4. Recommendations for the management of pharmaceuticals in freshwater

This final chapter presents the case for a life cycle, multi-sector approach to the management of pharmaceuticals in freshwater. Drawing from policy messages and case studies from the previous chapters, the report concludes with a set of recommendations on the management of pharmaceutical residues in freshwater for central government and other stakeholders.

    

4.1. Key messages: A life cycle, multi-sector approach to managing pharmaceutical residues in freshwater

No single policy instrument is capable of managing all sources of pharmaceutical pollution in freshwater. Likewise, there is no single culprit responsible for pharmaceutical pollutants reaching water bodies. In order to not only reduce existing known environmental threats, but to also minimise potential hazards, an approach for addressing pharmaceutical pollutants requires the involvement of central and local government agencies from various sectors (e.g. environment, agriculture, health, chemical safety), pharmaceutical industry, human and animal health care providers, patients and farmers, and water, wastewater and solid waste service providers. France, Germany, the Netherlands, Sweden and the UK have all established multi-stakeholder dialogues to address the pharmaceutical challenge.

An efficient abatement strategy combines policy options at various stages of the pharmaceutical life cycle, using source-directed, use-orientated and end-of-pipe measures. A focus on preventive options early in the pharmaceutical life cycle, may deliver the most long-term, cost-effective and large-scale benefits.

Three important actions to consider are: the promotion of green pharmacy and good manufacturing practices; the inclusion of environmental risks in the risk-benefit analysis of marketing authorisation for new pharmaceuticals; and post-authorisation monitoring and mitigation of high-risk pharmaceuticals (including of those already approved on the market). Data sharing and institutional coordination is necessary to reduce the knowledge gaps and increase efficiency at least cost to society.

4.2. A policy toolbox for a life cycle, multi-sector approach

The presence of pharmaceutical residues in water bodies is well documented and the hazards this creates are beginning to be understood (see Chapter 1). It is time to take effective action. Chapter 2 outlines the weaknesses of the current ERA process, and documents advances in monitoring and modelling to reduce uncertainties. Chapter 3 argues that current policy approaches in many countries to manage pharmaceutical residues in water are often reactive (i.e. measures are adopted only when risks can be proven and routine monitoring technologies exist), substance-by-substance (i.e. environmental quality norms for individual substances) and resource intensive. Such approaches are ill-adapted to emerging challenges, and the growing knowledge of environmental and health hazards triggered by pharmaceutical residues in freshwater ecosystems.

The large amount of substances, diverse entry-pathways into the aquatic environment and time-sensitive dynamics, underline the complexity of designing policies to manage pharmaceuticals in water. Solutions that are tailored for the reduction of point-source pollution (e.g. WWTP upgrades), for example, generally do not address the issue of diffuse pollution (typically from the use of veterinary pharmaceuticals in agriculture), and vice versa. Likewise, policies that deal with seasonal inputs do not necessarily solve the issue of constant discharges. Additionally, there exists a variety of goals across OECD countries, including the conservation of ecosystems, securing drinking water quality, or protecting recreational areas, which require diverse policy approaches.

The complexity of the issue suggests that there is no single-best policy instrument for this problem. Only a carefully designed package of policies has the potential to comprehensively reduce pharmaceuticals in water. This way, policies can be designed in proportion to the scale of the problem, collectively acting at different political levels and scales, and adopting different policy instruments in different sectors (Metz and Ingold, 2014[1]). Such an approach demands action throughout the pharmaceutical life cycle (source-directed, use-orientated and end-of-pipe measures) to minimise adverse effects on freshwater ecosystems and human health. Finally, voluntary measures alone will not deliver; economic and regulatory drivers are needed to incentivise action.

There are several mitigation options for water quality improvement in the pharmaceutical life cycle (Figure 4.1), including improvements in the design (e.g. green pharmacy), registration and authorisation, production, use and waste phases, and finally technological interventions of WWTPs (Van Wezel et al., 2017[2]). A focus on preventive options early in a pharmaceutical’s life cycle, may deliver the most long-term and large-scale benefits (chapter 3 documents some effective preventative measures). Relying on end-of-pipe WWTP upgrades only is costly, energy intensive and toxic transformation products may be formed (Haddad, Baginska and Kümmerer, 2015[3]). However, in combination with source-directed and use-orientated approaches, extra treatment at the level of WWTPs may play a role in reducing human pharmaceuticals reaching the environment, particularly in light of growing demand for pharmaceuticals by society.

Figure 4.1. The pharmaceutical life cycle

Source: Author

Policies that cost-effectively manage pharmaceuticals for the protection of water quality and freshwater ecosystems rest on five strategies:

1. 1. Reporting on the occurrence, fate, and risks of pharmaceutical residues in water bodies, consideration of environmental risks in the risk-benefit analysis pre-authorisation of new pharmaceuticals, and continued monitoring of high-risk pharmaceuticals post-authorisation (including of those already approved on the market).

2. 2. Source-directed approaches to impose, incentivise or encourage measures in order to prevent the release of pharmaceuticals into water bodies;

3. 3. Use-orientated approaches to impose, incentivise or encourage reductions in the inappropriate and excessive consumption of pharmaceuticals;

4. 4. End-of-pipe measures – as a compliment to strategies 1-3 - that impose, incentivise or encourage improved waste and wastewater treatment to remove pharmaceutical residues after their use or release into the aquatic environment; and

5. 5. A collaborative life cycle approach, combining the four strategies above and involving several policy sectors.

Regulatory, economic and voluntary policy instruments are all part of the toolkit that is needed to manage multiple sources of pollution from different stakeholders at different stages of the pharmaceutical life cycle. Stakeholder engagement through inclusive water governance and information is increasingly recognised as critical to secure support for reforms, raise awareness about water risks and costs, increase users’ willingness to pay, and to handle conflicts. Policy-makers will need to factor in financing measures for the upgrade, operating and maintenance costs of wastewater treatment plants, as well as policy transaction costs to facilitate the transition from reactive to proactive control of pharmaceutical residues in water bodies.

