Q&A: Maximum Residue Limits (MRL)

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1. Can a veterinary medicinal product be authorised if no Maximum Residue Limits (MRLs) have been established?

For food producing animals: NO. To obtain a marketing authorisation for a veterinary medicinal product intended for food producing species, MRLs must be established in advance for all pharmacologically active substances for the concerned animal species (e.g. sheep, fin fish) and relevant tissues or products (e.g. milk, honey).

2. Where can I find detailed information about the establishment of Maximum Residue Limits (MRLs) in the European Union?

Specific legislation regarding the establishment of MRLs was set up in the European Union:

• Council Regulation (EEC) No 2377/90 of 26 June 1990 laying down a Community procedure for the establishment of maximum residue limits of veterinary medicinal products in foodstuffs of animal origin, Official Journal L 224 of 18 August 1990, pages 1-8

The Regulation has subsequently been amended by:

• Commission Regulation (EEC) No 762/92 of 27 March 1992, (Official Journal L 83 of 28 March 1992, pages 14-16)
• Council Regulation (EC) 434/97 of 3 March 1997 (Official Journal L 67 of 7 March 1997, pages 1-1), and
• Council Regulation (EC) No 1308/1999 of 15 June 1999, (Official Journal L 156 of 23 June 1999, pages 1-3).

The legislation is available at the European Commission website (see Eur-lex)

Substances with established MRLs are listed in the annexes to Regulation 2377/90 where the relevant MRL values and target animal species are identified. These annexes are updated by Commission Regulations published regularly in the L-series of the Official Journal of the European Communities (OJ) (see Eur-lex). The Commission also publishes on its DG Enterprise website the complete series of Commission and Council Regulations modifying Annexes I to IV of Council Regulation 2377/90.

Further detailed guidance on the procedure and assessment of applications for the establishment of MRLs can be found in Volume 8 of the Rules Governing Medicinal Products in the European Union: Notice to Applicants and Note for Guidance – Establishment of maximum residues limits (MRLs) for residues of veterinary medicinal products in foodstuffs of animal origin which is available on the European Commission DG Enterprise website (see Volume 8).

3. What does it mean for a substance to be included in Annex I, II, III or IV of Council Regulation (EEC) No 2377/90?

Annex I of the Regulation includes the substances for which definitive MRLs have been established.

Annex II of the Regulation includes the substances for which it is not considered necessary for the protection of public health to establish MRL values. These substances are allowed to be used in veterinary medicinal products for food producing species for the animal species identified and according to the conditions established, if any (e.g. specific route of administration). It should be noted that an entry in Annex II is not equivalent to the status “generally recognised as safe”. In fact only a sub-group of Annex II substances do fall under this category. For further details on the assessment of a substance you are advised to consult the MRL Summary Report of the substance concerned.

Annex III of the Regulation includes substances with provisional MRLs. Provisional MRLs are established, for a defined period of time, when not all requirements have yet been fully addressed. However, the outstanding issues must not concern any major human safety aspects, as it is necessary that the residues at the proposed levels do not present a hazard to the health of the consumer. Once the outstanding issues have been satisfactorily addressed, the substance can be included in Annex I.

Annex IV of the Regulation includes substances for which no maximum residue limit could be established because residues of these substances, at whatever limit, in foodstuffs of animal origin constitute a hazard to the health of the consumer. The administration of substances listed in Annex IV to food-producing species is prohibited in the EU.

4. What do I have to do if I want Maximum Residue Limits (MRLs) to be established for a new substance?

In order to obtain the establishment of MRLs for a new substance a 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 6 of Regulation 2377/90, as amended and further explained in Volume 8 of the Rules Governing Medicinal Products in the European Union. Volume 8 is available on the DG Enterprise website of the European Commission (see Volume 8).

Practical aspects for submission of the application are explained in the Agency Standard Operating Procedure (SOP) Submission and evaluation procedure for an application for the establishment of Maximum Residue Limits (MRLs).

