Future-Proofing mRNA Drug Manufacturing: The Value of Continuous Improvement
By Life Science Connect Editorial Staff
The dearth of marketed mRNA products, coupled with a lack of dedicated regulatory guidance surrounding their production, has meant that this largely preclinical industry is only beginning to understand the path forward for achieving successful mRNA therapeutic development. Uncovering the optimizations, both sequence-dependent and otherwise, that can streamline the manufacturing process for these drugs is key to furthering this industry with immense potential to target a wide range of indications.
In a recent panel discussion hosted by Advancing RNA’s Editorial and Community Director, Anna Rose Welch, John Stubenrauch, Chief Operations Officer at Nutcracker Therapeutics, and Hari Pujar, Chief Operating Officer at Tessera Therapeutics, explored the importance of fomenting a deeper understanding of the foundational science around these modalities to drive optimization as programs scale. The pair also discussed overcoming challenges related to raw material variability to better understand and establish “deterministic” IVT reactions.
Forging Internal Expertise to Improve Process & Product Control
The potential range of applications possible for mRNA, coupled with interest from researchers and developers, is set to spark a new wave of promising treatments for some of the most intractable diseases. When it comes to biomanufacturing, Pujar said the level of talent within an organization must reach “critical mass” to support an entirely in-house production paradigm. This can be challenging to achieve, particularly for smaller biotechs that cannot justify the degree of capital investment needed to reach that level. This is when outsourcing, in whole or in part, to a CDMO can prove valuable.
CDMOs across the space have invested significantly in capabilities and capacity related to mRNA since the pandemic, and this segment of the industry continues to grow in response to increasing research and development interest across the space. However, for organizations with a diverse pipeline of therapeutic assets, investing in internal expertise, capabilities and capacity may be the better route. “That typically ends up being preferable, because then you are able to better able to control costs, turnaround time, and quality – the three pillars,” Pujar said.
Many companies pursuing mRNA are likewise working to expand their internal capabilities and capacity to support their efforts to reduce raw material variability, particularly through building out more robust analytical capabilities. Although mRNA manufacturing is not a cell-based process, it still requires the use of biological raw materials such as enzymes, which can introduce their own variability and, as a result, require commensurate characterization. While these raw materials have not typically undergone the same degree of characterization as proteins, for example, the technical knowledge and tools are there and simple to leverage, Pujar explained. “The rest of the characterization is even simpler because they're all small molecules. DNA plasmid of course is different,” he added. “That can also be characterized quite well because DNA has been used as a vaccine candidate and as a therapeutic candidate. So, there are a number of tools and techniques that are well developed for characterizing plasmid DNA.”
Creative Solutions and Continuous Improvement: Progressing mRNA Technology
Ultimately, characterizing raw material inputs is important in controlling the variability of IVT. It can be especially valuable to prioritize optimization around the most expensive raw materials to control COGS from the outset of development. But companies shouldn’t expect to take on the bulk of the work around raw material standardization, Stubenrauch said. “Companies can't afford to take on all the work, and there are good suppliers looking for secondary sources and doing very robust technical analyses and assessments around their processes and ensuring that there are good quality systems that are in place as well,” he said. “It's going to be an evolution.” Even for research-grade materials, the regulatory data package must be strong, both to achieve regulatory acceptance and to ease the transition to GMP compliance.
The complexity inherent in the mRNA industry is also one of its strengths – namely, that the many avenues by which developers can arrive at a “final answer” for a therapeutic have resulted in a diverse array of technologies and techniques to support the industry. This enables a great degree of creativity in response to challenges, which can often be seen when an application reaches downstream stages. “We’re still in the early stages of fully engineering and understanding the IVT step, but once that’s complete, you can imagine a fairly abbreviated downstream process,” Pujar said.
By adopting a mindset that prioritizes continuous improvement, companies pursuing mRNA technologies can drive greater foundational understanding for these drugs. “I think what's important from my perspective is that you characterize your impurities, and you understand what they are,” Stubenrauch said. “Historically, I've seen companies or scientists stop short of really understanding, stop short of identification. You need to identify what your peaks are, and then based off of that, you need to do an assessment.” This strategy, combined with a quality-by-design (QbD) approach and a well-defined target product profile (TPP) and control strategy, represent key considerations in shepherding an mRNA product through clinical development and toward commercial success.