MT
31 of 30 the and Veterinary
Table of Provisions (16)
Statutory Text (16 Articles)
Ministry for Resources
and Rural Affairs
L.N. 360 of 2009
VETERINARY
SERVICES
ACT ACT
VETERINARY
SERVICES
(CAP. 437)
(CAP. 437)
Veterinary Medicinal Products (Amendment) (No. 2)
Regulations, (No.
Veterinary Medicinal Products (Amendment)
2) Regulations, 2009
IN powers
exercise conferred
of the powers
conferred
by article
31 of 30 the and Veterinary
31 of
IN exercise of the
by article
30 and
the Veterinary Services Act, the Minister for Resources and Rural
Affairs, for
after
consulting
the Head
of after
the National
consulting Veterinary
Services Act, the Minister
Resources
and Rural
Affairs,
the Head of
Laboratory,
has made
the following
regulations:-
the National Veterinary
Laboratory,
has made
the following
regulations:-
The title of these regulations is the Veterinary Medicinal
1. The title of these Products
(Amendment)
(No. 2) Medicinal
Regulations,
2009 and
they shall be
regulations
is the Veterinary
Products
(Amendment)
(No.
read
and they
construed
shall be as read
one and
with construed
the Veterinary
Medicinal
with the Products
and
as one
Veterinary
Regulations, 2004, hereinafter referred to as “the principal
Medicinal Products Regulations, 2004, hereinafter referred to as “the principal
regulations”.
The Schedule to the principal regulations shall be
substituted
with the following:-
The Schedule to the principal regulations shall be substituted with the following:-
“Schedule
CHEMICAL, PHARMACEUTICAL AND ANALYTICAL STANDARDS,
SAFETY AND RESIDUE TESTS, PRE-CLINICAL AND CLINICAL TRIALS
IN RESPECT OF TESTING OF VETERINARY MEDICINAL PRODUCTS
TABLE OF CONTENTS
INTRODUCTION AND GENERAL PRINCIPLES
B
REQUIREMENTS FOR VETERINARY MEDICINAL PRODUCTS OTHER
THAN IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS
PART 1: SUMMARY OF THE DOSSIER
A. ADMINISTRATIVE INFORMATION
B. SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND
PACKAGE LEAFLET
C. DETAILED AND CRITICAL SUMMARIES
PART 2: PHARMACEUTICAL (PHYSICO-CHEMICAL, BIOLOGICAL OR
MICROBIOLOGICAL INFORMATION (QUALITY))
Basic principles and requirements
A.
QUALITATIVE
AND
QUANTITATIVE
PARTICULARS
OF
THE
CONSTITUENTS
1. Qualitative particulars
2. Usual terminology
Quantitative particulars
Development pharmaceutics
B. DESCRIPTION OF THE MANUFACTURING METHOD
C. CONTROL OF STARTING MATERIALS
1. General requirements
1.1. Active Substances
1.1.1. Active substances listed in pharmacopoeias
1.1.2. Active substances not in a pharmacopoeia
1.1.3. Physico-chemical characteristics liable to affect bioavailability
1.2. Excipients
1.3. Container-closure systems
B
1.3.1. Active substance
1.3.2. Finished Product
1.4. Substances of biological origin
D. CONTROL TESTS CARRIED OUT AT INTERMEDIATE STAGES OF THE
MANUFACTURING PROCESS
E. TESTS ON THE FINISHED PRODUCT
1. General characteristics of the finished product
2. Identification and assay of active substance(s)
3. Identification and assay of excipient components
4. Safety tests
F. STABILITY TEST
1. Active substances(s)
2. Finished product
G. OTHER INFORMATION
PART 3: SAFETY AND RESIDUES TESTS
A. Safety tests
CHAPTER I: PERFORMANCE OF TESTS
1. Precise identification of the product and of its active substance(s)
2. Pharmacology
2.1. Pharmacodynamics
2.2. Pharmacokinetics
3. Toxicology
3.1. Single-dose toxicity
3.2. Repeat-dose toxicity
3.3. Tolerance in the target species
3.4. Reproductive toxicity including developmental toxicity
B
3.4.1. Study of the effects on reproduction
3.4.2. Study of developmental toxicity
3.5. Genotoxicity
3.6. Carcinogenicity
3.7. Exceptions
4. Other requirements
4.1. Special studies
4.2. Microbiological properties of residues
4.2.1. Potential effects on the human gut flora
4.2.2. Potential effects on the microorganisms used for industrial food processing
4.3. Observations in humans
4.4. Development of resistance
User safety
Environmental risk assessment
6.1. Environmental risk assessment of veterinary medicinal products not containing
or consisting of genetically modified organisms
6.2. Environmental risk assessment for veterinary medicinal products containing or
consisting of genetically modified organisms
