Nucleic acid technology came of age during COVID-19 with biopharma firms developing, testing, mass producing, and shipping mRNA vaccines in record time. However, as the pandemic ebbs, the industry now needs to find ways of making DNA and RNA products more efficiently.

This is the view presented in a new study by scientists at Penn State who looked at purification methods used in nucleic acid manufacturing and found room for improvement.

A big problem is the fact that current chromatography and membrane separation techniques were developed with proteins in mind, says co-author Andrew Zydney, PhD, the Bayard D. Kunkle Chair and professor of chemical engineering at Penn State College of Engineering.

“Typical recombinant proteins like monoclonal antibodies are around 10 nm in size. In contrast, plasmid DNA can easily be 100 nm in size. The large size of DNA and RNA leads to significant mass transfer limitations in the small pores of chromatography resins. In some cases, the DNA simply can’t access any of the pores and can thus only bind to the outer surface of the resin,” he explains.

“In addition, biophysical properties of the nucleic acids are quite different than those of proteins, including the fact that the nucleic acids can easily deform in the flow field, which can sometimes cause breakage to the DNA or RNA. This means that simply using manufacturing strategies that were originally developed for protein purification will result in processes that are far from optimal for the purification of DNA and RNA.”

COVID-19 disruption

The nucleic acids industry has been working on more efficient manufacturing methods for some time. However, the need to make vaccines quickly during COVID-19 had a negative impact on these efforts, maintains Zydney.

“Although there is a lot of ongoing work on how to optimize DNA and RNA manufacturing, most of the current processes are still using fairly traditional methods. This is in large part due to the unique timelines that occurred with the COVID-19 pandemic. The mRNA vaccines were produced on such an accelerated timeline that it was simply not possible to introduce new manufacturing technologies,” he points out. “In addition, the need for these vaccines was so high that there was less incentive to optimize the manufacturing process at least not if that type of optimization would delay the availability of the vaccines.”

However, as demand for and supply of COVID-19 vaccines stabilizes, Zydney is confident the industry will refocus on optimization.

“I think the next few years will likely see a burst of innovation in new technologies for manufacturing that will enable the commercialization and large-scale production of the next wave of mRNA and DNA therapies. And digital systems will be important, notes Zydney.

“Machine learning, digital twins, and AI will play an important role in the adoption of new manufacturing technologies for RNA and DNA production. This includes both the design and optimization of new manufacturing processes and the development of process control strategies that will ensure that these novel therapeutics are produced with the highest possible quality.”

Zydney also points to the recently established, FDA-funded Center for Continuous mRNA Manufacturing as a likely innovation driver, explaining, that “the aim is to work directly with industry to address the unique challenges in manufacturing mRNA.”

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