(478e) Optimization of Process Risk, Cost, and Environmental Sustainability during Late Stage Drug Substance Control Strategy Development
AIChE Annual Meeting
Wednesday, November 18, 2020 - 8:30am to 8:45am
sustainability, and risk to product quality, are important to consider. Optimization at this stage balances
these objectives against the complexity of evaluating and incorporating process adjustments. Here, we
present a series of process improvements made during late stage development of a small-molecule drug
substance. These improvements were supported by empirical and mechanistic process understanding
incorporating measures of risk, cost, and sustainability.
To direct the investment of limited development resources, a quantitative analysis was done to
calculate key process metrics. A key insight from this analysis was that the process to produce one
specific intermediate was estimated to account for three quarters of the drug substanceâs
manufacturing cost. This analysis directed investment into improving the process yield across the eight
chemical transformations, involving a wide variety of unit operations to make this intermediate.
Specifically, significant cost reduction was achieved through multivariate optimization of an oxidation
reaction, identification and mitigation of mass loss during extraction and distillation, and multivariate
optimization of yield vs. impurity purge during crystallization.
Another improvement later in the synthesis involved the reduction of significant process risk
present in a three-reaction telescope through the development of an additional isolation after the first
reaction in this sequence. The reduced process risk was quantitated as a failure rate, using multivariate
Bayesian modeling to ensure process robustness despite potential parameter variations. Finally, changes
were made to the penultimate process step that improved sustainability and reduced cost without
increasing process risk. These changes were enabled through generation of mechanistic models that
enhanced kinetic and thermodynamic understanding of the reaction and the subsequent water uptake
of the product. Developing fundamental engineering understanding and enhancing it with quantitative
metrics both informs where to focus development resources and provides a fully comprehensive data
package summarizing knowledge, residual risks, and documenting improvements in a format that is easy
to communicate to stakeholders and enables quality by design.