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Manufacture Vaccines, Small Molecules

The Road Ahead for mRNA Manufacturers

sponsored by Thermo Fisher Scientific

Over the course of this series, we’ve ridden the “mRNA highway,” covering process robustness, scale- up, optimization, and more. Here we summarize key findings and reveal pressing priorities for the next stages of the journey by speaking with Serena Smith, Director of Market Development and Strategy, mRNA Vaccines and Therapeutics at Thermo Fisher Scientific.

How will mRNA therapeutics help meet unmet medical needs?

I think the fact you’ve phrased the question with “will” rather than “might” says a great deal. Certainly, the speed at which mRNA vaccines can be developed and manufactured makes this an enabling technology for seasonal vaccines, as well as any future emergency response. However, mRNA is also highly versatile and can be used for other indications beyond vaccines; the current clinical pipeline consists of rare disease indications, personalized cancer treatments, and more. As more clinical data become available, I fully expect the clinical pipeline to continue to expand.

What lessons from mRNA-based SARS-CoV-2 vaccines can we apply to the next generation of mRNA therapeutics?

I think we can all agree that mRNA vaccines played—and continue to play—a significant role in the fight against SARS-CoV-2. The speed and partnership of drug manufacturers, governments, regulatory bodies, and raw material suppliers have been keys to success. But another important lesson learned relates to the misinformation among the global population of nonscientists; there was a significant amount of fear and skepticism in the general public about how quickly the SARS-CoV-2 vaccines were developed and the use of novel technology. Continuing to inform and educate the public about mRNA therapeutics and vaccines — and, frankly, about drug development and approval processes as a whole—could reduce that fear for the next generation of mRNA therapeutics.

What areas need to be prioritized?

mRNA is still a relatively immature therapeutic technology. One significant concern from drug developers and manufacturers is the cost of goods (COGs). COGs will come down as process yields and operational efficiencies are improved, which will happen with experience as the technology develops. To me, the main priorities lie in formulation; for example, reducing the amount of lipid nanoparticle (LNP) required or improving storage temperatures and shelf life will have a big impact on the success of this technology for indications beyond SARS-CoV-2.

COGs will come down as process yields and operational efficiencies are improved, which will happen with experience as the technology develops.

What impact or benefit do you think self- amplifying RNA and circular RNA will have?

Replicating RNAs, such as self-amplifying RNAs, and circular RNAs will enable lower doses and longer duration of effect. For some indications, this could improve clinical efficacy and potentially reduce the frequency of doses, which could improve the tolerability of the drug or adherence to the dosing regimens. Though there have been some technical challenges in bringing these technologies forward, I believe that they are crucial to the future of mRNA therapeutics.

mRNA Viewpoints

We asked specialists in the field for their view on the future of mRNA drug development

Hagen Richter, Head of Nucleic Acid Research, Wacker Chemie AG

Revolutionizing vaccines and beyond

“We have seen tremendous success with mRNA-based SARS-CoV-2 vaccines, which have pushed an entire field straight from research into commercial production. This includes also the pivoting by contract manufacturing organizations, such as Wacker Biotech, the CDMO branch of Wacker Chemie AG. While companies like Moderna and CureVac have long been involved in vaccine development, a major pillar of their development work has been cancer therapies. Besides the obvious developments in the vaccine space, many new routes to cancer treatment will open up. mRNA offers huge potential for CRISPR-Cas and other gene-editing approaches and, due to the transient nature of RNA, will help to overcome major hurdles, such as off-targeting effects. In vaccine development, it also provides scope for the development of platform-like processes for faster responses to emerging diseases or the development of vaccines for treating severe diseases where there is unmet need, such as malaria. Although the potential is huge, we must keep in mind that many of the developments are in their early stages.”

The need for varied expertise

“This is a dynamic and rapidly developing research area, and collaborations and partnerships will be very important. Current mRNA production and development processes require multiple areas of expertise: template and mRNA design, template DNA manufacturing, mRNA production, formulation of RNA, and final filling of the end product. On top of that, there are regulatory requirements that have to be met. All of these steps require different skill sets that can be ideally combined in smart partnerships. Only by partnering will companies be successful.”

Caryn Fenner, Executive Director: mRNA Hub, Afrigen

Lessons learned from SARS-CoV-2

“It has been shown that if certain bureaucracies are cut, product development times can be expedited, without compromising on safety, quality, and efficacy. The value of a true platform was also demonstrated during the SARS-CoV-2 crisis; in other words, the mRNA platform established by Moderna and others meant that safety data, formulation technologies, and so on established over a long time could be used and built upon to fast-track development of a new product.”

