Scale up for tablet

1. SUBMITTEDBY:
SiddhantPadhi
RollNo.190317003
M.PharmIndustrial
Pharmacy
SCALE-UPFOR
TABLET
MANUFACTURING
UNDERTHEGUIDANCEOF:
Dr.MahalaxmiRathnanand
AssociateProfessor
Dept.OfPharmaceutics
MCOPS,MAHE

2. FACTORSTOBECONSIDERED:
 Theprimaryresponsibilityofthepilotplantstaffistoensurethat
thenewlyformulatedtabletsdevelopedbyproductdevelopment
personnel will prove to be efficiently, economically, and
consistentlyreproducibleonaproductionscale.
 Thedesignandconstructionofthepharmaceuticalpilotplantfor
tabletdevelopmentshould incorporate featuresnecessary to
facilitatemaintenanceandcleanliness.
 Ifpossible,itshouldbelocatedonthegroundfloortoexpeditethe
deliveryandshipmentofsupplies.
 Indesigningthefacilityandlayout,theimpactonGMPsmustbe
keptinmind.Thelayoutshouldaddresstheneedforflexibility,
restrictedareas,personnelflow,andmaterialflow.Forexample,
the movement of portable equipment is made easier by
constructionofwidecorridorsanddoorswithheightof10ftor
above.
 Adequate cleaning,construction,lighting and ventilating are
importantfactorsinaproductionoperation.
 Thevariousoperatingareasshouldhavefloordrainstosimplify
cleaning.
 Thereshouldbeenoughfloorspacewhereequipmentneededfor
manufacturingofdosageformsislocated.
 Operatingareasshouldbeairconditionedandhumiditycontrolled.
 Thereshouldbehighdensityconcretefloors,wallsshouldbe
enamelcementfinishedconcreteandthesectionaluseofdifferent
colouredpaintsinlongcorridorstoavoidatunnellikeimpression.
STAGESOFTABLETPRODUCTION
Materialhandling Drymixing Granulation Drying Sizing
Blending Compression(tabletting) Tabletcoating

3. 1.MATERIALHANDLING:
 Inlargescaleoperations,mechanicalmeansofhandlingmaterials
suchasmechanicaldevicesforliftingandtiltingdrumsandmore
sophisticatedmethodsofhandlingmaterialssuchasscrew feed
systems,vacuum loadingsystems,andmeteringpumpsbecome
necessaryunlikeinthelaboratorywherematerialsaresimply
scooped,dumpedorpouredbyhand.
 Anymaterialhandlingsystem usedmustdelivertheaccurate
amountoftheingredienttotheintendeddestinationwithminimal
losses.
 Lengthytransferlinesmayresultinmaterialloss,forwhichthese
mustbecompensation.
 Ifasystemisusedtotransfermaterialsformorethanoneproduct
stepsmustbetakentopreventcrosscontamination.
 Thetypeofsystemselectedalsodependsonthecharacteristicsof
thematerials.
2.DRYMIXING(DRYBLENDING):
 Alltheingredients(excipientsandactiveingredients)aremeantto
befreeoflumpsandagglomeratespriortothedryblend.
 Failuretoremoveorbreakupallagglomeratescouldcauseflow
problemsthrough theequipmentcreating anon-reproducible
compression.
 Screeningand/ormillingoftheingredientspriortomixingshould
bedonetomaketheprocessmorereliableandreproducible.
 Powderstobeusedforencapsulationorforgranulationpriorto
tabletingmustbewellblendedtoensuregooddrugdistribution.

4.  Inadequateblendingcouldresultindiscreteportionsofthebatch
beingeitherhighorlowinpotency.
 Mixingisacriticalstep,incaseoflowdoseorhighpotencydrugs.
Ifthedoseisverylow(1:100)thenmixingisdividedintotwosteps,
primarily1:10dilutionanda1:10blending,inordertoobtainthe
finaldilution.Ifthepowderiscohesive,thisstepbecomescritical.
Equipmentusedforblendingare:V-blender,Doubleconeblender,
Ribbonblender,Slantconeblender,Binblender,Orbitingscrew
blendersverticalandhorizontalhighintensitymixers.
Scaleupconsiderationindryblending
a.Variationsoftheblendergeometrybetweenscalesacceptable:
Mixingactionisdeterminedbythemechanicsofthemixerand
canonlybechangedbyconvertingfrom onetoanotherorby
modifyingtheblenderthroughadditionofbafflesorplates.
b.Theorderofadditionofcomponentstotheblender:Alow-dose
activeingredientmaybesandwichedbetweentwoportionsof
directlycompressibleexcipientsin theblendertoimprove
dispersionand/oravoidlosstothesurfaceoftheblender.
c.Theblenderload (load levelorfilllevel):Theamountof
materialvolumetothetotalmixervolumeaffectstheefficiency
oftheblender.Eachblenderhasanoptimum workingvolume
andanormalworkingrange.Overloadingablenderretardsthe
freeflowofthegranulationandreducestheefficiencyofthe
blender.Conversely,iftheloadistoosmall,thepowdersslide
ratherthanrollinablenderandpropermixingdoesnotoccur,
ortimeofmixingincreases.
d.Rateofrotation(rpm)ormixingrate:Mixingspeeddiffersfor
differenttypeofmixersexample-bladerotation speed of
planetarytypemixer,andmixertumblingorrotationalspeed
foratwinshell,conetype,orsimilartypeofmixer.
e.TimeofMixing:themixingtimecanbedecreasedifavailable
datashowthematerialstobeconsistentlyanduniformlymixed

5. inlesstimethanoriginallydirected.Alternatively,thetimemay
needtobeincreasedifthemixingtimeisshowntoproduce
materialwithborderlineuniformity.Mixingtimealsoaffects
thecompressibilityofthefinishedblend.Excessivemixingtime
mayfracturefragileexcipientsandruintheircompressibility.
InProcessQualityControltest:Contentuniformitytest.
3.GRANULATION:
Themostcommonreasonsgiventojustifygranulatingare:
i.Toimpartgoodflowpropertiestothematerial,
ii.Toincreasetheapparentdensityofthepowders,
iii.Tochangetheparticlesizedistribution,
iv.Uniformdispersionofactiveingredient.
Traditionally,wetgranulationhasbeencarriedoutusing,Sigma
blademixer,andHeavy-dutyplanetarymixer.
Wetgranulation can alsobeprepared using tumbleblenders
equippedwithhigh-speedchopperblades.
Morerecently,theuseofmultifunctional“processors”thatare
capableofperformingallfunctionsrequiredtoprepareafinished
granulation,suchasdryblending,wetgranulation,drying,sizingand
lubricationinacontinuousprocessinasingleequipment.
Scale-upconsiderationsforFluidizedBedGranulations:
i.ProcessInletAirTemperature
ii.AtomizationAirPressure
iii.AirVolume
iv.LiquidSprayRate
v.NozzlePositionandNumberofSprayHeads
vi.ProductandExhaustAirTemperature
vii.FilterPorosity

6. viii.CleaningFrequency
ix.BowlCapacity.
Drygranulation(slugging):Materialtobegranulizedisfirstmade
intoalargecompressedmassor"slug".Adrypowderblendthat
cannotbedirectlycompressedbecauseofpoorfloworcompression
propertiesmayinsomeinstancesbeprocessedusingaslugging
operation.Duringscaleupofsuchoperation,thepilotplantscientist
shouldpayattentiontotheforcesusedforslugging,thediameterof
thepunches,andthesubsequentsizingandscreeningoperation.
Wetgranulation:Traditionally,wetgranulationhasbeencarriedout
using sigma blade orheavy duty planetary mixer.Production
equipmentofthis type equipped with large motors of7-10
horsepowercanprocess100-200kgofmaterial.Bindersareusedin
tabletformulationaddedeitherindrystateordissolvedordispersed
inthegranulatingfluidtomakepowdersmorecompressibleand
imparttheirbindingproperties.Insomeinstances,thebindingagent
impartsconsiderableviscositytothegranulatingsolutionsothat
transferofthefluideitherbypumpingorpouringbecomesdifficult.
Duringthescaleupofgranulationprocesstheviscosityofthe
granulating solution can be adjusted to avoid such problems.
Occasionallynon-aqueoussolventsorsolutionsareusedtodisperse
poorlysolubledrugs.
IPQCTest:hardnessofgranules,flowproperties,moisturecontent.
Binders:Used in tabletformulations to make powders more
compressibleandtoproducetabletsthataremoreresistantto
breakageduring handling.In someinstancesthebinding agent
impartsviscositytothegranulatingsolutionsothattransferoffluid
becomesdifficult.Thisproblem canbeovercomebyaddingsomeor
allbindingagentsinthedrypowderpriortogranulation.Some
granulation,whenpreparedinproductionsizedequipment,takeona
dough-likeconsistencyandmayhavetobesubdividedtoamore

