Chemicals & raw materials
made since then have refined the process and turned it into the commercial enterprise we see today, and as a result patients around the world have benefited from peptide-based therapeutics. One of the major impacts has been among patients with both type-1 and type-2 diabetes, where glucagon-like peptide 1 (GLP-1) medications can be a boon when traditional oral medications can’t get blood sugar levels under control. Currently, there are 80 approved peptide drugs on the market worldwide that exist to treat anything from cancer and autoimmune diseases to neurodegenerative and cardiovascular pathologies. Of these peptide therapeutics, 38 were approved in the United States, Europe and Japan after the turn of the century, and there’s 170 currently being trialled for safety and effectiveness. It’s clear from these numbers that the peptide therapeutics market is growing rapidly – but manufacturers have a problem. “The process mass intensity of peptide manufacturing using Solid Phase Peptide Synthesis is a disaster,” Walter Cabri, full professor of organic chemistry in the Department of Chemistry ‘Giacomo Ciamician’ at the University of Bologna in Italy, says. He’s describing the total mass of materials used to produce a specified mass of peptide products – the measure used by chemists and engineers to evaluate levels of waste within their production processes.
But what does this look like in numbers? According to research highlighted in a recent paper co-authored by Cabri, peptides have a typical process mass intensity (PMI) of between 3,000kg and 15,000kg per 1kg of active pharmaceutical ingredient (API). “This PMI is one of the worst in the pharma industry,” says Cabri. Part of the reason for this, as Alessandra Tolomelli, associate professor in the Department of Chemistry ‘Giacomo Ciamician’ and co-author of the paper, explains, is that the peptide drugs sold today contain synthetic amino acids, and they can come at a high cost and require a large amount to achieve coupling due to being less efficient than their natural counterparts. “The problem of applying peptide synthesis for the production of these molecules is that you will have a high cost, because you’re using a very precious and expensive reagent that will be used in excess, and from the point of view of the atom economy, a lot of material goes to waste,” Tolomelli adds. “To refine the fragment you’re building from the excess of these reagents, you have to wash and wash with a large amount of solvent.” There’s some context necessary to understand this point: The ‘solid’ part of SPPS refers to the resin upon which the reactions take place; the amino acids must be deprotected to prepare the chain for additional coupling steps, but to avoid any unwanted side reactions, any leftover reagents are
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dissolved, or ‘washed’, from the mixture using a solvent. The more reagent used to achieve a desired reaction and the longer it takes to complete the steps prior to the final ‘cleaving’ step, where the amino acid is removed from the resin, the more solvent that’s required to wash away the excess and prevent a compromising reaction. There’s also a final ‘purification’ stage that requires even more solvent to remove impurities, and the amount of these can vary depending on the efficiency of the coupling process.
Reliance on DMF
The reliance on solvent during the process, coupled with the fact that it’s estimated to account for between 80-90% of the PMI associated with peptide synthesis, means a huge amount of waste is generated, and that’s one reason for Cabri’s sentiments. The other reason is that dimethylformamide, or DMF as it is commonly referred to, is most often the solvent of choice, and it’s been under fire for some time now due to its less-than-ideal safety profile. DMF is the most common solvent seen in peptide synthesis due to its efficient reagent solubility and resin swelling properties, efficient removal of protective groups, and sufficient peptide coupling kinetics. “Technically, it’s perfect. But from an environmental and safety point of view, it’s a disaster,” says Cabri.
“The problem of applying peptide synthesis... is that you will have a high cost, because you’re using a very precious and expensive reagent that will be used in excess.”
Alessandra Tolomelli
These aren’t just risks subject to discussion and analysis among the academic community either; as of 12 December 2023, the industrial use of DMF will be heavily restricted in countries within the European Union due to an amendment to Annex XVII of the European Chemicals Agency’s regulatory framework REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals). The reasons cited in a press release by the regulator when the restriction was announced in November 2021 was to protect workers from “liver and developmental effects and reproductive harm”. The case for reducing solvent use in peptide manufacturing has been apparent for some time now, and there’s no shortage of research papers that propose green alternatives to DMF, or a mixture of solvents made to achieve a more efficient synthesis process. Cabri and Tolomelli themselves proposed such a mixture in a 2019 paper, but as Cabri notes, “people in production are very comfortable with the use of DMF”. There are
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