Q&A: Maximum Residue Limits (MRL)

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Update: As of 1 January 2017 it will be mandatory for applicants to use the eSubmission Gateway / Web Client for all veterinary procedural submissions to the Agency. For more information, including links to guidance on registration with the system, see:

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1. Can a veterinary medicinal product be authorised if no maximum residue limits (MRLs) have been established for the active substances of the product?

For food producing animals: NO. To obtain a marketing authorisation for a 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 tissues or products (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.

2. Do substances other than the active substances included in a medicinal product require a maximum residue limits?

YES, if they have pharmacological activity at the dose that is intended to be administered to the target species, they require MRLs.

3. 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:

  • Regulation (EC) No 470/2009 of the European Parliament and of the Council of 6 May 2009 laying down Community procedures for the establishment of residue limits of pharmacologically active substances in foodstuffs of animal origin, repealing Council Regulation (EEC) No 2377/90 and amending Directive 2001/82/EC of the European Parliament and of the Council and Regulation (EC) 726/2004 of the European Parliament and of the Council, Official Journal L 152 of 16 June 2009, pages 11-22.
  • Commission Regulation (EC) No 37/2010 of 22 December 2009 on pharmacologically active substances and their classification regarding maximum residue limits in foodstuffs of animal origin, Official Journal L 15 of 20 January 2010, pages 1-72.

Regulation (EC) 470/2009 replaces Council Regulation (EEC) No 2377/90 and Commission Regulation (EC) No 37/2010 replaces Annex I to IV of Council Regulation (EC) No 2377/90. The legislation is available at the European Commission website (see Eur-lex).

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 and target animal species 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). The Commission also publishes on its website the complete series of Commission Regulations modifying the Annex to Commission Regulation (EC) No 37/2010.

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 Health & Consumers website. Although Volume 8 makes reference to the old Regulation (Regulation 2377/90), the scientific principles still apply. Furthermore, Volume 8 is being updated at present.

4. What does it mean for a substance to be included in table 1 or table 2 of the Annex to Commission Regulation (EC) 37/2010?

Table 1 of the Annex 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:

  • definitive MRLs established for the relevant food commodities (these were previously in Annex I of Council Regulation 2377/90),
  • provisional MRLs established for the relevant food commodities (these were previously in Annex III of Council Regulation 2377/90). Provisional MRLs can be established, for a defined period of time, when not all the requirements have been fully addressed. However, the outstanding issues do not relate to any major human safety concerns, so it is possible to conclude that residues at the proposed levels do not present a hazard to the health of the consumer. Once the outstanding issues have been satisfactorily addressed, provisional MRLs are replaced by definitive MRLs,
  • a statement that there is no MRL required (these were previously in Annex II of Council Regulation 2377/90). For these substances it is considered that it is not necessary to establish MRLs for the protection of human health. These substances may 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). 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.

5. 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 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) 470/2009 and further explained in Volume 8 of the Rules Governing Medicinal Products in the European Union. Although Volume 8 makes reference to the old Regulation (Regulation 2377/90), the scientific principles still apply. Furthermore, Volume 8 is being updated at present.

Practical aspects for submission of the application are explained in European Medicines Agency Standard Operating Procedure (SOP) Evaluation procedure for applications and requests for the establishment of Maximum Residue Limits (MRLs) under Articles 3, 9, 10 and 15 of Regulation (EC) No 470/2009 (SOP/V/4051).

6. 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 and target animal species. However, the procedure is essentially similar to that for full applications.

7. 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 basis for the request for the modification. 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 made to the European Medicines Agency under Article 3 of the Regulation.

8. What fee do I have to pay for 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 abovementioned Regulation (see Eur-lex). Fees for MRL applications.

9. Are the fees for MRL applications for minor animal species or for substances intended for the treatment of rare diseases the same as for major species and common 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 - seeEur-lex) 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.

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 European Medicines Agency, also taking into consideration the availability of funds.

10. 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 on-going basis in the L-series of the Official Journal of the European Union (OJ) (see Eur-lex). The Commission also publishes, on its website the complete series of Commission and Council Regulations modifying the Annex to Commission Regulation (EC) No 37/2010.

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

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

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

For substances included in the annex to Regulation (EC) No 37/2010, European Public MRL Assessment Reports (EPMARs), which were called until 2007 “Summary Reports”, on the scientific evaluations carried out by the Committee for Medicinal Products for Veterinary Use (CVMP), are published on the European Medicines Agency website.

