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Oct 1, 2012 (Vol. 32, No. 17)

Up- and Downstream Go Single Use

  • Single-use bioprocessing product lines made their debut mainly in the form of disposable bags for mixing and buffer supply. They gradually moved into the heart of the bioprocess stream with the emergence of single-use bioreactor systems.

    Single use has more recently made inroads in downstream process flows for separation, purification, and fill and finish applications. This evolution in the industry is clearly illustrated at bioprocessing conferences, in which presentations highlight the range of product areas and biopharmaceutical R&D and manufacturing applications targeted by single-use technologies.

    Examples include IBC’s recent “Single-Use Applications for Biopharmaceutical Manufacturing” conference in San Francisco, and Visongain’s upcoming “Single Use Bioreactor” conference in London. Compared to early single-use bioreactors, which were essentially disposable bags mounted on platforms to achieve mixing, the emerging, more complex generation of single-use systems more closely mimic conventional stirred-tank glass and stainless steel bioreactors. They incorporate impellers, sparge lines, and sensors for better control of process parameters and have aspect ratios that mirror those of traditional stirred tank reactors.

    With the launch of its new ambr 250™ mL automated, scalable, single-use bioreactor system in August, TAP Biosystems aimed to increase the complexity and functionality of single-use bioreactors for use in process development while maintaining their ease of use in terms of set-up, operation, and user interface.

    Andrew Tait, product development scientist at TAP Biosystems, will describe the company’s new technology and how it achieves these dual goals in his presentation at the Visongain conference.

    Meeting its initial goal meant providing core stirred tank bioreactor technology for both microbial and mammalian applications, with an impeller and width-to-height ratios of conventional steel bioreactors. The system’s single-use bioreactor incorporates gas and liquid supply lines with connectivity to the bioreactor control unit.

    The system is configurable for automated, independent, parallel control of 12 or 24 bioreactors, each with a maximum working volume of 250 mL. Each bioreactor can be individually controlled for temperature, pH, and dissolved oxygen, has four liquid feed lines, and off-gas analyzers for microbial applications. Up to 24 bioreactors are integrated into a dedicated biosafety cabinet.

  • Facilitating Flexibility

    Click Image To Enlarge +
    The FlexFactory flexible platform enables biomanufacturers to accelerate deployment of new manufacturing capacity while lowering risk, decreasing time to market, and reducing capital costs, according to Xcellerex, which reports that the approach enables the deployment of new production facilities in 9 to 18 months at a total cost less than 50% that of conventional plants.

    The main advantages of single-use systems are flexibility and speed to a functional, multiproduct facility, reduced footprint, elimination of clean-in-place, sterilize-in-place protocols, reduced water use, and increased overall throughput and productivity, according to Joe Makowiecki, senior manager, purification process development at Xcellerex.

    The primary limitation at present is scale. “We are at the 2,000 liter single-use bioreactor scale already, and then from harvest all the way down to bulk drug substance it is single-use, except for the chromatography resins,” he said.

    Single-use pumps are gradually replacing peristaltic pumps, offering low shear and flow rates >150 L/min, with tubing sets available up to 1 inch in diameter. Flow capacity for sensors is lagging a bit behind—ranging from about 20–80 L/min—but is slowly increasing.

    Makowiecki pointed to several key trends driving technology development in single-use bioprocessing, including high-titer expression systems resulting in increasing amounts of biomass for downstream processing, and higher flow rates leading to, for example, the development of membranes with higher binding capacity.

    Emerging on the market are new types of sensors, multicolumn chromatography, and “smart” mixers for automated adjustment of pH and conductivity. “Smart mixers will be ubiquitous in downstream processing,” predicted Makowiecki.

  • Click Image To Enlarge +
    Thermo Scientific HyClone Single-Use Bioreactors shown in a process- development lab illustrating their modularity and scale-out potential.

    “Flexibility is one of the hallmarks of single-use, and that bleeds into economics,” said William Whitford, senior manager at Thermo Fisher Scientific. “Single-use lends itself to varying production schedules,” easing not only normal operations, but making it easier and faster to mothball equipment or establish surge capacity.”

    Minimizing up-front expenses reduces risk if a product fails, noted Whitford. In a new or expanded facility, single-use systems can reduce initial plumbing needs, the cost of having to validate complex cleaning systems, and the personnel needed to operate and maintain those systems.

    “As a CMO, we have to be as flexible as possible,” to be able to operate a multiproduct facility at different scales, said Kai Lipinski, Ph.D., head of cell culture and virus production at Vibalogics. “We do not want to invest in equipment for one client that we might not use again.”

    There are a “lot of restrictions currently for scalable adherent cell culture for virus and vaccine production,” continued Dr. Lipinski.

    Several commercially important anchorage-dependent cell lines are not adaptable for suspension culture, noted Dr. Lipinski, including WI-38, A549, MRC-5, VERO, and CEF cells. Existing planar systems that support adherent cell culture such as roller bottles, T-flasks, and cell factories are labor intensive.

    Vibalogics has performed studies using VERO and A549 as model cell lines to assess virus production when the cells are grown in the ATMI iCELLis™ semi-single use cGMP nano bioreactor system. Instead of containing a donut-shaped basket as in ATMI’s fully single-use, commercial-scale iCELLis 500, the nano system has a cylindrical fixed bed composed of the same polyethylene terephtalate microfibers. Linear scalability between the systems is given as the bed height is the same, explained Dr. Lipinski.

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