Messenger RNA (mRNA) vaccine and therapy makers face some unique formulation hurdles. But a study by Moderna suggests the sector could still learn from biopharma’s approach to manufacturing shelf-stable products.
From a manufacturing standpoint, mRNA molecules are hard to work with says Mark Brader, PhD, a research fellow at Moderna. He cites the need to protect these sensitive molecules without impacting their functionality as one of the major issues.
“The unique formulation and stabilization challenges derive from 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 “An additional significant challenge derives from the need to deliver mRNA into the cell, whereas protein-based drugs are limited to druggable targets outside the cell.”
Then there is the inherent problem of mRNA stability, or lack thereof. The challenge, Brader points out, is getting the molecules to their cellular targets while bypassing 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 a short-lived intermediary molecule products based on it are rapidly broken down unless protected.
Brader and Moderna colleagues had 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-medicine is a relatively new idea.
“Because mRNA science has not evolved with a central emphasis on biomedical applications, the interrelationships among primary sequence, higher-order structure, biological activity, and pharmaceutical stability have only relatively recently become the focus of intense research,” Brader tells GEN.
Which means, for example, that techniques to measure whether mRNA molecules will be stable in various formulation are relatively under developed.
Fortunately, some of the approaches developed by the biopharmaceutical industry to try and ensure drug products are heat-stable on the pharmacy shelf have the potential to help mRNA vaccine developers, albeit in directly.
The study authors write “The accelerated thermal degradation of proteins has been studied extensively throughout biopharmaceutical history as a means of connecting fundamental thermodynamic measurables to the ultimate practical resilience of the intended therapeutic product.”
And these measurement techniques can allow mRNA developers to better understand how their molecules will react when encapsulated in formulation, Brader says.
“We report that measurements of the thermal unfolding behavior of mRNA provide some fascinating insights, and that this approach is one that has been successfully applied to biologic drugs,” he says.