42
Chapter 2
these substrates in the medium. Similarly the formation rates o f metabolic products and biomass
are determined from measurements of the corresponding concentrations. It is therefore possible
to determine what flows into the total pool of cells and what flows out of this pool. The inflow of
a substrate is normally referred to as the substrate uptake rate and the outflow of a metabolic
product is normally referred to as the product formation rate. Clearly the product formation rate
directly gives a measure for the productivity of the culture. Furthermore, the yield can be derived
from the ratio o f product formation rate and the substrate uptake rate, and this quantifies the
efficiency in the overall conversion of the substrate to the product o f interest.
In the production of novel pharmaceuticals, which typically belong to the category of low
volume/high value added products the three above mentioned design parameters are normally not
that important. For these processes time-to-market and product quality is generally much more
important, and change o f the process after implementation is often complicated due to a
requirement of FDA approval. In the initial design phase it is, however, still important to keep
these three design criteria in mind, and especially the requirements for high final titer is
important since the cost for purification (or down stream processing) often accounts for more
than 90% of the total production costs.
2.2.4 Strain Improvement
A key issue in process optimization is to improve the properties of the applied strain,
as
this is
clearly responsible for the overall conversion of substrates to the product of interest. One may
see the cell as a small factory, and through engineering of the pathways it may be possible to
redirect the carbon fluxes such that the productivity or yield is improved. Engineering of the
cellular pathways can be obtained through altering the genome, as this may lead to different
expressions of the enzymes that catalyze the individual biochemical reactions or processes.
Traditionally strain improvement through introduction o f mutations was done through random
mutagenesis and selection of strains with improved properties. This is well illustrated by the
industrial penicillin production, where introduction of new strains has resulted in a significant
increase in the final titer of penicillin (see Fig. 2.10). In this process there have been several
strain improvement programs, some carried out by the major penicillin producing companies and
some by companies designated to carry out strain improvement. Similarly there has been made
improvements in the properties of baker’s yeast
S. cerevisiae
and in microorganisms applied for
the production of enzymes and many different metabolites.
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