Sorina Morar-Mitrica began her presentation by drawing an analogy between decision-making in protein particle science and poker, highlighting the uncertainty and complexity inherent in the field. Unlike chess, where all information is available, protein particle science deals with complex systems where variables such as conformational states or aggregation pathways are not fully understood and only partly measurable.
She then dove into the fundamentals of protein particle science, explaining that they are a subset of aggregates, defined as materials with sizes above 0.1 microns. These particles are further classified into sub-visible particles (0.1 to 100 microns) and visible particles (above 100 microns). Due to their potential immunogenicity, they are considered one of the highest critical quality attributes and need to be monitored, minimised, and characterised.
Sorina discussed insights from a decade of protein particle trending at Novartis, revealing that non-monoclonal antibodies had a higher aggregation propensity compared to monoclonal antibodies. Most issues were related to visible particles, followed by sub-visible particles. Interestingly, the majority of particles were not detected at small scale during development but appeared at large scale upon scaling up manufacturing processes.
She emphasised the need for risk assessment and mitigation strategies for protein particles, calling for collaboration across industry and disciplines. Prevention involves optimising drug substance and product formulation, while characterisation requires using an extended analytical toolbox to detect and differentiate protein particles early in development.
The presentation concluded with a discussion on future directions in protein particle research, including the shift from prevention and characterisation to particle qualification and acceptance in clinical trials. This involves linking particle fingerprints with clinical outcomes and incorporating patient-centric specifications. Emerging clinical evidence suggests that typical particle levels in therapeutic protein products do not promote an enhanced immunogenic response or risk.
Morar-Mitrica's take-home message was that protein aggregation and particle formation remain major challenges without a unified strategy across the industry. She called for continued innovation and collaboration to advance risk mitigation and particle qualification strategies.
