(626b) Optimal Design of Separation Systems for Continuous Manufacturing of Nevirapine, an Active Pharmaceutical Ingredient (API) for H.I.V. Treatment

Affordability and accessibility of essential medicines remains a pressing issue for the treatment of diseases prevalent in developing countries. The treatment of HIV continues to be one of the most prominent global health challenges, with 36.7 million people living with HIV by the end of 2016, and approximately 70% of those being in low- and middle-income countries [1]. The development of efficient, cost-effective manufacturing routes towards APIs for HIV treatment is paramount to ensure global, affordable access to such medicines [2].

Continuous pharmaceutical manufacturing (CPM) has emerged as a new production paradigm for its promise of enhanced efficiency and greater economic viability over currently implemented batch protocols [3]. The utility of CPM platforms for the development of active pharmaceutical ingredients (APIs) for HIV treatment [4] has been demonstrated in the literature. While experimental demonstration of feasible API continuous flow synthetic routes is the foundation of any CPM campaign [5], the design of essential continuous separation processes for integration into upstream CPM plants for HIV API production is essential to realise the benefits of end-to-end continuous manufacturing [6].

Nevirapine is a widely-prescribed API for HIV-1 treatment, whose continuous flow synthesis was recently demonstrated [7]. Process intensification of the synthetic route compared to commercial reaction pathways allowed enhanced yields, improved material efficiency (reduced process mass intensity, PMI) and reduced number of unit operations. Systematic comparison of continuous separation processes is essential to further aid the development of leaner manufacturing routes towards this societally-important API. Process modelling and optimisation methodologies can be used to establish cost-optimal design configurations [8].

This paper presents a combined experimental and modelling study for the upstream continuous flow synthesis and separation of nevirapine. Reaction kinetic parameter estimation from API continuous flow synthesis experiments is performed, followed by continuous separation process model validation and subsequent nonlinear optimisation of the integrated upstream CPM plant. Optimal process configurations for CPM of nevirapine are presented with a critical analysis of experimental and modelling methodologies implemented. This work illustrates potential advantages attainable via end-to-end CPM and the importance and utility for modelling and optimisation studies at the early stages of design.

REFERENCES

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