Biomanufacturing Innovation Science; a Key for Future Resilience
Lakshmi Krishnan, Ph.D.
National Research Council Canada
Director General, Human Health Therapeutics
Kelley Parato, Ph.D.
National Research Council Canada
Program Director, Cell and Gene Therapy (Health Challenge) Program
Frank van Lier, P.D.
National Research Council Canada
Director, Research and Development, Bio-process Engineering Human Health Therapeutics
The COVID-19 pandemic imposed unprecedented health and societal challenges and notably highlighted the global lack of pandemic preparedness and weaknesses in supply chains across diverse industrial sectors. Nevertheless, this same threat inspired a rapid and global response, coordinated across sectors and sometimes among nations, culminating in the expedient arrival of life-saving vaccines and therapeutics.
The speed at which COVID-19 vaccines were developed, evaluated, and authorized is due to numerous important underlying factors: decades of investment in prior research in platform technologies such as the mRNA delivery system; global coalitions/partnerships and unprecedented government incentives to engage in multi-sectoral collaboration to rapidly re-orient vaccine platforms and enable manufacturing; rolling regulatory review of candidate vaccine dossiers to accelerate their emergency authorization.
In Canada, like in many other countries, the federal government recognizing the national technology and innovation gap prioritized procurement of life-saving vaccines from the global supply chain. At the same time, national spending was triggered towards supporting early-stage SMEs to de-risk and accelerate their vaccine candidates to enter clinical trials and secondly, investing rapidly to build out biomanufacturing facilities, including publicly owned ones. While these investments have not yet translated into a made-in-Canada authorized vaccine, the return on investment will lie in having strengthened Canada’s future resilience. Preparing for the next pandemic, we opine that besides investment in infrastructure, Canada needs a coordinated investment in the continuum of Biomanufacturing innovation science (Fig. 1). This is needed to bolster multi-disciplinary innovation for various design elements that can de-risk the manufacturing process, and ensure robust population scale manufacturing for multiple product types. Below we identify the key themes that should be addressed under such a science policy.
Product Development Bridge for a pipeline of innovative biologics for COVID-19 and beyond
Biologics are the fastest growing class of newly approved drugs and include products such as vaccines, antibodies, cell and gene therapy to treat a plethora of rare or chronic diseases and emerging infections.  A recent scan revealed that Canada has an impressive pipeline of innovative Biologics in development; nearly 133 groups in Canada are developing over 328 biologics.  This number has doubled within 4 years and represents a rich pipeline of early-stage products from academia to SME developers that require next-stage de-risking including biomanufacturing. While investment in the Clinical Trial Fund to move such candidates to first-in human trials is much needed and identified in the 2021 federal budget, equally important will be ensuring feasibility of manufacturing scale-up. This will require an early partnership between R&D and manufacturing facilities to design and optimize the production process and product characterization. Furthermore, pandemic preparedness will require technology readiness for rapid production at population scale (preferably within weeks rather than years to move from concept to production and testing). Lastly different types of products such as vaccines, antibody therapies or cell and gene therapy will require different models; distributed and/or central manufacturing. Therefore, investment in de-risking manufacturability will need to go hand-in-hand with early stage product development.
Foundational Science Supporting Turn-key or Plug-and-Play Platforms:
A second crucial pillar of innovation is the area of turn-key plug-and-play production and delivery platforms. Safe and effective COVID-19 vaccines arrived so quickly because they were rapidly built upon decades of research on the mechanism of action and safety, for novel platform technologies (e.g., Adenovirus vaccine vectors, encapsulated mRNA delivery systems) developed for other applications. The ability to have an inventory of such platforms, qualified and de-risked, with companion manufacturing already ironed out, ready to deploy for target vaccine of interest will be key to future pandemic preparedness. Today, Canada has limited capacity for large-scale manufacturing of mRNA-based candidates, such as Pfizer and Moderna COVID vaccines, despite the fact that the early-stage innovation for lipid nanoparticle delivery system for mRNA originated here. Furthermore, other innovative delivery and production technologies such as virus-like particles, customized viral vectors and even cell-free production platforms are emerging. Ideally these platforms will be developed alongside optimization of the manufacturing process with predictability by integrating AI modelling for improved yield and advanced analytics for end-product characterization. Canada also has a breadth of expertise in cross-disciplinary areas such as synthetic biology,  and quantum science,  microfluidic devices and advanced materials and robotics which could be positioned for next generation manufacturing to digitalize and automate precision manufacturing. Overall, a coordinated investment in next generation technologies that links together teams of developers to include platform-specific manufacturing process design will position Canada for rapidly unlocking domestic capacity to bring forth solutions for emerging and/or complex diseases.
