From BPI West: A Roundtable Discussion On Continuous Manufacturing

By Tyler Menichiello, contributing editor

This is part two of my coverage on continuous manufacturing from this year’s BioProcess International (BPI) U.S. West conference. In my last editorial, I shared a brief conversation I had with AstraZeneca’s director of bioprocess technologies, engineering, and biopharmaceutical R&D, Ken Lee, Ph.D. after his Fireside Chat: “Continuous Vs. Fed-Batch: The Ongoing Debate.” After our chat, Dr. Lee was kind enough to gather some of his friends in process development to further the discussion on continuous manufacturing.

This impromptu roundtable discussion included Michael Coolbaugh, Ph.D., head of advanced manufacturing implementation at Sanofi; Vishwanath Hebbi, Ph.D., a senior scientist at Merck; and Gujie Mi, Ph.D., an upstream R&D manager at MilliporeSigma. Standing around a sun-soaked table in the San Diego Convention Center, we talked about the benefits and promise of continuous manufacturing, as well as the industry’s hesitancy to adopt this technology en masse.

Editor’s Note: Everyone in this discussion supports continuous manufacturing, and while they balanced their views with pragmatism, there were no dissenting voices present. If you hold a different view or are skeptical of continuous manufacturing, please reach out. I’d love to hear from you and broaden my perspective!

There Is No One-Size-Fits-All Continuous Manufacturing Solution

At the onset of our conversation, I asked the roundtable about some common misconceptions around continuous manufacturing. Coolbaugh shared one he previously held, which is that continuous processing isn’t an all-or-nothing ordeal. Rather, it’s a tool to solve specific problems. “There isn’t a one-size-fits-all solution,” he said.

Companies don’t have to commit to fully end-to-end continuous processes; they can integrate these systems into hybrid models or apply them selectively for standalone intensification. “Sometimes, you really have to break it down,” said Mi — whether by separating upstream from downstream or by focusing on different unit operations.

This approach can help lower the bar for entry by significantly reducing complexity, Mi said. It may also be easier for regulatory agencies to accept. “Even though they encourage new technologies, there are still different risk tolerances,” he said. Integrating continuous technology a little bit at a time can lighten the lift of adoption and allow manufacturers to demonstrate safety and control of their processes.

Companies looking to adopt continuous bioprocesses should approach it thoughtfully. “We should consider a holistic approach when implementing,” said Hebbi, and consider the entirety of a process to determine where it makes the most sense to start from a cost of goods (COGs) perspective. Coolbaugh similarly believes in a pragmatic approach — understanding the full potential and then scaling back to what’s most necessary. “When you do technology development, you need to develop the most complex version and then pull back and figure out what makes sense to implement in manufacturing,” he said.

Barriers To Adopting Continuous Bioprocessing

Continuous manufacturing isn’t new, but it has yet to be widely adopted across the industry. Our roundtable discussed some of the perceived barriers to adoption — some of which are valid, and some of which are “potentially overblown,” said Coolbaugh.

One common perception is that continuous bioprocessing adds more complexity to process development and characterization. The experts don’t disagree. “It’s hard because no one’s done it before,” Lee said, “especially in downstream.” While continuous upstream manufacturing has been done for a while, he said, continuous downstream manufacturing is quite novel. “Fed-batch only looks easy now because so many people do it and the process is so optimized.” Yet, there was once a time when fed-batch seemed complicated compared to batch manufacturing.

Though adoption may not be easy, it’s important to consider the technology’s potential. “How much more can we realistically squeeze out of the fed-batch platform versus the potential we have for continuous platforms?” asked Coolbaugh. Despite being an immature platform, manufacturers are already seeing three- to five-fold productivity improvements in continuous processes, he said.

Continuous bioprocessing can also be especially beneficial in downstream for biopharmaceuticals with more structural complexity (e.g., multispecifics), as they are less stable and susceptible to misfolding and aggregation, which makes storage challenging. The less stable a molecule is, the faster you have to move process streams without storing it in tanks, Hebbi said.

While the potential is there, early adoption invariably requires a fair amount of risk tolerance, and this can especially dissuade smaller companies. However, “we need to be able to accept some level of risk,” Lee said, to reap the benefits of continuous manufacturing. Of course, that’s easier said than done.

“It’s hard to convince an individual project team that their molecule is the one — that they’re the ones who are going to go first,” Coolbaugh said. After all, adding risk to intrinsically risky projects doesn’t help inspire confidence. Understanding this natural aversion — and addressing it through proper training and support — is the first step in successfully implementing continuous processes.

Implement Gradually And Build Cross-Functional Teams

One silver lining, the roundtable agreed, is that risk diminishes over time. Like anything, the first time is the worst time, but your company’s continuous manufacturing process won’t improve — nor will the risk go down — if you don’t start somewhere. “You have to get something in place first, and then you grow, and you evolve from there,” Coolbaugh said. Don’t try to overhaul everything at once. Implementation should be gradual, starting with the most important aspects of your process.

This stepwise adoption of continuous technology mirrors the evolution of fed-batch systems over time, said Hebbi. He alluded to technologies like Single-Pass Tangential Flow Filtration (SPTFF) and multi-column chromatography, two technologies that were once new and complicated but gradually became the standard.

It is critical to provide proper training when implementing these technologies. Both Hebbi and Coolbaugh talked about the importance of building teams with cross-functional expertise spanning automation, downstream process development, and analytical development. Teams that combine such diverse knowledge areas are better suited for the dynamic decision-making needed for operations, Hebbi said.

Effecting Change Through Collaboration

Ultimately, the potential of continuous manufacturing can only be realized through the collective effort of manufacturers and stakeholders across the industry. Mass adoption is possible, but everyone at the roundtable agreed that it requires a change in mindset.

Yes, updating processes and integrating new technologies is hard, but so is nearly everything about biopharmaceutical development. Being an early adopter is risky, but there is no advantage in ignoring technological developments that can markedly improve production capacity and process efficiency.

Whole processes don’t have to change overnight. Progress begins with intention, and even implementing continuous bioprocessing technology in one unit operation can reduce the COGs.

Everyone at the table agreed that the way towards industry-wide adoption is through collaboration. There is an opportunity for manufacturers to work together to standardize these workflows and the approach to continuous bioprocess development, said Mi. The more CMOs that offer continuous bioprocessing capabilities, the less companies will need to perform a full equipment technology transfer on top of the process transfer, Lee said.

Change can’t happen in a vacuum. “At the end of the day, we compete on the quality of our drugs, not on the quality of our manufacturing processes,” Coolbaugh said. “If we can all do better, then it’s better for the patients.”