Representing a versatile treatment modality for a variety of indications, messenger RNA (mRNA) technologies have paved the way for a new era of biotherapeutics used for therapeutic protein replacement, gene editing, cell therapy, vaccines, cancer therapy, and more over the last five years. Recognizing the transformative potential of mRNA-based medicines, it is even considered as the most suitable modality for the personalized therapeutics, and the biopharma industry has invested heavily in RNA technologies to support growing demand. 

Realizing the possibilities new mRNA therapeutics in the pipeline could offer patients in the future will only be possible with effective manufacturing processes to meet demand at both large and small scales.

However, the path to commercialization for mRNA therapeutics is not simple, and extensive expertise and experience are vital in overcoming the many challenges involved since the manufacturing standard and regulatory guidelines are not completely established yet.

This article examines the challenges mRNA producers are currently facing, including the need to meet unique manufacturing requirements while ensuring fast-tracked delivery. Looking to the future, emphasis should also be placed on the growing importance of adopting flexible manufacturing processes throughout mRNA production.

Setting the stage for a novel transformative drug modality

Before the last decade, mRNA therapeutics were relatively unheard of. Despite innovations enabling mRNA technologies to be efficiently and safely used as a therapeutic tool, their progress was slow as investment in the field was limited.

In 2020, the onset of the COVID-19 pandemic quickly pushed mRNA technologies into the spotlight, due to the many benefits they offered as a potential vaccine. Providing inexpensive, cost-effective, and scalable manufacturing positioned mRNA as a valuable technology in the global vaccine roll-out. Compared with traditional biologics, such as purified or recombinant proteins, live attenuated viruses, etc., mRNA technologies also offered the benefit of rapid production due to the lack of cell-based expansion. The fact that mRNA can be synthesized using a relatively simple in vitro transcription (IVT) reaction, which provides high yields in a small GMP facility footprint, further solidified mRNA as an ideal platform for vaccine development.

The field of mRNA-based therapeutics has subsequently grown rapidly as developers and investors increasingly recognize the potential of these revolutionary technologies. As well as vaccines, there are now over 300 mRNA technologies in the pipeline targeting a wide range of therapeutic areas, from rare diseases to cancers and metabolic disorders.¹

The customizable nature of mRNA technologies and ease of editing has presented biopharma companies with the opportunity to develop versatile platforms to engineer tailored medicines. With mRNA therapeutics offering a “plug-and-play” style platform, it is no surprise that their global market is expected to continue expanding, valued at $33.60 billion in 2021 and expected to reach $38.15 billion by 2030.²

Flexibility to meet changing mRNA therapeutic demand

With demand for mRNA therapeutics steadily rising, the biopharma industry must continue to seek support from contract development manufacturing organizations (CDMOs) to deliver these innovative therapies to patients at speed.

CDMOs played a critical role in supporting the development and manufacturing of mRNA technologies throughout the pandemic. Although few manufacturers were initially able to support mRNA production, those taking on the challenges to work with the widely unfamiliar modality quickly adapted their facilities to help meet global vaccine demand. Expanding and optimizing cold chain capabilities was a critical adaptation needed to ensure the stability of the temperature-sensitive mRNA molecules.

As well as facility changes, many manufacturers also had to rapidly determine how the lipid nanoparticles (LNPs) used for mRNA encapsulation would behave. Time was also needed for manufacturers to understand the impact of processing conditions on the characteristics of the final drug product. As many biologics manufacturers had worked predominantly with water-like solutions before the pandemic, the unfamiliarity of these molecules presented further challenges. 

Now, in the post-pandemic era, CDMOs that adapted their facilities to support mRNA production and gained experience supporting this once unfamiliar drug modality are well situated to meet the rising demand for mRNA technologies. Although these CDMOs are now fully equipped to support mRNA manufacturing, from plasmid DNA (pDNA) linearization to IVT, purification and LNP formulation, changing needs mean manufacturers must continue to demonstrate flexibility.

As opposed to the global demand for large-scale mRNA manufacturing following the onset of the pandemic, small-batch mRNA production is now required to meet the growing need for personalized medicines. Targeting chronic diseases and various types of cancer, personalized treatments represent the predominant driving force behind the expanding mRNA therapeutics market.

