The European Medicines Agency's (EMA) Committee for Veterinary Medicinal Products (CVMP) is responsible for recommending MRLs, which, when adopted by the European Commission, become legally binding food safety standards. EMA provides guidance on establishing MRLs and submitting an application.
The European Union (EU) requires by law that foodstuffs such as meat, milk or eggs must not contain residue levels of veterinary medicines or biocidal products that might represent a hazard to the health of the consumer. Regulation (EC) No 470/2009 lays down the rules and procedures for the establishment of MRLs.
Before a veterinary medicine intended for food-producing animals is authorised in the EU, the Committee for Veterinary Medicinal Products (CVMP) evaluates the safety of its pharmacologically active substances and their residues and recommends MRLs. The Agency has published scientific guidance relevant to the establishment of MRLs for veterinary medicines.
EMA uses human dietary exposure assessments to establish MRLs of pharmacologically active substances of veterinary medicines.
EMA worked closely with the European Food and Safety Authority (EFSA) to ensure a common approach on assessing human dietary exposure to residues in food from animal origin.
For more information, see:
The CVMP is responsible for establishing MRLs for pharmacologically active substances in biocidal products for use in animal husbandry. Whilst the same principles and guidelines apply to the establishment of MRLs for pharmacologically active substances in medicines and in biocides, the Agency has published additional guidance on the risk characterisation and assessment of MRLs for biocides.
Active principles of biological origin used in immunological veterinary medicines fall outside the scope of the Regulation (EC) No 470/2009 and are therefore exempt from an MRL evaluation.
Certain other biological substances may not require a full MRL assessment.
Substances considered not to exert pharmacological effects (non-active substances) may also be considered to fall outside the scope of Regulation (EC) No 470/2009 and thus are also exempt from an MRL evaluation.
As of 19 June 2018, Commission Regulation (EU) 2018/782 describes the methodology to be used in the scientific risk assessment and establishment of risk management recommendations relevant to MRL applications. These rules replace previous guidance on MRLs as outlined in Volume 8 of 'The rules governing medicinal products in the European Union' .
As of June 2017, Commission Regulation (EU) 2017/880 sets out the principles and minimum criteria for the extrapolation of an MRL to either another foodstuff from the same species or to the same foodstuff from another species.
When finalising an MRL evaluation, the CVMP routinely considers if its conclusions can be extrapolated to additional species and foodstuffs, regardless of whether the applicant has specifically requested this. This aims to increase the availability of veterinary medicines.
The CVMP uses the same criteria when evaluating extension applications.
The Agency sends the CVMP opinion on the MRL application to the European Commission, which confirms the classification of the substance by including it in the annex to Commission Regulation (EU) No 37/2010.
Substances that may be used in veterinary medicines for food-producing species or biocidal products for use in animal husbandry are listed in table 1 (allowed substances) of the annex with the following information:
Substances considered to represent a hazard to the health of the consumer at any level are included in table 2 (prohibited substances) of the annex. These substances must not be used in veterinary medicines for food-producing animals or in biocidal products for use in animal husbandry.
The Agency publishes the following information on MRL assessments:
Biological substances other than active principles of biological origin used in immunological veterinary medicines can be either 'chemical-like' or chemical-unlike'.
'Chemical-like’ substances present similar concerns to chemical substances and are subject to a full MRL assessment.
‘Chemical-unlike’ substances are more complex substances that may contain multiple chemical types whose residues can be cells, amino acids, lipids, carbohydrates, nucleic acids and their breakdown products. The CVMP decides on a case-by-case basis whether 'chemical-unlike' substances require a full MRL assessment.
For full details, see Annex I.6 of Commission Regulation (EU) 2018/782.
Applicants who consider that a biological substance is ‘chemical-unlike’ can submit an application via Service Now by selecting Veterinary Regulatory > Pre-Submission-Vets for the CVMP to evaluate the need for an MRL assessment.
The application should include a report and supporting information explaining the scientific basis for the request. It should also address the points in Annex I.7 of Commission Regulation (EU) 2018/782.
