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When asked to share an Antimicrobial Viewpoint article on pollution discharges resulting from the manufacturing of antibiotics, I reflected on more than 20 years of studies reporting on river concentrations of these drugs from pharmaceutical manufacturing waste.¹ These reports of pollution discharge, of which there are now many,² routinely detailed concentrations of active pharmaceutical ingredients (API) of antibiotics in rivers near or higher than what you would expect to find in the blood of someone under antibiotic treatment.³ The reports universally revealed a systematic problem with the pharmaceutical industry’s obscure waste handling practices and the potential global effects on the transmission and spread of antimicrobial resistance (AMR) in the environment.  

Recognition of pharmaceutical manufacturing as a source of pollution 

Most pharmaceutical manufacturing, particularly of generic antimicrobials, has been moved to newer and larger markets, often in countries where human resources are inexpensive and environmental regulations are insufficient.^4,5 However, when researchers routinely examine the downstream concentrations of pharmaceuticals in the environment (PiE), i.e., in rivers within countries with a reputation of higher environmental regulations and enforcement,^6,7 they also find levels that well exceed concentrations purely reflective of the chemical’s ‘use’ within the population.⁷ 

AMR has no borders, as such, we are as vulnerable as our weakest link; at the moment those links appear to be our inability to safely collect and properly treat our sewage, and the widespread misuse of antibiotics in humans and animals.

The early reports brought with it a wave of concern and outrage.^8,9 However, it comes as little surprise that it is that way, simply because it’s cheaper for a manufacturer to only care about 1) what they are regulated to care about and need to comply with and 2) what the regulators enforce. Yet, the O’Neill report¹⁰ raised the profile of manufacturing pollution, bringing to light the risks to which institutional insurance investors have unknowingly been exposed.¹¹ The standard business model is to assess whether the cost of the potential fine is higher than the cost of solving the problem – in this case, the cost to maintain the status quo is lower. However, one could turn this problem around and force us to look at our health systems as the source of the problem. Arguably, it is the beneficiaries of the cheap drugs that are at fault, as they hold up no standard of best practice to the industry as a metric of what ‘good enough’ looks like. If cheap drugs made with poor environmental standards are not purchased, the industry would, arguably, self-correct. This metric of ‘good enough’ is what the Access to Medicines Foundation tried to establish.  

The drive toward solutions 

The Access to Medicines Foundation stepped into this space to offer an objective, third-party view of the industry. They devised a benchmarking system to help nudge the manufacturers towards a future where manufacturing was more transparent and environmentally sustainable, with open and auditable data. The desire was for the industry to be part of the solution of tackling AMR, not just making the drugs.¹² The Foundation also published a report on responsible manufacturing, which shows the current state of the industry’s efforts and points for improvement.¹³

The polite game of nudging businesses to do the right thing has pivoted to the early stages of formal guidance – i.e., a top-down approach, which comes in the form of: “WHO Guidance on waste and wastewater management in pharmaceutical manufacturing with emphasis on antibiotic production.”¹⁴ This guidance proposes an ecosystem of constructive measures that, if implemented, would go a long way towards limiting the adverse effects of antimicrobial manufacturing on the environment and humans. At present, discharge limits for antimicrobials from the manufacturing plants would likely mirror the British Standards Institution (BSI)¹⁵ and AMR Industry Alliance¹⁶ guidance – two organisations that have collaborated on a ‘third-party assurance’ standard to be used, in a self-regulatory capacity, to demonstrate that antibiotic residue emissions from manufacturers are effectively controlled. Although there is no consensus within academia as to whether the BSI/AMR Industry Alliance approach is sufficiently protective (or overprotective), it does strike me as an excellent opportunity for the community to build on and adjust over time. However, challenges remain concerning regulating mixtures of antimicrobial resistance-driving chemicals¹⁷ and transparency.

Pollution from manufacturing sites represents a potential focal point for the evolution of antimicrobial resistance genes and their dissemination, as they are discrete point sources and relatively rare.

Another challenge is whether a standard that is focused on meeting chemical thresholds in the receiving environment, as well as possibly accounting for the mass balance of “ingredients” going into API production, is truly protective given that wastewater effluent from the manufacturing facility and wastewater treatment plant will contain significant numbers of antimicrobial-resistant bacteria.¹⁸ Notably, the industry is currently self-regulating and should move towards governmental regulation, inspections, auditing and enforcement. 

Doing better than just implementing the precautionary principle 

Pollution from manufacturing sites represents a potential focal point for the evolution of antimicrobial resistance genes and their dissemination, as they are discrete point sources and relatively rare. The degree to which antibiotic manufacturing pollution has already contributed to the AMR pandemic is nearly impossible to conclusively demonstrate – not only because it would be unclear what the ‘smoking gun’ should look like but also because there have been essentially no (longitudinal molecular) studies that have asked the question. Each manufacturing site would require researchers to examine the unique antimicrobial resistance genes that are selected for and the degree to which they have disseminated globally from each point source. Ideally, these studies would commence at the start of any new antimicrobial’s production.  

The fact that we live in a world where there seems to be a lack of evidence rather speaks to the incuriosity of funders, politicians, public health officials, and the wider academic community in funding or pushing for research into essential and pragmatic questions. Should evidence be found at each manufacturing location, it would justify hastening the implementation of the aforementioned WHO guidance. However, should this remain elusive, even after multiple longitudinal investigations, the academic community must set aside the precautionary principle as it would no longer be needed given the lack of identified risk. Although it intuitively feels like the precautionary approach is the right approach – it still needs to be thoroughly tested, as the absence of conclusive evidence, if found to be accurate, is an incredibly important finding with wide-ranging implications. 

