March 12, 2022 PAO-02-022-CL-07
Before the emergence of the COVID-19 pandemic, mRNA therapy was regarded as a niche opportunity within the biopharmaceutical industry. However, this view was completely upended by the rapid and successful development of the COVID-19 mRNA vaccines. Today, not only is the entire industry familiar with mRNA technology but wide swathes of the globe are, too. That level of recognition is quite important, not only with respect to advancing mRNA vaccines and therapeutics and bringing products to the market, but also in terms of patients’ perception of mRNA products, because they are no longer considered strange or foreign.
Given that background, mRNA and plasmid DNA (pDNA) technologies are poised to be truly disruptive. They are elegant solutions with the potential to solve unmet therapeutic challenges and resolve patient needs in oncology, immune diseases, genetic disorders, and beyond. The applicability of mRNA technology to a multitude of prevalent diseases with which the global patient population currently struggles is truly unique.
In addition, compared with the processes required to produce recombinant proteins and monoclonal antibodies, mRNA production methods are far less complex, thereby presenting an inherently biological approach to protein delivery for patients. It also reduces the opportunities to introduce impurities that represent primary toxicity concerns, such as endotoxins and mycotoxins from cell lines and protein aggregates. The challenge — and opportunity — is to advance the technology from eliciting a general immune response (vaccines) to targeting specific disease cells (therapeutics).
While the rapid success of the COVID-19 mRNA vaccines and the attention they brought to mRNA technology has made it seem to some that the technology was developed especially rapidly, that success is underpinned by decades of development. RNA therapeutics have been on the market for several years; the underlying technology needed for the production of mRNA has been used for decades in the manufacture of other pharmaceuticals. Specifically, microbial fermentation is used in the production of plasmid DNA — the key raw material for mRNA manufacture — and biocatalysis and enzyme complex purification are key processes in mRNA synthesis.
On the other hand, the development and manufacture of mRNA therapies and vaccines, somewhat akin to antibody–drug conjugates, requires expertise in two very different technologies — biomanufacturing and chemical synthesis.
A CDMO that offers expertise in both microbial fermentation and chemical synthesis, biocatalysis, and enzyme purification is therefore well positioned to support customers developing mRNA products. BIOVECTRA is one such organization. The company started as a manufacturer of small molecules via chemical synthesis, then added microbial fermentation for small molecule production approximately 30 years ago. Large molecule manufacturing via microbial fermentation began in 2008, and, in 2014, dedicated development and manufacturing capacity was added with the construction of a biologics facility in Nova Scotia. In many ways, it is in BIOVECTRA’s DNA to continually expand into new frontiers and diversify its capabilities, clients, and technologies.
For BIOVECTRA, a move into DNA and mRNA therapeutics and vaccines means organic growth into an analogous capability that marries our existing available technologies and decades of experience in both the fermentation of biologics and small molecules, and complex chemical synthesis, including not only biocatalysis but the manufacture of lipids and PEGylation reagents. Indeed, BIOVECTRA has played an active role in the mRNA supply chain in various ways over the last five years, from formulation development to the commercial manufacture of lipid and protein-based, nanoscale delivery systems for similar products. Formally expanding into plasmid DNA and mRNA production is a logical next step.
Making the formal move into mRNA at BIOVECTRA involves the development of a state-of-the-art facility specializing in the production and manufacturing of mRNA vaccines and therapeutics –– one of the first of its kind in Canada. The total investment in the mRNA vaccine and biomanufacturing facility is approximately U.S. $65 million, and it adds 36,000 ft2 in Prince Edward Island and 18,000 ft2 in Nova Scotia to our biomanufacturing footprint.
The facility located at BIOVECTRA’s Charlottetown, Prince Edward Island location will support the development and manufacture of nucleic acids, recombinant proteins, and other therapeutics expressed via microbial fermentation, including the production of up to 160 million doses of an mRNA vaccine per year. In addition, fill/finish capabilities are being incorporated into the site, with the capacity to prepare and package 70 million final doses per year for commercial distribution.
Co-locating the mRNA capabilities with our chemical API production facility will extend the capabilities of our pilot-scale microbial fermentation suite already at the site. Approximately one-quarter of the funds will be directed toward additional new process development capabilities to strengthen existing capabilities and expand on proven, highly successful technologies, including high-throughput and robotic systems that allow us to really match the need that we’re seeing in the market for increased speed.
