Scale-up strategies

High-volume (to 10 0001) tank fermenter systems with conventional cell densities of 1-2 X10 mH. 

Low-volume (under 11) but very high density (1-2 x 10 mH) heterogeneous systems (e.g. hollow-fibre bioreactors). 

Intermediate systems using a spin-filter to increase cell density to 1-2 x 10 mH but to a volumetric scale of 5001 only. 

High-density (1 x 10 mH) scaleable systems (to 2001) based on porous microcarriers. 

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Many industrial processes which employ bubble column reactors (BCRs) operate on a continuous liquid flow basis. As a result these BCR s are a substantially more complicated than stationary flow systems. The design and operation of these systems is largely proprietary and there is, indeed a strong reliance upon scale up strategies [1]. With the implementation of Computational Fluid Dynamics (CFD), the associated complex flow phenomena may be anal)rzed to obtain a more comprehensive basis for reactor analysis and optimization. This study has examined the hydrodynamic characteristics of an annular 2-phase (liquid-gas) bubble column reactor operating co-and coimter-current (with respect to the gas flow) continuous modes. 

Scale-up strategy applied to solid-acid alkylation process. Oil Gas J., 48-54. 

Yabannavar et al. [81] used Eqs. (19) and (20) for scale-up purposes. Based on successful operation conditions determined for an existing 12-L bioreactor, they calculated the spin-filter dimensions and operation conditions for an existing 175-L bioreactor. Experiments with the spin-filter designed for the large-scale bioreactor resulted in an absence of filter clogging with cell retention efficiency similar to the 12-L bioreactor. This was considered as an evidence that the suggested scale-up strategy is adequate. 

Hence, once again, the value of taking a systematic, sound scientific approach (and one that excludes personal bias) to process development as the basis for scale-up strategies has been confirmed. 

This chapter covers the general principles involved in the scale-up of biotechnology-derived products. Sections 1 and 11 focus on technologies currently used in the manufacture of commercial products. Sections III and IV include a practical approach to process design and scale-up strategies used to translate process development to large-scale production. 

Trappier, E. Scale-up Strategy for a lyophilized process. American Pharmaceutical Review Fall 2001. 

Our understanding of chiral catalyst has greatly increased in recent years, and we are beginning to see catalysts that are less substrate dependent. The advantages of chiral catalysts on an industrial scale are obvious. With the enormous potential of pericyclic reactions, particularly because more than one carbon-carbon bond and a number of stereogenic centers can all be created at the same time, it can only be a matter of time before they become a key weapon in the process scale up strategy to chiral compounds. 

Krishna, R., van Eaten, J.M. and Ursenau, M.I. (2000a), Three-phase Eulerian simulations of bubble column reactors operating in the churn-turbulent regime a scale-up strategy, Chem. Eng. Sci., 55, 3275-3286. 

The concept of parity in scaling up or down implies that the performance features, selectivity behavior, and recyclability of the stationary phase material used for the analytical and the preparative separation are identical, with the exception of particle size. Both robust experimental methods as well as rules of thumb, acquired by experienced investigators, have been developed that enable such comparisons to be made. An extensive scientific literature is now available to indicate sound foundations for such scaling up strategies, coupled with suitable experimental methods for their validation. Table 1 summarizes some of this information. 

Table 1 summarizes the experimental parameters investigated in the operation units of the preparation, and the equipment used at the different scales. In the first step of the scaling-up strategy, a first set of preparation parameters were optimized at lab-scale (50-100 g of solid) precipitation pH, V/Al atomic ratio, V concentration in solution ([V]) and precipitation temperature. Then, in a second step, namely at pilot scale (> 1 kg of solid), the optimized preparation parameters were precipitation and ageing time,... 

Despite the central role of the scale-up issue in biotechnology and the comparably large body of literature, no common, generally applicable strategy seems to be established. For each product, process, and facility, a suitable scale-up strategy has to be elaborated. 

A wholistic scale-up strategy consists of a comprehensive and detailed process characterization to identify key stress factors and key parameters influencing product yield and quality the most, and of an appropriate process control and process design ensuring optimum mixing and reaction conditions, supported by appropriate knowledge and data-driven models [234,235] as well as computational tools. 

Diaz A, Acevedo F (1999). Scale-up strategy for bioreactors with Newtonian and non-Newtonian broths. Bioproc. Engin. 21 21-23. 

The scale-up strategy starts with a lab process that has been optimized experimentally. 

Figure 7.17 Scale-up strategy for closed loop recycling chromatography.

The design strategy described so far is a theoretical approach. In practice, additional aspects will influence the scale-up strategy. They are characterized by three decision cycles that are depicted on the right-hand side of Figure 7.17 ... 

Third, the conditions for scale-up from lab to process plant are constant figures for the dimensionless parameters. But in practice it is not certain that the packing of the columns is always identical. Slight variations of the void fraction and HETP may occur. Additionally, differences in the fluid dynamics, especially at the column inlet and outlet, have to be taken into account. The theoretical scale-up strategy ignores these deviations. But in order to make sure that real numbers of plates of both plants are really the same, it is recommended to determine the Van Deemter plot, void fraction, and friction number for the new packing and to correct the interstitial velocity, the flow rate, and the injection volume. 

Batch chromatography is a special case of the CLRC. Therefore, the same scale-up strategy is applicable if the reduced time of one injection and the recycle number are set ... 

Although process scientists develop scale-up strategies aimed at reproducing process results obtained at a small scale, we must remember that ... 

Mixing calculations are a key component of scale-up strategies. Such calculations can be executed with a variety of tools, from simple spreadsheets to advanced modeling. The models used by spreadsheets are often developed within an organization over years of experience with certain processes and equipment. Advanced models such as those used by VisiMix were developed using much broader databases of processes and equipment, enhanced with research focused on mixing and scale-up. 

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