Significant leaps in therapeutic innovation begin with a series of long-term scientific discoveries. Translating that innovation and those discoveries into the lab, clinical development, and ultimately the marketplace for curative medicines requires a supply of consistently high-purity test material produced via innovative manufacturing technologies.
Messenger RNA (mRNA), discovered in 1961 as the intermediary between genomic DNA and proteins, can be manufactured synthetically. Once inside a cell, this manufactured mRNA will do what mRNA normally does: make proteins. When combined with a non-viral vector, such as a lipid nanoparticle (LNP), these mRNA medicines produce proteins to safely provide a clinical benefit. Pioneers in the field include the vaccine unit of Novartis and the rare disease unit at Shire, as well as mRNA specialty companies, such as BioNTech, Curevac, and Moderna.
The level of research and investment in the foundational mRNA technologies over the past 20 years set the stage for mRNA to find its rightful place in the clinic by the mid-2010s. The rapid and agile deployment of mRNA vaccines for COVID-19 put this versatile platform further into the spotlight, increasing demand for the development of mRNA drug products and further establishing the chemistry, manufacturing, and controls (CMC) framework for this class of medicines. As a platform technology, mRNA-based approaches can be applied to numerous applications, including vaccines, personalized medicine, and cellular therapies. The growing demands of the field of mRNA medicines and the associated supply chain needs led to the founding of Vernal Biosciences, with its mission to be a trusted source for manufacturing high-purity mRNA for all use cases ranging across early-stage discovery to clinical development and beyond.
Vernal Biosciences Addresses Challenges in the mRNA Ecosystem
In 2014, Vernal Biosciences’ Founder and Chief Executive Officer Christian Cobaugh, Ph.D., was the first scientist that Alexion Pharmaceuticals’ assigned to their pioneering partnership with Moderna Therapeutics for the discovery and development of mRNA medicines to treat rare diseases. Cobaugh expanded his mRNA experience through R&D, process development, and drug discovery efforts at Arcturus Therapeutics, Translate Bio, and at Omega Therapeutics, where he also led manufacturing. The combination of these experiences influenced Cobaugh’s commitment to the requirements for success in the development of mRNA medicines, including the supply of high-purity drug substances and products.
"The number one issue that holds back important discovery and clinical programs is the lack of a reliable supply of high-purity mRNA," shared Cobaugh. “Without that reliability, all research, ranging from cell-based screening to preclinical studies and then further into clinical development, is at tremendous risk.”
Using lessons from that formative period at Alexion, Cobaugh’s teams have made a commitment to continuously improve the reliability of mRNA and LNP–mRNA supply. To do this, these teams have focused on robust manufacturing and quality control processes, incorporating U.S. FDA regulatory feedback on the process and analytical technologies to scale from bench to bedside. Curiously, this fully integrated approach has not been easy to find among mRNA and LNP outsourcing options.
“In my recent past, we began to notice profound gaps in quality, scale, and integration when we first issued requests for proposals for clinical manufacturing,” recalled Cobaugh, “Additionally, the simple acts of receiving meaningful responses, quickly scoping out the work, and negotiating contracts was overly time-consuming. Given all the other things that some of these CDMOs offered, we were left unsatisfied with their urgency and their lack of a fully integrated approach for a robust and sustainable supply of clinical material. This acute pain on the buy side of the market led me to create Vernal Biosciences.”
Providing End-to-End, Full Life Cycle mRNA Therapeutics Solutions with Platform Processes
While a piecemeal marketplace of suppliers and service providers supporting mRNA medicines discovery, development, and commercialization has grown in capacity, there remains a pressing need for a collaborative, fully integrated CDMO partner for the entire lifespan of mRNA programs.
"To address the shortcomings and barriers in the marketplace, Vernal built capabilities to serve all three areas critical to the manufacture of mRNA products — plasmid manufacturing, mRNA manufacturing, and lipid nanoparticle formulation,” commented Duncan Liew, Senior Vice President, Commercial, at Vernal Biosciences. “We’re not dependent on a network of suppliers and collaborators, as dependencies can cause delays, particularly as the interest and investment in mRNA therapeutics continue to escalate. Additionally, we’ve taken the time to develop platform processes and analytical technologies so that our clients don’t have to do all that work. Within our platform, an entirely new product can be made solely by changing the mRNA sequence. Our extensive platform experience on these technologies, supply chain, and our facilities becomes our client’s experience.”
