With the onset of the COVID-19 pandemic, an array of new and novel modalities were placed center stage by the biopharmaceutical industry, highlighting their potential. As a result, biopharma companies have started to further explore more unfamiliar technologies, including mRNA-based drugs.

With an upsurge in demand for these new technologies, contract development and manufacturing organizations (CDMOs) were compelled to rapidly expand their capability to support this kind of development. For example, accommodating mRNA-based vaccine manufacturing commercially requires cold chain capabilities and more robust aseptic fill-finish technologies.

Despite the challenges involved in having to quickly pivot to meet this new market demand, preparing for the new product modalities has placed these CDMOs ahead of the curve. With a wave of novel therapeutics on the horizon, including cancer-targeting mRNA-based drugs and cell and gene therapies (C>), these companies are well prepared for the transition ahead.

In this article, we’ll explore the challenges that CDMOs have faced as they welcome a new era of mRNA-based technologies and also discuss the opportunities that have arisen for companies supporting mRNA manufacturing in exciting new development areas.

Pivoting to work with multi-modalitie under pressure
Prior to the onset of the COVID-19 pandemic, mRNA-based therapeutics were predominantly aimed at treating oncology indications as opposed to infectious diseases. However, technical and scientific advancements have allowed researchers and drug developers to expand the use of mRNA to new and different therapy areas. Carriers for mRNA were also developed, further increasing the potential of mRNA by prolonging antigen expression in vivo.² Consequently, these improvements facilitated the success of mRNA-based COVID-19 vaccines and highlighted the expansive abilities of mRNA technologies.

With mRNA-based drugs witnessing a surge in popularity in such a short time frame, companies supporting their development and manufacturing had to adapt quickly to overcome the challenges involved. The investment in its potential has been tremendous. At the end of 2019, the combined market capitalization of the five publicly listed companies focusing on mRNA platforms was $15 billion.³ As of August 2021, that capitalization was more than $300 billion. Solving these challenges came with the added pressure of working around the difficulties presented globally by COVID-19.⁴

New and expanded capabilities were needed
As mRNA is a fragile molecule, extensive cold chain capabilities are required to prevent its degradation throughout manufacturing, storage, and transport. However, at the onset of the COVID-19 pandemic, many manufacturers were not equipped to support the new and novel mRNA-based technologies and lacked cold chain capabilities expansive enough to suit their production at scale.

Likewise, unfamiliar techniques used in the vaccines, including the use of lipid nanoparticles to encapsulate mRNA and enable delivery into cells, slowed production. It was not known how the nanoparticles would behave throughout manufacturing and how this could affect the characteristics of the mRNA products.

However, accommodating these projects as well as maintaining production of other essential medications that required the same type of facilities necessitated careful management of process lines and consumables. Balancing these requirements by leveraging the expertise and experience of people also necessitated both flexibility and scalability to successfully support the development of a wide variety of essential products.

With a sudden surge in mRNA-based projects, CDMOs had to adapt to take on additional projects using new technologies and offer optimized processes that meet the characteristics of the products. Only by expanding their facilities and capabilities were they able to meet the demand of these products.

Speed to market had to be further accelerated
A key aim for most biopharmaceutical companies is to achieve commercialization in the shortest time possible while maintaining high quality. During the COVID-19 pandemic, the urgency involved meant that mRNA-based products had to achieve this in an even shorter timeframe. Even when using regulatory agencies’ fast-track approval procedures, further tactics needed to be employed to achieve this.

Therefore, CDMOs had to also increase the efficiency of production while meeting capacity demand. All aspects of development and manufacturing had to be optimized to reduce risk and ensure a quality product could be quickly delivered.

Supply chains needed extensive management
With people across the globe being impacted by COVID-19, supply chains witnessed abrupt and enduring delays not only associated with transport disruptions but also increased demand for consumables.

As so many companies were aiming to produce their own vaccines and treatments globally in a short time frame, many shortages were seen that could impact CDMO productivity including extended procurement timelines for glass vials to syringes. Some biomanufacturers were reported to be waiting up to a year for single-use equipment.³ The pandemic also highlighted how reliant biopharmaceutical manufacturing was on certain countries. For example, manufacturing that relied on sterile bags for cell cultivation in bioreactors was dependent on only a handful of companies globally to source their supply.⁵ These shortages had the potential to delay both mRNA-based projects and previously ongoing projects, increasing the severity of the risk.

Manufacturers had to carefully manage supply chains as well as identify several potential alternative sources of equipment and consumables to rely on in the event of delays. Additional efforts had to also be taken to ensure that the alternative equipment and consumables were suitable for use and optimize these processes in preparation for when they were needed.

