During a year marked by global financial recessions and uncertainty, one can look to the biotech industry—the bioprocessing sector in particular—as a bright spot, with manufacturers of bioreactor and fermentor systems reporting continued strong growth.

Despite shifting fortunes between some subsectors of the market, performance has, in general, been stable or on an upswing in both the conventional stainless steel and glass reusable reactor markets and in the evolving single-use sector. In fact, a comfortable balance seems to have been reached in which these technologies are concurrent rather than competitive and are jointly spurring growth in the overall market.

Vendors are expanding the range of options offered and the flexibility of systems, allowing users to experiment with different combinations of bioprocessing components for R&D through pilot-scale and commercial production, mixing and matching strategies and systems to find the best solution for a particular application.

“The market continues to grow,” says Ken Clapp, senior product manager, single-use bioreactors, Xcellerex (part of GE Healthcare Life Sciences), and single-use and conventional re-usable systems continue to co-exist.”

Although single-use cell culture is well-established, especially in process development, with use in production scale expanding, “there are certain processes today that cannot be run in single-use, for myriad reasons.” At Xcellerex, product development has been driven largely by continuing demand for the company’s FlexFactory® and XDR bioreactor products.

“Demand has been strong at all sizes. However, small- and large-scale systems have exceeded the middle range,” says Clapp. “Demand at the two ends of the spectrum has been driven by single-use-based process successes across the globe. The small scale is also driven by customer pipelines, burgeoning with new therapeutic candidates. The increase at the large scale is the result of all the biologics that have come up from smaller scales and/or have transitioned from conventional.”

Striking a Balance

“The debate between stainless or single use has reduced as the industry has gotten on with the business of implementing flexible single-use manufacturing process flows for volumes up to 1,000 liter,” says Barney Zoro, product manager at TAP Biosystems. “For larger volumes, practical issues such as bag handling still favor larger stainless facilities for large-scale production.”

“We clearly see growth in the single-use bioreactor area, higher than in the classical glass and stainless steel sector,” says Christel Fenge, vp fermentation technologies at Sartorius Stedim Biotech.

“On top of the strong single-use growth, in 2011 we also saw quite significant growth in the benchtop systems, mainly driven by Asia—and in particular Korea, which is strongly investing in development programs for biosimilars that use large numbers of benchtop bioreactors operated in parallel—with nice contributions also from Europe and the U.S.”

The company hopes to further boost benchtop systems sales through the recent introduction of its new generation of Biostat B process development bioreactors. The system can operate both traditional glass and single-use vessels equipped with optical pH and DO probes to minimize contamination risk associated with existing single-use benchtop systems.

“We believe the industry has not yet reached a plateau of growth in single-use bioreactors,” she says. The sweet spot is in the 50–200 L and up to the 1,000 L scale. Fenge describes growing investments by CMOs and pharma companies that want to create multipurpose clinical trial facilities, moving products up from the evaluation stage; they are looking for technology that will help them achieve greater efficiency in product development, to accelerate changeover times, and to skip cleaning and related qualification steps in making clinical trials material.

“Some manufacturers are starting to adopt single-use technology for commercial manufacturing, but I think it is still the early days in that area,” adds Fenge.

The entire single-use market has been growing about 15–20%/year and “is primarily being used for pilot–clinical scale production,” reports Mani Krishnan, director of processing systems at EMD Millipore.

“Our customers are particularly interested in integrating fermenters or bioreactors from 10 L (seed) up to 1,000 L, 5,000 L, and more,” says Doru Felezeu, marketing & business development director, Pierre Guerin.

“As a supplier of both technologies (traditional stainless steel and single-use equipment), we have observed a ‘pause’ in single-use investments due to the weaknesses of this technology in term of security of persons and products, scalability, and operation (a lot of manual operations are required versus a stainless steel full automated system),” says Felezeu. “However, depending on the process and application, some companies still invest in such technologies.” He notes a trend toward increased mixing of traditional and single-use technologies.

Erik Kakes, international sales and marketing director, Applikon Biotechnology, reports substantial growth on the production-scale side in the Far East, particularly China and India, as well as a lot of investment in R&D systems in China as companies there increase their focus on internal product development.

“In Europe, we are seeing an increase in the single-use market, mirroring the growth we previously saw in North America. China is also looking in that direction,” says Kakes.

Clapp of Xcellerex notes that “with more and more customers switching to or using single-use, they are expecting options analogous to those on conventional systems: e.g., exhaust condensers, foam management, more agitation choices, etc. The need to integrate more and better process analytical technologies has a big effect on single-use innovation. This has been a clear signal of single-use acceptance.”

ATMI reports particularly strong market growth in the human therapeutic protein and veterinary vaccine sectors, where there is a strong trend toward single-use technologies. Cell therapies are another important growth area, and ATMI is focusing on optimizing the microenvironment in which the cells grow, including shear force and mass transfer of oxygen, to improve reactor efficiency with an increasingly smaller footprint.

