Monitoring of ultra- and diafiltration processes by Kalman-filtered Raman measurements

Area of Science:

• Biopharmaceutical Manufacturing
• Process Analytical Technology (PAT)
• Spectroscopy

Background:

• Ultrafiltration/Diafiltration (UF/DF) is critical in biopharmaceutical production.
• Real-time monitoring of protein and excipient concentrations is essential for process automation and control.
• Existing methods like UV and IR spectroscopy have limitations in monitoring low concentrations.

Purpose of the Study:

• To evaluate the combination of Raman spectroscopy and an Extended Kalman Filter (EKF) for monitoring UF/DF processes.
• To assess the performance of this combined approach for protein and excipient concentration monitoring.
• To demonstrate the potential for process automation through adaptive control.

Main Methods:

• Utilized Raman spectroscopy for in-line measurement of protein and excipient concentrations.
• Integrated Raman measurements with a semi-mechanistic model using an Extended Kalman Filter (EKF).
• Conducted three case studies to validate the combined approach, comparing it with density and VP-UV measurements.

Main Results:

• Kalman-filtered Raman measurements showed improved sensitivity for excipient monitoring compared to density measurements.
• Raman spectroscopy offered faster measurement speeds than VP-UV but with slightly lower protein prediction accuracy.
• Protein concentration monitoring via Raman relied on background signal changes, indicating potential batch variability concerns.

Conclusions:

• The combination of Raman spectroscopy and EKF is a promising tool for monitoring UF/DF steps.
• This integrated approach can enhance process automation by enabling adaptive process control.
• Further development is needed to address batch variability in Raman-based protein concentration measurements.