Sustainable Production of Therapeutic Monoclonal Antibodies

Todd M. Przybycien, PhD, Professor of Chemical and Biological Engineering at Rensselaer Polytechnic Institute, received undergraduate degrees in chemical engineering and in chemistry from Washington University in St. Louis and Masters and PhD degrees in chemical engineering with a minor in biology from Caltech. Todd started his professional career with Monsanto Agricultural Company where he worked in downstream bioprocess development for recombinant somatotropins about two years. He then launched his academic career at Rensselaer Polytechnic Institute, where he worked for eight years, followed by another twenty years at Carnegie Mellon University, where he was a faculty member in the Chemical Engineering Department and the Founding Head of the Biomedical Engineering Department. In Fall 2018, he returned to RPI. In Summer 2025, he became the Department Head. Todd’s primary research interests are in the downstream manufacturing (purification) of biotherapeutics. His group develops new separation unit media, operations, and processes for recombinant protein, mRNA and virus manufacture, with a particular focus on continuous processing. His group also develops antibody-drug conjugate surrogates and virus surrogates to support process development and validation. This work relies heavily on the application of biophysical, colloidal and interfacial sciences to establish structure-function-processing relationships for biotherapeutics that aid the design and operation of bioprocesses. This includes the connection of solubility, conformation/denaturation, aggregation and adsorption phenomena to macroscopic, process-level behavior. Todd is active in the American Chemical Society, the American Institute of Chemical Engineers, and the National Institute for Innovation in Manufacturing Biologicals and has held elected and appointed leadership positions in each organization. He recently served on the National Academies’ Committee on Identifying Innovative Technologies to Advance Pharmaceutical Manufacturing, a committee commissioned by the US Food and Drug Administration to help it prepare for new biomanufacturing technologies that may be included in future new drug approval applications. He has been recognized with a Career Award from the National Science Foundation, an Early Career Award from the faculty of Rensselaer, a Camille Dreyfus Teacher-Scholar Award from the Dreyfus Foundation, the James Van Lanen Distinguished Service Award from the Division of Biochemical Technology of the American Chemical Society, an Erskine Fellowship from the University of Canterbury in Christchurch, New Zealand, and has been named a fellow of the American Chemical Society, the American Institute of Chemical Engineers and the American Institute of Medical and Biological Engineering.

The current platform process for monoclonal antibody (mAb) and related therapeutic production is complex and cannot sustainably meet the global need. The demand for mAbs in high-income countries and the unmet need in low and middle income countries (LMICs) is large and growing. New disease targets for mAbs, including pandemic infectious disease, Alzheimer’s and high cholesterol, have patient populations at least 10x of the current anti-inflammatory and anti-cancer therapeutic mAbs.  The shortage of tocilizumab for rheumatoid arthritis patients due to treatment of inflammation in Covid-19 patients during the pandemic highlighted current capacity limitations.  About 80% of global mAb production is consumed by the US, Canada and Europe; even if sold at current cost of goods, $50 to $200/gram, mAbs are out of reach for most patients in LMICs. 

     The economic sustainability bottleneck for mAb manufacture is the protein A (ProA) affinity chromatography-based platform downstream process (DSP).  Industrial process development thought leaders have suggested that upstream titer increases beyond 8 g/L may be pointless due to platform DSP limitations.  The platform DSP also has poor environmental sustainability with process mass intensities typically >10,000 with the ProA capture step alone using on the order of a liter of buffer per gram mAb produced.

     In a bid to sustainably meet the growing need for mAbs, including the economic, environmental and social dimensions of sustainability, we have developed a new, fully continuous, precipitation-based process for mAb downstream processing, drawing inspiration from the manufacturing process for blood plasma products.  This new process can be significantly cheaper, greater in capacity, and less raw material-intensive than current mAb manufacturing technology.  We’ll describe the genesis and evolution of the process, key process parameters, process performance in terms of mAb critical quality attributes and sustainability metrics, and the path forward.