“The market values innovation for improved efficiency while also asking for a standardization of technologies,” says Jeffery Craig, global director of business development and marketing at ATMI.

“Single-use technologies offer compelling value but are a long way from engineered standards such as connectivity of one technology to another, vessel design, or the interchangeability of one unit operation with another. These types of standards tend to evolve later in the industrial cycle of manufacturing technologies. Importantly, standards that involve patient safety such as leachable and extractable profiles are evolving more quickly.

“I think it’s interesting that there is a debate about whether standards stifle innovation or drive industrialization,” Craig says. “The industry needs to put its collective heads together to industrialize like the microelectronics sector, for example. Experience shows that standards help industries to grow, and I assure you that we can expect ongoing innovation by driving standardization.”

Customers want single-use systems that are easier and more reliable to implement, and that offer the types of options and advances they’ve come to expect with reusable processing equipment, according to Krishnan of EMD Millipore. The key goal is to make the technology easier to use.

Whereas with conventional systems the main difficulty is cleaning, preset protocols are well-established, and users already have years of experience doing this. “With single-use you are installing the single-use component for every batch. You are introducing new variables that the operators do not have a lot of experience with,” says Krishnan. They have to install the components the correct way every time, and they are looking to the supplier to make that as easy as possible.

“Despite an increasing demand for single-use bioreactors, stainless steel and glass bioreactors are still our bread and butter business,” says Fenge of Sartorius Stedim Biotech. The company recently introduced its Biostat D-DCU line of configurable stainless steel bioreactors up to 200 L volume. Options range from basic batch setup configurations that support advanced gassing and feeding strategies, clean-in-place, and automatic transfer of seed to a larger bioreactor or sterile harvest into a stainless steel vessel or single-use bag.

When it came to designing its single-use bioreactors, the company sought to design them as similar to existing stainless steel or glass systems as possible in terms of factors such as bioreactor geometry (height-to-diameter ratios, impeller-to-vessel diameter ratios, and impeller design, for example). The result is the company’s stirred tank single-use bioreactor, the Biostat STR (50 L to 1,000 L) and Univessel SU (2 L), which are intended to provide seamless technology transfer from benchtop bioreactors to single-use pilot-scale systems, and from single-use to existing large-scale stirred tank facilities.

Trending Downward

Kakes of Applikon sees a trend toward more scale-down, with the goal of getting more data more quickly for process development at small scale. “In the old days, you would do screening in shake flasks and try to select the best-producing strain based on a lot of cultures and very little data on the process.”

Now the emphasis is on collecting more data at small scale in shake flasks or microtiter plates to make better data-driven choices. “What we used to do at the 3–15 L scale, we can now do in mini-bioreactors at 50–250 mL scale, and I think in the future will be even smaller.”

Applikon introduced its mini-bioreactor product line in 2011 and, at the time, predicted that “it would cannabilize part of our classic laboratory line that we have been selling for 30–40 years,” says Kakes. “But on the contrary, we are selling a lot of the mini-bioreactors, and it has boosted the sales of the standard lab line. Customers can now go from initial screening done in microtiter plates through the minis and lab scale and up into production scale with either single-use or reusable technology.”

“We see a clear trend for a greater number of bioreactor experiments,” says Zoro of TAP, which offers the ambr™ advanced microscale (10–15 mL) bioreactor system. He identifies cost and other practical issues as limiting factors in the number of parallel benchtop reactors a company can manage. Greater reliance on automated microscale reactors is an increasingly popular strategy for improving bioreactor experiment throughput, according to Zoro.

“Ongoing pressure to decrease time to market and progress more projects within the same teams continues to drive efficiency increases in process development (PD) workflows,” he says.

“Optimized clone screening and process development schemes are increasingly sophisticated, with higher-throughput approaches for early screening and PD tools. These include smaller-scale fed-batch models, greater use of automation, and implementation of microscale reactors, enabling bioreactor design of experiment (DoE) studies for both media and PD.”

“Many biopharmaceutical companies are taking strategic positions in the biosimilar space, building capability in this area either via aggressive (biosimilar) or defensive (biobetter) approaches,” says Zoro. “In either case, key tools required include a scalable early model for clone screening on the basis of product quality and a platform for DoE bioreactor studies to enable rapid optimization of media and process conditions to achieve product quality targets.”

“The past five years in particular have seen increasing demand for parallel bioreactor systems, driven by overall fast growth in the bioprocessing market and ongoing demand for shorter bioprocess development times,” says Kathrin Schmale, Ph.D., strategic marketing manager at DASGIP Information and Process Technology, which manufactures parallel bioreactor systems and was acquired by Eppendorf earlier this year.

DASGIP is operating under the assumption that users want all-in-one solutions that combine bioprocessing hardware, process control, and a range of software functionality for data management, analysis, and storage.

“We believe users are looking for all-in-one solutions that combine bioprocessing hardware, process control, and a range of software functionality for data management, analysis, and storage, as well as DoE and automated processing by interconnectivity with third-party lab devices,” says Dr. Schmale.

