How do pharma companies manage AMR risk during manufacturing?
Antibiotic manufacturing processes can increase drug resistance in two main routes: by releasing antibacterial residue directly into the environment; and by manufacturing antibacterials with too little of the active ingredient. Both routes give microbes extra opportunities to develop resistance.
Pharmaceutical companies can minimise their impact on resistance by adopting environmental risk-management strategies that aim to limit AMR. They must also ensure medicines meet internationally agreed quality standards. Furthermore, considering their pivotal position in manufacturing and supply chains, companies can require their suppliers to meet these same quality and environmental standards – even extending them to the waste-treatment plants that are contracted to dispose of their manufacturing waste.
The 2020 AMR Benchmark assesses the manufacturing processes of eight large R&D-based companies and nine generic medicine manufacturers, and whether these processes aim to minimise the risk of AMR.
- By adopting a clear environmental risk-management strategy that applies to their own manufacturing sites, to the sites of their third-party suppliers and to waste-treatment plants;
- By publishing information on the risk-management processes they implement and their outcome and;
- By manufacturing products of high quality following international standards accepted by recognised authorities.
Do companies adopt clear environmental risk-management strategies?
The 2020 Benchmark assesses whether companies are adopting clear environmental risk-management strategies. The majority of companies have adopted a strategy for their own sites, which they routinely audit. Plus, almost all of the companies with a strategy also set limits for the acceptable concentration of antibacterial ingredients that can be present in their manufacturing discharge (wastewaters). Nevertheless, the Benchmark finds that the depth and breadth of companies’ environmental strategies vary widely (scroll down for the full breakdown).
Environmental strategies are largely determined by AMR Industry Alliance framework
Of the 17 companies assessed, 12 are part of the AMR Industry Alliance, a coalition of pharmaceutical companies formed in 2016 to deliver on the commitments made in the Davos Declaration on curbing AMR. This includes all of the large R&D-based companies assessed in this area, together with four generic medicine manufacturers (Aurobindo, Cipla, Mylan and Teva). As Alliance members, these companies commit to manage AMR risk from antibacterial manufacturing discharge.
- Environmental regulations do not typically set limits on the levels of antibacterials allowed in manufacturing discharge.
- While it is important for governments to take action and introduce relevant regulation, companies should not wait for this to happen, but voluntarily set limits to mitigate the risk of emergence and/or spread of AMR.
- To manage the risk of emergence and/or spread of AMR in the environment, limits should be set, per active ingredient, either at or below the predicted no-effect concentrations (PNECs) for resistance selection.
- PNEC: is the concentration below which no harmful effects are expected to occur.
Six companies require suppliers to set antibacterial discharge limits
Of the 13 companies with an environmental risk-management strategy, 12 set limits for antibacterial discharge. These limits are based on 'Predicted No-Effect Concentrations', or PNECs. These are the concentrations below which no harmful effects are expected to occur. The 13th company, Fresenius Kabi, has a strategy to minimise the impact of antibacterial discharge, but shows no evidence of setting limits.
Pharmaceutical companies do not typically manufacture all of the ingredients used in the medicines they sell. Instead, they rely on extensive networks of suppliers, including for the active antibacterial ingredients. The Benchmark assesses whether companies require these suppliers to have environmental risk-management strategies in place that are at least as stringent as their own.
Six companies report requesting their suppliers to set discharge limits. Johnson & Johnson additionally reports conducting sampling at suppliers’ sites, while GSK reports that it will discontinue operations with any supplier that does not comply by 2021 with limits set. To date, no company has shown that its supplier contracts include requirements to manage AMR-related risks, for example to meet discharge limits. This is a bar that all companies are encouraged to meet.
No company assesses whether external waste-treatment plants meet limits
Some antibacterial manufacturing sites have on-site treatment plants for their wastewaters and other waste, while others rely at least partly on external, privately owned plants to treat wastewaters and other waste from antibacterial manufacture. Both on-site and external plants have a role to play in minimising AMR risk from the discharge of antibacterials into the environment.
The 2020 Benchmark assesses whether companies require external private waste-treatment plants to have environmental risk-management strategies that are at least as stringent as their own strategies – including audits and, for plants treating wastewater, limits and monitoring of discharge levels.
However, no companies currently require the external wastewater-treatment plants that handle their antibacterial manufacturing waste to set limits for antibacterial discharge. No companies report monitoring (or asking plants to monitor) these discharges. Nonetheless, companies that set discharge limits at their own sites typically do so for all sites, including those that send wastewaters to external plants for treatment.
Do companies publish their environmental strategies and their outcomes?
By publishing their strategies, pharmaceutical companies enable independent third parties to analyse and compare their processes and performance with their peers. This can promote good practice and give procurers (such as governments and other public institutions) the information necessary to identify companies that manufacture responsibly.
All companies evaluated by the 2020 Benchmark publish some of the elements looked for by the Benchmark. For example, 12 compares are members of the AMR Industry Alliance, which has published a list of recommended antibacterial discharge limits. Yet, no company publishes its discharge levels, audit results or the identities of third-party suppliers.
Quality systems align with Good Manufacturing Practice
Pharmaceutical companies are expected to produce their antibacterials using the highest standards to ensure quality, such as standards of Good Manufacturing Practice (GMP). By using these standards, companies help to minimise the risk that patients are exposed to sub-therapeutic levels of antibacterials. The Benchmark reports on the systems companies have in place to ensure high-quality production in own and third-party facilities used to manufacture antibacterial APIs and drug products.
Of the companies evaluated in this area, almost all report having a quality system consistent with international GMP standards at all sites manufacturing antibacterial APIs and/or drug products. The remaining company, Hainan Hailing, publishes very limited information about its quality system, but the Benchmark has been able to determine that it operates in markets under FDA and EU (EMA) purview.