Environmental aspects of the authorisation of human medicinal pro | Umweltbundesamt

The UBA is legally mandated to assess environmental risks as part of the market authorisation process for human and veterinary medicinal products and to impose environmental protection measures when necessary. If risk mitigation measures are not feasible for a veterinary medicine, the UBA can refuse authorisation for environmental reasons. So far, human medicinal products are always approved, even if they pose an environmental risk.

Legal framework

The authorisation and trade of medicinal products for humans and animals are regulated by the laws governing the circulation of medicinal products (Human Medicinal Products – Medicinal Products Act, AMG; Veterinary Medicinal Products – Veterinary Medicinal Products Act, TAMG). The purpose of these laws is to ensure the quality, efficacy, and safety of medicinal products in the interest of proper pharmaceutical supply. The issue of pharmaceutical residues in the environment was first addressed by legislators in the mid-1990s. Since 1998, the UBA has been involved as a co-evaluating authority in the approval process for veterinary medicinal products. It assesses the potential environmental risks posed by veterinary medicines. The UBA determines which veterinary medicines may only be authorised with conditions to protect the environment and, under certain circumstances, can refuse market authorisation. For human medicinal products, refusal of market authorisation on environmental grounds is not currently provided for.

It was only with the EU Directive 2001/83/EC, amended by Directive 2004/27/EC, that an assessment of possible environmental impacts became mandatory for human medicines. Since then, documents enabling the evaluation of the potential environmental risk of a medicinal product must be submitted as part of the approval process. The authorisation of human medicinal products may also be subject to conditions for environmental protection.

The Community Code 2001/83/EC and EU Regulation 726/2004/EC set out the legal requirements for the approval of new human medicines. Since 7 July 2019, the new Regulation (EU) 2019/6 of the European Parliament and the Council of 11 December 2018 on veterinary medicinal products has been in force, repealing Directive 2001/82/EC.

The European pharmaceutical legislation reform strengthened the environmental safety requirements for human and veterinary medicines through the amending Directives 2004/27/EC and 2004/28/EC. Germany implemented these EU regulations in 2005 through its Medicinal Products Act, which governs the import, export, and circulation of medicinal products.

Laws and regulations are listed here: Legal basis for the environmental assessment of pharmaceuticals (in German)

Process of environmental risk assessment of medicinal products for human use

Companies wishing to place medicinal products for human use on the marketmust conduct an Environmental Risk Assessment (ERA) and submit it with their application for authorisation. The requirements for the ERA are outlined in a guideline issued by the European Medicines Agency (EMA). This guideline was first adopted by the Committee for Medicinal Products for Human Use (CHMP) in June 2006 and was replaced by a revised version on 1 September 2024 (1). The guideline:

• specifies which medicinal products require an ERA. For example, herbal substances, vitamins, and amino acids are exempt.
• describes the testing strategy and scope of testing.
• defines the specific data requirements for environmental exposure, fate, and behaviour of the active substance as well as its ecotoxicity.

In principle, the active substance is assessed. The environmental evaluation consists of Risk Assessment and Hazard Assessment (PBT/vPvB Assessment). Both assessments are conducted using a two-tier process.

Phase I Risk Assessment

The Phase I risk assessment must always be carried out. It follows a decision tree to identify products considered environmentally relevant, for which a more detailed Phase II risk assessment is required.

A Phase II risk assessment is not required in the following cases:

• The active substance is a naturally occurring substance.
• It is an application for a generic product, where the same active substance has already been assessed, the standard market penetration factor was used, and no increase in environmental exposure compared to the existing environmental assessment is expected.
• The active substance is a non-natural peptide or protein that is readily biodegradable.

For products not covered by the conditions mentioned above, the need for a Phase II risk assessment depends on the Predicted Environmental Concentration in surface water (PECsw). The trigger value, known as the "action limit," is 0.01 micrograms per litre. If the calculated PECsw exceeds this limit, a refined Phase II risk assessment must be submitted.