These reports of pollution discharge, of which there are now many, routinely detailed concentrations of active pharmaceutical ingredients (API) of antibiotics in rivers near or higher than what you would expect to find in the blood of someone under antibiotic treatment.

So long as the precautionary principle prevails, we must focus on shifting the paradigm around pharmaceutical manufacturing to ensure that best practices are implemented and deemed protective. The ‘ecosystem’ needs not only to be driven by the WHO along with other regulatory agencies and governments but also by the general public, patients, health systems and regulators, who currently give no thought to where their drugs come from or the impact antimicrobial manufacturing waste could be having on the environment and their future health. Education, raising awareness and a transparent pipeline empower stakeholders to identify the need for change and push for it. Any new ecosystem must disincentivise manufacturers not adhering to industry best practices – translating into financial penalties, including the loss of business. Future reflections on the industry’s waste disposal must, aspirationally, include evidence of compliance with compulsory discharge thresholds for antibiotics and antibiotic-resistant organisms. It should also include results from longitudinal studies testing the hypothesis that manufacturing waste represents a ‘smoking gun’ for novel and clinically relevant antimicrobial resistance in the world. 

AMR has no borders, as such, we are as vulnerable as our weakest link; at the moment those links appear to be our inability to safely collect and properly treat our sewage,¹⁹ and the widespread misuse of antibiotics in humans and animals.^10,20 Although solving the manufacturing challenge will come at a cost to the consumer, it is within our power to rather “easily” reduce this risk. Yet, we must find a way to do so without jeopardising access to cheap and effective antibiotics for those who need them worldwide. 

References

1. Larsson DGJ, de Pedro C, Paxeus N (2007) Effluent from drug manufactures contains extremely high levels of pharmaceuticals. J Hazard Mater; 148(3):751-5.
2. Larsson DGJ (2014) Pollution from drug manufacturing: review and perspectives. Philosophical Transactions of the Royal Society B; 369(20130571).
3. Fick J, Söderström H, Lindberg RH, Phan C, Tysklind M, Larsson DGJ (2009) Contamination of surface, ground, and drinking water from pharmaceutical production. Environmental Toxicology and Chemistry;28(12):2522-7.
4. Cardoso O, Porcher J-M, Sanchez W (2014) Factory-discharged pharmaceuticals could be a relevant source of aquatic environment contamination: Review of evidence and need for knowledge. Chemosphere;115:20-30.
5. Martin Armstrong (2022) China Dominates the Antibiotics Market. [Accessed 19/09/24] 
6. Phillips PJ, Smith SG, Kolpin DW, Zaugg SD, Buxton HT, Furlong ET, et al. (2010) Pharmaceutical Formulation Facilities as Sources of Opioids and Other Pharmaceuticals to Wastewater Treatment Plant Effluents. Environmental Science & Technology;44(13):4910-6.
7. Prasse C, Schlüsener MP, Schulz R, Ternes TA (2010) Antiviral Drugs in Wastewater and Surface Waters: A New Pharmaceutical Class of Environmental Relevance? Environmental Science & Technology;44(5):1728-35.
8. Wasley A, Davies M (2016) Dirty production of NHS antibiotics in India helping to create superbugs. [Accessed 19/09/24]  
9. Davies M (2017) Global Superbugs: Big Pharma coalition to take on superbugs. [Accessed 19/09/24]
10. O’Neill J (2016) Tackling drug-resistant infections globally: final report and recommendations. [Accessed 19/09/24]
11. Investor Action on AMR (2022) Investor Action on Antimicrobial Resistance Progress Report: Investor efforts, achievements and opportunities ahead. [Accessed 19/09/24]
12. Access to Medicines Foundation (2021) Antimicrobial Resistance Benchmark. [Accessed 19/09/24]
13. Access to Medicines Foundation (2023) Methods matter: What steps are companies taking to help curb AMR by manufacturing responsibly? [Accessed 19/09/24]
14. WHO (2024) WHO Guidance on waste and wastewater management in pharmaceutical manufacturing with emphasis on antibiotic production. [Accessed 19/09/24]
15. BSI (2024) BSI Kitemark™ for minimized risk of antimicrobial resistance. [Accessed 19/09/24]  
16. Alliance AI (2022) Antibiotic Manufacturing Standard: Minimizing risk of  developing antibiotic resistance and aquatic ecotoxicity in the environment resulting from the manufacturing of human antibiotics. [Accessed 19/09/24]
17. Singer AC, Shaw H, Rhodes V, Hart A (2016) Review of antimicrobial resistance in the environment and its relevance to environmental regulators. Frontiers in microbiology; 7:1728.
18. Larsson J. (2022) Industrin sätter standard för utsläpp på egna villkor. [Accessed 19/09/24]
19. Tipper HJ, Stanton IC, Payne RA, Read DS, Singer AC (2024) Do storm overflows influence AMR in the environment and is this relevant to human health? A UK perspective on a global issue. Water Research;260:121952.
20. EclinicalMedicine (2021) Antimicrobial resistance: a top ten global public health threat. eClinicalMedicine;41.