Applicants should notify EMA that they intend to apply at least two months before submitting their application, via Service Now by selecting Veterinary Regulatory > Pre-Submission-Vets including the following:
The evaluation has a:
EMA charges a fee for evaluating the application. It invoices the fee to the applicant's address after it has validated the application.
When the outcome of the assessment is that the biological substance does not require a full MRL evaluation, EMA publishes a summary of the CVMP's assessment and includes the substance in the following list:
Non-active ingredients considered not to exert pharmacological effects, including many excipients, are considered to fall outside the scope of the MRL Regulation.
The CVMP determines on a case-by-case basis whether a non-active ingredient exhibits pharmacological effects and poses a risk to the consumer. If the CVMP concludes that no MRL evaluation is required, EMA includes the substance in the following list:
Applicants who consider that a component of their product is not pharmacologically active can submit a request to the CVMP to have the substance included in the above list. For more information, see:
Applicants need to submit an application to EMA to have an MRL established for a new pharmacologically active substance or to extend an existing MRL to a new animal species.
EMA charges a fee for MRL applications. It may grant a total or partial fee exemption for veterinary medicinal products classified as eligible for authorisation according to Article 23 of Regulation (EU) 2019/6, i.e. applications for limited markets.
Applicants should:
The data requirements and dossier structure are laid down in Commission Implementing Regulation (EU) 2017/12.
Applicants can request the clarification on specific issues and/or a pre-submission meeting Service Now by selecting Veterinary Regulatory > Pre-Submission-Vet Requests. For pre-submission meetings should include details of the intended application, including:
EMA provides more pre-submission guidance in the form of questions and answers.
For submitting an application applicants should use the MRL application form and consult the recommended submission dates:
Applicants need to submit their application through the eSubmission Gateway / Web Client portal. For more information and guidance on registration with the system, see the Veterinary eSubmission website.
The submission procedure is defined in Article 8 of Regulation (EC) 470/2009 and further described in Commission Implementing Regulation (EU) 2017/12.
For information on the practical aspects of the submission of the application and its evaluation, see:
For non-biological veterinary medicinal products for food-producing animals: NO. Article 5(5) of Regulation (EU) 2019/6 states that "a marketing authorisation for a veterinary medicinal product intended for one or more food-producing animal species may only be granted if the pharmacologically active substance is allowed in accordance with Regulation (EC) No 470/2009 and any acts adopted on the basis thereof for the animal species concerned". Therefore, to obtain a marketing authorisation for a non-biological veterinary medicinal product intended for food-producing species in the European Union, MRLs must be established in advance for all pharmacologically active substances for the concerned animal species (e.g., sheep, fin fish) and relevant foodstuffs (e.g. milk, honey). These include the active ingredient(s) and excipients, depending on whether the substance has pharmacological activity at the dose that is intended to be administered to the target species.
For non-immunological biological veterinary medicinal products for food-producing animals, either MRLs are needed or, in certain cases, the CVMP may conclude that a biological substance does not require a full MRL evaluation and can be included in the list of biological substances considered as not requiring an MRL evaluation as per Commission Regulation (EU) 2018/782.
The active principles of biological origin intended to produce active or passive immunity or to diagnose a state of immunity and used in immunological veterinary medicinal products are exempted from MRL requirements as per Regulation (EU) No 470/2009.
YES, if they have pharmacological activity at the dose that is intended to be administered to the target species, they require MRLs.
Specific legislation regarding the establishment of MRLs is applicable in the European Union:
Allowed substances for use in veterinary medicinal products intended for food-producing species are listed in Table 1 of the Annex to Commission Regulation (EC) No 37/2010, where the relevant MRL values or a "No MRL required" classification for the concerned target animal species and relevant foodstuffs are identified. The Annex is updated by Commission Regulations published regularly in the L-series of the Official Journal of the European Union (OJ) (see EUR-Lex).
Table 1 of the Annex to Commission Regulation (EU) No 37/2010 includes substances that are allowed in veterinary medicinal products for use in food-producing species and in biocidal products for use in animal husbandry.
For each substance the table includes either:
For further details on the assessment of a substance, the reader should consult the European Public MRL Assessment Report (EPMAR, previously called the Summary Report) for the substance concerned.