A selection of key mitigation and policy options for different stakeholders at different stages of the pharmaceutical lifecycle is presented in Table 4.1.

Table 4.1. Selection of key mitigation options for different stakeholders across the life cycle of pharmaceuticals
Step in pharmaceutical lifecycle	Relevant stakeholders	Mitigation options
Cross-cutting	Government, Industry, Research organisations	Targeted monitoring and prioritisation of high-risk APIs Harness new innovations in water quality monitoring, modelling, scenario development and risk assessment Centralised database with regulatory oversight to share ERAs and environmental monitoring data of APIs Environmental quality norms / water quality standards
Design	Industry	Innovation in green pharmacy, biological therapies, personalised or precision medicines
Authorisation	Government, Industry	Legislation and standardised methodology for environmental risk assessment and incorporation into benefit-risk assessment of pharmaceutical marketing authorisation More stringent conditions for putting a pharmaceutical on the market that is of high-risk to the environment (e.g. increased risk intervention and mitigation options, eco-labelling, prescription only, post-approval monitoring)
Production	Industry, Government, Intergovernmental Organisations	Green public procurement with environmental criteria Environmental criteria for Good Manufacturing Practices, effluent discharge limits and disclosure of pharmaceutical wastewater discharge from supply chains1
Consumption (professional use)	Agriculture, Health sector, Government	Emission prevention through disease prevention and sustainable use of pharmaceuticals ● improved human and animal health and well-being ● improved diagnostics, avoided prescriptions ● improved hygienic standards in health facilities, stable management and livestock handling ● personalised medicines, vaccinations, targeted delivery mechanisms ● prescription of environmentally-friendly pharmaceutical alternatives2 ● restrictions or bans of unnecessary high-risk pharmaceuticals (e.g. veterinary use of antibiotics for preventative measures and hormones as growth promoters in livestock)
Consumption (over-the-counter purchases/ self-prescription)	Health sector, Industry, Consumers	Eco-labelling of high-risk over-the-counter pharmaceutical products to improve consumer choice selection and awareness
Collection and disposal	Solid waste utilities, Industry	Education campaigns to avoid disposal of pharmaceuticals via sink or toilet Public pharmaceutical collection schemes for unused drugs Extended producers responsibility schemes Improved manure management by passive storage or anaerobic fermentation in biogas plants
Wastewater treatment	Wastewater utilities	Upgrade of wastewater treatment plants
Drinking water treatment	Drinking water utilities	Upgrade of drinking water treatment plants Water safety planning
← 1. GMP criteria may need to be redefined under the auspices of the WHO, including provision of globally harmonised environmental standards as part of the regulatory controls for pharmaceutical products. When negotiating environmental criteria for GMP, care would need to be taken to avoid withdrawal of countries from existing GMP agreements.
← 2. Requires that substitute pharmaceutical is available with lower environmental risk. An alternatives assessment would be required to confirm this, in order to prevent pollution-swapping.
Source: Author

4.3. The interlinkages between freshwater, pharmaceutical, and human and animal health policies

The life cycle approach refers to interlinkages between the control of pharmaceutical residues in freshwater and sector-specific policies to promote sustainable pharmaceutical industry and use. A summary of OECD recommendations on the management of pharmaceutical residues in freshwater is provided after the executive summary of this report. This section focuses on three sets of initiatives that can contribute to controlling pharmaceutical residues in freshwater at least cost to society:

• Improvements to environmental risk assessment and marketing authorisation of pharmaceuticals (section 4.3.1);

• Overcoming barriers to facilitate green pharmacy (section 4.3.2); and

• Opportunities to minimise costs related to data collection and bridging knowledge gaps (section 4.3.3). They can contribute to improving decision making under uncertainty, a feature of commonality of health-care and environmental policy (section 4.3.4).

Finally, equity should be considered in decision making regarding policies and investments to ensure that the needs of the most vulnerable populations, and that the allocation of costs, risks and benefits, are distributed in an equitable manner. This especially relates to pharmaceutical companies and manufacturers in two ways: i) a responsibility to prevent pollution and contribute to the costs of treating wastewater in line with the polluter pays principle, and ii) a responsibility to not simply outsource pollution to developing and emerging economies where environmental regulation and enforcement may be less stringent.

4.3.1. Improvements to environmental risk assessment and marketing authorisation of pharmaceuticals

One of the key steps from a regulatory view is to strengthen the ERA in the pharmaceutical marketing authorisation process. As mentioned in Chapter 2, current drug approval for human pharmaceuticals is based on safety, efficacy and quality; environmental effects are not considered in the risk-benefit analysis for marketing authorisation. This issue has been raised by several scientists (e.g. (Ågerstrand et al., 2015[4]) (Küster and Adler, 2014[5])) as well as within national action plans related to pharmaceuticals in the environment. The following improvements have been suggested:

• Improve the availability and transparency of ERA data and information. Establish a central database of ERA data with access rights to minimise duplication of testing (including animal testing) and improve consistency of ERAs. Such a database would require independent regulatory oversight.

• Use all available information subject to quality assurance and validation, and not only studies produced by the industry themselves.

• Develop a standardised methodology for integrated decision-making for assessing, comparing and communicating the therapeutic benefits and environmental risks for the benefit-risk assessment of pharmaceutical marketing authorisation.

• Assess environmental risk data requirements.

• Include environmental risks in the risk-benefit analysis.

• Include the risk potential of developing AMR in risk-benefit analysis.

• Ensure environmental risks are translated into enforced mitigation measures. Improve risk management options.

• Generate data and ERAs on existing pharmaceuticals on the market (i.e. pharmaceuticals authorised before ERAs became mandatory).

• Ensure environmental risks and impacts observed post-marketing are monitored and reported.

