The European Union's Regulatory Framework on Veterinary Medicinal Products

Gudrun Gallhoff, Brussels, Belgium

Introduction

The European Union^[26] has in accordance with Article 152 of its founding Treaty^[27] to ensure a high level of human health protection in the definition and implementation of all its policies. The European Union's regulatory framework on pharmacologically active substances and veterinary medicinal products (veterinary drugs or animal drugs) has been in place since the early 1990s and has been further developed and detailed to meet the needs of protection of human and animal health as well as the environment. Its was prompted by the increased awareness of residues of potentially harmful substances in food in Europe in general and the envisaged completion of the European Single Market by 1992^[28].

European Union's regulatory framework on residues

EU legislation on pharmacologically active substances and veterinary medicinal products consists of Directives, Regulations and Decisions. In European Union law http://www.wordiq.com/definition/EuropeanUnionLaw, a directive http://www.wordiq.com/definition/EuropeanUniondirective is a form of legislative act addressed to the Member States http://www.wordiq.com/definition/EuropeanUnionmemberstates. The directive binds the Member States to reach certain objectives in their national legislation. Regulations have a general scope, and are obligatory in all their elements and directly applicable in all Member States http://www.wordiq.com/definition/EuropeanUnionmemberstates (most powerful or influential form of EU law). Decisions are also binding in their entirety upon to who the are addressed (e.g. Member States or particular companies).

Directives and Regulations on food safety are subject to approval by Member States (in the Council) and the European Parliament (Co-decision procedure). This procedure takes usually around 2 years once the European Commission has presented a proposal. EU Commission Regulations, Directives and Decisions are acts which implement provisions. They are adopted in a committee system (Comitology). The Standing Committee for the Food Chain and Animal Health is the committee, made up of representatives from Member States http://www.wordiq.com/definition/Memberstates and chaired by the Commission, which deals with food safety and the Standing Committee on Veterinary Medicinal Products deals with proposals related to veterinary medicinal products.

The European Union's regulatory framework on pharmacologically active substances and veterinary medicinal products consists mainly of the following pieces of legislation:

Directive 2001/82/EC^[29] as amended by Directive 2004/28/EC (the Code on Veterinary Medicinal Products) provides that veterinary medicinal products have to be authorised before they are put on the market. For use in food producing animals, a product can only be authorised if pharmacologically active substances contained therein have been assessed as safe according to Regulation 2377/90 (see below). Moreover the Directive contains rules concerning the documentation of use, re-designation (off label/extra label), prescription and distribution of veterinary medicinal products intended for use in food producing animals.

Directive 96/22/EC^[30] prohibits the use of certain substances for specific purposes in food producing animals.

Regulation 2377/90^[31] (MRL Regulation) introduced European Union procedures to evaluate the safety of residues of pharmacologically active substances according to human food safety requirements. A pharmacologically active substance may be used in food producing animals only if evaluated favourably and included in Annex I, II or III of the Regulation by means of a Commission Regulation. If considered necessary for the protection of human health, maximum residue limits (MRLs) are established. They are the points of reference for the establishment of withdrawal periods in marketing authorisations as well as for the control of residues in the Member States and at Border Inspection Posts.

Rules on food control in general have recently been modified with the adoption of Regulation (EC) No 882/2004 (General Control Regulation)^[32]. Additionally Directive 96/23/EC (Residue Control Directive)^[33] contains specific requirements, in particular for the control of pharmacologically active substances that may be used as veterinary medicinal products in food producing animals. This includes primarily sampling and investigation procedures, requirements on the documentation of use, indications for sanctions in case of non-compliance, requirements for targeted investigations and for the establishment and reporting of monitoring programmes.

Concerning imports, Directive 97/78/EC (Third Country Control Directive)^[34] requires that each consignment imported from third countries is subject to veterinary controls that may include analytical tests for residues of pharmacologically active substances, in order to verify whether the consignments fulfil the requirements of Community legislation.