Flexible Infrastructure – Flexible Platforms – Myriad Outputs:
In considering what types of vaccines or other biopharmaceutical development could be supported with Canada’s new Biomanufacturing infrastructure, it is important to realize that not all products use the same production process. There are then two ways of approaching this issue from strategic investment; creating centres for excellence for specific platform types across different sites (e.g., those that focus on mRNA production versus viral vectors versus protein vaccines), or an integrated facility that is designed with dedicated sections for different types of products. This latter approach may be feasible in certain cases where the know-how for producing most biological products is leveraged as conserved requirements for multiple product types. Such flexibility allows us to not only think about rapidly responding to emerging infections in urgent situations, but also to re-orient this infrastructure and platforms at other times to accelerate product development for other diseases (cancer, autoimmunity, rare diseases etc). Pivoting from product to product as need arises is most feasible with a publicly-funded investment strategy that can and should respond to policy directives. The advantage is that public policy could be geared towards manufacturing for societal needs for areas such as rare diseases or anti-microbial resistance that are often not supported by a free market economic growth lucrative to the industry.
Coordinating the Value Chain: the Trinity of partnerships
The collective power of academia, industry and intramural government R&D units working together to rise to a challenge of forging effective solutions for a crisis situation cannot be overstated. The global COVID-19 vaccine development response has been rapid, effective, and scalable because of the incentive and support available to unite contributors of basic science, established vaccine platform technologies, experienced bioprocess engineering and manufacturing processes, and expertise in bringing products through regulatory approval and to the commercial market. These same principles can be leveraged to address other health imperatives nationally and globally. Whether addressing vaccines for emerging infections, gene therapies for rare and ultra-rare diseases, cell or antibody therapies for cancer, personalized cell products to treat chronic disease, or novel agents to combat antimicrobial resistance, a coordinated investment and governance to coordinate clusters of excellence to accelerate product development and streamline the value chain is bound to accelerate the arrival of effective solutions.
Building for the Future:
Canada has deep fundamental science capabilities in many disciplines including a vibrant research community in life sciences. To create value of our discoveries and advance novel vaccines and biologic therapies to benefit the society, investment in enabling manufacturing infrastructure and delivery platforms is imperative. Our burgeoning biomanufacturing sector will benefit from an integrated science policy that address key elements (Fig 2).
An underpinning need to achieve this action plan will be the availability of highly qualified personnel. Various estimates have suggested that Canada needs >3000 highly qualified personnel over the next 3-5 years to support the burgeoning Biomanufacturing sector.  This requires directed integration of academic training centres with manufacturing facilities and regulators to provide a comprehensive skills training, as well as re-skilling and up-skilling to bridge work-force gaps from early stage R&D to commercialization. Additionally, Canada will need to foster C-suite talent in this highly competitive space where global demand will influence brain-drain and/or -gain. Canada is poised to achieve its vision of an integrated Life Sciences strategy  that can drive bioeconomy ; biomanufacturing innovation science needs to be an integral theme of its implementation.
- Rapid growth in biopharma: Challenges and opportunities | McKinsey https://www.mckinsey.com/industries/life-sciences/our-insights/rapid-growth-in-biopharma
- Mathew Starek and Raymond Eileen; National Research Council of Canada; compiled from MedTrack and GlobalData and company web-sites.
- White Paper: Engineering Biology | CAN-DESyNe https://www.candesyne.ca/white-paper-engineering-biology
- Can we afford not to participate in the quantum race? – CSPC https://sciencepolicy.ca/posts/can-we-afford-not-to-participate-in-the-quantum-race/
- Biomanufacturing_Strategy_EN_WEB.pdf https://www.ic.gc.ca/eic/site/151.nsf/vwapj/Biomanufacturing_Strategy_EN_WEB.pdf/$file/Biomanufacturing_Strategy_EN_WEB.pdf
- The Bio Revolution: Innovations transforming economies, societies, and our lives | McKinsey https://www.mckinsey.com/industries/life-sciences/our-insights/the-bio-revolution-innovations-transforming-economies-societies-and-our-lives