• Review ERAs on a regular basis to include new information, including data on actual use and effects, not just on default worst-case assumptions.

Considering the environment in benefit-risk analysis does not necessarily mean that pharmaceuticals should not authorised, rather that substances with high clinical importance, high environmental risk and no ‘green’ alternatives should be authorised with more strict monitoring (e.g. targeted monitoring, measured environmental concentrations, updated ERA with consumption data, spatial modelling) and environmental risk mitigation options (e.g. wastewater treatment at manufacturing plants, disposal instructions on packages, and prescription-only medicine). In rare cases when there are no appropriate measures available to minimise a serious environmental risk, and when other medicinal products or medical treatments are available on the market that offer adequate, equivalent health care, the marketing authorisation could be rejected based on environmental risk (UBA, 2018[6]). For more details on ERA and pharmaceuticals authorisation, refer to section 2.2.

4.3.2. Overcoming barriers to facilitate green pharmacy

A promising medium-term approach to reducing the environmental risks of pharmaceuticals, and possible health risks at source, is the rational design and manufacture of new green pharmaceuticals. Green pharmacy or 'benign by design’ (Kümmerer, 2007[7]) is often referred to as: i) the development of new substances that are more efficiently biodegraded but retain their effective pharmaceutical properties, or ii) the re-design of existing pharmaceuticals for environmental biodegradability. The expected outcome is better biodegradable and pharmacologically active drug molecules that do not accumulate in, or cause adverse effects to, the environment.

Although research on green pharmacy has expanded in recent years, the share of green pharmaceuticals on the market is still low, and an agreed definition of green pharmacy has not been reached. Barriers delaying immediate progress, and policy options to overcome them, are presented in Table 4.2.

Table 4.2. Common barriers and policy solutions to facilitate green pharmacy
Barrier	Policy solution options
Technical barriers: uncertainties, and lack of cross-cutting expertise, definitions, metrics and transparency of data	● Develop a realistic and risk-based definition of ‘green pharmacy’ agreed between environmental chemists, clinical chemists, drug discovery scientists and other relevant stakeholders. ● Facilitate knowledge creation and accessibility, through R&D spending and shared databases ● Provide technical assistance for implementation to drive innovation. Demonstrate the feasibility of new green pharmaceuticals as new business opportunities for industry.
Economic and financial barriers: costs, lack of incentives, and markets	● Facilitate access to data (including testing) to avoid costly replication. Revise medicine regulations to allow cross-referencing of ERA information. ● Demonstrate feasibility of new green pharmaceuticals which can present new business opportunities for industry ● Create tax incentives and access to inexpensive capital to drive innovation. A return on public investments in new pharmaceuticals should be considered when assessing subsidies for the private sector in pharmaceutical development. ● As part of combatting AMR, address economic models of new antibiotics, which currently link profit (sales) with volume (consumption). Options may include partnerships, grants and seed funding to stimulate innovation, or prizes and tax concessions aimed to reward at the end of the development process. ● Develop and implement evidence-based technical guidelines on sustainable procurement of pharmaceuticals. Integrate environmental criteria into good manufacturing practices utilised by authorities to pre-qualify pharmaceuticals for procurement ● Implement eco-labelling schemes of green pharmaceuticals, with or without a green premium ● Consider granting additional intellectual property protection, and thus longer period of exclusivity, to offset the costs of innovation and reduce financial risks (provided exclusivity can be tied to ongoing environmental risk management during period of exclusivity)
Regulatory barriers: a regulatory focus on risk control, rather than risk prevention	● Ensure environmental risks are adequately taken into account in marketing authorisation of new pharmaceuticals, and translated into enforced mitigation action to incentivise investment in green pharmacy ● Allow for an easy or fast-track marketing authorisation process for green pharmaceuticals based on the biodegradability of APIs and their metabolites and transformation products after use
Source: Author

4.3.3. Data sharing and institutional coordination to reduce the knowledge gaps

Reaching a rational assessment of the risks posed by pharmaceuticals as environmental pollutants needs to be done with a minimum investment of resources, which means avoiding reinvention and rediscovery of environmental testing and risk assessment. In order to address knowledge gaps and perform robust ERAs, it is necessary to harmonise data types and forms, and share existing information. Open source, good quality databases (with independent regulatory oversight), efforts to link databases to toxicity and exposure, and greater collaboration between stakeholders and across borders are called for in this regard (Ågerstrand et al., 2017[8]). In particular, collaboration between the traditionally separated environmental, chemical and medical sciences has a critical role to play. Collaborations among the environmental, chemical and medical sciences are important because in the final analysis, human health, animal health and the health of ecosystems are intimately tied, and in many respects, indistinguishable.

The following list of recommendations can facilitate harmonisation across political boundaries:

• Define protocols used in data collection for quantifying pharmaceutical usage by substance, and for determination of potential adverse effects on human and ecosystem health (including AMR and mixture effects).

• Define common indicator substances. With more precise and diverse monitoring approaches, an even greater amount of pharmaceuticals will be found in water bodies or living organisms, which again create new demands on research. At the same time it is a challenge for policymaking to deal with such volumes of scientific results and to adapt to new research developments. Indicator substances are single, defined substances which are easy to monitor due to existing knowledge on analytic methodologies. The detection of an indicator substance in a waterbody reveals the presence of more substances and, thus, points to a larger pollution issue. The advantage of an indicator approach is that costs and complexities are kept to a minimum, and a solid knowledge base is built for further pollution reduction measures.

• Define uniform standards for data quality and storage. Internationally coordinated policy guidelines, which clearly define data gathering and storage methods, and set baselines on what substances to scrutinise, is a necessary policy step in the process of building a robust knowledge base on pharmaceuticals, and modelling future scenarios of concentrations of pharmaceuticals in water.

