Disposable bioreactors have become the vanguard of single-use processing, a litmus test of sorts for the acceptance of single-use equipment in biomanufacturing. Adoption has been slower than expected, but progress has been encouraging nonetheless. The steady uptake of disposables in critical unit operations suggests that, eventually, single-use bioreactors will be more the rule than the exception, particularly at small- to mid-scale.
Jeffery Craig, global director for business development at ATMI, calls the evolution of disposable bioreactors “part of a natural maturation process” for single-use.
Until recently, ATMI maintained a low profile in the life sciences. The Belgium-based company, which manufactures its own animal-derived component-free plastic films, has for years supplied microelectronics firms with ultraclean, single-use bags. It subsequently introduced its own disposable mixing technology and, in 2008, acquired LevTech, which specialized in disposable, magnetically levitated impeller mixing driven by a superconducting magnet.
This year ATMI extended its commercial alliance with Sartorius Stedim Biotech by adding new technologies to the marketing and distribution partnership, specifically ATMI’s Magnetic Mixer. Sartorius Stedim Biotech retains distribution and marketing rights to ATMI’s LevMixer® mixing system, as it has since early 2008. The agreement also opens up ATMI’s bioreactor-related products to Sartorius Stedim Biotech.
Integration, regulatory compliance, and the emergence of standards have been among the predominant trends in single-use bioreactors, and these have been driven by compliance and quality concerns. Users are more interested in complete, plug-and-play processes rather than standalone unit operations, says Craig, despite the persistence of a “custom mentality”—a leftover from disposables’ early days.
“The role of standards in the acceptance of single-use bioreactors is analogous to the adoption of plastics in the microelectronics industry. Standards, particularly for leachables and extractables, benefit everyone.”
Standardization does not imply a lack of innovation. ATMI’s Integrity™ disposable bioreactors, which range in size up to 1,000 L, are cube-shaped vs. the more common cylinders or flat, oblong bags. The reactors are designed to “move a lot of fluid,” provide good mixing and oxygenation with low shear, and are scalable from bench to manufacturing scale.
When Xcellerex broke the 1,000 L ceiling in 2008 with its XDR-2000 disposable bioreactor (with a fully inflated volume of 2,500 L), observers believed the upper size limit for bio-bags had been reached. Supporting massive, fluid-filled bags presents engineering issues, disposal of used bags raises environmental concerns, and bioreactions above 1,000 L capacity were said to be the exclusive domain of stainless steel.
Despite these objections, Xcellerex is working on even larger disposable bioreactors, with a 5,000 L unit under development.
Parrish Galliher, CTO, explains that such large systems benefit from economies of scale. “It takes one operator to run a 1,000 L reactor and one operator to run a 5,000 L reactor. Quality control and release-related costs are also lower because you’re producing fewer batches. And while a 5,000 L bag will be more expensive than a 2,000 L bioreactor, it won’t be two-and-a-half times as expensive.”
The standard rule of thumb for costing stainless steel reactors states that cost goes up by a factor of 20.4 power (a factor of about 1.32) when size doubles. This rule applies to disposable bioreactors as well.
Galliher also suggests that the value of disposables relative to stainless reactors improves at larger scale. More steam, cleaning fluids, time, and personnel are required to sanitize a stainless steel reactor, while outlays for the disposable’s cleaning and cleaning validation remain at zero.
In September, Project GreenVax announced that it would use XDR GMP single-use bioreactors from Xcellerex in a new facility under construction in Bryan, TX. Project GreenVax is an offshoot of the Texas Plant-Expressed Vaccine Consortium consisting of G-Con and Texas A&M University.
Located at the Texas A&M Health Science Center, the 21-acre facility will house 145,000 square feet of biomanufacturing space that will be built and managed by G-Con.
Project GreenVax, which uses tobacco plants rather than the current egg-based or cell-based vaccine technology, could shorten vaccine production to a fraction of the current time, allowing rapid response to newly emerging viruses. Eventually the consortium hopes to produce 100 million vaccine doses per month.
Earlier, Xcellerex entered an agreement with SK Chemicals one of South Korea’s largest conglomerates, to commercialize SK-developed vaccines with Xcellerex’ FlexFactory® biomanufacturing platform. At the time, SK’s CEO Chang Geun Kim noted that the flexibility provided by disposable bioreactors would accelerate development and commercialization of his company’s cell culture-derived influenza and pneumococcal conjugate vaccines.
FlexFactory is based on the combination of single-use technologies, controlled-environmental modules, and process automation including electronic batch records. The company’s TransPlant services facilitate installation, validation, and operation of FlexFactory-based manufacturing plants.
G-Con president Barry Holz said that the XDR system was chosen because of its “competitive capital costs” and lower operating costs compared with stainless steel bioreactors.