Defining process design space for monoclonal antibody cell culture

Area of Science:

• Biopharmaceutical Manufacturing
• Process Analytical Technology
• Cell Culture Engineering

Background:

• The design space is crucial for in-process control in biopharmaceutical manufacturing.
• Mapping the design space involves studying operational variables' impact on productivity and quality.
• Characterizing the process is essential for defining operational limits.

Purpose of the Study:

• To describe an efficient methodology for mapping the design space of a monoclonal antibody cell culture process.
• To identify key operational parameters influencing process performance and product quality.
• To link upstream process parameters with downstream purification for impurity clearance.

Main Methods:

• Failure Modes and Effects Analysis (FMEA) for process characterization.
• Integrated study of inoculum stages (shake flask, seed bioreactor).
• Two-stage Design of Experiments (DOE): Resolution IV followed by Central Composite Design (CCD).

Main Results:

• Identification of the edge of failure for operational parameters.
• Classification of parameters as non-key, key, or critical.
• Models generated provide insights into balancing productivity and quality.
• Identified production bioreactor parameters affecting antibody charge variants and glycosylation in CHO systems.

Conclusions:

• The described methodology efficiently maps the design space for monoclonal antibody cell culture.
• Operational parameters can be classified, enabling better process control.
• Understanding parameter impact allows for optimization of productivity and product quality.
• Linking upstream and downstream processes aids in impurity clearance.