Despite growing interest in single-use systems for bioprocess development applications, “I feel that there is no shift from glass to single-use bioreactors up to now,” she says.

“This is mainly due to economic factors: in R&D and PD applications, where usually multiple bioreactors have to be operated in parallel, the reduction of setup times correlated with single-use bioreactors does not add up with the current relatively high purchase costs. As long as there is no economic attractive solution available for these applications, the market will choose reusable bioreactors. But I am convinced that we can expect a broader range of single-use solutions with a better price-performance ratio in the near future.”

“Single-use replacements for glass benchtop reactors have had a modest uptake, as the incremental benefits in time saving vs. autoclavable reactors are limited; experimental throughput is not substantially increased. By contrast, use of automated disposable microbioreactors is rapidly becoming standard industry practice, due to improved scalability of results vs. shaken models, combined with improved data consistency and an order of magnitude increase in the number of reactors each scientist can operate, greatly increasing bioreactor experiment throughput,” says Zoro from TAP.

Trending Forward

Infors has been expanding its focus beyond the traditional markets of cultivating microorganisms and cells for biopharma applications, adding dedicated technology targeting second- and third-generation biofuels development and photosynthetic applications. Infors developed the laboratory-scale Labfors 5 BioEtOH bioreactor for the second-generation bioethanol sector, allowing for simultaneous saccharification and fermentation.

Mixing of the pretreated lignocellulose slurry prior to enzymatic hydrolysis into a liquid form is a critical and challenging step. “To solve this issue, different kinds of impellers have been developed and a special motor was designed to fulfill both the different needs of the high viscous slurry and the liquid after hydrolysis,” says Daniel Egger, marketing manager, Infors.

To simulate sunlight in the laboratory for photosynthetic applications, the company developed the Labfors 5 Lux illumination system for small-scale algae photo bioreactors. High-powered LEDs produce irradiation as strong as bright sunlight and an irradiation spectrum that approximates sunlight, according to the company. Its Iris parallel bioprocess software can simulate the day/night sunlight curve of the irradiation unit.

Infors created the Multitron Cell incubator shaker system to facilitate better growth of suspended cells.

Later this year, Infors plans to introduce an automatic cleaning and sterilize-in-place feature (LabCIP) to its Labfors 5 benchtop glass bioreactor line (for sizes 2 L–13 L total volume) and, working with an industrial development partner, has shown that it can be used to double productivity. This will offer a sterilizable option for microbial bioprocessing in a reusable system.

Kakes predicts future growth and standardization in sensor technology. Users still often rely on classic sensor technology because they are not yet confident in the new single-use sensors, in Kakes’ view. To facilitate the transition, Applikon integrates both options into its systems, so users can run a bioreactor initially using classic sensors and then, “when they are confident that the new technology gives the same results, they can switch over to the single-use sensors.”

Looking toward the future, Applikon is developing new types of sensor technology, in particular optical sensors capable of cell-image analysis. During the second half of this year, the company will also introduce a new data-analysis system for easier data integration and processing.

EMD Millipore recently introduced the Mobius CellReady family of single-use bioreactors, which includes 50 L and 200 L sizes. The design of the single-use bioreactor process container includes a rigid base and top panel to simplify and ensure the accuracy of its installation into the stainless steel holder. “We created the base and top panel slots to make the installation process easier,” says Krishnan. Users can only install the bag one way to minimize the chance for errors.

To further enhance the flexibility of single-use systems, EMD Millipore has taken sensors away from the bioreactor and built them into an external loop system that users can configure as needed, reducing the need to customize bags.

Millie Ullah, senior global product manager for bioreactors at Thermo Fisher, highlights two main trends in the bioprocessing market: customer demand for increased standardization and for more components to support process analytical technology (PAT). For PAT the emphasis is on emerging single-use sensor technologies to measure parameters such as pH, dissolved oxygen, metabolites, biomass, and carbon dioxide.

The drive toward standardization is twofold, focusing on connectivity and integration between different products upstream and downstream of the bioreactor, and secondly standardization of the regulatory and quality aspects of supply chain for traceability.

Standardization of system design presents a dilemma. “Although many people want standardization of products, at the end of the day, it does not work for everyone’s process, and in the end we find that customers want to customize to their process specific needs,” says Ullah. Different single-use systems will necessarily have different designs, depending on what type of cell culture processes they are optimized for, such as microcarrier-based cultures or perfusion processes.

While Thermo Fisher has been focusing much of its product development on meeting the varied needs of bioreactor systems, it offers customers the choice of off-the-shelf products with shorter delivery times or of process-specific products tailored to a particular application.

New to the Thermo Fisher bioprocessing line this year is the HyPerforma Single-Use Bioreactor (S.U.B.) Turn-Key (TK) system that combines either a 50 L or 250 L S.U.B. bioreactor with an integrated controller platform composed of PC and Delta V controller systems from Finesse. The company also introduced the second-generation S.U.B., with an updated look and added features.

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