Environmental Risk Assessment - ERA

Environmental Risk Assessment (ERA) human

In accordance with Article 8(3) of Directive 2001/83/EC, as amended, an evaluation of potential environmental risks that may be caused by a medicinal product must be submitted. An Environmental Risk Assessment (ERA) is required for all new marketing authorisations of a medicinal product via central, MRP, DCP or national procedure as well as for applications submitted under Article 10 of Directive 2001/83/EC. The exact criteria, standards and tests as well as the structure of the ERA must be based on the EMA Guideline and the associated Q&A document:

Guideline on the environmental-risk assessment of medicinal products for human use 01 June 2006 EMEA/CHMP/SWP/4447/00 Corr 2Questions and answers on the Guideline on the environmental risk assessment of medicinal products for human use 26 May 2016 EMA/CHMP/SWP/44609/2010 Rev. 1 Further information:

European Medicines Agency pre-authorisation procedural advice for users of the centralised procedure 14 March 2017 EMA/339324/2007 Volume 2B, Module 1 CTD Directive 2001/83/EC as amended AGES Medical Market Surveillance Contact for further questions: bpsa_praeklinikbasg.gvat"

Does the same apply to national authorizations?

The requirements are the same for all types of procedures.

Environmental Risk Assessment for Veterinary Medicinal Products

The Environmental Risk Assessment (ERA) should be carried out in accordance with the guidelines VICH GL6 (CVMP/VICH/592/98) and VICH GL38 (CVMP/VICH/790/03). EMA has also published a supporting guideline (EMEA/CVMP/ERA/418282/2005-Rev.1) providing additional information on how to implement the VICH guidelines. The supporting guideline provides algorithms, models, and default values (standard values) for the calculation of the extent of environmental exposure of a substance. It is meant as a technical guidance document designed to facilitate the preparation of the ERA report and to harmonise the interpretation of the VICH guidelines.

Whenever applicable, an ERA report should also outline preventive and risk mitigation measures designated to minimise identified environmental risks, which will ultimately become part of the summary of product characteristics (SPC) in the form of warning statements.

Assessment of the potential environmental risks is a two-phased procedure:

  • A Phase I assessment pursuant to VICH GL6 is to be carried out for all products and serves to estimate the environmental impact of a given product, its active substance(s) and excipients. Based on what is referred to as the decision tree (a set of 19 questions about the product in question), a pre-screening for ‘water’ and ‘soil’ is carried out. If the calculated concentrations in the soil (‘predicted environmental concentration,’ PECsoil < 100 µg/kg) or water (‘environmental introduction concentration,’ EICaquatic < 1 µg/L) remain below the specified trigger values, the assessment ends in Phase I.
  • If the trigger values are exceeded, a Phase II assessment pursuant to VICH GL38 will be performed. Phase II assessments must be carried out for all ecto- and endoparasiticides intended for use in pasture animals and for all veterinary medicinal products used in fish farms without controlled discharge. Phase II assessments are further subdivided into Tiers A and B; based on the properties of a given substance (physicochemical, pharmacological, toxicological) and its estimated concentration in the environment, Phase II assessments deal with the degradation behaviour and the possible effects of the substance on the environment, specific water organisms, algae, and evertebrates. The risk quotient calculated in Tier A (RQ = ratio between PEC/PNEC*) determines whether the assessment can stop after Tier A (‘basic data set’) or whether further studies in Tier B are required (‘extended data set’).
    *PEC, predicted environmental concentration; PNEC, predicted no effect concentration.

For detailed information on the criteria, standards, and tests to be used and on the structure of the ERA, please refer to the Guidelines. The complete ERA must be contained in Part III of the dossier; the corresponding expert report, including the curriculum vitae and signature of its author, must be contained in Part IC.

When is an ERA required?

