title: A systematic approach for scale-down model development and characterization of commercial cell culture processes.
abstract: The objective of process characterization is to demonstrate robustness of manufacturing processes by understanding the relationship between key operating parameters and final performance. Technical information from the characterization study is important for subsequent process validation, and this has become a regulatory expectation in recent years. Since performing the study at the manufacturing scale is not practically feasible, development of scale-down models that represent the performance of the commercial process is essential to achieve reliable process characterization. In this study, we describe a systematic approach to develop a bioreactor scale-down model and to characterize a cell culture process for recombinant protein production in CHO cells. First, a scale-down model using 2-L bioreactors was developed on the basis of the 2000-L commercial scale process. Profiles of cell growth, productivity, product quality, culture environments (pH, DO, pCO2), and level of metabolites (glucose, glutamine, lactate, ammonia) were compared between the two scales to qualify the scale-down model. The key operating parameters were then characterized in single-parameter ranging studies and an interaction study using this scale-down model. Appropriate operation ranges and acceptance criteria for certain key parameters were determined to ensure the success of process validation and the process performance consistency. The process worst-case condition was also identified through the interaction study.
authors.affiliation: Process Engineering and Cellular Science and Technology, Amgen Inc., Thousand Oaks, California 91320, USA. fengl@amgen.com
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Hashimura
authors.forename: Robert
authors.initials: R
authors.lastname: Pendleton
authors.forename: Jean
authors.initials: J
authors.lastname: Harms
authors.forename: Erin
authors.initials: E
authors.lastname: Collins
authors.forename: Brian
authors.initials: B
authors.lastname: Lee
mesh_terms: D000818:Animals; D019149:Bioreactors; D016466:CHO Cells; D002245:Carbon Dioxide / Q000494:pharmacology; D018929:Cell Culture Techniques / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D006224:Cricetinae; D003470:Culture Media / Q000494:pharmacology; D004867:Equipment Design; D019544:Equipment Failure Analysis / Q000379:methods; D006863:Hydrogen-Ion Concentration; D007218:Industrial Microbiology / Q000295:instrumentation* / Q000379:methods; D008954:Models, Biological; D010100:Oxygen / Q000494:pharmacology; D011994:Recombinant Proteins / Q000096:biosynthesis; D015203:Reproducibility of Results; D013696:Temperature; D013997:Time Factors
chemical_list: D003470:Culture Media; D011994:Recombinant Proteins; D002245:Carbon Dioxide; D010100:Oxygen