Regression to the Rescue: The Use of Statistical DOE to Derive a Novel Manufacturing Control Strategy for Ensuring the Quality of an Antibody-Drug Conjugate

• Activity Number: 293
• Type: Topic Contributed
• Date/Time: Tuesday, August 2, 2011 : 8:30 AM to 10:20 AM
• Sponsor: Biopharmaceutical Section
• Author(s): Lisa J. Bernstein*+ and Daniel A. Coleman
• Companies: Genentech Inc. and Genentech Inc.
• Keywords: antibody-drug conjugate (ADC) ; design of experiments (DOE) ; split-plot ; biologic ; manufacturing

Abstract

ADC-X is an antibody-drug conjugate therapeutic candidate consisting of a monoclonal antibody linked to a potent cytotoxin by a chemical linker. The Drug-to-Antibody Ratio (DAR), the average number of toxin molecules per antibody, is a critical quality attribute related to both safety and efficacy; hence it must be controlled in manufacturing. This talk describes how a sequential experimentation strategy characterized the ADC-X manufacturing process. Multiple laboratory constraints on experimentation were managed by incorporating blocking and split-plotting into fractional-factorial designs. These characterization studies identified the important factors in each process step and provided a regression model relating those factors to the DAR and other attributes. The presentation will also show how the designed experiments uncovered a serious challenge to commercial ADC-X manufacturing and then provided a tool that met the challenge: the regression model formed the basis for a novel process control strategy involving an adjustable setpoint for the amount of linker in each batch. This control strategy has been successfully implemented in large-scale manufacturing.