Bioprocessing batch

The alternative to batch mode operation is continuous operation. In the continuous mode there is a continuous flow of medium into the fermentor and of product stream out of the fermentor. Continuous bioprocesses often use homogenously mixed whole cell suspensions. However, immobilised cell or enzyme processes generally operate in continuous plug flow reactors, without mixing (see Figure 2.1, packed-bed reactors). 

Figure 2.5 Possible technological solutions to bioprocess problems a) Fed-batch culture b) Continuous product removal (eg dialysis, vacuum fermentation, solvent extraction, ion exchange etc) c) Two-phase system combined with extractive fermentation (liquid-impelled loop reactor) d) Continuous culture, internal multi-stage reactor e) Continuous culture, dual-stream multi-stage reactor f) Continuous culture with biomass feedback (cell recycling). (See text for further details).

Most industrial bioprocesses are now operated in a batch mode. Batch processing is the method of choice for small-scale production,... 

Lau, J.,Tran, C., Licari, P. andGalazzo, J. (2004) Development of a high cell-density fed-batch bioprocess for the heterologous production of 6-deoxyerythronolide B in Escherichia coli. Journal of Biotechnology, 110,... 

Due to the complexity of bioprocesses, and the lack of direct in-process measurements of critical process variables, much work is being done on development of soft sensors and model predictive control of such systems. Soft sensors have long been used to estimate biomass concentration in fed-batch cultivations. The soft sensors can be integrated into automated control structures to control the biomass growth in the fermentation. 

There are several barriers to the successful control of bioprocesses due to particular circumstances that are related to their characteristics the complexities of microbial metabolisms, the nonlinearity of microbial reactions, the frequent use of batch and fed-batch operations, and the limited availability of sterihzable online sensors for important process variables such as cell and product concentrations. Furthermore, it is difficult to construct mathematical models that can predict the entire range of batch or fed-batch operations that many fermentation processes require. 

Liquid-Flow Rate Liquid flow rate is measured when a medium is fed into a biore-actor in continuous and fed-batch operation. The flow rate of cooling water is also monitored in industrial bioprocessing plants. 

To date, bioprocessing is primarily conducted on a batch basis. This provides flexibility in shifting the products to be made from lime to time and. in particular, any failure to provide aseptic conditions may result in the condemnation of only one batch versus what could happen in the case of a continuous process. Notably, in the case of pharmaceutical biologicals. it is practical to keep track of the product by batch number from start to final use. Even with these kinds of problems, however, the many attractions of continuous processes are being thoroughly studied and applied in limited instances. 

A bioprocess system has been monitored using a multi-analyzer system with the multivariate data used to model the process.27 The fed-batch E. coli bioprocess was monitored using an electronic nose, NIR, HPLC and quadrupole mass spectrometer in addition to the standard univariate probes such as a pH, temperature and dissolved oxygen electrode. The output of the various analyzers was used to develop a multivariate statistical process control (SPC) model for use on-line. The robustness and suitability of multivariate SPC were demonstrated with a tryptophan fermentation. 

Gerigk, M.R., Maass, D., Kreutzer, A., Sprenger, G., Bongaerts, J., Wubbolts, M. and Takors, R. (2002) Enhanced pilot-scale fed-batch L-phenylalanine production with recombinant escherichia coli by fully integrated reactive extraction. Bioprocess and Biosystems Engineering, 25, 43. 

It is important to control culture parameters to insure consistency of glycosylation of a recombinant protein in a culture bioprocess. However, this may not be so easy given that the extent of glycosylation may decrease over time in a batch culture (Curling et al., 1990). This is likely to be due to the continuous depletion of nutrients (particularly glucose or glutamine) and accumulation of metabolic byproducts, which have been shown... 

Portner R, Schilling A, Liidemann I, Markl H (1996), High density fed-batch cultures for hybridoma cells performed with the aid of a kinetic model, Bioprocess. Eng. 15 117-124. 

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