The main challenge of CHEM21 was to improve the environmental footprint of drug manufacture and to identify and synthesise new catalysts which could help achieve this. With the aim of developing a portfolio of sustainable technologies for green chemical manufacture, the CHEM21 scientists had to identify reactions and methodologies that address current bottlenecks in the sustainability of processes applied to synthesising active pharmaceutical ingredients.
The key project achievement was the integration of chemical, biocatalytic and synthetic chemistry methods with improved engineering methods, supported by objective green metric methods for impacts. As a result of this, the consortium developed a unified metrics toolkit that facilitates the comprehensive evaluation of the sustainability of chemical and biochemical reactions based on a series of parameters. The toolkit uses a blend of both qualitative and quantitative criteria to assess how green the chemical reaction is.
An early breakthrough for CHEM21 was for a more efficient method for the synthesis of flucytosine, an antifungal medication regularly used to treat fungal infections that are associated with HIV. Flucytosine is not available or registered in Africa and is too expensive to be broadly used. If the medicine could be manufactured more innovatively and cheaply, 500 000 HIV-related deaths per year in Africa could be prevented.
Prior to CHEM21’s development of a more efficient method for making flucytosine, there wasn’t any cheap manufacturing process or supplier available. CHEM21 demonstrated that the flucytosine could be made, on an industrial scale, at a much reduced cost.
Another important result was the development of a new toolbox of biocatalysts (biocatalysts are enzymes used to speed up reactions). CHEM21 successfully enabled the wide usage of biocatalysis as a clean chemistry option, especially for smaller companies who did not routinely use this method before. Several new classes of enzymes were delivered with examples of improved properties, and the new access models made these rapidly available. CHEM21 scientists accelerated the development of imine reductases (IREDs), a novel class of enzyme which is now widely adopted and used by the industry in an exceptionally short time.
Use of technologies that were previously not widely utilised within the pharmaceutical industry, such as synthetic biology, chemocatalysis and biocatalysis, led to the development of more sustainable routes, based on CHEM21 metrics, to analyse various problems in medicine production. Within the project, several flow chemistry methods were developed: fluorination, oxidation, hydrogenation, and nucleophilic displacement. All of these methodologies demonstrated cleaner reactions with better green metrics.
CHEM21 also led the development of simple synthetic biology methods to synthesise pharmaceutically relevant molecules. For example, 2-Amino -1-butanol is a key intermediate in the production of ethambutol, a WHO essential medicine used to treat tuberculosis. Usually it is made in India through a very environment-unfriendly, dirty process, but the project succeeded in using yeast for its manufacture.
- Training – online and free education on green chemistry for current and future scientists, as well as for the wider pharmaceutical industry. Around 8 000 students graduated from this open course.
- Developed “Vision 2020” by reviewing the state of the art and uptake of green chemistry and biotechnology in pharmaceutical manufacture over the last 20 years.
- Studied the future needs for the type of molecules that will be the main targets in the 2020 pharmaceutical drugs portfolio.
A green legacy
The biggest impact of the CHEM21 project is the changed work procedures in early stage process development in EFPIA members and the launch of the new tool that led to metric-based analysis at early stages, meaning that ‘green chemistry’ is embedded in the overall approach to chemical development. Many tools that CHEM21 produced are used by the pharmaceutical industry, with EFPIA members making follow on investments by using the CHEM21 technologies on a widespread basis. Thanks to the project, Bisy (an SME involved in enzyme production that was a spinout from project partner ACIB) significantly expanded to other areas of chemistry production. CHEM21 also provided hundreds of new cleaner catalysts with less use of critical elements, which EFPIA members are now routinely using. All of the technologies used by the project: synthetic biology, chemocatalysis and biocatalysis that are often underused by the industry; thanks to CHEM21, they got the attention they deserveand today are being used to provide greener options for medicine production.
- Read our interview with the project leaders