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Points to consider for manufacturers and inspectors: environmental aspects of manufacturing for the prevention of antimicrobial resistance
1. Introduction and scope
1.1 Background:
According to research by UN Environment (1), growing antimicrobial resistance (AMR) linked to the discharge of drugs and particular chemicals into the environment is one of the most worrying health threats of today. AMR accounts for an estimated 700 000 deaths per year worldwide and, by 2030, will represent up to US$ 3.4 trillion in gross domestic product (GDP) loss (2). AMR has been identified as a priority at the World Health Assembly since 1998 (3), with rising momentum throughout the years. Since 1998, there have been a series of World Health Assembly resolutions on AMR. These paved the way to the Sixty eighth World Health Assembly in May 2015, where the World Health Assembly endorsed a global action plan to tackle AMR, including antibiotic resistance, the most urgent drug resistance trend (4). More recently, the Thirteenth General Programme of Work (2019–2023) highlighted the need to address this emerging threat, under the section for “Tackling antimicrobial resistance” (2). It is only recently that the need to address waste and wastewater management from pharmaceutical production has been explicitly addressed. Namely, on 30 November 2018, the World Health Organization’s (WHO’s) Executive Board meeting decided that technical input will be provided to good manufacturing practices (GMP) guidance on waste and wastewater management from the production of critically important antimicrobials (5, 6). The present Points to consider document was written further to this recent decision.
We are entering a post-antibiotic era, where simple and previously treatable bacterial infections can kill and where routine medical procedures that rely on antibiotic preventative treatment, such as joint replacements and chemotherapy, will not be possible. The 2014 O’Neill report commissioned by the Government of the United Kingdom of Great Britain and Northern Ireland estimated that antimicrobial-resistant infections may become the leading cause of death globally by 2050 (7).
The environment plays an important role in antimicrobial resistance. Microorganisms in soil, rivers and seawater can develop resistance through contact with resistant microbes (transfer of resistance genes), antibiotics and disinfectant agents released by human activity (1), as well as heavy metals (8, 9) that may propagate AMR in the environment. People and livestock could then be exposed to more resistant bacteria through food, water and air (1).
Pharmaceuticals entering the environment from industrial manufacturing activities are not the major source of antimicrobial resistance, but in countries that contribute the most to the production of antimicrobials, this issue can be significant. The levels of pollution with antimicrobials have been measured in waters in the proximity of pharmaceutical production facilities. Antimicrobial concentrations in some effluents are too low to be lethal to exposed bacteria but may still be sufficient to induce antimicrobial resistance (1, 10), but high concentrations have been found downstream of antimicrobial manufacturing sites in several countries. Scientific literature reports a correlation between the type and number of highly resistant bacteria and the level of antimicrobial pollution (10). This led to manufacturing sites being identified as one of the hot spots for development of AMR, but this knowledge dates from only a few years ago (11).
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Table of Contents
3. Review of the
environmental aspects of good manufacturing
WHO TRS (Technical Report Series) 1025, 2020 Annex 6:
