4/7/2011

1
BioreactorScaleupandScale
down
SadettinS.Ozturk,Ph.D.
ScaleupandScaledown
Selectgeometry,configuration,dimensions,and
operating conditions so that the performance of operatingconditionssothattheperformanceof
bioreactoratdifferentscaleiscomparable
Focuson:
Mixingandagitation
MassTransfer
HeatTransfer
Wewillfocusonscaleup,sameprinciplesare
appliedtoscaledownaswell
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2
GeometricSimilarity
Aspectratio
ImpellertoDiameterratio
Impellertypeandlocation
H
V
N
H/ D
T
D/ D
T
Spargertype
D
D
T
CharacteristicTimes
SomeTimeConstants
TransportProcesses Equation p q
Flow L/vorV/Q
Diffusion L
2
/D
OxygenTxfr 1/k
L
a
HeatTxfr VpC
p
/UA
Mixing t
m
=4V/(1.5ND
3
)
Growth 1/
HeatProduction pC
p

k
T/rH
See N.W.F.Kossen in T. K. Ghose, ed. Biotechnology and Bioprocess
Engineering, United India Press Link House, 1985, pp. 365-380.
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3
ScaleupConsiderations
Keepthesamepowerinputpervolume
Keepthesameimpellertipspeed
Keepthesamemixingtime
P
o
= P V
v = ND
Keepthevolumetricmasstransfercoefficient
u = f (1/ N)
k
l
a
Scaleupofagitationandmixing
parameters
ND
2
ReynoldsNumber(dimensionless)
N
Re
=
ND
2
p
u
N
p
=
P
o
N
3
D
5
p
H
V
N
PowerNumber(dimensionless)
D
D
T
velocity =
v
ND
pumping number =
Q
ND
3
Blending time = u N
DimensionlessParameters
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4
ScaleupbasedonConstantPowerNumber
N
p
=
P
o
N
3
D
5
p
Underturbulentconditions(highRe),powernumberisconstant
N
Re
=
ND
2
p
u
ScaleupbasedonConstantPowerNumber
Constantpowernumber
N K P /V
H
V
N
UseconstantPowernumbertoscaleup
agitationandmixingparameters
Alsokeepdimensionlessparametersconstant
N
P
= K = P /V
P
o
= K ( N
3
D
5
p)
v
K
Tip speed
D
D
T
ND
= K
1
Q
ND
3
= K
2
u N = K
3
Tipspeed
Pumpingrate
Mixingtime
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5
ScaleupbasedonConstantPowerNumber
TipVelocity
3 5
P
o
/V = constan t =
N
3
D
5
D
3
= N
3
D
2
N
3
D
2
= Constan t = C
v = K
1
N D = K
1
(C D)
1 3
Tipvelocityincreasesbyapowerof1/3
ScaleupbasedonConstantPowerNumber
Pumping
N
3
D
2
C
Pumpingincreasesbyvolume.However,pumpingpervolumedecreases
N
3
D
2
= C
Q = K
2
N D
3
= K
2
( N
3
D
9
)
1/ 3
= K
2
( N
3
D
2
D
7
)
1/ 3
Q = K
2
( N
3
D
2
)
1/ 3
D
7 / 3
= K
2
C
1/ 3
D
7 / 3
Q = K
2
'
D
7 / 3
Q/V ~ Q/ D
3
= K
2
'
D
7 / 3
/ D
3
= K
2
'
D
2 / 3
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6
ScaleupbasedonConstantPowerNumber
MixingTime
u N K u N = K
3
u = K
3
/ N
N = (C/ D
2
)
1/ 3
= C
1/ 3
D
2 / 3
u = K
3
/ N = (K
3
/C
1/ 3
) D
2 / 3
= K
3
'
D
2 / 3
Mixingtimeincreaseswithscale
Differentresultsareobtainedfor
differentscaleupcriteria
4/7/2011
7
MixingandShear
OtherConsiderationsforScaleup
Shearanddamagetothecellsshouldalsobe
id d d i l consideredduringscaleup
Aeration(masstransfer)characteristicsshould
bemaintainedaswell
Heattransfershouldalsobeconsidered
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8
MixingandShear
c = ( N N
3
D
i
5
)/V
RateofEnergyDissipation KolmogorovTheoryofTurbulence
Sizeoftheeddies
Velocityoftheeddies
n = (v
3
/c)
1/ 4
u = (c v)
1/ 4
c ( N
p
N D
i
)/V
Cellsinthebioreactorcanbedamagedunder
Intensemixingconditions
sizeoftheeddiesbecomescomparable
tothesizeofthecells
highshearvelocity
ScaleupofAerationSystems
k (C
*
C ) X OCR OTR
Masstransfercapacitycanlimitthenumberofcellsachievableinthebioreactor
>Keepsamevolumetricmasstransfercoefficientduringscaleuptomaintainthe
samecelldensity
k
l
a (C C
L
) = q
O2
X
v
= OCR = OTR
Volumetricmasstransfercoefficientisaffectedby:
Spargerdesign(geometry,location,dimensions,orificesize)
Mi i t (i ll d i ) Mixingsystem(impellerdesign)
Operatingcondition(spargerflowrate,agitationrate)
Mediumproperties(viscosity,surfacetension,density)
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9
ScaleupofAerationSystems
Sparger design
Macrospargers
O i Openpipesparger
Venturi sparger
Ringsparger
Microspargers
Sinteredmetal
Porouspolymers
ScaleupofAerationSystems
MacrospargerScaleup
GasOut
Keepthetypeofthespargerandthe
orificesizethesame
Multiplythenumberoforificesto
maintainthesamegasflowrateper
orifice
Locatethespargerbelowthe
impeller
Scaleupgasflowrateandagitation
V
p g g
ratebasedonscalingparameters
Q
G
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10
ScaleupofAerationSystems
SuperficialGasFlowRate(Linearrate)
u = Q
G
/ A
k a o(P/V)
|
(u)

