A cleaner, greener future for pharma

The pharma industry is centred on the mission of providing life-saving medicines for healthcare. In this vein, human health and climate change are two sides of the same coin. For instance, 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. So, for good reason, addressing environmental impact is high on the agenda for pharma companies.

That said, the healthcare industry, as a whole, has a relatively large carbon footprint, accounting for around 5% of global CO₂ emissions. Most of these emissions are thought to come from the pharma sector, which is surprising for an industry that accounts for only around 0.5% of gross world product.

To put this in context, a study by Lotfi Belkhir and Ahmed Elmiligi at McMaster university, found that in 2015 the pharma industry had an emissions intensity (CO₂ equivalents [CO2e] per million dollars of revenue) that was approximately 55% greater than the automotive industry.

Where are we now?

However, a lot has changed since 2015. First and foremost, the business community as a whole is more attuned to the climate crisis. Emissions monitoring and environmental stewardship conditions can be found in stock exchange listing requirements, regulations, and standards. Put simply, it is now impossible to ignore the issue of environmental impact.

Additionally, aside from the moral reasons to reduce impact on the environment, there are also established business reasons to do so. For example, the link between environmental and financial performance, which is, in part, driven by an appreciation that improved environmental performance is typically achieved through reduction and elimination of wasteful activity. In turn, this leads to reduced costs and bigger profit margins.

To a greener future & beyond…

Against this backdrop, pharma companies have been making strides to reduce environmental impact. Many of the largest pharma companies have made pledges to reduce carbon emissions, or even reach net zero emissions in the near-to-mid-term.

There are several facets of the pharma industry that can add to the large carbon footprint of producing drugs. Some of the major factors include synthesis, formulation, storage and transportation of drugs. Here, we take a look at some of the measures being used to combat waste and make the pledges a reality.

Formulation, storage & transportation

A particular area of concern is the formulation of inhaled drugs. Metered dose inhalers use propellants which often comprise a chlorofluorocarbon (CFC) component. The impact of CFCs can be so great that they outweigh many other contributing factors to a pharma company’s environmental footprint. For example, metered-dose inhalers are responsible for 45% of GSK’s total carbon emissions. GSK are tackling this directly with an initiative to find new more environmentally friendly propellants for their range of metered-dose inhalers. One propellant which is currently in preclinical testing is anticipated to reduce inhaler related emissions by up to 90%.

The way a drug is formulated can also 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 utilised similar mRNA technology. Differences in formulation between the two vaccines contributed to a sizeable difference 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 amount of energy required to transport and store those products (and ultimately the environmental impact).

In the transportation of drugs, a notable success story comes from Lilly, one of the major manufacturers of insulin. Insulin requires storage at low temperatures for transportation, as a result, insulin has typically been transported by air. However, by building temperature stable containers, Lilly’s insulin can now be shipped by sea - slashing transportation emissions by 50%.

Synthesis

The synthesis of drugs requires the use of solvents, temperature control, and purification methods; and in the case of small molecules protecting group strategies are often required. Many of these aspects of synthesis create large volumes of waste. Additionally, the labs in which drugs are made tend to require powerful extraction, air conditioning and round-the-clock lighting. For large scale production, each of these requirements consumes vast amounts of energy.

To decarbonise energy requirements, many companies are increasing the amount of energy supplied from renewable sources. Another simple change that can reduce a pharma company’s environmental impact is the assessment of the sustainability reports of supplier companies like contract research organisations (CROs), industrial chemical suppliers, and contract manufacturers. In this way, application of pressure from the top is expected to improve green credentials throughout the supply chain.

Synthetic methods can also be optimised for reduced environmental impact. However, the arrangement of the regulatory framework can disincentivise companies from changing the methods used to make their pharmaceutical products.

For example, 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 demonstrated to be sufficient to preserve drug identity, strength, quality and purity. This is an important part of how regulatory authorities can ensure that drugs are produced consistently and have the same consistent effect. A negative consequence, however, is that synthetic methods to produce an authorised drug can’t easily be changed.

Nevertheless, marketing authorisation applications tend to be based on synthetic methods 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 (GMP). Still, there is often room for improvement in the environmental impact of manufacturing processes. That said, inventive measures to reduce the environmental impact of products and processes are taken by many companies.

Amgen has been working on improved methods for its bioreactor facilities to make blockbuster drugs such as Enbrel. By creating a higher yielding cell-line used in the bioreactor, Amgen achieved a 73% reduction in energy consumption, 54% reduction in water use and 69% reduction in carbon emissions for the process.

The development of new small molecule chemical syntheses is another important area for the future direction of the pharma industry. Broadening the tools available to process chemists will help to improve the efficiency of synthetic methods. Indeed, organocatalysis received special recognition this year 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.

The Sheppard lab at UCL has been working on organocatalysts for direct amide formation for a number of years. Amide formation reactions are extremely widely used in medicinal chemistry. However, they typically proceed in a highly inefficient manner, requiring stoichiometric reagents and creating vast quantities of waste. The Sheppard group have shown that a simple borate ester (B(OCH₂CF₃)₃) 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 efficiency measure, process mass intensity (PMI: [raw material in]/[bulk product out]), the simple borate ester is up to 9 times more efficient than existing large-scale amidation methods used in the pharma industry. Innovations like this which are potentially widely applicable in process chemistry could help to significantly reduce waste and improve efficiency in pharmaceutical synthesis.

Looking to other areas of development in catalysis, Professor Sheppard says “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 indicates that continuous manufacturing can provide technical improvements such as increased yields, reduced waste, improved product consistency and reduced factory footprint; showcasing that it is not just what goes into a reaction, but how the process is arranged that can impact the overall efficiency.

Conclusions

With COP26 still fresh in people’s minds, and public net zero pledges from pharma companies, the impetus to reduce environmental impact at all stages of a drug’s journey from bench to patient is certainly increasing.

Interestingly, the drive for cleaner and greener synthetic routes at earlier stages in a drug’s lifecycle could also have the effect of providing stronger patent protection for methods of manufacture. In theory, having fewer details of a drug’s manufacture in the public domain reduces the pool of disclosures that may be detrimental to novelty and inventiveness.

Undoubtedly, alongside ambient temperature formulations and improved storage containers, green reagents, methods, and synthetic routes will continue to be key areas for innovation.