Hollow-fiber bioreactor continuous production

Figure 8. Continuous production of rifamycin B in a dual hollow-fiber bioreactor.

Production of an optically active diltiazem intermediate (2R, 3S)-methoxyophenylglyci-date methyl ester ((-)-MPGM) from racemic MPGM by the action of lipase from Serratia marcescens in a toluene aqueous biphasic system (Tanabe Seiyaku Co., Ltd.). For the continuous production of (-)-MPGM, a hollow fiber bioreactor was set up in collaboration with Sepracor Inc. The introduction of this enzymatic step allowed the shortening of the diltiazem synthesis from nine down to five steps. 

Wee YJ, Yun JS, Kang KH, Ryu HW (2002) Continuous production of succinic acid by a fumarate-reducing bacterium immobilized in a hollow fiber bioreactor. Appl Biochem Biotechnol 98 1093-1104... 

Until now, bioreactors of various types have been developed. These include loop-fluidized bed [14], spin filter, continuously stirred turbine, hollow fiber, stirred tank, airlift, rotating drum, and photo bioreactors [1]. Bioreactor modifications include the substitution of a marine impeller in place of a flat-bladed turbine, and the use of a single, large, flat paddle or blade, and a newly designed membrane stirrer for bubble-free aeration [13, 15-18]. Kim et al. [19] developed a hybrid reactor with a cell-lift impeller and a sintered stainless steel sparger for Thalictrum rugosum cell cultures, and cell densities of up to 31 g L1 were obtained by perfusion without any problems with mixing or loss of cell viability the specific berberine productivity was comparable to that in shake flasks. Su and Humphrey [20] conducted a perfusion cultivation in a stirred tank bio-... 

Scheme 15. The proposed continuous production of polar head modified phospholipid (1), its purification by PA removal (2) and hydrolysis to the corresponding OP (3). The three enzymes are immobilized in hollow fiber hydrophobic membrane bioreactors [179]...

An example of aldehyde formation is the production of isovaleraldehyde by Gluconobacter oxydans R (Fig. 16.2-45) 202, 206. Glycerol-grown Gluconobacter oxydans slowly oxidizes 3-methyl-l-butanol to isovaleraldehyde, with yields of over 90%. The product was recovered by bisulphite trapping or cold traps 202. Extractive bioconversion in a hollow-fiber membrane bioreactor allowed continuous produc-... 

The use of membrane reactors offers several advantages, including (1) a high specific surface area, (2) instantaneous reaction and separation of substrate and product, (3) reusing the lipase, and (4) continuous operation. Immobilization of lipase onto a membrane offers many advantages, such as a low drop in pressure when continuously operated, and high operational stability with low external and internal diffusional resistance (Giorno and Drioli, 2000). In these bioreactors, the lipase is immobilized on a membrane, which may be either a flat sheet (FSMR) or hollow fiber (HFMR). 

Production The production culture may be a batch of several hundred roller bottles, 30 to 50 cell factories, or a single bioreactor for suspension (100 to 10,000 L) or microcarrier (50 to 500 L) ceUs. Although batch-type production is still the most common process, continuous processes where the product is harvested daily over a long period (20 to 100 d) are being increasingly used. Culture systems based on hollow fibers, porous microcarriers, or other immobilization techniques are used for continuous perfusion processes. During the production phase, the virus seed or a promoter (e.g., for interferon) may be added. 

Added productivity of lactic acid fermentations can be achieved by combining continuous systems with mechanisms that allow higher bacterial cell concentrationsResearch is concentrated on two mechanisms (1) membrane recycle bioreactors (MRBs) and (2) immobilized cell systems (ICSs). The MRB consists of a continuous stirred-tank reactor in a semiclosed loop with a hollow fiber, tubular, flat, or cross flow membrane unit that allows cell and lactic acid separation and recycle of cells back to the bioreactor. The results of a number of laboratory studies with various MRB systems demonstrate the effect of high cell concentrations on raising lactic acid productivity (Litchfield 1996). O Table 1.12 lists examples of published results employing various MRB systems. 

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