Cell culture scaling

Drapeau D, Luan Y, Whitford JC, Lavin D, Adamson R. (1990) Cell culture scale up in stirred tank bioreactor. SIM Annual Meeting, Orlando, Florida, 1990. 

Meier SJ. (2005) Cell culture scale-up mixing, mass transfer, and use of appropriate scale-down models. Biochem. Eng. XIV. Harrison Hot Springs, Canada. 

Biopolymer Extraction. Research interests involving new techniques for separation of biochemicals from fermentation broth and cell culture media have increased as biotechnology has grown. Most separation methods are limited to small-scale appHcations but recendy solvent extraction has been studied as a potential technique for continuous and large-scale production and the use of two-phase aqueous systems has received increasing attention (259). A range of enzymes have favorable partition properties in a system based on a PGE—dextran—salt solution (97) ... 

MammaBan. For mammalian proteins, mammalian cells offer the most natural host for expression. Problems of incorrect processing and post-translational modification are avoided using these cells. Mammalian cells are usually grown in continuous cell culture, reducing the variabiUty in results (see Cell CULTURE technology). Moderate-level production of native protein is possible. The procedure, however, is slow and very cosdy, and the level of protein expression is low. Thus large-scale production of proteins in mammalian cells is not practical. When low quantities of protein are sufficient, this system offers the several advantages described. 

J. N. Thomas, in A. S. Lubrniecki, ed., Farge Scale Mammalian Cell Culture Technology, Marcel Dekker, New York, 1990, pp. 93—145. 

R. Fleischakei, in B. K. Lydeisen, ed.. Large Scale Cell Culture Technology, Hansei, New York, 1987, pp. 59—79. 

Cancer now afflicts one out of four adults. One of the more promising therapies for certain kinds of cancers involves the use of interferon, a protein that occurs in minute quantities in the body where it is an essential part of the body s immune system. Interferon can be produced outside the body in cultures of transformed lymphoblastoid cells. A few years ago, it was possible to culture these human cells on scales up to a few hundred milliliters. Chemical engineers have now developed reactors for the aseptic culture of human cells on a scale 100,000 times larger, making it possible to produce human interferon in practical useful quantities. 

Griffiths B (1992) Scaling-up of animal cell cultures. In Freshney RI (ed) Animal cell culture A practical approach. Oxford University Press, Oxford, p 47... 

Insect cell systems represent multiple advantages compared with mammalian cell cultures (1) they are easier to handle (Table 2.1) (2) cultivation media are usually cheaper (3) they need only minimum safety precautions, as baculovirus is harmless for humans (4) they provide most higher eukaryotic posttranslational modifications and heterologous eukaryotic proteins are usually obtained in their native conformation (5) the baculovirus system is easily scalable to the bioreactor scale. However, because of the viral nature of the system, continuous fermentation for transient expression is not possible - the cells finally die. 

In spite of several drawbacks (i.e. expensive and laborious handling procedures, low space-time yields (Table 2.1), high demand on biosafety, potential contaminations, limited applicability for continuous fermentations [129], and problems obtaining the same glycosyla-tion profile from batch to batch [130]), mammalian cell cultures are widely used for small-scale expression and more recently even on a multi-cubic-meter scale. The system works like insect... 

Another limitation is that there is no quantitative relationship between active drug transport in the cell culture models and in vivo e.g. [92, 93]. The reason may be that the expression level of the transporter in Caco-2 cells is not comparable to that in vivo or that there is a difference in effective surface area (see Section 4.3.2.2 below). One solution to this problem is to determine the apparent transport constants, Km and Vmax, for each transporter and subsequently, to determine a scaling factor. However, this is not readily done. In addition these studies are further complicated by the lack of specific substrates. For example, there are almost no specific substrates for the drug efflux transporters [18]. Therefore, other epithelial... 

From an industrial perspective, quantitative knowledge of the existence of different transporters within the cellular system used in screening procedures is of major importance as it can influence both the predictive value of the permeability coefficients and interpretation of the results. In addition, information on species differences or similarities or discrepancies between cell culture models and animals now provide an important basis for the scaling of data during the early phases of drug discovery for animals or humans [48]. 

Large-scale plant and animal cell culture... 

The 1980 s and the early 1990 s have seen the blossoming development of the biotechnology field. Three-phase fluidized bed bioreactors have become an essential element in the commercialization of processes to yield products and treat wastewater via biological mechanisms. Fluidized bed bioreactors have been applied in the areas of wastewater treatment, discussed previously, fermentation, and cell culture. The large scale application of three-phase fluidized bed or slurry bubble column fermen-tors are represented by ethanol production in a 10,000 liter fermentor (Samejima et al., 1984), penicillin production in a 200 liter fermentor (Endo et al., 1986), and the production of monoclonal antibodies in a 1,000 liter slurry bubble column bioreactor (Birch et al., 1985). Fan (1989) provides a complete review of biological applications of three-phase fluidized beds up to 1989. Part II of this chapter covers the recent developments in three-phase fluidized bed bioreactor technology. 

The most widespread biological application of three-phase fluidization at a commercial scale is in wastewater treatment. Several large scale applications exist for fermentation processes, as well, and, recently, applications in cell culture have been developed. Each of these areas have particular features that make three-phase fluidization particularly well-suited for them Wastewater Treatment. As can be seen in Tables 14a to 14d, numerous examples of the application of three-phase fluidization to waste-water treatment exist. Laboratory studies in the 1970 s were followed by large scale commercial units in the early 1980 s, with aerobic applications preceding anaerobic systems (Heijnen et al., 1989). The technique is well accepted as a viable tool for wastewater treatment for municipal sewage, food process waste streams, and other industrial effluents. Though pure cultures known to degrade a particular waste component are occasionally used (Sreekrishnan et al., 1991 Austermann-Haun et al., 1994 Lazarova et al., 1994), most applications use a mixed culture enriched from a similar waste stream or treatment facility or no inoculation at all (Sanz and Fdez-Polanco, 1990). 

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