For completeness it has to be mentioned that feed additives and pesticides are subject to a separate set of rules, although they may contain the same substances (dual use substances).

The Reflection Paper, a review of EU framework on residues

The European Union's regulatory framework on residues is at this time under reconsideration. This is necessary to accommodate for the significant restructuring of EU legislation following the adoption of Regulation (EC) N° 178/2002 (Food Law)^[35] and the adoption of the General Control Regulation.

Reconsideration of the legal framework on residues is also necessary to address a number of problems related to the decreased availability of medicines for use in food producing animals and the implementation and enforcement of legislation related to the control of residues in foods of animal origin causing difficulties in the functioning of the Single Market and in international trade.

The European Commission launched a respective discussion with the publication of the Reflection Paper on Residues in foodstuffs of animal origin^[36]. This discussion paper presents points that need to be considered and debated with a view to possibly modify Community legislation concerning residues of veterinary medicinal products. The goal is to determine new means to balance consumer protection, animal health, animal welfare and trade requirements concerning residues of pharmacologically active substance used in veterinary medicinal products in food producing animals. On the basis of the comments received^[37], the Commission will make proposals on the necessary amendments of the Community legislative framework in this sector.

However, as a change of the European Union's regulatory framework on residues involves the modification of Directives, Regulations and Decisions, effects of such modifications can only become effective in several years' time.

Substances without ADI/MRL

Veterinary medicinal products containing pharmacologically active substances intended for use in the European Community have to be authorised. The scientific, technical and regulatory requirements are laid down in Directive 2001/82/EC. Article 6 of this Directive requires prior classification in Annexes I, II or III of Regulation 2377/90 if a substance is to be authorised as veterinary medicinal product in the European Union or to be used off label (extra label) in food producing animals.

It is prohibited to use substances which have not been evaluated or which have been listed in Annex IV of Regulation 2377/90. In addition, it is prohibited to use substances which have been excluded according to Directive 96/22/EC in food producing animals and there are restrictions as regards the use for some pharmacologically active substances detailed in this Directive.

Directive 96/23/EC (Article 29) requires that in order to be included on the lists of third countries that may import food of animal origin into the Community, the third country must provide guarantees which have an equivalent effect as the measures Member States must implement according to the same Directive.

In consequence, the results of the human safety evaluation summarised in Annex I to IV of Regulation 2377/90 (i.e. substance and species specific MRLs, substances for which no MRLs are necessary and prohibited substances) and those prohibitions according to Directive 96/22/EC are also valid for imported products. Hence, it is unlawful to import products into the Community if residues are present in these products that exceed the established limits or that contain residues of substances, which after evaluation have been classified as substances hazardous at whatever limit and included in Annex IV of Regulation 2377/90. Residues of substances, for which no evaluation has been conducted, either due to the fact that no application for establishment of MRLs in accordance with Regulation 2377/90 has been received or due to lack of data to complete the evaluation are likewise not tolerated.

As no reference points have been established for these substances, any amount of residue found can be considered non-compliant. The EU legislative framework does not provide a specific procedure for setting import tolerances for residues of veterinary medicinal products used in food producing animals, as the framework is directed towards the safe use of authorised veterinary medicinal products in the European Union.

The comments received on the Reflection Paper concerning legislation on prohibited substances highlight the conflict between the term at whatever limit in Article 5 of Regulation 2377/90 and the practical problems in routine food control. Several proposals to address the issue have been made, e.g. setting of a general default limit for substances not hitherto evaluated, establishment of harmonised action limits for food that contains residues of unauthorised substances, setting of limits for all substance/matrix combinations where there is a potential for misuse

It was, however, also stressed that solutions should not lead to the effect that the use of currently prohibited substances is thus indirectly tolerated in the European Union or in third countries producing for the EU. Consequently, all results should be reported, unauthorised use of substances should be followed up and the respective enforcement measures should be defined and employed in a harmonised way.

