title: Application of a quality by design approach to the cell culture process of monoclonal antibody production, resulting in the establishment of a design space.
abstract: This case study describes the application of Quality by Design elements to the process of culturing Chinese hamster ovary cells in the production of a monoclonal antibody. All steps in the cell culture process and all process parameters in each step were identified by using a cause-and-effect diagram. Prospective risk assessment using failure mode and effects analysis identified the following four potential critical process parameters in the production culture step: initial viable cell density, culture duration, pH, and temperature. These parameters and lot-to-lot variability in raw material were then evaluated by process characterization utilizing a design of experiments approach consisting of a face-centered central composite design integrated with a full factorial design. Process characterization was conducted using a scaled down model that had been qualified by comparison with large-scale production data. Multivariate regression analysis was used to establish statistical prediction models for performance indicators and quality attributes; with these, we constructed contour plots and conducted Monte Carlo simulation to clarify the design space. The statistical analyses, especially for raw materials, identified set point values, which were most robust with respect to the lot-to-lot variability of raw materials while keeping the product quality within the acceptance criteria.
authors.affiliation: API Process Development Department, Chugai Pharmaceutical Company, Ltd, Tokyo, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nagashima
authors.forename: Akiko
authors.initials: A
authors.lastname: Watari
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Shinoda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Okamoto
authors.forename: Shinya
authors.initials: S
authors.lastname: Takuma
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D001709:Biotechnology / Q000379:methods; D016466:CHO Cells; D018929:Cell Culture Techniques / Q000379:methods*; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D008954:Models, Biological; D009010:Monte Carlo Method; D015999:Multivariate Analysis
chemical_list: D000911:Antibodies, Monoclonal
keywords: antibody; biotechnology; cell culture; design of experiments; design space; failure mode and effects analysis; mathematical models; multivariate analysis; proteins; quality by design