Chemicals & raw materials
As sustainability becomes a more urgent concern for the field, many have proposed ways of making peptide manufacturing kinder to the planet. There’s scope, for example, to make the process more efficient or to swap out hazardous substances for greener ones.
Implementing these efforts is a work in progress.
But it’s certainly high on the agenda, says Alessandra Tolomelli, associate professor in the University of Bologna’s department of chemistry. “We began this work [on peptide manufacturing sustainability] in 2019,” she says. “Now, it’s the main topic of each congress.”
“We need to substitute the TFA; there are studies looking into that. But so far, there’s not a good substitute.”
Professor Fernando Albericio Less waste
Perhaps one of the most pressing issues in peptide manufacturing is the sizable amount of waste that’s produced. Consequently, the process has a high E-factor – a metric used to measure environmental impact. A high E-factor means more waste is generated per unit of product. Currently, the standard method for making peptides is solid- phase peptide synthesis (SPPS). Most peptides are produced via SPPS, says Fernando Albericio, research professor at University of KwaZulu-Natal and emeritus professor of organic chemistry at the University of Barcelona. “And solid-phase synthesis uses a lot of solvents.” To give an example, depending on the length of the peptide chain, a 2024 paper in the Journal of Organic Chemistry estimates that up to 14 tonnes of solvent can be used to make 1kg of synthetic peptide medicines via SPPS. With SPPS, peptide chains are attached to a solid resin and built up, amino acid by amino
80%
Most waste from the synthesis process is due to washing.
Green Chemistry 68
acid. To prevent unwanted reactions, each amino acid has protective groups over its reactive functional groups. When a new amino acid is added to the chain, a protective group is removed (this is called deprotection) so the next one can attach (coupling). When the peptide chain is complete, it’s cleaved off the resin and any other remaining protective groups are removed. The peptide is then precipitated, collected and purified.
Solvents are used to remove the protective groups each time, while the coupling steps are activated via reagents. Plus, after each step, solvents are used to remove
excess reagents, by-products and other solvents – which is known as washing, and they’re also used for purification.
This generates a lot of waste: 80% of waste from the entire synthesis process is due to washing, according to a study published in the journal Green Chemistry, on which Tolomelli is an author. But work is under way to change that. In another
paper, co-authored by Albericio and also published in Green Chemistry, he and his colleagues propose a method that combines the coupling and deprotection steps. Rather than washing out reagents after coupling and adding another (piperidine) for deprotection, piperidine is added directly to the coupling cocktail.
“This strategy brings about a saving of 75% of the solvent,” notes the paper. “Which implies a 4-times reduction of the PMI and E-factor.” PMI compares the mass of materials used to make a product with the mass of product obtained; a higher PMI means a less efficient, more wasteful process. Another approach is to avoid SPPS altogether. For instance, liquid phase peptide synthesis (LPPS) instead allows peptides to form within a solution. Here, molecules called ‘tags’ are used to anchor the peptide chain. Removing impurities after each coupling or deprotection step can be done via precipitation or filtration. And while you could wash your peptide with solvent, you’d typically use less than with SPPS, explains Tolomelli. Plus, “during the reaction steps, you need a lower excess of reagents”.
Greener chemicals It’s also important to ensure that any waste you do produce isn’t hazardous. Industrial waste must be treated and disposed of, which is often done through energy-intensive processes such as incineration. It can also release harmful emissions during production and disposal. “The treatment of waste has become a huge problem,” Tolomelli adds. For SPPS, solvents represent over 80% of the total waste produced. And typically, SPPS has relied on use of the toxic solvent dimethylformamide (DMF). Within the EU, use of DMF has been restricted since 2023. But that isn’t the case in the US, where, according to Precedence Research, North America held approximately 46% of the global peptide therapeutics market revenue share in 2024. Plus, other hazardous solvents including NMP and
www.worldpharmaceuticals.net
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