Chemicals & raw materials
dichloromethane (CH2Cl2) are still widely used around the world for chemical reactions and
washing. Yet a number of greener solvents have been put forward. Leading pharma companies, including Pfizer and GlaxoSmithKline, have published lists of more sustainable alternatives, while research into the matter is ongoing. Some examples include dipropylene glycol dimethyl ether (DMM) and tetrahydrofuran (THF), which are both biodegradable. Though because there’s no universal solvent that’s guaranteed to work for every peptide, companies must determine which greener alternative fits the bill on a case-by-case basis. Your chosen method of synthesis will also factor in here. For instance, an advantage of LPPS is that it reduces reliance on toxic solvents, including DMF. “Both for the part of the process that is performed in solution, and also for the part where you have to precipitate [your peptide] for washing, you can use green solvents,” says Tolomelli.
Or you could use bio-fermentation to make your peptide. This is where a gene that’s coded to create your desired peptide is grown in a microorganism, such as yeast or E. coli. The cell then produces the peptide. “From the point of view of the safety of your waste, bio-fermentation is great, because you only have the biological material, so all your waste is biodegradable,” Tolomelli explains. But there’s a few caveats, she adds. Not only do you end up producing a lot of waste, but the process is less efficient than chemical synthesis. But solvents aren’t the only chemicals used in peptide manufacturing. There have also been efforts to avoid use of trifluoroacetic acid (TFA), which is a type of PFAS or “forever chemical”. These substances don’t degrade in nature and can have harmful effects on humans, animals and the environment. TFA is used in the final step of SPPS, and often LPPS, to cleave the peptide from its support. “We need to substitute the TFA; there are studies looking into that,” says Albericio. “But so far, there’s not a good substitute.” Plus, high volumes of TFA are typically used for cleavage, adds Tolomelli. “It’s a good percentage of the waste that you have to manage at the end.”
A more efficient way forward Streamlining the process can help reduce demands on resources and energy, too. One possible solution is flow chemistry, where chemical reactions happen in a continuous flow stream rather than via step-by-step, separate reactions (known as batch chemistry). Instead of mixing chemicals in a beaker, smaller amounts of reagents are pumped through tiny tubes into a reactor where the peptide is synthesised.
www.worldpharmaceuticals.net
The idea is that the process happens faster with less waste, making it more energy and cost-effective. And because it’s possible to automate it, this would potentially make it easier to scale up production. It’s something that Tolomelli thinks more companies will take up
in the coming years, particularly since flow chemistry is already being used for other therapeutics. “Some companies are trying to use it [for peptides],” she says. “It’s still in progress.”
Efforts to optimise the steps in the manufacturing process are also advancing. For instance, there’s interest in hybrid synthesis – where long peptide chains are cut into fragments and the best, most efficient synthesis method is identified for each. And as well as LPPS and SPPS, there’s also CEPS: chemo-enzymatic peptide synthesis, where fragments are coupled using an enzyme. “This allows us to increase the purity of the peptide,” Tolomelli explains, because the enzyme will only couple pure fragments – which could reduce the need to perform additional purification steps. Improving the yield at each step is also something Tolomelli and her colleagues are looking into. This is crucial when scaling up to industrial standards, adds Albericio.
“From the point of view of the safety of your waste, bio-fermentation is great, because you only have the biological material, so all your waste is biodegradable.”
Associate Professor Alessandra Tolomelli
However, adopting greener methods and strategies is often easier said than done. Companies must test and iterate on which greener solvents, reagents and methods work best for their peptide – as well as assessing their environmental impacts. This also likely means that they will need to change their processes and documentation, all while satisfying regulatory requirements. “It takes time and it takes effort, and not all companies are ready to do it,” says Tolomelli.
Approximately 80 peptide medicines are currently approved for use worldwide. And as demand grows, investing in sustainability is more crucial than ever. As well as those relevant to type 2 diabetes and weight management, “there are a huge number of other hormones, proteins and peptides involved in other diseases”, says Tolomelli. “I think that the market, both the academic and industrial research and development, will have a lot of work to do.” ●
46%
North America had almost half the global peptide market share in 2024.
Precedence Research 69
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