The Future of Drugmaking

Rising demand from aging, health-conscious baby-boomers promises to keep pharmaceutical manufacturing plants humming for many years to come. But what will these facilities look like? Genetics and biochemistry promise new generations of small-molecule and protein products, gene therapies, viral vectors, personalized medicine, and ever more-complex delivery and dosage forms. The more esoteric of these products may still be years from the marketplace, but the goal of safer, targeted, more effective medicines is already at hand, and with it, the goal of less-wasteful drug manufacturing.

Today's pharmaceutical engineers are borrowing ideas and technology from other process industries to assure that manufacturing keeps up with science. Facility designs routinely specify process integration, barriers or isolators to replace highly-classified space, and automation and controls to reduce human intervention. Like Japan's fabled automotive plants, larger pharmaceutical facilities today already operate, almost, in "lights out" mode, says Jeffrey Sarvis, director for facilities integration at Fluor Corp. (Greenville, S.C.).

If technical innovation continues at its present pace, tomorrow's processing suites may routinely be built in modular fashion hundreds or thousands of miles from their final locations, as some are already. Plants could be staffed by robots that see in the dark and never take a coffee break. Materials and products will be tracked continuously, automatically, flawlessly as they move through the supply chain. For biotech manufacturing, small, ultra-streamlined processing facilities might be built adjacent to rows of corn or soybeans, or above abandoned copper mines converted to farms, and fed by crude proteins provided by transgenic plants and animals.

As its importance increases, bioprocessing is nudging pharmaceutical manufacturing into the future. So far, the U.S. Food and Drug Administration (FDA) has approved 155 biotechnology drugs and vaccines, according to the Biotechnology Industry Organization. More than 70% of approvals occurred since 1998, and more than 370 biotech products targeting more than 200 diseases are now in clinical trials.

Monoclonal antibodies, biotech's fastest-growing product segment, also present its major manufacturing challenge. Administered in high doses, often for extended periods, the drugs require a constant supply flow, but the mammalian cell culture used to make the drugs is prohibitively expensive.

Nonetheless, significant strides have been made. During the past two decades, cultured cell densities have risen from about one million cells to between eight and 10 million cells per milliliter, according to Florian Wurm, Ph.D., chief scientist at Excellgene (Churm, Switzerland). At the same time, specific productivity has risen from one picogram of protein per cell per day to fifty picograms.

However, even this 500-fold increase in volumetric productivity can't keep pace with demand for cell culture capacity, and bioprocessors are scurrying for alternatives to large bioreactors. Inserting multiple protein-producing genes into cells promises to improve productivity, as does engineering cheaper and easier-to-grow bacterial or yeast cells.

Transgenic animals and plants will probably give biotech, and pharmaceutical manufacturing, its next boost. Proteins from transgenic plants and animals are untested in the marketplace and even more foreign to regulators. But their potential economic benefits are breathtaking: fermenters replaced by corn fields, hundreds of millions of dollars saved in upstream facilities and unlimited capacity. As for the naysayers, common wisdom circa 1975 held that FDA would never approve products made from hybridomas (engineered human cancer cells). Today, hybridomas are the workhorses of the monoclonals industry.

Transgenics' true test will not be whether corn or cows can churn out medicines--that has already been established. Companies can make protein for pennies per gram upstream, notes Cardinal Health's Brandon Price, but downstream purification still makes up 30% to 60% of total manufacturing costs in a traditional process. "If transgenics can't show at least a three- to five-fold reduction in overall manufacturing costs, they will be much less attractive, especially when you consider regulatory uncertainty," he says.

Whether change can occur quickly enough to resolve today's cost concerns is anyone's guess. Nevertheless, cost-containment, process integration, and a better appreciation for product segregation are manufacturing trends that are sure to be part of any facility design twenty years hence.

Because of the high ongoing costs of cleanroom operation, designers of new facilities are turning to isolation technology to protects workers from toxic products and sensitive materials from contamination, according to David DiProspero, senior director for business development at Sear Brown (Melville, N.Y.). Fluor's Sarvis agrees. When barrier/isolator systems are employed, he says, the building envelope takes on much lower priority with respect to product quality. "The goal," he says, "is to divorce product quality from facility construction by enclosing processes, rather than installing a lot of classified space."

However, deploying barrier technology guarantees that the equipment itself will be more expensive to acquire and install, as will facilities. The savings, according to experts, is in long-term lower operating costs associated with having with less classified space.