Despite established purification steps and unit operations in the manufacturing workflow, the technique and raw materials used to synthesize mRNA remain highly variable. This lack of standardization and cost-effective techniques for manufacturing and analytics for product characterization create challenges when it comes to establishing CMC principles for mRNA-based products.
The unique needs of mRNA
As we move toward a future where the mRNA toolbox will likely play a vital role in patient care, there are several areas of consideration where biopharma must focus to minimize bottlenecks and drive fast and efficient mRNA manufacturing. For example, the mRNA molecule and the impurity profile can differ from product to product, calling on different purification strategies to ensure the removal of impurities downstream while preserving the mRNA molecule. Many of today’s resins and membranes have low capacity for large mRNA molecules and poor resolution for impurities due to their similarity to the target product. This means the biomanufacturing industry will need to develop improved solutions to accommodate downstream mRNA purification.
The diversity of mRNA presents its own CMC development challenges, as there are many variants of interest that will be manufactured at different scales, from the large scale required during the pandemic down to much smaller scales for personalized mRNA therapeutics. As a result, manufacturers will need to identify the most efficient way to scale mRNA production out rather than up, likely running multiple lines in parallel. This will also require biomanufacturers to determine how to manage data from multiple lines to secure proper quality control and documentation management.
Setup, manufacturing, and control of the lipid nanoparticle (LNP) formation are also critical in mRNA manufacturing, protecting the mRNA from degradation and enabling more efficient delivery to the target tissue cells. Techniques for lipid nanoparticle production were developed and utilized during the pandemic response, but further exploration will accommodate the continued rise of mRNA therapeutics. Biopharma companies entering the mRNA manufacturing space will need to establish the capabilities and/or work with a partner that can assist with encapsulation.
Finally, as with any emerging area of medicine, the biopharma industry needs regulatory authorities to provide a framework for compliance to streamline CMC development and ensure the safety and quality of novel products. To do this, biomanufacturing experts making the mRNA vaccines and therapeutics and the regulators creating the guidelines will need to work hand-in-hand. And now that the industry is no longer facing the urgent demand dictated by the early days of the pandemic, there is an opportunity to develop thorough mRNA quality standards to facilitate the delivery of these innovative products.
An expert outlook: critical steps in mRNA development
Overall, overcoming the challenges of CMC development and ultimately paving a more streamlined path to commercial success will require collaboration and communication across the industry in order to learn from the lessons experienced along the way. This was the focus when host Matt Pillar sat down with Dr. Akhilesh Bhambhani, Sr. Director, Biologics Drug Product Development at Ultragenyx Pharmaceuticals and Roberta Duncan, VP and mRNA Program Lead at Seqirus, for a live event by Bioprocess Online.
They covered some of the most critical steps to mRNA vaccine and therapeutic commercialization, including CMC development, scale-up, tech transfer, and regulatory strategy. A Q&A immediately after the event addressed a wide range of audience inquiries. To dig deeper into this topic and learn more about CMC development for mRNA, watch CMC, scale up, and the road to mRNA regulatory approval.