Development of a premium Quality Plasma derived IVIg (IQYMUNE®) utilizing the principles of Quality by Design - A worked through case study

Polyvalent human normal immunoglobulins for intravenous use (IVIG), indicated for rare and often severe diseases, are complex plasma-derived protein preparations. A Quality by Design (QbD) approach has been used to develop the LFB new generation IVIG, targeting a high level of purity to generate an enhanced safety profile while maintaining a high level of efficacy. A modular approach of QbD was implemented consisting of five consecutive steps to cover all the stages from the product design to the final product control strategy. A well-defined target product profile was translated into 27 Product Quality Attributes (PQAs) that formed the basis of the process design. In parallel, a product risk analysis was conducted and identified 19 Critical Quality Attributes (CQAs) among PQAs. Process risk analysis was carried out to establish the links between process parameters and CQAs. Twelve critical steps were identified and for each of these steps a risk mitigation plan was established. Among the different process risk mitigation exercises, five process robustness studies were conducted at qualified small scale with a Design of Experiment (DoE) approach. For each process step, critical process parameters (CPPs) were identified and, for each CPP, Proven Acceptable Ranges (PARs) were established. The quality risk management (QRM) and risk mitigation outputs, including verification of PARs, were used to design the process verification exercise at industrial scale. Finally, the Control Strategy was established using a mix, or 9hybrid9, of the 9traditional approach9, plus elements of the QbD 9enhanced approach9 as illustrated, to more robustly assign material and process controls, and in order to securely meet product specifications The advantages of this QbD approach were improved process knowledge for industrial design and process validation and a clear justification of the process and product specifications as a basis for control strategy and future comparability exercises.