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Bioprocess Scale-up

Scale-up means increasing the scale of a fermentation, for example from the laboratory scale to the pilot plant scale or from the pilot plant scale to the production scale. Increase in scale means an increase in volume and the problems of process scale-up are due to the different ways in which process parameters are affected by the size of the unit. It is the task of the fermentation technologist to increase the scale of a fermentation without a decrease in yield or, if a yield reduction occurs, to identify the factor which gives rise to the decrease and to rectify it.

Main components of fermentation process which are affected due to scaled up


(1) Inoculum development: An increase in scale may mean that extra stages have to be incorporated into the inoculum development programme. (2) Sterilization: Sterilization is a scale dependent factor because the number of contaminating micro-organisms in a fermenter must be reduced to the same absolute number regardless of scale.

When the scale of a process is increased the sterilization regime must be adjusted accordingly, which may result in a change in the quality of the medium after sterilization.

(3) Environmental parameters. The increase in scale may result in a changed environment for the organism. These environmental parameters may be summarized as follows: (a) Nutrient availability, (b) pH, (c) Temperature, (d) Dissolved oxygen concentration, (e) Shear conditions, (f) Dissolved carbon dioxide concentration, (g) Foam production. All the above parameters are affected by agitation and aeration, either in terms of bulk mixing or the provision of oxygen. Thus, agitation and aeration tends to dominate the scale-up literature.

The solution of the scale-up problem


(i) The identification of the principal environmental domain affected by scaleup (e.g aeration and agitation in the fermentation, for oxygen concentration, shear, bulk mixing.) (ii) The identification of a process variable (or variables) which affects the identified environmental domain. (iii) The calculation of the value of the process variable to be used on the large scale which will result in the replication of the same environmental conditions on both scales.

Agitation and Aeration scaleup


Suppose a cylindrical 1 m3 pilot-scale stirred tank is scaled up to 100 m 3. If the tanks are geometrically similar, the length of the flow path in the large tank is about 4.5 times that in the small tank. Therefore, to keep the same mixing time, fluid velocity in the large tank must be approximately 4.5 times faster. P/V v2 This would entail a (4.5)2 or 20-fold increase in power per unit volume. So, if the power input to the 1 m3 pilot-scale vessel is P, the power required for the same mixing time in the 100 m3 tank is about 2000P.

This represents an extremely large increase in power, much greater than is economically or technically feasible with most equipment used for stirring. Because The criterion of constant mixing time can hardly ever be applied for scale-up, it is inevitable that mixing times increase with scale. If instead of mixing time, P/V is kept constant during scale-up, mixing time can be expected to increase in proportion to vessel diameter raised to the power 0.67

if dissolved oxygen concentration is the over-riding environmental condition then power consumption per unit volume and volumetric air flow rate per unit volume should be maintained constant on scale-up.

Power consumption per unit volume is kept constant then impeller tip speed increases and flow per minute per volume decreases. If impeller tip speed is kept constant then power consumption (hence KLa) and mixing decrease

The widely used scale-up criteria are the maintenance of a constant KLa or constant shear conditions. Constant shear be achieved by scaling up on the basis of constant impeller tip speed. Constant KLa may be on the basis of constant power consumption per unit volume and constant volumetric air-flow rate.

The constant power per unit volume, for a mechanical agitated vessel is given by

From power consumptions in a bench-scale bioreactor, the necessary agitation rate is calculated for the scale up ratio, using Equation

The agitation rate is proportional to impeller diameter to the power of 2/3

that is true for the rotational speed of large tank, which is related to a small tank with the ratio of impeller diameter of large and small tanks to the power of 2/3.

The mass transfer coefficient KLa is constant; the general correlation is considered by many as proportional to the power per unit volume with constant exponent, and gas superficial velocity to another constant power as shown below:

Constants in mass transfer correlation for various fermenter size

Scale-up Based on Shear Forces Scale-up calculation is based on constant shear forces, where shear is directly related to impeller tip velocity.

Shear forces are defined as

where, t is the shear stress, du/dx is the shear rate, and m is the fluid viscosity.

Since the shear is defined as S, which is proportional to NDi, the concept of constant impeller tip velocity and constant power per unit volume were applied.

Now introduce variable S for impeller tip velocity NDi into aboveEquation, then multiply both sides and divide by impeller diameter, so that the power equation is reduced to shear forces related to impeller diameter:

Scale-up for Constant Mixing Time The function of mixing, f(t) is defined as constant mixing time:

where, tm is the mixing time, g is gravity, Dt is the tank diameter, and Y the depth of the liquid. The mixing time:equation is

where tmS and tmL represent the mixing time for small and large fermentation vessels.

That is proportional to impeller diameter to the power of 0.65. Then, solving for mixing time

The scale-up of air-lift reactors Bubble columns


Tend to be scaled-up on the basis of geometric similarity and constant gas velocity Under these conditions the KLa and shear rate in the two scales will be similar.

The major difference will be the height of the vessels resulting in increased pressure at the base of the larger vessel. This would result in higher oxygen and carbon dioxide solubility which would give a higher KLa but might result in carbon dioxide inhibition. .

Scale up of sterilization

Deindoerfer and Humphrey (1959) used the term InNo/Nt as a design criterion for sterilization, which has been variously called the Del factor, Nabla factor and sterilization criterion. The Del factor is a measure of the fractional reduction in viable organism count produced by a certain heat and time regime.

The Del factor does not include a volume term, i.e. absolute numbers of contaminants and survivors are considered, not their concentration. Thus, if the size of a fermenter is increased the initial number of spores in the medium will also be increased, but if the same probability of achieving sterility is required the final spore number should remain the same, resulting in an increase in the Del factor.

For example, if a pilot sterilization were carried out in a 1000-dm3 vessel with a medium containing 106 organisms cm-3 requiring a probability of contamination of 1 in 1000, the Del factor would be:

The Del factor to be achieved in a continuous sterilization process has to be increased with an increase in scale. Thus, if the volume to be sterilized is increased from 1000 dm3 to 10,000 dm3 and the risk of failure is to remain at 1 in 1000 then the Del factor must be increased from 34.5 to 36.8. When a fermentation is scaled up it is important to appreciate that the inoculum development process is also increased in scale and a larger.

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