May 1, 2007 (Vol. 27, No. 9)
Angelo DePalma Ph.D. Writer GEN
Practical Considerations for Ensuring Integration, Flexibility, and Foresight
Changing technology, improved volumetric productivity, and the need for smaller process facilities are causing an evolution in the way bioprocess facilities are designed, built, and utilized.
Through biotech’s infancy up until about a decade ago, facility design depended on the demands of a company’s first successful product. A knowledgeable person could walk into an unknown facility and know where they were simply by looking at the equipment. Consequently, facilities evolved in ways that did not serve a manufacturer’s future product portfolio. Today standardization is more the rule than the exception, a consequence of the relatively small number of design/build/engineering firms and equipment standardization.
Radical changes in facility design to accommodate new technologies can yield a significant payback, or they may not, as we have seen with isolators replacing cleanrooms. While the benefits of isolators are unquestioned, the return on investment, given the cost of isolator systems, is not always tangible.
Smaller, Nimbler, but with Limits
Disposable bioprocessing affects nearly every aspect of facility design, construction, and utilization. Disposables provide versatility and shorter production turnaround times, which especially benefit multiproduct facilities. “If you can add a few more batches per year that is significant,” says David Marks, president of engineering consulting firm DME Alliance (www.dmealliance.com). Specifying disposable processing can help keep down facility-related capital costs, especially for larger processes. Large disposable processes present challenges to facility designers as well.
Disposables have the greatest impact upstream, where process volumes are still quite large. Designers must therefore account for transporting products and intermediates in roll-around containers, into and out of production suites and storage areas and through doorways and hallways. Ergonomics become critical when a person or piece of equipment needs to move those bags, and perhaps as importantly, stop them once they are in motion. Multistory facilities should include industrial-strength elevators capable of carrying 2000 L of process fluid weighing 2000 lbs, plus the holding/transporting vessel, and a worker or two.
Hard-piped facilities must anticipate all material flows and clean/steam-in-place utility needs in advance. When a process changes, or a new one is brought into a facility, processors must deal with the inflexibility, either by re-routing utilities or redesigning the process. Processes that are small enough to fit into disposable equipment hardly ever force these decisions. Disposables allow process engineers to concentrate on floor plan and access-corridor designs instead of plumbing layouts.
Although large-scale disposable solutions exist for sampling, sterile filtration, product transfer, or sterile additions, cGMP processes are practically limited to about 1,000-L capacity. This is becoming less and less of a limitation with rising efficiencies, but it is nevertheless a barrier. And while disposable bags need not be cleaned, the costs of disposing large, wet, bulky, heavy, irregularly shaped bags is not trivial. “You reach a price break or trade-off at a certain size,” observes Marks. At a certain point the cost of a holding tank, transporter, and facility changes may be as high as for a new stainless system.”
Most new facilities today are therefore design hybrids. “We don’t see truly all-disposable facilities today, not yet, except at maybe very small scale,” says Marks. “That will probably not change much, but the mix of disposable and hard-piped processes will certainly evolve as manufacturers become comfortable with validation and compliance issues related to disposables versus classical stainless systems.”
Nonprofit Facilities on the Rise
To Matt Smith, senior manager at architecture and design firm CH2M (www.ch2m.com), the evolution of early clinical-scale facilities into late-phase and production plants is the wave of the future. “These facilities are becoming more specialized and more focused on taking products farther along in clinical development,” he says.
Smith is referring to state, university, and nonprofit biotech facilities that have sprung up since the early 1990s. Some were originally built as teaching plants for academic biotech programs, others for collaborative R&D between academia or government and industry. Now, these facilities are taking on a life of their own by participating fully in contract research, development, and manufacturing needs for biotech firms of every type and size. University and nonprofit pilot-scale facilities bridge the R&D gap between big biotech and big pharma at one end of the spectrum and startup/virtual biotech at the other.
A number of factors, primarily higher protein titers and process streamlining, have pushed up the commercial capabilities of almost every biomanufacturing facility several notches. Smaller facilities originally designed for research can now produce preclinical batches, while those suitable for early-stage manufacturing can carry a product into Phase III, and so on. The need for such facilities is growing, as pilot-scale manufacturing at larger firms seems to be close to fully utilized.
The growing significance of smaller facilities arises from big pharma’s ongoing fascination with biotechnology and its need for pilot facilities to serve preclinical and early clinical-stage products. “They’re investing gobs of money because so many of their discovery compounds are biotech products,” according to Smith. Biotech and pharmaceutical firms that take advantage of this excess capacity obtain not only bioreactor volume but also considerable process-development expertise.
