Throwing it All Away

In their quest for efficiency, versatility and lower costs, biomanufacturers are putting their stainless steel reactors and storage vessels into mothballs and turning to single-use plastic equipment. Replacing steel with plastic is hardly a new idea, but for biopharmaceutical companies, the switch is nothing short of revolutionary.

Disposability supports biotech's need for leaner, safer, more agile manufacturing. Cleaning and cleaning validation are practically eliminated wherever disposable bags, filters and tubing replace stainless. Costs associated with cleaning materials, lost production time, scheduling inefficiencies, and time restraints for sterilization and steam-and-hold become passe.

Disposables resolve potential product segregation issues because contact surfaces see one product, one time, before they're discarded. And although few new facilities specify disposable processing during design, doing so could save millions in capital expenditures for water and steam plants, not to mention bioreactors and fermenters.

The seeds for disposable biomanufacturing were sown in the blood products industry, where multiple-product facilities are common and safety reigns supreme. In biotech, especially at contract manufacturers, disposables address "myriad issues" for non-dedicated manufacturing sites, says Greg Page, Ph.D., pharmaceutical life science practice leader at Deloitte (Jericho, NY).

Ever since biotech caught the disposables bug, processing "in plastico" has spread horizontally and vertically into various niches through the process chain. Plastic bags replaced steel tanks for media and buffer storage, then morphed into mixing containers and bioreactors. Plastic tubing, valves and connectors encroached on stainless steel pipes and manifolds. Membrane filters appeared housed in single-use cartridges. Downstream, disposable membrane chromatography cartridges replaced some ion exchange resins, while process engineers rethought the economics of cleaning and validating even expensive resins. In short, the high value of biotech products provides fertile ground for disposable manufacturing.

Many disposable products evolved in stages. Neil Holman of Millipore cites ultrafiltration as an example. First came cleanable filters, then disposable filters in stainless steel holders. "As filters became higher-performing, it made sense to enclose smaller-area membranes completely in plastic," Holman notes. The newer filter units, individually too small for large processes, were manifolded together and voila: A completely disposable filter operation.

Disposability's greatest benefits are evident with batches of up to about 1,000 liters, bucking biotech's yen for huge bioreactors. Economies of scale and the success of high-dose monoclonal antibody therapies have pushed bioreactor sizes well above 20,000 liters.

Yet several factors could reverse the bigger-is-better trend in commercial cell culture, making disposables even more indispensable. Therapeutic trends in favor of smaller, disposable processes include personalized medicine; treatments based on genotyping, gene and viral therapy, and radioimmunotherapy all rely on smallish batches. The biggest boost for smaller batches, however, will come from improved volumetric productivity (product per volume of culture fluid), which has already increased at least fifty-fold in the past two decades. Higher productivity equals smaller batches, a boon to disposables.

Fully-disposable large-scale processing is probably a few years away. Its arrival will depend on manufacturers adopting disposables early, and carrying the idea forward during scale-up and process development. But even when the "big disposable" arrives, it will not be appropriate for every manufacturer. Large-scale fermentations will probably not benefit any time soon since process bags are limited to about 2,000-liter volumes. Similarly, already-approved processes are unlikely to switch over. Non-biotech drugmakers, whose processes often employ organic solvents, high heat and caustic reagents, will probably avoid plastics altogether.

"It's unlikely that disposable reactors will replace ten- or twenty-thousand liter stainless steel reactors any time soon," predicts Maik Jornitz, group vice president at Sartorius North America (Edgewood, N.Y.). "Mixing and process control are serious concerns in plastic reactors and exemplify the design benefits of stainless steel fermenters," Jornitz says. "Mixing device and gas distribution determine whether cells thrive or die."

A related roadblock, according to Vijay Singh, Ph.D., CEO of Wave Biotech (Bridgewater, N.J.) is the dearth of throwaway instrumentation for monitoring culture pH, dissolved oxygen, turbidity and conductivity. Singh believes instrument makers eventually will catch up, perhaps with optical detection and microprocessor control, which could eliminate end-user calibration. "Medicine has been using such devices for years," Singh says.

Even as storage vessels, 5,000 liters may be the upper limit for plastic containers, at least with current bag-making technology. Stedim Inc. (Concord, Calif.), which claims to be the only biobag producer that casts its own plastic film, manufactures its larger bags from four plastic sheets heat-sealed at the edges. End-users may be concerned about the structural integrity of very large bags, even when they're supported by steel holding tanks. Plus, as Stedim marketing manager Greg Ja notes, "Above about 5,000 liter capacity bags get quite heavy. You need special equipment just to lift them without damaging them."