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Bioreactor Scale-Up
To take a manufacturing process from the laboratory scale to a desired large scale at which it is commercially feasible.
3 Stages◦ Bench Scale ( 2 – 20 L)◦ Pilot Scale (100 – 500 L)◦ Plant Scale (500 – 20,000 L)
What is Scale-Up?
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
Scale-Up Parameters
Parameter Definition Scale-Up Factor
Why is this Important?
Mixing Time
Amount of time it takes the bioreactor to create
a homogeneous environment
N2=N1(D1/D2)1/4
N2 agitation speed in scale-upN1 agitation speed in scale-downD1 impeller diameter of scale -downD2 impeller diameter of scale-up
•Want to ensure that the materials are well-mixed
in a timely manner
Power Input per Volume (P/V)
Amount of power transferred to a volume of cell culture through the agitator shaft and
impellers
P/V ≈N3/D2
P- power suppliedV- Volume of BioreactorN- Agitation SpeedD- Impeller Diameter
•Mammalian 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
Tip Speed Related to the shear rate produced from the impellers moving
through the cell culture media
N2=N1(D1/D2)N2 agitation speed in scale-upN1 agitation speed in scale-downD1 impeller diameter of scale -downD2 impeller diameter of scale-up
•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
Agitation Parameters
Parameter Definition Scale-Up Factor
Why is this Important?
Vessel Volumes per
Minute (VVM)
means the volume of gas flow (usually
measured in slpm, standard liters per
minute) per bioreactor volume
per minute.
Volume of Gas Flow/time
•necessary to ensure that enough oxygen will be supplied to
the cells
Superficial Gas Velocity (Vs)
volume of gas per cross-sectional area
of the vessel.
Vs = Qgas/AvVs- superficial gas velocityQgas- gas volumetric flow rateAv- inside cross-sectional area of vessel
•increasing Vs causes•An increase in foam generation•A decrease in P/V•An increase in oxygen transfer
Gassing Parameters
Overall, scaling up process parameters is tricky
Each scale-up parameter is dependent on another◦ Cannot keep all constant during scale-up
Not one scale-up process is correct
Technicians determine which parameter is critical to the process and try to “find a happy medium” between each of the remaining parameter
Scale-Up Review