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Aug 1, 2008 (Vol. 28, No. 14)

Flexibility Crucial in Bioreactor Systems

Capacity and Technological Innovations Drive the Market

  • The declining value of the dollar has benefited U.S. suppliers in the bioreactor and fermentor market overseas, according to Dick Bonyun, vp of sales and services at ABEC.

    “In the last year, bioreactor sales were at an all-time high,” Bonyun says. “Sales have been robust and definitely the best in recent memory, more global from a distribution standpoint. The value of the dollar has worked in our favor to give us more opportunities in the global market and bring greater value to overseas customers.”

    Mike Sattan, vp of marketing at New Brunswick Scientific an Eppendorf company, concurs on the banner-year status. “We are having a record year in all systems,” he reports. “Our overall business in both cell culture and fermentation is strong, from bench scale through our pilot (3,000 L) systems.”

    While sales are increasing, some report that volumes are starting to decrease. In the last few years, ABEC’s capacities and reactor volumes have both increased, explains ABEC’s Paul Kubera, vp of engineering, “but the technology is improving, and it is now possible to grow culture to higher densities and achieve higher product titers in smaller reactors. We are seeing a little of that. But clients are still building 10,000+ L bioreactors; that has not changed.”

    “Specifically in the bioreactor area,” notes Nigel Darby, GM, biotechnologies, GE Life Sciences, “If we look at it from the macroperspective, the big question five years ago was whether there was going to be a capacity crunch. That’s driven a lot of activity to build plants with high volume capacity. The monoclonal antibody market has been a key driver in maximizing capacity, but as capacity has been built, technology has evolved.

    “Historically, antibody expression was low, less than a gram a liter. We’re looking now at 5–10 grams produced per liter, requiring smaller overall manufacturing volumes, which has produced an interesting debate about how to utilize available capacity. As culture volumes potentially decrease, people are looking to use their available capacity more flexibly and there is substantial interest in developing flexible multiproduct facilities.”

    Howard Weber, director of sales and marketing at Applikon Biotechnology, agrees that the market seems to be getting smaller, not in sales but in volume. “Scientists are looking for more information and higher throughput—titers that are up to 4 g/L.”

    Applikon has two new products that address the smaller volume issue and provide increased information.

    “We have the Micro-24 for screening and testing of new cells and new strains, and optimizing media when you move to more expressive lines. The Micro-24 provides 24 individual bioreactors that allow independent control of pH, DO, and temperature with agitation from 0 to 800 rpms. All this with a volume of 7–10 mL. The system has shown excellent results with many cell lines including microbial, insect, and CHO cell lines,” Weber says.

    “The second product is the Micro Flask. This product uses either 24- or 96-well plates. The investment is small as the system uses existing orbital shakers already found in the lab. The results are as good as or better than shake flasks, and you receive hundreds of results instead of a few dozen thus, much more information in the same space and time.”

    Applikon and Aber Instruments recently inked an agreement for the exclusive supply of an integrated bioreactor controller and sensor for viable cells. Applikon will offer the viable cell sensor and controller option in its ez-Control bioreactor controller portfolio.

  • Microbial Applications

    Millie Ullah, product manager, disposable bioreactors at Sartorius Stedim Biotech, notes that the development of single-use bioreactor technologies are focused on bringing new designs into the market for effective oxygen transfer and cultivation of, not only cell culture processes, but also of microbial cultures.

    Demand and interest are growing in flexible, scalable systems due to capital and labor cost savings and reduced cross contamination, she says. “Disposables can be limited in size, but the limits continue to expand upward. We currently have a a disposable stirred tank bioreactor that utilizes disposable sensor technology under development with a number of partners.”

    Ullah also reports that disposable sensor technology is now capable of controlling cell culture systems. “Utilization of superior gas-mixing systems and tighter process control in a disposable system can be used to cultivate microbial cells successfully. Cell culture has always been strong, but now there is a strong interest in microbial systems, as well. This trend will continue as products inreasingly show comparable or better growth and productivity in disposable systems. The most successful disposable bioreactor designs will be those that closely mimic a traditional bioreactor in shape, form, and function.”

  • Eyes on Vaccine Production

    The vaccine market is another area to follow, reports Darby. “Concerns about bioterrorism, emerging diseases, and influenza pandemic make it necessary to think about bioreactor capacity, flexibility, and turnaround. Interest in this area is definitely on a large scale.”

    NBS equipment is currently used in the production of several vaccines including rabies vaccines, reports Sattan. “In the United States, we are also seeing increasing customer demand related to the PAT initiative,” he adds. “Regulatory agencies are pushing for more automated batch control through SCADA and the inclusion of external sensors. This is done to minimize the possibility of human error and variability.”

