Pfizer’s green chemistry team turns 25

It has been a quarter of a century since the biopharmaceutical giant Pfizer launched its green chemistry team.¹ In that time, the group has helped redesign the manufacturing process of Viagra to make it more sustainable, and played a key role in improving the environmental profile of the antiviral Paxlovid, which the company developed during the Covid-19 pandemic. What began as a modest initiative at Pfizer’s Connecticut R&D facility to optimise individual drug manufacturing routes has since become embedded across the company, extending into areas such as discovery, safety and commercial manufacturing.

With about 15 members spanning subfields of chemistry and beyond, the Pfizer green chemistry team implements the goals of the company’s broader green chemistry programme.

‘The team began as a group of chemists, engineers and [individuals] other scientific disciplines who started collecting information about our production processes that would help serve as metrics to better understand how green or not they were and help address gaps there,’ recalls Juan Colberg, who has been at Pfizer almost 34 years and currently serves as the company’s green chemistry programme leader.

An organic chemist by training, Colberg earned a PhD from the University of Puerto Rico and was shocked by the scale of operations when he joined Pfizer’s manufacturing facility on the island. ‘We began working on projects that required hundreds and even thousands of kilograms of material to manufacture our drugs,’ he recounts. ‘Coming from school, working on milligrams of materials, that was eye-opening,’ he recalls. ‘It really gave me the idea that maybe we could improve the kind of chemistry we use.’

This eureka moment led Colberg to head up a project at Pfizer investigating the active ingredient of the antidepressant Zoloft, sertraline hydrochloride. This effort, which began around 1994, streamlined the drug’s manufacturing process from three steps to a single step.

‘I tend to say that I was a green chemist before the term “green chemistry” came to be coined,’ says Colberg. Synthetic chemists Paul Anastas and John Warner outlined the ‘12 principles of green chemistry’ in 1998. By the time Colberg arrived at Pfizer’s Groton, Connecticut facility in the mid-1990s, there was already a passion to change how the company was doing chemistry to reduce waste.

From grassroots to global

At the centre of that movement was Berkeley ‘Buzz’ Cue, a medicinal chemist who later became vice president of pharmaceutical sciences at the Groton site. He created Pfizer’s green chemistry team in 2001 as a grassroots effort. With backing from senior leadership, the team officially launched in 2002 and then expanded to other R&D groups at Pfizer’s San Diego, California, and Sandwich, UK, facilities.

‘Organic chemistry is a remarkably mature science – we’ve been doing it for 200 years and unfortunately didn’t realise the impact we were having on the environment until a lot later, and then regulations came and green chemistry spun out of those,’ states Paul Richardson, who directs analytical and synthesis technologies at Pfizer’s San Diego site. ‘Often regulations are about the fact that we are creating waste and how do we trap it, deal with it or scrub it,’ he tells Chemistry World. ‘But a central principle of green chemistry is to try and prevent this waste from being generated at the source, and Buzz was really a player in seeing this in the Pfizer space.’

In 2006, Pfizer became the first pharmaceutical company to formalise its green chemistry programme globally by appointing a full-time green chemistry lead. That job went to process chemist Peter Dunn, who was based at the Sandwich site and had previously served as Pfizer’s director of chemical R&D.

‘The position that Pete Dunn took was not just in the chemistry research and development organisation of Pfizer, it had very close ties with environmental health and safety,’ explains Richardson. ‘And this really kick-started the recognition of the potential to influence the corporate agenda.’

Pfizer voluntarily committed four years ago to reach net zero greenhouse gas emissions by 2040, aiming to reduce emissions by 95% in its operations and 90% across its value chain relative to 2019. In doing so, the company set itself a target a decade earlier than the Paris Agreement’s 2050 goal.

Pfizer is not alone. Most major pharmaceutical companies have formal net zero goals. For example, Novartis has committed to being fully net zero by 2040, Roche aims to achieve net zero by 2045 and Sanofi says it is moving towards net zero by 2045.

Viagra yield doubled, solvents and reagents removed

One of the early wins to come out of Pfizer’s green chemistry team was the company’s redesign of the manufacturing process for sildenafil citrate,² the active ingredient in Viagra, in the early 2000s.

‘There is very, very high efficiency in terms of how we make Viagra,’ Richardson explains. ‘It has a very low waste-to-product ratio, based on the fact that a lot of the chemistry has been reduced to one or two solvents, and you are able to push intermediates through the process without purifying until right at the end.’ This method for making Viagra has more than doubled the chemical yield, reduced solvent use by 95%, and removed the harmful reagents tin chloride and hydrogen peroxide from the process.

Pfizer’s green chemistry team created a solvent selection guide in 2008 and a reagent selection guide in the late 2010s to help its chemists make more sustainable, efficient, and safer choices. The methodologies were formalised and shared within the broader scientific community.³ ‘When we created our solvent guide, we saw essentially a complete phasing out of some chlorinated solvents, using greener solvents like ethanol, or maybe using tetrahydrofuran versus other classes of esters that are more dangerous,’ says Colberg.