Table 2 of the Annex includes substances that are prohibited for use in veterinary medicinal products for use in food-producing species and in biocidal products for use in animal husbandry (these were previously in Annex IV of Council Regulation 2377/90). Residues of these substances are considered to represent a risk to the safety of the consumer at any level or the data made available for the establishment of MRLs were insufficient to allow a recommendation.
In order to obtain the establishment of MRLs for a new substance an MRL application has to be submitted to the European Medicines Agency.
The procedure for the submission of an application for the establishment of MRLs is defined in Article 8 of Regulation (EC) No 470/2009 and further explained in Commission Implementing Regulation (EU) 2017/12 of 6 January 2017 regarding the form and content of the applications and requests for the establishment of maximum residue limits in accordance with Regulation (EC) No 470/2009 of the European Parliament and of the Council.
Applicants should notify the Agency of their intention to submit an MRL application. A letter of intent indicating the name of the substance, intended use, target specie(s) and intended submission date should be submitted to the Agency 6 months before the intended submission of the application for the establishment of MRLs. If the applicant has a valid micro, small and medium-sized enterprise (SME) status or a limited markets classification, this information should also be included. Applicants are advised to liaise with the Agency in order to agree on an adequate time delay between submission of the MRL application and submission of any related MA application.
Once the applicant has notified his intention to submit an application, the CVMP appoints a rapporteur and, if appropriate, a co-rapporteur. The applicant is notified of the appointment of the rapporteur (and co-rapporteur if appropriate), as well as of the preferred submission date (closest to the submission date identified by the applicant). For applications for extensions or modifications of MRLs, usually no co-rapporteur is appointed.
For an MRL application for a new substance a full dossier should be submitted respecting the requirements of Commission Implementing Regulation (EU) 2017/12 and following the methodological principles outlined in Commission Regulation (EU) 2018/782.
The practical aspects for submission of such an application are explained in the EMA standard operating procedure (SOP) on the Standard operating procedure for evaluation procedure for applications and requests for the establishment or review of Maximum Residue Limits (MRLs).
The establishment of MRLs for a new animal species requires the submission of an application for the extension of the existing MRLs to the new animal species. In such a case, normally only a residue file is required, because the acceptable daily intake (ADI) is the same regardless of the indications and target animal species. However, the procedure is essentially similar to that for full applications.
Extension applications may also make reference to the principles and criteria of the CVMP for extrapolating an MRL established for a pharmacologically active substance derived for one species or foodstuff to another foodstuff or species (MRLs in line with Article 5 of Regulation (EC) No 470/2009). These are described in Commission Regulation (EU) 2017/880. The CVMP uses the same criteria when evaluating extension applications.
In order to modify existing MRLs, a new application for their modification is required. The data required depend on the basis of the modification request. If the proposal is to amend the MRLs based on new residue data only, then no safety data would be required. However, if the intended modification of the MRLs is based on a request for the amendment of the acceptable daily intake (ADI) for the substance, the relevant safety data would also be required. An application for the modification should then be submitted to the European Medicines Agency under Article 3 of the Regulation (EC) No 470/2009.
When submitting an MRL application, a fee is payable to the European Medicines Agency as required by the legislation in force. Please refer to fees for MRL applications.
The legislation on fees (Council Regulation (EC) No 297/95) makes no distinction between fees for MRL applications for major species/uses or minor species/uses. However, Article 9 of the above mentioned Regulation provides, in principle, for the possibility of granting total or partial fee exemptions for veterinary medicinal products for the treatment of rare diseases affecting minor animal species or for extensions of existing MRLs to additional animal species. In particular, partial fee exemptions may be applicable for MRL applications for active substances used in products that have been classified as intended for a limited market (Art 4(29) of Regulation (EU) 2019/6) and for which the benefit of its availability on the market to animal or public health is greater than the risk inherent in the fact that less than usual data is provided (Art 23 of Regulation (EU) 2019/6). Further information on the classification of such products is available on the veterinary limited markets webpage of the Agency’s website.
