Mastering mRNA Manufacturing: A Focus on Raw Materials & Supply Assurance
By Life Science Connect Editorial Staff
The rapid advancements in mRNA-based therapeutic development today have highlighted the critical role of raw material quality and supply chain management in ensuring the successful production of these innovative medicines. The intricate nature of mRNA manufacturing processes, coupled with evolving regulatory requirements, necessitates a meticulous approach to sourcing and managing raw materials.
The quality and availability of raw materials directly impact the efficacy, safety, and consistency of mRNA-based products. As mRNA vaccines and mRNA-based drugs continue to see increasing interest from developers across the space, the need for a commensurate increase in raw material availability to support these applications has begun to emerge. In the wake of the COVID-19 pandemic, these supply chains have matured into a diversified, robust array of options for developers and manufacturers.
Despite the relative strength of the raw materials supply chain for mRNA that exists today, organizations still have plenty to consider when it comes to vetting these crucial process inputs. Ultimately, the quality of the materials forming the basis of the in vitro transcription (IVT) reaction determines the quality of the final mRNA/RNA drug substance. In turn, identifying reliable supply that can pass regulatory muster, and is positioned to scale effectively is crucial to ensuring the ultimate success of these products.
The mRNA Raw Material Supply Chain: Quality and Management Considerations
For the key raw materials used in the IVT reaction, such as the DNA template, nucleotides, RNA polymerases, and buffers, the degree of characterization performed by the supplier is often a critical consideration when assessing quality. A good supplier is able to work with organizations to better understand how the critical quality attributes (CQAs) of a raw material may be impacting an overall process.
One of the biggest problems mRNA gene therapy applications face is supply chain lead times. The competition for raw materials and the many variables that can impact the supply chain often converge to create significant slowdowns. Unlike mRNA vaccines, which typically undergo a number of changes throughout development, developers pursuing mRNA gene therapy applications are encouraged to establish GMP master cell banks as early as possible, which can significantly slow timelines as these programs face challenges linked to intellectual property (IP). Everything from the cap structure to the initiation codons, nucleotide modifications, untranslated regions, and other key features of an mRNA sequence may be flagged, forcing organizations to identify workarounds or pay to license existing IP.
Small companies facing this dual challenge — securing reliable supply and managing the legal aspects of sourcing raw materials — can significantly benefit from the right supplier. A few suppliers in the space today have moved toward democratizing their IP, offering access to customers at comparatively little cost. This can be readily seen with many of the caps available on the market; some allow for a Freedom to Operate (FTO) option that enables operators to utilize a cap only up to a certain production level, while other caps may have IP limitations so stringent that many suppliers refuse to work out the legal ramifications themselves, leaving it to a company to secure IP rights on their own.
While the right supplier should be able to establish a baseline understanding of a raw material and help companies secure the right inputs for a given process, there is still a great degree of exploration biotechs need to carry out for mRNA therapeutic modalities to establish the foundational process understanding. For example, at this stage in the industry, suppliers do not currently have the same depths of foundational understanding to recommend a specific nucleotide modification to employ for a gene editing application, for example; it is still up to developers to uncover the foundational science that will inform future optimization across the space.
The Future of mRNA Raw Material Supply Chains
As other novel applications focused on new modalities like circular RNA and next-generation delivery vehicles advance in the development pipeline, this knowledge expansion is likely to lay the groundwork for more robust supply chains for these novel applications.
Conversely, the differences and complexities inherent in novel mRNA modalities are likely to result in the emergence of new purification strategies and delivery vehicles for these applications. Such developments will likely spur the need for new materials and, in turn, spark new challenges in identifying and characterizing their CQAs. Moreover, other advances in the space could serve to simplify the supply chain needed for a given application. A successful circular RNA production process, for example, would eliminate the need for capping or tailing that exists for linear RNA.
Likewise, self-amplifying RNA could, theoretically, enable dosing low enough to circumvent the reactogenicity seen in many vaccines — both traditional and mRNA-based. These potential shifts toward lower or less frequent dosing, coupled with improved stability and supply chain simplification, promise lower cost of goods, lower scaling requirements, better thermostability, and other crucial advantages on the CMC side of development.
The Importance of Continued Focus on Raw Material Quality and Supply
Ultimately, the successful development and manufacturing of mRNA-based therapeutics requires careful consideration of raw material quality and supply chain management. While the mRNA supply chain has matured, organizations still need to carefully vet suppliers and secure reliable sources of high-quality raw materials. As such, collaboration between developers, suppliers, and regulators is essential to establish appropriate standards for raw materials and ensure the successful development and commercialization of mRNA-based therapeutics. By addressing these challenges and leveraging the expertise of suppliers, organizations can overcome hurdles and bring innovative mRNA therapies to market faster.