title: Application of the quality by design approach to the drug substance manufacturing process of an Fc fusion protein: towards a global multi-step design space.
abstract: The article describes how Quality by Design principles can be applied to the drug substance manufacturing process of an Fc fusion protein. First, the quality attributes of the product were evaluated for their potential impact on safety and efficacy using risk management tools. Similarly, process parameters that have a potential impact on critical quality attributes (CQAs) were also identified through a risk assessment. Critical process parameters were then evaluated for their impact on CQAs, individually and in interaction with each other, using multivariate design of experiment techniques during the process characterisation phase. The global multi-step Design Space, defining operational limits for the entire drug substance manufacturing process so as to ensure that the drug substance quality targets are met, was devised using predictive statistical models developed during the characterisation study. The validity of the global multi-step Design Space was then confirmed by performing the entire process, from cell bank thawing to final drug substance, at its limits during the robustness study: the quality of the final drug substance produced under different conditions was verified against predefined targets. An adaptive strategy was devised whereby the Design Space can be adjusted to the quality of the input material to ensure reliable drug substance quality. Finally, all the data obtained during the process described above, together with data generated during additional validation studies as well as manufacturing data, were used to define the control strategy for the drug substance manufacturing process using a risk assessment methodology.
authors: Department of Biotech Process Sciences, Merck Serono S.A. Corsier-sur-Vevey, Fenil-sur-Corsier CH-1809, Switzerland. alex.eon-duval@merckgroup.com
authors: Alex
authors: A
authors: Eon-duval
authors: Pascal
authors: P
authors: Valax
authors: Thomas
authors: T
authors: Solacroup
authors: Hervé
authors: H
authors: Broly
authors: Ralf
authors: R
authors: Gleixner
authors: Claire L E
authors: CL
authors: Strat
authors: James
authors: J
authors: Sutter
mesh_terms: D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000096:biosynthesis / Q000737:chemistry*; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D011786:Quality Control; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000737:chemistry*; D018570:Risk Assessment; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D007141:Immunoglobulin Fc Fragments; D004364:Pharmaceutical Preparations; D011993:Recombinant Fusion Proteins