The birth of the biotechnology industry was accompanied by regulatory uncertainty as well. Neither regulatory agencies nor
sponsors had a clear road map for the monitoring and approval of biopharmaceutical products. Questions surrounding the purity
and safety of recombinant proteins were different from those associated with small molecules. As the new industry grew, regulatory
agencies worked with companies to improve and standardize biopharmaceutical manufacturing, and to develop purity and safety
Throughout the 1990s, the biopharmaceutical industry struggled to meet the needs of a growing pipeline as well as a burgeoning
demand for newly released products on the market. In response to this demand, companies focused on scale, constructing more
manufacturing plants and procuring additional bioreactors and equipment to satisfy the market. It was the age of stainless
steel in the industry. But with unpredictability in product yields, regulatory approval, and commercial demand, essentially
every company struggled with over- or under-capacity.
Like many in the industry, Wyeth has had to deal with adjusting manufacturing capacity to unpredictable requirements in demand.
In 1998, when Wyeth and Immunex launched a soluble TNF receptor–fusion protein (used for the treatment of rheumatoid arthritis)
the product was manufactured under contract by Boehringer Ingelheim. However, US demand alone for the new molecule exceeded
the predicted worldwide demands in the first six months after launch. Neither Wyeth nor Immunex could have anticipated the
tremendous demand for this drug, which could not be met through internal capacity or the capacity available at Boehringer
Ingelheim. Both Wyeth and Immunex (which had merged with Amgen by 2002) responded by renovating older facilities and building
up their own capacity. By 2005, three large facilities were generating ample drug product to meet market demands that continue
to grow dramatically.
BIOLOGY VERSUS STAINLESS STEEL
At Wyeth, we believe that the productivity and economics of biopharmaceutical manufacturing are about to change dramatically.
While the nature of clinical development and product markets will remain unpredictable, process development and manufacturing
will become more efficient, less costly, and better able to adapt to rapid changes in clinical prospects and market demand.
As a company, we have made it our highest priority to bring about a transformation in manufacturing processes and technology.
Currently, more than one-third of our research and development pipeline consists of biopharmaceuticals (vaccines and protein-based
drugs), while our commercial biotech portfolio brings in annual revenues of approximately $7 billion. This number is expected
to grow in the coming years. Thus, it became a strategic imperative to reject the status quo and find a better, more efficient
way to manufacture our products. We needed to find a better way to manage the direct costs associated with biopharmaceutical
manufacturing, as well as the potential costs related to product development delays (due to process modifications, batch variability,
and non-robust operational systems) and lost sales due to insufficient capacity. To continue with business-as-usual was untenable.
Over the past five years, we have been working on innovations in cell biology, bioprocess engineering, and workflow, resulting
in dramatic increases in yields and efficiencies that will eventually filter through to the rest of the industry. Our objective
is to break through the paradigm that biotechnology drugs are expensive to produce. Here, the biopharmaceutical industry has
an opportunity that is not available to manufacturers of small-molecule therapeutics: improving production efficiency through
In the past 10 years, we have been successful in increasing the volumetric productivity of our clinical monoclonal antibody
processes more than 10-fold and as much as 30-fold for next-stage processes, where new technology has been applied.1,2,3 We can achieve volumetric productivity levels of 10 grams per liter in fed-batch cultures. These results have been achieved
through cell engineering efforts, increasing the amount of protein produced per cell, as well as increasing the viable cell
density of the production culture through proprietary fermentation technology. A single 5,000-L bioreactor can now produce
the same amount of product (about one metric ton per year) equal to that produced by 100,000 L of fermentation capacity using
previous technology. In addition, advances in purification technology have led to streamlined processes that use limited chromatography
steps, resulting in high process yields (80%) and purity, while reducing water and buffer usage, suite labor, and ultimately,
lowering the cost of goods.
The goal is to replace stainless steel with biology, to put more resources and efforts into improving the efficiency of biological
expression rather than building more reactors and more manufacturing plants. A 10- to 30-fold improvement in manufacturing
efficiency has the potential to transform the business model of the entire biopharmaceutical industry, influencing decisions
about whether or not to build facilities and about how to allocate resources, plan product portfolios, and respond to shifting