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Disposable equipment components find use in small-volume aseptic biopharmaceutical manufacturing.
Single-use systems (SUS) are increasingly used as an alternative to stainless-steel equipment for biopharmaceutical manufacturing processes. These polymeric systems can be replaced rather than cleaned between different products, which increases flexibility and reduces cleaning costs. Speed to market, scalability, and flexibility are the key drivers for using SUS, says Nick Johnson, director of biopharmaceutical product management for CPC (Colder Products Company), which develops and manufactures couplings, fittings, and connectors for plastic tubing used in single-use components and systems. He points out that facilities are capacity constrained, and that SUS enable biopharmaceutical manufacturers to make the most of their existing space.
“Purpose-built single-use systems can be optimized for the targeted processes so they’re ready to be deployed when needed,” says Johnson. “With SUS, the production suite can be changed over quickly to accommodate the next process. Part of that efficiency comes from eliminating downtime between production runs because SUS don’t require cleaning or equipment requalification in between batches. The ability of SUS to eliminate the risk of cross-contamination between processes is huge, too.”
BioPharm International spoke to Johnson about trends and best practices in using SUS for biopharmaceutical development and manufacturing.
BioPharm: What do you see as trends in SUS in biopharmaceutical development and in commercial manufacturing?
Johnson (CPC): There’s no question that demand for single-use systems continues to grow. About 90% of respondents in the Report and Survey of Biopharmaceutical Manufacturing Capacity and Production use single-use devices in some development and manufacturing phase (1).
The flexibility SUS provide is a primary driver. A biomanufacturer can use one manufacturing space to process multiple drugs simultaneously or make rapid equipment changeovers between production runs without compromising sterility. Modular, ready-to-use single-use bioprocess equipment makes the flexibility possible. As a result, contract development and manufacturing organizations, contract manufacturing organizations (CMOs), and biopharma companies are adopting and deploying SUS at a rapid pace.
Most new and upgraded facilities are incorporating single-use bioprocess equipment. We’re seeing interest in moving away from stainless steel as the equipment ages and requires replacement. Also, for organizations building new facilities, the length of time from groundbreaking to a qualified facility using stainless steel can be approximately five to seven years. In contrast, a SUS-based facility might take two to three years.
As with any system, manufacturers look to optimize efficiency. SUS is no exception. There’s a push to standardize on single-use technologies across CMOs and within biopharma companies’ various sites. The drive to standardization starts with the components purchased from SUS equipment suppliers. To streamline processes, you need the same equipment, the same standard operating procedures (SOPs), and a shared supply chain. It makes a lot of sense from an efficiency standpoint, so you can expect more interest in this approach.
The industry also continues to explore continuous processing and automatic processes, taking advantage of automation and robotics. SUS components will need to work in automated equipment as the industry moves away from reliance on operators—a big change.
The number one concern across the market is supply-chain assurance. With COVID-19, there has been significant disruption in everything from obtaining raw materials used to create components to the ability to ship sterilized equipment in a timely way. This isn’t exclusive to SUS, but it’s had an impact throughout the supply chain. Of course, facilities have prioritized vaccine production, which has a had a ripple effect on other drug production. That’s where you can really appreciate the value of SUS for quick changeovers and facility optimization.
BioPharm: How are SUS sterilized, and are there any particular considerations for types of sterilization and types of materials?
Johnson (CPC): Some drug manufacturers build their own equipment in-house, which is then typically sterilized via an autoclave process within their own manufacturing environment. The majority of single-use process equipment is manufactured into a closed system by an original equipment manufacturer/system integrator, then gamma irradiated. The sterilized assembly is then supplied to the drug manufacturer or CMO in a ready-to-use state.
This trend has strained the gamma irradiation market, though, which has less flexibility to qualify new capacity quickly because gamma processing is highly regulated. Due to this capacity crunch and associated backlog, the industry is seriously evaluating X-ray sterilization as an alternative to gamma irradiation. Organizations such as the BioPhorum Operation Group and the Bio-Process Systems Alliance are working to characterize the risks and equivalency of the sterilization types. There’s widespread recognition that viable options are needed to avoid future supply disruptions due to sterilization capacity limitations.
BioPharm: What are the important considerations for SUS in small-volume production?
