It’s no secret that biomanufacturing is an expensive and resource-intensive industry, but the best teams see this paradigm as an engineering problem, not a fixed reality.
There are a myriad of approaches development and manufacturing teams use to improve process performance and efficiency, and earlier this year, we hosted an interactive panel discussion with leading experts to hear their thoughts on how the best teams do exactly that.
David Scherr, Ph.D., and Vadim Klyushnichenko, Ph.D., joined forces in our Bioprocess Online Live event exploring the levers and tradeoffs that drive process productivity. Scherr is a senior scientist in bioprocessing technologies and engineering at AstraZeneca, and Klyushnichenko is the VP of biopharmaceutical development and quality at Calibr-Skaggs Institute for Innovative Medicines.
Together, they examined how upstream decisions affect downstream outcomes and the tools and technologies pushing process productivity to the next level, as well as shared their thoughts on the most effective ways teams can move the needle on their own process efficiency.
Productivity Gains Upstream Apply Pressure Downstream
In past Live events, we’ve challenged the traditionally siloed relationship between upstream and downstream teams. It’s simple: Coordination between these teams is critical at the institutional level, as decisions made upstream tend to have an effect downstream.
One example Scherr and Klyushnichenko discussed pertaining to mAbs was how higher titers upstream can put pressure on downstream teams who are only capable of purifying so much material at a time.
“It’s a big balancing act,” Scherr said. While both teams should strive for respective improvements in efficiency, yield, and throughput, a lack of coordination can lead to one foot running faster than the other, so to speak.
“When you hit that titer ceiling, the issue is that you just can’t purify it fast enough as it’s being produced,” he explained. That’s not necessarily a bad issue to have, but it’s a challenge to contend with nonetheless.
“There’s a few things that you can do to deal with it,” Scherr told the audience. “Mainly, having an overflow vessel that can be drained.” He also noted the advent of newer technologies like high-capacity affinity resins that are able to capture 80 to 100 grams per liter of product.
Molecular Complexity Impacts Performance
Molecular complexity can also factor into the interplay between upstream and downstream teams, impacting overall process productivity. Specifically, Klyushnichenko and Scherr referenced the mispairing of heavy- and light-chains in bispecific and trispecific antibodies.
“If you have a kappa-lambda bispecific and you have a lot of lambda-lambda mispairing, that’s pretty difficult to separate,” Scherr said. “I think getting rid of those mispaired species with traditional bind-and-elute cation-exchange can be a little difficult.”
“With these more complex molecules, you have more impurities,” Scherr said. “And typically, if you have a process that has a high yield, you also have more impurities.”
The propensity of these antibody chains to mispair makes purifying these molecules difficult enough, so anything that can be done upstream to minimize it is a win.
“In our practice, we put quite a lot of effort into developing clones that produce correct heterodimers for bispecifics and trispecifics,” Klyushnichenko told the audience. “Otherwise, yield can drop significantly.”
According to Klyushnichenko, minimizing the occurrence of mispairings begins even before cell line development, starting with the molecule’s construct itself. “That’s where our institute puts quite a lot of effort,” he said. (This aligns with my conversation with another SME on how molecular design impacts manufacturability.)
Preventing these impurities from being present in the end product is the responsibility of the entire manufacturing team, upstream and downstream alike.
“You can’t have the teams be siloed,” Scherr said. “You need to have good communication between all of these groups, and it is a team effort.”
Simplifying Downstream Unit Operations
As our panelists explain during the event, achieving both high yield and high purity is extremely difficult. In the world of bioprocessing, it’s sort of like having your cake and eating it too. While purity is of course more important than product yield from a quality and patient-safety perspective, there are ways to increase yield without sacrificing purity.
Perhaps the most advisable is through simplifying downstream processes as much as possible, even going so far as to eliminate certain unit operations (where feasible).
“For eliminating unit operations, it’s more of looking at the molecule and looking at the product- and process-related impurities and just thinking, How can I get rid of these impurities while keeping the process robust and my yield high?” Scherr told the audience.
He used precipitation as an example.
“Precipitation happens downstream, and you need a depth filter in order to get rid of it, but sometimes, precipitation only happens when you reach a target pH.” Scherr explained. By avoiding certain pH ranges during operation, you can theoretically avoid precipitation and negate the need for a depth filter, thus effectively getting rid of that unit operation.
Klyushnichenko advised the audience to try and limit purification to no more than three chromatographic steps. “Two is ideal,” he said, admitting that it’s a difficult to achieve. “But three chromatographic steps is optimal, not only in terms of purity of the protein itself, but also for viral clearance, which is quite important.”
These sentiments echo those shared by Siren Biotechnology’s SVP of vector development, Nathalie Clément, Ph.D., who joined me on the “Better Biopharma” podcast to discuss advancements in downstream AAV production. She too advocates for combining and eliminating unit operations wherever possible.
The Benefits And Tradeoffs Of Continuous Manufacturing
Our panelists also talked about how continuous manufacturing workflows can reduce facility footprints and improve process efficiency. Scherr in particular is a proponent of utilizing perfusion upstream.
“The big advantage of perfusion is it’s just smaller, and that modularity makes your life easier for facility fit and for tech transfer,” he told the audience. You’re also able to produce the same amount of mass in a 50-liter perfusion bioreactor as you would in a 500-liter fed-batch bioreactor, Scherr said.
However, there are some caveats with perfusion to be aware of. With a perfusion process, cell line stability is imperative, as these processes need to theoretically be able to run reliable for several months to a year. “If your cell line is not stable, then there will be a problem,” Klyushnichenko warned.
The other risk with perfusion is the cost of mistakes, said Klyushnichenko. Because perfusion is a continuous process, real-time analytics are critical to detect issues early to prevent media, product, and material loss. While analytics are equally important in a traditional fed-batch model, a ruined batch generally results in less wasted material than a failed perfusion run.
For more insights into the tools and ways teams are finding success in improving process performance, watch the full Live event recording here. Stay tuned to Bioprocess Online and subscribe to our newsletters to be notified about upcoming Live events!
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