Digital Twin for Continuous Production of Virus-like Particles toward Autonomous Operation

Area of Science:

• Biopharmaceutical Manufacturing
• Process Engineering
• Digital Twins

Background:

• Previous lentiviral vector and virus-like particle (VLP) manufacturing utilized batch or fed-batch upstream and downstream processes.
• Continuous upstream processing in perfusion mode has been explored, presenting challenges in separating particles of similar sizes.

Purpose of the Study:

• To develop and validate a digital twin for autonomous manufacturing of human embryo kidney cell-based VLPs.
• To demonstrate the benefits of integrating a physical-chemical mechanistic model with process analytical technology for autonomous operation.

Main Methods:

• Model calibration of a digital twin using experimental data for VLP manufacturing.
• Integration of a Quality-by-Design (QbD) approach, including risk assessment for design and control space definition.
• Development of innovative tangential flow filtration for efficient separation of VLPs, cells, and debris in continuous perfusion mode.

Main Results:

• A twofold increase in VLP manufacturing productivity was achieved through simulation case studies.
• Application of the digital twin with advanced process control demonstrated an additional 20% productivity gain.
• The system achieved 99.9% reliability in autonomous operation.

Conclusions:

• Digital twins offer significant benefits for autonomous biopharmaceutical manufacturing, enhancing productivity and reliability.
• Innovative filtration strategies are crucial for efficient continuous processing of VLPs.
• The developed digital twin provides a validated framework for optimizing VLP production.