Making medicines in an environmentally sustainable fashion

In an ideal world, pharmaceuticals would never reach the environment. Patients would use them for their benefit and the pharmaceutical activity would vanish like a patient’s disease. But this would be too simple. Through normal use, misuse, inappropriate disposal, and limitations in wastewater treatment facilities, drugs can enter the environment. 

The first time this phenomenon rose to prominence was in the 1990s, when veterinarians in India used a widespread painkiller to treat cattle. Because cattle aren’t eaten in India, dead cattle were typically left for the vultures. Although harmless for human beings and animals, traces of the chemical compound were lethal for the birds, leading to the decimation of vulture populations around the country. 

“People just weren’t thinking about micropollutants much before that,” says Jutta Hellstern, Head Water Resources, who has been leading several of the efforts at Novartis to address pharmaceuticals in the environment. “But since then, there’s been increasing interest in the impacts on non-target organisms like fish and algae – and people are starting to worry about their drinking water too.”

Over the past decades, regulatory agencies and academic researchers have also found traces of contraceptives, antidepressants, and antibiotics in public wastewater and aquatic environments. But the extent of the problem is not yet fully understood and regulations are sparse. Initiatives such as the E.U. Water Framework Directive are working to gather more information about the scale and impact of pharmaceuticals in the environment, as well as beginning to explore potential solutions. 

To help minimize active pharmaceutical ingredients, often abbreviated as APIs, in the environment, Novartis has established more environmentally conscious protocols for every step of its value chain. 

On top of that. Novartis has also joined an ambitious Innovative Medicines Initiative (IMI) public-private project – called Prioritisation and Risk Evaluation of Medicines in the EnviRonment (PREMIER) –, which aims to better understand this field and to seek tools to make new APIs environmentally friendly by design.

Environmental disasters such as the pollution of the Cuyahoga river in Cleveland or the 1986 Rhine river chemical spill led to many of the environmental regulations that are in place today. But it wasn’t until more recently that researchers had technologies capable of measuring the minute concentrations of less conspicuous pollutants, such as pharmaceuticals. 

“People were more worried about the big, pressing environmental topics, but it was just a matter of time, and more sensitive technologies, before people became aware of micropollutants,” says Jutta Hellstern. “Now there’s much broader awareness and this topic is on the radars of authorities and regulators too.”

Avoiding pharmaceutical contamination is particularly challenging because, whenever people use drugs, small quantities may end end up in public wastewater facilities. These facilities aren’t designed to remove such micropollutants and there are currently no regulations for pharmaceuticals in wastewater. 

Wastewater from manufacturing processes can also contain trace pharmaceuticals, which potentially end up in the environment. To reduce this risk, Novartis set several ambitious environmental targets in 2018, one of which aims for the company’s manufacturing effluents to have no impact on water quality, including targets for pharmaceuticals. 

“We want to reduce any negative impact from our products – across the entire lifecycle,” says Hellstern.

To this end, Novartis is also collaborating with several pharmaceutical associations, including the European Federation of Pharmaceutical Industries and Associations (EFPIA), Medicines for Europe, and with peers from other pharma companies. In addition, Novartis is committed to combatting the development of antimicrobial resistance as a result of antibiotics in the environment.

Hellstern and her colleagues have also created the new Novartis Global Operating Procedure for Pharmaceuticals in the Environment, which went into effect at the end of 2019. It outlines guidance for every step of the product lifecycle, including early research, market access, production, patient use and disposal. This includes using green solvents and environmentally friendly reagents during manufacturing, as well as carefully managing manufacturing wastewater. 

“During the late development stages, our standard processes assess the biodegradability of the drug itself, all raw materials, every intermediate produced during manufacturing, and all waste materials,” explains Michael Parmentier, a researcher in Chemical & Analytical Development. “We’re working to make our processes as green as possible.”Another key provision is to hold all Novartis suppliers accountable to these same high standards. To this end, the Global Drug Development division has implemented a tool called Process Mass Intensification (PMI), which requires both internal associates and suppliers to report how much waste is generated during the production of active ingredients. “With this new tool we can try to track what suppliers are doing and it will help Novartis select suppliers based on the efforts that they’re making for the environment,” says Parmentier.

At the other end of the drug pathway, Jutta Hellstern also highlights the importance of properly disposing of unused medicines at collection points, such as pharmacies. “Studies have shown that when patients don’t know how to dispose of unused medications, they dispose of them down the sink or toilet,” says Hellstern. “That’s definitely a no go – that’s the worst thing they can do.”

One of the most challenging approaches, and theoretically the most effective, is the idea of making pharmaceuticals themselves more environmentally friendly. Proactively designing green drugs has so far largely been an academic venture, but the PREMIER project aims to bring together academic and industry experts to see if this could be feasible in an industrial context. 

“It’s very, very ambitious,” says Daniela Angst, a research investigator in Global Discovery Chemistry, who is part of the project. “It’s so difficult to find just one molecule that is both safe and effective – it will be very challenging to go even further and to predict what will happen in the environment as well.”

But PREMIER has the intellectual firepower to achieve this feat. Academic partners such as the University of York, in the U.K., and Radboud University, in the Netherlands, specialize in modeling and predicting the ecological risks of pharmaceuticals. Another partner, the Leuphana University of Lueneburg, in Germany, has also pioneered approaches for green and sustainable pharmaceutical design. 

The anticipated start date for the project is fall of 2020, and the teams will have five years and 10 million euros of funding to pursue their research program. In preparation for the kick-off, Angst and Parmentier already see opportunities to incorporate some environmental practices into Discovery Chemistry. 

“Drug discovery has always been about safety and efficacy, not about environmental sustainability, so it’s a really challenging opportunity,” says Hellstern. “This project will bring together smart people to see if developing green APIs could become a reality.”