Recent developments in downstream processing of novel biotherapeutic modalities

There is rising interest in the biopharma industry in exploring next-generation complex therapeutic modalities that offer unique advantages over their traditional counterparts. These include antibody-drug conjugates, nucleic acid-based therapeutics (plasmid DNA and messenger RNA), virus-like particles, adeno-associated virus (AAV)-based gene therapies, and monoclonal antibody (mAb) derivatives such as bispecific antibodies, nanobodies, and antibody fragments. Each of these moieties displays distinct structural, physicochemical, and functional attributes that translate to unique manufacturing challenges. This review showcases major developments over the last 5 years in downstream processing of these next-generation therapeutics, such as chromatographic and nonchromatographic separation strategies, process intensification, and automation and process control. Overall, these advancements indicate that the purification of such biotherapeutics requires an appropriate separation process tailored to modality-specific physicochemical characteristics and cannot be derived from mAb manufacturing expertise; this will be crucial for their scalability and cost-effectiveness.