In addition, cell line development and cell banking services, which were previously outsourced, will be established internally at the new facility. These capabilities will be used in-house but also made available as a service for clients and partners. BIOVECTRA will be in a position to initiate programs from the gene of interest, identify optimal plasmid expression, create master cell banks, and advance further in the development of plasmid DNA and mRNA therapies.
Establishing a dedicated development and manufacturing center for mRNA was determined to be the best way to address client needs and the anticipated growth in the market. With much of the infrastructure already in place, the new facility should be operational sometime in early to mid-2023. The added fill/finish capabilities will present the biggest learning curve. BIOVECTRA has extensive experience producing both chemical and biologic APIs, but this latest expansion will be the company’s first venture into final drug product manufacturing and delivery. The added drug substance production capacity is required, given the vibrant nature of existing business.
One of the challenges faced in adding a dedicated mRNA development and production facility is the need to access clinical-scale single-use (SU) equipment. BIOVECTRA has traditionally used stainless-steel bioreactors and today has equipment ranging in size from 1 L to 17,000 L. Other than the COVID-19 vaccines, most mRNA manufacturing programs will require much smaller production scales. BIOVECTRA wants to be in a position to cater to all demands in the market, from personalized medicines to global vaccines. To that end, this expansion is geared toward the smaller scale and leverages SU technologies. Recognizing the current supply chain issues surrounding SU systems, BIOVECTRA proactively formed a partnership with SU supplier ABEC that is pivotal in enabling the company to meet its short timeline for facility startup.
In that same vein, BIOVECTRA has also established partnerships with various consultants, engineers, builders, and construction firms in support of the accelerated timeline. Working with these preferred partners on previous expansions has led to the development of strong relationships and a high level of trust. Success breeds success and. in this case, helps us to streamline the process. As a result, many decisions can be made by these preferred partners, streamlining the process. In addition, no extensive search is needed to find the right people for the job, reducing the time before a project can be initiated.
The regulatory decisions that were made regarding the COVID-19 vaccines were based on available science. As more data are generated and greater understanding of the products and their production processes is realized, changes in regulations are to be expected. In an emerging field, such as pDNA and mRNA therapeutics and vaccines, working closely with regulatory authorities is essential to ensure the successful development of formulated products and manufacturing processes. It is also important to communicate with regulators when designing new production facilities.
As such, BIOVECTRA is engaging with Health Canada with respect to the new mRNA facility design and the potential processes that will be implemented at the site. The company fully expects regulations to evolve as more pDNA and mRNA products advance through the clinic and receive marketing authorization. Staying abreast of these developments through strong relationships with health regulators will ensure successful completion of the facility and pursuit of client projects in alignment with the latest regulatory guidance and requirements.
The need to reduce the cost and time required for getting a drug from concept to market has led biopharma companies to increase strategic partnerships with CDMOs that can provide end-to-end services. Eliminating the cost, time, and complexity involved with managing multiple service providers and the transfer of projects between them has become critical for both emerging and established pharma firms.
Unlike many service providers that have only recently gained this capability by acquiring other providers, BIOVECTRA has always had the ability to provide services across the entire life cycle of a product, from the pre-toxicity study stage through phase I/phase II and onto commercial manufacturing.
For mRNA and pDNA therapeutics, the ability to provide end-to-end support is even more important, because the majority of candidates are currently in early clinical development. Some of those will be fast-tracked, and, given the similarities from product to product, the approval process may be further accelerated compared to that of traditional drug products. CDMOs that can reliably support mRNA candidates as they rapidly progress from development to launch will be crucial to the success of these important novel medicines.
With a dedicated plasmid DNA and mRNA facility, BIOVECTRA will be positioned to support candidates at all phases from preclinical to clinical and commercial. In addition, manufacturing trains comprising SU bioreactors ranging from 50 L to 1000 L and the complementary downstream equipment will enable the support of products targeting patient populations from the very small to the very large.
One of the reasons it was possible for companies like Moderna and BioNTech to rapidly develop vaccines against the SARS-CoV-2 virus was their access to already established platform technologies. Once the spike protein of the COVID-19 virus was genetically sequenced, the specific information needed to develop the vaccine was incorporated into those existing platforms, allowing for rapid establishment of cell lines and ultimately vaccine production.
