The Integration of Drug Substance and Drug Product Manufacturing Models: The Missing Link for Model-based End-to-End Process Development

Demonstrations of pharmaceutical process modelling have been made in the literature in the pursuit of accelerated development. Modelling activities for drug substance (DS) and product (DP) manufacturing are often conducted separately, as project time constraints often require that the DS and DP processes be developed simultaneously, each with fixed decision criteria and requirements. We illustrate how connecting DS and DP process models is essential for a full process understanding and how key attributes of an isolated DS can propagate through a DP tableting line to impact the DP dissolution. We do so by performing an uncertainty analysis on a flowsheet model of a crystallization and direct compression line. The dissolution sensitivity highlights the need for end-to-end flowsheet modelling to realize the full benefits of modelling. We also discuss the key technical and regulatory obstacles that must be overcome to achieve this.