One could argue that the negative impact of medicine production on the environment is an unfortunate but necessary side effect to the drive to produce life-saving medications. This reasoning is seriously flawed. The pharmaceutical industry produces significant amounts more waste products and pollutants than any other chemical sector. These substances and pollutants are damaging not only the environment but also our health.
There is still hope. Over the past few decades, the field of green chemistry the design of chemical products and processes that reduce or eliminate the generation of hazardous substances has been moving fast, and pharmaceuticals are a vital part of this.
The safety and effectiveness of a medicine are the top priorities when it is being developed. However, there is a growing drive to develop pharmaceuticals that do this while also leaving a smaller carbon footprint.
James Clark, director of University of York’s Green Chemistry Centre of Excellence, states that chemical professionals are now looking at raw materials, products, and end of lives. All of these factors are important in determining sustainability or whether a product is green.
Although green chemistry principles are relatively simple to use and often result in a more environmentally friendly process, they do not guarantee it.
Claire Adjiman, a chemical engineering student at University College London
It is not surprising that it is complex. The 12 principles of green chemistry (American Chemical Society; Figure) are widely applicable. These principles can be used in a variety of ways. Claire Adjiman is a chemical engineer at University College London. She says: It is important to look at the entire manufacturing process, including carbon emissions, overall waste generation, and other pollutants. It might be better to choose a reaction with more impurities than one that is easy to remove. She says that this balance is a major challenge in the manufacturing industry. Although green chemistry principles can be applied easily and often lead to a more sustainable process, they don’t guarantee it.
Adjiman says pharmaceuticals can be a difficult case. The molecules themselves can be more complex than the assembly. You must ensure that the molecules are pure (a higher level than you would require for plastics). You need the right molecules in the correct form to ensure optimal absorption. Tablets are the best way to take medicine. This means it is difficult to manufacture. This makes it difficult to implement a holistic green process.
Industry take-up
Green chemistry, like corporate social responsibility is a field where big companies can make big declarations and use a variety of metrics and measurements without actually taking any action. Companies are more likely to refer inquiries to the corporate website than to answer questions directly. There are changes, and some of them have become part of the mainstream.
In recent years, pharmaceutical companies have changed the manufacturing processes for several well-known medicines such as sitagliptin, artemisinin for malaria treatment and ibuprofen. These are less environmentally harmful.
The University of Nottingham’s GSK Carbon Neutral Laboratories for Sustainable Chemistry project opened its laboratory in February 2017. It was funded by a 12m dollar fund from the pharmaceutical company. The building will consume around a third of the energy of a conventional laboratory for chemistry and use far less water.
The ACS Green Chemistry Institute Pharmaceutical Roundtable was established in 2005 and now has more than 20 members. These include AstraZeneca (Pfizer), Johnson & Johnson (J&J), Merck and Eli Lilly. It hosts the annual ACS Green Chemistry Institute Pharmaceutical Roundtable. Green Chemistry Challenge Awards, which is intended to solve real-world environmental problems with groundbreaking scientific solutions. Merck won 2021 for developing a more sustainable manufacturing process (see Box) for the chronic cough medicine gefapixant citrate (seeBox). Bristol Myers Squibb won 2021 for a new category of sustainable reagents, substances that can cause a chemical reaction.
Box: Gefapixant citrate is developing a greener synthetic pathway
Merck won the Green Chemistry Challenge 2021 award. This award recognizes greener pathways to commercial manufacturing for gefapixant Citrate, an investigational medication for chronic cough.
The initial manufacturing process involved many steps. This was a measure for process efficiency for biopharmaceutical manufacturing of 366.
The new process has an improved PMI of 88 which is more than four times better. These are the main innovations:
- Implementation of a highly efficient, two-step methoxyphenol synthesizing process
- A novel diaminopyrimidine synthesizing process using a hybrid flow batch process
- A simplified direct sulfonamide synthesis;
- A novel salt metathesis method that consistently delivers the correct salt form with high production.
The new process resulted in a six-fold decrease in raw material costs and a significantly higher product yield. The alkylation step, which involved highly dangerous chemicals, was removed and energy-saving processes were implemented that reduced carbon dioxide, carbon monoxide, and other emissions.
Merck was also a winner in 2020. This time, the company developed a more sustainable, efficient, and safer manufacturing process to produce uprifosbuvir. Merck has developed a catalyst that can be used in the synthesis of uprifosbuvir. The new process is more efficient than 75% in terms of process mass intensity, which is a measure for process efficiency for biopharmaceutical production energy and water use.