5. What do I have to do to have existing MRLs established for a new animal species?

The establishment of MRLs for a new animal species requires 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, but the procedure is essentially similar to that for full applications.

For certain extensions to new species, in particular if the new species is a minor species and the existing MRLs in different species have the same or similar values, the existing MRL can be extrapolated, the MRLs for the new species would have the same value as MRLs previously set for another species. In such cases only a very limited residues file would be expected. The data requirements for extrapolation of MRLs to a minor species are set out in the CVMP Guideline on Safety and Residue data requirements for veterinary medicinal products intended for Minor Uses or Minor Species (EMEA/CVMP/SWP/66781/2005).

Further details on extrapolation of MRLs can be found in the CVMP Note for Guidance on the Risk Analysis Approach for Residues of Veterinary Medicinal Products in Food of Animal Origin, EMEA/CVMP/187/00-FINAL. To access the documents click here.

For MRL extrapolations from a major to a minor species within the same class, i.e. from cattle to goats, the CVMP would consider to carry out the assessment for such extrapolation without the payment of fees based on a substantiated request provided that the requirements as detailed in the above mentioned guidelines are fulfilled and appropriate data are available. Applicants are advised to contact the European Medicines Agency secretariat for further advice (see Pre-Submission Guidance; or email: mrl@ema.europa.eu).

6. How can the MRLs established for a substance be modified?

In order to modify existing MRLs a new application for their modification is required. The data required depend on the request for the modification; if it concerns residue issues only, no safety data are 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, safety data to support the modification are also required.

7. Is a fee required for the submission of an application for the establishment of MRLs? If so, how much?

Yes. When submitting an MRL application a fee is payable to the European Medicines Agency as required by the legislation in force (Council Regulation (EC) No 297/95 on fees payable to the European Medicines Agency, as amended by Commission Regulation (EC) No 312/2008). The fees for MRL applications are established in Article 7 of the above mentioned Regulation (see Eur-lex). Click here to see the fees for MRL applications.

8. Are the fees for MRL applications for minor animal species or for substances intended for the treatment of rare diseases the same as for other major species and frequent diseases?

The legislation on fees (Council Regulation (EC) No 297/95 on fees payable to the European Medicines Agency, as amended by Commission Regulations (EC) No 2743/98, (EC) No 494/2003, (EC) No 1905/2005 and (EC) No 312/2008 - see Eur-lex) makes no distinction between fees for MRL applications for major species/uses or minor species/uses. However, Article 9 of the abovementioned 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.

The Management Board of the European Medicines Agency has agreed that this is, in general, also applicable to MRL-applications for minor animal species, provided that they fulfil one or more of the following criteria:

• The product is for a specific claim (not necessarily a rare disease or circumstance);
• The product is not yet authorised for a similar claim in a major species;
• No other product is licensed in the Community for this claim in this species;
• The control of the disease is imperative for the health of the minor species concerned.

Furthermore, sufficient funds must be available for any fee reduction to be considered.

A fee reduction or waiver can only be considered upon the written request of the applicant and following a favourable recommendation by the Committee for Medicinal Products for Veterinary Use (CVMP). The decision to grant such a fee reduction or waiver then lies with the Executive Director of the Agency, also taking into consideration the availability of funds.

9. Where can I find a listing of all established MRLs?

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 Communities (OJ) (see Eur-lex). The Commission also publishes on its DG Enterprise website the complete series of Commission and Council Regulations modifying Annexes I to IV of Council Regulation 2377/90.

The European Medicines Agency publishes the document “Status of MRL Procedures” where all substances included in Annex I, II, III or IV of Regulation 2377/90 are listed in alphabetical order with the indication of the respective annex and the number of the Regulation which established these MRLs. In addition, the list includes substances for which MRL recommendations have been made by the CVMP and are now undergoing the decision-making procedure by the European Commission. The list also includes the substances for which the CVMP concluded that due to insufficient data provided a recommendation for inclusion of the substance in Annex I, II or III of Regulation 2377/90 could not be made.

