Continuous manufacturing processes are helping drug firms intensify output. But the large volumes of waste media they generate are a concern from a sustainability perspective, according to Merck & Co. engineers, who say new approaches are needed.

Continuous manufacturing is not a new idea for biopharma. For example, perfusion bioreactors—in which culture media is removed and replaced on a constant basis—have been used to increase upstream productivity for decades. Unlike culture processes in fed-batch reactors that usually run for 10 to 14 days, processes in perfusion reactors typically run for 30 to 60 days and, as a result, they generate more product. However, the longer run times also mean they use much more media.

Media management

The big question for industry is what to do with the used media, particularly at a time when continuous processes are gaining in popularity. The traditional approach has been to treat it as waste and remove it from the processes.

But this “strategy” is not ideal from a sustainability standpoint, says Xiaowen Wang, PhD, senior scientist at Merck & Co.’s upstream process development unit in Kenilworth, NJ.

“For perfusion culture in an integrated continuous process the media is removed as permeate and fed directly into continuous protein A capture system where the product is captured and the media minus the produce becomes purification waste,” he says.

Instead, Wang and colleagues argue biopharmaceutical manufacturers could develop ways of reusing old media—which they call Protein A flow through—and returning it to the process stream.

“We conducted an initial assessment of the feasibility of recycling proA flow through as culture. First, we evaluated a few polishing materials to remove some of the in-process impurities in the proA flow through,” Wang tells GEN. “Then we assessed the culture performance of various ratios at which the proA flow through is mixed with fresh media to minimize the performance impact. All these were done at bench-top scale and not in real-time.”

And the idea has potential according to the authors, who write that when the various polishing and treatment steps are combined “comparable or higher productivities relative to control can be achieved.”

There are also potential operational benefits, points out Wang, who says most biopharmaceutical manufacturers would be able to adopt media reuse without additional investment in equipment.

“Theoretically, this strategy can utilize technologies that already exist in a common bioprocess environment,” he says. “The ultimate goal for permeate reuse is to improve process sustainability and ideally it will reduce cost as well. Although more development work needs to be done to get to that point.”