The profound impact of pharmaceuticals on the environment has been acknowledged for decades. In the EU, two key mechanisms that assess this risk are the Environmental Risk Assessment (ERA), and Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH). As both frameworks are under assessment, this article looks at the key considerations within the ERA.

 

Regulatory Rapporteur

 

March 2023   |   Volume 20   |   No.3

 

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EU environmental regulation landscape

Environmental risk assessment (ERA)

ERAs were introduced by the EMA in 2006 (EMEA/CHMP/SWP/4447/00) following a seven-year consultation. ERAs are featured in Module 1.6 of the Common Technical Document format with associated labelling and wording to be included in the relevant text. Absence of an ERA from the application can be accepted in certain cases such as for generic medicines. The ERA requirement is split into two phases:

  • Phase 1: Estimation of exposure.
  • Phase 2: Environmental Fate and Effects Analysis.

In Phase 1, an assessment is made of the likely environmental impact of the product. This is conducted through screening for likely persistence, possibility for bioaccumulation, and predicted toxicity. Under the rules of the Convention for the Protection of the Marine Environment of the North East Atlantic (OSPAR), substances of concern are represented by a unitless scale of relative ability to absorb soil and living organisms.

The n-Octanol/ water partition coefficient – Kow – offers a ratio of the concentration of a given substance in the two solvents at a given temperature. LogKow is an important indicator of the distribution of a substance in an environment, and a value below 4.5 assumes that organism lipid affinity is insufficient for bioaccumulation. Above this figure, the ERA guidance expects stepwise screening according to the relevant European Chemicals Bureau guidance.

The Predicted Environmental Concentration (PEC) in Phase 1 is limited to the aquatic environment and makes broad assumptions regarding route of entry into the water system, patient metabolism and so on. This is arbitrary given the many ways in which the drug substance could enter the water system. A resulting action to move to Phase 2 is only required if the PEC value in the surface water model is equal or above 0.01µg/L. The exception to this is in the case of drug substances that may affect vertebrates, or lower order animals, at weaker concentrations.

In Phase 2, environmental fate [1]and effects analysis is conducted by assessing that ratio between PEC and predicted-no-effect-concentration (PNEC). At this point, experimental testing is required in accordance with protocols issued by the EC, the Organisation for Economic Cooperation and Development (OECD), the International Organisation for Standardisation (ISO) as well as compliance with Good Laboratory Practices (GLP). The expectations are that all relevant data should be considered including pharmacodynamics and metabolism.

Assessment of impact is made according to a tiered system:

  • Tier A considers physicochemical properties and the fate of the substance in the environment.
  • Tier B is enacted if a potential risk has been identified in Tier A and refines PEC and PNEC for metabolic factors, although further transformation in the environment is not taken further unless experts consider this necessary.

Analysis conducted in Tier A also considers ground water systems.Toxicity testing is intended to predict non-effect concentration in water and is conducted according to OECD protocols listed in the guidance. The PNEC is calculated and adjusted from the no-observable effect using an assessment factor – the degree of uncertainty in extrapolation from test data.

In Tier B, a series of refinements are applied to the environmental fate analysis and surface water assessment. These include parameters such as dilution in water systems, sewage treatment capacity, and suspended matter absorption. Effects on other systems such as sediment dwelling organisms and specified microorganisms – Ps. putida – are also considered. Lastly, a terrestrial (soil and sludge) environmental fate and effect analysis is conducted unless the substance is readily biodegradable. Tier B therefore follows from the considered routes of excretion and long-term toxicity.

The existing guidance also includes labelling considerations which are aimed at minimising material discharge, and in particular appropriate disposal measures.

While the 2006 ERA guidance was a considerable step forward at the time, it is limited in scope and does not capture all the potential ways in which pharmaceutical products may impact upon the environment, particularly as the primary focus is on the drug substance.

REACH

The EU chemicals regulation ‘REACH’ (Registration, Evaluation, Authorisation and Restriction of Chemicals, EC 1907/2006) came into force in 2007 to place the responsibility for the management of chemicals’ intrinsic risk properties on manufacturers. REACH has been covered in detail in previous editions of Regulatory Rapporteur so it will only be summarised here. It applies to all chemical substances – including pharmaceuticals – and is based on a risk assessment built around data collection of properties and hazards. Chemicals must be registered, and restrictions can be applied to those with established risks. This applies to any chemical substance being brought into the EU.