CHAPTER II: PRESENTATION OF PARTICULARS AND DOCUMENTS
B. Residue tests
CHAPTER I: PERFORMANCE OF TESTS
1. Introduction
2. Metabolism and residue kinetics
2.1. Pharmacokinetics (absorption, distribution, metabolism, excretion)
2.2. Depletion of residues
3. Residue analytical method
B
CHAPTER II: PRESENTATION OF PARTICULARS AND DOCUMENTS
1. Identification of the product
PART 4: PRE-CLINICAL AND CLINICAL TRIAL
CHAPTER I: PRE-CLINICAL REQUIREMENTS
A. Pharmacology
A.1. Pharmacodynamics
A.2. Development of resistance
A.3. Pharmacokinetics
B. Tolerance in the target animal species
CHAPTER II: CLINICAL REQUIREMENTS
1. General principles
2. Conduct of clinical trials
CHAPTER III: PARTICULARS AND DOCUMENTS
1. Results of pre-clinical trials
2. Results of clinical trials
TITLE II
REQUIREMENTS FOR IMMUNOLOGICAL VETERINARY MEDICINAL
PRODUCTS
PART 1: SUMMARY OF THE DOSSIER
A. ADMINISTRATIVE INFORMATION
B. SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND
PACKAGE LEAFLET
C. DETAILED AND CRITICAL SUMMARIES
PART
2
CHEMICAL,
PHARMACEUTICAL
BIOLOGICAL/MICROBIOLOGICAL INFORMATION (QUALITY)
A.
QUALITATIVE
AND
QUANTITATIVE
PARTICULARS
CONSTITUENTS
1. Qualitative particulars
2. "Usual terminology"
3. Quantitative particulars
4. Product development
B. DESCRIPTION OF MANUFACTURING METHOD
C. PRODUCTION AND CONTROL OF STARTING MATERIALS
1. Starting materials listed In Pharmacopoeias
2. Starting materials not listed in a pharmacopoeia
2.1. Starting materials of biological origin
2.2. Starting materials of non-biological origin
D. CONTROL TESTS DURING THE MANUFACTURING PROCESS
E. CONTROL TESTS ON THE FINISHED PRODUCT
1. General characteristics of the finished product
2. Identification of active substance(s)
3. Batch titre or potency
4. Identification and assay of adjuvants
5. Identification and assay of excipient components
6. Safety tests
Sterility and purity test
Residual humidity
Inactivation
F. BATCH TO BATCH CONSISTENCY
G. STABILITY TESTS
B
H. OTHER INFORMATION
PART 3: SAFETY TESTS
A. INTRODUCTION AND GENERAL REQUIREMENTS
B. LABORATORY TESTS
1. Safety of the administration of one dose
2. Safety of one administration of an overdose
3. Safety of the repeated administration of one dose
4. Examination of reproductive performance
5. Examination of immunological functions
6. Special requirements for live vaccines
6.1. Spread of the vaccine strain
6.2. Dissemination in the vaccinated animal
6.3. Reversion to virulence of attenuated vaccines
6.4. Biological properties of the vaccine strain
6.5. Recombination or genomic reassortment of strains
7. User safety
8. Study of residues
9. Interactions
C. FIELD STUDIES
D. ENVIRONMENTAL RISK ASSESSMENT
E. ASSESSMENT REQUIRED FOR VETERINARY MEDICINAL PRODUCTS
CONTAINING OR CONSISTING OF GENETICALLY MODIFIED ORGANISMS
PART 4: EFFICACY TESTS
CHAPTER I
1. General principles
B
2. Performance of trials
CHAPTER II
A. General requirements
B. Laboratory trials
C. Field trials
PART 5: PARTICULARS AND DOCUMENTS
A. INTRODUCTION
B. LABORATORY STUDIES
C. FIELD STUDIES
PART 6: BIBLIOGRAPHICAL REFERENCES
TITLE III
REQUIREMENTS
FOR
SPECIFIC
MARKETING
AUTHORISATION
APPLICATIONS
1. Generic veterinary medicinal products
2. Similar biological veterinary medicinal products
3. Well-established veterinary use
4. Combination veterinary medicinal products
5. Informed consent applications
6. Documentation for applications in exceptional circumstances
7. Mixed marketing authorisation applications
TITLE IV
B
REQUIREMENTS FOR MARKETING AUTHORISATION APPLICATIONS
FOR PARTICULAR VETERINARY MEDICINAL PRODUCTS
1. IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS
2. HOMEOPATHIC VETERINARY MEDICINAL PRODUCTS
INTRODUCTION AND GENERAL PRINCIPLES
1. The particulars and documents accompanying an application for marketing
authorisation pursuant to regulations 12 to 13(1) hereof shall be presented in
accordance with the requirements set out in this Schedule and shall take into account
the guidance published by the Commission in The rules governing medicinal
products in the European Union, Volume 6 B, Notice to applicants, Veterinary
medicinal products, Presentation and Contents of the Dossier.
