Antibacterial waste must be properly managed to help reduce the risk of antimicrobial resistance emerging in local waterways.
Pharmaceutical companies need to set limits on the concentration of APIs that can be present in manufacturing wastewaters, and require their suppliers and contractors to meet the same standards.
A huge number of manufacturing sites around the world are involved in the
production of antibacterials, with many based in India and China.1
If these sites do not manage their waste appropriately, the discharge of wastewaters containing active pharmaceutical ingredients (APIs) into the environment may lead to the development of resistant bacteria, or the emergence of new forms of resistance which existing medications cannot effectively treat.2,3,4
It is therefore critical that companies take responsibility for, and are cautious about, their manufacturing processes.5,6
Companies that operate manufacturing sites can reduce the risk of antimicrobial resistance (AMR) by implementing a robust environmental risk-management strategy. This governs how sites manage and dispose of waste that potentially contains APIs, including by auditing and monitoring to ensure the levels of antibacterial residues present in wastewaters do not exceed limits that are considered safe.
Pharma companies can leverage their positions in the supply chain to raise standards at suppliers’ sites by requiring them to meet specific limits, and by extending those standards to the waste treatment plants they contract to dispose of manufacturing waste.
Companies apply limits in the environment itself
While solid waste containing antibacterials is typically sent for incineration, liquid waste is discharged into the environment. As recommended by the AMR Industry Alliance, companies generally assess whether they have met limits by calculating concentrations in the receiving environment (e.g. the river) rather than directly in the wastewater leaving the manufacturing site after on-site treatment. As such, the wastewater will often be strongly diluted at the point where limits are applied. Applying limits directly to the wastewater before it is discharged into the environment would be a more desirable approach in the fight against rising AMR. This is because selection of antibiotic-resistant bacteria can still occur in the wastewater itself, due to the presence of bacteria and high concentrations of antibacterials. In addition, if wastewater containing high levels of APIs is sent to public wastewater treatment plants, it also poses a risk as these plants are known hotspots of selection for resistance.
Wastewater contains APIs and resistance bacteria
When companies treat wastewater on-site, especially using biological methods, many bacteria will still be present in the wastewater, leading to the risk of resistance.
It is important to note that public wastewater treatment plants also receive other wastewater from municipalities, which can contain high levels of bacteria but also antibacterial residue as result of human use.
Key terms explained
A strategy developed specifically to minimise the impact of manufacturing processes used at a manufacturing site on the environment, and to address the associated risk of AMR.
CAPA stands for 'Corrective and Preventive Action' - set of actions or improvements which can be implemented by a company in order to tackle non-compliance, and to make sure these issues do not occur in future.
A PNEC - or 'predicted no-effect concentration' - is the highest estimated concentration of an antibacterial at which no adverse effects on the environment, such as the opportunity for resistance selection or harm to aquatic life, are expected to occur.8, 9, 10
How levels of antibacterials are quantified by companies
Rather than measuring antibacterials in wastewater samples, it is common practice for companies to calculate the final concentrations in the receiving environment. This is also known as the "mass balance" approach and consists of:
Estimating how much of the antibacterial ingredient is lost in the production process and will end up in waste, i.e. the mass balance;
Estimating how much antibacterial residue is removed by on-site treatment (and other treatment plants if applicable);
Applying dilution factors due to water flows from treatment plants and rivers, if applicable.
Nine of the 17 companies evaluated in the 2021 Benchmark report that, only when deemed necessary, mass balance calculations are verified by sampling wastewater and performing chemical analysis. This verification is helpful to make sure the approach used for calculations is accurate, or to check whether calculations are correct and whether limits have truly been met or exceeded.
The role of the AMR Industry Alliance
The AMR Industry Alliance is a coalition of pharmaceutical companies formed
in 2016 to deliver on the commitments made in the Davos Declaration on curbing AMR.
Twelve of the 17 companies in scope have made a public commitment to assess their own and suppliers’ sites through the AMR Industry Alliance’s Common Antibiotic Manufacturing Framework (CAMF). These companies include all the large research-based companies in scope, as well as the generic medicine manufacturers Aurobindo, Fresenius Kabi, Teva and Viatris.
CAMF is a publicly available tool that provides strategic recommendations on handling and treatment of antibacterial waste, risk assessment, and auditing to minimise AMR risk from antibacterial manufacturing.
As implementation is an ongoing process, long-term action plans need to be developed and tailored by each company.
How does the Benchmark assess companies in Responsible Manufacturing?
The Benchmark looks at whether companies’ environmental risk-management
Management systems and treatment practices, including details of techniques and processes to collect and treat both solid waste and wastewater;
Details on plans for periodic audits for sites, including how to identify problematic processes and to initiate corrective and preventive action (CAPA, see key terms above);
Defined limits, set specifically for the maximum levels of antibacterial residue present in waste/wastewaters, such as predicted no-effect concentrations (PNECs, see key terms above);
Details on plans for risk assessments and monitoring of discharge levels at all sites, so that compliance with set limits can be assessed. It is critical that pharmaceutical companies implement strategies at their own sites, as well as requiring their suppliers and waste-treatment contractors to meet the same environmental standards.
Companies and products in scope
Seventeen pharmaceutical companies – made up of 8 large research-based companies and 9 generic medicine manufacturers – are in scope for the 2021 AMR Benchmark, manufacturing a combined total of 801 antibacterial products.
Of these 801 antibacterial products, 688 (86%) have an established science-based PNEC target laid out in the recommended list by the AMR Industry Alliance. In February 2021, a default value was added to the list for those active ingredients which do not have a specified target as of yet.
Twelve of the 17 companies apply the PNECs as voluntary targets. However, there are currently no legally binding limits for antibacterial discharge from manufacturing. This means there are no legal consequences for companies when targets are not achieved. Responsibility lies with governments to develop a regulatory framework with limits for emissions of antibacterial waste, in order to incentivise action when safe levels are not met.
Manufacturing sites in scope
The Benchmark examines the pharma companies’ policies and practices with regards to a combined total of 1,057 antibacterial manufacturing sites, based on data reported by the companies.
Together, their antibacterial manufacturing sites consist of:
93 sites operated directly by large research-based companies
94 sites operated directly by generic medicine manufacturers
870 sites operated by third-party suppliers to the companies in scope
*No data on directly-operated sites is available for two companies: Alkem and MSD. No data on suppliers’ sites is available for five companies: Alkem, Fresenius Kabi, Hainan Hailing, MSD and Sun Pharma..
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