Evolution and Genetic Engineering - Bioprocess Engineering: Kinetics, Biosystems, Sustainability and Reactor Design - page 722

conditions. Process efficiency to reduce manufacturing cost, although important, is of less
concern, since these products are required in relatively small amounts. They can command
high prices, and the selling price is determined by the costs of process development and
regulatory approvals, particularly clinical trials. Thus, for large molecular therapeutic prod-
ucts, the choice of biological system and processing equipment is dictated by the need to
produce highly purified material in an absolutely consistent manner.
Other protein products are acquired strictly on an economic basis, and manufacturing
costs play a much more critical role in the viability of a proposed process. In this case, regu-
latory demands are of lesser importance than in the production of therapeutic proteins. For
animal vaccines or animal hormones, the products must be very pure and render favorable
cost ratios. For example, the use of bovine somatropin to increase milk production requires
that the increased value of the milk produced be substantially greater than the cost of the
hormone and any increase in feed costs due to increased milk production.
For food use, product safety is important, while purity requirements are less stringent than
for an injectable therapeutic product. The volume of the required product is often substantial,
at minimum several metric tons per year. The price is critical because alternative products
from natural sources may be available. Proteins used as specialty chemicals (e.g. adhesives
and enzymes for industrial processes) usually can tolerate the presence of contaminating
proteins and compounds. The manufacturing costs for such proteins will greatly influence
the market penetration.
For nonprotein products based on metabolically engineered cells, processing costs
compared to costs of other routes of manufacture (usually nonbiological) will determine
the success of such a process. Another important factor is the process safety and environ-
mental impacts. Public perception and acceptance can also influence how a product is
produced.
The constraints on production can vary widely from one product class to another. These
constraints determine which host cells, vectors, genetic constructions, processing equipment,
and processing strategies are selected.
14.7. HOSTeVECTOR SYSTEM SELECTION
While overall optimization for a product manufacture is the ultimate goal, most if not all of
the bioprocesses today are still based on heuristic approaches. The success or failure of
a process often hinges on the initial choice of host organism and expression system. These
choices must be made in the context of a processing strategy. Table 14.7 summarizes many
of the salient features of common host systems. The most important initial judgment must
be whether posttranslational modifications of the product are necessary. If they are, then
an animal cell host system must be chosen. If some simple posttranslational processing is
required (e.g. some forms of glycosylation), yeast or fungi may be acceptable. Whether post-
translational modifications are necessary for proper activity of a therapeutic protein cannot
always be predicted with certainty, and clinical trials may be necessary.
Another important consideration is whether the product will be used in foods. For
example, some yeasts (e.g. Saccharomyces cerevisiae ) are on the FDA GRAS list (generally
regarded as safe), which would greatly simplify obtaining regulatory approval for a given