Improving the Manufacture of mRNA Biologics

By Mike May, PhD November 1, 2024

The success of the mRNA-based vaccines against SARS-CoV-2 merely hint at the healthcare implications of mRNA technology. More mRNA-based vaccines are in the works, as are mRNA-based therapeutics for various maladies. However, the medical boons promised by mRNA technology won't be realized unless there are improvements in mRNA manufacturing.

The most obvious improvement has to do with scale. As mRNA technology proves itself, demand for mRNA-based vaccines and therapeutics will soar, necessitating increases in production. But it is unclear, exactly, how issues of scale should be addressed, particularly since mRNA technology is still evolving. Fortunately, the chemistry, manufacturing, and controls (CMC) for mRNA-based vaccines and therapeutics are evolving, too. The situation is well summarized by Ye Gu, PhD, co-founder and CTO of Crystal Bio in Cranbury, NJ. She says, “We're still exploring, and nobody can say that they have the best way to do it.”

Applying phase-appropriate analytics

Crystal Bio provides advanced analytical services to support the development of biologics, including mRNA-based biologics, from discovery through clinical trials, and CMC is a crucial component across the life cycle of a therapy.

"Over the past two decades, modern analytical techniques have significantly reduced the CMC failures in biotherapeutics, particularly for antibodies," Gu observes. "However, mRNA—as a relatively new and a rapidly emerging field—is still in the process of establishing standardized characterization and testing methods, so the analytics and quality controls for mRNA vaccines and the therapeutics still have gaps."

To address these gaps, Crystal Bio offers phase-appropriate analytical strategies throughout the development process. According to Gu, such strategies provide "drug developers with cost-effective, regulatory-guided testing, ensuring that the analyses are tailored to each stage of development."

As a product moves into clinical trials, for example, the U.S. Food and Drug Administration (FDA) "requires more detailed information about the quality attributes at the later stages," Gu states. "At Phase I, they give you time to develop methods based on the gradually collected knowledge regarding the mRNA molecule or drug product."

To analyze mRNA being manufactured, Crystal Bio uses a variety of tools. In some tests, for example, "you need to have a good separation, and then you have a good analyzer or detector," Gu says. "These two techniques need to be coupled together, and you need to carefully select the right technique for this type of analysis, which requires a lot of method development, especially for challenging analytical projects."

The separation can be performed with processes such as high-performance liquid chromatography or capillary electrophoresis. For in-depth characterization of mRNA, Crystal Bio utilizes high-resolution mass spectrometry following a suitable separation. This approach can provide high sensitivity and high accuracy in analyzing critical quality attributes of the mRNA, including the capping efficiency of the mRNA and the distribution of the poly(A) tail.

As Gu explains, "The effective and timely application of advanced technologies, such as high-resolution mass spectrometry, can help you understand the molecular characteristics and assess the suitability of the manufacturing platform early in development, and thereby mitigate the risk of CMC delays later on."

Original link for the GEN article: Improving the Manufacture of mRNA Biologics