Single-use technology (SUT), or disposable biopharmaceutical process equipment, is showing up in a growing number of biopharmaceutical development and manufacturing operations. Not only in downstream processes and filling, but in such newer applications as vaccine and biosimilar manufacturing, CMOs, generics and name-brand pharmaceutical companies are taking advantage of the savings in cleaning and cleaning validation that SUT can offer.
Typically, SUT is showing up in hybrid operations, used along with traditional stainless steel bioprocessing equipment. However, some manufacturers are emphasizing the use of disposable equipment throughout their facility designs, while vendors envision a day when entire facilities might be based almost entirely on SUT.
Plant experience with the equipment so far has suggested that SUT isn’t suitable for every operation. It’s useful in situations where there is a risk of cross contamination or material carryover, says Marc Pelletier, director of strategy for CRB Consulting Engineers’ Biopharmaceutical Solutions Group, who spoke on this subject at the Interphex conference in New York City last month. In such cases, he says, SUT reduces overall costs and timelines by minimizing the need for equipment cleaning and sanitization.
However, Pelletier noted, SUT is generally limited to biopharma operations of 2K Liter scale or less. In addition, he says, in applications such as solutions preparation, where there is often less of a need to maintain aseptic conditions, SUT may not be the best choice.
SUT continues to face challenges surrounding questions on quality, materials compatibility and integrity. Would-be users are also demanding better monitoring and analytical approaches for use with SUT, and suppliers are responding with statistical and sensor technologies, as well as installation changes that could reduce human error and potential contamination.
Among contract manufacturers who have recently invested in SUT are Fujifilm Diosynth Biotechnologies, whose mammalian cell culture cGMP manufacturing facility in Billingham, UK, which came online in 2013, emphasizes SUT in both upstream and downstream operations. SUT is also a prominent part of CMC Biologics’ multi-purpose, single-use facility in Seattle, WA, which handles early-phase clinical manufacture of biopharmaceuticals including monoclonal antibodies and other mammalian cell culture-based recombinant proteins.
Growth in Asia, Specialized Biopharma
Increased use of SUT is a global trend, says Christel Fenge, Ph.D., vice president of marketing and product management, Fermentation Technologies, at Sartorius Stedim Biotech. Starting from a base in contract manufacturing and biopharma multiproduct facilities, SUT now figures in more biosimilars manufacturing operations, because it allow users to adapt capacity to market needs. Process development operations are another new growth area, Fenge says.
Bioreactors, liquid and powder storage and transportation operations continue to see steady growth, according to Roman Rodriguez, global market development manager of Single Use Technologies at EMD Millipore. Cell therapy operations represent a new demand base, he says, while personalized medicine shows great promise.
There is huge demand for SUT in Asia, where many of the new biopharmaceutical facilities are being built, says Rodriguez. Most attractive to end users is the fact that SUTs have already demonstrated their ability to help reduce upfront capital investments and increase speed to market.
Also noting new applications for SUT, Ken Frank, president of Pall BioPharmaceuticals, expects to see SUT, not only in more formulation and filling operations, but also in clinical operations and more low-to-medium-volume facilities. The technology will be especially important, he says, for CMOs that require the greatest degree of flexibility and multi-purpose capability in their facilities.
In the future, Sartorius Stedim’s Fenge expects to see more fully single-use bioprocessing operations. “This trend is now overlaid by a growing demand for increased automation, she says. Not only is the market demanding new sensors to monitor and control processes in SUTs, but users are also using statistical approaches such as multivariate data analysis or design of experiments to help translate data into information and decrease project costs and timelines.”
Potential contamination of SUT by extractables and leachables is driving a move for greater quality assurance and product traceability. Materials compatibility is also a major concern. “Reliable and reproducible growth performance is an especially hot topic, as some users of single use bioreactors have reported occasional growth issues,” said Sartorius’ Fenge.
Biopharmaceutical companies have been vigilant about studying and reporting on these issues. Fenge notes Amgen, for instance, whose technical teams identified a growth inhibitor that they ultimately traced to an antioxidant used to make single-use bags. This compound can be generated when the antioxidant degrades, and can inhibit cell growth. Manufacturers of bioprocessing bags, especially single-use bioreactors, must be sure to control presence of this compound in a reliable, reproducible way if they are to prevent batch-to-batch variability, and ensure a rate of cell growth that is comparable to reference levels, Fenge says. “Quality continues to remain a key topic as more and more processes using SUT move into Phase III and commercial production,”Fenge says. “In essence, the industry is looking for strong assurance of supply, both in terms of manufacturing process control but also control and traceability of raw materials used for bag manufacture. Finally, integrity is key to ensure a contained process and protect the product.”
As SUT moves into more clinical-scale projects, it is also moving closer to the patient, making vendor quality control even more important. Extractables and leachables remain an issue, and a lot of activity has focused on improving robustness to avoid leaks and potential contamination, as well as to reduce particle contamination, says EMD Millipore’s Rodriguez. “A more recent trend,” he says, “is ensuring that processes are fully traceable, down to the components and contingency plans.”
Vendors are focusing on shipping, unpacking and installation areas, to prevent any problems that could result in leaks, and to address potential quality problems. Sartorius, for instance, offers new polyethylene film and its Flexsafe range of bags. It recently introduced Sartocheck4 Plus, a bag tester designed to help detect any mistakes that could generate leaks before cell culture. This approach is comparable to the pressure decay testing used for stainless steel bioreactors.
The latest SUT products include bioreactors, connectors, mixers, sampling systems and final fill solutions for the manufacture of biopharmaceuticals. Within a few short years, these single-use technologies have become widely accepted across the biopharma industry.
According to Mr. Rodriguez of EMD Millipore, “interest in SUT has moved downstream, and vendors have responded with products that, among other things, use a combination of single-use technologies and automated control and management systems.”
Sartorius recently introduced AMBR15, a single-use multiparallel minibioreactor with a working volume of 15 ml, which, Fenge says, enables clone and media selection and other early process development activities in a stirred tank format.
The AMBR250 is designed to handle the next step in process development, where more in-depth processes are performed and production parameters are established and optimized, very often multivariate experimental design approaches are applied.
It consists of 12 or 24 parallel vessels, where all liquid handling and sampling is fully automated, and Fenge says “it is designed to enable seamless scale-up and scale down to larger scale single-use bag based stirred tank systems.”
Vendors are also looking to improve the plastic films used to make SUT. “Most single-use technologies use a plastic film made of multi-layer films, very often with a Poly-Ethylene or EVA contact material layer,” noted Mr. Rodriguez of EMD Millipore. Driving development are demands for more inert, cleaner and more robust processes, and for better traceability and control of the manufacturing process.
Sartorius will soon introduce a new polyethylene film for single use bioreactors in the 50-L to 2,000-L range, including the rocking motion cell culture bags and other bioprocessing bags for storage, mixing and shipping, Feng adds. The company’s Flexsafe bioprocessing bag range, which the company plans to launch in the next few months, will be based on this film, she says.
SUT has changed significantly in the relatively short length of time that disposable bioprocess equipment has been around. As demand for quality and improved process control continue to drive biopharmaceutical manufacturers, whether operating companies or contract manufacturers, we can expect to see continued change over the next few decades.