Advancing Sustainable Processes in Pharma and Allied Industries via Green Chemistry Innovations

The design and validation of new molecules with desired properties is crucial for advancing human health or agriculture, yet it remains a costly and time-consuming endeavor. While generative Artificial Intelligence (AI) has accelerated the in silico exploration of novel chemical space, current models struggle to design molecules whose syntheses adhere to the 12 Principles of Green Chemistry. Conversely, heuristic-based computational tools can propose sustainable synthesis routes for known molecules but lack the capability to discover novel scaffolds.

In this work, we introduce Saturn-RXN, a generative molecular design framework that explicitly enforces reaction constraints during generation. Leveraging a sample-efficient generative language model and reinforcement learning, Saturn-RXN proposes property-optimized molecules while satisfying specific synthesis constraints, such as avoiding hazardous reaction types or mandating specific building blocks. This approach directly addresses key Green Chemistry principles: Atom Economy (minimizing reaction steps), Waste Prevention/Use of Renewable Feedstocks (utilizing bio-based building blocks or waste-derived feedstocks), and Less Hazardous Synthesis (avoiding deprotections or enforcing milder conditions). We demonstrate the framework’s utility in a computational case study, where Saturn-RXN successfully designs novel molecules derived from industrial waste building blocks, promoting greener processes without sacrificing molecular utility.

This “sustainable-by-design” approach establishes a new paradigm in molecular discovery. By synergizing human expertise with AI, Saturn-RXN offers a pathway to transform the pharmaceutical and agrochemical industries through the creation of property-optimized molecules via sustainable synthesis.

Aralez Bio uses biocatalysis to unlock the synthesis of noncanonical amino acids. Using directed evolution, we develop enzymes to synthesize new amino acids needed for innovations in pharmaceuticals, food, agriculture, and functional materials. Our proprietary enzymes catalyze an array of bond-forming and transformation reactions with a broad range of readily available substrates, enabling us to manufacture over a thousand enantiopure noncanonical amino acids from mg to 100 kg scale. Through increased efficiency and product scope, Aralez Bio supports the development and manufacture of new peptides more quickly and cleanly than ever before.

High-throughput Experimentation Enabled Late-stage Functionalization as a Tool for Sustainable Chemistry.

Olpasiran is a siRNA therapeutic that consists of a double-stranded oligonucleotide conjugated to a liver-targeting tri-N-acetylgalactosamine (GalNAc) ligand. Synthesis of this hybrid molecule comprises multiple complex steps: multistep batch manufacturing of a small molecule GalNAc ligand; solid-phase oligonucleotide synthesis (SPOS), including conjugation of the GalNAc ligand; and final downstream purification of the siRNA conjugate. At Amgen, synthetic process design is driven by green chemistry principles, and these principles were tightly integrated into the development of a process for multi-kilogram manufacturing of olpasiran.

This presentation will discuss developments to both the GalNAc ligand synthesis and the conjugation process that enabled significant reductions in waste, solvent use, and hazardous reagents compared with the discovery route. These include 1) replacement of time- and solvent-intensive chromatographic purifications of GalNAc intermediates with robust precipitations, 2) replacement of a two-step process to a starting material with a catalytic one-pot process, enabling 81% reduction in step PMI, and 3) reduction of GalNAc equivalents and solvent volumes in the solid-phase conjugation step. These, and other, improvements resulted in scalable processes that have been demonstrated on >30 kg scale with corresponding reduction in E-factors (up to 37%). Overall, the optimized process will provide over 25% reduction in solvent and waste at peak production.

Process development for Repotrectinib (BMS-986472) exemplifies how innovative strategies can advance sustainable pharmaceutical manufacturing. By integrating green chemistry principles, the team transformed the synthetic route to this API, achieving a fourfold increase in overall yield (11% to 45%), reducing isolations from 10 to 6, and eliminating dioxane and all halogenated solvents and reagents. The second generation process underscores the importance of deep process understanding of the reaction conditions, workup, and isolation, combined with modeling and optimization to ensure robust scalability, reflecting a commitment to delivering scalable, sustainable solutions for complex drug synthesis.