COVER STORY CLEAN Tanks of up to 3,000-L capacity located in a classified clean area are used to prepare solutions at Biogen's new manufacturing facility. 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-la, 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 deA. MAUREEN ROUHI, C&EN WASHINGTON velopment of a process—from the time the molecule comes out of research AST MONTH, THE BIOPHARMACEUTIbeing forced to invest in manufacturing asthrough the final commercial process—to cal company Immunex announced sets. A case in point is Biogen. The Camsee titers improve by up to eight times," record revenues of almost $987 milbridge, Mass.-based biopharmaceutical Ward says. Investing $2 million to $4 million for 2001. Of this, $762 million comes company recently successfully validated a lion over two years in process development from Enbrel, its blockbuster rheumatoid large-scale manufacturing facility in Rearthritis drug. In fact, observers say, sales can cut capacity requirements by 25%, he search Triangle Park, N.C. When fully opof Enbrel (etanercept) in 2001 could have adds. "That's an absolutely high return on erational, by mid-2002, the plant will boost reached $1 billion had there been no con- Biogen's manufacturing capacity a small investment." straints in manufacturing capacity Using alternatives to mamfrom 12,000 L to 102,000 L. malian cell expression is anothThe active ingredient in Enbrel is a "We started considering er way to get around the capacmonoclonal antibody (MAb) that binds tuwhether to build this plant back ity crunch. Companies can try mor necrosis factor, a protein involved in in 1997," says John P. Ward, Bioinflammation. MAbs are produced by enusing bacterial cells, transgenic gen's senior director for global gineered mammalian cells in fermenters. plants, or transgenic animals. engineering. The decision was Commercial-scale facilities for this type Early in the development of a made with great apprehension, of biopharmaceutical production take up drug, these alternatives ought to he says. At the time, companies to five years and more than $400 million be considered in parallel. that had built capacity but whose to design, construct, start up, validate, and But that's easier said than products then failed had severe CUSTOM operate. Immunex could have avoided the done. "In the beginning you're problems and eventually were CHEMICALS crunch only by investing in capacity in trying to make the pure molebought out, he explains. 1996, well before Enbrel was approved by cule, and people aren't thinking of comthe Food & Drug Administration in 1998. BIOGEN THEN HAD two promising prod- mercialization," Ward says. 'And then they make decisions early in the process that The spectacular success of MAbs such ucts in the pipeline, but neither had yet as Enbrel is part of the reason for the camake it hard to make changes later on." been approved. One of them—Amevive pacity crunch. For example, 2 0 0 0 sales of (alefacept), an immunomodulator—is now A SECOND OPTION is to partner with anRemicade, the Johnson & Johnson brand under review by FDA for treatment of other pharmaceutical company that has competing with Enbrel, were more than psoriasis. capacity An example is Biogen's partner200% higher than in 1999; 2001 sales were "We were seriously concerned about ship with Elan, a pharmaceutical compaabout 95% higher than in 2000. Few prebuilding a plant and not using it," Ward ny headquartered in Ireland. The two have dicted in the late 1990s how quickly desays. 'And that's how we found that there agreed to a 50/50 split on the manufacture, mand for these products would grow was not enough capacity out there even development, and commercialization of With the capacity shortage projected just for us." Elan's discovery Antegren. The drug is an to last until 2005, financially able compaRealizing the capacity shortage in light adhesion inhibitor and is in Phase III clinnies developing MAb-type products are of Biogen's internal demand "was the main
NO VACANCY
There's no quick fix for the capacity crunch in biopharmaceutical manufacturing
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HTTP://PUBS. ACS.ORG/CEN
SUCCESS Sales of some products are growing at an unpredicted pace SALES ($ MILLION)
2000-01
$2,158 3,430
11.5% 29.4
10.0% 26.6
$761 1,360 254
$972 1,447 269c
22.5% 21.5 77.6
27.7% 6.4 na
$652 276 370 419 444 427
$762 347 721 431 819 516
77.7% 46.8 219 -6.3 61.5 45.7
16.9% 25.7 94.9 2.8 84.5 20.8
2000
2001
$1,760 2,093
$1,962 2,709
INTERFERON Avonex Multiple sclerosis Intron Ab Hepatitis Rebif Multiple sclerosis
$621 1,119 U3
MONOCLONAL ANTIBODY Enbrel Rheumatoid arthritis Herceptin Cancer Remicade Rheumatoid arthritis ReoPro Coronary disease Rituxan Cancer Synagis Pediatric infection
$367 188 116 447 275 293
ERYTHROPOETIN Epogen Anemia Procrit3 Anemia
ANNUAL CHANGE 1999-00
1999
THERAPEUTIC AREA
a Sold as Eprex in Canada, b Data are for sales of the so-called Intron A franchise, which includes Intron A, PEG-lntron, and Rebetron combination therapy, c For the first nine months of 2001. na = not available at C&EN press time.
ical 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 N o r t h Carolina. Whatever route a company takes, a lot of activities take several years to implement. "%u'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 Francois Darrort, president of Clariant's HTTP://PUBS.ACS.ORG/CEN
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 & E N 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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