A
u
CrossSectional
Area
Superficial
GasFlowRate,
cm/min
MassTransferCoefficientisdependenton
Powerpervolume(relatedtoagitationrate)
andsuperficialgasflowrate
vvm= Q
G
/V
k
l
a = o(P/V)
|
(u)

Q
G
GasFlowRate(L/min)
ScaledGasFlowRateisimportantaswell
ScaleupofAerationSystems
k
l
a = o(P/V)
|
(u)

Specific to sparger impeller bioreactor

Increasing power input (agitation rate) disperses and breaks the bubbles thus
|
Specifictosparger,impeller,bioreactor
configuration,andmediacomposition
o

Variesbetween0.20.8formacrospargers
Variesbetween0.30.8formacrospargers
Increasingpowerinput(agitationrate)dispersesandbreaksthebubbles,thus
createssmallerbubblesandhighergasexchange(interfacial)area
Increasinggasflowrategeneratesmorebubblesinthesystemandincreasesturbulence
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11
ScaleupofAerationSystems
k
l
a = o(P/V)
|
(u)

Specific to sparger impeller bioreactor

Increasingpowerinput(agitationrate)
|
Specifictosparger,impeller,bioreactor
configuration,andmediacomposition
o

Variesbetween00.2formicrospargers
Variesbetween0.30.8formicrospargers
dispersesandbreaksthebubbles,thus
createssmallerbubblesandhighergas
exchange(interfacial)area
Increasinggasflowrategeneratesmore
bubblesinthesystemandincreases
turbulence
ScaleupofHeatTransfer
Heattransferisimportanttomaintainandcontrolthetemperature
Heating:
Importantforbothmicrobialandcellcultureapplications
Cooling:
Microbialfermentation:Isneededtoremovetheheatgenerated
bythecells
CellCulture:temperatureshiftforcellcultureproduction
cellharvestingattheendoftheculture
HeatTransferMethods
Surface
WaterJacket(steamorchilledwater)
Electricblanket(forsmallerbioreactors)
Coilsinthebioreactor
Usedformicrobialfermentation
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12
ScaleupofHeatTransfer
HeatTransferRate
q = h A (T T) q h A (T
m
T)
A
h
T
m
Surfaceareaforheattransfer
Temperatureofheating(cooling)fluid
Heattransfercoefficient
Maintainasimilarheattransfercoefficient,calculatesurfaceareaneeded
Surfaceareadecreasesasvolumeincreasesforsurfaceheattransfer
ScaleupPredictionsbasedon
ComputationalFluidDynamics(CFD)
Flowsimulation,orComputationalFluidDynamics (CFD),isthescienceof
predictingfluidflow,heattransfer,masstransfer,chemicalreactions,and
related phenomena b sol in the mathematical eq ations hich o ern relatedphenomenabysolvingthemathematicalequations whichgovern
theseprocessesusinganumericalprocess (thatis,onacomputer).
Theresultisdetailedinformationaboutallflowvariablesinthesystem
Speciesconcentration
Flowpattern
Turbulencelevels
Localrateofmixing
Th i i t l i t i t f t ft th t Themixingtoolisacustomuserinterfacetoasoftwareprogramthat
performsflowsimulationofstirredtankreactors
Tounderstandhowitworks,letslookinmoredetailattheCFDprocess
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FlowSimulation:WhatisCFD
Flowsimulation,orComputationalFluidDynamics (CFD),isthescienceof
