Developing Flow Solutions to Enhance Process Sustainability

Key highlights of the late-stage flow manufacturing campaign for the Kat6i program include greener practices implemented during the continuous steps 1–3 process.

Continuous-flow chemistry is widely regarded as an inherently green technology due to advantages in heat and mass transfer, safety, and process intensification. However, whether these benefits translate into measurable environmental performance is rarely demonstrated quantitatively. Here, we examine how sustainability is framed, inferred, and documented in the modern flow-chemistry literature using a structured, text-mining–assisted review of 113 machine-readable research articles drawn from a larger corpus of 680 publications. We identify a pronounced “metrics gap.” Fewer than 10% of full-text articles report quantitative sustainability metrics such as Process Mass Intensity (PMI), E-factor, solvent intensity, or energy intensity, while more than 80% report sustainability-relevant performance improvements (e.g., higher yields, shorter reaction times, milder conditions, or improved safety). These results indicate that most flow platforms are already “metrics-ready,” but lack standardized pathways for translating existing data into green metrics. To address this gap, we propose a practical, modular framework for embedding PMI, solvent intensity, and energy intensity directly into routine continuous-flow experimentation. This approach emphasizes clear system boundaries, deliberate capture of mass and energy flows, transparent metric calculation, and integration of sustainability objectives into automated optimization workflows.

Mechanochemistry, powered by mechanical energy rather than heat or solvents, is emerging as a key enabler of sustainable chemical manufacturing by reducing waste, lowering energy consumption, and eliminating hazardous solvents. To accelerate industrial-scale adoption, this presentation introduces WAB-GROUP^®’s advanced technologies and their integration into large-scale continuous mechanochemical processes. The WAB IMPA°CT REACTOR^®, a unique system combining continuous flow chemistry with bead milling, will be showcased alongside an equipment characterization while focusing on applications.

The session will also cover optimization strategies for process control, and energy efficiency, alongside a green impact analysis highlighting reduced solvent use and improved sustainability metrics. The presentation will conclude by showcasing the broad applicability of mechanochemistry, including its role in pharmaceutical intermediate synthesis, underscoring its potential as a scalable and environmentally responsible alternative for industrial manufacturing.

The widespread use of peptide-based drugs underscores the critical need for efficient, sustainable, and environmentally friendly amidation methods in the pharmaceutical industry. However, conventional approaches typically rely on hazardous organic solvents and large excesses of auxiliary reagents, highlighting the urgent need for a paradigm shift toward greener alternatives.
Herein, we report a novel protocol for peptide synthesis via amide bond formation using 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ) in water as a sustainable reaction medium, with hydroxypropyl methylcellulose (HPMC) serving as a cheap and readily available surface-active enabler. During the coupling process, EEDQ releases quinoline, which effectively acts as an in situ base. This feature enables efficient peptide bond formation without the addition of any external base, thereby significantly improving process atom economy compared to commonly used carbodiimide- or uronium salt–type coupling agents. Importantly, this strategy affords fast, racemization-free peptide couplings across a broad range of amino acid substrates. Impurities are efficiently removed through a simple work-up procedure consisting solely of filtration, washing with water, and drying, without the use of any organic solvents, rendering the overall process entirely solvent-free.
Following systematic parameter optimization and exploratory studies under small-scale batch conditions, the protocol was translated into a scalable continuous slurry-flow process using a novel split-and-recombine plate-type flow reactor, coupled with an oscillator pump to provide efficient active mixing and optimal mass transfer. Finally, the process was further scaled up using a commercially available agitated continuous stirred-tank reactor (CSTR) cascade, achieving productivities on the multikilogram-per-day scale.

This work introduces a novel radio-frequency (RF) electrothermal heating approach for sustainable high-temperature, non-contact, and scalable material processing. This method addresses key limitations of traditional furnace-based heating systems which suffer from slow heating rates, poor thermal uniformity, and high energy consumption. Electrification of heating could reduce both operational costs and associated greenhouse gas emissions. RF induction coils were designed to heat conductive materials, specifically Hi-Nicalon Type S silicon carbide fibers, to temperatures exceeding 1200 °C in an inert, controlled environment. The system achieves rapid heating rates reaching up to 200 °C/s at only 1 W of applied power, demonstrating highly efficient energy conversion. Experimental heating results were complemented by COMSOL Multiphysics simulations, which show good agreement in temperature profiles, validating that the heating behavior observed in experiments can be reproduced and predicted through simulation.

