Responsible Manufacturing Can Help Curb Drug Resistance

Antimicrobial resistance (AMR) already kills millions of people worldwide each year, and this urgent global health threat is rising faster than predicted. Among the drivers of drug resistance is the release of antibiotic waste into the environment. By responsibly managing and disposing of their antibiotic manufacturing waste, pharmaceutical companies can help combat AMR and limit their impact on the environment. A new report from the Access to Medicine Foundation, an independent non-profit organisation, zeroes in on responsible manufacturing, setting out three clear areas pharmaceutical companies can focus on to ensure they limit AMR risk when manufacturing their antibiotics.

• A handful of companies are taking promising action, with the report’s recommendations highlighting what needs to be done to boost efforts and how more companies can step up.
• Specifically, companies can employ effective methods to limit and to quantify AMR risk before releasing their wastewater into the environment, as demonstrated by Centrient, Sandoz and Shionogi.
• Notably, Centrient, GSK, Pfizer and Shionogi report compliance with discharge limits at the majority of their upstream suppliers, showing how companies can transform the antibiotic supply chain.
• The report also demonstrates how proactively adopting and scaling responsible manufacturing practices is a critical way for companies to safeguard their business for the future, especially considering how the global policy and procurement landscapes are shifting.

With the need to tackle AMR growing ever more urgent, it is critical to consider all the various drivers than can fuel drug resistance – including the release of antibiotic waste into the environment.

During the manufacture of antibiotics, waste that is generated at a manufacturing site is typically released into rivers and waterways. If this wastewater contains high levels of active pharmaceutical ingredients (APIs), it poses a serious risk to the spread of AMR.

It is therefore vital than when manufacturing antibiotics, pharmaceutical companies engage in responsible manufacturing practices that limit their impact on AMR and the environment.

Since launching the first AMR Benchmark in 2018, the Foundation has been assessing how some of the world’s leading producers of antibiotics perform on limiting AMR risk from manufacturing. Despite progress, significant gaps remain. This new report analyses responsible manufacturing more closely, identifying clear examples from companies that are developing practices to limit AMR risk from manufacturing more effectively.

The report analyses selected companies of varying sizes that manufacture and market antibiotics – including research-based pharmaceutical companies, generic medicine manufacturers and business-to- business providers. The report specifically mentions Abbott; Aurobindo; Centrient; Fresenius Kabi; GSK; Pfizer; Novartis and its generics division, Sandoz; Shionogi; Teva; and Viatris.

Pharmaceutical companies like these, which hold market authorisations for antibiotics, are uniquely positioned to drive change across the antibiotic supply chain, and can help transform the industry. Not only can they prioritise responsible manufacturing at the manufacturing sites they own and operate, but they have the ability to influence the standards and practices of the various third-party suppliers they contract in the production of their lifesaving medicines.

“The role of the pharmaceutical industry in tackling AMR has never been more critical. Responsible manufacturing is among the ways in which they can help prevent drug resistance from becoming uncontrollable – and can ensure that the production of their lifesaving antibiotics does not cause unintended harm to human health or the environment. We have seen that progress is possible, but we now need more companies to seize the opportunities we have identified to accelerate industry-wide change" said Jayasree K. Iyer, CEO, Access to Medicine Foundation.

To support and enable progress, this report identifies three specific areas that companies need to focus on to strengthen their responsible manufacturing practices and limit AMR risk more effectively.

What did the report find?

1. Companies need to prioritise effective wastewater management methods to establish, quantify and monitor discharge limits for ensuring wastewater safety at their own manufacturing sites.

Specifically, to minimise AMR risk more effectively, companies can develop and implement comprehensive methods to ensure the safety of their wastewater before it is released into the environment.

By implementing comprehensive wastewater treatment processes at their manufacturing sites, Centrient and Shionogi show that reaching compliance in wastewater before releasing it is feasible. Notably, Centrient reports achieving this at its site in Tonsa, India, and in consultations for this report, Shionogi stated that it complies with discharge limits directly in its wastewater for all five of the antibiotics it manufactures.

There are also other ways in which companies can work towards limiting AMR risk in their wastewater. Sandoz, for example, uses a membrane filtration process at its main antibiotic manufacturing site in Kundl, Austria, to remove bacteria from its wastewater. To more accurately determine whether discharge limits are being met, Abbott’s pharmaceuticals division implements a synergistic combination of the mass balance approach and analysis of wastewater samples.

2. By utilising their unique positions in the supply chain, companies can transform the industry.

While pharmaceutical companies can consider replacing non-compliant suppliers, they are also in the position to share resources, expertise and analytical capabilities to support suppliers in achieving

compliance with discharge limits, as demonstrated by Abbott, which provides its suppliers with wastewater sample analysis free of charge. This is particularly critical for the sustainability of the antibiotic supply chain, as there is often a heavy reliance on a limited number of producers of a certain API that is needed to manufacture an antibiotic, for example.

For this reason, pharmaceutical companies generally prefer to prioritise long-term partnerships and support suppliers in achieving compliance. Encouragingly, Centrient, GSK, Pfizer and Shionogi report that the majority of their supplier sites have achieved compliance in receiving waters. While Centrient and Shionogi do have a smaller number of supplier sites, GSK and Pfizer demonstrate that achieving compliance on a larger scale is also possible.

3. Ensuring transparency and accountability across the antibiotic supply chain is crucial.

To foster progress, and to encourage other companies to follow suit, companies need to report progress at their own sites and those of their suppliers.

However, to date overall transparency has been lacking. While Centrient, GSK, Shionogi, Teva and Viatris publicly report specific details on their waste management practices, only Shionogi provides clarity on its antibacterial manufacturing supply chain. Critically, no company currently reports actual antibiotic discharge levels at its own sites or supplier sites.

What’s next?

As demonstrated by the most up to date, best-in-class examples assessed in this report, progress is possible. Moreover, beyond curbing AMR, engaging in responsible manufacturing practices will also be critical to ensuring business continuity within the context of the wider global health landscape.

“Stakeholders – including procurers, investors and regulators – are already looking to pharmaceutical companies that demonstrate their commitment to limiting their impact on AMR and the environment. This report offers practical examples that both large and small players can follow to ensure they meet these expectations. By investing in responsible manufacturing, companies can help curb rising drug resistance while positioning themselves favourably in the market.” commented Marijn Verhoef, Director of Operations and Research, Access to Medicine Foundation.

Procurers, for example, who can consider criteria related to the environment and sustainability when making purchasing decisions, are increasingly expecting companies to demonstrate comprehensive and effective practices to keep antibiotic waste within limits.

Notably, three companies in scope of the report – Fresenius Kabi, Sandoz and Viatris – were awarded with tenders as part of the Norwegian Hospital Procurement Agency’s 2019 sustainable pilot procurement programme. The companies won the tenders partly by achieving the highest score on environmental criteria, which specifically considered whether companies had environmentally friendly production in place to reduce the risk of AMR.

More investors also now view AMR as a systemic risk that needs to be considered within environmental, social and governance (ESG) standard-setting and reporting frameworks. There are also signs that

regulation aimed at reducing AMR risk from manufacturing, which is currently lacking, may be introduced, or strengthened, in several countries.

By following the recommendations in the report, pharmaceutical companies can ensure the production of their lifesaving antibiotics do not contribute to AMR, or negatively impact the environment, while proactively responding to stakeholders that are increasingly expecting them to demonstrate their commitment to responsible manufacturing.