7. granular and porous mass to facilitate drying.This can be
accomplishedbypassingthewetmassthroughanoscillatingtype
granulatorwithasuitablylargescreenorahammermillwitheithera
suitablylargescreenornoscreenatall.
4.DRYING:
 Themostcommonconventionalmethodofdryingagranulation
continuestobethecirculatinghotairoven,whichisheatedby
eithersteamorelectricity.
 Theimportantfactortoconsideraspartofscale-upofanoven
dryingoperationare:
o airflow
o airtemperature
o depthofthegranulationonthetrays.
 Ifthegranulationbedistoodeeportoodense,thedryingprocess
willbeinefficient,andifsolubledyesareinvolved,migrationofthe
dyetothesurfaceofthegranules.
 Dryingtimesatspecifiedtemperaturesandairflowratesmustbe
establishedforeachproduct,andforeachparticularovenload.
 Theimportantfactortoconsideraspartofscaleupoffluidizedbed
dryingoperationinclude:
o Optimumload
o Airflowrate
o Inletairtemperature
o Humidityofincomingair
Fluidizedbeddryerisanattractivealternativetothecirculatinghot
airovens.Theirmainadvantage.Theirmainadvantageisreductionin
dryingtime.Fluidizedbeddryingtimesareusuallylessthan1hour.
First,optimum loadsmustbeestablishedthen,rateofairflow and
inletairtemperatureaswellasthehumidityoftheincomingairmust
beestablished,sincetheseallaffectthedryingtime.Iftheairis

8. drawnfrom outsidetheplantwithoutbeingconditioned,thelarge-
scaleseasonalvariationintermsoftemperatureandhumiditythat
mayexistcanalterthedryingprocess.
IPQCTEST:moisturecontent
5.REDUCTIONOFPARTICLESIZE:
 Compressionfactorsthatmaybeaffectedbytheparticlesize
distributionareflowability,compressibility,uniformityoftablet
weight,contentuniformity,tablethardness,andtabletcolour
uniformity.
 Firststepinthisprocessistodeterminetheparticlesize
distributionofgranulationusingaseriesof“stacked”sievesof
decreasingmeshopenings.
 Particlesizereductionofthedriedgranulationofproduction
sizebatchescanbecarriedoutbypassingallthematerial
throughanoscillatinggranulator,ahammermill,amechanical
sievingdevice,orinsomecases,ascreeningdevice.
 Agranulationwithtoolargeparticlesizeandinsufficientfines
isunabletofillthediecavitiesuniformlyduringcompression.
Both oversized and undersized granulationscan adversely
affecttabletcontentuniformity.
Scaleupconsideration:
 Hammermillsarefrequentlyusedtomilldriedgranulations.
 Theyhavearapidthroughput,andtheparticlesizedistribution
canbecontrolledbyvaryingthescreensize,thespeedofthe
mill,thetypeandno.ofbladesusedandtherateofmaterial
feed.
 Usually,thesemillsareoperatedatamediumtoslowspeedwith
theknivesforwardduringsizingtopreventovermillingofthe
granulation.
 Topreventavariableparticlesizedistributionauniform feed

9. ratemustbemaintained,andscreensshouldbefullyexamined
before and after use to ascertain whether any metal
contaminationhasoccurred.
 Finally,thelubricantsandglidantsareaddedindrytothedry
granulation because some of the additives, especially
magnesium stearate,tendtoagglomeratewhenaddedinlarge
quantitiestothegranulationinablender.
6.BLENDING:
 Someoftheexcipientssuchasmagnesium stearateandstarch
(extragranular)areaddedtothegranulesandblended.
 Forscale-upoperation,equipmentofrightdesignischosen.
 Inanyblendingoperation,bothsegregationandmixingoccur
simultaneouslyareafunctionofparticlesize,shape,hardness,
anddensity,andofthedynamicsofthemixingaction.
 Particleabrasionismorelikelytooccurwhenhigh-shearmixers
withspiralscrewsorbladesareused.
 Whenalow doseactiveingredientistobeblendeditmaybe
sandwiched between two portions ofdirectly compressible
excipientstoavoidlosstothesurfaceoftheblender.
Inscaleupofblending,followingparametersshouldbeconsidered–
 Blender-type,load(fillcapacity),capacity
 Parameters-mixingspeed,blendingtime
 Materials-particlesize,shape,anddensity
 Problems-segregation,excessivefines,non-uniformity.
7.COMPRESSION:
Compressionmeansareductioninthebulkvolumeofthematerialby

10. applyingsomelevelofmechanicalforceasaresultofdisplacementof
thegaseousphaseandincreaseinthemechanicalstrength.
Stagesofcompressionprocess:
•Fillingofemptydiecavitywithgranules
•Pre-compressionofgranulation(optional)
•Compressionofgranulation
•Ejectionofthetabletfrom thediecavityandtake-offofcompressed
tablet
Parameterstobeconsideredduringcompression:
 Forceandspeedofcompression:Dependinguponthedesignof
thepressitalsodeterminestheusablerangeofcompression
forcesatwhichthemachinecansafelyoperateandthepress
speedatwhichoutputcanbeoptimizedwithoutnegativeimpact
on the quality. Sometimes, because of raw material
characteristics,aparticularproductcannotbecompressedat
theupperspeedrangeofapress.Whenthisoccurs,pressspeed
isreduced.Preproductiontrialsinthepilotplantareimportant
foridentifyingproblemslikecapping,tablethardness,sticking
etc.
 Feedrateofgranulesfromthehopper:Thegranulationdelivery
mustnotbeinterrupted,norshouldtheflowratevary.Itshould
notchangetheparticlesizedistributionandsystem should
neithercausesegregationofcoarseandfineparticlesnorshould
inducestaticcharges.Thediefeedsystemmustbeabletofilldie
cavitiesadequatelyinashortperiodoftime.
 Compressionpressure,pressrotationspeedandsizeoftheroller:
Compressionoccursastheheadsofthepunchespassoverthe
lowerandundertheupperpressurerollers.Therapidityand
dwelltimeinwhicheventoccursisdeterminedbytherotational
speedofpressandbythesizeofcompressionroller.Thelarger
thecompressionroller,themoregraduallytheforceisapplied
andreleased.

