In a world challenged by microbes resistant to antibiotics, many medical interventions that rely on these medicines to ward off infection — chemotherapy, organ transplants, C-sections, and hip replacements, to name a few — will continue to become riskier than they already are.

Many factors contribute to this bleak scenario. These include poor infection control, misdiagnosis, misuse and overuse of antibiotics, and the use of substandard or falsified medicines. Another key contributor is the presence of antibiotics in the environment. These can come from agricultural applications (animal and crops) and run off, from human and animal waste, and from wastewater emitted by antibiotic manufacturing plants.

Researchers from the University of York reported last year that the concentrations of antibiotics in some of the world’s rivers exceed the predicted no-effect concentrations (PNECs) published by the AMR Industry Alliance, a private-sector coalition that aims to provide sustainable solutions to curb antimicrobial resistance. PNECs represent antibiotic concentrations at which the alliance believes — based on the best evidence available — there will be no adverse environmental impact and at which selection pressure is minimal on microbes in the environment to mutate and develop drug resistance.

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The results of the York study, led by Alistair Boxall and his colleagues, are worrisome, as are other reports over the past several years that have highlighted relatively high concentrations of active pharmaceutical ingredients, including antibiotics, near some manufacturing plants.

Manufacturers stepping up

While concerns about resistance are real, with more than 35,000 thousand people in the U.S. alone dying each year because of resistance to antibiotics and other antimicrobials, an estimated 5.7 million people around the world die each year from lack of access to these medicines.

That presents a dual challenge to be solved: ensuring the continuity of a cost-effective supply of antimicrobials in a manner that minimizes their emission into the environment.

While human and animal use and waste are likely greater contributors to antibiotics in the environment, improperly controlled emissions from antibiotic manufacturing can cause relatively high concentrations of drug residues in factory wastewater. That can increase the selection pressure on bacteria in the environment to develop resistance to the particular antimicrobials they encounter.

A coalition of the willing from a broad cross section of life sciences companies has been making headway on this problem. In our respective roles as director of global sustainable antibiotics at Centrient Pharmaceuticals and lead of the AMR Industry Alliance’s Manufacturing Working Group, we are committed to working to drive the industry to minimize any contribution to antimicrobial resistance that may arise as a result of the processes used to make these important medicines.

In 2018, in the absence of national or international standards for antimicrobial manufacturing emissions, the alliance developed and published a common manufacturing framework to set requirements for responsibly manufacturing these medicines. All manufacturing members of the alliance have committed to implement the framework across their supply chains.

The framework applies to all types of factories that make antibiotics, including those that produce active pharmaceutical ingredients and those that formulate those ingredients into medicines. The framework has five main components — regulatory compliance; environment; health and safety management systems; training, waste, and emissions; and site audits.

Also in 2018 — and two years ahead of schedule — the alliance published a methodology to set PNECs for antibiotics that included a table of PNECs for 120 antibiotics. Alliance member companies are committed to work across their supply chains to meet these very low targets, typically under 1 microgram per liter (1 part per billion).

To put that in context: In a factory making one million antibiotic tablets per year whose wastewater stream has an antibiotic concentration of 1 microgram per liter, extracting all of the antibiotic from that wastewater for a year would not yield enough to make a single tablet.

We were pleased when the framework and PNECs were acknowledged as examples of real progress by Alex Azar, secretary of the U.S. Department of Health and Human Services in his opening remarks at the Centers for Disease Control and Prevention’s AMR Challenge event in September 2018.

Progress to date

A good start has been made, as companies that adhere to the framework assess their manufacturing sites and those of their suppliers across the globe. Put simply, this means ensuring almost no antibiotic leaves a manufacturing site in the wastewater and that all production processes are reviewed in detail (using a mass balance process or, where appropriate, sampling and analysis) to ensure this is the case.

Changes may need to be made to accomplish this. These may include vacuum cleaning residual powder from production equipment rather than washing it down the drain or, at the other end of the spectrum, installing new wastewater treatment technology to absorb or chemically destroy antibiotic before wastewater leaves the factory.

Meeting these requirements may affect supplier selection and retention. If suppliers are unable to meet these requirements, then alternate supply arrangements should be considered. To help suppliers adhere to the framework, training sessions are conducted through organizations such as the Pharmaceutical Supply Chain Initiative that focus on technical aspects such as calculating antibiotic concentrations in wastewater.

Because alliance companies account for only one-third of the global supply of antibiotics, more effort is needed to drive changes across the entire supply chain. As membership in the alliance continues to grow (up 40% in the past year) and more organizations commit to meet the publicly available alliance standards, the impact on antibiotic emissions will likewise continue to grow.

Other recent developments are also encouraging. Medicines for Europe, a trade association for European generics companies, has made committing to the framework and PNEC targets a condition of its membership.

Continuing to make an impact

Although progress is being made to minimize environmental emissions of antimicrobials from the manufacturing supply chain, there is much more to do. We estimate it will take between four and seven years for the majority of antimicrobial manufacturers that are members of the alliance to meet PNEC targets.

We can’t solve the challenge of antimicrobial resistance on our own. The entire supply chain needs to adopt these standards for responsible antimicrobial manufacturing.

Other levers may need to be pulled to bring all manufacturers along. These could include national regulations or placing better value on robust quality and environmental management systems in large and institutional procurement processes.

Responsibly manufactured antimicrobials aren’t just a social good. They are a universal necessity.

Alba Tiley is the director of global sustainable antibiotics at Centrient Pharmaceuticals, a member of the AMR Industry Alliance. Steve Brooks is chair of the alliance’s Manufacturing Working Group and former head of environmental, health, and safety for Pfizer. The alliance welcomes new life science companies that share its commitment to addressing the global crisis of antimicrobial resistance.

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