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Feature Articles : Aug 1, 2010 ( )
Disposable & Reusable Manufacturing Trends
Room Exists in Growing Market for Both Single-Use and Stainless Steel Systems!--h2>
Demand for single-use, disposable technology for unit operations such as buffer and media preparation, seed culture production, and virus inactivation, as well as for process development and manufacturing for both cell culture and microbial fermentation continues to increase. Mike Sattan, vp of marketing at New Brunswick Scientific (NBS), describes a growing shift “away from glass vessels—and the cleaning and validation required—and toward scalable single-use stirred tank bioreactors for R&D, process development, and production of seed cultures.”
Single-use systems are “especially advantageous for process development,” says Ken Clapp, senior director, global marketing and product management at Xcellerex. They allow users to increase or decrease process scale, and to modify sparging, the number of probes, and the types of probes without having to completely change the system.
Another continuing trend “is a huge demand” for real-time information and control through the ability to integrate and interface remotely with supervisory systems and analyzers, says Matthias Arnold, Ph.D., CSO at Dasgip. The ability to achieve on-stream feedback and process control will help to advance PAT and QbD initiatives.
Leveraging the capabilities of the recently released Apple iPad™, Dasgip, which specializes in benchtop, parallel bioreactor systems for process development, introduced an iPad application for its Remote Control Suite that enables online bioreactor control.
The company’s new iApp allows users to monitor and control process values in as many as 16 parallel reactors running at locations around the world. Display options include a choice of multiple windows, zoom, and rotation functions. A graphic timeline makes it possible to compare historical and real-time process data, and trend charts provide views of reference and process values as well as the control profile.
Understanding the process “is all about information,” says Dr. Arnold; it requires precise, relevant, and reproducible data and access to the information in real time. Dasgip designed the iApp for two scenarios: remote monitoring of the control system—including data, process values, and alarms—from within the company; and mobile access from anywhere there is Internet access with an interface that allows for remote control of processes by individuals with the appropriate access level.
Modularity Enhances Flexibility
“We continue to see growth in both the stainless steel and single-use markets, with increasing interest in biologicals, especially from biotech companies in China and India,” says Doru Felezeu, director of marketing and business development at Pierre Guerin Technologies. He also notes that “interesting applications are developing in green biotech along with a demand for reactors suitable for producing algae and biomass.”
To satisfy market demand for greater flexibility and modular system design, Pierre Guerin, through its Biolafitte division, introduced the TRYTONi™ series of open-design, modular, autoclavable bioreactors that can be used for cell culture or microbial fermentation.
This industrial version of the company’s TRYTON series of bioreactors is scalable from 1 L to 50,000 L. It is also waterproof and features a touchscreen user interface. Users can add or remove individual modules to customize the system for more or less complex operations. A key focus at Pierre Guerin over the next six months will be on the development of new software tools for process control.
In June, Xcellerex began construction of a new biomanufacturing facility at its Marlborough, MA, headquarters to expand its contract services operations. This is the company’s second facility that will house its FlexFactory® modular single-use bioprocess manufacturing platform, in which unit operations are self-contained in their own controlled environment modules, eliminating the need for cleanroom facilities.
Xcellerex and Pfenex announced in May that, together with their collaborators, they had demonstrated the capability to produce purified swine flu H1 hemagglutinin in 42 days, starting with the protein’s amino acid sequence. For this 24-month project funded by U.S. government defense agencies, Xcellerex contributed its microbial PDMax™ high-speed process-development system and its FlexFactory single-use manufacturing technologies to grow microbial production strains to high cell densities and to purify model vaccine and antibody molecules.
Earlier this year, Xcellerex announced a collaboration with Humacyte to develop a manufacturing process for Humacyte’s lead regenerative medicine product—vascular grafts for transplantation—using Xcellerex’ XDR™ single-use bioreactor system on the FlexFactory platform.
In development at Xcellerex is a redesign of the 50 L single-use vessel for the XDR system. The company has completed conversion of its 200 L, 500 L, 1,000 L, and 2,000 L vessels to a modular design. “This gives users more flexibility to locate the vessel remotely from the control system,” says Clapp.