• Define common standards on how to prioritise contaminants and susceptible water bodies. Because time and resources are not infinite, research must focus on the pharmaceuticals that represent the greatest threat, to the most sensitive and susceptible water bodies and ecosystems. The relative risk of pharmaceuticals should also be compared with other pollutants (e.g. heavy metals, persistent organic pollutants and other contaminants of emerging concern) to achieve improvements in water quality and ecosystems in the most cost effective way. Defining common standards and ranking approaches on how to prioritise contaminants and susceptible water bodies could be helpful in this regard. Several prioritisation approaches have been developed in academia to support decision-making (e.g. (Donnachie, Johnson and Sumpter, 2015[9]; Guo et al., 2016[10]; Roos et al., 2012[11]).

• Establish data exchange platforms. The exchange of, and access to, data of standardised quality is of utmost importance in order to improve knowledge on active pharmaceutical ingredients. It would be a fruitful contribution by the policy community to install a harmonised platform, or an international registry system, where data on pharmaceuticals and other emerging pollutants is stored and available for further research. Such a policy initiative would have to define how public authorities, research institutes, and private companies report data into the platform, and at which time intervals. Several efforts are underway to create platforms for sharing data1.

• Harmonise policy guidelines on analytical methods and risk assessment of pharmaceuticals. Research on analytical methods and risk assessment regarding pharmaceuticals is a growing field; its geographical and disciplinary diversity is important for research innovation. However, it is necessary to integrate knowledge and gain an overview about the latest developments regarding monitoring methods from industry. To that end, existing repositories, data and published literature on pharmaceuticals are often underutilised. And in many cases, the data (ecotoxicity, properties and sales figures) for pharmaceuticals are confidential. In addition, ERAs of pharmaceuticals are not collected in any standardised way and are generally not accessible or searchable in a database. Harmonised analytical methods for ERAs and a coordinated higher-level synthesis of monitoring programmes and risk assessment would be useful for policy making. Synergies with existing harmonisation programmes can be used, such as the OECD’s work on Test Guidelines or the Working Party on Hazard Assessment, RiBaTox2, which assists the ERA, prioritisation and mitigation of contaminants. Other examples include the NORMAN3 network and the EU SOLUTIONS project, which are both working on developing new, easier and more cost-efficient chemical analytical methodologies and software tools. The OECD Mutual Acceptance of Data (MAD) system4 goes some way to achieving the exchange of information between OECD countries and produces savings from the reduction of duplicative testing for the assessment of new pharmaceuticals (OECD, 2019[12]).

4.3.4. Decision- and policy-making under uncertainty

Uncertainty is pervasive in health-care and environmental decision making (OECD, 2005[13]). A key challenge is to combine an evidence informed policy making approach with the need to make decisions under conditions of unpredictability, uncertainty and complexity. In health care and environmental management, the stakes for decisions are high, and may carry financial, health and environmental risks and rewards. How can decision making be transformed to cope with uncertainty and avoid paralysis? Evidence, including information on whether a new policy or technology presents value for money, plays a key part in aiding decision makers to make informed choices.

Opportunities to enhance understanding (and reduce uncertainties) on pharmaceuticals in the environment include: harmonisation of environmental monitoring and risk assessment approaches; better data quality and gathering; forecasting and scenario development; heightened transparency and sharing of information; integrated planning; and improved accessibility to tools and guidance. However, evidence is not always available to make informed decisions, and even when it is, some uncertainty will remain. The overarching imperative and responsibility for decision makers is to make decisions, even if on poor quality evidence. To defer consideration of a matter until the perfect evidence is available is, in effect, to decide.

As part of the ERA process and the authorisation of new pharmaceuticals, it is important to capture uncertainties and factor them into decision-making and development of policy responses to mitigate adverse environmental effects. Precautionary measures should be explored when scientific evidence is uncertain and when the possible consequences of not acting are high. For example, it is worthwhile considering a more proactive policy approach where future concerns are anticipated before any major environmental, health or economic consequences are felt, particularly because the damage caused at the population and ecosystem levels can take years to repair. This is particularly relevant to pharmaceuticals identified as high-risk as part of the marketing authorisation process (or post-authorisation) and the development of mitigation measures to minimise environmental impact.

Action should be in line with wider development objectives of safeguarding consumer, health and environmental protection, and supporting the principles of circular economy. Measures taken should be proportional, non-discriminatory, consistent with comparable measures, based on an examination of the potential benefits and costs of action or lack of action, subject to review, and capable of assigning responsibility for producing the missing scientific evidence. Scenario development can aid in decision-making, and exploring plausible benefits and consequences of precautionary measures and a range of policy options (Box 4.1).

Box 4.1. Scenario development and testing as a means to manage uncertainties

Despite the uncertainties surrounding pharmaceuticals in the environment (e.g. ecotoxicological effects, population dynamics, new pharmaceutical development, innovations in diagnostics and health care services, global environmental change), scenario development and resilience modelling can help in planning and testing long-term policy options for water security, and healthy humans, animals and environment (OECD, 2018[14]). Scenarios can inform today’s thinking about strategic decisions through exploring different possible futures. This allows decisions to be stress-tested against whether they lock-in trajectories towards less desirable end states, and/or consideration of strategies that are robust to alternative directions (OECD, 2018[14]). Potential scenario choices may reflect:

• improved attitudes toward sustainability, circular economy and green pharmacy

• an innovative future in health services and diagnostics, reduction in chronic disease, and wastewater treatment technologies

• various IPCC climate change scenarios which effect: temperature and rainfall variability; stress on ecosystems and the services they provide; frequency and intensity of natural disasters; disruption of wastewater, drinking water and health care services; and the occurrence, rate and spread of disease

• financial constraints that for whatever reason may impede investment opportunities in WWTP and improved environmental performance

• uncontrolled consumerism where economic growth, intensive agriculture and aquaculture production, and health care is pursued with little regard for the environment or social equity

• various population scenarios affecting pharmaceutical consumption, including level of ageing, life expectancy and urbanisation

• business as usual, extrapolating current trends and policy approaches.