CH2M encourages its clients to investigate disposable technologies for its obvious benefits, not the least of which is lower capital costs. “In the long-term companies are going to figure out how to get out from under those $300 million to $400 million facilities,” says Smith. Advanced manufacturing technology, along with yield enhancements, will allow them to produce the same amount of active out of processes that are one-tenth the size of today’s plants. “As yields rise, the scale of biomanufacturing processes goes down.” Eventually, Smith believes that the manufacture of biotechnology therapeutics may approach the efficiency of industrial and agricultural bioprocessing.
It would seem that rising titers and shrinking processes, and the attendant capital cost savings, would tend to level the playing field between large and small biomanufacturers. But Smith does not believe this will happen any time soon.
Streamlined, high-yield processes don’t arise from nowhere. With every unique bioprocess, companies must still invest considerable sums into process development. Platform techniques for common product classes (e.g., mAbs) can help, as Wyeth (www.wyeth.com) and Bayer (www.bayer.com) have shown time and time again, but continuous process improvement occurs through clinical development and even post-marketing.
Smaller, more efficient manufacturing does offer advantages to smaller companies in terms of versatility, or nimbleness, but this advantage dissipates in proportion to a product’s market impact. Few companies have the resources to test a new bio-drug in thousands of patients, or market it for a major indication, without outside help.
Wyeth Biotech’s history as a biomanufacturer illustrates the importance of a multifaceted strategy, based on continuous improvement, to managing facilities and capacity. Cell-line productivity and downstream efficiency have enabled Wyeth to match its manufacturing capacity to rising demand for its products.
Wyeth’s Andover, MA biomanufacturing facilities, built in the late 1980s, consisted of three manufacturing suites, each holding four 2,500-L fermentors. The company designed the suites for flexibility in manufacturing bone morphogenic protein and two hemophilia drugs for Factor 8 and Factor 9 deficiency. Despite its relatively low volumetric capacity, Andover served quite well for these products, which were expressed at low titers but administered at low dose.
Today many biotech products, especially high-dose monoclonal antibodies, are produced at the metric-ton scale. Wyeth’s Enbrel fusion protein, which it produces with Amgen(www.amgen.com), is just one example.
Wyeth now employs its Andover site for development of the company’s 22 current pipeline products. The company applies a plug-and-play approach to fermentation, harvest, and downstream purification—platform technologies optimized for chromatography steps and buffer/water usage. “The vast majority of our pipeline products are made through the same backbone process,” states Michael E. Kamarck, Ph.D., senior vp.
Relatively low-volume products are today manufactured in Andover, but through the dual wonders of process improvement and cell-line engineering, protein titers have risen a thousand-fold since the 1980s. Those same 2,500-L tanks can now turn out hundreds of kilograms of material per year, sufficient for most biotech products. When products are promoted from development to full production at Andover, people and processes move as well.
Very high-volume products are shipped overseas to Wyeth’s Grange Castle, Ireland, facility, which houses six 15,000-L fermentors plus downstream capability. Grange Castle is configured to take on up to half a dozen multiple-ton-per-year products. “It’s hard for those of us who have been in the industry for a while to imagine that we’re making a metric ton of a biotech product.” The company recently reported achieving a protein titer of 10 g/L of fermentation broth. The roughly thousand-fold improvement over 10 mg/L in the 1980s translates directly to lower capacity requirements.
In 2000 Wyeth expanded Grange Castle and now, in addition to the drug substance facility, operates vaccine manufacturing, a vial-filling and lyophilization plant, and one suite dedicated to prefilled syringes. Grange Castle is not the largest bulk substance production site in the world, but it is believed to be the largest integrated production-fill-finish plant.
Over the last four to five years the company has made its strategy to invest in biology rather than stainless steel. Dr. Kamarck refers to the process as “titering” capacity through continuous biology improvements to meet increasing capacity needs without adding facilities.
Wyeth is also undertaking an ambitious overhaul of how it manages capacity and facilities. Internally this initiative is known as Project Gretzky, named for the hockey great Wayne Gretzky. When asked about his hockey philosophy, Gretzky allegedly said, “A good hockey player plays where the puck is. A great hockey player plays where the puck is going to be.” Wyeth is targeting even more process improvements, changing the way facilities are utilized, and remodeling its organizational in anticipation of future manufacturing needs, in other words where the puck will be, not where it is.