What does the future of regulation in Europe look like?

Ten years after publication of the ERA guidance, the Safety Working Party (SWP) of the EMA issued a concept paper – EMA/CHMP/SWP/65429/2016 – to consult over updates. Areas tackled by this concept paper were the loose justification for perceived lack of environmental impact, sharing of information between stakeholders to make informed decisions on the environmental impact of a product, and to address holistically how products might appear in the environment from a variety of sources. Furthermore, it included a review of the tiered approach strategy, and triggers for further assessment such as consumption data. It was acknowledged at the release of the concept paper that current scientific knowledge should be incorporated.

Toxicity testing is intended to predict non-effect concentration in water and is conducted according to OECD protocols listed in the guidance…

In 2018, a new draft ERA[2] was released for consultation. The new guidance included a mandatory requirement for an ERA. It would be based on ‘the use of the product and the physico-chemical, ecotoxicological, and the fate properties of its active substance.’ The scope has been expanded to include a wider consideration of drug substance effects across aquatic, terrestrial, and soil environments. Finally, the applicant was required to consider precautionary or risk mitigation measures.

The first notable change in the draft guidance was a consideration of the bioaccumulative and toxic properties of active substances regardless of the levels of exposure. Hence potential effects are assessed on the intrinsic properties of the active substance. While there may be a case for not submitting ERA studies, the guidance now includes decision trees to make specific cases for not doing so – this was absent in the previous iteration.

Risk assessment is a key element throughout and expands on the principles currently in place, except for the likelihood of exposure. Risks are included within the Summaries of Product Characteristics wording along with mitigation. The risk remains based on unmetabolised parent molecule but calls out prodrugs and combination products for specific consideration.

There have been significant updates to the test mechanisms, treatment of impacted systems, and calculations of test results. This process demonstrates a developing appreciation of the increasing levels of detail to which companies will need to examine the risks their products may pose in the future. Required labelling also contains stronger wording than before, in order to educate a pharmaceutical’s user.

The environmental impact of products covered by the updated ERA guidance remains limited to the active substance and not all elements of the medical product or its packaging. It is only required in applications for new products and there is currently no requirement for generic products, or follow-on applications, to consider their environmental impact.

The draft guidance remains unpublished – the COVID-19 pandemic having delayed much of the EMA’s work. The published schedule has been updated to expect a new release imminently – Final programming Document 2022-2024, EMA/32271/2022.

With respect to REACH, the EC is currently working on an impact assessment and revision to this regulation based on a recent consultation.

Conclusion

Within the EU, the ERA mechanism to review the impact of new products has been in place since 2006. As things stand, the now 16-year-old framework is currently not fit for purpose when the full environmental impact of a pharmaceutical is considered across a product’s lifecycle. With public health concerns now coming to the forefront across many industrial sectors, it is likely that additional regulation will soon come to pharmaceuticals. Indeed, the EC Directorate-General for the Environment has recently published its strategic approach to pharmaceuticals in the environment, indicating the legislative direction of travel.

In 2016, an 18-month timeline was proposed for an updated version (post-consultation) which resulted in the SWP’s new draft being released in November 2018. Currently, it has not been formally issued. But the length of time for new guidance to be drafted – and then put into practice – can quickly be out of step with rapidly changing public and political opinion.

It is worth noting that companies are increasingly setting internal standards for their environmental, social, and governance, and are consequently leading in areas such as recycled packaging and water stewardship. Regulators and stakeholders have a role in learning from this direction of travel and agreeing regulation based on best practice, which should go hand in hand with advancement in the knowledge base.

References

[1] Environmental fate encompasses what happens to a substance after it has been released into the environment and is based on the inherent properties of the substance and the environmental conditions. This predominantly concerns the transportation, transformation and distribution of a substance and consists of degradation processes and partitioning between different compartments – including biota.

[2] EMA. (2015) Environmental risk assessment of medicinal products for human use – Scientific guideline. Available at: Environmental risk assessment of medicinal products for human use - Scientific guideline | European Medicines Agency (europa.eu)

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