Vaccine manufacturing and quality control

The main areas of focus of the consultation were:

One of the key needs identified during the consultation on manufacturing and quality control was the need to support technologies that will address the current global vaccine supply shortage. overarching principles that could increase production speed, production yields and production predictability were Quality by Design (QbD) approach and improvements in process analytical technology (PAT) mechanisms. After a decade of development, PAT has become a reality for small molecule production, and has proven its ability to increase process robustness and reduce costs. However, this concept is still emerging for bio manufacturing, and technologies and know-how need further development to be applied in vaccines. Currently the specificity and reliability of these tools are lower for vaccines and cannot be used for quantitative purposes. Therefore, very basic in-process assays are not yet established. Further work is also required to better monitor impurities as well as measuring the 3D structure of the vaccines. This would allow better characterisation of the folding of the antigen being presented and thereby allow better predictability of its potency. The panel of experts consulted emphasised that innovative technological approaches are also desirable to make vaccines easier to deliver and administer. This should include work to develop thermostable vaccines to overcome the need to keep vaccines in a cold chain^{27 28}. Participants also agreed that new delivery systems could enhance the ability to deliver vaccines and thereby increase vaccination coverage.

The need to be able to rapidly produce large quantities of vaccine in a very short time is essential to the ability to respond to future epidemics and pandemics. This is already a priority in a number of countries(e.g.BARDA²⁹ in the US), but should become a priority throughout Europe. This will require innovation in the process, in disposable technologies and in the approval and release process. Progress made for epidemic and pandemic preparedness is likely to be rapidly transferable to the production of routine vaccines.
The main need identified by the participants was for modular facilities, combining platform technologies flexible enough to manufacture a multitude of candidates and processes/ facilities that are easy to switch and scale up. Modular facilities would allow the facilities to be used for routine vaccines and then switch rapidly to production of epidemic and pandemic vaccines as was done for the flu vaccine during the H1N1 pandemic. Alternative models include disposable technologies or the combination of warm-based production and stockpiling as is done for the smallpox vaccine. Today, most current facilities are at or close to full capacity. There is, therefore, the need for a global increase in vaccines production capacity³⁰. Approaches such as insect cell culture- based vaccine production may offer greater flexibility with lighter infrastructure, which could in turn reduce costs by 80-90% compared to traditional approaches³¹. Disposable bioreactors and downstream equipment also offer the ability for flexible production in BSL2 environments. However, these approaches are not currently possible for all vaccines and work is required to extend their use and develop other novel approaches. Other production goals include the need to develop scaffold- based technologies able to express a large range of antigens in a highly stable form, and as close as possible to native conformation, that could be combined with other antigens in combination vaccines with minimal risk of conflicting formulations.

There are also human and organisational facilitators to vaccine production process optimisation. For example, early and continuous collaboration between the manufacturing teams, process development teams and early research teams is essential. There is also a need to develop tools that allow researchers and companies to better predict from a mL scale production to how a candidate vaccine will behave at commercial scale. Improved understanding in this area will help to de-risk the scale-up phases, identify early potential production bottlenecks or constraints and thus accelerate the time to market of vaccines as well as optimise vaccines affordability. Lastly, novel expression systems such as algae or plants offer the potential for high capacity production in cell lines that are easier to work with and represent a far wider species gap. This would provide a further strategy for addressing the global supply shortage. However, these approaches have yet to prove themselves fully and further development is required.

There are other technologies, such as fully synthetic biology, whereby proteins, DNA or mRNA molecules could theoretically be synthesised chemically rather than biologically. such an approach would bring huge benefits but would require significant advances in chemistry and associated adaptation of production facilities and regulatory and release requirements³².