BIOPHARMACEUTICAL MANUFACTURING - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 332

the supply of proper culture medium (with the appropriate growth factors, pH,
osmolality, etc.), and the control/monitoring of appropriate temperature, CO 2 ,
and DO parameters.
Selection of Stable Strains The ability of the producing strain to maintain its
high productivity during both culture maintenance and fermentation is a very
important quality. Therefore, certain characteristics of the producing organism
that affect the process are critical for its selection; otherwise, there is a risk to its
commercial success. Some examples of these characteristics are strain stability,
resistance to phage infections, response to dissolved oxygen, tolerance of medium
components, the production of foam, the production of undesirable byproducts,
and the morphological form of the organism.
Culture Media The quality and composition of culture media play an impor-
tant role in the production process. Development studies are typically necessary
for selecting the most suitable media for fermentation/cell culture processes;
otherwise, there is a significant risk that process and product quality will be
compromised. Generally, the media selected should produce maximum yields
and concentration of product per gram of substrate used. Selected media should
also permit the maximum rate of product formation with a minimum yield of
undesired products. In addition, media quality should be consistent, be readily
available, and should cause minimum problems during preparation and steriliza-
tion. Media should also cause minimal problems in other aspects of the production
process, such as aeration and agitation, extraction, purification, and waste treat-
ment. Another consideration to be kept in mind while selecting appropriate media
is that the selection of media can sometimes affect the design of the fermenter
or bioreactor to be used.
Oxygen Requirements The majority of fermentation processes is aerobic and,
therefore, requires the provision of oxygen enrichment. The oxygen demand of
industrial fermentation and cell culturing processes is normally supplied by aer-
ating and agitating the fermentation broth or culture medium. However, there is
a risk that cellular metabolism of many processes can be limited if there is not
enough oxygen availability. It is critical that factors affecting the fermenter's or
bioreactor's efficiency in supplying microbial or animal cells with oxygen are
considered and carefully monitored to ensure that there is enough oxygen in the
reactor.
Sterilization A biotechnology product is produced by the culture of a specific
organism or organisms in a nutrient medium, and foreign microorganism contam-
ination can have serious consequences. For example, a foreign microorganism
can contaminate the reactor and compete with the desired culture organism for
nutrients, thereby ruining the fermentation and causing costly delays in pro-
duction. Therefore, procedures should be employed to avoid the risk of con-
tamination. Examples of such procedures are using a pure inoculum to start