Scenario development needs to be an inclusive and participatory activity, to ensure that a wide range of stakeholder views are taken into account; this will make the scenarios more robust and realistic (OECD, 2018[14]).

Data and integrated planning with stakeholders at the basin scale can help set the ambition for improved water quality, and provide the basis for understanding the total financial spend requirements, and the relative priorities of different objectives. The full breadth of the evidence base can be aggregated so that a complete picture is presented of the state of the environment in the basin, together with current and future pressures and how these interact on society and the economy. Integrated planning can help to determine the type of policies to mitigate adverse effects, including the type and level of charges to recover costs, based on polluter or user pays principles to recover costs. Inevitably, this process will result in trade-offs, but these can be understood and arrived at through a negotiated process with stakeholders (OECD, 2018[14]).

Decision makers need not be limited to “all or nothing” approaches. There are opportunities for low regret options or staged roll-out of new policies. Options which are scalable and can be adopted incrementally will be able to respond better as more certainty emerges about the future. Low regret options may include: prevention of infection with improved sanitation and hygiene practice and education (therefore reducing the need for antibiotics and other pharmaceuticals); reduction of unnecessary use and release of antibiotics and hormones used for preventative measures and as growth promoters in agriculture and aquaculture; reduction of self-prescription and illegal sales of pharmaceuticals; and reduction of unknowns on relationships between pharmaceuticals, and human and environmental health. A summary of short- and medium-term measures for reduction of pharmaceuticals in the environment is provided in Table 4.3.

Table 4.3. Short- and medium-term options for reduction of pharmaceuticals in the environment
Short-term options	Long-term options
Develop monitoring programmes and incidence reporting of APIs in the environment, and their impact on human and ecosystem health. Utilise innovative monitoring and modelling techniques and methodologies	Review and revise the pharmaceutical authorisation process and ERA guidelines to improve environmental risk management of APIs. Include consideration of environmental risks in the risk-benefit analysis of authorisation of new pharmaceuticals. Ensure identified environmental risks are translated into enforced mitigation measures
Assess, map and prioritise APIs and water bodies of highest concern. Model projected risks based on future trends and potential scenarios in population dynamics	Require inclusion of ERA and effluent discharge data in sustainability and environmental reports of pharmaceutical manufacturing companies
Ensure identified environmental risks and impacts post-marketing are reported and ERAs are updated. Establish a centralised database with independent regulatory oversight to share ERA and API data	Factor pharmaceutical risks into drinking water safety plans
Avoid unnecessary prescriptions with improved diagnostics	Develop environmental criteria for green public procurement of pharmaceuticals
Avoid/ban/restrict unnecessary treatment (e.g. veterinary antibiotics for preventative measures and hormones as growth promoters)	Develop environmental criteria for good manufacturing processes. Reduce discharge of APIs in effluent from pharmaceutical manufacturing plants to below safe levels (e.g. PNEC concentrations)
Improve hygienic standards in hospitals and stables and other farming activities	Investigate eco-labelling of over-the-counter pharmaceutical products to improve consumer awareness of environmental impact
Roll out education campaigns to avoid disposal of pharmaceuticals via sink or toilet, or inappropriate animal manure management	Investigate the feasibility of prescription of environmentally-friendly pharmaceutical alternatives
Establish regular education and training of human and animal health practitioners and staff
Improve health and well-being as a preventative measure (e.g. prophylactic vaccination)
Incentivise green pharmacy, biological therapies, personalised and precision medicines. Research galenics to maximise absorption of drugs and minimise the excretion of APIs
Mandate public take-back schemes for unused pharmaceuticals
Develop technologies to remove pharmaceuticals in WWTPs, and cost-benefit analysis and financing options
Notes: API: Active pharmaceutical ingredient. ERA: Environmental Risk Assessment. PNEC: Predicted no effect concentration. WWTP: Wastewater treatment plant.
Source: Author

4.4. A life cycle, multi-sector approach: Experience from selected OECD countries

Several countries have developed national action plans to address pharmaceuticals in the environment and have started a multi-sector dialogue to tackle the problem. At the EU level, a Strategic Approach to Pharmaceuticals in the Environment places an emphasis on sharing good practices, on cooperating at international level, and on improving understanding of the risks. It identifies actions for stakeholders throughout the pharmaceutical life cycle.

Common denominators in these plans are that actions and recommendations place a high importance on the exchange of data and knowledge between different sectors, and on education and communication. Each of these plans advocate for action throughout the life cycle of pharmaceuticals, with a strong emphasis on source-directed and use-oriented approaches (as opposed to end-of-pipe treatment options).

4.4.1. Germany: a multi-stakeholder dialogue to reduce contaminants of emerging concern in water

Germany has developed a multi-stakeholder dialogue to facilitate action on The Trace Substance Strategy. The dialogue was established 2014 on behalf of the Federal Health Ministry, coordinated by the Federal Environment Agency and with contributions from the Federal Institute for Drugs and Medical Devices. A key output of the dialogue was Recommendations for reducing micropollutants in water (UBA, 2018[6]), which provides specific recommendations to reduce human and veterinary pharmaceuticals in the environment. A summary of the recommendations is provided in Table 4.4. Some of these actions offer effective and immediately-feasible options to reduce human and veterinary pharmaceuticals in the environment, but most are expected to become effective only in the medium- to long- term horizon.

