title: Defining process design space for monoclonal antibody cell culture.
abstract: The concept of design space has been taking root as a foundation of in-process control strategies for biopharmaceutical manufacturing processes. During mapping of the process design space, the multidimensional combination of operational variables is studied to quantify the impact on process performance in terms of productivity and product quality. An efficient methodology to map the design space for a monoclonal antibody cell culture process is described. A failure modes and effects analysis (FMEA) was used as the basis for the process characterization exercise. This was followed by an integrated study of the inoculum stage of the process which includes progressive shake flask and seed bioreactor steps. The operating conditions for the seed bioreactor were studied in an integrated fashion with the production bioreactor using a two stage design of experiments (DOE) methodology to enable optimization of operating conditions. A two level Resolution IV design was followed by a central composite design (CCD). These experiments enabled identification of the edge of failure and classification of the operational parameters as non-key, key or critical. In addition, the models generated from the data provide further insight into balancing productivity of the cell culture process with product quality considerations. Finally, process and product-related impurity clearance was evaluated by studies linking the upstream process with downstream purification. Production bioreactor parameters that directly influence antibody charge variants and glycosylation in CHO systems were identified.
authors.affiliation: Manufacturing Sciences & Technology, Bristol-Myers Squibb Co., 6000 Thompson Road, East Syracuse, New York 13057, USA.
authors.forename: Susan Fugett
authors.initials: SF
authors.lastname: Abu-Absi
authors.forename: LiYing
authors.initials: L
authors.lastname: Yang
authors.forename: Patrick
authors.initials: P
authors.lastname: Thompson
authors.forename: Canping
authors.initials: C
authors.lastname: Jiang
authors.forename: Sunitha
authors.initials: S
authors.lastname: Kandula
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schilling
authors.forename: Abhinav A
authors.initials: AA
authors.lastname: Shukla
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis*; D019149:Bioreactors; D001709:Biotechnology / Q000379:methods*; D016466:CHO Cells; D018929:Cell Culture Techniques / Q000379:methods; D006224:Cricetinae; D003412:Cricetulus; D004345:Drug Industry / Q000379:methods*; D011994:Recombinant Proteins / Q000096:biosynthesis
chemical_list: D000911:Antibodies, Monoclonal; D011994:Recombinant Proteins