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
Achievements & News
The processes and chemicals used in drug production are often toxic, expensive and produce a lot of waste – posing a threat to the environment and the sustainability of the industry. In response, IMI’s CHEM21 project has developed new manufacturing processes for the pharmaceuticals industry to reduce the use of expensive and toxic materials. It has also developed new, more environmentally friendly methods that save time and costs, while reducing waste. ### Nick Turner, director of the UK’s Centre of Excellence for Biocatalysis, Biotransformations and Biocatalytic Manufacture (CoEBio3), says the project was diverse and complicated but has resulted in huge successes. ‘Our flagship outcome is the development of a new, more efficient and cheaper way of producing flucytosine,’ he says. ‘This medicine is used to treat a common and often deadly fungal form of meningitis in HIV/AIDS sufferers. Producing it at low cost will make it more accessible to those in Africa, helping in the prevention of 500 000 deaths per annum.’
Additionally, the project has developed new, more efficient screening methods to find more enzymes that can be used as biocatalysts for chemical reactions. The discovery of new ones could make drug manufacturing processes more efficient and safer as they can eliminate production steps and could be substitutes for expensive or toxic substances currently used by the industry. Turner concludes: ‘The development and launch of pharmaceuticals is a long process, so it is to be expected that many more benefits will become realised in the next 5-10 years.’
- Read the full story
IMI’s CHEM21 project has contributed strongly to a massive open online course (‘MOOC’) on industrial biotechnology run by the University of Manchester. The course has six modules – three on the core principles of industrial biotechnology, and three on specific applications. All modules comprise a mixture of recorded presentations, videos, reading material and multiple choice tests. ### CHEM21 is devising new, more environmentally friendly ways of synthesising medicines, and scientists from the project were heavily involved in the design of the course. As a result, the sustainability principles underpinning CHEM21’s work are integrated into the entire course, particularly in the module on pharmaceuticals. The course was launched in July and the organisers hope that the bite-sized, modular nature of the course will make it attractive to both undergraduates and existing professionals who are using it as part of their continuing professional development.
Scientists from the IMI project CHEM21 have developed a new, more efficient way of producing flucytosine, a medicine used to treat a common and often deadly fungal form of meningitis in people with HIV / AIDS. The new method, which is described in a paper in Organic Process Research & Development (OPR&D), is expected to decrease drastically costs of production, and so make the medicine more affordable for the many people with HIV/AIDS who live in low income countries.###
Flucytosine is very expensive, as its patented manufacture involves carrying out a sequence of four chemical reactions. That could now change thanks CHEM21 scientists from the University of Durham in the UK, who have cut the number of reactions needed from four to one. Because it involves just one selective reaction instead of four, the new method uses significantly less energy and raw materials and produces less waste than conventional techniques to manufacture flucytosine. It is also less expensive. Pharmaceutical company Sanofi, which is also part of CHEM21, contracted MEPI, a French non-profit association, to investigate ways to scale up the process. With input from scientists from Durham and Sanofi, MEPI succeeded in setting up a small reactor capable of producing 1 kg per day of raw material. The next challenge will be for the team at Sanofi to transform the raw material into an active medicine that meets international standards. The University of Durham and Sanofi will also work on a technical and economic evaluation of the process. Meanwhile, the University of Durham has applied for a patent for the technique. The hopes of the team are summed up in the closing paragraph of the OPR&D paper: ‘We envisage that this one-step low cost synthesis of flucytosine will help to raise awareness of the neglected [cryptococcal meningitis] health epidemic and ultimately contribute to meeting the urgent requirement for large quantities of flucytosine for low income nations.’
Interested in the greening of the drug development process? Don’t miss the new online training platform which was launched by IMI’s CHEM21 project as part of their recent workshop ‘Practical Aspects of Green Chemistry in the Pharmaceutical Industry’.### The platform comprises a range of free, shareable, and interactive educational and training materials created to promote the uptake of green and sustainable methodologies, with a particular focus on the synthesis of pharmaceuticals. This online resource is supplemented by a book, Green and Sustainable Medicinal Chemistry, edited and authored by CHEM21 consortium members and collaborating external experts. Available in both hardcopy and electronic format, the book addresses current challenges in modern green chemical technologies and sustainability thinking. It covers a broad range of CHEM21 topics, providing an overview of the key green chemistry tools, guidance and considerations aimed at developing greener processes, as well as cutting-edge synthetic methodologies. IMI’s CHEM 21 project is Europe’s largest public-private partnership dedicated to the development of manufacturing sustainable pharmaceuticals. One of the primary aims of this project is to promote the uptake of green and sustainable methodologies and to embed them in everyday practice.
Austrian scientists working on IMI’s CHEM21 project have successfully used yeast and bacteria to generate complex molecules such as carotene and violacein. They achieved this by inserting up to nine genes into yeast, which allowed the yeast to carry out the series of reactions needed to synthesise these molecules in parallel.### Scientists have inserted foreign genes into yeast before. However, to insert so many genes successfully is a real achievement, and the scientists, who work at the Austrian Centre of Industrial Biotechnology, have filed a patent for the method used. The researchers’ findings are published in a paper in Chemical Communications. The team is now looking at ways of increasing the number of genes inserted to constitute biosynthesis pathways for valuable products. CHEM21’s goal is to develop new, more sustainable ways of synthesising medicines, as current methods can be energy and resource intensive and require the use of rare substances such as precious metals.
