Since the late 1990s, single-use technology has become a mainstay of pharmaceutical manufacturing. Unlike stainless-steel systems, which incorporate fixed components, such as bioreactors, filters, and pipes, single-use systems incorporate presterilized disposable components. They require no cleaning. Also, they can reduce costs, cross-contamination risks, and manufacturing times.
“Single-use systems are ready to use, and they save lots of time and manpower—and water,” said Anika Manzke, product manager, viral clearance, Sartorius Stedim Biotech, during her presentation at BioProcess International Europe 2019. At this event, which took place April 2–4 in Vienna, she and several other single-use experts offered their insights.
Flexible filtration systems
A major trend in single-use technologies, according to Manzke, is the design of equipment to manufacture batches of product with larger volumes. As batch volumes increase from pilot to manufacturing scale, production processes become increasingly complex with single-use capsules requiring multiple connectors. These complex connections can increase the risk of handling errors.
“If you have a stainless-steel system, you need all this piping and inventory, which increases capital expenditure and reduces your flexibility as well as increasing time to market,” stated Manzke. “And if you have a cartridge in stainless-steel housing, you need to open the housing to replace the cartridge. It’s an open system where the operator can get in contact with the product.”
Sartorius Stedim Biotech has designed a single-use virus filtration system that is preassembled and presterilized and can be used for large batch volumes of 5000 L or more. The MaxiCaps® MR Virosart® filtration system can incorporate a filter area of up to 15 m2 (27 m2 for sterile filters) in three, six, or nine capsules. According to Manzke, this is the first large-scale single-use system available for virus filtration that can be fully integrated into the process while maintaining sterility.
“The market is looking into flexible, ready-to-use solutions,” explained Manzke. “People like fully closed sterile systems, which pose no risk to the operator.”
In the future, the company hopes to help customers perform integrity tests and diffusion tests (diffusion testing is one kind of integrity testing) across the filtration membrane within a single-use system. Manzke said that the company also supports customers who want to use single-use virus filtration in continuous manufacturing. As she explained, these customers need to be certain the viruses are being safely filtered out throughout the manufacturing process.
Bioreactors made to size
“Continuous processing is the biggest trend we see right now,” declared Alex Boscolo, field application specialist, Thermo Fisher Scientific. He argued that continuous processing helps customers accelerate productivity gains. Personalized medicine, he explained, is another key trend with customers who want to manufacture clinical batches with quite limited volumes.
According to Boscolo, Thermo Fisher Scientific has designed an improved single-use bioreactor that can support low batch volumes. To achieve this feat, the bioreactor ensures that mixing and gas transfer are great enough to sustain high cell densities. “Customers can now start working at 20% of full volume, which means they can skip one or two steps in their seed train,” said Boscolo, and still generate an adequate number of cells for the inoculation of a production bioreactor.
He argued that, in general, the market trend is toward flexibility in single-use technologies. Ideally, bioreactors should be tailored to the customer, rather than the other way around. In the future, he said, flexible single-use bioreactor technology will extend to ever-larger volumes—up to 2000 L and more—volume ranges currently dominated by stainless-steel bioreactor technology.
Tests for extractables and leachables
“Single-use technology is more important when batch volumes are low, for example, in clinical phase studies, because you need more flexibility,” said Michel Eppink, PhD, director, downstream processing, Synthon Biopharmaceuticals. “If you’re looking at large-scale commercial production, with lots of batches in a year, the stainless-steel approach remains quite good.”
Synthon adopted single-use technology to support the production of antibody-drug conjugates (ADCs), a specialty the company initially considered outsourcing to a contract manufacturer. Ultimately, the company decided to develop this specialty in-house. The company found that single-use technology facilitated rapid shifts in production between batches and multiple products, but that it also raised some challenges with respect to extractables and leachables. These are compounds in single-use plastics that may leak into the environment or, in extreme cases, the product or patient.
Eppink, who is also a part-time professor at Wageningen University and Research Center, delivered a presentation that focused on Synthon’s strategy for extractable and leachable testing in ADC development. “I think this strategy is quite new,” he asserted. “In past years, the information from suppliers was quite limited. ADCs were relatively new in the field, and knowledge of single-use technologies was just starting to be built up.”
Automated bulk filling systems
“Once a molecule has gone through downstream processing, you have a very pure product that can be worth millions,” said Graeme Proctor, product manager (single-use technologies), Parker Bioscience Filtration. If the product’s value is to be preserved, the next processing stage, final bulk filling, must proceed without a hitch.
“The idea behind our system,” explained Proctor, is that it can “automatically sterile filter and dispense high-value product in a closed way,” avoiding contamination by the operator and surroundings. The system, he continued, can also “protect the operator from the drug product.” All this, he maintained, can be accomplished with single-use consumables.
Proctor elaborated on these assertions by describing Parker Bioscience Filtration’s SciLog® SciPure FD system, a large-scale system that uses single-use technologies for bulk filtration and dispensing into final bulk product containers for either storage or shipping to the final fill location. The system incorporates a patented single-use sensing technology for feedback, monitoring, and automated integrity testing among other functions, alongside a patented bottle technology that stops caps loosening during freeze/thaw and transport.
Although Graeme emphasized large-scale systems—the SciLog® SciPure FD, after all, is a large-scale system—he noted that many customers are interested in systems that are like the SciLog® SciPure FD, but smaller. Small-scale systems are needed for gene and cell therapy and for dispensing product in the laboratory in a robust, automated fashion.
There is also growing demand, Graeme pointed out, for automated sensing technology that would allow biomanufacturers to standardize their products and processes. Whether single-use technology will become prevalent over the whole biomanufacturing process, or just for certain disposable items, he concluded, only time will tell.
Cold-chain handling and storage
“When you look at the landscape of the biologics market, there’s a trend toward single-use systems, and there’s also growth in the need for cold-chain storage for biologics stored between −40 and −80 °C,” said Joe Cintavey, product specialist, W.L. Gore & Associates.
Drugs are increasingly being manufactured in different geographical locations to bulk drug substance, often due to regulatory requirements, global partnerships, or the use of contract manufacturers, he explained. In accordance with this trend, high-value bulk drug products end up being shipped around the globe.
In addition, companies adopting single-use manufacturing technologies, especially closed systems, are often turning to single-use bags for storage and shipping. “Bottles filled under hoods with a cap screwed on afterward present challenges in ensuring a closed system,” Cintavey cautioned. In contrast, in a closed single-use system, a bag can be attached to the rest of the system with aseptic connectors, minimizing the risk of exposure to the environment.
Current single-use bags, he asserted, have an unfortunate tendency to become brittle and crack at low temperatures. He added that the problem continues to grow with the need for lower temperature storage. The growing markets in biologics and, similarly, in gene therapy, increasingly require fast freezing and even lower storage temperatures. In response, Gore & Associates has designed a bag made of a proprietary polytetrafluoroethylene composite film. The bag is designed, Cintavey said, to remain flexible and durable at low temperatures.
