Based on Article 8(3) of Directive 2001/83/EC, the ERA is legally required for all new marketing authorisation applications (MAA) of a medicinal product. The ERA is also required for variation applications and applications for the extension of an authorisation (line extensions), especially if the result is a higher usage and a greater environmental burden (e.g. new indication(s) or dosage form(s)). However, an ERA is generally not required for renewals unless new environmentally relevant data are available which necessitate an update of the assessment.

As part of an ERA, potential hazards of the active substance(s) are identified, and risk mitigation measures and reporting are addressed. The ERA should also include preventive and safety measures to mitigate an identified environmental risk, which should ultimately be reflected in the form of appropriate warnings in the product information. The ERA is based on the medicinal product’s use as well as the physicochemical and ecotoxicological properties and fate characteristics of the active substance(s). The Guideline on the environmental risk assessment of medicinal products for human use - Revision 1 (EMEA/CHMP/SWP/4447/00 Rev. 1 - Corr.) became effective in its revised form on September 1^st, 2024. This guideline describes how the ERA is to be conducted and how potential risks to the environment, particularly to aquatic and terrestrial ecosystems, are to be assessed. Several methods described in this guideline are based on methods specified in the Regulation on the Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH) (e.g., ECHA, 2016; ECHA, 2017; ECHA 2023 a-c), the environmental quality standards of the Water Framework Directive (EQS) (European Commission, 2018), as well as in OECD guidelines and technical guidelines. In the event of future revisions of these guidelines or the regulatory adoption of new tests, the revised version of the relevant method or test guideline should be applied.

The complete ERA should be submitted in the eCTD dossier in Module 1.6, including the corresponding expert report with the curriculum vitae and dated signature of the author. Missing data or studies should be adequately justified by the applicant.

In the interest of animal welfare, the principles for the replacement, reduction, and refinement (3Rs) of animal testing should be implemented as far as applicable, according to Directive 2010/63/EU.

According to current requirements, the result of the ERA should not be a reason for rejecting a marketing authorisation (MA).

For the exact criteria, standards, and tests as well as the structure of the ERA, the EMA guideline should be consulted: 

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

Further information:

https://www.ema.europa.eu/en/human-regulatory-overview/marketing-authorisation/pre-authorisation-guidance

Directive 2001/83/EC as amended

An ERA is conducted to assess potential risks and hazards to the environment that may arise from the use, storage, and disposal of a medicinal product, however risks originating from synthesis or manufacturing are not part of the assessment. The goal of the ERA is to safeguard aquatic and terrestrial ecosystems, comprising surface water, groundwater, soil, species at risk of secondary poisoning, and microbiological processes in sewage treatment plants. The objective is to detect potential hazards of the active substance in a medicinal product, including those that are persistent (P), bioaccumulative (B), and toxic (T), as well as those that are very persistent and very bioaccumulative (vPvB).

The ERA process involves several steps and consists of two central assessments: the Risk Assessment and the Hazard Assessment of the active substance of the applied medicinal product. For fixed-dose combination product applications, a separate ERA is required for each active substance.

There are two phases:

Phase I: 

In Phase I of an ERA, threshold values for risk and hazard assessment are used to determine whether a more detailed assessment in a Phase II ERA is necessary.

• Risk Assessment: A calculation of the Predicted Environmental Concentration (PEC) in surface water is performed. If the PEC value is ≥ 0.01 µg/L, a detailed assessment in Phase II is required.
• Hazard Assessment: The log K_OW (logarithm of the n-octanol/water partition coefficient) is used to determine whether the substance has properties that are potentially harmful to the environment regardless of exposure level. This mainly concerns substances that are persistent (P), bioaccumulative (B), and toxic (T) or very persistent and very bioaccumulative (vPvB).

For endocrine-active substances (EAS), antibiotics, and antiparasitics, the guideline proposes a tailored risk assessment.

Phase II: 

Phase II is divided into two tiers: Tier A and Tier B.

