A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 1: CDI-Promoted Amide Bond Formation

Abstract

This article details process characterization efforts and the development of corresponding process models to inform a process control strategy to produce a carfilzomib drug substance intermediate, morpholine amide 3. Model calibration for relevant unit operations and development of a dynamic integrated flowsheet-level model in gPROMS FormulatedProducts software allowed an investigation of the impact of process disturbances and model uncertainties on critical quality attributes (CQAs) and identification of critical process disturbances and failure modes to guide the process control strategy. The main CQA for this step was the conversion of Boc-D-leucine monohydrate (≥95%). The model was used to ensure that a state of control would be maintained in the presence of disturbances to target process parameters. The process was found to be robust against the analyzed disturbance scenarios, including worst-case combined disturbances. One case study highlights the dynamics of flow blockage for a key reagent, N,N′-carbonyldiimidazole (CDI), resulting from line clogging and the relationship between blockage duration and reaction conversion. The blockage was studied in silico, and the model demonstrated that the acceptance criteria for reaction conversion were met even with a flow rate reduction of 40%. The detrimental impact on the product concentration in the downstream process, however, required modification of the final distillation operation. The revised distillation column operation was demonstrated to address this concern and tolerated variable concentrations of morpholine amide while achieving the target water specification (<0.25 wt %). The results of this in silico analysis were verified with a production-scale demonstration of morpholine amide synthesis at a throughput of 12 kg/day to experimentally evaluate the impact of disturbances on the control strategy and overall performance of the system.

Reactor design and selection for effective continuous manufacturing of pharmaceuticals

“…There are other publications that report on reactions performed in CSTRs-in-series [71][72][73][74][75][76][77], which are not discussed in detail here.…”

Impurity incorporation in solution crystallization: diagnosis, prevention, and control

“…[26][27][28][29][30] Consequently, most recent examples of end-to-end synthetic pharmaceutical manufacturing involve a number of crystallization steps where the main role is to purify an intermediate product, limiting the accumulation of impurities along the main process stream. 25,26,[31][32][33][34][35][36][37][38] Despite the widespread use of these purification steps, our understanding of how impurities incorporate in crystals is far behind, current models for predicting purity in solution crystallization are limited to a narrow design space, 25,28 and process design is still largely based on extensive solvent screenings and trial and error. 24,26,[38][39][40][41] This is, in part, due to the number and complexity of mechanisms by which impurities incorporate in growing crystals, and the limited understanding of kineticdriven interactions between impurities and solute molecules in the crystal-solution interphase.…”

A Virtual Plant for Integrated Continuous Manufacturing of a Carfilzomib Drug Substance Intermediate, Part 2: Enone Synthesis via a Barbier-Type Grignard Process

“…In recent years, academia, industry, and regulatory agencies have been advocating for a transition from batch processing to continuous manufacturing of pharmaceuticals. − As described by the U.S. Food and Drug Administration (FDA), continuous manufacturing offers several advantages over batch processes, including reduction of equipment size and footprint, consequential improvement of heat and mass transfer that can make possible the implementation of highly exothermic and diffusion-limited heterogeneous reactions, and the ability to divert material in cases of detected process failure . Academically and industrially, there have been various demonstrations of continuous processing for individual unit operations and a limited number of demonstrations of end-to-end continuous processes, as discussed in Part 1 of this series () . However, along with the advantages come some unique challenges for continuous manufacturing.…”

“…3 Academically and industrially, there have been various demonstrations of continuous processing for individual unit operations and a limited number of demonstrations of end-toend continuous processes, as discussed in Part 1 of this series (10.1021/acs.oprd.0c00187). 4 However, along with the advantages come some unique challenges for continuous manufacturing. Specifically, continuous processing results in more direct and complex interactions among the series of integrated unit operations.…”

“…15 Part 1 of this series introduces the end-to-end continuous process to prepare an epoxy ketone intermediate used for the manufacture of carfilzomib via a four-step synthetic sequence. 4 Part 1 also focuses on the development of a continuous manufacturing process to produce the first isolated product, morpholine amide 1, from Boc-D-leucine monohydrate and introduces the methodology of using a virtual plant for in silico disturbance analysis and control strategy development.…”