RNA Industry Should Look to Biopharma to Address Formulation Challenges

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Manufacturers of messenger RNA (mRNA) vaccines and therapies face unique formulation hurdles. But research from Moderna suggests the industry could still learn from biopharma’s approach to making shelf-stable products.

From a manufacturing perspective, working with mRNA molecules is difficult, says Mark Brader, PhD, research scientist at Moderna. He cites the need to protect these sensitive molecules without affecting their functionality as one of the major issues.

“The unique formulation and stabilization challenges stem from the instability of unmodified mRNA and its limited history as a drug or vaccine,” he says. Creating formulations that support functionality is also a hurdle, according to Brader, who notes that “a significant additional challenge arises from the need to deliver mRNA into the cell, whereas protein-based drugs are limited to drug targets outside the cell”.

Then there is the inherent problem of mRNA stability, or lack thereof. The challenge, Brader points out, is to get the molecules to their cellular targets while bypassing the natural mechanisms that break them down.

“Compared to other types of molecules, there is an intrinsic rapid biodegradability of mRNA, which is a challenge,” he explains, adding that because mRNA functions biologically as an intermediate short-term molecule shelf life, products based on it are quickly broken down unless protected.

Evolving Science

Brader and Moderna colleagues took an in-depth look at some of the formulation and manufacturing challenges facing the mRNA industry in a study last month. They conclude that a big part of the problem – beyond the sensitive nature of the single-stranded molecule itself – is that the concept of an mRNA-based drug is a relatively new idea.

“Because mRNA science has not evolved with a central focus on biomedical applications, the interrelationships between primary sequence, higher-order structure, biological activity, and pharmaceutical stability have only become relatively recently the subject of intense research,” Brader said. GEN.

Which means, for example, that techniques for measuring whether mRNA molecules will be stable in various formulations are relatively underdeveloped.

Fortunately, some of the approaches developed by the biopharmaceutical industry to try to ensure that pharmaceuticals are heat-stable on pharmacy shelves have the potential to help mRNA vaccine developers, albeit directly.

The study authors write, “Accelerated thermal degradation of proteins has been studied extensively throughout biopharmaceutical history as a means of relating measurable fundamental thermodynamic parameters to the ultimate practical resilience of the intended therapeutic product.”

And these measurement techniques can give mRNA developers a better understanding of how their molecules will react when encapsulated in a formulation, says Brader.

“We report that measurements of mRNA thermal unfolding behavior provide fascinating insights, and that this approach is one that has been successfully applied to biologic drugs,” he says.

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