Scaleup And Scaledown

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. The major factors involved in scale-up are:

(i) Inoculum development. An increase in scale may mean that extra stages have to be incorporated into the inoculum development programme. This aspect is considered in Chapter 6.

(ii) 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. Thus, 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. This aspect is considered in detail in Chapter 5.

(iii) 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,

(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. Points a, b, c and e are related to bulk mixing whilst d, e, f and g are related to air flow and oxygen transfer. Thus, agitation and aeration tends to dominate the scale-up literature. However, it should always be remembered that inoculum development and sterilization difficulties may be the reason for a decrease in yield when a process is scaled up and that achieving the correct aeration/agitation regime is not the only problem to be addressed.

Scale-up of aeration/agitation regimes in stirred tank reactors

From the list of environmental parameters affected by aeration and agitation it will be appreciated that it is extremely unlikely that the conditions of the small-scale fermentation will be replicated precisely on the large scale. Thus, the most important criteria for a particular fermentation must be established and the scale-up based on reproducing those characteristics. The problem of aeration/agitation scale-up has been extremely well illustrated by Fox (1978) in his description of the 'scale-up window'. The scale-up window represents the boundaries imposed by the environmental parameters and cost on the aeration/agitation regime and is shown in Fig. 9.21. Suitable conditions of mixing and oxygen transfer can be obtained with a range of aeration/agitation combinations. The two axes of Fig. 9.21 are agitation and aeration and the zone within the hexagon represents suitable aeration/agitation regimes. The boundary of the hexagon is defined by the limits of oxygen supply, carbon dioxide accumulation, shear damage to the cells, cost, foam formation and bulk mixing. For example, the agitation rate must fall between a minimum and maximum value — mixing is inadequate below the minimum level and shear damage to the cells is too great above the maximum value. The limits for aeration are determined at the minimum end by oxygen limitation and carbon dioxide accumulation and at the maximum end by foam formation. The shape of the window will depend on the fermentation — for exam-

Aeration And Agitation Fermentation
Fig. 9.21. The 'scale-up' window defining the operating boundaries for aeration and agitation in the scale-up of a fermentation. After Fox (1978) reproduced from Lilly (1983).

pie, the supply of oxygen would be irrelevant in an anaerobic fermentation, whereas the limitation due to shear would be of major importance in the scale-up of animal cell fermentations.

The solution of the scale-up problem is three-fold:

(i) The identification of the principal environmental domain affected by aeration and agitation in the fermentation, e.g. 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.

The process variables which affect mixing and mass transfer are summarized in Table 9.6 (Oldshue, 1985; Scragg, 1991). Thus, if dissolved oxygen concentration is perceived as 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. However, as a result, the other parameters will not be the same in the larger scale and, therefore, neither will the environmental factors which they influence. This phenomenon is well illustrated by Oldshue's example summarized in Table 9.7 where a 125 fold increase in scale is represented. If power

Table 9.6. The effect of process variables on mass transfer or mixing characteristics

Process variable Mass transfer or mixing characteristic affected

Power consumption per Oxygen-transfer rate unit volume

Volumetric air flow rate Oxygen-transfer rate

Impeller tip speed Shear rate

Pumping rate Mixing time

Reynolds number Heat transfer (see previous section)

consumption per unit volume is kept constant then inipcllci up speed (i.e. shear) increases and flow min"1 u,l 1 i, c mixing) decreases. If mixing is kept constant, .in ^innmous (and totally uneconomic) increase in power is required and shear increases 5 fold. If impeller lip speed (shear) is kept constant then power oiiMimpiion (hence, K, u) and mixing decrease. This analysis indicates that it is economically impossible to maintain the same degree of mixing on scale-up and, ilicicloie. a decrease in yield may be due to mixing anomalies.

I Ik- must important environmental domains affected by aeration and agitation for the majority of fermentations are oxygen concentration and shear. Thus, the most widely used scale-up criteria are the maintenance of a constant KLa or constant shear conditions. Constant shear may be achieved by scaling up on the basis of constant impeller tip speed. Constant K, a may be achieved on the basis of constant power consumption per unit volume and constant volumetric air-flow rate. The operating variable dictating constant power consumption in geometrically similar vessels is the agitator speed. The agitator speed on the large scale is then calculated from the correlations between KLa and power consumption and between power consumption and operating variables. An example of this approach is given in the previous section describing the effects of operating variables on power consumption.

Hubbard (1987) and Hubbard et al. (1988) summarized the procedure for scaling up both Newtonian and non-Newtonian fermentations and proposed two methods to determine the large scale conditions:

Method 1

(i) Determine the volumetric air flow rate (Q) on the large scale based on maintaining Q/V constant (V = working volume of the fermenter).

(ii) Calculate the agitator speed that will give the same KLa on the large scale; this is achieved using the correlations between power consumption and N and between Kta and power consumption.

Method 2

(i) Calculate the agitator speed keeping the impeller tip speed constant, vrND,.

(ii) Calculate Q from power correlations and K, a correlations.

The accuracy of these scale-up techniques is only as good as the power and Kha correlations, so it is worth expending some considerable time to test the validity of potential correlations for the fermentation in question.

Table 9.7. The effect of the choice of scale-up criteria on operating conditions in the scaled-up vessel. Based on scale-up from 80 dm3 to 104 dm3 (Based on Oldshue, 1985)

Criterion used in scale-up Effect on the operating conditions on the large scale

(Large scale value/Small scale value)

Table 9.7. The effect of the choice of scale-up criteria on operating conditions in the scaled-up vessel. Based on scale-up from 80 dm3 to 104 dm3 (Based on Oldshue, 1985)

Criterion used in scale-up Effect on the operating conditions on the large scale

(Large scale value/Small scale value)

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