Expertise is also critical to serving as an effective end-to-end solutions provider, particularly in an emerging field like mRNA, and Vernal Biosciences has assembled a highly experienced and capable team.
“There is no learning curve at Vernal like there is within other organizations; we have the experience and the expertise, and we’re ready to go,” Liew said. "We’re built to scale with all use cases in mind. Our processes or facilities are designed so that no customer will feel compelled to tech transfer out for commercial production.”
"Additionally, we have structured our organization to allow products to move through our organization, from research to the clinic, fluidly — that’s one way we are differentiating ourselves in the market. Larger CDMOs are entering the mRNA space with gaps somewhere in the value chain. Perhaps they don’t address all stages of discovery and development, or only make mRNA and not LNP-mRNA, or require clients to bring a process. Often, fragmented facilities are required to complete all the unit operations, making it extremely difficult to coordinate schedules and the inevitable shifting timelines, a problem of particular note for smaller biotechs,” Liew continued.
Quality Built on Quality-by-Design Principles
Assuring quality in mRNA manufacturing is considerably different than many other products. For example, protein-based products generally rely on extensive downstream purification processes to achieve target product profiles.
"mRNA is fairly unforgiving," shared Grant Henderson, Vernal Biosciences' Senior Director, Manufacturing Science. "Regardless of the sequence, from the point of view of the chromatography column or whatever downstream tools you are working with, mRNA generally looks the same and behaves the same way in the purification process. If you have a heterogeneous mixture of mRNA coming out of your in vitro transcription (IVT) reaction, it's tough and costly to correct the problem with downstream operations.”
Henderson continued, “We've developed a quality control system built on QbD (quality by design) principles, beginning with the end in mind. We fully define and understand all critical quality attributes (CQAs) important to the final drug product. We then closely monitor these CQAs using sophisticated tools to optimize product quality and build in robustness. This approach aims to avoid the potential risk of encountering unanticipated process variability that could have huge and undesirable impact on the end product.”
From Research Use to GMP: State-of-the-Art mRNA Production Facilities
Vernal Biosciences was founded and structured to serve mRNA developers from early-stage research to commercial manufacturing.
The current facility, located just outside of Burlington, Vermont, produces mRNA products for research use and will be ready to manufacture GMP supply by April 2023. Additionally, a fully dedicated state-of-the-art, 20,000 ft.2 commercial-scale GMP facility is under construction in Essex Junction, Vermont. The plant, expected to become operational in mid-2024, will include GMP plasmid, mRNA, LNP formulation, and fill/finish capabilities.
"There are several companies that have been doing mRNA work for many years," Cobaugh commented. "The challenge many of these companies have is being locked into early-generation processes, and their inputs often date back to the 1970s. Vernal Biosciences is at an exciting point on the technology curve using all next-generation technologies, unencumbered by investments and decisions made decades ago.”
Serving the Diverse Needs of the mRNA Market
Vernal Biosciences designed its team, capabilities, and facilities to fluidly provide the complete set of services needed by an mRNA developer, from discovery to commercialization. In addition to serving the entire product life cycle, the organization is designed to serve a diverse cross-section of customers.
Vernal’s capabilities and expertise are well-suited for various organizations, from emerging biotechs to large pharma.
“We are well-suited to work with emerging biotechs,” expressed Cobaugh. "Not only do we have the expertise to formulate and manufacture mRNA products, but we're also helping our customers with dosing matters, such as routes of administration, estimating clinical supply needs, designing stability studies, creating bioanalytical techniques, and other critical issues. This willingness to advise and collaborate empowers all our customers. Additionally, the Essex Junction facility effectively positions us to provide surge capacity for large-scale clinical supply, including global vaccine programs.”
A Dynamic Future for mRNA
While manufacturing, process development, and quality assurance capabilities are critically important, thinking about future applications of mRNA technologies and how they can help facilitate this progress is what truly excites the Vernal Biosciences team.
"We are excited about applications where mRNA is being used to make designed and engineered proteins, such as precision nuclease like Cas9 or zinc finger nucleases that can edit a genome or therapeutically regulate endogenous gene expression,” Cobaugh reflected. "We are only at the beginning of using of mRNA medicines; in some ways, the uses for mRNA medicines are only limited by our imaginations. Our entire organization is excited to drive the breakthroughs of our clients and revolutionize healthcare as a highly collaborative mRNA manufacturer."
References
- Dolgin, Elie. "The tangled history of mRNA vaccines." Nature. 14 Sep. 2021. https://www.nature.com/articles/d41586-021-02483-w