Development and Characterization of a Cell Culture Manufacturing Process Using Quality by Design (QbD) Principles

Abstract

The principles of quality by design (QbD) have been applied in cell culture manufacturing process development and characterization in the biotech industry. Here we share our approach and practice in developing and characterizing a cell culture manufacturing process using QbD principles for establishing a process control strategy. Process development and characterization start with critical quality attribute identification, followed by process parameter and incoming raw material risk assessment, design of experiment, and process parameter classification, and conclude with a design space construction. Finally, a rational process control strategy is established and documented.

Glucose withdrawal-induced Chinese hamster ovary cells apoptosis and its potential role in process robustness assessment

“…To demonstrate the process robustness, process characterization should be performed. Process characterization is associated with high workload and is time-consuming [35,36]. This study showed that a more robust process (process 1) allows CHO cells to tolerate glucose withdrawal for a longer period.…”

“…Process characterization studies could be used to demonstrated the process robustness of the cell culture [35,36] but have requirements of long study duration, high personnel, and good equipment. Therefore, an easy method is required to judge the robustness of the process during cell culture process development.…”

Critical Analysis of cGMP Large-Scale Expansion Process in Bioreactors of Human Induced Pluripotent Stem Cells in the Framework of Quality by Design

“…Indeed, ATMPs were included in the pharmaceutical legislation only in 2009 [ 50 ]. While several authors already focused on QbD application to cell manufacturing [ 21 , 31 , 36 , 51 ], very few highlighted the challenges related to hiPSC large-scale expansion in bioreactors within the framework of QbD [ 8 , 52 ].…”

“…In the last decade, several studies focused on applying QbD to cell culture, both as an upstream process for the production of specific proteins (e.g., monoclonal antibodies) [26][27][28][29][30][31][32][33] and, more recently, for CTP manufacturing [21,25,[34][35][36]. The manufacturing of CTPs for clinical application requires several of the following steps: acquisition or generation of the starting cell type; cultivation; modification; harvest; concentration; purification; formulation, and fill and finish (preparing the CTP at the correct concentration and composition, dispensing it into the final product 'container', and any post-fill processing); storage; and shipping of the product [21].…”

Clever Experimental Designs: Shortcuts for Better iPSC Differentiation

“…DOE methodologies are now standardized by the International Organization for Standardization (ISO), while authorities including the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) recommend using DOE for pharmaceutical product development [ 14 , 22 ]. Notably, the success of Quality by Design (QbD) concepts in medical fields has urged DOE-based process evaluations in cell production facilities [ 23 , 24 , 25 ].…”