Nate Spangler, Ph.D., Director of Innovation & Strategy at Aldevron discusses the challenges of manufacturing mRNA under the increased demand and helpful strategies to solve them.
Nate was interviewed by Michael Dunnet for TIDES TV.
Can you describe Aldevron's mRNA manufacturing experience?
For many years, Aldevron has been excited by the potential for In vitro transcribed messenger RNA as a new type of drug or vaccine that will rapidly fill gaps not met by current medicines and emerging therapies.
About five years ago, we began making plans, and three years ago we made our first batch of mRNA for clinical studies. And since then we have produced clinical grade mRNA for a wide range of uses, including cancer immunotherapies, protein replacement therapies, infectious disease vaccines. By doing this, we have come to understand the range of product and client requirements across these fields of use. Our ability to make RNA is also supported by more than 20 years of experience, manufacturing, DNA and recombinant proteins for preclinical, clinical and commercial uses.
There has been a huge growth, and an interest, about mRNA. With that growth, what sort of outsourcing challenges, does mRNA and biopharma face?
Because mRNA for vaccines and therapies is new, there is not a lot of suppliers of raw materials and process proteins that are needed for its production, especially in quality grades that are suitable for use in GMP. On top of that, with a sudden and unexpected demand created by mRNA based COVID-19 vaccines, shortages are causing delays and we seek to minimize that with proactive sourcing and contingency plans.
Another challenge relates to the general lack of clinical experience with mRNA combined with the pressure of short sponsored timelines. This requires manufacturers to rethink well-established cadences and production, quality control and quality assurance without compromising what we deliver.
When developing an mRNA production process that will be scaled up, what are the most important considerations?
There are many, and I think first and foremost, it is scalability of the process, especially downstream steps. What worked well in R&D and pre-clinical stages might not be practical for later stages of development. This could be a purification method that does not scale up easily, like size exclusion chromatography or HPLC. Or it could be chromatography media and raw materials that are very expensive and difficult to source. It is important to develop a process early on that will be robust and economical at the large scales needed for later clinical and commercial stages. This is where a CDMO's experience can be highly valuable to sponsors.
For the design of mRNA therapeutics and vaccines, what are some important considerations?
The design of the DNA template and the mRNA transcript are very important and much of that is going to happen before the CDMO becomes involved. For example, untranscribed sequence elements are going to be important to help the mRNA vaccine or therapy works. Certain applications will need to minimize the immune stimulating activity of In vitro transcribed mRNA. This could involve the use of base-modified NTPs and sequence optimization. The way the mRNA will be used - therapy or vaccine - in addition to other requirements, will impact the choice of capping method and DNA template promoter design. The poly(A) tail requirement, such as exact length or maximal length, will determine the tailing method, which will also impact the DNA template design. The choice of restriction enzyme to manufacture the linear DNA template can have a big impact on the template manufacturing cost and quality. If any of these points need to be reevaluated, when sponsors engage the CDMO to scale up manufacturing, unexpected delays can result. We recommended begin working with your CDMO as early as possible to ensure a smooth transition when the to scale up comes.
How will mRNA affect future vaccine development and manufacturing, in your opinion?
I think for a long time, mRNA has been seen as a potentially better way to make vaccines against infectious diseases, especially in response to emerging threats, and this has been shown to be true with COVID-19. An mRNA-based vaccine against a new disease can be developed and made more quickly, easily and economically than a new vaccine using conventional technologies.
The manufacturing requirements for mRNA vaccines are simpler than for other types of vaccines, which makes it easier to rapidly scale up to meet urgent need. And as a manufacturer of RNA, we can satisfy a wide range of needs without having to develop product specific process processes from scratch and without having to build a product dedicated facilities for each new disease.