Biogen's LSM Plant; On Line, On Time, On Budget

If Biogen's Research Triangle Park (RTP), N.C. Large Scale Manufacturing facility proves anything, it's that plant construction needn't be a bottomless pit of delays, regulatory snags and cost over-runs. Biogen completed the 250,000 square foot LSM, as it refers to the plant, just 32 months after ground-breaking and one month ahead of schedule. Biogen beat its original budget of $175 million as well, by $2 million.

When LSM was conceived in the late 1990s, biotechnology faced an apparently dire capacity shortage. Whether this capacity crunch was real or not is the subject of another discussion, but predictions of capacity shortfalls were related to monoclonal antibodies (MAbs), the predominant biopharmaceutical product class. MAbs tend to be administered in high doses and are produced through mammalian cell culture, a finicky, time- and capital-intensive operation.

In 1999, when LSM was still being designed, Genentech, South San Francisco, and Boehringer Ingelheim, Biberach, Germany were the only companies worldwide with enough cell culture capacity to produce large quantities of multiple MAbs. At the time, Genentech was just bringing its Vacaville, Calif., plant on line. "We knew there weren't many options for large-scale cell culture," says John Ward, Biogen's vice president of global engineering, "and that, from a competitive standpoint, we'd be in a great position if we had that kind of capacity and our competitors did not."

Biogen's prescience was rewarded almost immediately in the form of a joint venture with Dublin, Ireland-based Elan, to produce Antegren, a Phase III protein for Crohn's disease and multiple sclerosis, at LSM. Before partnering with Biogen, Elan considered investing several hundred-million dollars in its own facility for making the drug but backed down. "Companies need an active pipeline and robust capital structure to assume that level of risk,"explains Ward. "In the future, only companies with reliable revenue streams and pipelines will be able to justify that level of investment."

Cost of goods (COG) provided a direct incentive for building LSM. COG, which falls with batch size, becomes more critical with successful, high-volume products. According to Ward, LSM's proposed 15,000-liter bioreactors offered the potential to reduce COG by approximately 75 percent over 2,000-liter batches.

New drug development drivers also helped push Biogen into construction mode. Antova, an anti-CD40 antibody under study for autoimmune diseases, and Amevive, which was recently approved for moderate to severe psoriasis, both looked promising. Biogen halted clinical development of Antova in 1999, two years after construction began on RTP. Amevive manufacture, however, is in full swing at RTP.

LSM was conceived by Biogen CEO Jim Mullen, who set up a cross-functional team of company experts to investigate design, construction, validation, engineering, regulatory and human resource factors for the proposed plant. Biogen's program approach to LSM reflected its approach to drug development: diverse, multidisciplinary teams working out potential problems before they materialized. "We knew that designing and building the plant would be the easy part,"says Ward.

Biogen's decision to build LSM adjacent to its existing RTP manufacturing facility helped compress construction timelines and keep costs down. The original RTP plant was built with room to expand, and the brain-power needed for designing and commissioning LSM was already in place. No small consideration was Biogen's cordial relationship with local and state officials in business-friendly North Carolina. Even with these green flags, Biogen delayed the expansion as long as possible, pending clinical data from Amevive.

After Biogen decided to move forward, events occurred rather quickly. Conceptual design began in July, 1998, and ground-breaking in July, 1999. Rudimentary commissioning on structures and utilities commenced in late 2000, was done by July 2001, and validation was completed by fourth quarter 2001. Biogen produced its first qualification batches of Amevive in January, 2002, and received approval for the manufacturing process in July, 2003.

Originally, management budgeted $175 million for LSM, but its contractor immediately countered that the plant would certainly cost more than that. The final tally was just shy of the original budget, at $173 million.

Keeping a project of this magnitude under budget was no accident. Biogen had deployed and tested most of the plant's systems very early in construction. "Everyone operated under budget constraints, including manufacturing," says Ward, "so we all had a stake in meeting our targets." As a result of these built-in efficiencies, validation cost about half as much as it normally would ---five percent of project capital versus ten-plus percent for a typical biomanufacturing plant of this size.

Biogen's secret weapon during planning and construction was none other than Engineering VP Ward, who once worked for Fluor, the primary contractor for LSM. "Knowing how Fluor operates helped us follow the most efficient, timely path with Fluor," says Ward.

Biogen chose Fluor so early in the planning process that potential contractors did not even have data or designs to bid on. Rather than relying on mere numbers, Biogen picked Fluor based on its nearly 20 years' experience in biotech, its "quality people," and its familiarity with RTP. Biogen's first RTP site was built by ADP Marshall, which was subsequently acquired by Fluor. So, along with Fluor's expertise and reputation, Biogen re-acquired the services of many of the engineers who had worked at the original facility. "We had a great experience with them first time, and had no qualms about getting that same team together for the expansion project," says Ward.