Table 4.4. Assessment matrix of selected source-directed and use-orientated measures to reduce human and veterinary pharmaceuticals, Germany
Measures	Effectiveness	Specific or Broad spectrum	Costs	Horizon	Feasibility
Developing and harmonising risk-reduction measures within the authorisation process	-/0	S	0/+	2	+
Banning PBT and vPvB substances in veterinary medicinal products	+	S	n.d.	2	-
Researching environmentally friendlier APIs or dosage forms	-	S	-	3	0
Target-group specific communication and information	0	B	+	2-3	+
Running information campaigns on the proper disposal of unused drugs	+	B	+	2-3	+
Over-the-counter regulatory system for APIs	+	S	0	3	+
Considering widening the requirements for prescription taking into account environmental concerns	n.d.	S	0	n.d.	0
Research on how modifying ‘the right to dispense’ many potentially affect the use of veterinary pharmaceuticals	n.d.	S	0	n.d.	0
Note: Expected effectiveness: (+ high), (0 moderate), (- low), (n.d. no data, uncertain), (S: measure is substance-specific), (B: measure has a broad spectrum effect), Costs: (+ low), (0 moderate), (- high), (n.d. no data, uncertain), Effectiveness horizon: (1 = short term < 5 years), (2 = medium term < 10 years), (3 = long term > 10 years), Feasibility: (+ immediately feasible), (0 not yet immediately feasible), (- still clear deficits/need for action (need for research, funding or acceptance).
Source: (UBA, 2018[6]).

4.4.2. France: Priority actions to reduce pharmaceuticals in water and empower local stakeholders5

In 2016, the second French National Plan against Micropollutants was launched as The National Plan against Micropollutants 2016-2021 (Ministry of Ecological and Solidarity Transition, 2014[15]). The Plan builds on three objectives: i) reduce micropollutants, ii) acquire knowledge, and iii) prioritise action. Some of the key actions in the plan that specifically target pharmaceutical residues include:

• Implement the national guide on handling pharmaceutical waste and liquid waste in healthcare facilities

• Assess the management of unused pharmaceuticals in healthcare facilities and suggest evolutions

• Assess the relevance of the Swedish ranking of active substances (Box 3.2, chapter 3) based on their impact on the environment and the acceptability of such a ranking for pharmaceuticals by health professionals in France

• Assess mixture effects of micropollutants on aquatic flora and fauna, especially those linked with endocrine disruption

• Work on data sharing to improve knowledge of hazards and exposure regarding human and veterinarian pharmaceutical residues in waters

• Derive threshold values and methodologies to better assess water quality taking into account endocrine disruptors and relevant metabolites

• Identify metabolites of pharmaceutical products and assess analytical capacities in order to establish an early monitoring system.

Despite its non-binding nature, the Plan is a first step in the preparation of a broader toolbox of legally-binding policies in the future.

Recognising that CECs may not be great candidates for classic water quality regulation, the French Ministry of Ecological and Solidarity Transition established a five-year (2013-2018) subsidy programme (EUR 10 million) aimed at stimulating new innovative projects to manage CECs and empower local stakeholders.

A total of 13 projects were selected, targeting various stages of the life cycle of CECs, including management of: domestic point source pollution, health-related practices, and diffuse source pollution. A common denominator of the projects was that they all focus primarily on source-oriented solutions, a strategy that the Plan emphasises. All projects include solutions for better diagnostics, cost-efficient reduction of CECs and changes in practices of various stakeholders. In addition to encouraging innovation, the subsidy programme provides a platform promoting collaboration between various stakeholders in order to create an integrated strategy. It also takes into account socio-economic aspects to encourage stakeholders to accept practice changes. While the exercise has shown that there is potential for innovation at the local level, communication of the benefits and replication at the national scale remain a challenge.

4.4.3. Sweden: Increased consideration of the environmental risks of human pharmaceuticals

In Sweden, Parliament approved “Greater environmental considerations in international and EU pharmaceutical legislation by 2020” (now extended to 2030). Four specific measures are considered appropriate to reduce the environmental impact caused by the production and use of pharmaceuticals: including i) increase access to information on the impact of medicinal products; ii) establish more appropriate and better environmental testing, and revise the ERA guidelines; iii) consider environmental risks in risk-benefit authorisation of human pharmaceuticals in order to manage risk mitigation; and iv) establish mandatory minimum requirements for good pharmaceutical manufacturing practices.

In 2018, the Government commissioned the Swedish Medicine Agency to establish a knowledge centre for pharmaceuticals in the environment. The centre aims to gather Swedish actors and provide a platform for dialogue and cooperation. A budget of SEK 5 million has been allocated by the government (Government Offices of Sweden, 2017[16]).

4.4.4. United Kingdom: A “whole catchment” approach to managing pharmaceuticals in the environment6

In 2010, the UK Water Industry Research programme, with the support and collaboration of government and environmental regulators, initiated a multi-million pound Chemical Investigation Programme (CIP) into the scale of challenges to meeting existing Environmental Quality Standards (EQSs) detailed in the WFD, as well as emerging concerns such as pharmaceuticals.

The objectives of the CIP are to: i) gain definitive evidence of the true extent of discharges from WWTPs of both currently regulated chemicals and those of emerging concern; ii) explore mitigation options, such as new technologies; and iii) appraise options including their economic and environmental costs. In parallel, the UK Environment Agency and the Department for Environment, Food and Rural Affairs have been developing evidence on the economic impact of chemicals in treated effluents and receiving water bodies, and the benefits of mitigation. Fourteen pilot trials of new wastewater treatment processes are being conducted as part of the CIP (e.g. ozone, sand filtration, membrane bioreactor). The CIP is due for completion in 2020.

General preliminary findings of the CIP, which may have relevance to the future management of pharmaceuticals in the UK, include:

• A number of pharmaceuticals are statistically likely to be exceeding PNECs in the water environment7. Diclofenac, ibuprofen, EE2, propanol, erythromycin, azithromycin, clarithromycin and ranitidin were all detected at universal, or near-universal, high levels with high or very high severity, and with a high confidence of exceedance of PNEC. Other pharmaceuticals detected with a significant number of face value fails were E1, E2, ciprofloxacin, fluoxetine and metformin.

• The source of most pharmaceuticals is domestic. However, whole catchment studies have revealed that WWTP effluent is not always the main contributor. Water quality upstream of WWTPs can be poor due to diffuse sources of pollution. This suggests that catchment or source-directed approaches may be required for basic efficacy, rather than relying on end of pipe mitigation.