Xcellerex also completed a redesign of its controlled environment modules to support upstream and downstream unit operations in the FlexFactory, incorporating a modular design for ease of scale-up and added capabilities to control chromatography, filtration, seed reactors, and bulk handling of the biological products. Also, the new control module is more readily compatible with plant-wide data-management systems to facilitate the flow of manufacturing and process data.
The primary local controller used to operate the XDR bioreactors is based on a Rockwell Automation platform, coupled with Wonderware human/machine interface software to support GMP operations with a server class computer, RAID, and built-in redundancy for improved protection of manufacturing data. For companies that utilize an Emerson DeltaV automation platform, Xcellerex offers the comparable functionality available with the Rockwell-Wonderware control system, allowing companies to integrate Xcellerex process equipment into their existing infrastructure.
Expanded Mixing Options
Sartorius Stedim Biotech continues to expand its single-use stirred tank reactor (STR) technology, which includes the Cultibag STR 50 L and 200 L systems. A 1,000 L system recently entered beta site testing. The Cultibag STR features a top-driven stirrer with magnetic coupling and is operated by the company’s Biostat® STR controller.
Sartorius also offers the Biostat Cultibag RM in scalable working volumes from 2 L to 600 L for low-shear mixing via rocking motion. Both the STR and RM systems are available in single or twin versions, have disposable pH and dissolved oxygen sensors, and include BioPAT® MFCS/DA data-logging software.
On the near horizon, says Maik Jornitz, group vp marketing, is the Cultibag-OBR, which will make orbital agitation technology available in a single-use system to facilitate scale-up of more sensitive cells that cannot withstand the shear forces generated in a stirred tank reactor. The orbital shaker Cultibag system will launch in the second quarter of 2010 with a 200 L and a 1,000 L unit.
Although “single-use bioreactors are a large portion of our product portfolio, I wouldn’t say they are dominating the market,” says Jornitz. Demand remains strong for the company’s multiuse, stainless steel reactors, and Sartorius Stedim Biotech is developing larger volume versions of its Biostat in situ sterilizable bioreactors, designed for clinical material and process-development applications. The company is planning new design features for its autoclavable reactor line.
“Most of our clients want an entire solution, not just a bioreactor.” They are looking to develop and initially scale up a process in a single-use system and then expand into a traditional stirred tank reactor. Companies need to take more of a “process view, not just a product view.”
New Brunswick Scientific’s CelliGen® BLU stirred tank bioreactor system is available with single-use vessels in 5 L or 14 L total volume capacities. The vessels utilize a noninvasive sensor technology in which the optical pH probe and reusable DO probe each fit inside a protective sleeve to prevent them from coming in contact with the contents of the vessel. “This elegant adaptation significantly reduces turn-around time between runs and eliminates the risk of contamination due to probe insertion,” says Mike Sattan.
“As single-use reactors are increasingly being used for scale-up of processes and production of seed cultures for manufacturing, we offer full validation packages including IQ/OQ [installation qualification and operational qualification] and material test reports for leachables and extractables needed for use in GMP applications.”
NBS plans to introduce additional vessel sizes to the CelliGen BLU line and to add packed bed capability with its FibraCel® disks to enable operation in perfusion mode for production of secreted proteins.
NBS and Pall recently announced a joint product development and marketing agreement to produce new disposable bioreactor systems combining the capabilities of Pall’s Allegro™ single-use biocontainer platform and the NBS CelliGen® bioprocess controller; the systems will be suitable for applications ranging from process development to cGMP manufacturing.
In September, Applikon Biotechnology will introduce the Rambio® shaker-incubator, which utilizes ResonantAcoustic® mixing technology to achieve the high oxygenation levels required by microbial cultures to obtain high cell densities and protein-expression rates. High-intensity acoustic energy vigorously mixes the contents of the culture flasks, and the Oxy-Pump® Stopper in the mouth of each 250 mL shake flask acts like a piston for active pumping of air into the flasks.
For small-scale parallel cultures, Applikon’s MicroFlasks contain 24 or 96 individual deep, square wells on a plate that is loaded onto a standard orbital shaker incubator. Designed for high-throughput, parallel cell culture screening, MicroFlasks “provide oxygen transfer rates equal to baffled shake flasks,” according to the company. The wells are sealed to minimize evaporation, prevent cross-contamination, and optimize gas exchange.
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