Scale-up of Bioreactors

An important factor in scale-up is to maintain constant tip speed (i.e., the speed at the end of the impeller is equal to the velocity in both the model and full-scale plant). If the speed is too high, it can lyse (i.e., kill) off the bacteria, and if the speed is too slow, the reactor contents will not be well mixed. 

Choose a fermenter volume required based on the desired capacity. 

Determine the reactor s dimension (e.g., DT = tank diameter) based on geometric similarity, with the impeller diameter being the characteristic length. For example, 

Choose the mass transfer correlation for kLa (i.e., mass transfer coefficient of the air bubble). 

Using the Perez and Sandall [21] correlation for non-Newtonian fluid 

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This chapter solely reviews tlie kinetics of enzyme reactions, modeling, and simulation of biochemical reactions and scale-up of bioreactors. More comprehensive treatments of biochemical reactions, modeling, and simulation are provided by Bailey and Ollis [2], Bungay [3], Sinclair and Kristiansen [4], Volesky and Votruba [5], and Ingham et al. [6]. 

This chapter discusses the kinetics, modeling and simulation of biochemical reactions, types and scale-up of bioreactors. The chapter provides definitions and summary of biological characteristics. 

The combination of kinetics, hydrodynamics and transport phenomena that provide the proper scale-up of bioreactors from laboratory to the industrial scale also has to be taken into account [4]. Different process solutions will be discussed within this chapter in detail, starting from concrete problem and illustrating possibilities to overcome this problem. 

Design and scale-up of bioreactors to generate large quantities of transformed microbes or cells and the products which they generate. 

Osterhuis, N. M. G., Scale-Up of Bioreactors A Scaled-Down Approach, Ph.D. Thesis. Delft University of Technology, Delft, The Netherlands, 1984. 

Mitchell DA, Krieger N, Stuart DM, Pandey A. (2000). New developments in solid-state fermentation. II. Rational approaches to the design operation and scale-up of bioreactors. Process Biochem, 3, 1211-1225. 

Kossen and Oosterhuis (1985) proposed two ways to solve the problem of scale-up of bioreactors first, by acquiring more knowledge about the hydrodynamics and interaction of the hydrodynamics with other mechanisms in production scale fermenters, and second, by developing scale-up procedures that give an adequate estimation of the performance of production scale fermenters based on small scale investigations. This approach is discussed in detail in later sections. 

The core of double membrane stirrer perfusion bioreactors is a stirrer on which two microporous hollow fiber membranes are mounted, one of them being hydrophobic and used for bubble-free aeration, the second of them being hydrophilic and used for cell-free medium exchange [15]. This system has been reported to provide viable cell densities of 20 million cells per miUiliter for more than two months [106]. Although Lehmann et al. [15] have described the scale-up of this system to the 20-L and 150-L scale, it has been most commonly employed at the bench-scale. 

In this paper the fundamental aspects of process development for the production of core and virus-like particles with baculovirus infected insect cells are reviewed. The issues addressed include particle formation and monomer composition, chemical and physical conditions for optimal cell growth, baculovirus replication and product expression, multiplicity of infection strategy, and scale-up of the process. Study of the differences in the metabolic requirements of infected and non-infected cells is necessary for high cell density processes. In the bioreactor, the specific oxygen uptake rate (OURsp) plays a central role in process scale-up, leading to the specification of the bioreactor operational parameters. Shear stress can also be an important variable for bioreactor operation due to its influence on cell growth and product expression. 

Hua J, Erickson LE, Yiin T-Y, Glasgow LA. A review of the effects of shear and interfacial phenomena on cell viability. Grit Rev Biotechnol 1993 13(4) 305-328. Tramper J, de Gooijer KD, Vlak JM. Scale-up considerations and bioreactor development for animal cell cultivation. Bioprocess Technol 1993 17 139-177. Griffiths B, Looby D. Scale-up of suspension and anchorage-dependent animal cells. Methods Mol Biol 1997 75 59-75. 

Deo YM, Mahadevan MD, Fuchs R. Practical considerations in operation and scale-up of spin-filter based bioreactors for monoclonal antibody production. Biotechnol Prog 1996 12 57-64. 

For scale-up of inoculum conditions of hairy root cultivation, a 1-L bioreactor (working volume of 800 mL) was used. This bioreactor had a height/diameter aspect ratio of 7.14. The bubble bioreactors had no internal mechanical agitation parts. The supplied aeration rate was 0.1 wm at the bottom by sparger. Each bioreactor was inoculated with 0.2-2.0 % (w/v) g fresh weight of hairy roots and cultured for 32 d. 

However, scale-up of this type of system is limited due to the fact that oxygen transfer is a function of the area of the wave-containing liquid surface. Since the area increases with the square and the volume with the third power of a linear dimension, it is expected that this technology will reach a scale limit. Nevertheless, the companies that market this type of bioreactor offer bioreactors up to at least 500 L working volume (Wave Biotech, 2006). 

When bioreactors coupled to cell retention devices are used, it is also necessary to evaluate the scale-up of the cell separation equipment. In the case of the spin-filter (see Chapter 11), parameters such as filter rotation velocity and the ratio of filtration area to bioreactor working volume are particularly relevant (Deo et at, 1996). 

Maranga L, Cunha A, Clemente J, Cruz PE, Carrondo MJT (2004), Scale-up of viruslike particles production effects of sparging, agitation and bioreactor scale on cell growth, infection kinetics and productivity, J. Biotechnol. 107 55-64. 

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