11.  Ejectionrate:Thisinvolvesthewithdrawaloftabletfromthedie
cavity.Theforcesusedincompressiongiverisetoadhesive
bondsbetweenthepunchdiesurfaceandtablet.Agoodinternal
lubricantisnecessarytopreventsticking.
IPQCTest:Appearance,weightuniformity,disintegration,dissolution
anddrugcontent.
8.Tabletcoating:
Itistheapplicationofacoatingcompositiontoamovingbedof
tabletswiththeuseofheatedairtofacilitateevaporationofsolvent.
Coatingisdonetomaskthetaste,provideprotection,andcontrolthe
releaseofdrug.
Operatingconditionsthatmustbeestablishedforeitherpanorcolumn
operationare:
•Optimumtabletload
•Operatingtabletbedtemperature
•Dryingairflowrateandtemperature
•Solutionapplicationrate
•Sizeandshapeofnozzleaperture
•Atomizingairpressureandliquidflowrate
Theatomizingnozzlefortypicalpharmaceuticalapplicationscanbe
high-pressureairlessorairatomizing.Forairlesssprayers,thesizeand
shapeofthenozzleapertureisimportant.Forair-atomizedsprayers,the
atomizingairpressureandliquidflow ratearecritical.A highflow
airflow yieldsafinespray,butitalsocreatesmoreturbulenceand
causesa spray drying effect.With the adventofcomputersand
microprocessors,automatedprocessingsystemsareavailabletomake
coatingmorecontrolledandreproducibleprocess.
IPQCTest:Appearance,weightuniformity,disintegration,dissolution
anddrugcontent,coatingthickness.

12. LAYOUTOFTABLETMANUFACTURINGPLANT
 Itrefersto the allocation ofspace and the arrangementof
machinesandnecessaryservicesneededinaproductionprocess
withinafactorybuildinginothertoperform thevariousunit
operationsinvolvedinthemanufacturingprocessofdosageforms.
 A properlayoutincreased productivity and helps in proper
utilizationofman,money,materialandmachines.
 3types:
 Circularflow
 Parallelflow
 Crossoverflow
 ThedisadvantageoftheCircularFlowandtheParallelFlowwhen
comparedtotheCentralWarehouselayoutisthatmorespaceis
requiredsincethesupplyarea(thewarehouse)isnotnexttoeach
manufacturingstage.

13.  The disadvantages of the Central Warehouse layout are
contamination between mixtures during the change from

14. machiningprocesstoanotherand,also,theincreaseincrossover
traffic.
 Contaminationintheabovelayoutsisreducedbycontrollingthe
pressureandbyairextractionandfiltration.
 Pressurecontrolisan importantaspectforthereduction in
contaminationsincethereisadifferenceinpressurebetweenthe
corridorsandtheoperationrooms.
 The corridors are equipped with higherpressure than the
surroundingrooms,sothattheairtranslatesfrom thecorridorto
therooms,leavingthecorridorsuncontaminated.
 Theroomsarethenextractedandfilteredtoreduceanytoxic
wasteescapingtotheenvironment.
REFERENCES:
 Thetheory&practiceofindustrialpharmacybyLeonLachman,
HerbertA.Lieberman,JosephL.kenig,3rdedition,publishedby
VarghesePublishinghouse
 MichaelLevin,MetropolitanComputingCorporation,EastHanover,
New Jersey,PharmaceuticalProcessScale-Up,MarcelDekker,
Inc,2001.
 LippincottWilliamsand Wilkins,Remington,“Thescienceand
practiceofpharmacy”,21stedition,900-901.
 CVS Subrahmanyam and JThimmasetty,“IndustrialPharmacy
SelectedTopics”1
st
edition,387-392.
 Chaudhary,K.,Rana,A.C.,Bala,R.,&Seth,N.(2012).Scaleup
Process of tablet production; a perspective discussion.
InternationalJournalofPharmacyandBiologicalScience,2(3),
2230–7605.
 https://pharmamanufacture.wordpress.com/2016/04/21/plant-
layout/