Commission Regulation (EU) 2018/782Show full title

III. RESIDUE FILE U.K.

III.1. In general a full residue data package shall be required. If data are not provided for standard endpoints this shall be thoroughly justified. U.K.

III.2. Detailed and critical summary U.K.

III.2.1. A detailed and critical summary of the residues file shall be required for all applications. U.K.

III.2.2. The detailed and critical summary shall: U.K.

(a)

include a clear position on the adequacy of the data presented, in light of current scientific knowledge;

(b)

have an introduction describing the actual or proposed pattern of use of the substance under review in animal husbandry and a summary of any other experience of its use;

(c)

consider the extent to which the substance concerned has similarities to other known substances, which may be relevant for the evaluation;

(d)

cover all standard data requirements, as set out in Implementing Regulation (EU) 2017/12 provide a critical evaluation of the available experimental studies and an interpretation of the results;

(e)

provide scientific justification for the omission of any standard studies;

(f)

provide a description and explanation of the key findings for each study. The following issues shall be discussed: the animal species used (species, strain, sex, age, weight, etc.), test conditions (husbandry, diet, etc.), time points and numbers of animals per time point, milk and egg production if applicable, sampling (sampling size, collection and storage), and analytical methods used;

(g)

summarise and discuss relevant scientific literature, including reports of evaluations undertaken by other scientific bodies (such as EFSA or JECFA). If detailed references to published scientific literature are used, all the requirements set out under General principles point 5 (I.5) shall be met, as far as possible;

(h)

include information on the quality of batches of test substances used in the residue studies. Any association between findings and the quality of the test substances and/or the medicinal products shall be indicated. When necessary, a critical evaluation of the impurities present in the active ingredient shall be presented and information shall be provided on their potential influence on pharmacokinetics, metabolism, residue kinetics and analytical methods for the determination of residues. The implications of any differences of the chirality, chemical form and impurity profile between the substance used in the residues studies and the form to be marketed shall be discussed;

(i)

discuss the GLP status of the studies submitted;

(j)

discuss possible deficiencies in the design and conduct of the studies and their documentation, making reference to published Agency and other guidance. Any deviations from applicable guidance shall be highlighted and the impact of the deviation discussed and scientifically justified;

(k)

comment on the use of experimental animals in the studies and whether the studies were conducted in accordance with Directive 2010/63/EU;

(l)

justify the omission of particular studies and discuss the requirements for additional studies;

(m)

provide a section on risk management considerations, addressing the issues described in Annex II below, and explaining the derivation of the proposed MRLs.

III.2.3. Annexes to the detailed and critical summary shall include: U.K.

(a)

list of references — a list of all references shall be provided in accordance with internationally accepted standards. The references themselves shall be included in the dossier;

(b)

tabulated study reports — tabular summaries of study reports to the detailed and critical summary shall be provided. In addition, a complete set of study reports shall be included in the dossier.

III.3. Metabolism and residue kinetics in the target species U.K.

III.3.1. Metabolism and residues data shall be required to characterise residues present in relevant food commodities, to demonstrate the time course of their depletion to a safe level (usually based on the ADI) and so to allow derivation of MRLs. U.K.

III.3.2. The data shall be provided in the form of a total residues depletion study providing quantitative data on the parent drug and its major metabolites in relevant food commodities, and the change in the levels of these over time. Total residues studies usually use radiolabelled drug although data from non-radiolabelled studies may be provided where appropriate (for example if the substance is known not to be metabolised). A separate marker residue depletion study shall often also be provided, using unlabelled drug and monitoring the depletion of the marker residue in relevant food commodities over time. Total residues and marker residue data may be provided by means of a single radiolabelled study that also uses an appropriately validated non-radiolabelled method to monitor depletion of the marker residue. U.K.

III.3.3. The test material shall contain the substance of concern in a representative concentration. It shall be administered by the intended route of administration of the proposed product, at the highest intended dose and for the maximum intended duration of treatment or for the time required for steady state to be achieved in edible tissues. Studies shall be conducted in animals that are representative of the proposed target populations. U.K.

III.3.4. Guidance provided in VICH GL46: Studies to evaluate the metabolism and residue kinetics of veterinary drugs in food-producing animals: metabolism study to determine the quantity and identify the nature of residues (1) shall be followed in order to monitor (quantify) the depletion of total residues and key metabolites over time. These studies shall normally be performed using radiolabelled drug. U.K.

III.3.5. Guidance provided in VICH GL49: Studies to evaluate the metabolism and residue kinetics of veterinary drugs in food-producing animals: validation of analytical methods used in residue depletion studies (2) shall be followed in order to demonstrate the analytical method standards and in order to obtain marker residue depletion data of an acceptable quality. U.K.

III.3.6. Specific guidance relating to residue studies to be undertaken for substances intended for use in honey bees provided in VICH GL56: Studies to evaluate the metabolism and residue kinetics of veterinary drugs in food-producing species: study design recommendations for residue studies in honey for establishing MRLs and withdrawal periods (3) shall be followed. U.K.

III.3.7. The total residues study (usually performed with radiolabelled drug) shall provide information on: U.K.

(a)

the depletion of residues over time from relevant food commodities of treated animals;

(b)

the identity of the major components of the total residues in relevant food commodities;

(c)

the quantitative relationships between the major residue components and the total residues.

