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Erythromycin Erythromycin A All food-producing
species
200 μg/kg Muscle For n sh the muscle MRL
relates to ‘muscle and skin in
natural proportions’.
MRLs for fat, liver and kidney do
not apply to n sh.
For porcine and poultry species
the fat MRL relates to ‘skin and
fat in natural proportions’.
Anti-infectious
agents/Anti-biotics
200 μg/kg Fat
200 μg/kg Liver
200 μg/kg Kidney
40 μg/kg Milk
150 μg/kg Eggs
Glutamine Not Applicable All food-producing
species
No MRL
required
Not applicable No entry No entry
Kanamycin Kanamycin A All food-producing
species except n
sh
100 μg/kg Muscle For porcine and poultry species
the fat MRL relates to ‘skin and
fat in natural proportions’.
Not for use in animals from
which eggs are produced for
human consumption.
Anti-infectious
agents/Anti-biotics
100 μg/kg Fat
600 μg/kg Liver
2500 μg/kg Kidney
150 μg/kg Milk
Levamisole Levamisole Bovine, ovine,
porcine, poultry
10 μg/kg Muscle For porcine and poultry species
the fat MRL relates to ‘skin and
fat in natural proportions’.
Not for use in animals from
which milk or eggs are produced
for human consumption.
Antiparasitic
agents/Agents
against
endoparasites
10 μg/kg Fat
100 μg/kg Liver
10 μg/kg Kidney
156 7 Authorisation of Veterinary Medicines
7.6.3 Marketing Authorisations
The procedures and timelines for obtaining marketing authorizations for veterinary
products are essentially the same as those for human medicines. These are now set
out in Regulation (EU) 2019/6, which apply to new marketing applications since 28
January 2022. Extensive guidance can be found in ‘The Rules Governing Medicinal
Products in the European Union, Volume 6 – Notice to Applicants, Veterinary
Medicinal Products’. The products that may follow centralised procedures and
receive Union authorisations are shown in Figure 7.5. All other products must
obtain authorisations from national Competent Authorities using Mutual Recog-
nition, Decentralised or National procedures. In the case of Union authorizations,
the CVMP and the Standing CVMP perform roles identical to those played for
human medicines by the CHMP and the Standing Committee for Human Medicinal
Products. As already noted, authorisations cannot be granted for use of veterinary
products in food-producing animals unless all active substances are entered in the
Annex of the MRL regulations. Authorisations of vaccines may be limited to certain
states or regions, on the grounds that immunisation would interfere with diagnostic
procedures used to prevent, control or eradicate the disease in other areas. For
example, Ireland as an island nation would tend to pursue policies of testing to
eradicate and achieve disease free status in favour of vaccination strategies.
7.6.4 Presentation of the Dossier
The requirements for the contents of a technical dossier are now set out in Annex
II of Regulation No. (EU) 2019/6. The dossier should be assembled in four parts as
outlined in Figure 7.6 with variations depending on the type of product involved.
The application form, Summary of Product Characteristics and labelling, expert
reports and quality sections are quite similar in content to human medicines
Mandatory
● Biotech products based on recombinant DNA, gene expression, or hybridoma/
monoclonal antibody technologies.
● Products intended primarily for use as performance enhancers to promote the growth of
treated animals or to increase yields from treated animals.
● Veterinary medicinal products containing an active substance that has not been autho-
rised as a veterinary medicinal product within the Union at the date of the submission
of the application.
● Biological veterinary medicinal products thatcontain or consist of engineered allogeneic
tissues or cells.
● Novel therapy veterinary medicinal products, such as products based on gene therapy,
regenerative medicine, tissue engineering, blood product therapy, phage therapy,
nanotechnologies, or other therapy, which is considered as a nascent eld.
Optional
● Any veterinary medicinal product that has not previously been granted a marketing
authorisation within the Union
Figure 7.5 Veterinary products that may be authorized via centralised procedures
according to Regulation No. (EU) 2019/6.
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7.6 Authorisation of Veterinary Medicines in the EU 157
PART 1 Administrative Documentation & Summary of the Dossier
A. Administrative Data (Application form, etc.)
B. Summary of Product Characteristics Label & Package Insert
C. Detailed and critical summaries (Expert Reports; Quality, Safety, Ecacy)
PART 2 Pharmaceutical (physico-chemical, biological or microbiological
information (quality))
A. Qualitative and Quantitative Composition
B. Description of Manufacturing Methods
C. Control of Starting Materials
D. Control tests of intermediate products
E. Control tests on nished products
F. Stability
G. Other information
PART 3 Safety and Residues Documentation
A. Safety Tests
B. Residue Tests
PART 4 Pre-clinical & Clinical Data Ecacy Documentation
A. Pharmacology (Pharmacodynamics, Pharmacokinetics)
B. Tolerance in the Target Species
Figure 7.6 Outline of the dossier structure for a marketing application for a standard
veterinary product.
submissions. The target species and relevant withdrawal periods for food-producing
animals must be stated in the SPC and labelling. The outer labels should also bear
the warning statements ‘For animal treatment only’ and ‘keep out of the sight
and reach of children’. Data in Parts 3 and 4 are presented on the basis of the
purpose for which the study was conducted i.e. safety or ecacy. This diers from
human medicines dossiers where data is segregated on the basis of how it was
obtained i.e. non-clinical or clinical studies. The type of information presented in
the Safety and Ecacy Parts of the dossier will vary depending on whether it for an
immunological product or not. For example, residues or resistance documentation
would not normally be part of a vaccine dossier.
