Biomedical Engineering Reference
In-Depth Information
industry. Many blockbuster biologics—such as Enbrel (etanercept from
Immunex Corporation), Avastin (bevacizumab from Genentech (Roche)),
and Humira (adalimumab from Abbott Laboratories)—are produced using
large-scale bioreactors. The current state of manufacturing thus represents
the peak of what we conveniently call the “age of stainless steel.”
The method of manufacture of biological drugs progressed through an
expected route. Fermentation in large vats, whether it was done for wine or
industrial chemicals or drugs such as penicillin, was a well-established tech-
nique, so when the time came to manufacture recombinant drugs, the same
systems were transported over to this new class of drugs around 30 years
ago. Large stainless steel fermenters were a good fit as their science and tech-
nology was well developed. However, lurking in the bush was a new enquiry
by major regulatory agencies: the quest to control cross-contamination and
viral clearance, the two most important causes of the side effects of these
drugs. The quality guidelines by the FDA and EMEA began emphasizing
the safety issues for cleaning validation and viral clearance, and the industry
responded with more robust validation plans to prove compliance. The costs
of manufacturing soared, but that did not make any difference because all
of these molecules were under patents, and the companies were able to get
whatever price they needed to justify these huge investments.
However, the honeymoon for the biological manufacturing industry began
to end with the expiry of patents and the eagerness of the EMEA to start
awarding generic approvals of these drugs; suddenly, the cost of production
did become a consideration.
While the stainless steel manufacturers reaped huge profits selling their
multistory fermenters and bioreactors, the industry of flex-bag drug formu-
lation and administration and of intravenous bags also thrived. However,
few saw the need to connect the two, for there was no financial incentive to
do so.
The first “disruptive” innovation came to the industry when the first dis-
posable Wave Bioreactor
™
was introduced in 1996, which coincided with
the highest ever number of biotechnology drugs approved in a single year
between 1982 and 2007. Almost immediately, the biological manufacturing
industry (and more particularly the stainless steel industry) began a debate
on the safety and utility of plastic bags to manufacture biological drugs, and
the greatest fear inculcated in the heart of prospective users was the issue of
extractables and leachables, a topic that gets a detailed review in this topic.
Ironically, this issue was long resolved, when the FDA allowed the use of
plastic bags to administer drugs of all types, of both aqueous and lipid origin
and including hyperalimentation solutions. The risks to patients were mini-
mal vis-à-vis the convenience of administration. In reality, the leachables in
biological manufacturing are of little importance as the exposure to these
possible chemicals comes at a very early stage in the production, and the
robust downstream purification that removes even the isomers of the com-
pounds is more than adequate to remove these contaminants. The greater risk