With robust supply chain management processes in place, companies that adapted their supply chains during COVID-19 were able to minimize the impact of delays and support company growth under challenging conditions. These companies are also now better prepared for similar challenges and will be able to fully support clients’ needs.

mRNA technologies offer disease fighters new tools to ward off future threats
Embracing the challenges of working with new technologies in the form of mRNA-based vaccines during a time of immense pressure has placed CDMOs in good stead for future projects. By expanding their cold chain and fill-finish capabilities required for the sterile production of mRNA-based products, these manufacturers will be able to meet demands for COVID-19 based products that are unlikely to relent. Boosters and vaccines targeting new variants will likely be needed for years to come.

However, not all mRNA products will be aimed at targeting COVID-19.

As mRNA technologies offer the ability to be easily edited, it has unprecedented versatility, resulting in its potential to be used to target a huge variety of different diseases. Synthesis of mRNA relies on in vitro transcription reactions. This means that vaccines based on mRNA also have the additional benefit of being relatively inexpensive, cost-effective, and rapid to manufacture in a way that is easily scalable. It also allows high yields to be achieved with a small GMP facility footprint.

The growing popularity of mRNA-based vaccines is reflected by the number of these drugs currently at clinical trial. As of July 2021, over 70 mRNA therapeutics were in clinical pipelines globally and there are many more assets currently in early development.⁶ Those in clinical phases include mRNA technologies for the treatment of cancers (ovarian, lymphomas, melanomas, and glioblastomas), ischemic heart disease, rare diseases (caused by Zika virus, Chikungunya virus), and more common diseases (caused by Rabies virus, HIV).⁶

Preparing for future advancements: C>s
It is likely that the demand for the development and manufacture of mRNA technologies will be present and unrelenting for years to come. Manufacturers that altered their capabilities to support previously unfamiliar products now have the experience and expertise necessary to work with and scale the new wave of mRNA technologies on the horizon.

They will not only be well prepared for mRNA technologies but also for the anticipated advancements in C>s. The American Society of Gene and Cell Therapy documented in its Gene, Cell, and RNA Therapy Landscape Quarterly Data Report (Q3 2021) that 3,366 C>s are currently in development globally.⁸ Reflecting this, the global C> manufacturing services market is predicted to grow at a compound annual growth rate (CAGR) of 12.4% in the next five years, with the market predicted to be valued at USD 13.8 billion by 2026.⁹ The huge number of therapies in development and the expected market increase in the C> area demonstrate the need and the potential for opportunities within this growing area.

Looking forward, CDMOs will need to keep adapting to solve challenges associated with C>, as well as develop their services to provide both end-to-end mRNA and C> capabilities to meet growing demand.

Moving forward to new modalities and lessons learned
The COVID-19 pandemic has highlighted the importance of being prepared and staying ahead of any challenge that could occur. CDMOs that demonstrated their agility and ability to respond to the shift in market dynamics, as well as adapt their manufacturing capabilities for new technologies, are best suited for the future.

By adapting their capabilities and facilities, optimizing processes, and solving challenges surrounding an unfamiliar technology, CDMOs that embraced the change can offer client satisfaction and preserve high drug quality for the patient. 

References

1. https://www.clinicaltrialsarena.com/comment/evolution-mrna-vaccine-trials-oncology/
2. Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines – a new era in vaccinology. Nat Rev Drug Discov. 2018;17(4):261-279.
3. https://www.nature.com/articles/d41573-021-00147-y
4. https://bioprocessintl.com/bioprocess-insider/upstream-downstream-processing/single-use-lead-times-up-to-12-months-as-covid-takes-its-toll/
5. https://asgct.org/global/documents/asgct-pharma-intelligence-quarterly-report-q3-2021.aspx
6. https://www.statista.com/statistics/1262846/clinical-pipeline-of-mrna-therapeutics-by-therapy-area-worldwide/
7. https://clinicaltrials.gov/
8. https://asgct.org/global/documents/asgct-pharma-intelligence-quarterly-report-q3-2021.aspx
9. https://www.europeanpharmaceuticalreview.com/news/160051/cell-and-gene-therapy-manufacturing-services-market-to-value-13-8-billion-by-2026/

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James Park is a Senior Vice President and Chief Business Officer at Samsung Biologics. With over 25 years of organizational leadership experience in the biopharmaceutical and pharmaceutical industries, Mr. Park has held various technical and operational positions, as well as business development management leadership positions in biopharmaceutical companies in the U.S., including ALZA Corporation, Watson Pharmaceuticals and Merck. From 2004 to 2015, Mr. Park participated in and directed 100+ CMC due diligences on assets ranging from pre-clinical to commercial products, and managed global manufacturing and supply BD activities including licensing, outsourcing and M&A at Bristol-Myers Squibb.