The World Health Organization (WHO) has released new guidance on what it calls an "important but neglected challenge" in efforts to tackle antimicrobial resistance (AMR).
The guidance, released yesterday, provides targets aimed at limiting the emergence and spread of AMR from antibiotic manufacturing plants, which are a documented source of antibiotic pollution but remain largely unregulated. Developed in collaboration with international experts, the document also includes risk management plans to help antibiotic manufacturers ensure that they meet the established targets, engage with independent auditors, and are transparent.
The guidance addresses the growing concern that the unregulated release of antibiotic residues from manufacturing sites into local waterways is promoting the development of resistant pathogens and helping undermine the effectiveness of antibiotics globally.
"Pharmaceutical waste from antibiotic manufacturing can facilitate the emergence of new drug-resistant bacteria, which can spread globally and threaten our health," Yukiko Nakatani, MD, PhD, the WHO's interim assistant director-general for AMR, said in a WHO press release. "Controlling pollution from antibiotic production contributes to keeping these life-saving medicines effective for everyone."
Limiting concentrations of antibiotic residues
The aim of the guidance, which covers all steps from the manufacturing of active pharmaceutical ingredients (APIs) to formulation into finished products, is to establish an "independent and scientifically derived framework" for applying targets for managing both liquid and solid wastes from antibiotic manufacturing facilities. The targets, expressed as PNECs (predicted no-effect concentrations), are for concentrations of antibiotics that are not likely to select for resistance (PNECres) or disturb the ecosystem (PNECeco).
Targets are needed because liquid effluent and solid waste from antibiotic manufacturing sites, as well as the downstream water bodies that receive that effluent and waste, can contain very high concentrations of antibiotic residues, even higher than those found in wastewater containing excreta from people and animals being treated with antibiotics.
The concern is that those residues interact with bacteria in the environment and create selection pressure for the development of resistance. While resistance may develop first in non-pathogenic bacteria, it could spread to pathogenic bacteria through the transfer of AMR genes.
Pharmaceutical waste from antibiotic manufacturing can facilitate the emergence of new drug-resistant bacteria, which can spread globally and threaten our health.
Although it's unclear how much this pollution contributes to the emergence and spread of resistant pathogens that threaten human and animal health, the WHO and the experts who contributed to the guidance believe that setting PNEC targets for antibiotic manufacturing can help reduce unnecessary risk.
"There's potential to make a very serious problem even worse," One Health Trust Director Ramanan Laxminarayan, PhD, MPH, who was among the experts who reviewed the guidance, said today in a WHO webinar. "These pockets of high concentrations are something that could get us into a lot of trouble."
Laxminarayan added that setting PNEC targets for antibiotic manufacturing is necessary because more local antibiotic manufacturing sites are needed to address the lack of access to antibiotics in many low- and middle-income countries (LMICs).
"The ability to make antibiotics in LMICs is critical, but we need to make sure that we don't do it in ways that endanger local populations," he said.
The guidance is not the first attempt to regulate pollution from antibiotic manufacturing. In 2022, the AMR Industry Alliance and the British Standards Institute (BSI) collaborated on a voluntary standard that requires antibiotic manufacturers to have an effective environmental management and wastewater treatment system that minimizes API discharges in wastewater. In 2023, the groups created a verification scheme, managed by BSI, that provides certification for manufacturing sites that meet the standard.
Steve Brooks of the AMR Industry Alliance, who also provided input on the report, said the targets in the WHO guidance are similar to those created by the alliance. And while there are some differences, he believes the groups can work together to promote responsible antibiotic manufacturing.
"I believe that together we can do more than we can do separately," Brooks said during the webinar.
Guidelines need to be adopted 'broadly and quickly'
Although the guidance isn't binding, the hope is that national or regional regulatory bodies, wastewater management services, antibiotic procurers, and third-party auditors will adopt the targets and create mechanisms that either require or incentivize antibiotic manufacturers to meet them.
For example, agencies that regulate pharmaceutical manufacturing in countries could use the targets to introduce laws that set antibiotic pollution limits for manufacturing sites. Or agencies that procure antibiotics for healthcare systems could require that antibiotic manufacturers are certified as meeting the WHO targets in order to win contracts.
Laxminarayan said that while setting standards is an important first step, it's only the beginning.
"We need regulatory bodies to act and we need procurers and consumers to get on board," he said. "Guidelines can easily sit on shelves and gather dust, unless there is a push to adopt them broadly and quickly."