These data shall be used to establish the marker residue and the ratio of marker to total residues for each relevant food commodity.

III.3.8. A suitable marker residue shall be identified. The marker residue may be the parent drug, any of its metabolites or a combination of any of these. The marker residue shall have the following properties: U.K.

(a)

it shall have a known relationship between it and the total residue concentration in the edible tissue/food commodity of interest;

(b)

it is appropriate for use in testing for the presence of residues at the time point of interest;

(c)

it shall have a practicable analytical method to measure it at the level of the MRL.

III.3.9. The ratio of marker to total residues describes the relationship between the marker residue and total residues in each relevant food commodity. This ratio may be different in different food commodities and, as it may vary over time, it shall be established until the time corresponding to that at which residues of concern are expected to be below the ADI. The ratio of marker to total residues shall be used in the intake calculation to calculate potential consumer exposure to total residues from data relating to the marker residue. U.K.

III.3.10. By monitoring the depletion of total residues in the edible tissues/food commodities, the time point at which total residues deplete to below the ADI (or the fraction of the ADI available for use) shall be established. In each tissue/food commodity, the concentration of the selected marker residue at this time point shall be taken as the starting point from which the MRL shall be developed. U.K.

III.3.11. Information from the metabolism study shall also allow comparison of the metabolites produced in the target animal species with those produced in the laboratory animals species in order to ensure that the major residues to which consumers will be exposed (i.e. the major metabolites produced in the target species) were adequately tested in the laboratory animal toxicity studies. U.K.

III.3.12. Any departures from established guidance shall be justified and the impact discussed. U.K.

III.4. Monitoring and exposure data, if relevant U.K.

III.4.1. Monitoring or exposure data of the pharmacologically active substance shall not be required. However, if available, it may provide valuable additional information in certain cases, i.e. for substances that are already present in the environment (either naturally or as a result of use in the veterinary or other sectors). Such data may be useful in determining background levels to which consumers may already be exposed. If such data are available, whether as published results from official residue monitoring bodies or as results of academic or other research, these shall be provided. U.K.

III.5. Residue analytical method U.K.

III.5.1. A validation report of the analytical method used for quantification of the marker residue in the residues study shall be provided. Validation shall demonstrate that the analytical method complies with the criteria applicable for the relevant performance characteristics. The specific guidance on validation of analytical methods is provided in VICH GL49 shall be followed. U.K.

III.5.2. Analytical methods shall be provided at least for those food commodities and species in which MRLs are requested. U.K.

III.5.3. The availability of standards shall be confirmed and contact details provided in order to allow an exchange of information, if necessary, between representatives of the EU and national reference laboratory staff and the company. U.K.

III.5.4. Any departures from the requirements above shall be justified and the impact discussed. U.K.

III.5.5. The analytical method shall be evaluated for compliance with VICH GL49 and the additional points raised above. In addition, the Agency shall consult the European Reference Laboratory for control of residues for the particular substance type on the adequacy of the available methods and validation data. U.K.

III.5.6. Following the Agency's opinion, the validation data may be shared with other EU and national reference laboratories in order to facilitate development of appropriate methods by those authorities. U.K.

III.6. Potential effects on the microorganisms used for industrial food processing U.K.

III.6.1. The residues evaluation shall include an assessment of the potential effects of microbiologically active residues on microorganisms used for industrial food processing, in particular as regards the manufacture of dairy products. U.K.

III.6.2. The data shall be used to establish a residue concentration without effect on starter cultures. This shall be taken into consideration when deriving MRLs, to ensure that residues present in relevant food commodities (i.e. milk) are not present at levels that impact on dairy starter cultures. U.K.

III.6.3. The studies to be performed shall follow Agency's guidance for the assessment of the effect of antimicrobial substances on dairy starter cultures(4). U.K.

III.6.4. Any departures from the established guidance shall be justified and the impact discussed. U.K.

III.6.5. If no testing of microorganisms used for industrial food processing is undertaken, the absence of such data shall be scientifically justified and the impact of its absence discussed. U.K.

III.7. Findings of other EU or international scientific bodies U.K.

III.7.1. If relevant residues evaluations of the substance have been undertaken by other EU or international scientific bodies including EFSA, ECHA, JECFA and JMPR this shall be presented, along with the conclusions reached. U.K.

(1)

VICH GL46 Studies to evaluate the metabolism and residue kinetics of veterinary drugs in food-producing animals: metabolism study to determine the quantity and identify the nature of residues (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001516.jsp&mid=WC0b01ac058002dd37).

(2)

VICH GL49 Studies to evaluate the metabolism and residue kinetics of veterinary drugs in food-producing animals: validation of analytical methods used in residue depletion studies (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001513.jsp&mid=WC0b01ac058002dd37).

(3)

VICH GL56 Studies to evaluate the metabolism and residue kinetics of veterinary drugs in food-producing species: study design recommendations for residue studies in honey for establishing MRLs and withdrawal periods (http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/safety_residues_pharmaceuticals/general_content_001815.jsp&mid=WC0b01ac058002dd37).

(4)

Note for guidance for the assessment of the effect of antimicrobial substances on diary starter cultures (http://www.ema.europa.eu/ema/index.jsp?curl=pages/includes/document/document_detail.jsp?webContentId=WC500004533&mid=WC0b01ac058009a3dc).