Tier A: This tier assesses whether a substance poses a risk to water bodies and soils. Physicochemical properties such as water solubility, octanol/water partition coefficient, and dissociation constants are determined. Tests on adsorption to soils and sewage sludge are conducted to evaluate the distribution of the substance between environmental compartments. Long-term tests on aquatic toxicity (algae, daphnia, fish) are also conducted to determine the Predicted No Effect Concentration (PNEC). These data are used to calculate the risk quotient (RQ), which estimates the environmental risk potential. If the ratio between PECSW/PNEC, i.e., the RQ, is < 1, it is assumed that there is no risk to the environment.

Tier B: Tier B is conducted if a risk is identified in Tier A, i.e., the risk quotient (RQ) is ≥ 1. In Tier B, more detailed and refined assessments are carried out. These include refined calculations of the Predicted Environmental Concentration (PECSW) in surface water, considering additional factors such as metabolism and fate characteristics. Furthermore, a targeted risk assessment for soil, groundwater, and the risk of secondary poisoning is conducted if certain trigger values are reached.

The ERA is required for various types of procedures:

1. New Marketing Authorisation Applications (MAAs): An ERA is mandatory for all new central, decentralized, and national procedures, as well as for the mutual recognition and repeat use procedures:

• New applications (full applications with new or known active substances)
• Generic, bibliographic, fixed-dose combinations product, hybrid, and "informed consent" applications, as well as biosimilar applications

2. Variation Procedures (Type II Variations and Line Extensions): An ERA is necessary for variation applications (Type II Variations) and applications for the extension of an authorisation (Line Extensions) if an expected increase in environmental exposure is present. Typical situations requiring an update of the ERA include:

• New indications that result in higher exposure of the active substance
• New dosage forms, such as the extension of authorisation from an oral dosage form to transdermal patches, as these represent a new route of exposure
• Extensions of the patient population, such as the authorisation of a medicinal product for additional age groups
• Increase in the maximum daily dose, leading to higher excretion of the active substance

For variation and extension applications, originally existing ERA data can serve as a basis but require an update if environmental exposure changes. The applicant is responsible for assessing whether such an increase in exposure is present.

3. Renewal of Authorisation (Renewals): An ERA is generally not required for renewals of authorisation unless new environmentally relevant data become known that necessitate an update of the assessment. These shall be filed as Type IB Variations (C.I.z). This may be the case if new post-marketing studies show that a substance is persistent in the environment or has toxic effects.

4. Gene Therapies (GTMPs): For medicinal products containing genetically modified organisms (GMOs), specific requirements apply, which are described separately in the guidelines for the authorisation of GMO medicinal products (see EMA Q&A 3.4.3).

Additional Information for generic applications: 

An ERA is required for generic medicinal products. However, if no new environmental exposure is expected (e.g., same indication, same dosage form, and same dosage), the original ERA of the reference medicinal product can serve as a basis, and repetition of the ERA studies is not required.

An automatic cross-reference to ERA data of the EU reference medicinal product is not possible, regardless of whether the data protection period for the EU reference medicinal product has expired or not.

The generic applicant is required to create their own ERA, either based on their own data, based on data from the EU reference medicinal product with its consent in the form of a "Letter of Access," or based on publicly available data that allow for a complete and independent assessment.

A reference to ERA data from the dossier of the EU reference medicinal product is only possible with its consent. Data such as a toxicological profile or publications that only provide study endpoints or summaries cannot replace an ERA but can only supplement it.

Furthermore, it is not possible for authorities to access ERA data from the dossier of the EU reference medicinal product or another similar dossier without the consent of the respective company.

If a medicinal product has a naturally occurring substance as the active ingredient (e.g., vitamins, minerals, amino acids, peptides, proteins, nucleotides, carbohydrates, and lipids), the ERA can be a justification for why no ERA was performed.

According to Directive 2004/24/EC, the same exemption applies for herbal medicinal products, but in case that the active substance is known to be carcinogenic, mutagenic, or toxic to reproduction (CMR) or as PBT/vPvB, additional justification for the absence of studies might be needed.

In general, it is unlikely that vaccines without adjuvants pose a risk to the environment, so the ERA can consist of an appropriate justification.