Process and product understanding is at the root of manufacturers’ efforts to produce safe and effective medicines. Researchers in our group at MIT are building novel first-principles and data analytics-based mathematical modeling tools for the manufacturing of biopharmaceuticals. To experimentally validate these modeling tools and to fully understand the impact of model choice on product quality, a fully instrumented and integrated continuous testbed for the manufacturing of monoclonal antibodies (mAbs) was constructed. The testbed consists of 4 parallel upstream systems including 4 perfusion devices, with one reactor assembly integrated with a fully continuous downstream system including Protein A chromatography, in-house designed viral inactivation, and ion exchange chromatography.

For process characterization in the upstream system, in-reactor probes for capacitance, optical density, DO, pH, and Raman spectra were integrated into the system. Additional analytics are made possible by the MAST autosampling system, which directs cell-containing samples to the Nova FLEX2 cell culture analyzer and cell-free perfusate samples to the Gilson liquid handler. There, samples can be navigated to an Agilent 1260 Bio-Inert HPLC for product titer and aggregation analyses or to an Agilent 6545XT LC-QTOF for at-line characterization of glycosylation profiles. Further characterization of product CQAs is performed in off-line workflows using the Agilent AssayMAP Bravo for sample preparation for subunit and peptide-level analyses. This presentation describes the instrumentation and discusses data collection and process integration within the testbed. The experimental data generated by this highly instrumented integrated continuous biomanufacturing testbed enable the evaluation, development, and validation of modeling methods and control strategies, and ultimately contribute to improved process understanding for better informed risk-based decisions during manufacturing campaigns.

3 Key Learning Objectives:

Information on assembly of a highly instrumented continuous manufacturing testbed

Process development on the testbed

Analysis of monoclonal antibody critical quality attributes using HPLC and LC-MS

Chris Colangelo

Agilent Technolgies, Inc.

Appearances