The generic drug manufacturers are now working in [the green chemistry]You can also use space
James Clark, director of University of York’s Green Chemistry Centre of Excellence
The generic drug manufacturers are now working in [the green chemistry]Clark also mentions space. It will be interesting to see how this develops in the future. Theres an assumption that these firms are cheap and cheerful but I think they are showing signs of being rather more responsible.”
There are three areas of focus: solvents, biocatalysis, and continuous manufacturing.
Solvents
Chris Price, a chemical process engineer at the University of Strathclyde (Glasgow), says that solvents are a big deal. He has spent 14 years in innovation and process development at GSK. Solvents are essential for manufacturing: they are substances (which could be water) that dissolve different materials at the right temperature. To ensure high quality, the industry uses solvents as one of its key tools. [used]Adjiman explains how you can make sure that a tablet stays together.
Green chemistry is interested in solvents for many reasons. Four kilograms of organic solvents are required to make one kilogram worth of active pharmaceutical ingredient. This includes water. Heating and cooling solvents take a lot of energy. Price says that while the amount of waste produced in an oil industry is approximately 10%, the difference in the pharmaceutical industry is 1000-fold. The majority of that waste is solvent. Solvents are often not recycled and sent off to be incinerated. This uses more energy and produces more waste products. Adjiman also pointed out that water isn’t always the right solution. While you might think that a process that uses water is better than one that uses a more toxic solvent, you could end up with more waste and more dangerous waste.
Price says that over the past 20 years, there has been an industry shift to less toxic and environmentally harmful solvents. GSK and other firms began to create red/amber/green list of solvents around the turn of the millennium. This encouraged staff to create drugs to move to the greenlist. You will now see a decrease in the use of these undesirable solvents. It had a tremendous impact because everyone came to a consensus and stuck with it.
Biocatalysis
Catalysts refer to chemicals that can either make a chemical reaction occur or speed it up. Biocatalysis relies on the fact there are many natural catalysts available, including enzymes which are proteins that enable all kinds of biological processes to occur. In the last few decades, chemists used enzymes in many commercial and industrial areas. Biocatalysis is now part of the push towards greener pharmaceuticals.
Biocatalysts may be existing enzymes, or new enzymes. They are created by inserting mutations in the amino acid chains that make up the proteins. It’s a numbers game, says Ahir Pushpanath (team leader at Johnson Matthey, speciality chemicals and sustainable technology company). There are millions and millions of natural enzymes. It is important to have a variety of enzymes that can catalyze this reaction. Enzymes are preferred because they are made from renewable, biodegradable material and also because they don’t use as much energy than synthetically derived catalysts..Computers are a large part of the research process. This saves time and work in the laboratory, but it also allows for huge amounts of candidates to be screened.
Pushpanath cites several examples, including sitagliptin for diabetes and sacubitril for heart failure, whose greener manufacturing was possible by biocatalysis. This is due to transaminases, a specific class of enzyme, but there are many others and we are working on more.
Continuous manufacturing
Many companies are also moving towards continuous manufacturing, with Eli Lilly being one of the leading players in this field. This is the way most chemical industries work. All components of the product can be manufactured simultaneously as opposed to batch production, which requires each stage to be tested and performed separately.
Waste is the enemy to sustainability. This process is much more wasteful.
Chris Price is a chemical and process engineering student at the University of Strathclyde in Glasgow
It is not necessarily more sustainable, but it is more environmentally friendly. Price says that it works because of the chemicals used and also because it produces less waste. This process is much more wasteful than the enemy of sustainability. It should produce a consistent high standard of product. Pharmaceutical products that don’t meet the specifications are incinerated. It is resource-efficient because everything bought is used in the product. Another area of waste in this sector is time-expired material. It is very beneficial if you can create a supply chain that delivers consistently and with very few materials going obsolete at any stage.
Moving into a new century
The pharmaceutical industry is the leader in green chemistry metrics. They have developed methods and measures to measure the various components of green chemicals, such as solvents. Clark says that this has been very useful in industry. Clark also noted that most of the industry work is hidden from the public and is rarely revealed to the general public. They have made some great innovations, but the strength of their efforts does vary. This is frustrating because they aren’t often publicized. They have invented routes we don’t know exist in terms of process chemistry. The ones that are made are not as popular as the ones that have been.
There is still a lot of room for improvement. Price and Clark both argue that the pharmaceutical industry has not advanced in many ways in over a century. Clark said that although I have seen manufacturing facilities with very high-quality equipment, and the process looks very efficient, if you look at the chemical reactions, you will see some very old chemistry. Price adds that pharmaceutical manufacturing is the last bastion in 19ThCentury technologies. While the equipment is excellent, my grandfather would have recognized what is happening there. There are many opportunities to make improvements.
