Process Design and Optimization for the Continuous Manufacturing of Nevirapine, an Active Pharmaceutical Ingredient for HIV Treatment

Abstract

Development of efficient and cost-effective manufacturing routes towards HIV active pharmaceutical ingredients (APIs) is essential to ensure their global, affordable access. Continuous pharmaceutical manufacturing (CPM) is a new production paradigm for the pharmaceutical industry, whose potential for enhanced efficiency and economic viability over currently implemented batch protocols offers promise for improving HIV API production. Nevirapine is a widely-prescribed HIV API, whose continuous flow synthesis was recently demonstrated. This paper presents technoeconomic optimisation of nevirapine CPM, including the continuous flow synthesis and a conceptual continuous crystallisation. Arrhenius law parameter estimation from published reaction kinetic data allows explicit modelling of the temperature-dependence of reaction performance and an experimentally validated aqueous API solubility computation method is used to model crystallisation processes. A nonlinear optimisation problem for cost minimisation is formulated for comparative evaluation of different plant designs. Higher reactor temperatures are favoured for CPM total cost minimisation, while lower pH (less neutralising agent) is required to attain the desired plant capacities for cost optimal configurations compared to batch crystallisation designs. Suitable E-factors for pharmaceutical manufacturing are attained when higher solvent recoveries are assumed. Implementing CPM designs significantly lowers the nevirapine cost of goods towards reducing the price of societally-important HIV medicines.

Design Space Identification and Visualization for Continuous Pharmaceutical Manufacturing

“…Different assumptions of solvent recovery, SR = {0%, 40%, 80%} (reflecting worst case, intermediate and laboratory-scale demonstrated recovery demonstrations, respectively), are considered. The CPM flowsheet for nevirapine is shown in Figure 16 [72].…”

“…Different assumptions of solvent recovery, SR = {0%, 40%, 80%} (reflecting worst case, intermediate and laboratory-scale demonstrated recovery demonstrations, respectively), are considered. The CPM flowsheet for nevirapine is shown in Figure 16 [72]. The extent of modeling, simulation and optimization for the different API case studies considered vary: ibuprofen, artemisinin and diphenhydramine implement process simulation for design space investigation; warfarin and nevirapine studies implement Nonlinear Programming (NLP) for plantwide optimization for total cost minimization; atropine CPM implements Mixed Integer Nonlinear Programming (MINLP) for process synthesis to optimality, i.e., plant total cost minimization.…”

“…This highlights that beyond this API recovery that cost benefits are incremental at best. Nevirapine has significantly higher E-factors than other APIs due to the purification implemented prior to crystallization via pH change, as described in the original literature studies [71,72]. are often used to quantify the complexity/difficulty to synthesize a molecule with respect to its structure.…”

“…For nevirapine, total OpEx components reduce with increasing Solvent Recovery (SR) assumption due to less fresh solvents being required. The values of SR considered are 0% (worst case scenario = no recovery), 40% (intermediate) and 80% (best case scenario = recovery attained in the laboratory-scale demonstration [71]); other values can easily be compared to these results using the published plantwide model and optimization framework [72].…”

Technoeconomic Mixed Integer Nonlinear Programming (MINLP) optimization for design of Liquid‐Liquid Extraction (LLE) cascades in continuous pharmaceutical manufacturing of atropine

“…Theoretical methods have been widely implemented in the plantwide design and optimization of pharmaceutical manufacturing processes to screen for optimal designs with significant efforts in pursuit of continuous pharmaceutical separation process development. Plantwide CPM modeling and optimization with a focus on separation process design toward total cost minimization have been previously implemented in the literature for various APIs …”