Respecting the Role of the CDMO in the mRNA Era

Not that many years ago, mRNA-based therapeutics were relatively unheard of – with little investment and slow progress in the field. Although innovations in molecular biology and genetic engineering enabled mRNA to be researched as a therapeutic tool, it wasn’t until the onset of the COVID-19 pandemic that the mRNA-based medicine field rapidly expanded. As a result, the global mRNA therapeutics market was valued at $33.60 billion in 2021 and is expected to reach $38.15 billion by 2030 (1).

Vaccines that rely on mRNA technologies have the potential to offer inexpensive, rapid, cost-effective, and scalable manufacturing. Indeed, the ability to synthesize mRNA products using relatively simple in vitro transcription (IVT) reactions to provide high yields in a small GMP facility footprint were significant benefits during the global rollout of COVID-19 vaccines.

Post-pandemic, the biopharma industry continues to recognize the therapeutic possibilities of mRNA technologies. Offering ease of editing, the customizable nature of mRNA therapeutics allows for precise targeting of biological pathways. The versatility of this drug modality also presents biopharmaceutical companies with the opportunity to develop tailored medicines for a wide range of therapeutic areas in the form of a “plug-and-play” platform – one that is easily edited with minimal effort. Currently, over 300 mRNA therapies are in development – targeting everything from rare diseases to cancers and metabolic disorders (2).

Evidently, mRNA technologies are paving the way towards a new era of biotherapeutics as a customizable treatment option for a wide variety of indications. However, to realize its potential and ensure efficient delivery on both a large and small scale, mRNA drug developers and manufacturers must overcome numerous hurdles.

The role of the CDMO
 

CDMOs were essential during the COVID-19 pandemic – and will remain important partners for companies looking to develop and manufacture new mRNA vaccines and therapeutics. Until the onset of the pandemic, few manufacturers were able to support mRNA therapeutics, so it fell to CDMOs to take on the challenges of working with this widely unfamiliar technology. CDMOs had to quickly adapt their facilities, and expand and optimize cold chain capabilities to suit the temperature-sensitive nature of mRNA molecules. It was also important to determine how lipid nanoparticles (LNPs) used in mRNA encapsulation would behave and how processing conditions would impact drug product characteristics. Determining the behavior of LNPs was particularly challenging because, pre-pandemic, manufacturers predominantly worked with water-like solutions.

Right now, there is little expertise in mRNA manufacturing outside of CDMOs, and services are in high demand because prior experience in mRNA development and manufacturing can help expedite timelines. CDMOs have also been applying learnings gained throughout the pandemic to implement management systems to safeguard and secure supply chains, including securing scarce materials for IVT and LNP production – again, a valuable service.

The voice of experience is also important when it comes to regulatory compliance. As mRNA therapeutics are an emerging technology, regulatory bodies have been under pressure to quickly react to new information, ensuring that guidance reflects the growing understanding in the field. As a result, there is still some discrepancy in regulatory guidance, and critical quality attributes (CQAs) are currently not fully defined. Preventing potential setbacks that could come as a result of these regulatory discrepancies requires manufacturers to have the in-depth expertise needed to suitably define CQAs, as well as robust analytical methods to ensure CQAs are met.

Pushing facilities even further
 

To effectively provide mRNA therapeutics on both a large and small scale and guide mRNA production through to a commercially viable product, CDMOs will need to evolve further and to ensure their facilities are state of the art.

There are now CDMOs with facilities fully equipped with the necessary capabilities to successfully support mRNA production, from plasmid (pDNA) linearization to IVT, purification and LNP formulation. However, the demand for flexibility in mRNA therapeutic production continues.

In contrast with the global demand for the large-scale manufacturing of COVID-19 vaccines seen in 2020, there is now a growing need for small-batch mRNA therapeutic production. Personalized medicines, targeting chronic diseases and different cancer types, are now a predominant driving force behind the growing mRNA therapeutics market (3). This trend puts CDMOs under pressure to provide GMP manufacturing for clinical and commercial from small to large scale and from IVT pDNA linearization up to the finished product.

There are also challenges stemming from increasing demand for timeline acceleration. Throughout the pandemic, successfully delivering mRNA vaccines to the global population to limit the impact on patient health relied heavily on the ability of CDMOs to shorten timelines. To achieve streamlined timelines, manufacturers had to ensure all aspects of development and manufacturing were highly optimized. The pressure to deliver mRNA therapeutics to key milestones on the journey to market has not wavered since. Patients still need critical therapies delivered as soon as possible to treat diseases and improve their quality of life. Financers also wish to see a rapid return on their investment in the drug product.

With a growing number of mRNA therapeutics in pre-clinical and phase I stages, many biotechs are focused on streamlining timelines to produce material needed for testing and clinical trials to gather data needed to progress to the next key milestones. To meet the need for accelerated development pathways, CDMOs must continue to increase efficiency in existing processes to enable faster delivery while maintaining quality. And that’s why you’ll see so many CDMOs offering the so-called “one-stop-shop” approach; end-to-end mRNA manufacturing capabilities from process development to fill and finish can help minimize the need for lengthy tech transfer steps, which helps reduce timelines.

Going forward, CDMOs must continue to demonstrate flexibility in response to changes in the market and adapt to enable accelerated timelines. By leveraging their previous experience, expertise, and carefully designed facilities, such organizations will be poised to help meet the ever growing demand for both large- and small-scale production of mRNA-based medicines.