For reasons of confidentiality, ongoing applications for MRLs for new substances or new indications for old substances are not included. Only after an opinion with regard to the establishment of maximum residue limits has been adopted by the CVMP the information is made public.

• Status of MRL procedure

10. Is it possible to obtain information on the European Medicines Agency MRL recommendations before MRLs are published in the Official Journal of the European Communities?

All opinions of the CVMP including MRL recommendations are summarised in the CVMP Press Release, which is published on the Friday following each CVMP meeting. In accordance with the European Medicines Agency policy on transparency the Agency 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.

• The Summary Opinions are listed by substance name in alphabetic order.

11. Where can I find further information on substances for which MRLs have been established?

For substances where MRLs have been published in accordance with Council Regulation 2377/90, as amended, Summary Reports, or since 2007 European Public MRL Assessment Reports (EPMARs), on the scientific evaluations carried out by the Committee for Medicinal Products for Veterinary Use (CVMP), are published on the Agency website.

• The documents are listed by substance name in alphabetical order.

12. Why can’t I find the Report for some substances included in Annex II?

A number of substances are included in Annex II of Regulation 2377/90 that fall into the category “Substances generally recognised as safe” (see Commission Regulations Nos 2796/95 and 1931/99). The Committee for Medicinal Products for Veterinary Use (CVMP) recommended the inclusion of these substances in Annex II based on the fulfillment of specific criteria ensuring consumer safety (e.g. rapid metabolisation to simple organic metabolites such as carbon dioxide, acetic acid and ethanol, low oral bioavailability). No individual Summary Reports are available for these substances.

13. How frequently is the information on MRLs updated on the European Medicines Agency website?

1. CVMP Summary Opinions on the establishment of MRLs are published on the Agency website on the Monday following the CVMP meeting at which the Opinion was adopted. Click here to see the list.

2. EPMARs or Summary Reports on substances for which MRLs have been established are published on the Agency website (click here to see the list) as soon as possible (usually within 2 weeks) after publication of the MRLs in the Official Journal of the European Communities (for the Official Journal see Eur-lex).

3. The document “Status of MRL procedures” (EMEA/CVMP/765/99), is updated approximately every 3-4 months to include the new CVMP recommendations on MRLs and publications in the Official Journal (click here to see the document).

14. Can I obtain the studies/data referred to in the Summary Reports or EPMARs?

The data submitted with an application for the establishment of MRL are proprietary information of the applicants. Therefore, they must be handled by the European Medicines Agency as confidential information and cannot be disclosed to third parties.

15. Can I obtain the analytical methods referred to in the Summary Reports or EPMARs?

The analytical methods evaluated by the CVMP for the establishment of MRLs are those submitted by the applicant as part of an MRL application. Therefore, they are considered proprietary information of the applicants and must be handled by the European Medicines Agency as confidential information, which cannot be released to third parties.

In order to allow for residue monitoring under Council Directive 96/23/EC the analytical methods are sent by the Agency to the European Commission, to the Member States Competent Authorities and to the Community Reference Laboratories for residue surveillance purposes.

16. I want to submit an application for a Marketing Authorisation. What is the legal status of the excipients, preservatives or adjuvants in my product in relation to Council Regulation (EEC) No 2377/90?

The legislation (Directive 2001/82/EC, as amended) requires that all pharmacologically active substances contained in a veterinary medicinal product for food producing species need to be included in Annex I, II or III of Regulation 2377/90. This applies for the active principle as well as other pharmacologically active substances contained in the product, e. g. excipients, preservatives or adjuvants.

Historically, many of these substances have been included in Annex II of Regulation 2377/90, and others in the list of substances not falling within the scope of the Regulation, often called “out-of-scope” list.