In accordance with Directive 2001/82/EC as amended by Directive 2004/28/EC, complete ERAs must be submitted for all centralised, national, mutual recognition, and decentralised procedures:

  • New applications (full applications for new or known active substances)
  • Generic, bibliographic, hybrid, and informed consent applications
  • Extensions (considered full applications) and type II variations under certain conditions

Extensions: An ERA is required only if the submitted changes will result in an increase in environmental risk (i.e., when there is an increase in environmental exposure or when the active substance enters a previously unaffected compartment).

Thus, the following extensions may require an ERA:

  • Change or addition of a food-producing target species
  • Change or addition of a route of administration

If an increase in environmental exposure is not expected and if the original application for marketing authorisation contained an ERA, a reasoned justification for the omission of the ERA is sufficient.

Type II Variations: In most cases, type II variations will not result in an increase in environmental risk. As with extensions, an ERA for type II variations is required only if the submitted changes result in an increase in environmental risk (i.e., when there is an increase in environmental exposure or when the active substance enters a previously unaffected compartment).

Thus, the following type II variations may require an ERA:

  • Dose increases for an existing food-producing species
  • Addition of a new indication for an existing food-producing species

If an increase in environmental exposure is not expected and if the original application for marketing authorisation contained an ERA, a reasoned justification for the omission of the ERA is sufficient.

Type IA and IB variations: do not require an ERA.

Renewals: Although ERAs are not explicitly required, renewals in accordance with Directive 2001/82/EC and Regulation EC 726/2004 require the risk-benefit ratio to be re-evaluated, and this includes an evaluation of the risk of undesirable effects on the environment. The quality and extent of the data required are to be decided case by case on the basis of existing data; if omission of the ERA is considered justified, a scientific explanation should be provided.

However, an ERA will be required,

  • if existing or new data indicate that an active substance and/or its metabolites may have environmentally toxic effects and pose an environmental risk.

In principle, the authorities can request additional data for environmental toxicity assessments to be submitted or risk-mitigating measures to be implemented whenever a potential environmental risk has been identified.

Do all generic, bibliographic, hybrid, and informed consent applications require an ERA?

Yes. Pursuant to Articles 13(1) and 13a(1) of Directive 2004/28/EC, applicants for marketing authorisations for generic medicinal products are merely exempt from the obligation to submit the results of safety and residue tests and the results of preclinical and clinical studies.

However, they are not exempt from submitting the results of pharmaceutical studies (= Part II of the dossier) and the results of studies designed to assess any potential environmental risks of the medicinal product (i.e., ERAs).

Can generic applications (i.e., all applications referring to full application dossiers of other products) simply refer to ERA data obtained with reference or originator products?

No, referring to ERA data obtained with the reference product or the originator is not automatically possible, regardless of whether or not the patent protection of the originator has expired.

Generic applicants are required to carry out ERAs for their own products. These ERAs can be based either on data obtained with the generic product, data obtained with the originator product (with the approval of the product’s marketing authorisation holder [MAH]), or on publicly accessible data that allow a complete and independent assessment to be performed.

Reference to ERA data from the dossier of the originator product can only be made with the approval of the MAH of the originator product. Data such as toxicological profiles or publications merely presenting study endpoints or summaries can complement ERAs, but they cannot replace ERAs. Also, authorities cannot simply access ERA data from the dossier of the originator product or some other similar dossier without the permission of the MAH of such a product.

Are there substances for which no ERA is required?

Yes, an ERA is not required for natural substances, such as

  • Vitamins
  • Minerals
  • Amino acids
  • Peptides
  • Proteins
  • Carbohydrates
  • Lipids

Also exempt are:

  • Vaccines
  • Herbal medicinal products

Could an ERA showing a significant environmental impact lead to a marketing authorisation being put into question?

Yes, pursuant to Art 19 para 2 of the Austrian Medicinal Products Act (Arzneimittelgesetz, AMG), Official Federal Gazette 153/2005, the authorisation of a proprietary medicinal product for veterinary use shall be refused if it appears questionable that the product is free of untoward effects on the environment that are not outweighed by the therapeutic benefits of the product.

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