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“We consider the UK as a leader in excellent science and innovation so of course having them on board for proposals and projects for us is crucial.” Dr Laura Rodríguez should know. As one of the scientific leaders at the heart of an ambitious Europe-funded research effort, Rodriguez has been at the centre of the Europe-wide partnership between her company, IRIS Technology Solutions in Barcelona, and several research partners.

This sharing of expertise has made the research effort more than the sum of its parts, she says. “The multicultural and multidisciplinary environment is crucial to the results.” All this is made possible by Horizon Europe, the European Union’s flagship €96 billion research and innovation funding program.

The goal of Rodriguez’ collaboration is to minimise the environmental footprint of the pharmaceutical industry by rethinking the entire life cycle of medicines—from the moment a molecule is designed to how a patient disposes of the leftover pills. The science is so complex that it requires the expertise of world class researchers, innovative small-to-medium sized enterprises (SMEs) and leading pharmaceutical companies from across Europe. That’s how IRIS Technology Solutions has come to partner with UK companies such as Quotient Sciences, headquartered in Nottingham, as well as the pharmaceutical giant AstraZeneca.

Cleaner Chemistry

“The manufacture of pharmaceuticals generates more waste and by-products compared to all other chemical sectors [per quantity of end product],” says Dr Sara Sànchez, also at IRIS. For every kilogram of medicine, the industry produces more than ten kilograms of waste and by products, far more than industries that are generally thought of as “dirtier” such as petrochemicals. While fuels are produced in massive, continuous flows, medicines are typically manufactured in discrete batches. This requires frequent, intensive cleaning between products, which generates significant chemical runoff and waste.

“The nature of these wastes and products have a huge impact on the environment,” says Rodríguez, “so it is not only about the amount of waste and sub-products, but also the complexity of the chemicals and the dangers they pose.”

To tackle these issues, the Horizon Europe innovation programme has funded a €5.9 million project called ETERNAL which brings together 16 partners from across the continent in a 4-year partnership. The project is exploring green chemistry techniques to help reduce the use of solvents and help minimise residues in wastewater; it is studying mechanochemistry—how mechanical forces like grinding and compressions can trigger chemical reactions and reduce the reliance on solvents and energy-hungry heat; and developing digital twins to create virtual replicas of manufacturing processes that predict how changes will affect the environmental impact before a single chemical is poured.

A “clean” supply chain doesn’t end at the factory gate; it includes the patient. So ETERNAL is launching campaigns to influence behaviour by nudging consumers to dispose of medicines responsibly, for example by returning unused pills to a pharmacy rather than flushing them down sinks and lavatories.

Positive reactions

The challenge begins with the way drugs are designed to start with. In the early stages of drug development, pharmaceutical companies are generally focused on bringing effective and safe medicines to market quickly. So, factors such as the amount of by-product produced can become a secondary concern. The result is that inefficient chemical pathways can become locked into the manufacturing processes.

One way to change this is to better understand reactions as they are in progress. To this end, IRIS and Quotient are using a technique called Raman spectroscopy, a kind of chemical fingerprinting technique that monitors chemical reactions while they are in progress, allowing more control and therefore less waste.

The technology involves firing a laser into the reaction vessel and analysing the light that comes back. That light is frequency-shifted based on the vibrations of chemical bonds in substances within the mixture, allowing the researchers to infer how quickly a reaction is progressing. If adjustments to reaction conditions such as temperature or pressure are needed, they can be done in real-time without the chemicals needing to be sampled.

But neither partner could have done this on their own. IRIS has expertise in building the optical hardware and creating the software to analyse the results, while Quotient has the detailed understanding of the complex chemical reactions at work.

Dr Rowena Howie at Quotient’s Alnwick site says the company could not have pursued the Raman approach on its own. “One of the best things about our collaboration with IRIS is the access it gives us to technology and expertise that we wouldn’t otherwise have,” she says.

Once the technique has been fully validated, it should open up a new pathway to understanding and monitoring the chemical processes at the heart of drug manufacture more precisely. “The real-time interface is what’s really going to help,” she says.

And the hope is that the partnership will continue beyond ETERNAL, allowing the technique to be applied to other chemical processes.

IRIS also collaborated with AstraZeneca to develop membranes that filter active ingredients or impurities from solvents, a technique that uses significantly less energy than traditional separation techniques like distillation. A key task is to find the best pore size for the filter, which would conventionally be done with multiple experiments that are time consuming and wasteful.

Digital twins

IRIS has built a digital twin of the process — a computer simulation that models the fluid dynamics around the pores, incorporating the properties of the solvent, the solutes and the membrane. “A digital simulation, of course, is much cheaper and faster,” says IRIS’s Dr David Nettleton. It allows researchers to run dozens of ‘what-if’ scenarios—virtually testing different experimental parameters—to identify the most efficient process before a single drop of real chemical is used.

Again, this is a problem that neither side could have cracked on its own. Nettleton describes the partnership as an iterative process, where AstraZeneca defined the problem and IRIS built prototypes of the simulation model. “We get the feedback … and we make updates,” he says, until the simulation is a close approximation to its real-life twin.

This free flow of ideas between participants in the collaboration has been crucial to this success, says Dr Rory MacDonald at Quotient Sciences. “All partners, I think, have just been completely open.” That openness will outlive the formal end of the ETERNAL project in August because much of the data will be put in the public domain. “It will be delivering benefits in terms of reduced environmental impact with all the various partner companies that have worked here,” he says.

Rodríguez agrees that on the scientific level, working together has been “fluid and collaborative” while personal connections have thrived. But there is one realm where national rivalries have proved impossible to eliminate.

“We try not to talk about soccer,” she admits. In Barcelona, a proud footballing city, European collaboration it seems has its limits.

Find out ����

Listen to the New Ů��С��Ƶ Colab podcast, How UK and Spanish scientists are reimagining the future of green pharma