Johnson (CPC): The first thing to note is the increase in small-volume (< 10 L) biopharmaceutical processes. There’s a growing number of companies engaged in small-volume processes. A 2021 report from the Alliance for Regenerative Medicine (ARM) states that there are now 1195 cell, gene, and tissue-based therapy developers worldwide (2). You’ll see very small volumes in cell therapy, for example, where cell availability is limited or media is
expensive, and in the development of small-batch autologous therapies. In general, there’s an increase in early-stage drug development, which involves small-volume benchtop research and development processing.
R&D processes need to be reliable and efficient. Yield protection is critical in autologous therapy development. Single-use aseptic closed systems support these goals.
Historically, few convenient options have existed to facilitate sterile processing at small volumes. Biosafety cabinets can only handle a limited number of processes at one time. Tube welding, an older method of creating a closed aseptic system, is labor intensive and the equipment is expensive—easily $15,000 or more per welder—and it takes up valuable space in a cleanroom. Small companies with limited resources may not have the capital to purchase tube welders, so SUS assemblies are a solution for them.
The industry is catching up in creating SUS components specifically for small-bore tubing in small-volume work, in applications such as sampling, seed train expansion, analytical processing, buffer/media transfers, and early cell-culture processes involving shaker flasks and rocker tables. Until recently, tube welding was the only option for creating sterile closed systems at small volumes.
Successful tube welding requires good operator technique and can involve a dozen steps or more, while aseptic connections with new micro connectors can be completed in three steps and up to four times faster than an operator using tube welding (3). Operators using tube welders have to maneuver the tube welder into position, deal with equipment maintenance, and follow a precise technique to create a successful weld. SUS aseptic connectors help biomanufacturers avoid the risks of faulty welds, welder breakdowns, or production delays due to weld equipment downtime.
BioPharm: What would be the benefits and challenges of standardizing SUS for small-volume processing?
Johnson (CPC): The challenges of standardizing lie in part with current practice. Microtiter plates and shaker flasks are still widely used in early bioprocesses because they’re low cost and easy to handle, but the processes are difficult to control and monitor. Users are trying miniature bioreactors to better mimic the function and fluid dynamic of larger bioreactors used during scale up.
The benefits of standardizing SUS for small-volume processes are similar to the benefits at any scale. Modular system designs allow flexibility across multiple processes. Standardization supports system/SKU rationalization. It can also avoid the waste that occurs when less frequently used system components expire before they can be deployed.
Standardization streamlines operator training, SOP creation, and tech transfer across multiple sites within an organization. And in terms of scalability, if you apply SUS from the outset, it’s easier to move into the next phases of production with the same approach and equipment.
BioPharm: What are some best practices for scale up from lab to small-volume scale?
Johnson (CPC): Whenever possible, keep processing steps as simple as possible. Use intuitive technologies. Reduce the number of steps to help increase the likelihood of higher yield. Simpler, proven processes early on may ultimately aid in easier manufacturing during scale-up.
It’s also important to remember that just because the technology works in the lab doesn’t mean it’s right for commercial production. In manufacturing, labor costs may exceed the cost of supplies in certain situations. Generally, the opposite is true in the laboratory. The best process in the lab, where the time required is not necessarily a critical factor, may not be the most efficient process in the plant.
From a materials standpoint, ensure that the materials specified in SUS assemblies stand up to your critical processing needs. Today, many high-performance polymers, elastomers, and other materials are available for use. Select those optimized for your applications. Also, choose technologies that have robust supporting qualification packages, which saves time.
BioPharm: What do you predict for the future of SUS in bioprocessing, and in small-volume lines in particular?
Johnson (CPC): Automated single-use bioprocessing will become more common. SUS will support continuous manufacturing in upstream and downstream processing. We’re already seeing this happen with autologous therapy’s low-volume batches and with monoclonal antibodies. There’s been tremendous growth in the number of processes that involve small volumes. Greater adoption of SUS equipment by existing organizations as well as innovations from suppliers will continue to drive technological advancements in manufacturing systems and processes. We expect that biopharma, cell therapy, and gene therapy newcomers also will adopt single-use technology because it enables efficiencies in both R&D and commercialization timelines.
1. BioPlan Associates, 15th Annual Report and Survey of Biopharmaceutical Manufacturing Capacity and Production (2018).
2. Alliance for Regenerative Medicine, Regenerative Medicine in 2021: A Year of Firsts and Records (2021).
3. CPC internal data.
Jennifer Markarian is the manufacturing editor for BioPharm International.
Vol. 34, No. 11
When referring to this article, please cite it as J. Markarian, “Single-Use Systems Enhance Flexibility,” BioPharm International 34 (11) 29–31 (2021).