    Sattan has also seen growth in the cell culture arena, citing greater customer flexibility, adding additional probes, scales, pumps, and metabolite analyzers to enhance their research and production. “We recently introduced the BioFlo and Celligen 510 fermentor and bioreactor in 19.5 L and 40 L sizes,” Sattan explains. “This stainless steel, fully SIP system for pilot-scale work allows customers to choose the options they need now, add options in the future as their needs change, and integrate numerous ancillary probes or other equipment.”

    Xcellerex is also involved in the vaccine market. “The flexibility factor is going to serve us well, especially as the vaccine market continues to expand, says Joe Zakrzewski, CEO. “One of the things we are looking to do is to make it possible to create three million doses of vaccine in a 12-week period in the event of a flu pandemic. Since our bioreactors run on air, water, and electricity it’s conceivable that you can have this bioreactor flying around on a 747 making products.”

    The impact of disposables in small volume production and seed train use is significant, according to Kubera. “Plants are being designed with disposable bioreactors up to the 500–1,000 L sizes.” He notes that some companies are looking for greater volumes at 2,000 to 5,000L. “Anything greater than 1,000 L in the biodisposable space is in development right now—not in production.”

    In fermentation, Sattan insists that stainless steel is still king due to the short runs, high mixing speed, and high cell concentrations. “The industry is definitely headed toward disposables on the bioreactor/cell culture side with more stirred tank designs replacing the rocking bag method. I think this trend will continue as more advanced, stirred tank designs are produced that mimic the stainless steel tank systems that are so widely accepted.”

  • Advances Work Their Way Upstream

    Another trend is the increasing involvement of downstream providers in the upstream market. GE’s acquisition of Wave technology dovetails with some of the developments it has experienced downstream, Darby says. “We have primarily been a downstream company, but we are increasingly interested in disposable bioreactors.” As expression levels for antibodies are increasing, disposables have advantages over stainless steel, and as a result, disposable technology is pretty hot at the moment.”

    For its part, Xcellerex has essentially three businesses: service, equipment, and biologics. “We sell downstream and entire systems from bioreactor to final purification. We call them Flex Factories; they are disposable, cost effective, and provide for customers expertise in streamlining processes. We use the CMO service piece to drive the other two businesses,” continues Zakrzewski.

    “Our service business feeds 200–2,000 L bioreactors. We get the same results as stainless steel about 75% of the time and 50% of the cost. And, we can get our equipment online immediately, cutting capital costs.”

    Zakrzewski notes that Xcellerex has ready-to-sell 2,000 L products on the market now. “Next year, we hope to get 5,000 L capacity up and running. People are looking for scalability, not size. We can sell bioreactors or the entire Flex Factory. We can grow E. coli, yeast, CHO, insect, blue-green algae, fungi, and Pseudomonas organisms of all scales.”

    NBS has focused on its RPC Reactor Process Controller, the heart of many NBS fermentors and bioreactors. “This controller allows great flexibility in our users’ processes, enables them to add additional equipment such as gas analyzers or scales, and integrates data directly into the fermentor’s or bioreactor’s control strategy,” says Sattan. “It monitors the process, complete with alarms and data logging, and it provides sophisticated cascade and control flexibility to optimize processes.”

  • Looking Ahead

    “This is a billion dollar industry and a supplier needs to be in a position to take advantage of that opportunity,” says Bonyun. “Customers are looking for reduced delivery times, and the average time-to-market is dropping.

    “ABEC is in the process of two major capacity expansions so that we are in a position to respond to delivery demand. We see increased involvement on the part of our clients—they put together an assembly team, users, and quality personnel—as much activity as can be pushed upstream to document and QC, executing to make sure nothing has changed—all of this goes with an eye toward equipment not only installed but ready to run.”

    In addition, companies are looking at improvements coming off the bench, according to Kubera.

    “They want to push more capacity, more product, getting the most out of what you have, looking for process-train optimization, locating and fixing bottlenecks, and doing all this around bioreactors and fermentors,” he says. “We are routinely pressured to move both upstream and downstream from the bioreactor and fermentor. There is a lot more heat in integrated turnkey processes—this all falls under the productivity umbrella.”

    Weber notes that there is more work to be done. “With more information coming up from small scale and the advancement of much more sophisticated controllers, increased value can be accomplished at the bench level with the 1 to 15 liter size bioreactors.”

    Customer support is key, Darby concludes. “If a customer wants a turnkey process, we can provide that and any support needed. It’s all about integrating what we know from our downstream experience and getting the upstream solutions in sync with them. We are in this space for the long-term and have an interest in providing the best products and the best solutions, both up- and downstream.”


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