To demonstrate scalability and relevance to continuous green manufacturing, the RF apparatus was integrated into a roll-to-roll configuration, enabling continuous contactless heating of silicon carbide fiber tows. This establishes a pathway for continuous, high-temperature RF-based processing of industrially relevant materials. This work defines a new platform for sustainable high-throughput thermal treatment of conductive materials and highlights its applicability to next-generation composite and ceramic manufacturing, as well as other advanced industrial thermal processes.

AMG 193 is a cooperative inhibitor of PRMT5 with methylthioadenosine (MTA), selectively inhibiting PRMT5 in methythioadenosine phosphorylase (MTAP) null cancers, and is currently progressing through clinical trials. This presentation will discuss various aspects of the end-to-end commercial process development for a key chiral morpholine fragment (CFAM) in the synthesis of AMG 193, with a focus on the continuous manufacturing (CM) of a ketone intermediate, TOMBOC.

TOMBOC is generated from an aryl bromide and morpholinone via a highly reactive aryl lithium intermediate. This talk will highlight the development of this multistep CM process to enable large-scale manufacture of TOMBOC. To maximize time and material efficiency, transient flow experiments – which involve the continuous manipulation of reaction parameters in a controlled manner within a single run – were used in the process optimization. Overall, this robust flow process delivers excellent purity TOMBOC while offering safety and cost improvements over previous magnesium-based syntheses.

Next, TOMBOC undergoes a deprotection and cyclization to form an imine CFIM. Finally, CFIM undergoes biocatalytic asymmetric reduction using an imine reductase (IRED) catalyst to produce CFAM, which is isolated as a hydrochloride salt. Ultimately, >900 kg of CFAM.HCl has been produced in high quality (100 A% purity, meeting all proposed commercial specifications) to support fast-moving clinical supply demands.

Sustainable pharmaceutical manufacturing requires not only greener chemistry but engineered reactor platforms capable of delivering superior selectivity, conversion, safety, and measurable environmental performance. This presentation highlights industrial case studies implemented using AmarFLO continuous flow reactor systems, demonstrating how advanced multiphase reactor engineering directly improves green metrics across pharmaceutical intermediates and APIs.
A landmark example is the continuous synthesis of para-aminophenol (PAP) from p-nitrochlorobenzene, a key intermediate for paracetamol. This first-of-its-kind engineered continuous technology achieves ~99% conversion and selectivity with >95% yield and excellent operational stability. Intensified gas–liquid hydrogenation in slurry-capable AmarFLO reactors enhances hydrogen utilization (>95%), improves heat transfer, and ensures precise residence time control, resulting in lower effluent generation, reduced water usage, improved space–time yield, and significant reductions in Process Mass Intensity (PMI) and E-factor compared to batch processing.
For Entacapone intermediates, AmarFLO developed a mixed-acid-free nitration process converting vanillin to nitrovanillin with ~100% conversion and near-quantitative selectivity, eliminating sulphuric acid waste and reducing neutralization load and corrosion impact. The intensified flow condensation of ethyl cyanoacetate with diethylamine, traditionally a >24-hour batch operation, achieves >85% yield with reduced impurity formation and lower solvent consumption.
In ether hydrolysis of methyl dolutegravir, process intensification reduced a five-day batch cycle to a few hours of continuous operation while achieving API-grade purity and lowering energy demand, solvent inventory, and carbon footprint per kg product.
Another case study on continuous oxidation of 3-methylpyridine to niacin and niacinamide further demonstrates reactor modularity and enhanced gas–liquid mass transfer efficiency.
Across these case studies, AmarFLO systems demonstrate 20–50% reductions in PMI and E-factor, lower solvent intensity and specific energy consumption, improved atom economy, enhanced catalyst productivity, reduced reaction inventory, and increased inherent safety. Collectively, these results illustrate how advanced continuous reactor engineering enables practical implementation of the Principles of Green Chemistry and green process engineering in pharmaceutical manufacturing.

