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### Scale up of bioreactor

Dr. Saleha Shamsudin

Scale-up

Generally, fermenters maintain a height-to-diameter ratio of 2-to-1 or 3-to-1. If the height-to-diameter ratio remains constant, then the surface-to-volume ratio decreases dramatically during scale-up.

This change decreases the relative contribution of surface aeration to oxygen supply and dissolved-carbon-dioxide removal in comparison to the contribution from sparging.

Scale-up

If cells have altered metabolism due to mass transfer limitations, then data obtained in a small fermenter may be unreliable in predictiong culture response in a larger fermenter.

Perhaps even more importantly, it can be shown that the physical conditions in a large fermenter can never exactly duplicate those in a smaller fermenter if geometric similirity is maintained.

Scale-up

Four cases are treated in Table 10.2:

Scale-up based on Constant power input (Po/V)

Scale-up based on Constant liquid circulation rate inside the vessel, (Q/V)

Scale-up based on Constant shear at impeller tip (NDi)

Scale-up based on Constant Reynolds number (NDi2р/μ)

Scale-up

Note that,

Fixing N and Di fixes all the quantities in Table 10.2. Since these quantities have different dependencies on N and Di, a change of scale must result in the changes in the physical environment that the cells experience. When these changes alter the distribution of chemical species in the reactor, or they destroy or injure cells, the metabolic response of the culture will differ from one scale to another.

Scale-up

In some cases cells respond to modest changes in mechanical stress by changing physiological functions even when there is no visible cell injury or cell lysis.

Thus, different scale up rules (constant P/V implies constant OTR, Constant Re implies geometrically similar flow patterns, constant N to give constant mixing times and constant tip speed to give constant shear) can give very different results.

These scale-up problems are all related to transport processes. In particular, the relative time scales for mixing and reaction are important in determining the degree of heterogeneity in a fermenter.

Scale-up

As we scale up, we may move from a system where the microkinetics (the cellular reactions) control the system response at small scale to one where transport limitations control the system response at large scale. When a change in the controlling regime takes place, the results of small-scale experiments become unreliable with respect to predicting large scal performance.

Scale-up

Traditional scale-up is highly empirical and makes sense only if there is no change in the controlling regime during scale-up, particularly if the system is only reaction or only transport controlled.

Common scale-up are the maintainance of constant power-to-volume ratios, constant Kla, constant tip speed, a combination of mixing time and Renolds number, and the maintanance of the constant substrate or product level (usually dissolved-oxygen concentration). Each of these rules has resulted in both succesful and unsuccesful examples. Results are more favourable with Newtonians broths than with non-Newtonian systems.

Scale-upExample (1)

After a batch fermentation, the system is dismantled and approximately 75% of cell mass is suspended in the liquid phase of 2L, while 25% is attached to the reactor walls and internals in a thick film (0.3cm). Work with radioactive tracers shows that 50% of the target product (intracellular) is associated with each cell fraction. The productivity of this reactor is 2 g/L at 2L scale. What would be the productivity at 20000 L scale if both reactor had a height-to-diameter ratio of 2 to1?

Scale-upExample (2)

Consider the scale up of a fermentation from 10L to 10000L vessel. The small fermenter has a height-to-diameter ratio of 3. the impeller diameter is 30% of the tank diameter. Agitator speed is 500 rpm and three Rushton impellers are used. Determine the dimensions of the large fermenter and agitator speed for:

Constant P/V

Constant impeller tip speed

Constant Reynolds number

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