Biomedical Engineering Reference
In-Depth Information
Figure 2.3. A schematic for manufacturing of a biotechnology product. The manufacture of a
biotechnology product generally involves many steps. Manufacture often being with the
thawing of frozen cells then continues through a series of cell culture expansions into the final
productionbioreactor. Aharvesting step to remove cells andother culture components precedes
downstream purification. For purification, the product then undergoes a series of purification
steps, such as affinity, ion-exchange, hydrophobic, or size exclusion chromatography.
The purified bulk product is then concentrated and formulated and may be lyophilized.
Additional processing steps such as proteolysis or conjugationmay occur as part of manufactur-
ing. These steps would generally be followed by some purification to remove step residuals.
product and continues through the final production cell culture to the harvesting
of unpurified bulk product. Downstream process steps include initial purification
(e.g., chromatography), modifications (e.g., conjugation), and final polishing steps
leading to the bulk drug substance. Filling and/or lyophilization of the drug substance
are then performed. Many of the important attributes of a biotechnology product are
impacted by the upstream manufacturing. The cells used to manufacture the product
are miniature factories affected by many variables including subtle differences in media
composition, aeration, metabolites, shear forces [30], and cell density. Differences in
these factors can impact a wide variety of product structural attributes including
glycosylation, oxidation, cellular proteolytic processing, and so on. Many challenging
process impurities are generated during upstream manufacturing, such as host cell
proteins, DNA, and media components. Systems biology approaches to clonal selection
or alteration [31], cellular metabolism, and biosynthesis along with better defined media
components, improved models for bioreactor fluid dynamics [32], more sophisticated
monitoring (e.g., beyond pH and dissolved O 2 ), and multivariate statistical analysis [33]
may improve the understanding associated with these complex process steps. An
improved process understanding linking process parameters to important product
attributes could allow for a better design of an upstream process. Improved process
understanding could also allow for broad design spaces and opportunities for changes in
scale, equipment, and so on without prior FDA approval.
Although there are many potential opportunities for upstream processing, many
challenges remain in understanding such complex process steps. Downstream processing
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