Scientific and Regulatory Lessons Learnt on Building a Chemistry, Manufacturing, and Controls (CMC) Package for COVID-19 Variant Vaccine Updates in the EU-A Regulator's Perspective.

Abstract

During the COVID-19 pandemic, eight COVID-19 vaccines were authorised in the European Union (EU); as a result of emerging SARS-CoV-2 variants and waning immunity, some of these have been adapted to broaden the immunity against circulating variants. The pace at which variants emerge challenges the technical feasibility to make adapted vaccines available in a suitable timeframe and in sufficient quantities. Despite the current absence of a clear-cut seasonal spread for COVID-19, the EU regulatory approach thus far is a pragmatic approach following a pathway similar to that of seasonal influenza. This approach currently requires chemistry, manufacturing, and controls (CMC-the design, development and consistent manufacture of a specified medicinal product of good quality) and non-clinical data (from product laboratory and animal studies), as well as demonstrating that updated vaccines induce an immune response that can predict clinical efficacy and safety in humans. For CMC data, COVID-19 mRNA vaccine adaptations generally made use of the same formulation, control strategy, manufacturing process, and inclusion of registered manufacturing sites for the drug product; therefore assessment was generally streamlined. The experience gained from the vaccine adaptations, combined with a continuous early regulator-developer scientific discussion, permits increasingly greater predictability for timing and positive regulatory outcomes. Here, we review key aspects of the quality control and manufacture of updating COVID-19 vaccines to protect against new variants. Although most experience has been gained with mRNA vaccines, we note that investment in the streamlining of manufacturing processes for recombinant protein vaccines would facilitate future strain updates/adaptations thereby safeguarding availability of different COVID-19 vaccine types, which is considered of value for public health. We also reflect on the challenges and opportunities in establishing more predictable regulatory mechanisms for future COVID-19 vaccine adaptions and more widely for future vaccines containing rapidly evolving pathogens with the potential to cause health threats.