An excipient for a new product that is not listed in Annex II (or Annex I or III) or the out-of-scope list can be used, if it has been proven that the substance is not pharmacodynamically active at the dose at which it is/will be administered to the target animal following the approach agreed by the CVMP and described in its Position Paper on the definition of substances capable of pharmacological action in the context of Council Directive 2001/82/EC with a particular reference to excipients and manufacturing materials (EMEA/CVMP/072/97-Rev.1).

The assessment whether the substance is pharmacodynamically active at the dose to be used in the target animal species or not can be carried out within the marketing authorisation application. Unless it concerns an application for a centralised marketing authorisation, no involvement of the European Medicines Agency is necessary.

Alternatively, the applicant may choose to have the opinion of the CVMP on the matter prior to the submission of the marketing authorisation application. Then, a request for Scientific Advice would need to be submitted. For this procedure a fee has to be paid. For guidance to applicants regarding scientific advice: scope, structure of the request, fees payable, etc. see EMEA/CVMP/172329/2004-Rev.2 on the Agency Website. The procedure for providing scientific advice to applicants is explained in the Standard Operating Procedure (SOP) SOP/V/4016.

However, there are cases where an excipient could be included in the list of substances not falling within the scope of Regulation 2377/90 without a full scientific advice procedure, e. g. in case of an excipient that is also used as foodstuff. For such a substance a justified request to the CVMP (without payment of a fee) would be adequate. Applicants are advised to contact the Agency secretariat for further advice (see Pre-Submission Guidance; or email: mrl@ema.europa.eu).

Furthermore, the applicant may of course choose to submit a MRL application for the excipient.

The approach regarding preservatives and adjuvants is still under discussion and further guidance is being prepared. For further information please contact the Agency secretariat (see Pre-Submission Guidance; or email: mrl@ema.europa.eu).

17. Are substances included in Annex I, II or III of Council Regulation (EEC) No 2377/90 related to the use as additives in feedstuffs?

The requirement to establish MRLs under Regulation 2377/90 applies to veterinary medicinal products only. Feed additives have a different authorisation procedure in the EU, established by different legislation (Council Directive 70/524/EEC). Regulation 2377/90 is not applicable to those substances. The Agency is not involved in the procedure for evaluation/authorisation of feed additives; therefore questions concerning additives and their conditions of use should be addressed to the European Commission in Brussels at the following address:

EUROPEAN COMMISSION
Directorate General for 'Health and Consumers'
B-1049 BRUSSELS
http://ec.europa.eu/dgs/health_consumer/mailbox/index_en.htm

18. Where can I find information on the withdrawal periods established in the EU for specific substances?

The establishment of withdrawal periods is part of the Marketing Authorisation procedure of each individual veterinary medicinal product and is not simply substance related.

For veterinary medicinal products authorised via the "centralised procedure" for which the European Medicines Agency has the responsibility for the scientific assessment, detailed product information – including information on withdrawal periods, where applicable – is available on the Agency website. Click here to see the list of products, or refer to the Eudrapharm website.

The Agency however, does at present not have the information available on the withdrawal periods established for products authorised by the different Member States.

For products authorised via the Mutual Recognition” or “Decentralised” Procedure information can be found on the website of the Heads of Medicines Agencies (see HMA - VMRI Product Index).

Questions regarding withdrawal periods for veterinary medicinal products authorised nationally in specific Member States should be addressed to the Competent Authority of the Member State concerned. Addresses of the Members States Competent Authorities are available on the website of the Heads of Medicines Agencies (see HMA - VMRI Product Index).

19. Where can I get information on how to calculate withdrawal periods?

The CVMP developed guidelines concerning the establishment of withdrawal periods for meat (EMEA/CVMP/036/95) and for milk (EMEA/CVMP/473/98).

These guidelines are available on the Agency website under the Veterinary Scientific Guidelines - Safety and Residues - Pharmaceuticals - Residues / Withdrawal periods. Software Applications for the calculation of the withdrawal periods in accordance with these guidelines are available free of charge on the Agency website in the same section.