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.
If We Build It, Will They Come?
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.
In the Beginning
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.
Although Fluor is listed as the construction managers, they didn't actually hammer the nails or pour the footings. That work was subcontracted, mostly to North Carolina firms picked by Fluor and approved by Biogen. Subcontractors included Southern Industrial (electrical work), GE Automation Systems (control systems), Environmental Air Systems (HVAC), Kinetic Systems (high purity piping) and several construction contractors. Approximately 30 local North Carolina subcontractors were used for foundation work, structural steel, mechanical equipment installation, piping, electrical, instrumentation and automation, and architectural specialties or treatments such as paneling, windows, drywall, doors, floors, rugs, treatments, and painting.
Maximizing Gray Space
Anticipating numerous changes to LSM's design, and in keeping with its vision of LSM as a flexible facility, Biogen came to value contractor flexibility. For example LSM was designed to maximize use of unclassified areas, or "gray" space, to reduce overhead, capital layout and ongoing costs.
Gray space plants are easier to build, less expensive to maintain, and use standard industrial treatments and architectural finishes. "Plus workers are happier in such facilities," says Ward. "Unclassified biotech space uses more or less normal industrial materials and construction methods," observes Harold Boman, vice president of life sciences operations at Fluor. All operations except for purification, small scale cell culture, and harvest were located in gray space.
LSM's utilities are typical for a large biotechnology facility. In addition to general utilities, the plant uses process gases, purified water, water-for-injection, clean steam, and HEPA filtration to serve upstream and downstream operations. The site's principal processing suites include cell culture harvest, purification, buffer preparation and media preparation.
Modular construction of critical systems has been used by oil exploration companies for decades and to some extent for pharmaceutical plants. But with RTP, Biogen pioneered modular construction on a scale which had never been attempted for a biomanufacturing facility. Biogen's modular strategy required that about 20 percent of the mechanical, electrical, and piping work be carried out off site.
Many of LSM's systems were constructed off site, for example, cell culture, buffer prep, buffer hold, clean-in-place systems and bioreactors. Buffer hold, a module measuring 60 by 120 feet, was completely built offsite, partially disassembled, put on trucks and reassembled on site. The advantage was all modular systems could be tested before they were brought on line, which saved a great deal of time and effort. Companies will try to replicate Biogen's "modular miracle," Ward believes. "Biogen pushed modular from day-one and did a good job of sticking to that strategy," Fluor's Boman adds.
Relying on buffer concentrates helped streamline plant design further by allowing three- to five-fold reductions in buffer holding tank volumes. With buffer concentrates, buffers are formulated in highly concentrated form and diluted in-line as they enter bioreactors. Without buffer concentrates, buffer tank volume must equal that of the bioreactor " in the case of RTP, that's 15,000 liters. By using concentrates, buffer holding tanks could be scaled down to 3,000 liters.
Fluor initially estimated that LSM would cost around $210 million, a price tag which Biogen immediately rejected. The two companies then sat down and had a "value engineering session" to eliminate space, simplify processes, reduce the number of control points and automation, eventually whittling down the estimate to about $180 million.
Most drug-makers would be satisfied with a $5-million over-run, but Biogen realized that once its magic threshold was crossed, going higher and higher still would be too easy. Throughout the design and construction, Biogen encouraged Fluor to identify any additional cost-cutting measures. Meanwhile, Biogen worked hard to keep its contractor on course. For example, when Biogen realized it needed an additional cell culture seed train, it asked Fluor to provide an independent group to develop this process to avoid distracting the main project team.
Biogen originally specified a single purification train into its $175-million budget. However, it subsequently determined the need for a second purification train, which was recently built as an add-on to the main RTP building.
"The final cost was truly remarkable," comments Boman. "In our experience with value engineering, 80% of the cost you take out typically finds its way back into the project. I think it's a real tribute to Biogen's leadership for sticking to its cost-cutting measures throughout the project."
Commissioning as Validation
In the typical construction project, commissioning and validation are delay and cost overrun rivals, but Biogen managed to keep even these unruly activities tightly under control. Although FDA views the two processes as distinct, Biogen believes good commissioning programs lead to successful validations, to the point of treating commissioning essentially as the first step in validation. "Some people jump straight into validation," says Ward, "but they inevitably encounter numerous validation problems that were not addressed in the commissioning phase."
The last step in validation, process validation, entails running a product through the plant and gathering data that demonstrate process consistency. A successful Biological License Application (BLA) is based on three consecutive, successful runs. Some manufacturers call this entire procedure process validation and individual batches "BLA-enabling runs." Biogen prefers to call them process validation runs.
According to Biogen, commissioning and validation went "very smoothly," in case-study fashion, from design to construction to validation to commissioning to FDA filings. "We had no 483 observations during the pre-approval inspection, which is quite remarkable," says Nicholas Barthelemy, vice president of manufacturing and general manager at LSM, referring to the numerical moniker for the form that FDA inspectors use to document variances from good manufacturing practices. "If we could replicate what happened at RTP in future projects, I'd be truly pleased,"Barthelemy says. "It doesn't get any better than this."
With its approvals behind it, RTP and its 430 workers are well into commercial production of Amevive, as they make process validation runs of Elan's Antegren product. Because the two products are expected to utilize only part of LSM's available capacity over the next few years, Biogen anticipates adding several more over time. LSM's utilization is expected to increase steadily through 2006-2007, at which point Biogen anticipates operating it at full capacity. "When we open the envelope from the Phase III studies, we'll be ready to support Antegren's launch," says Barthelemy. Biogen expects results of its two-year multiple sclerosis trials for Antegren in mid-2005.
Because LSM has only been approved for one process, ultimately utilizing RTP's full capacity for a portfolio of products requires increasing LSM's flexibility even further. Finishing touches for a second purification suite should be in place to increase the flexibility of the plant as early as next year.
From now until maximum utilization is achieved, Biogen will continue to debottleneck the Amevive and Antegren processes to achieve maximum throughput and efficiencies and get the most from every square inch of manufacturing capacity.
Biogen's approval track for Amevive, and for RTP in general, follows the standard practice among pharmaceutical and biotech firms to get a product approved as quickly as possible. "Trying to get the whole plant approved at once is inefficient because it takes longer and costs more money before the business need is there," states Barthelemy.
Although LSM is the second largest facility of its kind in the world, there are other large plants under construction. In June 2003, Biogen announced its planned merger with IDEC Pharmaceuticals, in San Diego, which should take place late in 2003. The new entity, Biogen Idec, plans a 500,000 square foot site including a plant very similar in size and capacity to LSM, called NIMO (New IDEC Manufacturing Operation) in San Diego.
Before teaming up with IDEC, Biogen had planned to construct another massive manufacturing site in Denmark. Although a European production facility would provide manufacturing close to key overseas markets, the Danish plant is now on hold. "Looking at our combined portfolios, we decided to put off Denmark until our business [can] support it," says Barthelemy.