Under pressure to adapt to meet changing and growing market needs for mRNA-based medicines, it will become increasingly important for CDMOs to continue to offer flexibility in the future. This includes supporting GMP manufacturing for clinical and commercial from small scale to large scale, as well as from DNA template preparation for IVT up to the finished product.

A rising need to accelerate the journey to market

Throughout the pandemic, delivery of mRNA vaccines to the market and subsequently to the global population had to be achieved at an unprecedented pace to limit the impact of the virus on patient health. Achieving this feat relied heavily on the ability of CDMOs to streamline timelines while maintaining high quality. Accelerating the journey to market required all aspects of development and manufacturing to be highly optimized.

Pressure to streamline timelines to key milestones as mRNA products progress to commercialization is still prevalent. In the case of personalized mRNA cancer vaccine, short timeline from the diagnosis to delivery of final medicine to the patient is critical for the success of the treatment. The desire to deliver medicines to patients to treat disease and improve quality of life is a prominent driving force behind this demand, as is the wish of investors to see a rapid return on their investment in the drug product.

To continue to meet the need for streamlined pathways to market in the future, CDMOs must consider adopting new strategies and tactics while aiming to improve the efficiency of existing processes. Various approaches manufacturers can take to achieve shorter timelines and deliver critical mRNA medicines to patients faster include:

1. End-to-end solutions
Offering a one-stop solution and providing end-to-end service from process development to manufacturing, including fill and finish capabilities, allows CDMOs to effectively accelerate timelines. Manufacturers with the ability to deliver projects from preclinical to commercial levels from one facility can help reduce delays by minimizing the need for lengthy tech transfer steps. Additionally, transparent communication between all teams involved allows risks to be quickly identified and solved, further preventing possible delays.

2. Leveraging experience
The mRNA technology space is still relatively new. Having previous experience in overcoming the challenges in the production of this new drug modality can help to expedite timelines. CDMOs experienced in supporting mRNA projects in the past can apply their learnings to overcome difficulties and provide solutions rapidly to improve timelines.
For example, CDMOs that helped to produce mRNA vaccines throughout the pandemic will understand the importance of having a robust supply chain management approach to secure scarce materials for IVT and LNP manufacturing. With an effective supply chain management system already in place, delays, and issues because of supply disruptions can be prevented.

3. Expertise to navigate unique regulatory challenges
Understanding the unique needs of mRNA therapeutics and ensuring regulatory compliance is vital when developing efficient processes with speed in mind. As mRNA therapeutics are an emerging technology, regulatory bodies have had to quickly respond to new information and adapt guidelines accordingly. Consequently, the critical quality attributes (CQAs) identified based on the severity of harm to patients are currently not fully defined by regulatory bodies.

Ensuring the quality of mRNA therapeutics and preventing potential regulatory setbacks and delays requires in-depth expertise to define suitable CQAs as well as development of robust analytical methods designed to meet them. Tremendous efforts to reduce impurities during manufacturing efficiently and better understanding of the cascade effect of RNA therapeutics in human body are required yet challenging. A close relationship between the R&D center and the mRNA manufacturing group will strengthen the understanding of the characteristics, allowing suitable CQAs to be determined quickly and effectively. 

CDMOs supporting the future of mRNA technologies

To successfully hit key milestones while maintaining mRNA product quality in the face of changing demand, developers and manufacturers must continue to demonstrate flexibility. Leveraging previous experience and expertise and relying on partnerships offering end-to-end solutions can help meet the growing need for shortened timelines in the production of small-batch personalized medicines.

Understanding the evolving mRNA market, CDMOs are adapting to meet these changing needs, solidifying the vital role they will play in the future of mRNA therapeutics production and ensuring medicines reach the patients who need them as quickly as possible.

References
1. https://asgct.org/global/documents/asgct-citeline-q2-2023-report.aspx
2. https://www.globenewswire.com/en/news-release/2023/03/23/2633561/0/en/Global-mRNA-Therapeutics-Market-Size-To-Grow-USD-38-15-Billion-By-2030-CAGR-of-2-2.html
3. https://www.grandviewresearch.com/industry-analysis/mrna-therapeutics-market-report

---

Eonyoung Park is a lead engineer in mRNA manufacturing at Samsung Biologics. Before joining Samsung Biologics in 2021, Park, Ph.D. in RNA biology from Seoul National University, researched and developed RNA and antibodies at multiple U.S.-based labs for more than 12 years.