• Previous regulatory source-directed measures implemented in the UK have worked for other CECs. Notably, time series data demonstrates that concentrations of brominated diphenylethers (flame retardant) in WWTP effluents is declining by approximately 30% every five years in response to a ban of brominated diphenylethers, which was implemented over a decade ago. This clearly has implications for future investment in treatment technology; pharmaceuticals may also respond more quickly to source-directed approached than more ubiquitous legacy contaminants.

• The pilot trials of advanced wastewater treatment processes showed that removal of hormones was consistently good across all trialled processes, but removal of other pharmaceuticals was seen as variable. The new technologies currently remain subject to technical issues and contaminant removal mechanisms are not fully understood.

• Concerns remain within the water industry and regulatory agencies that advanced wastewater treatment processes are expensive to construct, operate, and maintain (in terms of both money and carbon). A high-level preliminary estimate of the costs of widespread “end of pipe” investment to tackle particular pharmaceutical concerns in the UK was made in 2013 at GDP 27-31bn over 20 years. Evaluating these costs with respect to the benefits is challenging, not least because of the underlying uncertainties surrounding the adverse effects to flora, fauna and humans of pharmaceuticals present in the water environment.

4.4.5. The Netherlands: “Chain approach” to pharmaceutical residues in water8

In the Netherlands, a holistic “chain approach” is being used to address the issue of pharmaceutical residues (both human and veterinarian) in water. The programme started in 2016 and considers the entire cycle, from the source to the end of the pipe, and supports various stakeholders in their voluntary efforts to reduce pharmaceutical pollution in water. When initiating the programme, four ‘rules of the game’ were established and agreed upon: 1) patients must keep access to the medicines they need (i.e. medicines shall not be banned), 2) all actions taken in the pharmaceutical chain should have a pragmatic approach and should be aimed at solving problems (measures for the sake of appearances to be avoided), 3) all stakeholders act where they can, within acceptable costs, and 4) stakeholders should not wait for other stakeholders to take the first step.

The two main drivers behind the programme were improved water quality and protection of drinking water. It is estimated that 140 tonnes of pharmaceuticals are discharged from WWTPs each year into Dutch waters. The programme links together the health care and water sectors9 in the Netherlands. Although striving for the same goals, it quickly became clear that stakeholders were unfamiliar with each other’s worlds, pinpointing the importance of cross-sector collaboration. An ongoing discussion is being held about the costs of potential measures and who should pay. This has raised questions regarding the applicability of the Polluter Pays Principle and who should be considered the polluter. Is it the patient who excretes the pharmaceutical residues, is it the doctor who prescribed the pharmaceuticals, the pharmacist that delivered them, or the industry that designs and produces them?

A total of 17 possible measures to reduce or mitigate the impacts of human pharmaceutical residues in water has been identified for further investigation (Table 4.5). The challenge will be to take measures at all relevant stages of the pharmaceutical chain, and to keep the enthusiasm that all stakeholders have shown to date.

Table 4.5. Examples of possible measures to reduce medicine residues at different stages of the pharmaceutical chain identified by the Netherlands
Possible measure	Stage in the pharmaceutical chain	Sector responsible
Identify pharmaceuticals that have negative environmental effects	Environmental monitoring	Water authorities and drinking water sector
Identify effects of veterinary pharmaceuticals in water	Environmental monitoring	Water authorities
Quantify emissions of veterinary pharmaceuticals to surface water and groundwater	Environmental monitoring	Several (new chain)
Develop ‘green medicines’ that have less environmental impact	Development & authorisation	Pharmaceutical companies and research institutions
Develop management system for environmental risks of medicines (Eco Pharmaco Stewardship)	Development & authorisation	Pharmaceutical companies
Improve access to environmental data on APIs	Development & authorisation	Pharmaceutical companies, authorising agencies, (international) authorities
Identify pairs of pharmaceuticals with same medic effect, but different environmental impact	Prescription & consumption	Several; led by Ministry of Water Management
Research prevention and adequate use of pharmaceuticals	Prescription & consumption	Ministry of Health
Identify possible measures in the phase of ‘prescription and use’	Prescription & consumption	Health care sector and water sector
Establish collection schemes of surplus pharmaceuticals	Waste & wastewater treatment	Municipalities and chemists
Evaluate improved treatment at WWTPs, including overview of existing innovative treatment options and overview of costs	Waste & wastewater treatment	Water authorities and research institutions
Identify WWTPs with highest impact on aquatic ecology and drinking water sources	Waste & wastewater treatment	Water authorities
Start pilots with improved treatment at existing WWTPs	Waste & wastewater treatment	Water authorities and research institutions
Develop communication instrument to explain the pharmaceutical chain	Cross cutting	Ministry of Water Management
Develop communication strategy and execute	Cross cutting	Led by Ministry of Water Management
Learn from best practices abroad	Cross cutting	Led by Ministry of Water Management
Put issue on international agenda (e.g. river basin commissions of Rhine and Meuse, European Commission, others)	Cross cutting	Led by Ministry of Water Management
Source: Marc L. de Rooy, Ministry of Infrastructure and Water Management, Netherlands.

4.4.6. European Union: A Strategic Approach to Pharmaceuticals in the Environment

In March 2019, the European Commission adopted the EU Strategic Approach to Pharmaceuticals in the Environment (EC, 2019[17]). The approach was informed by a number of studies and reports, and the outcomes of extensive public and targeted consultation. It takes account of international environmental commitments (such as SDG 6 on water and sanitation, and the EU One Health Action Plan against AMR) and circular economy considerations.

The Approach identifies six action areas concerning all stages of the pharmaceutical life cycle, where improvements can be made. It addresses pharmaceuticals for both human veterinary use.

