Separations experts may argue otherwise, but fermentation and cell culture are what biotechnology is all about — the sine qua non of bioprocessing. Facilities, equipment and cells are the three pillars of large-scale fermentation.
Biologicals developers who prefer to maintain full control over products must plan fermentation or cell culture facilities (which will be discussed broadly as cell culture facilities in this article) as carefully as they select a cell line in which to express their product.
Planning, designing and building cell culture facilities present "dual challenges" of creating the perfect environment for current products while maintaining flexibility for contingencies — typically drugs that fail testing and must be replaced, says David Marks, founder and president of DME Alliance, Inc. (Allentown, Pa.), which specializes in cGMP bioreactor design. Marks, who formerly worked "down the road" at bioreactor fabricator ABEC and who now represents that company, offers the following advice:
- Understand process and business goals
- Create a contingency plan, which includes expansion if a product is highly successful
- Build in flexibility in anticipation of products dropping from the picture or, in the case of successful products, as their lifecycles mature.
Risk mitigation in facility design and construction depends on the size of the proposed facility. Pilot plants' flexible designs reflect the number and types of products they must handle. At this scale, Marks suggests making "rational" use of disposable plastic equipment for storage and even reactors, and keeping processing scales manageable. "If nothing else, after you're done building you can use it as a toll manufacturing facility," he says.
With full-production facilities, which are often dedicated to a single, successful product, flexibility is much more elusive. Long timelines between concept and construction dampen most sponsors' enthusiasm for built-in flexibility. Moreover, large scale demands more automation, greater physical layout for equipment, and hard-wired utilities.
|A technician works on a 1000-L bioreactor at New Brunswick Scientific. Courtesy of New Brunswick Scientific.
This is not to say that flexibility is unachievable at very large scale. But it won't come cheap. One way to hedge bets for super-large facilities is to set aside shell space, perhaps with bare-bones utilities servicing those areas.
As the design emerges, sponsors can expand into the free space as needed. "I've seen projects where the owner has taken that approach and, before completing the core facility, discovers uses for the free shell space," says Marks. "Space has a tendency to disappear as the detailed design progresses."
Some flexibility may be gained by specifying, if not acquiring, long-lead-time equipment early. Production-worthy bioreactors, for example, can take six months or longer to design and build to owners' specifications, especially if simultaneously ongoing process development suggests tweaking the original design.
"For a relatively small investment as a percentage of total cost, it often pays to do preliminary engineering and conceptual design, before pulling the trigger and moving forward with the project," Marks notes. "Problems arise when owners try to complete engineering while building is going on. In this scenario they're assuming risk with each piece of equipment they purchase, and with every commitment made with regard to facility construction."
Small is big
Large-scale cell culture came of age with the success of high-dose, chronically administered monoclonal antibodies (MAbs). While the number of cell culture processes with 10,000L, 20,000L, and higher capacities is growing, most cell cultures are smallish operations ranging from a few hundred mLs to several thousand liters of working volume. In biotech, 100 Ls typically divides pilot plants from full-scale manufacturing. Smaller units are typically skidded.
The interplay between cell culture productivity and process size is a theme we'll be hearing a lot about over the next few years. Different vendors note different trends. Globally, more biopharmaceutical manufacturers are becoming more interested in larger capacity bioreactors, says Mike Sattan, marketing director for New Brunswick Scientific (NBS; Edison, N.J.) And, despite the success of cell culture products, he says that interest in microbial fermentation has not abated.
NBS specializes in bioreactors in the 75- to 3,000-L range and somewhat smaller microbial fermentation vessels, focusing on biotech's "sweet spot": small to mid-sized manufacturers and sponsors with development-stage products that typically need equipment quickly, often within three months of concept.
The company is working with Wave Biotech (Bridgewater, N.J.), a specialist in bio-disposables, to incorporate NBS's FibraCel disks into Wave's Cellbag disposable bioprocess bags. Cells, especially those of the anchorage-dependent variety, attach readily to porous, polymeric FibraCel disks.
The NBS collaboration provides Wave customers with the potential of multiplying effective cell density within the same culture volume. With cells that secrete proteins, the combination of FibraCel and disposable bags creates a relatively inexpensive route to perfusion cell culture.
Wave has also partnered with Nunc (Rochester, N.Y.), known for its cell culture bottles, to incorporate Nunc's 2DMicroHex carriers, which work similarly to FibraCel, into disposable process bags. 2DMicroHex carriers are flake-like polystyrene hexagons about 125 Î¼m in diameter. Nunc coats them with Nuclon, the same material it uses to make its T-flasks.