predictingfluidflow,heattransfer,masstransfer,chemicalreactions,and
related phenomena b sol in the mathematical eq ations hich o ern relatedphenomenabysolvingthemathematicalequations whichgovern
theseprocessesusinganumericalprocess (thatis,onacomputer).
Theresultisdetailedinformationaboutallflowvariablesinthesystem
Speciesconcentration
Flowpattern
Turbulencelevels
Localrateofmixing
Th i i t l i t i t f t ft th t Themixingtoolisacustomuserinterfacetoasoftwareprogramthat
performsflowsimulationofstirredtankreactors
Tounderstandhowitworks,letslookinmoredetailattheCFDprocess
HowCFDWorks
Flowinthestirredtankis
calculatedusingthefinitevolume
method
Thecalculation
domainisa2000L,
baffledvessel
with 2 A315 method
Thecalculationdomainisdiscretizedintoa
finitesetofcontrolvolumesorcells.
Generalconservation(transport)equations
formass,momentum,energy,etc.,
di ti d i t l b i ti
Fluidregionof
tankdiscretized
intofinitesetof
controlvolumes
(mesh).
with2A315
Impellers

+ V I = +
c
c
V A A V
dV S d d dV
t
o
o po po A A V
unsteady convection diffusion generation
arediscretizedintoalgebraicequations.
All equationsaresolvedtorenderflowfield.
Eqn.
continuity 1
x-mom. u
y-mom. v
energy h
o
ASingle
Control
Volume
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14
CFDModelingforAeration:VelocityVectorsand
Pathlines
CFDModelingforAeration:Qualitativepredictionofgas
distribution
Bubbletrajectoriesarecalculated
inthecontinuousphaseflowfield
sin DPM particle trackin usingDPMparticletracking
Bubblescannotbreakupor
coalesce
Inherentinmodelsunderlying
assumptionofnointeraction
betweenparticles
Morerigorousmethods
accountingforthisareavailablein
FLUENT
Significantcomputational
overheadisassociatedwith
thesemethods
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15
CFDModeling:TheEffectsofSpargerGeometry
Thediscreteholesofthespargerare
notmodeled.
A strip along the top and/or bottom Astripalongthetopand/orbottom
ofthespargergeometryisusedto
introducethegasflow.
Thestrip,whichcovers15%of
thespargersurfaceareais
largerthanthesumoftheareas
ofthediscreteholes.
Impactofreducedsparge
velocityisinsignificantrelative
tolocalimpellerinducedflow.
Bubbles come to equilibrium Bubblescometoequilibrium
withsurroundingliquidflow
fieldinaveryshortdistance
Detailofrepresentativespargersurface
CFDModeling:SpargingandMassTransfer
Relevanttok
L
a predictions,themultiphaseflowmodelprovidesfielddatafor:
Turbulentdissipationrate
Gasvolumefraction
Bubblediameter(specifiedorpredicted)
Thisdatacanbeusedtoevaluatethemasstransfercoefficientk
L
andthespecificinterface
surfacearea,a.
Anumberofcorrelationsfork
L
areavailable.OnesuggestedcorrelationisbasedonHigbies
penetrationtheory:
Thespecificinterfacialsurfacearea,a,canbedeterminedusingtherelation:
( )
2 / 1 4 / 1
314 . 0

= Sc k
L
cv
o 6
whereo
air
isthevolumefractionofair.
Assumessphericalbubbles
Reflectstotalsurfaceareaavailableformasstransferperunitvolume
b
air
d
a
o 6
=