The CHEM21 project has developed a unified metrics toolkit to comprehensively evaluate the sustainability of chemical and bio-chemical reactions. Details of the toolkit are published in the journal Green Chemistry.### The toolkit uses a blend of both qualitative and quantitative criteria to assess how green a reaction is, as well as considering factors both upstream and downstream of the reaction itself. This ensures a truly holistic approach.
The Toolkit allows the user to assess/demonstrate the ‘green credentials’ of their research; benchmark against current state of the art for a particular reaction or pathway and evaluate new methodologies to ensure that solving one problem does not give rise to others elsewhere in the process. The Toolkit is specifically structured with a series of ‘passes’ to cover everything from bench top research right through to industrial scale with increasing levels of complexity.
The acceptability of a particular process or reaction step is shown by a system of flags: green denotes ‘preferred’, amber is ‘acceptable – some issues’ and red is ‘undesirable’. The purpose of the toolkit is to ensure a holistic approach is taken so that no parameter is looked at in isolation. CHEM21’s aim is that this Toolkit will encourage continuous improvement whilst training researchers to think critically about sustainability and environmental acceptability, making analysis of their synthetic routes and the use of greener and more sustainable techniques part of everyday practice.
To celebrate Chemistry Week, researchers at the University of York released a series of short films about how PhD students participating in IMI’s CHEM21 project are working towards a greener pharmaceutical industry.### CHEM21 (full name ‘Chemical manufacturing methods for the 21st century pharmaceutical industries’) aims to generate a range of methods to make the drug development process more environmentally friendly. The methods developed by CHEM21 will also help the pharmaceutical industry to cut costs, resulting in cheaper medicines for patients. CHEM21 started in October 2012 and will last for 4 years. Chemistry Week was a themed week of events promoted by the UK’s Royal Society of Chemistry (RSC), running from 16 to 23 November. The event is held every two years to promote a positive image of chemistry and increase public understanding of the importance of chemical science in our everyday lives. This year’s theme for Chemistry Week was health.
- Watch the videos on the Green Chemistry at York YouTube channel
CHEM21 workshop on green chemistry in the pharmaceutical industry
IMI’s CHEM21 project will hold a workshop entitled ‘Practical aspects of green chemistry in the pharmaceutical industry’ in London, UK on 13-15 June 2016. This highly interactive workshop will be delivered by CHEM21 academics and industry experts in the field. ### It will involve group work, problem solving exercises and seminars to explore a broad range of cutting-edge case studies and industrial examples on greening the synthesis of active pharmaceutical ingredients (APIs). The workshop is free and is open to students, academics and industrialists. Places are limited and will be allocated on case by case basis – details of how to apply to take part can be found on the CHEM21 website. The goal of the CHEM21 project is to generate methods to make the drug development process more environmentally friendly.
ParticipantsShow participants on map
- Bayer Pharma AG, Berlin, Germany
- Glaxosmithkline Research And Development LTD., Brentford, Middlesex, United Kingdom
- Janssen Pharmaceutica Nv, Beerse, Belgium
- Orion Oyj, Espoo, Finland
- Pfizer Limited, Sandwich, Kent , United Kingdom
- Sanofi Chimie, Gentilly, France
Universities, research organisations, public bodies, non-profit groups
- Leibniz - Institut Fur Katalyse Ev An Der Universitat Rostock, Rostock, Germany
- Stichting Vu, Amsterdam, Netherlands
- The University Of Manchester, Manchester, United Kingdom
- Universiteit Antwerpen, Antwerp, Belgium
- University Of Durham, Durham, United Kingdom
- University Of Leeds, Leeds, United Kingdom
- University Of Stuttgart, Stuttgart, Germany
- University Of York, York, United Kingdom
Small and medium-sized enterprises (SMEs)
- Acib GMBH, Graz, Austria
- CatScI Ltd, Wentloog, Cardiff, United Kingdom
- Evolva AG, Reinach, Switzerland
- Reaxa Limited, Leeds, United Kingdom
- charnwood technical consulting ltd, quorn, United Kingdom
- Technische Universitaet Graz, Graz, Austria
- Universitaet Graz, Graz, Austria
|Name||EU funding in €|
|Acib GMBH||780 387|
|CatScI Ltd||172 871|
|charnwood technical consulting ltd||232 578|
|Evolva AG||432 490|
|Leibniz - Institut Fur Katalyse Ev An Der Universitat Rostock||733 400|
|Reaxa Limited||150 100|
|Stichting Vu||504 773|
|The University Of Manchester||1 577 900|
|Universiteit Antwerpen||565 403|
|University Of Durham||152 505|
|University Of Leeds||1 254 942|
|University Of Stuttgart||1 210 524|
|University Of York||1 501 571|
|Name||Funding in €|
|Technische Universitaet Graz||389 507|
|Universitaet Graz||170 687|
|Total Cost||9 829 638|