For decades now, it has been said that "the process is the product" for biologics. Great care and consistency must be applied
in their upstream manufacture—during fermentation, harvest, and early purification—to preserve their complex structure, which
confers their activity and specificity. As the product moves to late-stage purification, however, the relative concentration
of impurities and altered product forms is diminished. Also, the final dosage form of most large molecule biopharmaceuticals
is the relatively simple liquid formulation of parenteral dosage form. In contrast, manufacturing the solid dosage forms common
for small-molecule drugs involves more complex processes, such as mixing dry powders, granulation, manufacturing controlled-release
matrices, and tableting.
W. Alan Moore
Because upstream processes of biotech products are more complex than downstream processes, process analytical technology (PAT)
should be implemented at these earlier stages to realize the greatest quality benefits. For example, improving control over
the processing of critical raw materials can improve quality and yield, and allow for early detection of lots that do not
meet specifications. It is also more efficient to implement new technologies in upstream stages than it is to obtain regulatory
approval for new methods for product release tests.
Now, many technologies are available for process monitoring and quality control. One that may prove highly beneficial is a
tool for rapid microbiological methods that focus on monitoring and screening for adventitious agents.
Historically, methods for detecting adventitious agents have had limitations. For example, standard polymerase chain reaction
(PCR) testing traditionally has been too specific to be useful. As a result, companies have continued to rely on traditional
broad-based detection methods, such as mycoplasma culture, despite the fact that these methods take six weeks to complete.
However, through multiplexing the PCR reactions, eight or more common mycoplasma contaminants of mammalian cell culture systems
can be screened in the same reaction. These technologies can provide results for more than 30 gene targets in a single test,
thus permitting the assembly of specific panels or "plexes" of potential contaminating agents. In addition, the technology
can be customized to target specific agents based on the nature of the production cell line, raw materials used, or the contamination
history of similar products. Thus, such methods are now sophisticated enough to be effective for at-line and in-line analysis.
These technologies continue to advance, becoming more automated, providing higher throughputs, and producing faster results.
A multiplex for mycoplasma detection, for example, may be enlarged to include more species, formatted in an array or microarray,
combined with other technologies for sample capture and enrichment, and simultaneous speciation of a contaminating agent in
the future. In addition, as genomic information on various agents accumulates, it may be possible to design molecular tools
capable of detecting unknown and unclassified agents.
In the past, the impractical outlay of time and money for broad-based adventitious agent testing was a strong argument for
relying solely on traditional end-product testing to ensure quality. However, emerging molecular tools can now quickly and
economically provide confidence in forward processing decisions. The challenge lies in applying these emerging technologies
quickly and in an intelligent fashion.
FDA. Innovation or stagnation? Challenge and opportunity on the critical path to new medicinal products. 2004 March. Available
W. Alan Moore, executive vice president and chief business officer, Althea Technologies, Inc., 11040 Roselle Street, San Diego, CA 92121.