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Nov 1, 2010 (Vol. 30, No. 19)

Disposable Bioreactors Enter Mainstream

Single-Use Systems Slowly but Surely Gaining Acceptance in Critial Unit Operations

  • Click Image To Enlarge +
    The XDR single-use bioreactor line from Xcellerex ranges from 50 L (shown) to 2,000 L. All systems are GMP ready and directly scalable.

    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.

  • Smaller Bags Still the Sweet Spot

    Click Image To Enlarge +
    GE Healthcare reports that its Wave Cellbag bioreactors and ReadyCircuit assemblies are quickly configurable with ReadyToProcess filters, including both cross flow and nominal flow, for sterile bioprocessing operations.

    While some suppliers have demonstrated the feasibility of 1,000 and even 2,000 L bioreactor bags, smaller units remain the largest group in terms of sales. In fact rather than being held back by disposables’ real or imaginary size limitations, suppliers are embracing the technology’s unquestioned benefits, particularly for development groups. A good deal of innovation is occurring within the 500 L and smaller category as well.

    GE Healthcare’s 2007 acquisition of Wave Biotech provided what Gerard Gach, director of marketing for RTP (Ready to Process) at GE, calls “a great foundation” in the disposable bioreactor marketplace. While GE remains committed to the Wave product line and its 500 L working volume limit, the company is “exploring other platforms.”

    Gach admits that while demand exists for disposable bioreactors of 1,000 and 2,000 L working volumes, the sweet spot for 500 L bioreactor bags continues to grow.

    Rising volumetric productivity has greatly expanded markets for the small-by-comparison Wave bioreactors. Five hundred liters is not such a small process volume for many vaccines and diagnostics, and serves clinical programs for many therapeutic proteins as well.

    Gach notes that the decline of the blockbuster model and the rise of targeted and personalized treatments means that batch sizes will continue trending downward to serve shrinking patient populations. And where 500 L is too small, several Wave reactors may be daisy-chained.

    Not unnoticed by GE in the discussion of cell culture sizes and throughput is the impact of upstream processing on downstream operations, particularly with respect to process bottlenecks. Running smaller batches helps processors synchronize upstream and downstream events.

    “Many people who saw the 500 liter limit as a shortcoming are reassessing that opinion,” Gach reports.

    The recent flurry of activity around small, benchtop-capable reactor bags suggests that this market is far from exhausted.

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