Higher volumetric productivity is contributing to smaller scale manufacturing. In addition, noted Whitford, volume demand is decreasing, with emerging products such as personalized medicines with companion diagnostics targeted to screened populations, and cancer vaccines generally required in substantially smaller amounts.
Another trend described by Whitford is “scaling out” instead of scaling up, also known as distributed manufacturing. Instead of running one 10,000 L batch, a company might opt to run five 2,000 L reactors in parallel.
Among values inherent in this flexibility, this minimizes the potential loss if one batch were to become contaminated or unusable for some other reason. Single-use systems also simplify geographic distribution of manufacturing capacity. To duplicate a facility in another location would require only purchase of the same devices and transfer of the process, whether to an adjacent building or another country.
Manufacturers of single-use devices are pursuing R&D to create new, cleaner materials for single-use products and new ways of producing these materials. For example, Paul Killian, Ph.D., senior scientist at EMD Millipore, described research under way on new methods for sterilizing single-use materials that would reduce the amount of leachables created. At present, most single-use systems are gamma-irradiated, a process that generates small oxygenated compounds that contribute to the leachables load.
Raising the ceiling for “large-scale” processing in single-use bioreactors from 1,000 L vessels to the new generation of 2,000 L vessels has expanded the utility of single-use systems for commercial-scale batch production. Sartorius Stedim Biotech plans to introduce a 2,000 L scale single-use bioreactor in 2013. Davy De Wilde, director of marketing for fermentation technologies for the company does not anticipate any volume increase beyond that.
“Improved cell strains, media, and process conditions have led over the past years to a significant increase in product yields per volume,” he says. “This enables the industry today to reach their required product volumes already at 1,000 L or 2,000 L scale, while previously required bioreactor volumes were up to five times higher.”
This is helping to drive uptake of single-use systems overall, according to Alison Rees-Manley, fermentation application specialist at Sartorius Stedim Biotech.
Other factors contributing to the increase in adoption of single-use bioreactors, in De Wilde’s view, are reduced cost of ownership and increased flexibility, thus allowing users to switch more easily between processes and to increase capacity rapidly due to reduced lead times and utility requirements.
User needs are a critical driver of technology and product development, and in response Sartorius Stedim Biotech plans to introduce a point-of-use integrity test for single-use bioreactor bags, beginning with a test for its bioreactors up to the 200 L system by the end of 2012 and shortly followed by tests for bags up to 1,000 L.
Need for Standardization
The issues and uncertainty surrounding extractables and leachables from single-use systems remain an ongoing topic of discussion. “The risks change depending on where the material is used,” said Dr. Killian.
An overall lack of standardization and regulatory guidance continues to present an obstacle to more rapid adoption of single-use technology.
“The regulatory agencies still put the onus on drug companies to demonstrate that there is no or low risk to the patients,” continued Dr. Killian. With increased use, confidence in the materials is growing among biopharmaceuticals producers.
As the industry has matured, companies have used their experience to modify their approach to performing extractables and leachables studies and evaluating the data.
For example, whereas before companies might have carried out leachable studies across all single-use devices—an expensive and challenging task—now they might take an extractables-to-leachables approach in which they would perform leachable studies only on devices identified as high-risk, explained Dr. Killian.
Similarly, they may be able to limit the scope of the studies required by comparing the results of some initial tests to established standards and use these quick evaluations to define what areas require more extensive data collection and analysis.
Downstream Adoption Is Looking Up
Unlike for the single-use bag systems developed for upstream buffer preparation, mixing, and storage, and designed to replace conventional glass and stainless steel bioreactors and fermentors, when it comes to downstream processing systems, “single-use” may not mean intended for disposal after a single run.
“We like to call it ‘single-use, batch-dedicated,’ or ‘single-batch,’” explained Makowiecki.
“Prepacked does not mean single-use,” emphasized Paul Lynch, production manager for Life Technologies' prepacked Poros® chromatography resins. The main advantage of prepacked columns is time savings, as they are ready to be dropped into a process without the need for validation.
“They save about 80% of the set-up time,” Lynch said, as well as the associated overhead of personnel needed to pack and validate the column.
At the June conference in San Francisco, Richard Garretson, business development manager at Life Technologies, led a workshop in which he described the advantages of the company’s GoPure™ columns prepacked with POROS chromatography resins.
Garretson compared prepacked columns to disposable membrane absorbers, which can be used in place of anion exchange chromatography, for flow-through polishing of monoclonal antibody preparations to remove DNA, viruses, and host-cell proteins. The high mass transfer capability of the POROS prepacked resin allows for high flow rates, short bed lengths, and small column sizes.
“The resin has the same sort of mass transfer profile as a membrane absorber,” said Garretson. Once users have selected the ideal column bed length for the separation they want to achieve, they can then increase or decrease the diameter of the column as desired for scale-up or scale-down, Garretson explained.
In contrast, scale-down—for process modeling, process characterization, and viral clearance studies, for example—is “problematic with filters,” he added, due to more limited availability of membrane sizes.
In terms of single-use capability, the prepacked chromatography resin, like a traditional self-packed column, can be re-used multiple times or replaced after a single use. It would typically be used for a single production campaign. In contrast, a functionalized filter is a consummable product intended to be disposed of after one use.
Producing relatively small drug batches or material for toxicology studies or clinical trials can mean switching product streams, and thus chromatography columns, more frequently. In this scenario, the use of prepacked columns can save time and money, contended Michael Killeen, business development manager, GE Healthcare.
Killeen’s presentation in San Francisco was entitled “‘Out of the Box’ Thinking for Process Chromatography.” The company’s ReadyToProcess™ prepacked columns can be used for multiple runs; however, the resins cannot be removed and repacked and are intended for use in a single campaign.
When combined with GE Healthcare’s ÄKTA™ ready disposable chromatography flow path, there is no need to clean or validate the system before use, pointed out Killeen. With flow rates up to 510 L/h, the systems are appropriate for pilot to small batch production.
A side-by-side analysis that compares the cost of processing one batch with a prepacked versus traditional column at pilot scale “can show significant savings,” added Killeen. “If you can get ten molecules produced instead of eight,” that is a good value proposition for the customer.”
Editor’s Note: As GEN went to press Eppendorf North America reported the release of the first single-use vessel to incorporate New Brunswick’s proprietary packed-bed impeller system. The New Brunswick CelliGen® BLU 5L comes pre-loaded with 150 g of Fibra-Cel® disks.