The (Minimum) Required Performance Limit ((M)RPL) approach

As the foreseen changes in the European Union's regulatory framework on residues can only become effective in several years, an attempt has been made to address the urgent problems related to prohibited substances while the general revision is considered in parallel.

The evaluation according to Regulation 2377/90 does in many cases not produce clear points of reference for the evaluation of consignments. In cases where points of reference have not been established, the only legal safe ground for food inspectors in the European Union is to consider any amount of the substance found in food in question non-compliant with EU legislation. This has been addressed as the policy of zero tolerance. The term itself does not appear in EU legislation.

In practice zero tolerance means not detectable with the method employed and is therefore determined under the competence of the laboratory in charge (i.e. the individual laboratory's detection limit). This practice leads inevitably to a perceived inconsistency in the application of measures since the same sample can theoretically be tested positive or negative for a substance - depending on the sensitivity of the method employed. As in the EU more than hundred laboratories are engaged in residue control, it is clear that this practice leads inevitably to apparent inconsistencies in the application of measures.

Moreover, detection limits steadily decreased over time. Today's detection limits are ten times lower than what was considered state-of-the-art in 1994, when e.g. chloramphenicol was included in the list of prohibited substances of Regulation 2377/90. It is possible that the development of time-of-flight analysers will further reduce detection limits to 10 to 100 fold.

In pursuit of legal certainty and proportionality it seems therefore imperative that risk managers establish a harmonised approach for the evaluation of consignments.

Commission Decision 2002/657/EC^[38] introduced Minimum Required Performance Limits (MRPLs) intended to promote harmonised implementation of Directive 96/23/EC for substances for which no permitted limited has been established. MRPLs are defined as minimum content of an analyte in a sample, which at least has to be detected and confirmed.

This approach has, however, not been embraced by all Member States with respect to the intended harmonisation. The European Commission has in consequence proposed that the term minimum required performance limits (MRPL) should be replaced by required performance limits (RPL) and be used as reference points for action to ensure a harmonised implementation and legal certainty. The respective proposal for a Decision is under discussion in the Standing Committee for the Food Chain and Animal Health. In contrast to maximum residue limits (MRLs) for substances that may be used in food producing animals in the EU, RPLs would be control tools based on expert advice on feasibility of controls, an other legitimate factor in risk analysis (Article 6 of Regulation 2002/178/EC Food Law and Codex Alimentarius^[39]). Consignments containing residues above the RPL would be rejected. If guarantees are provided, they may be returned to the sender.

It is important to stress that the proposal to use RPLs as reference points for action is not tantamount to tolerating the use of prohibited substances in third countries in the products destined for the EU market. The EU would still demand from its trading partners to prohibit the use of substances banned in the EU or to establish split systems and ask third countries to provide respective guarantees. In consequence detection of prohibited substances below the RPL would still be documented and reported. The European Commission would in cases pointing to a pattern of misuse of a particular substance address the issue with the third country in question and ask for explanations. If the third country cannot provide sufficient explanations and further guarantees, it would face more intensive sampling and at worst delisting. The effect of the proposal is therefore rather a switch of focus from analytical performance and action against individual consignments to a more comprehensive approach on control of the use of veterinary medicinal products in Member States and third countries.

The proposed RPLs as reference points for action measure is deemed temporary and the approach will be reconsidered and factored in the revision of the EU legislation related to residues of veterinary medicinal products and other substances. Here particular attention will be paid to ascertain a level playing field for European Union and third countries producers.

Conclusion

European Union residue legislation aims at a high level of human health protection, but has also to strike a balance between different other legitimate interests such as animal health and animal welfare, protection of the honest user of medicinal products and lawful pharmaceutical manufacturers and compliance with trade agreements. In the implementation of the current legal framework a number of difficulties have been identified. These have been highlighted in a Reflection Paper. Adjustment of the framework can only become effective after a full legislative co-decision procedure. With the (M)RPL approach the European Commission has proposed a temporary measure to address urgent problems related to prohibited substances in particular in relation to third country trade.