1. 1. Increase awareness and promote prudent use of pharmaceuticals

2. 2. Support the development of pharmaceuticals intrinsically less harmful for the environment and promote greener manufacturing

3. 3. Improve environmental risk assessment and its review

4. 4. Reduce wastage and improve the management of waste

5. 5. Expand environmental monitoring

6. 6. Fill other knowledge gaps

The Approach is not legally binding, but may set the future direction of policy as and when related EU directives and legislation are updated (e.g. the Industrial Emissions Directive, Directive for Medicinal Products for Human Use, Directive for Veterinary Medicinal Products, Codes of Good Agricultural Practice, Water Framework Directive and the Urban Wastewater Treatment Directive).

A collection of policy briefs from the EU project “SOLUTIONS for present and future emerging pollutants in land and water resources management” compiles major findings and recommendations for policy makers and other stakeholders (see: https://www.springeropen.com/collections/solutions).

References

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[8] Ågerstrand, M. et al. (2017), “An academic researcher’s guide to increased impact on regulatory assessment of chemicals”, Environmental Science: Processes and Impacts, Vol. 19/5, pp. 644-655, https://doi.org/10.1039/c7em00075h.

[9] Donnachie, R., A. Johnson and J. Sumpter (2015), “A rational approach to selecting and ranking some pharmaceuticals of concern for the aquatic environment and their relative importance compared with other chemicals”, Environmental Toxicology and Chemistry, Vol. 35/4, pp. 1021-1027, https://doi.org/10.1002/etc.3165.

[17] EC (2019), European Union Strategic Approach to Pharmaceuticals in the Environment, European Commission, Brussels, http://ec.europa.eu/health/human-.

[16] Government Offices of Sweden (2017), Regeringen satsar för att få bort läkemedelsrester från miljön, https://www.regeringen.se/artiklar/2017/09/regeringen-satsar-for-att-fa-bort-lakemedelsrester-fran-miljon/ (accessed on 3 August 2018).

[10] Guo, J. et al. (2016), “Toxicological and ecotoxicological risk-based prioritization of pharmaceuticals in the natural environment”, Environmental Toxicology and Chemistry, Vol. 35/6, pp. 1550-1559, https://doi.org/10.1002/etc.3319.

[3] Haddad, T., E. Baginska and K. Kümmerer (2015), “Transformation products of antibiotic and cytostatic drugs in the aquatic cycle that result from effluent treatment and abiotic/biotic reactions in the environment: An increasing challenge calling for higher emphasis on measures at the beginning of the pipe”, Water Research, Vol. 72, pp. 75-126, https://doi.org/10.1016/j.watres.2014.12.042.

[7] Kümmerer, K. (2007), “Sustainable from the very beginning: rational design of molecules by life cycle engineering as an important approach for green pharmacy and green chemistry”, Green Chemistry, Vol. 9/8, p. 899, https://doi.org/10.1039/b618298b.

[5] Küster, A. and N. Adler (2014), “Pharmaceuticals in the environment: Scientific evidence of risks and its regulation”, Philosophical Transactions of the Royal Society B: Biological Sciences, Vol. 369/1656, https://doi.org/10.1098/rstb.2013.0587.

[1] Metz, F. and K. Ingold (2014), “Sustainable wastewater management: Is it possible to regulate micropollution in the future by learning from the past? A policy analysis”, Sustainability (Switzerland), Vol. 6/4, pp. 1992-2012, https://doi.org/10.3390/su6041992.

[15] Ministry of Ecological and Solidarity Transition (2014), National plan against micropollutants 2016- 2021 to preserve water quality and biodiversity, https://www.ecologique-solidaire.gouv.fr/sites/default/files/National%20plan%20against%20micropollutants%202016-2021%20to%20preserve%20water%20quality%20and%20biodiversity.pdf (accessed on 3 August 2018).

[12] OECD (2019), Saving Costs in Chemicals Management: How the OECD Ensures Benefits to Society, OECD Publishing, Paris, https://dx.doi.org/10.1787/9789264311718-en.

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Notes

← 1. Several efforts are underway to create platforms for sharing data, such as: iPiE Summary Database Search (iPiE*Sum) which provides high-level summarised access to the properties, environmental fate characteristics and ecotoxicity of APIs which are collected during the course of the iPiE project from 2015 to 2018, WikiPharma (a database of ecotoxicity data of pharmaceuticals from peer-reviewed articles); the German Environment Agency database for environmental measurements of pharmaceuticals; the EU Information Platform for Chemical Monitoring (IPCHEM) which populates European data on chemical exposure and its burden on health and the environment; the Global Portal to Information on Chemical Substances (eChemPortal) which provides access to information on chemical properties and (eco)toxicity; and U.S. EPA’s databases (Chemistry dashboard, IRIS, Toxcast).

← 2. See https://solutions.marvin.vito.be/.

← 3. NORMAN is a self-sustaining network of reference laboratories, research centres and related organisations enhances the collection and exchange of data on CECs and promotes the validation and harmonisation of common measurement methods and monitoring tools.

← 4. See http://www.oecd.org/env/ehs/mutualacceptanceofdatamad.htm

← 5. Summary of case study provided by Olivier GRAS, Ministry for the Ecological and Inclusive Transition, France.

← 6. Summary of case study provided by Nick Haigh, UK Department for Environment, Food and Rural Affairs (Defra). The author acknowledges the help and material provided by colleagues in Defra and UK Water Industry Research. (Comber et al., 2018[18]).

← 7. At least based on point data, which do not necessarily imply failures for the whole water body

← 8. Summary of case study provided by Marc L. de Rooy, Ministry of Infrastructure and Water Management, Netherlands.

← 9. The programme is led by the Ministry of Infrastructure and Water Management, in collaboration with representatives from the Union of Regional Water Authorities, the Association of Drinking Water Companies, the Ministry of Health, Welfare and Sport, and research institutes. The Ministry of Agriculture, Nature and Food Quality was also closely involved because of the importance of veterinary pharmaceuticals.

4. Recommendations for the management of pharmaceuticals in freshwater