A veterinary product approval case study is presented in Box 7.1.
Box 7.1 Veterinary Product Approval Case Study: OvuGel
OvuGel is a tradename given to triptorelin acetate, a veterinary medicine used to
synchronise ovulation in pigs (sows), thereby facilitating a timed insemination
breeding program. Triptorelin acetate is a synthetic analogue of the naturally
occurring substance gonadotropin-releasing hormone (GnRH). Structurally it is
a peptide, consisting of 10 amino acids.
Vetoquinol pharmaceuticals submitted a marketing authorisation application
for Ovugel to the EMA in May 2019 via the EU’s centralized application
procedure. The application was assessed by the CVMP and, following a positive
opinion, the European Commission issued a marketing authorization for the
product, valid throughout the EU, on 10 November 2020.
(Continued)
158 7 Authorisation of Veterinary Medicines
Box 7.1 (Continued)
Prior to the marketing authorization application, the EMA (CVMP) had consid-
ered an application for the establishment of MRLs in all food-producing species
for triptorelin in 2013. Following consideration by the CVMP of the information
provided, the European Commission adopted a decision in 2014 that a ‘no MRL
required’ classification was appropriate. The decision was underpinned by the
fact that:
● Due to its chemical structure (a peptide) its oral bioavailability would be neg-
ligible (supported by studies in rats showing no biological or toxicological
effects following the highest oral dose tested).
● As a peptide, it will be naturally degraded in the gastrointestinal tract into its
constituent amino acids.
● Pigs will be treated two to three times annually at most, and it is unlikely
that they will be slaughtered during the three to four-week period between
insemination after product use and confirmation of pregnancy.
7.7 Approval of Veterinary Medicines in the US
Depending on whether it is classied as a drug or a biologic, the applicant must
submit either a New Animal Drug Application (NADA) to the FDA CVM or
veterinary biologics licence applications to the USDA CVB.
Some regulatory terminology/classication that can aect the exact approval data
required/processes include:
● Major and Minor species: CVM classies horses, dogs, cats, cattle pigs, chick-
ens and turkeys as major species, with all other animals being considered minor
species.
● Companion animals (pets) vs. food-producing animals.
7.7.1 New Animal Drug Application (NADA)
The requirements for a NADA are set out in 21 CFR 514.1 and are summarised in
Figure 7.7. The main technical sections of an application centre on:
● Target animal safety (evidence that the drug is safe for the target animal species
when used according to the label).
● Drug eectiveness (primarily via eld study results in which the target animals
with the target condition were treated with the drug).
● Human food safety (tests illustrating that food products made from the treated
animals are safe for human consumption).
● Chemistry, manufacturing, and controls (CMC; drug quality-related data).
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7.7 Approval of Veterinary Medicines in the US 159
1. Identication
2. Table of contents & summary
3(a) Labelling
3(b) Chemistry, manufacturing and controls
3(c) Human food safety
3(d) Target animal safety
3(e) Eectiveness
3(f) Environmental impact
3(g) All other information
3(h) Freedom of Information summary (for public disclosure)
4. Sample submission
5. Veterinary Feed Directive (if applicable)
6. Commitments required by 21 CFR
7. Patent information
8. User fee cover sheet
Figure 7.7 Outline of requirements for a NADA submission.
● Environmental impact (Environmental assessment studies, describing how much
drug is likely to nd its way into the environment, and the potential resultant
environmental consequences).
A FDA-356v form must accompany each submission (see Figure 7.8). This is
similar to the form used for human drug submissions in that it captures basic
information on the submission and provides a checklist for accompanying doc-
uments or materials. The labelling should include instructions on how to use
the drug in the manufacture of medicated feeds, where such use is intended.
The CVM may request samples of the drug product itself, reference materials or
standards, and samples of food products from treated animals in order that they
can, in conjunction with the USDA Food Safety and Inspection Service (FSIS),
establish and verify the analytical procedures for the drug or its residues. Unlike
in Europe, the applicant does not have to submit a separate residues application
but instead can include proposed tolerances and withdrawal periods in the residue
section of the NADA application. The FDA will then set nal tolerances and
withdrawal periods as part of the conditions for approval of the new drug. Where
they exist, the FDA may rely on international residue limits established by the
Codex Alimenterius Commission. The FDA can approve a new drug as prescription
only, non-prescription, or as a drug for administration in animal feed under the
direction of a veterinarian – a Veterinary Feed Directive (VFD) drug. A VDF
categorisation allows general access to drugs that may enhance animal health or
performance while at the same time reducing the risk of abuse or drug resistance
that might exist if there was unrestricted availability. The timelines and process for
review and approval of a new animal drug are essentially the same as those for a
human drug.
