Achieving Short- and Long-Term mRNA Manufacturing Goals

The following article is an opinion piece written by Scott Ripley. The views and opinions expressed in this article are those of the author and do not necessarily reflect the official position of Technology Networks.

The work to prepare for future pandemics must begin now with the development of a rapid vaccine manufacturing and distribution strategy. The COVID-19 pandemic showed the importance of having a global vaccine development and manufacturing infrastructure in place. Global public health emergencies need coordination among governments, academia and the life science industry – no single organization can do it alone. The development of mRNA vaccines is an example of what can be done when key stakeholders work together. However, at the same time, we must also think about what needs to be done to meet the long term needs of mRNA manufacturing.

Although there is still a lot to be learned about the advantages and disadvantages of mRNA, there are more than 140 clinical trials underway looking at infectious disease, cancer and other application areas. mRNA vaccines have the potential to work for small- to medium-batch sizes as well as large-batch scale, making them suitable for personalized medicine. Additionally, mRNA systems in comparison to traditional ones, are much faster because they do not require animal cells. This also potentially makes them safer, although mRNA vaccines have yet to have the proven efficacy and safety of viral vector vaccines due to their novelty.

Combining the power of mRNA with advances such as CRISPR, in vivo cell therapy approaches and targeted intracellular antibodies opens a potentially powerful toolbox that could transform the global healthcare paradigm. Just as we needed collaboration to accelerate the development of COVID-19 vaccines, collaboration between industry stakeholders to industrialize the manufacturing ecosystem is needed.

While we work to industrialize and standardize processes to meet long term manufacturing needs, we must ensure they are flexible in both scale and process as new molecules emerge. At the same time, we must prepare for future global health needs. Scientists from the Coalition for Epidemic Preparedness and Innovations (CEPI) interviewed representatives from vaccine-development firms, international organizations, academia and industry to discuss what can be done to develop a vaccine in 100 days and published their findings in the New England Journal of Medicine. The following five areas were identified as the most important to focus on:

1.       Leveraging insights about new pathogens and technologies

2.       Supporting innovation in the vaccine development process

3.       Advancing analytics to inform processes

4.       Promoting collaboration among stakeholders

5.       Continuously reviewing evidence to support approval.

A rapid vaccine development strategy is crucial for global health preparedness. Current best practices must be implemented while working toward the outlined goals. Rapid testing of therapeutic candidates must also be a part of the strategy. The National Institute of Allergy and Infectious Diseases (NIAID) proposed to develop and characterize prototype vaccines and the goals of the plan include:

• Characterizing pathogens of concern
• Shortening timelines between pathogen emergence and countermeasures
• Bridging or eliminating gaps in research, infrastructure and technology

Key findings from previous pandemics and epidemics have shown how a lack of preparedness and coordination hinders the response. Making simplified and transferable manufacturing practices the norm and enabling scaled-up processes when needed is key to enabling the manufacturing ecosystem for long- and short-term global health needs.

mRNA process challenges

mRNA vaccines have the potential to be completed in as little as five weeks. At the same time, there are challenges that must be overcome. One of the biggest challenges is adapting the process. Most processes are designed and optimized for other molecules. The new areas of manufacturing and development have not yet been standardized leading to challenges with operations, personnel, process, quality control, contamination and others.

Another challenge for mRNA is that it is much smaller scale than traditional cell-based modality manufacturing. While this is a very attractive feature because it can provide considerable space and cost savings, it does require that manufacturers think differently about their space. Another benefit to mRNA manufacturing is that changing manufacturing parameters doesn’t present as many contamination risks.

DNA linearization and purity at various stages of the process is another challenge. Due to their size and varying impurity profiles, traditional chromatography resins don’t always interact well with mRNA molecules. Two ways to address this challenge are greater flexibility in purification technologies and allowing process development scientists to mix and match media based on the specific characteristics of the molecule. Continuous supply of raw materials and obtaining GMP-grade reagents are other challenges faced by scientists.

The key to success is flexibility

Flexible and resilient solutions will be one of the key drivers for enabling an ecosystem that can respond to changing demands. Building resilient and flexible solutions will allow researchers the ability to scale rapidly if needed. Currently, scaling is one of the most common bottlenecks in mRNA manufacturing. Ensuring equipment is scalable and supporting the transfer from process development to GMP manufacturing will be a critical success factor in building out the mRNA manufacturing ecosystem.  

Planning for the potential uptake of the therapy, assessing material suitability, sourcing materials early, and considering the fill finish process during early-stage development will also help build resilience and flexibility into the process.