July 31, 2023 PAO-07-23-CL-03
Sales of three COVID-19 vaccines are currently driving the value of the global market for mRNA products. Estimates vary widely, however, with different market research firms pegging the value at $33.61, $39.92, and $42.63 billion in 2021 and $34.74 and $51.05 billion in 2022. Compound annual growth rates for the global mRNA therapeutics and vaccines market also cover a wide range from 1.7% to 13.05%, with the mRNA market projected to reach $38.21 to $128.13 billion by 2030. Prophylactic vaccines against infectious diseases, including not only COVID-19 but also polio, rabies, human papillomavirus (HPV), influenza (flu), and hepatitis B, among others, will initially be the primary driver of growth. The emergence of cancer vaccines and mRNA therapeutics will add more fuel for the expansion of the sector as these candidates advance through the clinic. At present, more than 35 biopharma companies are evaluating nearly 200 mRNA-based candidates for the prevention and/or treatment of an extensive range of different diseases in clinical trials at various stages of development.5 The companies exploring mRNA vaccines and therapeutics span the range from the largest international pharma firms to dedicated mRNA-based startups. Increasingly, large pharma companies are establishing collaborations with smaller organizations specializing in mRNA development, gaining access to novel technologies that address efficacy, stability, and other issues that must be overcome to realize the full potential of mRNA. Collaborations between industry and academia are also prevalent in this field, with nearly 150 significant collaborations recently identified.5
Achieving proven success with mRNA therapeutics and vaccines targeting non-COVID-19 diseases has been key to advancing the mRNA sector from an exploratory space into a dynamic market. Making that happen will require addressing a range of challenges, from stability during manufacturing and shipment to efficient, targeted delivery in the body.
However, the use of mRNA as a drug substance and vaccine is not as novel as the dynamics might suggest. Decades of research and development work set the stage for the rapid commercialization of the COVID-19 vaccines when the emergent need arose, and the lessons learned are being applied, along with continuous new discoveries, to further advance mRNA technology.
The increased demand for mRNA manufacturing during the COVID-19 pandemic and the anticipation of further growth as the filed matures has created some new challenges, such as the need for more efficient, scalable, and cost-effective manufacturing processes. Finding solutions that enable the production of more stable mRNA products that can be readily shipped around the world is equally important. Achieving very high purity from an in vitro transcription reaction followed by various enzymatic reactions and/or capping reactions may require process development. Designing mRNA drug substances with sufficient bioactivity that do not trigger reactogenicity or undesired immunogenicity is at the center of product development efforts, with significant work involving the improvement of delivery systems to allow targeting of specific tissues or cells.
Beyond product and process engineering, outsourcing of mRNA drug product manufacturing can be a challenge. In most cases, pharma companies rely on a number of different contract development and manufacturing organizations (CDMOs) to provide different GMP raw materials and to perform different steps of the mRNA production process. In some cases, companies must coordinate the activities of five or six different CDMOs.
The need to complete multiple transfers from one CDMO to another only complicates an already complex manufacturing process. Significant issues can also arise as an mRNA candidate moves from phase I to phase II if the initial outsourcing partner failed to effectively design scalability into their production process.
Material-related challenges present another important issue. The supply chain tends to be sluggish with respect to provision of GMP-grade raw materials for mRNA manufacturing, and in many cases the cost of these key ingredients can be quite high. In fact, the expense of manufacturing mRNA is largely driven by the high cost of the enzymes, capping technologies, modified nucleotides, and specialized lipids required. While high costs were more acceptable during the pandemic when speed was the main priority, for mRNA products to be successful — in other words widely accessible and competitive in the marketplace — the cost of goods must be reduced significantly, which will likely require efforts and commitments from multiple suppliers and stakeholders.
The complex manufacturing process and unique process requirements associated with mRNA production, while daunting, can be effectively managed when all aspects of the process are performed in one location. A fully integrated CDMO can overcome the challenges presented by the use of multiple service providers, maximizing efficiency, reducing cost, and increasing the quality of plasmid DNA starting materials, mRNA drug substances, and mRNA–lipid nanoparticle (LNP) drug products.
mRNA developers also face challenges associated with the navigating through a complexity of discrete intellectual properties, which could potentially be avoided by working with a CDMO partner that offers a comprehensive, secured internal process platform.
One such CDMO is BIOVECTRA, a fully integrated CDMO solution designed to help mRNA therapy and vaccine developers overcome the challenges they face with current programs that rely on multiple outsourcing partners. Using BIOVECTRA as a single source of pDNA, lipids, and mRNA drug substances, as well as mRNA–LNP drug products, including all necessary analytical support and fill/finish activities, can drive synergies, reduce complexities, save on costs, and compress timelines for clients.
BIOVECTRA decided to enter the mRNA manufacturing space during the COVID-19 pandemic as a means to establish Canadian capacity in this crucial, next-generation technology. The company received a $40 million grant from the Canadian government (along with $10 million from the provincial government) to invest and build an mRNA and biomanufacturing center in Atlantic Canada. Our private equity owners also made significant investments to enable construction of a brand-new facility, which will be online for GMP manufacturing in 2023, with scales from shake flasks and smaller lab-scale equipment up to the 1,000-liter scale for pDNA and the 30-liter scale for mRNA drug substance, and complementary scales for mRNA–LNP drug product. Two separate fill/finish lines provide capacity for over 20,000 vials per day each, which equates to nearly 70 million doses per year of a typical mRNA vaccine.
