Two fundamental cornerstones of the new bio/pharmaceutical business model are the end of the blockbuster product and the need
to accumulate and conserve cash. These two realities have major implications for bio/pharmaceutical manufacturing strategies
and technologies and create new challenges for CMOs.
It is widely understood and accepted that the new products coming out of the bio/pharmaceutical pipeline will be sold in smaller
volumes than the products introduced a generation ago (albeit at higher prices). This situation partly reflects the failure
of bio/pharmaceutical R&D laboratories to come up with safe and effective drugs suitable for broad populations. More importantly,
it also reflects the growing understanding of how drug effectiveness varies within patient groups, the ability to develop
biomarkers to identify patients for whom new drugs will work best, and the expectation of regulatory authorities that new
drugs will incorporate that knowledge into clinical regimens. The classic example is Roche's/Genentech's Herceptin (trastuzumab),
which is highly effectively for the 20% or so of breast-cancer patients that test positive for expressing the HER-2 gene.
The need to accumulate and conserve cash is driven by the imperative that bio/pharmaceutical companies in-license or acquire
new development candidates and marketed products rather than depend solely on their in-house R&D operations. One prime target
for improving cash position is inventories. Bio/pharmaceutical companies have traditionally held two to four times as much
inventory relative to sales as have consumer-products companies. Turning inventories more frequently can release hundreds
of millions of dollars in cash for the large bio/pharmaceutical companies.
SMALL, FREQUENT BATCHES
The implication of these two realities— smaller volumes and faster inventory turns—is that bio/pharmaceutical companies must
manufacture smaller batches more frequently than they have traditionally. This new manufacturing imperative is triggering
major changes in manufacturing practices, strategies, and technology. For instance, the CEO of GlaxoSmithKline (GSK) recently
talked about how GSK is shortening its supply chain (thereby reducing inventory requirements) by moving manufacturing closer
to where the products are being sold rather than concentrating production in very large scale but distant manufacturing sites.
The new manufacturing paradigm will require facilities that are simultaneously smaller scale, more flexible, and lower cost
and will mandate major changes in the design of facilities and equipment. Most of today's bio/pharmaceutical manufacturing
facilities were designed 20 or more years ago to accommodate large-scale batch processing operations with separate suites
each housing individual pieces of process equipment and complex material flows. Those facilities have very high fixed costs,
and equipment often sits unutilized and requires long set-up times.
Pharmaceutical equipment manufacturers and companies that develop advanced manufacturing technologies have been responding
to the new manufacturing requirements for some time. The major advances already being used include:
- Higher-yielding expression and fermentation technologies that reduce the scale of biomanufacturing facilities
- Manufacturing equipment for both API and dose manufacturing that incorporate disposable parts for components that come into
contact with the product
- Microreactors for small-molecule API manufacture, which replace large-scale batch processes with continuous processes conducted
in a single, small piece of equipment
- Continuous process finishing and dose manufacturing technologies, such as spray drying and equipment that can blend materials
and extrude finished tablets
- FDA-endorsed methodologies, such as process analytical technology (PAT) and quality-by-design.
Some of these technologies and practices are not yet in widespread use or fully developed for commercial operation, but they
are clearly making their way into the mainstream. For instance, Lonza announced in early February 2012 that it will build
a "factory of the future" based on microreactor and continuous flow technology. Major bio/pharmaceutical companies are working
with equipment suppliers and engineers to develop proprietary highly-automated and continuous manufacturing systems for their
"factories of the future."