Many drugs taken by patients, regardless of their administration route, are excreted in urine and feces and discharged in the sewage system through which enter the aquatic and terrestrial ecosystems including surface water, groundwater and soil. With the aim to protect the microbial community, plants and animals living in these environments, the potential risk to the environment arising from the use of medicines should be evaluated.
The Environmental (Risk) Assessment (ERA or EA) shall accompany any application for marketing approval of human medicine intended for both European and U.S. markets. Therefore, before marketing authorization, the impact of all new drugs and generic compounds, as well as variations and extension applications with increased environmental exposure, must be assessed.
The environmental risk is regulated by EMA’s Scientific Guideline on Environmental Risk Assessment of Medicinal Products for Human Use, along with its draft revision, and U.S. FDA Guidance for Industry on Environmental Assessment of Human Drug and Biologics Applications, which are the main reference guidelines for preparing an ERA Report in support of EMA or FDA application. Additional updates to the U.S. FDA guidance are under consideration, as is the EMA revised guideline.
While the EMA gives more details on how and which studies to perform requiring a more robust ERA package, the approach as described by the U.S. FDA is much simpler, and reporting recommendations are more comprehensive. As with the EU, an EA must be documented in an expert report with demonstrated expertise.
Since the publishing of EMA’s Scientific Guideline in 2006, an ERA is required for all new Marketing Authorization Applications (MAA), regardless of legal basis, as is required in the U.S. The revision of the EMA guideline stresses that generic medicinal products are not exempted from providing an ERA. Although the guideline revision is still in draft, an increasing number of European Health Authorities are requiring a complete ERA for generic medicinal product.
Both EU and U.S. assessments start with a simple calculation to estimate/predict the concentration of the substance when it enters the aquatic environment. The EMA calculation accounts for the maximum daily dose of the active substance consumed per inhabitant, while the FDA approach is based on the predicted annual production of the drug in the five years following marketing authorization. If the predicted environmental concentration of the substance meets FDA criteria for limited risk, an EA is unnecessary, and a categorical exclusion can be requested if no extraordinary circumstances exist.
Otherwise, if an EA is required, it starts with the physical/chemical characterization of API to determine environments of potential concern among atmospheric (additional in respect to EMA approach), aquatic and/or terrestrial conditions, followed by the investigation of the environment depletion. If the EA is still required after completion of a microbial inhibition test and an octanol/water partition coefficient determination, the process follows a tiered approach based first on acute toxicity data (Tier 1 and 2) and then on a final Tier 3 in which chronic toxicity data (i.e. EC50 or LC50) should be evaluated.
The EMA approach is slightly different. An ERA is performed in a stepwise approach, starting with an initial screening phase I, based on the above mentioned calculation of predicted environmental concentration in surface water and in the partition coefficient determination aimed to investigate persistence, bioaccumulation and toxicity of active substance. If the approach results in the below trigged values, it is assumed that the medicinal product is unlikely to represent a risk for the environment following its prescribed usage in patients.
If significant environmental exposure is anticipated and the refinement approach is not able to lower the risk to an acceptable level, a number of studies (mainly chronic) aimed to identify the active substance NOEC or EC10 should be performed (Phase II).
Overall, an incomplete or absence of an ERA will not lead to refusal of European marketing authorization, however, this will lead to post-marketing commitments. Conversely, in U.S., failure to submit a claim of categorical exclusion or complete EA is sufficient grounds for refusing to approve the application.
