The following article originally appeared on August 16, 2021 in Drug Discovery World here.
An expert’s view by John Yoshi Shyu, Ph.D. Corning Life Sciences.
Most vaccines are manufactured using technology devised fifty or more years ago, in manufacturing plants that are sometimes even older. The vaccine production process is continually refreshed by new tools and technologies, and that fast-paced innovation gives researchers numerous opportunities to adjust their processes to achieve more cost-efficient or effective production scale-up — something that’s demonstrated itself to be immensely helpful during the COVID-19 pandemic.
Every vaccine is different and since, as the saying goes in biomanufacturing, “the process is the product,” every vaccine process is unique as well. The individuality of vaccine development and manufacturing complicates the search for platform processes and one-facility-fits-all scenarios in which, as if by magic, a pathogen enters through one door and safe, effective vaccines emerge from another door a short time later. Because each vaccine is a unique modular process, single-use technologies and modular production facilities may be the future of the most efficient and cost-effective vaccine development.
Production processes are continually evolving to meet the demand for vaccines against diseases like influenza and polio, and to combat emerging bacterial and viral pathogens as well, such as SARS-CoV-2. Manufacturing platforms, particularly those employing cell culture as a basis for production are still being considered for vaccines against HIV, cancer, and other potentially preventable (or treatable) illnesses. The search for manufacturing processes, both existent and new, to increase approvals of vaccines to combat the coronavirus pandemic is just one example of how to succeed in this area.
This climate of intense innovation provides numerous opportunities, not just for discovery-level projects and the search for novel expression systems, but also for the optimization of existing production methods to meet current and future challenges. The search and full-scale manufacturing of a vaccine to combat SARS-CoV-2, which compressed discovery, R&D, clinical trials, and manufacturing from its typical 10-15 years to under 12 months, could show how leveraging efficiencies in production methods (along with other factors) might help areas like vaccine development advance toward a goal.
Modular processes are one way to achieve the right balance between speed and flexibility, and product quality and safety. Assuming a manufacturing platform has already been established, a well-designed modular process allows development and manufacturing projects to begin ‘on a dime’ without the need to reinvent the wheel in terms of equipment, facility, or workflow.
Many in vaccine production are looking to design or augment their production plans in light of current events and are acutely aware of the fact that “plug-and-play” systems don’t really exist in the vaccine world. As new technologies reach the market, developers face the prospect of having to link the vaccines to legacy development and manufacturing systems (not to mention related information systems). Integrating new technologies and techniques into established practices requires a lot of customization. Sometimes, that leads to conflict, as people comfortable with existing processes are forced to adapt, and usually under severe time pressure.
Vaccine Manufacturing Journey
Sanofi, one of the world’s premier vaccine manufacturers, describes vaccine manufacturing as a ‘journey’. The Sanofi model picks up the process right after discovery, and runs through antigen production/purification, inactivation, valence assembly, formulation, and packaging. Keep in mind that the implementation of new technologies may occur at any one of those steps. Each stage leads to the next, but in its totality the ‘journey’ is unique with respect to that specific antigen and vaccine product. This further demonstrates the earlier point that ‘plug and play’ systems don’t really exist in the vaccine world. In other words, individual pieces of the ‘journey’ may be exquisitely well-characterized, tried and true, with previous regulatory approval, but once a new product comes along all bets are off.
Most bioprocesses – including those that rely extensively on ‘platform’ unit operations – and nearly all those occurring in single-use bioreactors, are customized. The reason, in part, is due to a lack of standardization for some connector parts, bioreactor sensor ports, and other components. Not too long ago single-use manufacturing was exclusively a benchtop-and pilot-scale manufacturing technology. Today it is used for GMP runs, especially during development and for biologicals like vaccines.
Due to the unique requirements for the design, validation, and qualification of vaccine manufacturing sites, it takes manufacturers of single-use systems between four and five months to deliver a fully customized single-use assembly. Vaccine developers must then modify or customize their process around this new component.
However, any lab of any size can customize its process so that it can incorporate future innovations. By following these tips, you can scale your processes and goals without locking yourself into a legacy set up.
Work only with suppliers with reliable field support. Suppliers who offer technical support often have fresh perspectives on legacy production equipment and practices, newer products, and how to merge the technologies through regulatory approved means. Expert opinions from outside one’s organization can help process development groups understand which optimization steps are critical, which new technologies to adopt, and how to combine new and old production methods to customize, troubleshoot, and scale up vaccine production cost-effectively.
Don’t Invest in Improvements You Don’t Need
Not every lab needs the most sophisticated bioreactor or the latest technological marvel, nor can they all afford these improvements. Smaller organizations must budget, and academic labs are at the mercy of granting agencies. Developers embarking on a new vaccine project should plot out short- and long-term therapeutic development objectives in consideration of their budget. At that point, vendors can help them get the most bang for their buck. The first questions a vendor should ask include:
- What is the level of scale you want to achieve?
- When do you want to get there?
- What’s the status of your current technology and infrastructure?
Modular vaccine platforms and processes that more easily allow affordable modification provide many benefits, including operational agility, short-term cost control, and the flexibility to add new technologies as their implementation makes sense and as budgeting allows. For vaccine makers, or any biomanufacturing organization with multiple products in preclinical stages, that flexibility can spell the difference between having one or two promising candidates and wishing you’d selected a different lead molecule. Modularization provides the flexibility to adapt and respond to both scientific and market trends. Scalable modular systems, moreover, allow relatively easy scale up, or can bridge short-term gaps in manufacturing capacity, for example, during clinical trials or right before product launch.
Demand Scientific Expertise from Suppliers
Engineers are critical to process development, but so are life scientists. Working with a supplier who staffs your project with both types of experts ensures that technology works toward your desired scientific outcomes. For example, yield and quality may require that cells remain in a particular growth stage for a specified time, or that apoptosis is maintained below a certain level. Identifying that before you begin could be critical in achieving your goals.
Process development isn’t only about validating new technologies or checking off boxes, it’s also about creating conditions in which you get the most productivity from your expression system, often relying on living cells. Engineers can help with heat and mass transfer, with designing a suitable holder for single-use bioreactors, and with scheduling unit operations. But you also need someone to help troubleshoot challenges related to cell expansion and productivity – perhaps with expertise in molecular and/or cell biology.
Bioprocessing facilities enjoy more options today than ever before to optimize their processes towards greater efficiency and profitability. For humanity, 2020 was a trying year. Never before have global healthcare systems faced the dual challenges of caring for millions of sick people while producing a vaccine in record time. It is up to vendors and developers to find the optimal path toward manufacturing excellence through efficient use of legacy manufacturing processes and prudent implementation of new approaches. The trick is to scale biomanufacturing processes up and out without locking your company in a high-priced legacy situation.
Corning’s model for current vaccine production development fully aligns with the vision of enterprise software developer SAP, which has had its finger on the pulse of biomanufacturing since the beginning: “The future of biopharma manufacturing lies in connecting data and processes, involving components of adaptive and modular manufacturing in a predictive and cognitive plant. This shall result in higher quality, efficiency, regulatory compliance and enable optimization, customization of processes and collaboration between all stakeholders involved in the manufacturing value chain. In addition, there shall be a reduction in time to market for biologics, errors due to process variability and associated costs giving manufacturers the competitive edge to stay on the growth path.”