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Process Analytical Technology (PAT) Implementation for Membrane Operations in Continuous Manufacturing of mAbs: Model-Based Control of Single-Pass Tangential Flow Ultrafiltration

Abstract

Control of single pass tangential flow ultrafiltration (SPTFF) is crucial for continuous manufacturing of monoclonal antibodies (mAbs). Integrating SPTFF technology into continuous manufacturing trains requires successful resolution of several challenges that arise due to the complexity of mass transfer interactions across multi-membrane configurations, the significant effect of feed material attributes and process variability on flux, and the need for advanced scheduling. In this paper, we propose a real-time, automated monitoring and control strategy for SPTFF in continuous processing of mAbs. The approach leverages a previously developed model for predicting the VCF across an SPTFF module based on the gel polarization model of protein ultrafiltration. A distributed control system (DCS) architecture was created for integrating the monitoring sensors and control elements, including NIRS sensors for concentration monitoring, as well as weighing balances, pressure sensors, pumps, and valves. Two different SPTFF control strategies were developed, firstly for final formulation of the drug product into the drug substance (ultrafiltration and diafiltration), and secondly for in-line concentration between two chromatography steps. Case studies were designed with 15 runs to test the strategy with a range of deviations induced in the feed and process conditions. The retentate concentration was controlled to within 10% of the target value in all runs. The combination of real-time sensor data and model-based control effectively enabled automated and tightly controlled operation of the SPTFF step and is a key enabler of quality by design in continuous mAb manufacturing.

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Funding

Authors would like to acknowledge funding support from Tata Consultancy Services, Pall Life Sciences, and the Department of Biotechnology, Ministry of Science and Technology through the Centre of Excellence scheme (No. BT/COE/34/SP15097/2015). GT would like to acknowledge support from TCS Research Scholar Program Cycle 15.

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Authors

Contributions

Garima Thakur: conceptualization, methodology, investigation, analysis, and writing—original draft. Vishnu Masampally: conceptualization, software integration, analysis, and validation. Amey Kulkarni: methodology and software integration. Anurag S. Rathore: conceptualization, funding acquisition, and writing—review and editing.

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Correspondence to Anurag S. Rathore.

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The authors declare no competing interests.

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Communicated by Anurag S. Rathore.

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Thakur, G., Masampally, V., Kulkarni, A. et al. Process Analytical Technology (PAT) Implementation for Membrane Operations in Continuous Manufacturing of mAbs: Model-Based Control of Single-Pass Tangential Flow Ultrafiltration. AAPS J 24, 83 (2022). https://doi.org/10.1208/s12248-022-00731-z

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  • DOI: https://doi.org/10.1208/s12248-022-00731-z

Keywords

  • Ultrafiltration
  • Monoclonal antibody
  • Model-based control
  • Single pass tangential flow filtration (SPTFF)
  • Distributed control system (DCS)