In the initial calculation, the maximum daily dose of the active substance, a market penetration factor of 1%, daily water consumption per person, and a dilution factor for the sewage treatment plant effluent into surface water are considered. If the initial PECsw is greater than 0.01 micrograms per litre, the value can be refined by including a market penetration factor specific to the medical indication and the treatment regimen.

If the refined PECsw still exceeds 0.01 micrograms per litre, a Phase II risk assessment is required. Otherwise, the risk assessment ends at Phase I.

For certain pharmaceuticals, such as endocrine-active substances and antiparasitics, environmental risks may exist even below the action limit of 0.01 micrograms per litre. For these substances, a detailed Phase II risk assessment is required regardless of the expected environmental concentration. In the case of substances with specific modes of action, such as endocrine-active substances, a tailored testing strategy is needed, depending on the specific mode of action.

Phase II Risk assessment: In-depth environmental risk assessment

In Phase II, the physico-chemical properties of the active substance are determined based on the data submitted by the applicant, including water and fat solubility and adsorption characteristics. Additionally, the biodegradability of the active substance is assessed, along with its potential toxicity to sewage treatment plant microorganisms, aquatic surrogate organisms, and sediment-dwelling organisms, to determine if there is a possible environmental risk.

Surrogate organisms typically include algae, water fleas, chironomid larvae, oligochaetes, and fish, which are tested in long-term studies. Tests on soil organisms are required only if the active substance has a high affinity for binding to sewage sludge and could be introduced into agricultural soils through sludge application. If the substance has low adsorption potential but high mobility, which could lead to leaching into groundwater, a groundwater risk assessment is necessary.

If the substance is sufficiently fat-soluble, its bioaccumulation potential in organisms must also be investigated. Based on these findings, the potential risk of secondary poisoning through the food chain may need to be evaluated. The environmental concentration calculated in Phase I (PEC) is compared with the Predicted No Effect Concentration (PNEC), which is derived from toxicity tests. The PNEC is determined from the lowest experimentally established No Observed Effect Concentration (NOEC), which is the concentration at which no adverse effects were observed in the tested environmental organism. A safety factor is then applied to this value. If the quotient of PEC and PNEC is greater than 1, an environmental risk is assumed. In such cases, the risk assessment can be refined by incorporating additional data into the PECsw calculation, such as the metabolism of the substance in the body and its degradability in sewage treatment plants, to reduce the PECsw value.

PBT/vPvB Screening

Regardless of the risk assessment, every active substance must undergo a PBT/vPvB screening to determine whether the substance is potentially persistent (P), very persistent (vP), (very) bioaccumulative (B or vB), and toxic (T). These characteristics are independent of environmental concentration, and the effects of long-term exposure are difficult to predict. Therefore, substances exhibiting all three properties are generally considered particularly hazardous. The PBT/vPvB screening follows a decision tree to identify substances that require a definitive PBT/vPvB assessment.

A PBT/vPvB screening is not required in the following cases:

• The active substance is a naturally occurring substance.
• It is an application for a generic product where a PBT/vPvB assessment already exists for the active substance and the current applicant has access to this data.
• The active substance is a non-natural peptide or protein that is readily biodegradable.

For active substances not covered by the above conditions, the need for a definitive PBT/vPvB assessment depends on their logKow value (n-octanol-water partition coefficient), which indicates lipophilicity. If the logKow value is greater than 4.5, a definitive PBT/vPvB assessment is required.

PBT/vPvB assessment

The PBT/vPvB assessment of pharmaceuticals follows the ⁠REACH⁠ guidance on PBT/vPvB assessment (R.11), which should be adhered to as closely as possible (2).

This involves evaluating whether the individual criteria are met based on experimental laboratory studies:

1. Persistence: Assessed through degradation behaviour in simulation studies, such as transformation in water/sediment systems or decomposition in soils.
2. Bioaccumulation: Determined through bioaccumulation studies in fish.
3. Long-term toxicity studies: Conducted on algae, water fleas (Daphnia), or fish.

