An automated buffer management system for small-scale continuous downstream bioprocessing

Abstract

Buffer management for biopharmaceutical purification processes include buffer preparation, storage of buffers and restocking the buffers when needed. This is usually performed manually by the operators for small scale operations. However, buffer management can become a bottleneck when running integrated continuous purification processes for prolonged times, even at small scale. To address this issue, a buffer management system for the application in continuous lab-scale bioprocessing is presented in this paper. For this purpose, an ÄKTA™ explorer chromatography system was reconfigured to perform the buffer formulation. The system formulated all buffers from stock solutions and water according to pre-specified recipes. A digital twin of the physical system was introduced in the research software Orbit, written in python. Orbit was also used for full automation and control of the buffer system, which could run independently without operator input and handle buffer management for one or several connected buffer-consuming purification systems. The developed buffer management system performed automatic monitoring of buffer volumes, buffer order handling as well as buffer preparation and delivery. To demonstrate the capability of the developed system, it was integrated with a continuous downstream process and supplied all 9 required buffers to the process equipment during a 10-day operation. The buffer management system processed 55 orders and delivered 38 L of buffers, corresponding to 20% of its capacity. The pH and conductivity profiles observed during the purification steps were consistent across the cycles. The deviation in conductivity and pH from the measured average value was within ±0.89% in conductivity and ±0.045 in pH, well within the typical specification for buffer release, indicating that the prepared buffers had the correct composition. The operation of the developed buffer management system was robust and fully automated, and provides one solution to the buffer management bottleneck on lab scale for integrated continuous downstream bioprocessing.

Keywords: Buffer preparation; Digital twin; Integrated continuous downstream process; Process automation; Process monitoring & control.