While BIOVECTRA is new to the mRNA manufacturing space, we have already established in-house manufacturing platform processes for pDNA, mRNA, and mRNA–LNP production. We are also very experienced in tech transfer, scale-up, and validation, having successfully completed numerous projects in the biologics and small molecule space over several decades. We are applying the principles of Managing Successful Programs (MSP) in engineering to our processes to ensure that we support our clients from the research stage through commercialization, which relates back to our commitment to being a one-stop supplier that enables streamlined and seamless development journeys for our clients.
It should be noted that while BIOVECTRA does not currently have specific plans in place to provide other important raw materials needed for mRNA drug substance and drug product manufacturing, we do have the capability to do so. Of particular consideration are in vitro transcription enzymes and other reagents that are either single-sourced or not available at GMP grade; such materials may be added to our portfolio in the future, given BIOVECTRA’s extensive experience in biologics manufacturing.
Access to the right talent is always crucial, but particularly so when entering a new technology space. BIOVECTRA recognized this important factor at the outset and has worked diligently to add highly skilled, talented, and qualified experts in mRNA development and manufacturing to our staff. As a result, our diverse community of approximately 630 professionals in science, quality, manufacturing, engineering, and business has been expanded with the addition of nearly 100 new positions in 2023 alone.
Access to talent is made possible through several new innovation centers, including our new process development just outside of Halifax, Nova Scotia, a strategic region with several universities producing young, eager professionals. BIOVECTRA has also hired a number of experienced consultants who have been in the mRNA and LNP sectors for decades. These experienced individuals are helping us develop our processes and train our existing associates in state-of-the-art techniques. Another successful approach has been to leverage the digital technologies available today that make remote work a realistic and executable strategy for many positions.
Additionally, BIOVECTRA has established internship programs with Canadian universities to allow ongoing access to students and the opportunity to secure the development of these young talents.
The decision to construct a brand new, state-of-the-art facility for mRNA production was made deliberately. BIOVECTRA chose not to attempt to repurpose existing equipment but to invest in fit-for-purpose, automated, and scalable production systems optimized for mRNA manufacturing. Where appropriate, we will use older, established technologies, but where newer solutions are the best option, we are not afraid to implement them. Finding the right equipment has been made possible through collaborations with equipment vendors. For instance, bioreactors designed for the production of traditional biologics often do not have features needed to ensure optimal generation of mRNA. They generally rely on impellers for mixing that can cause shear damage to mRNA molecules. BIOVECTRA has further invested time and resources to propose an internal platform, as well as analytical solutions, aimed at achieving high quality and reducing project development lead times.
Critical partnerships with key technology innovators are making it possible for BIOVECTRA to scale processes and offer GMP production for licensed clients. Other collaborators include a Canadian university consortium, the National Research Council of Canada, and the Canadian Alliance for Skills and Training in Life Sciences (CASTL).
The evaluation of BIOVECTRA-developed manufacturing platforms and technologies has occurred in partnership with BIOVECTRA’s clients. Various factors are taken into consideration, such as our clients’ desired final specifications, target dosage, necessary price points for market success, the indication, and the regional markets where they intend to launch. That information is combined with the knowledge that we have built over decades helping clients commercialize products in the biologics space. Overall, decisions are made by working closely with our customers and taking into account their data, regulatory requirements, and commercial scale, with a key focus on supply and sustainability of that supply.
Examples of next-generation solutions incorporated by BIOVECTRA to address mRNA manufacturing challenges include not only optimized processing equipment but the use of lower-cost and higher-performing enzymes. We have also placed an emphasis on automation to reduce manual manipulations and manufacturing risk.
As a manufacturer of both small molecules and biologics, BIOVECTRA is ideally positioned to support clients developing mRNA vaccines and therapeutics. We have longstanding capabilities in both complex chemical synthesis and microbial fermentation at small to large scales. That includes experience producing enzymes, proteins, lipids, and PEGylated molecules and diagnostic reagents, as well as formulating drug products within liposomal and LNP delivery systems. With this wide range of expertise, BIOVECTRA is very well-positioned to expand into the production of pDNA (via microbial fermentation) and add on capabilities in mRNA drug substance and mRNA–LNP drug product manufacturing consistent with the high quality and efficiency standards that BIOVECTRA has long brought to pharma and biopharma programs.
References
Jessica Madigan, B.Sc. (chemistry, 2008), has 14+ years of experience focused on nucleic acid manufacturing and development. Jessica played a key role at start-up company TriLink BioTechnologies (first CMO/CDMO for mRNA and inventors of CleanCap technology), leading to successful launch of mRNA, plasmid, capping analogs, and modified nucleotide products. Jessica also holds a Project Management Professional (PMP) Certification and successfully managed over 30 API manufacturing projects for mRNA early-phase clinical trials. At BIOVECTRA (2022–present), Jessica supports business development efforts for pDNA, mRNA, and formulation services.
.svg)