In addition, applicants may request the Executive Director to grant an ad hoc fee reduction. Such requests are expected to be exceptional and require the applicant to justify that the request is made (1) in exceptional circumstances and (2) for imperative reasons of public or animal health. Further information is available in the Explanatory note on general fees payable to the European Medicines Agency, available via the 'fees payable to the European Medicines Agency' webpage of the Agency’s website.
The establishment of MRLs, as a legal provision in the EU, is the responsibility of the European Commission. Established MRLs are published on an ongoing basis in the L-series of the Official Journal of the European Union (OJ) (see EUR-Lex).
All opinions of the CVMP including MRL recommendations are summarised in the CVMP meeting highlights, which is normally published on the Friday following each CVMP meeting. In accordance to its policy on transparency, EMA also publishes summary opinions on MRL recommendations on its website following the CVMP meeting at which the opinion is adopted. The summary opinion includes the name of the substance, the target animal species, the MRL values in the relevant target tissues and any other provision, if relevant. These can be found under the following link
For substances included in the Annex to Regulation (EC) No 37/2010, European Public MRL Assessment Reports (EPMARs, previously called Summary Reports), on the scientific evaluations carried out by the Committee for Veterinary Medicinal Products (CVMP), are published on the European Medicines Agency website. These can be found under the following link:
Some substances included in Table 1 of Annex to Commission Regulation (EC) No 37/2010 with a "No MRL required" status were considered, at the time of the evaluation, as falling into the category of "Substances generally recognised as safe" (for further details please refer to Commission Regulation (EC) 2796/95 and Commission Regulation (EC) 1931/99;, neither of them still in force). The Committee for Veterinary Medicinal Products (CVMP) considered a "No MRL required" status for these substances based on the fulfilment of specific criteria ensuring consumer safety (e.g., rapid metabolism to simple organic metabolites such as carbon dioxide, acetic acid and ethanol, low oral bioavailability etc.). No individual European Public MRL Assessment Reports (EPMARs, previously called Summary Reports) are available for some of these substances.
CVMP Summary Opinions on the establishment of MRLs are normally published on the EMA website on the Friday following the CVMP meeting at which the opinion was adopted. The documents are withdrawn after publication of the relevant MRL regulation in the Official Journal of the European Union (OJ) (see EUR-Lex).
European Public MRL Assessment Reports (EPMARs, previously called Summary Reports) on substances for which MRLs have been established are published on the EMA website as soon as possible (usually within 2 weeks) after publication of the relevant MRL regulation in the Official Journal of the European Union (see EUR-Lex).
The question of whether the MRLs established for a racemic mixture apply to the individual isomers requires case by case consideration. Up to now the CVMP has considered the specific cases of:
and concluded that for these cases the MRLs established for the racemic mixture also apply to the individual isomers.
Legislation (Regulation (EU) 2019/6) requires that all pharmacologically active substances contained in a veterinary medicinal product for food-producing species need to be allowed in accordance with Regulation (EC) No 470/2009 and any acts adopted on the basis thereof. It follows that the active substances as well as any other pharmacologically active ingredients (excipients including preservatives and adjuvants) need to be included in Table 1 of the Annex to Commission Regulation (EU) No 37/2010 and only substances that are considered not to be pharmacologically active do not.
Many excipients have been included in Table 1 of the Annex to Commission Regulation (EC) No 37/2010 with a "No MRL required" classification, while others, considered not to be pharmacologically active, have been entered into the list of substances considered as not falling within the scope of the Regulation (EC) No 470/2009, often called the "out of scope" list.
An excipient that is neither listed in Table 1 of the Annex to Commission Regulation (EC) No 37/2010 nor in the "out of scope" list, can only be used in a veterinary medicinal product intended for food-producing species if it is concluded that the substance cannot be expected to show pharmacodynamic activity at the dose at which it is/will be administered to the target animal.
In order to have an excipient included in the list of substances considered as not falling within the scope of Regulation (EC) No 470/2009, a request should be submitted to the Agency. Data requirements for such requests are laid out in the CVMP "Guideline on data to be provided in support of a request to include a substance in the list of substances considered as not falling within the scope of Regulation (EC) No 470/2009".