Sustainable pharmaceutical manufacturing requires innovative solutions that address both efficiency bottlenecks and the environmental footprint of legacy processes. In this work, we present the successful application of continuous flow chemistry to the synthesis of tulathromycin registered starting material (RSM), overcoming major sustainability and throughput challenges associated with the traditional batch approach.
Long batch holding times in the CBz protection step and the cryogenic demands of the Swern oxidation restricted output at manufacturing scale. By translating both CBz protection and Swern oxidation into a continuous flow regime, process intensification was achieved by reducing energy consumption, minimizing hazardous reagent excess, and streamlining waste management. The technology assessment and feasibility studies confirmed no inherent technical barriers to flow conversion.
Process engineering highlights:
Drastic reduction in energy demand: Reaction temperatures for Swern oxidation increased from -70 °C (batch) to as high as -40 °C (flow), and CBz protection progressed from -15 °C (batch) to up to 15 °C (flow), significantly reducing refrigeration loads.
Process intensification: Reaction residence times were cut from 4 hours (batch) to as little as 7–30 seconds (flow), boosting productivity and decreasing reactor volume per unit product.
Waste minimization: The flow regime reduced dichloromethane (DCM) use more than threefold and enhanced moisture management, thereby lowering solvent emissions and hazardous waste.
Scalability and robustness: Modular 3D-printed and Corning reactors enabled stable operation at throughputs up to 163 kg/day for Swern oxidation (200 mL reactor volume), with integrated design-of-experiment (DoE) optimization.
Practical sustainability: Continuous operation minimized hold-up, avoided intermediate storage, and improved safety by reducing handling of cryogenic and toxic reagents.

Macrocyclic peptides are a growing and promising asset class within the development pipeline at Merck & Co., Inc. For decades, batch-mode solid-phase peptide synthesis (SPPS) has been employed throughout peptide drug discovery and development; however, numerous drawbacks (e.g., high solvent volumes and long processing times) have persisted despite advancements in the technology. To address these limitations, Merck has invested in a novel platform technology, continuous flow solid-phase peptide synthesis (CF-SPPS), to optimize and deliver peptide fragments across reaction scales. Through the identification of key scaling parameters and development of novel variable bed reactors, we have enabled a rapid, data-rich workflow for peptide synthesis that dramatically reduces development efforts, timelines, and waste compared to batch-mode SPPS. Join us as we discuss how our cross-functional team has driven the evolution of CF-SPPS from proof-of-concept to kilo-lab scale.

An integrated continuous manufacturing process for generation of a drug substance encompassing a series of three reactions, crystallization, filtration and drying was established at lab scale and successfully scaled up to a commercial scale of 12kg/h. This talk focuses on the process intensification and continuous process development of the reactions, wherein a series of three reactions – acetonide deprotection, hydrolysis and salt exchange – were all telescoped and intensified enabling improved green metrics for metric tonnage requirement.

First preliminary studies were conducted in batch mode to understand the scope for process intensification, followed by establishing feasibility of carrying out these reactions in flow reactors. The process was optimized at lab scale to identify the critical process parameters and the residence time distribution and reaction kinetics were also well-characterized. A detailed understanding of the flow process at the lab scale enabled selection of commercial equipment based on reaction requirements. As acetonide deprotection step was acidic in nature, required a high temperature and was sensitive to mixing, a silicon carbide reactor from Chemtrix® was identified as the right choice. The hydrolysis was carried out in the Plantrix followed by a PFR to allow sufficient residence time and the salt exchange, which had some tendency to form precipitates, was carried out in a dynamic reactor from AM Technologies®. Next, the pilot scale feasibility and verification of design space were performed on these pilot scale equipment. Challenges faced during further scale-up to commercial equipment and their resolution will be discussed.

A control strategy comprising PAT and a diversion strategy based on residence time distribution and model-based sensitivity analysis was established for commercial operation. A greenfield facility capable of manufacturing 90 tons/annum of this API has been established. The reaction mass efficiency and process mass intensity were significantly improved with lower power and utility consumption as compared to the batch process.

Nitroaromatic amines are tremendously valuable key intermediates with a long history of being used as pharmaceuticals, dyes, and agrochemicals. The classical approach for the preparation of these kinds of vital compounds typically requires three chemical reaction steps involving acetylation of the aromatic amines, nitration followed by acetyl hydrolysis. Herein, we report an efficient and safe continuous-flow direct nitration of aromatic amines.