Gene therapy process change evaluation framework: transient transfection and stable producer cell line comparison

Abstract As the gene therapy sector grows, decisions related to the best time to switch from the typical transient transfection expression system to more reproducible and scalable stable producer cell line (SPCL) systems have garnered much interest. This paper describes the application of a decisional tool to identify the most attractive expression system and optimal timing for the process change for four hypothetical gene therapy products based on either lentiviral (LV) or adeno-associated virus (AAV) vectors using suspension culture processes. The tool comprised models to analyse the cost of goods, cost of drug development, project lifecycle cost and profitability to evaluate the major trade-offs such as the reliance on costly plasmid DNA supply with transient transfection versus the longer cell line development times with SPCL. The tool predicted that switching to SPCL early in development, with no delay to market, was the most attractive strategy from cost of drug development and project lifecycle cost perspectives for products requiring larger quantities of viral vector. If this scenario resulted in a 10-month delay to market, then the optimal solution from a profitability perspective changed to switching to SPCL post-approval or sticking with transient transfection. Scenario analyses were performed to identify critical thresholds for the plasmid DNA costs, delays to market and SPCL harvest titre values that affect the rankings of the strategies.