In the case of requests that do not require extensive evaluation, the CVMP may decide to include the substance in the "out of scope" list. In this case, no fee is charged. If a more in-depth scientific assessment is required, the applicant will be advised to make a formal request for scientific advice, in which case a fee for the scientific advice would have to be paid. Detailed guidance to applicants regarding scientific advice can be found on the European Medicines Agency website. The procedure for providing scientific advice to applicants is explained in the SOP on the "Standard operating procedure for evaluation procedure for CVMP scientific advice requests.
The applicant is advised to consider the MRL status of all product ingredients prior to the submission of the marketing authorisation application.
In some cases, particularly relating to branded excipients, the competent authority may accept inclusion of the relevant data in accordance with the CVMP guideline referred to above within the marketing authorisation application procedure dossier. In this case, the competent authority will conclude on whether the excipient falls within the scope of the Regulation (EC) No 470/2009 as part of the marketing authorisation application evaluation.
During the above considerations, it may be concluded that a maximum residue limit application is required, in which case a MRL application for the excipient should be submitted. See question 5 for further guidance on how such an application can be made.
The requirement to establish MRLs under Regulation (EC) No 470/2009 applies to pharmacologically active substances for use in veterinary medicinal products and to pharmacologically active substances for use in biocidal products for use in animal husbandry where residues may present a hazard to consumer health. Feed additives have a different authorisation procedure in the EU, established by different legislation (Regulation (EC) No 1831/2003) and Regulation (EC) No 470/2009 is not applicable to those substances. The European Medicines Agency is not responsible for the evaluation/authorisation of feed additives. Therefore, questions concerning feed additives and their conditions of use should be addressed to the European Commission in Brussels.
The establishment of withdrawal periods is part of the marketing authorisation procedure for each individual veterinary medicinal product and is not simply substance-related.
Information on the established withdrawal periods is accessible via the public portal of the Union Product Database established according to Article 55 of Regulation (EU) 2019/6.
Questions regarding withdrawal periods for veterinary medicinal products authorised nationally in a specific Member State should be addressed to the Competent Authority of the Member State concerned. Addresses of the Members States' Competent Authorities are available on the Heads of Medicines Agencies website (HMA National contacts).
The European Medicines Agency website contains numerous guidelines on data requirements and on the determination of withdrawal periods. Software applications for the calculation of the withdrawal periods in accordance with these guidelines are also available free of charge from the same section under the following pages: Approach towards harmonisation of withdrawal periods for edible tissues and Determination of withdrawal periods for milk.
Biocidal substances are used in many different situations and residues of biocidal substances may potentially enter the food chain as a result of a number of these uses (including exposure of plants to biocides, exposure of food-producing animals to biocides and contamination of foodstuffs with biocides). Regulation (EC) No 470/2009 gives the Committee for Veterinary Medicinal Products (CVMP) responsibility for performing MRL evaluations for pharmacologically active substances used in biocidal products for use in animal husbandry, where such an evaluation is deemed necessary. All other aspects of the evaluation of biocidal products are outside the responsibility of CVMP but are undertaken by the Competent Authorities for biocides in Member States supported by ECHA and the Commission. The CVMP has published a guideline on the risk characterisation and assessment of MRLs for biocides (Risk characterisation and assessment of maximum residue limits (MRL) for biocides).
Regulation (EC) No 470/2009 elaborates the principles by which the European Commission can establish so-called "Reference Points for Action" (RPAs) for residues of pharmacologically active substances for which MRLs have not been (nor cannot be) established. It is important to stress that RPAs are NOT MRLs. RPAs are residue concentrations whose detection by food control laboratories is technically feasible. In the event that the RPA is exceeded, the Member State is obliged to reject the consignment as it cannot be legally placed on the EU market (see Article 23 of Regulation (EC) No 470/2009). Therefore, RPAs are established by the European Commission in order to set the harmonised standards for the monitoring of unauthorised substances.
MRLs established by third countries do not have any legal force in the EU. Therefore, substances that do not have EU MRLs cannot be used to treat food producing species in the EU.