‘The whole basis of the project is sustainable chemistry. There are so many problems, and this proposal touched a few of them. The pharmaceutical industry sometimes compromises when it comes to developing really clean, high-efficiency synthesis because speed is vital in getting new drugs to patients,’ says Joe Adams, Scientific Leader and GSK Fellow within GlaxoSmithKline (GSK), and the industry co-ordinator of CHEM21. Emphasising the need for substantial improvements in pharmaceutical manufacturing, Joe Adams sees this as the basic reason why CHEM21 started - a real desire to have more sustainable, greener production processes.
The carbon footprint of the pharmaceutical industry is immense, comparable with the oil and mining, or meat and dairy industries. In most cases, to produce just 1 kg of an active ingredient, the industry uses 100 kg of materials. Inefficient production methods, combined with the use of expensive materials like precious metals as catalysts, raise the overall costs of medicines.
In order to pinpoint the main environmental issues within the pharmaceutical industry, the CHEM21 researchers took an in-depth look at the scale of CO2 emissions across the whole healthcare system of the United Kingdom. John Whittall, Research Exploitation Manager at CoEBio3 at the University of Manchester, who was responsible within CHEM21 for the academic-industrial interface, communication and dissemination, explains the results.
‘For the whole of healthcare delivery, the most significant release of CO2 was in drug manufacturing for patients,’ explains John. ‘And this identified that CHEM21 was on the right track to make maximum impact for contributing to the reduction of CO2 for healthcare in total. It meant that CHEM21 was a significant project.’ He added that the results have only arisen because CHEM21 was a large enough project to do the stakeholder consultation process early on and find where the real problems were.
With the main problems identified, the CHEM21 team generated a range of methods to make the drug development process more environmentally friendly. These novel, greener production methods were analysed by the CHEM21 Metrics Toolkit, whose purpose is to measure the sustainability of chemical and biochemical reactions. As Joe Adams says, ‘without being able to put a number on it, it is very hard to say how some parts of the production process are being improved.' The toolkit provides the numeric, measurable proof that some of the procedures used by the pharmaceutical industry can be changed for the better. ‘The toolkit enables these numbers to be generated relatively easily and quickly. Since the publication, we have looked at different syntheses, different methodologies that are used to create molecules. And by putting them through the toolkit– it is actually possible to put a number on how much greener the new synthesis is. It doesn't just feel a bit greener, there are the numbers to see it. It is obvious.' He says that the toolkit is actively used by the pharmaceutical industry. ‘I expect that others will come out with other tools, they might have taken advantage of some of the modern computational methods like machine learning, etc., but this metric-driven approach is here to stay,'says the project coordinator, who explains that the CHEM21 toolkit allows scientists to put their own methods, their own synthetic approaches into it, and get some real numbers at the end.
One somewhat neglected pharmaceutical industry method that CHEM21 revived was flow chemistry. The pharmaceutical industry traditionally uses classical batch chemistry. While this is effective when discovering new materials, when it comes to large-scale production, batch chemistry can be problematic, with issues such as heat and waste management. In contrast flow chemistry (in which reactions take place in a tube or pipe) is often safer, cleaner and much more cost effective. ‘CHEM21 results clearly show that this method reduces risks, reduces environmental impact, makes processes a lot cleaner, and allows cleaner reagents to be used in a safe manner when the reagents bring a degree of hazard to it,' says John Whittall, predicting the pharmaceutical industry’s switch to flow chemistry. ‘Traditional chemistry processing in large reactor vessels is being replaced by reactions in flow reactors, that significantly improve the environmental impact of chemical manufacturing,’ he stated.
An important breakthrough for CHEM21 was the demonstration of industry-scale production of the costly antifungal medicine flucytosine, by the direct fluorination of inexpensive cytosine using cheap fluorine gas, using continuous flow reaction techniques. ‘Flucytosine is used in conjunction with other HIV treatments to reduce the mortality of HIV patients,’ explains John Whittall, adding that because it is expensive, and because it is not registered for use there, it is unavailable in Africa, where it could prevent more than 500 000 deaths annually caused by HIV. ‘We have clearly demonstrated that flucytosine can be manufactured at a fraction of the current cost – in fact, at approximately one third of the current cost. Our method now needs the right people to take it forward. Whether they are the partners that have been in CHEM21, or somebody else, this result stands out clearly, and it would have a very large impact on the health of populations in poor countries. I really hope that somebody will take this forward,’ says Whittall. According to Adams, it is possible that generics pharmaceutical companies could pick that up and start the production of flucytosine.
Another important project achievement, along with the training of young scientists, was the development of biocatalysts (enzymes that make reactions go faster). ‘There are multiple examples of the industry using this CHEM21 technology in late phase development. The industry is using it because it is a great improvement,' said Joe Adams. Biocatalysts are just one of many examples of the further use of CHEM21’s impressive results. ‘This project will be delivering results on a technical level for the years to come. CHEM21 also introduced a training system and a way of working which has been embedded in the industry. The green chemistry training tool is used to train people from day one entering the pharmaceutical industry manufacturing sector, which is something which wasn't done a few years ago. Every person working in the pharmaceutical industry now has access to our training methods. And their companies see it as a priority, so CHEM21 will contribute to changing the way the industry works, therefore it would stand as the gold standard for the years to come,’ concludes John Whittall.