating
whichspecifictestparametersmaybethebestindicators
ofproductstability.
•Studiesoftheexposureofthedrugsubstanceordrug
producttoextremeconditionsmayhelptorevealpatterns
ofdegradation;ifso,suchchangesshouldbemonitored
underproposedstorageconditions.
•Whilethetripartiteguidelineonstabilitydescribesthe
conditionsoftheacceleratedandstressstudy,the
applicantshouldnotethatthoseconditionsmaynotbe
appropriateforbiotechnological/biological products.
•Conditionsshouldbecarefullyselectedonacase-by-case
basis.
•d)Light
•Applicantsshouldconsulttheappropriate regulatory
authoritiesonacase-by-casebasistodetermineguidance
fortesting.

26. 3).STORAGE CONDITIONS
•e)Container/Closure
•Changesinthequalityoftheproductmayoccurduetothe
interactionsbetweentheformulatedbiologicalproductand
container/closure.Wherethelackofinteractionscannotbe
excludedinliquidproducts(otherthansealedampoules),
stabilitystudiesshouldincludesamplesmaintainedinthe
invertedorhorizontalposition(i.e.,incontactwiththe
closure),aswellasintheuprightposition,todeterminethe
effectsoftheclosureonproductquality.Datashouldbe
suppliedforalldifferentcontainer/closure combinations
thatwillbemarketed.
•Inadditiontothestandard datanecessary fora
conventional single-use vial,theapplicant should
demonstrate thattheclosureusedwithamultiple-dosevial
iscapable ofwithstandingrepeated insertions and
withdrawals sothattheproductretainsitsfullpotency,
purity,andqualityforthemaximum periodspecifiedinthe
instructions-for-useoncontainers, packages, and/or
packageinserts.Suchlabellingshouldbeinaccordance
withrelevantnational/regionalrequirements.
•

27. 3).STORAGE CONDITIONS
f) Stability after Reconstitution of Freeze-Dried Product
•Thestabilityoffreeze-driedproductsafter
theirreconstitutionshouldbedemonstrated
fortheconditionsandthemaximum storage
periodspecifiedoncontainers,packages,
and/orpackageinserts.Suchlabellingshould
be in accordance with relevant
national/regionalrequirements.

28. 4).TESTING FREQUENCY
•The shelf-lives of biotechnological/biological
productsmayvaryfromdaystoseveralyears.Thus,
itisdifficulttodraftuniformguidelinesregarding
thestabilitystudydurationandtestingfrequency
thatwould beapplicable toalltypes of
biotechnological/biological products.
•Withonlyafewexceptions,however,theshelf-lives
forexistingproductsandpotentialfutureproducts
willbewithintherangeof0.5to5years.Therefore,
theguidanceisbaseduponexpectedshelf-livesin
thatrange.
•Thistakesintoaccountthefactthatdegradationof
biotechnological/biological productsmaynotbe
governed bythesame factorsduringdifferent
intervalsofalongstorageperiod.
•Whenshelf-livesof1yearorlessareproposed,the
real-timestabilitystudiesshouldbeconducted
monthlyforthefirst3months andat3month
intervalsthereafter.

29. 4).TESTING FREQUENCY cont’d
•Whilethetestingintervalslistedabovemaybe
appropriateinthepre-approvalorpre-licence
stage,reducedtestingmaybeappropriateafter
approvalorlicensurewheredataareavailable
thatdemonstrateadequatestability.
•Wheredataexistthatindicatethestabilityofa
productisnotcompromised, theapplicantis
encouragedtosubmitaprotocolwhichsupports
eliminationofspecifictestintervals(e.g.,9
month testing) for post-approval/post-
licensure,long-termstudies.

30. 5).SPECIFICATIONS
•Althoughbiotechnological/biological productsmaybesubject
tosignificantlossesofactivity,physicochemical changes,or
degradation duringstorage,internationalandnational
regulationshaveprovidedlittleguidancewithrespectto
distinctreleaseandendofshelf-lifespecifications.
•Recommendations formaximum acceptablelossesofactivity,
limitsforphysicochemical changes,ordegradationduringthe
proposedshelf-lifehavenotbeendevelopedforindividual
typesorgroupsofbiotechnological/biological productsbut
areconsideredonacase-by-casebasis.
•Each product should retainitsspecifications within
establishedlimitsforsafety,purity,andpotencythroughout
itsproposedshelf-life.
•Thesespecificationsandlimitsshouldbederivedfromall
availableinformation usingtheappropriate statistical
methods.Theuseofdifferentspecificationsforreleaseand
expirationshouldbesupported bysufficientdatato
demonstrate thatclinicalperformance isnotaffectedas
discussedinthetripartiteguidelineonstability.
•

31. 6).LABELLING
•Formost biotechnological/biological drug
substancesanddrugproducts,preciselydefined
storagetemperaturesarerecommended .
•Specificrecommendations shouldbestated,
particularlyfordrugsubstances anddrug
productsthatcannottoleratefreezing.
•These conditions, andwhere appropriate,
recommendations forprotectionagainstlight
and/orhumidity,shouldappearoncontainers,
packages,and/orpackageinserts.
•Suchlabellingshouldbeinaccordance with
relevantnational/regionalrequirements.

32. DEFINITIONS -1
•ConjugatedProduct
•Aconjugatedproductismadeupofanactiveingredient(for
example, peptide,carbohydrate) boundcovalentlyornon-
covalentlytoacarrier(forexample,protein,peptide,inorganic
mineral)withtheobjectiveofimprovingtheefficacyorstability
oftheproduct.
•DegradationProduct
•Amoleculeresultingfromachangeinthedrugsubstance(bulk
material)broughtaboutovertime.Forthepurposeofstability
testingoftheproductsdescribedinthisguideline,suchchanges
couldoccurasaresultofprocessingorstorage(e.g.,by
deamidation,oxidation, aggregation, proteolysis).For
biotechnological/biological productssomedegradationproducts
maybeactive.
•Impurity
•Anycomponent ofthedrugsubstance(bulkmaterial)ordrug
product(finalcontainerproduct)whichisnotthechemical
entitydefinedasthedrugsubstance,anexcipient,orother
additivestothedrugproduct.

33. DEFINITIONS -2
•Intermediate
•Forbiotechnological/biological products,amaterialproduced
duringamanufacturing processwhichisnotthedrugsubstance
orthedrugproductbutwhosemanufacture iscriticaltothe
successfulproductionofthedrugsubstanceorthedrugproduct.
Generally,anintermediatewillbequantifiableandspecifications
willbeestablishedtodeterminethesuccessfulcompletionofthe
manufacturing steppriortocontinuationofthemanufacturing
process.Thisincludesmaterialwhichmay undergofurther
molecularmodificationorbeheldforanextendedperiodoftime
priortofurtherprocessing.
•ManufacturingScaleProduction
•Manufacture atthescaletypicallyencountered inafacility
intendedforproductproductionformarketing.
•Pilot-PlantScale
•Theproductionofthedrugsubstanceordrugproductbya
procedure fullyrepresentative ofandsimulatingthattobe
appliedatmanufacturing scale.Themethodsofcellexpansion,
harvest,andproductpurificationshouldbeidenticalexceptfor
thescaleofproduction.

34. Dr.Raj Kumar Kudari, M.Pharm, PhD.
Professor
Hindu College of Pharmacy
Amravati Road, Guntur -522002 Andhra Pradesh.
.
Thank You !