To be successful, therefore, CDMOs seeking to support clients developing pDNA and/or mRNA therapeutics and vaccines will need to offer similar capabilities, because those clients will be expecting similar turnaround times and results. Drug developers will seek out CDMOs that have the ability to produce plasmids, develop cell lines, and manufacture mRNA active ingredients. To meet those expectations, CDMOs will need to have their own platform technologies.
BIOVECTRA recognizes this important aspect of providing pDNA and mRNA development and manufacturing services, especially when supporting virtual, small, and emerging biotechs with just a few people and a sequence. They need support from start to finish and at the fastest speed possible while still ensuring the highest quality and safety.
The company’s strategy to bring cell line development and cell banking capabilities in-house is geared at providing this platformized, end-to-end support. BIOVECTRA already has extensive experience working with small and virtual pharma companies on recombinant protein candidates, assisting them with product development essentially right out of the cell line to first bench transfer, regulatory strategies, and beyond.
Expansions like BIOVECTRA’s addition of pDNA and mRNA development and manufacturing capabilities can be truly transformational and completely reposition how companies are viewed in the marketplace. Beyond the obvious facility and equipment additions associated with this type of expansion, the additional process development and new fill/finish capabilities needed for pDNA and mRNA require developing capabilities that will have a huge impact on the company’s offering to its customers. Together, these really round out BIOVECTRA as a CDMO that provides true end-to-end mRNA support.
One of the challenges most companies face with such a transformational expansion is finding the right skill set complement. No stranger to growth, BIOVECTRA is embracing a robust recruitment strategy to secure the expertise required to make this new capability a success. The company will add at least 125 new positions to its employee base and will offer 225 student co-op placements to help grow the next generation of life sciences talent.
In addition to leveraging some of the company’s existing talent to get the project off the ground, BIOVECTRA is recruiting top talent from North America and beyond, with the additional advantage of being geographically well-positioned in proximity to excellent academic institutions. There are immigration programs in place in Canada –– particularly the Atlantic-Canadian region –– that offer options to employers to bring people on from abroad in a more expedient manner.
Training and upskilling is also a part of the solution, and BIOVECTRA was an early adopter of CASTL Online Learning Academy. CASTL (Canadian Alliance for Skills and Training in Life Sciences) brings to Canada a world-class technical training curriculum from Ireland’s globally recognized National Institute for Bioprocessing Research and Training (NIBRT), providing a “one-stop shop” for the biopharmaceutical manufacturing industry’s training requirements. The CASTL Online Academy powered by NIBRT has multiple applied learning streams and offers easy-to-access, interactive, and cost-effective online learning options on all aspects of biopharmaceutical manufacturing. CASTL provides companies like BIOVECTRA not only with an online training solution but with customizable, in-person holistic training opportunities in a realistic GMP-inspired manufacturing environment.
The evolutionary nature of the regulatory framework around mRNA products reflects the immaturity of the field. There are very few products on the market today. The rapid development of the initial COVID-19 mRNA vaccines and the work that has continued since then, however, have led to dramatic advances in technology that can be leveraged for the development of mRNA therapeutics.
Over the next several years, the field will become larger, maintaining a focus on vaccines while also expanding to include a wider range of therapeutics. The clinical pipeline for mRNA products already reflects this trend.
The level of success achieved by these candidates will depend not only on the mRNA technology itself but also the delivery approach, bioprocessing advances, changes in regulatory expectation, and the dynamics of their cost structures/pricing.
Even with these challenges, pDNA and mRNA technologies have the potential to revolutionize the use of personalized medicines. It is likely that affordable and very effective personalized mRNA medicines will be developed for the treatment of diseases for which no medications are currently available, particularly genetic disorders. As a result, mRNA could ultimately be the biggest development within the biopharmaceutical industry in the next five years.
Scott Doncaster earned a B.Sc. in biochemistry from Mount Allison University and completed a Master’s program in biochemistry at Queens University. Scott joined BIOVECTRA in 1995 where he served a series of roles before being appointed Vice President, Manufacturing Technologies & Engineering in 2014.