Richardson echoes these sentiments. ‘It’s nice sometimes to do very exotic chemistry but it can create problems downstream, so switching the narrative to why you shouldn’t use things like dichloromethane (DCM) is important,’ he states. ‘There’s going to be a day that we can’t use dichloromethane, and it’s coming soon – it’s better to stop it now and work around it.’

Pfizer pooled these two guides with those of other major drug companies through the American Chemical Society Green Chemistry Institute’s Pharmaceutical Roundtable. The company helped found this consortium in 2005 alongside Eli Lilly and Merck to address common sustainability challenges related to making medicines. Today the Pharmaceutical Roundtable has grown to more than 50 companies, over half of which are drug firms.

Another more recent Pfizer green chemistry success came during the Covid-19 pandemic. The company was able to quickly deliver the antiretroviral drug Paxlovid, an oral medication that received full US Food and Drug Administration (FDA) approval in May 2023 to treat mild-to-moderate Covid-19 in adults and adolescents, by optimising the chemical synthesis of its active ingredient nirmatrelvir.

‘The team took the initial route all the way to the commercial route in less than 18 months,’ Colberg recounts. ‘We were able to deliver that commercial product that makes thousands and thousands and thousands of kilograms of active pharmaceutical ingredient and use it at many manufacturing facilities, both internal and external, while maintaining a green chemistry approach,’ he continues.

Metrics matter

To determine the efficiency and environmental sustainability of its chemical manufacturing processes, Pfizer uses indicators like E-factor – the ratio of the total mass of waste generated during a process to the mass of the final product obtained – and Process Mass Intensity (PMI) – the total mass of all materials used to produce a given amount of a product.

‘These basically track how much waste you produce per kilogram of product … and then we are also using a life cycle assessment tool to track the carbon footprint of our processes,’ explains Colberg.

Working through the Pharmaceutical Roundtable, drug companies can share such metrics for their compounds in various stages of development. The data gets anonymised and that enables benchmarking across the field.

Tackling scope 3 emissions and changing mindsets

One of the biggest challenges in the green chemistry space is scope 3 emissions, according to Richardson. These are indirect greenhouse gas releases that occur in a company’s value chain and typically represent the largest portion of its carbon footprint. Meanwhile, scope 1 emissions are direct greenhouse gases emitted from sources owned or controlled by the company, and scope 2 emissions occur at facilities where the energy for the production is generated, like power plants, rather than sites where it is consumed. Most pharma companies report their goals for achieving net-zero using these three categories.

It’s nice sometimes to do very exotic chemistry but it can create problems downstream

‘The ecosystem that Pfizer exists in is that we make our drugs, but we buy starting materials to make our drugs, so how we work with those partners contributes to our scope 3 emissions,’ Richardson says, ‘but we often have different goals and so open communication and transparency are important.’

Another significant obstacle involves changing the mindset of colleagues like drug discovery chemists. ‘Spreading the message has been the biggest challenge I have encountered in my time in the industry,’ Richarson adds. ‘A lot of discovery chemists who work in pharma will never work on a compound that goes to commercialisation … and they say, “What I do doesn’t matter because if the product is successful it will go into development and somebody will fix it,” but that implies this bottomless vat of time that people have to fix problems.’

However, Richardson notes, with promising drug candidates there is a demand for ‘very quick turnaround for specific batches of the compound, on scale and at a set quality.’

Colberg agrees that accelerated timelines represent a major challenge. ‘Some of the green alternatives may not work right away, so you have to further develop them, and they might have to be left out of original filings with regulatory authorities like the FDA,’ he states. ‘Pfizer had been very successful filing for second-generation drugs – often we have been able to do a second-generation greener route.’

For organisations looking to embed green chemistry into their operations, Colberg emphasises the importance of securing leadership buy-in from the outset. ‘That’s something that Pfizer did very successfully right from the start,’ he says. ‘And as we have advanced through the last 25 years, we have had senior sponsors in different parts of the organisation .’

Richardson has more specific advice: replace solvents. He points out that solvents account for about 80% of the mass of waste streams in pharmaceutical manufacturing and associated chemical processes. ‘If you are using something bad, try to use something different – it’s very clear that dipolar aprotics are bad – the dimethylformamides of the world – and reducing the amount of these used is also important,’ he says.

Nevertheless, eliminating solvents entirely is a sensitive topic because they often play an important safety role, for example, by preventing fires or explosions through controlling temperatures and moderating chemical reactions.

Looking ahead, Richardson expects further uptake and integration of emerging technologies at drug companies in ways that enable active pharmaceutical ingredients (APIs) to be synthesised under more benign conditions. For example, he points to broader use of technologies such as electrochemistry, photochemistry and mechanochemistry as well as achievement of smaller manufacturing footprints through continuous manufacturing.

Meanwhile, Colberg anticipates that Pfizer’s green chemistry team will maintain its critical mass and perhaps grow as a new generation of green chemists joins the company.