The active ingredient in Enbrel is a monoclonal antibody (MAb) that binds tumor necrosis factor, a protein involved in inflammation. MAbs are produced by engineered mammalian cells in fermenters. Commercial-scale facilities for this type of biopharmaceutical production take up to five years and more than $400 million to design, construct, start up, validate, and operate. Immunex could have avoided the crunch only by investing in capacity in 1996, well before Enbrel was approved by the Food & Drug Administration in 1998.

The spectacular success of MAbs such as Enbrel is part of the reason for the capacity crunch. For example, 2000 sales of Remicade, the Johnson & Johnson brand competing with Enbrel, were more than 200% higher than in 1999; 2001 sales were about 95% higher than in 2000. Few predicted in the late 1990s how quickly demand for these products would grow.

With the capacity shortage projected to last until 2005, financially able companies developing MAb-type products are being forced to invest in manufacturing assets. A case in point is Biogen. The Cambridge, Mass.-based biopharmaceutical company recently successfully validated a large-scale manufacturing facility in Research Triangle Park, N.C. When fully operational, by mid-2002, the plant will boost Biogen's manufacturing capacity from 12,000 L to 102,000 L.

"We started considering whether to build this plant back in 1997," says John P. Ward, Biogen's senior director for global engineering. The decision was made with great apprehension, he says. At the time, companies that had built capacity but whose products then failed had severe problems and eventually were bought out, he explains. 

BIOGEN THEN HAD two promising products in the pipeline, but neither had yet been approved. One of them--Amevive (alefacept), an immunomodulator--is now under review by FDA for treatment of psoriasis.

"We were seriously concerned about building a plant and not using it," Ward says. "And that's how we found that there was not enough capacity out there even just for us."

Realizing the capacity shortage in light of Biogen's internal demand "was the main driver for us to commit to building a plant," Ward continues. "The absolute worst that could happen was that we would end up doing contract manufacturing. But we were highly confident that, with the shortage, it wouldn't take a lot to get somebody signed up."

With its billion-dollar product Avonex (interferon beta-1a, for treatment of multiple sclerosis), Biogen could take on the financial burden and risk. Lacking similar resources, what can other companies do?

At Outsourcing Biopharmaceutical Manufacturing, a conference organized by the Center for Business Intelligence and held last December in Alexandria, Va., Ward offered some suggestions. On top of his list is process improvement.

Process development can yield cell lines that are significantly more productive, media that allow faster cell growth and higher throughput, and purification steps that are optimal. "It's not unusual over the development of a process--from the time the molecule comes out of research through the final commercial process--to see titers improve by up to eight times," Ward says. Investing $2 million to $4 million over two years in process development can cut capacity requirements by 25%, he adds. "That's an absolutely high return on a small investment."

Using alternatives to mammalian cell expression is another way to get around the capacity crunch. Companies can try using bacterial cells, transgenic plants, or transgenic animals. Early in the development of a drug, these alternatives ought to be considered in parallel.

But that's easier said than done. "In the beginning you're trying to make the pure molecule, and people aren't thinking of commercialization," Ward says. "And then they make decisions early in the process that make it hard to make changes later on."

A SECOND OPTION is to partner with another pharmaceutical company that has capacity. An example is Biogen's partnership with Elan, a pharmaceutical company headquartered in Ireland. The two have agreed to a 50/50 split on the manufacture, development, and commercialization of Elan's discovery Antegren. The drug is an adhesion inhibitor and is in Phase III clinical trials for treatment of multiple sclerosis and Crohn's disease. Elan is expected to use part of the capacity at Biogen's Research Triangle Park facility in North Carolina.

Whatever route a company takes, a lot of activities take several years to implement. "You're always facing a timeline challenge. There isn't a quick fix," Ward says.

According to data compiled by the team of David T. Molowa, a managing director at J.P. Morgan H&Q, New York City, the biopharmaceutical industry has practically no room to spare. Molowa estimates the current mammalian cell culture capacity to be about 342,000 L. Most of this already is tied up with approved products. If the pipeline products that that capacity is being used for fail, only 12,150 L may be freed up.

Among contract manufacturers, the estimated current mammalian cell culture capacity is 95,000 L. The bulk belongs to Boehringer Ingelheim (75,000 L) and Lonza (16,000 L), and both companies seem to have been operating at full capacity for almost two years, according to Molowa.

However, by 2005, expansions are slated to add 890,000 L from the biopharmaceutical industry and 189,000 L from contract manufacturers. If all of these plans proceed, total capacity could be a little over 1.5 million L. Meanwhile, contract manufacturers without mammalian cell culture assets are considering entry into the field.

"WE CAN'T IGNORE the numbers of biotech-based drugs in the pipeline," says François Darrort, president of Clariant's life sciences and electronics division.

At Degussa, "we are having strong discussions about mammalian cell production," Peter Nagler, president of the company's fine chemicals business, says.

Is there a danger of overcapacity by 2005 and beyond?

"Companies have good plans for what they're building. It's not on a whim," Ward says. "We're planning a second major facility, in Denmark. But we're not committing the capital until we're sure we have a use," he adds.

The expression technologies are just one part of the biopharmaceutical manufacturing equation, says Kevin Cox, vice president for biotechnology at Avecia. Although one of Avecia's goals is to gain mammalian cell culture capabilities, "we think it's important to look at specific technologies applicable to our operation," he tells C&EN.

Avecia will not be making large-scale investments in mammalian cell culture assets at present, Cox says. It will more likely install early-phase development capability in the area. Avecia also will focus on downstream processes. Isolation, purification, and characterization are common across expression technologies, he says. Those are areas where Avecia has an advantage, based on existing skills in microbial technology, he adds.

"I'm glad I'm not in their shoes," Ward says of those biopharmaceutical companies that have not lined up manufacturing capacity for 2002–05. "If they're two to three years to commercialization, they probably will have to wait, partner, or spend money."

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