13. Why can’t I find the report for some substances for which a “No MRL required” status has been established?

Some substances included in Table 1 of 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” (see Commission Regulation 2796/95 and 1931/99). The Committee for Medicinal Products for Veterinary Use (CVMP) considered “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 Summary Reports are available for some of these substances.

14. How frequently is the information on MRLs updated on the European Medicines Agency website?
  1. CVMP Summary Opinions on the establishment of MRLs are normally published on the European Medicines Agency website on the Friday following the CVMP meeting at which the Opinion was adopted. The documents are withdrawn following publication of the MRLs in the annex to Regulation (EC) No 37/2010.
  2. EPMARs or Summary Reports on substances for which MRLs have been established are published on the European Medicines Agency website as soon as possible (usually within 2 weeks) after publication of the MRLs in the Official Journal of the European Union.

 

15. Do MRLs established for substances which correspond to racemic mixtures apply to individual isomers?

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:

  • Menthol
  • Ketamine
  • Ketoprofen

and concluded that for these cases the MRLs established for the racemic mixture also apply to the individual isomers.

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 Regulation (EC) No 470/2009?

The legislation (Directive 2001/82/EC, as amended by Directive 2004/28/EC and Directive 2009/9/EC) requires that all pharmacologically active substances contained in a veterinary medicinal product for food producing species need to be included in Table 1 of the Annex to Commission Regulation (EC) No 37/2010. 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 Regulation 37/2010 and only substances that are considered not 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, often called “out-of-scope” list.

An excipient that is not listed in either Table 1 of Commission Regulation (EC) 37/2010 or is not 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 470/2009 (EMA/CVMP/519714/2009) a request should be submitted to the Agency. Data requirements for such requests are laid out in CVMP’s 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 (EMA/CVMP/516817/2009).

In the case of requests that do not require extensive evaluation, the CVMP may decide to include the substance in the list of substances considered as not falling within the scope of Regulation (EC) No 470/2009. 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. For guidance to applicants regarding scientific advice: scope, structure of the request, fees payable, etc. see EMEA/CVMP/172329/2004 on the European Medicines Agency website. The procedure for providing scientific advice to applicants is explained in the European Medicines Agency Standard Operating Procedure (SOP) SOP/V/4016

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 above (EMA/CVMP/516817/2009). within the marketing authorisation application procedure dossier. In this case the competent authority will conclude on the whether the excipient falls within the scope of the Regulation 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.

Applicants are advised to contact the European Medicines Agency secretariat for further advice (see Pre-Submission Guidance; or email: vet.applications@ema.europa.eu)

17. Are substances included in Table 1 of the Annex to Commission Regulation (EC) No 37/2010 related to the use as additives in feedstuffs?

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 (European Parliament and Council Regulation (EC) No 1831/2003). Regulation (EC) No 470/2009 is not applicable to those substances. The European Medicines Agency is not involved in the procedure for evaluation/authorisation of feed additives; therefore questions concerning feed 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 for 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 European Medicines Agency website. See the list of products, or refer to the Eudrapharm Website.

The European Medicines Agency, however, does not, at present hold information on the withdrawal periods established for products authorised directly by the 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 (HMA Veterinary MRIndex).

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 website of the Heads of Medicines Agencies (HMA - Directory).

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

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 of the European Medicines Agency website.

20. What is the European Medicines Agency’s role in the evaluation of biocidal products?

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 food commodities with biocides). Regulation (EC) No 470/2009 lays down that the Committee for Medicinal Products for Veterinary Use (CVMP) is responsible for performing MRL evaluations for pharmacologically active substances used in biocidal products for use in animal husbandry, where the Member States or the CVMP deems that such an evaluation is necessary. All other aspects of the evaluation of biocidal products is outside the responsibility of CVMP, but is undertaken by the Competent Authorities for biocides in Member States supported by the Commission. The CVMP has published a draft guideline on Risk characterisation and assessment of Maximum Residue Limits (MRL) for biocides (EMA/CVMP/90250/2010).

21. What are reference points for action (RPA) and who establishes them?

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 which are technically feasible to detect by food control laboratories. 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 same standards for the monitoring of banned substances.

22. What is the legal status of MRLs established by third countries?

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.

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