The need to address costs

“Supply chain challenges still exist for raw materials, consumables (particularly single-use), reagents, enzymes, and so on. Suppliers are extending their capacity and capabilities but have not yet caught up to demand; extensive lead-times are still experienced, especially in Africa and other low- and middle-income countries. In short, we need to find innovations that can reduce COGS.”

Jean Luo, Vice President and General Manager, Purification and Pharma Analytics, Thermo Fisher Scientific

Opportunities for optimization

“The potential of mRNA is seemingly endless, but, as more novel applications are explored, more opportunities for optimization arise. As with all therapeutics, cost and yield are major drivers, so mRNA developers are continuously seeking higher productivity solutions. Looking at the downstream process, there are two pain points that many developers are keen to prioritize. The first is the need for higher-capacity and higher-throughput purification resins that are easily scalable with short process development timelines, which enables quick and concurrent manufacturing development along clinical trial progression. The second is the need for better tools to support the removal and quantification of double- stranded RNA (dsRNA). dsRNA is a by- product of the in vitro synthesis process and has become a major concern as it has been shown to be a major trigger of the immune pathway. In seeking to minimize the cellular immune response, it is critical to eliminate dsRNA contaminants. Resolving both challenges will require an intimate collaboration between purification solution providers and mRNA therapeutic developers.”

Partnering is crucial

“Partnership is critical at this early stage of mRNA therapeutics. All players within the industry need to work together to solve manufacturing challenges and help mRNA technology progress faster. Through our close interactions with mRNA vaccine manufacturers, we are pursuing collaborative opportunities to improve resin capacity and throughput to drive improved process economics. Moving forward, I see the mRNA market evolving to include both large-scale mRNA manufacturing, such as vaccines, as well as manufacturing of personalized mRNA therapeutic solutions. We are also seeing diversification as the industry evolves to include self- amplifying RNA and circular RNA. With this ever-changing landscape, it is crucial for solutions providers to closely partner with both large and emerging mRNA developers and manufacturers to understand their evolving needs and to continue developing new and innovative products that will continue to help advance this exciting modality.”

Patrick Jones, Vice President and General Manager, Nucleic Acid Therapeutics, Thermo Fisher Scientific

Enabling manufacturing of future mRNA vaccines

“Vaccine developers moved at an unprecedented speed during the early days of the SARS-CoV-2 crisis. This intense focus on identifying and manufacturing a solution resulted in extreme supply chain challenges, magnified for mRNA vaccines. mRNA production rapidly scaled, requiring inputs to scale just as rapidly. Many critical raw materials used for mRNA production were not initially available at the quality or scale suitable for commercial vaccine manufacturing. During this time, Thermo Fisher Scientific committed to enabling our customers by investing in capacity and the development of these critical raw materials. Our Thermo ScientificTM TheraPureTM GMP* portfolio delivers on that commitment by providing high-quality and reliable enzymes and nucleotides. And the investments we made during the response to SARS-CoV-2 will alleviate supply and quality constraints for future mRNA vaccines and therapeutics.”

How do you see mRNA evolving in the future?

I expect mRNA to evolve in two ways. First, towards personalized treatments— we already see this with cancer pipelines (including BioNTech’s iNeSTTM platform). And second, towards combination treatments; for example, Moderna has announced that it is working on a respiratory vaccine combination that would include mRNAs coding for antigens against influenza, SARS-CoV-2, and RSV. As the technology evolves and formulation challenges are addressed, I expect us to see additional innovations and vaccine combinations designed for different patient groups and, ultimately, combinations tailored to individual patients.

Closing words?

I am proud to work for an organization that has invested in novel products and services to enable our customers to develop and commercialize mRNA vaccines and therapeutics. Personally, I can’t wait to see the continued impact that mRNA technology will have on the future of medicines—spurred on by the amazing success during the SARS-CoV-2 crisis.

*“TheraPure GMP” refers to the quality level of the raw, ancillary, or starting materials to be used for further manufacturing. TheraPure GMP products are manufactured in facilities with ISO 9001–certified quality management systems operating in accordance with relevant good manufacturing practice (GMP) principles as outlined in ICH Q7 or equivalent guidance documents or standards.

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