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.