16-17 - SUSTAINABILITY: A force of nature

Pharma companies, for good reason, have environmental impact high on their agendas. The pharma industry centres around the mission of providing life-saving medicines for healthcare and – in this spirit – human health and climate change are two sides of the same coin.

After all, decreasing air quality contributes to respiratory disease, warmer global temperatures increase the size of areas affected by infectious diseases and increased levels of extreme weather intensify food insecurity.

Aside from moral imperatives, there are established business reasons to reduce environmental impact. For example, a strong link exists between environmental and financial performance. In part, this link is driven by an appreciation that improved environmental performance is typically achieved through reduction and elimination of wasteful activity. Which in turn leads to reduced costs and bigger profit margins.

Pharma has been making strides to improve its green credentials. Indeed, many of the largest pharma companies have made pledges to reduce carbon emissions, or even reach net zero in the near-to-mid-term. Some of the major areas in which advances can be made include synthesis, formulation, storage and transportation of drugs. With this in mind, it is interesting to take a look at what is being done to edge towards a greener future.

The way a drug is formulated can have a big influence on its environmental impact by affecting the temperature at which the product must be stored.

This was borne out by the breakthrough SARS-CoV-2 vaccines from Pfizer-BioNTech and Moderna, both of which utilise similar mRNA technology. Differences in formulation between the two vaccines contribute to a contrast in required storage temperatures. While the Pfizer-BioNTech vaccine needs special ‘deep freeze’ storage (between -80 °C and -60 °C), the Moderna vaccine can be stored at temperatures accessible with standard freezers (between -25 °C and -15 °C). Bringing the stable temperature of a drug’s formulation closer to ambient temperature reduces the environmental impact of transport and storage for those products.

A notable success story in the transportation of drugs comes from Lilly, one of the major manufacturers of insulin which requires low temperature storage for transportation. Consequently, insulin has typically been transported by air. By building temperature-stable containers, however, Lilly can now ship insulin by sea – slashing transportation emissions by 50%.

Another area of particular concern is the formulation of inhaled drugs. Propellants for metered-dose inhalers often comprise a chlorofluorocarbon (CFC) component. The impact of CFCs can be so great that they outweigh many other contributing factors to pharma’s environmental footprint.

For example, metered-dose inhalers are responsible for 45% of GSK’s total carbon emissions. GSK is tackling this directly with an initiative to find new, more environmentally friendly propellants for its range of inhalers. One propellant which is currently in preclinical testing is anticipated to reduce inhaler-related emissions by up to 90%.

Deeper consideration of suppliers is another way that big pharma can improve green credentials throughout the supply chain. Notably, assessing sustainability reports from supplier companies like contract research organisations and industrial chemical suppliers applies pressure from the top, and this can eliminate less ‘eco’ suppliers from the existing pool.

Specific synthetic methods for active pharmaceutical ingredients can also be optimised for reduced environmental impact. The existing regulatory framework, however, can fail to incentivise companies from changing methods used to make approved pharmaceutical products.

Regulatory agencies, such as the US FDA, require that – in addition to demonstrating safety and efficacy of a drug – the methods used in manufacture and the controls in place to maintain drug quality are sufficient to preserve drug identity, strength, quality and purity. This is important to ensure drugs are produced consistently and reliably have the same effect. A negative consequence is that synthetic methods to produce an authorised drug can’t easily be changed.

Despite this, marketing authorisation applications are frequently based on syntheses and formulations which are put in place at a relatively early point in the drug life cycle – often before a drug is tested in humans. Even at this early stage, synthetic methods are vetted for good manufacturing practice. Yet, further efficiency savings can often be made in the approved processes.

Encouragingly, inventive measures to reduce the environmental impact of products and processes are being taken up by many companies. Amgen has been working on improved methods for its bioreactor facilities to make blockbuster drugs such as Enbrel. By developing a higher yielding cell-line for the bioreactor, Amgen achieved a 73% reduction in energy consumption, 54% reduction in water use and 69% reduction in carbon emissions for the process.

Novel syntheses for small molecule chemicals is another hot area. Broadening the synthetic toolbox available to process, chemists will help to improve the efficiency of synthetic methods. Special recognition was recently given to organocatalysis, with the award of the Nobel Prize in Chemistry to Benjamin List and David MacMillan for their impact on pharmaceutical research and making chemistry greener.

Meanwhile, the Sheppard lab at UCL has been working on organocatalysts for direct amide formation for a number of years. They have demonstrated that a simple borate ester can be used in catalytic amounts to form amides directly, under high concentration conditions, producing water as the only waste product, and tolerating functionality elsewhere in the molecule.

By one measure, the borate ester is up to nine times more efficient than existing large-scale amide formation methods used in pharma. Such widely applicable innovations could significantly improve efficiency in pharmaceutical synthesis.

Looking to other areas of development, Professor Sheppard said: “I think biocatalytic reactions will become increasingly important in large-scale pharmaceutical synthesis. The scope of reactions that can be catalysed using enzymes is growing all the time, and new technologies are facilitating the rapid discovery of novel enzymes with improved catalytic efficiency and substrate scope.

“Enzymes can often perform reactions with exquisite levels of selectivity unavailable via traditional chemical approaches, and biocatalytic reactions are typically performed in water or other non-hazardous solvents which can significantly reduce the environmental impact of pharmaceutical synthesis.”

Continuous manufacturing methods, such as flow chemistry procedures also stand to contribute to improvements in process efficiency. A special report from CMAC and PwC indicated that continuous manufacturing can provide technical improvements such as increased yields, reduced waste, improved product consistency and a reduced factory footprint; showcasing that it is not just what goes into a reaction, but how the process is arranged that can impact overall efficiency.

The impetus to reduce environmental impact at all stages of a drug’s journey from bench to patient is certainly increasing. Alongside ambient temperature formulations and improved storage containers, green reagents, methods and synthetic routes will continue to be key areas for innovation. Make no mistake, as the global green revolution unfolds pharma’s role will become increasingly influential.