A 0.7pA_rms Electrochemical Readout IC for Continuous Monitoring of Antibody Biologics in Upstream Biomanufacturing

Biologics are antibodies produced by genetically engineered cells and are widely used in therapeutic applications. Examples include pembrolizumab (Keytruda) and atezolizumab (Tecentriq), both employed in cancer immunotherapy as checkpoint inhibitors to restore T-cell immune responses against tumor cells [1]–[2]. These biologics are produced by engineered cells in bioreactors, followed by extraction, filtration, purification, and separation, before being packaged into drug vials and shipped to hospitals for patient treatment. The production of monoclonal antibodies by cells is highly sensitive to the bioreactor environment, making it essential to integrate process analytical technologies (PAT) for closed-loop, real-time adjustments [3]–[4]. Parameters such as pH, ion concentrations, dissolved oxygen, carbon dioxide, pressure, and cell density, among others, are routinely monitored through in-line (using sensor probes immersed directly in the bioreactor) and on-line (utilizing a bypass channel that circulates medium back to the tank) approaches with discrete sensors [5] (Fig. 1). Recent trends have focused on leveraging integrated circuit (IC) solutions for system miniaturization and enhanced functionality. For instance, [6] demonstrates the first single IC with multi-channel capability, enabling monitoring of O<inf xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">2</inf>, pH, oxidation-reduction potential (ORP), temperature, and glucose levels. However, no current technology can directly and continuously quantify the concentration and quality of the produced biologics in real-time within the bioreactor. These critical measurements still rely on off-line methods such as immunoassays and mass spectrometry, which are time-consuming and not suitable for real-time process control.