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Principles of Biochemical
Engineering
ENCH 535 Winter 2016

Bioreactor Scale Up

March 28, 2016

Scale up of bioreactors

Reactor dimension

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Choosing the reactor type


Bioreactors

Submerged
cultures

Stirred tank

Airlift

Immobilized
cultures

Bubble
columns

Reactor types

Packed bed

Fluidized
beds

Airlift

Stirred tank

Figures source: http://en.wikipedia.org/wiki/File:Bioreactor_principle.svg


http://www2.hawaii.edu/~wsu/bioreactor/sld004.htm

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Reactor types

Figures source:

Bubble-Column

http://en.wikipedia.org/wiki/File:Bubble_column.svg
http://www.algaeindustrymagazine.com/algae-scale-up-bioreactors-from-biovantage-resources-inc/

Reactor types

Air-lift

Figures source: http://www.babonline.org/bab/045/0001/bab0450001f03.htm?resolution=HIGH


http://whs.inha.ac.kr/~kimdi/lab1.html

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Packed Bed Reactors


Hollow Fiber Cell Bioreactor

Fluidized Bed Reactors


gas
Effluent

ORP, pH
probes

Recirculation
pump

Water-jacketed
glass reactor
carrier

Glass
beads

wastewater

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Conceptual steps in scale-up

Scale-up issues
A scale-up problem is something that we do not see in the
small-scale experiment and are surprised and disappointed
to find in the large scale process

Heat transfer
Mass transfer (oxygen)
Power input
Foaming
Sterility
Product quality
By-product formation

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Scale-Up Parameters
Geometry
Height to Diameter Ratio is held constant
Called aspect ratio

Scale-Up Parameters
Agitation-based parameters
Mixing time
Power input per Volume (P/V)
Tip Speed

Gassing-based parameters
Vessel Volumes per Minute (VVM)
Superficial Gas Velocity (Vs)
NOTE: Cannot keep all parameters constant during scale
up because they scale by different values

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Parameter

Definition

Scale-Up Factor

Importance

N2=N1(D1/D2)1/4
Mixing time

Power input per


volume (P/V)

Amount of time it takes the


bioreactor to create a
homogeneous environment

Amount of power
transferred to a volume of
cell culture through the
agitator shaft and impellers

N2 agitation speed in scale-up


N1 agitation speed in scale-down
D1 impeller diameter of scale -down
D2 impeller diameter of scale-up

Cells cannot handle a lot of


power introduced into the
culture media as it can cause
small eddies that will shear the
fragile cell membranes

P/V N3/D2
P- power supplied
V- Volume of Bioreactor
N- Agitation Speed
D- Impeller Diameter

N2=N1(D1/D2)
Tip speed

Related to the shear rate


produced from the
impellers moving through
the cell culture media

Superficial gas
velocity (Vs)

Volume of gas per crosssectional area of the vessel.

Vessel Volume
per minute (vvm)

Volume of gas flow (usually


measured in slpm,
standard liters per minute)
per bioreactor volume per
minute.

Need to ensure that the


materials are well-mixed in a
timely manner

N2 agitation speed in scale-up


N1 agitation speed in scale-down
D1 impeller diameter of scale -down
D2 impeller diameter of scale-up

Vs = Qgas/Av
Vs- superficial gas velocity
Qgas- gas volumetric flow rate
Av- inside cross-sectional area of
vessel
Volume of Gas Flow/ ( time x
Reactor volume)

High shear rates can cause the


cell membrane to tear and the
cells to die.
If scale-up based on constant
tip speed is attempted, P/V and
mixing time will decrease
increasing Vs causes an
increase in foam generation
A decrease in P/V
An increase in oxygen transfer
Necessary to ensure that enough
oxygen will be supplied to the
cells

Interdependence of Parameters on Scale-Up


Scale-up criterion

Symbol Small
scale (80L)

P0 /V

Large scale (10000 L)


N
N Di
Re

Energy input

P0

1.0

125

3125

25

0.2

Energy input/volume

P0/V

1.0

1.0

25

0.2

0.0016

Impeller rotation

1.0

0.34

1.0

0.2

0.04

Impeller diameter

Di

1.0

5.0

5.0

5.0

5.0

Pump rate of impeller

1.0

42.5

125

25

5.0

Pump rate of
impeller/volume

Q/V

1.0

0.34

1.0

0.2

0.04

Impeller speed (max


shearing rate)

N Di

1.0

1.7

5.0

1.0

0.2

Reynolds number

NDi2/

1.0

8.5

25.0

5.0

1.0

Table source:

Schuler-Kargi, Bioprocess Engineering, Basic Concepts, Prentice-Hall, 2002

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Scale-up Strategies
Rules of thumb:

Constant specific power input


Constant kLa
Constant impeller tip speed
Constant DO

Trial and error:


only for small scale-ups (one order of magnitude)
Expensive

Rigorous simulation:
Not always possible
Experimental data needed for validation

Rigorous Simulation: CFD

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CFD
Definition: Numerical solution (computer simulation) of differential equations
describing fluid flow, heat, mass, and momentum transfer, chemical reactions.
Advantages

Disadvantages

Able to develop a virtual model of your


system of study

Need CAD experience to develop the


model

Perform virtual experiments in the


model that are difficult to perform in
the actual system

Need the meshing knowledge

Allows one to evaluate many changes,


configurations, and set-up in minimal
time

Need fluid dynamics experience


develop the equations for what you are
wanting to model

Gain a picture of the 3D space that is


difficult to quantify experimentally

Need a lot of computing capacity

Heat Transfer

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Mixing
Mixing is the achievement of uniformity
Purpose:
Blending: substrate, pH control
Suspending: solid particles, immobilized cells
Dispersing: two liquid phases, aeration

Agitated tanks - Impellers


Rushton turbine

Marine propeller

Lightnin A310

Pitched bladed turbine

Figures source: http://www.postmixing.com/

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Quantifying mixing power

Oxygen transfer coefficient

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Foaming
Foam is a natural byproduct mostly protein
bubbles but some lipids
Foam will block and wet filters causing pressure
back-up and contamination
Foam must be controlled by chemical dispersing
agents (antifoams) or mechanically broken
Maintaining 75% volume capacity of reactor
allows for foam to be retained within the vessel

Sterility
Sterilization in place (SIP)
cleaning of reactor and bed
without dismantling reactor or
feed tubes
Pressurized steam is used for inplace sterilization of probes,
valves and seals
All crooks, crevices and surfaces
are potential contaminants and
must be sterilized
Sterilization must be verified and
validated

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