The approval requirements and process are very similar for food producing and
companion animals, except that human food safety evaluation is not required in the
case of companion animal drug applications.
160 7 Authorisation of Veterinary Medicines
Figure 7.8 FDA form 356v.
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7.7 Approval of Veterinary Medicines in the US 161
Figure 7.8 (Continued)
162 7 Authorisation of Veterinary Medicines
Figure 7.8 (Continued)
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7.7 Approval of Veterinary Medicines in the US 163
7.7.2 Approval of Veterinary Biological Products
The USDA, as opposed to the FDA, is authorized(under the 1913 Virus-Serum-Toxin
Act, amended by the 1985 Food Security Act), to regulate veterinary biologics pro-
duced in the US, or imported into the US. Veterinary biologics include vaccines,
bacterins, and antisera, as well as diagnostic kits and other products of biological
origin which are used for veterinary purposes. Federal law prohibits the shipment
of veterinary biologics unless they are manufactured in accordance with regulations
contained in Title 9 of the Code of Federal Regulations, Parts 101 to 118. Regulatory
activity is undertaken by the CVB, which is part of the USDA’s Animal and Plant
Health Inspection Service (APHIS).
To market a new veterinary biological product an applicant, must submit separate
licence applications for the product and the establishment to the CVB. This diers
from human biologic products, where product and the facilities information may be
combined in one BLA submission. The requirements for each licence application
are set out in 9 CFR Part 102. The information required for a Veterinary Biolog-
ics Establishment License application is outlined in Figure 7.9. A prime concern
of establishment licensing is to ensure that viruses or toxins can be handled safely
under appropriate biocontainment conditions. Thus, evidence must be provided as
regards the suitability of the facilities and the competence of the operating sta.
The product license application focuses on establishing the safety and ecacy of
the biological product. As bio-safety is also a critical aspect of many biologic prod-
ucts, submissions will include data, as relevant, on the purity of master seeds/cell
stocks, the stability of genetically modied organisms, the validation of inactivation
procedures for killed organisms and the purity of products derived from organisms.
The type of information required for approval of a Veterinary Product LicenseAppli-
cation is outlined in Figure 7.10.
Biological products may also be imported into the US for research purposes or
for sale, in accordance with Title 9, Code of Federal Regulations, Part 104. APHIS
Form 2005 is used to apply for an import permit and the products imported must
meet the same requirements as those required for licensed (domestically produced)
products.
1. Application Form containing applicant details (APHIS Form 2001).
2. Application for at least one Product License (APHIS form 2003, see Figure 7.10)
supported by an outline of production, information on master seeds/master cells and
biocontainment if applicable, and protocols for studies of host animal safety and
ecacy.
3. Letter(s) of approval signed by appropriate company personnel.
4. Waterqualitystatementfromlocalauthorities certifying compliance with euent waste
regulations.
5. Facility documentation (facility will also be inspected).
6. Other relevant information.
Figure 7.9 Outline of requirements for a Veterinary Biologics Establishment License.
164 7 Authorisation of Veterinary Medicines
1. Application Form (APHIS Form 2003)
2. Outline of production
3. Test reports and research data sucient to establish purity, safety, potency and ecacy
of the product
4. Legends designating facilities used for each step
5. Labelling
1. Application form (APHIS form 2003).
2. Method of production.
3. Prior submissions (if any) for the product.
4. Other pertinent information.
Figure 7.10 Outline of requirements for a Veterinary Biologics Product Licence Application.
7.8 Chapter Review
This chapter examined the process of bringing veterinary medicinal products to
market. It is quite similar to the process for human drugs in that the developer
must progress through preclinical, clinical, and marketing authorisation phases.
However, some dierences of note do exist. As clinical trials do not involve human
subjects, but rather animals maintained under the normal eld conditions and
purposes for which they are reared, they do not come under quite the same degree
of regulatory oversight. The establishment of MRLs and appropriate withdrawal
periods is an additional step that must be completed in the case of chemical-based
veterinary pharmaceuticals intended for use in food-producing species. The USDA,
through its Centre for Veterinary Biologics, rather than the FDA, is responsible for
the oversight and approval of veterinary biologics.
7.9 Further Reading
European Regulations and Guidance
Veterinary Medicines Regulation (EU) 2019/6
MRLs – Regulation (EC) No. 470/2009 The Rules Governing Medicinal Products in the
European Union, Volume 6 – Notice to Applicants, Veterinary Medicinal Products
The Rules Governing Medicinal Products in the European Union, Volume 8 – MRLs
https://ec.europa.eu/health/documents/eudralex_en
US Code of Federal Regulations
Veterinary biologics – 9 CFR Parts 102,103
Veterinary drugs – 21 CFR Parts 511 & 514
https://www.ecfr.gov
VICH Guidelines
www.vichsec.org
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