Theodore A. Gazis a, Jonas Wuyts b, Areti Moutsiou a, Giulio Volpin c, Mark J. Ford c, Rodolfo I. Teixeira d, Katherine M. P. Wheelhouse e, Philipp Natho f, Polona Žnidaršič-Plazl gh, Sonja Jost i, Renzo Luisi f, Brahim Benyahia d, Bert U. W. Maes b and Gianvito Vilé *a
[a]Department of Chemistry, Materials, and Chemical Engineering “Giulio Natta”, Politecnico di Milano, Piazza Leonardo da Vinci 32, 20133 Milano, Italy. E-mail: admin@frankenthalerfoundation.org
[b]Organic Synthesis Division, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium
[c]Bayer AG, Crop Science Division, Alfred-Nobel-Straße 50, 40789 Monheim, Germany
[d]Chemical Engineering Department, Loughborough University, Epinal Way, LE11 3TU Loughborough, Leicestershire, UK
[e]Drug Substance Development, GSK Medicines Research Centre, Gunnels Wood Road, SG1 2NY Stevenage, Hertfordshire, UK
[f]Flow Chemistry and Microreactor Technology (FLAME-Lab), Department of Pharmacy – Drug Sciences, University of Bari “Aldo Moro”, Via Edoardo Orabona 4, 70126 Bari, Italy
[g]Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
[h]Chair of Micro Process Engineering and Technology – COMPETE, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia
[i]DUDECHEM GmbH, Köpenicker Str. 325, 12555 Berlin, Germany
Received 5th August 2025
First published on 17th November 2025
In the face of intensifying market needs and mounting environmental pressures, the pharmaceutical and agrochemical sectors must revisit core aspects of process design. This review proposes a forward-looking framework for “greener-by-design” manufacturing, emphasizing the integration of sustainability from the earliest stages of synthetic planning through to industrial implementation. We focus on four interdependent levers that collectively enable this transformation: (i) solvent choice, with an emphasis on minimization, substitution, or complete elimination; (ii) substrate sourcing, favoring renewable and biomass-derived feedstocks to reduce fossil dependency; (iii) catalyst development, exploring the use of base metals, novel heterogeneous systems, and biocatalysts; and (iv) continuous-flow processing, which enhances safety, scalability, and process control. These strategies are not meant to be applied in isolation but rather in a synergistic, end-to-end manner that accounts for the full lifecycle of chemical products. By aligning synthetic efficiency with environmental responsibility, this review outlines a practical and actionable roadmap for the sustainable production of high-value fine chemicals. The convergence of synthetic chemistry with process engineering, data science, and life cycle thinking will be critical to realizing this vision, ultimately enabling more robust, circular, and future-proof manufacturing paradigms.
The fine chemical industry, broadly defined by the production of high-value (>10 USD per kg), small- to medium-volume compounds, stands as a critical economic pillar of the European Union. It sustains over 1.2 million jobs and generates a turnover of 85 billion USD, with the lion's share originating from the pharmaceutical (55 billion USD) and agrochemical (15 billion USD) sectors. Pharmaceutical active ingredients are typically produced at relatively low volumes, often ranging from a few kilograms to several tens of tons per annum, reflecting their high value and targeted applications. On the other hand, many agrochemical ingredients, despite sharing comparable structural complexity and stringent purity requirements, are manufactured at volumes that can exceed several thousand tons per year. This positions agrochemicals at the interface between fine and performance chemicals. Globally, the pharmaceutical and agrochemical sectors are projected to expand at nearly 6% and 4% annually through 2030, driven by growing healthcare demands for chronic and infectious disease treatments, the expansion of lifestyle and personalized medicines, aging populations, and the need to enhance agricultural productivity and ensure food security for a rising global population. While this growth signals economic opportunities, it also raises substantial concerns around operational costs, resource consumption, and environmental impact.
Specifically, the pharmaceutical sector contributes an estimated 4–5% of worldwide carbon emissions, with its emission intensity in 2015 registering 55% higher than that of the automotive sector. It also generates significantly more waste per unit of product than the oil refining and bulk chemical industries. In comparison, the manufacture and use of crop protection products account for about 3% of the global warming potential (GWP = contribution to global warming in CO 2 equivalent) of crop production and between 1–4% of the total carbon footprint of crop cultivation. These emissions, however, must be evaluated in the broader agroecosystem context, where crop protection products boost yields, reduce land use, and improve other inputs, thus partly offsetting their direct negative environmental impact. Nevertheless, recognizing the urgency to mitigate these effects, the industry is increasingly emphasizing decarbonization efforts. For instance, the European Fine Chemical Group (EFCG) advocates for financial incentives to encourage eco-friendly manufacturing in Europe, alongside international collaboration to minimize environmental harm. Beyond combating climate change, such measures are viewed by the European Commission and other governing bodies as a critical lifeline to revitalize the industry's competitiveness.
Indeed, regulatory frameworks have progressively evolved to prioritize sustainability in pharmaceutical and agrochemical production. Central to this shift is green chemistry, a concept codified in the 12 Principles of Green Chemistry by Anastas and Warner in 1998. By promoting the reduction of hazardous substances and the use of safer, more sustainable alternatives, these principles align with global initiatives such as the United Nations Sustainable Development Goals. Notable policy milestones of this approach include the European Green Deal, the EU Chemicals Strategy for Sustainability toward a Toxic Free Environment, the Safe and Sustainable by Design (SSbD) framework, the US “Sustainable Chemistry Act”, and the Water Framework Directive, among others.
As a result of these intertwined economic, regulatory and environmental incentives, the fine chemical industry is undergoing a transformative shift toward more sustainable practices. A “greener-by-design” approach underpins this evolution, aiming for a circular economy through reduced chemical hazards, reduced pollution, and efficient resource utilization. However, it is important to acknowledge that reducing intrinsic chemical hazards can, in some cases, lead to unintended trade-offs, such as increased waste production, reduced atom economy, or diminished process efficiency. These potential drawbacks highlight the need for a holistic assessment of sustainability, ensuring that hazard reduction efforts do not undermine the overall environmental or economic performance of the process.
Today, according to a recent McKinsey & Company report, 50–70% of the top 20 Active Pharmaceutical Ingredients (API) manufacturers have set decarbonization targets, although fewer than 20% present detailed imp