If any one criterion is not met (e.g., persistence), the subsequent studies for bioaccumulation and toxicity can be omitted, and the substance is classified as non-PBT/vPvB.

Requirements for data quality

Regulatory authorities place great importance on the high quality of data used for the environmental risk assessment of pharmaceuticals. To ensure that only valid and plausible data are included in the evaluation, only studies conducted in accordance with standard test methods from the OECD (Organisation for Economic Co-operation and Development) or ISO (International Organization for Standardization) are typically considered. The submitted studies, as required by the EMEA guideline, must also be complete and conducted in accordance with Good Laboratory Practice (GLP). However, it is also permissible to submit literature data instead of studies, provided they meet a minimum standard of quality, reliability, and informational content. For instance, simple citations of endpoints such as EC50 values are not acceptable, as they do not provide information about the conditions under which the tests were conducted or whether the required plausibility and validity criteria were met. Further information on the regulatory requirements for literature data can be found in the following articles, which can help applicants assess the quality and usability of literature data:

• Moermond, C.T.A.; Kase, R.; Korkaric, M.; Agerstrand, M. CRED: Criteria for reporting and evaluating ecotoxicity data; Environmental Toxicology and Chemistry. 2016, 35, 5, 1297-1309,
• Agerstrand, M.; Kuster, A.; Bachmann, J.; Breitholtz, M.; Ebert, I.; Rechenberg, B.; Ruden, C. Reporting and Evaluation Criteria As Means Towards a Transparent Use of Ecotoxicity Data for Environmental Risk Assessment of Pharmaceuticals. Environ. Pollut. 2011, 159, 2487-2492,
• Küster, A.; Bachmann, J.; Brandt, U.; Ebert, I.; Hickmann, S.; Klein-Goedicke, J.; Maack, G.; Schmitz, S.; Thumm, E.; Rechenberg, B. Regulatory Demands on Data Quality for the Environmental Risk Assessment of Pharmaceuticals. Regul. Toxicol. Pharmacol. 2009, 55, 276-280,

Results of an environmental risk assessment and possible measures

The UBA's experience has shown that environmental risks are less frequently identified in the environmental assessment of human pharmaceuticals compared to veterinary medicines.

One reason is that veterinary medicines often involve pharmaceutical substances from the same classes, such as antiparasitics and antibiotics, which generally pose environmental risks.

In human medicine, active substances for which a risk has been identified in recent years were predominantly endocrine-active, including hormones and neuroendocrine substances. To mitigate the identified environmental risks, the entry of these active substances into the environment should be mitigate to the necessary minimum. However, the regulatory measures available during the authorisation process for pharmaceuticals are limited. The product information accessible to doctors and pharmacists, Section 5.3 provides warnings if an environmental risk has been identified for the active substance or if it is classified as PBT/vPvB. Additionally, all package leaflets contain a disposal notice, which was revised in 2019 as part of the Stakeholder Dialogue on the Federal Trace Substance Strategy:
"Never dispose of medicines via wastewater (e.g. not via the toilet or sink). Ask your pharmacy how to dispose of the medicine if you no longer need it. This helps protect the environment. For more information, visit www.bfarm.de/arzneimittelentsorgung."

The website of the Federal Institute for Drugs and Medical Devices (BfArM) refers users to www.arzneimittelentsorgung.de for an overview of regional disposal regulations.

Further information: Environmentally conscious disposal of leftover drugs

In addition, the package leaflet provides guidelines for the environmentally friendly use of products such as ointments and gels.

Further information: Pain relief gel – questions and answers

References

1. European Medicines Agency (2024). Guideline on the environmental risk assessment of medicinal products for human use: EMEA/CHMP/SWP/4447/00 Rev. 1-Corr.

2. ECHA (2023), Guidance on Information Requirements and Chemical Safety Assessment: Chapter R.11: PBT/vPvB assessment. Version 4.0,