2. In assembling the dossier for application for marketing authorisation, applicants
shall also take into account the current state of veterinary medicinal knowledge and
the scientific guidelines relating to the quality, safety and efficacy of veterinary
medicinal products published by the European Medicines Agency (Agency) and the
other pharmaceutical Community guidelines published by the Commission in
different volumes of The rules governing medicinal products in the European Union.
3. For veterinary medicinal products other than immunological veterinary medicinal
products, with respect to the quality (pharmaceutical) part (physico-chemical,
biological and microbiological tests) of the dossier, all relevant monographs
including general monographs and the general chapters of the European
Pharmacopoeia are applicable. For immunological veterinary medicinal products,
with respect to the quality, safety and efficacy parts of the dossier, all relevant
monographs including general monographs and the general chapters of the European
Pharmacopoeia are applicable.
4. The manufacturing process shall comply with the requirements of Commission
Directive 91/412/EEC 1 laying down the principles and guidelines for veterinary
OJ L 228, 17.8.1991, p. 70 .
B
medicinal products and with the principles and guidelines on Good Manufacturing
Practice (GMP), published by the Commission in The rules governing medicinal
products in the European Union, Volume 4.
5. All information which is relevant to the evaluation of the veterinary medicinal
product concerned shall be included in the application, whether favourable or
unfavourable to the product. In particular, all relevant details shall be given of any
incomplete or abandoned test or trial relating to the veterinary medicinal product.
6. Pharmacological, toxicological, residue and safety tests shall be carried out in
conformity with the provisions related to Good Laboratory Practice (GLP) laid down
in Directive 2004/10/EC of the European Parliament and of the Council 2 and
Directive 2004/9/EC of the European Parliament and of the Council 3 .
7. The Authority shall ensure that all experiments on animals are conducted in
accordance with Council Directive 86/609/EEC 4 .
8. In order to monitor the risk/benefit assessment, any new information not in the
original application and all pharmacovigilance information shall be submitted to the
competent authority. After marketing authorisation has been granted, any change to
the content of the dossier shall be submitted to the competent authorities in
accordance with Commission Regulations (EC) No 1084/2003 5 or (EC) No
1085/2003 6 for veterinary medicinal products authorised as defined in Article 1 of
such regulations, respectively.
9. The environmental risk assessment connected with the release of veterinary
medicinal products containing or consisting of Genetically Modified Organisms
(GMOs) within the meaning of Article 2 of Directive 2001/18/EC of the European
Parliament and of the Council 7 shall be provided in the dossier. The information
shall be presented in accordance with the provisions of Directive 2001/18/EC and
OJ L 50, 20.2.2004, p. 44.
OJ L 50, 20.2.2004, p. 28.
OJ L 358, 18.12.1986, p. 1.
OJ L 159, 27.6.2003, p. 1.
OJ L 159, 27.6.2003, p. 24.
OJ L 106, 17.4.2001, p. 1.
B
Regulation (EC) No 726/2004 of the European Parliament and of the Council 8 ,
taking into account guidance documents published by the Commission.
In cases of applications for marketing authorisations for veterinary medicinal
products indicated for animal species and indications representing smaller market
sectors, a more flexible approach may be applicable. In such cases, relevant
scientific guidelines and/or scientific advice should be taken into account.
This Schedule is divided in four titles
Title I describes the standardised requirements for applications for veterinary
medicinal products other than immunological veterinary medicinal products.
Title II describes the standardised requirements for applications for immunological
veterinary medicinal products.
Title III describes specific types of marketing authorisation dossiers and
requirements.
Title IV describes the dossier requirements for particular types of veterinary
medicinal products.
TITLE I
REQUIREMENTS FOR VETERINARY MEDICINAL PRODUCTS OTHER
THAN IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS
The following requirements shall apply to veterinary medicinal products other than
immunological veterinary medicinal products, except where otherwise set out in
Title III.
PART 1: SUMMARY OF THE DOSSIER
OJ L 136, 30.4.2004, p. 1.
B
A. ADMINISTRATIVE INFORMATION
The veterinary medicinal product, which is the subject of the application, shall be
identified by its name and by the name of the active substance(s), together with the
strength, the pharmaceutical form, the route and method of administration (vide
regulation 12 of these regulations) and a description of the final presentation of the
product, including packaging, labelling and package leaflet (vide regulation 12 of
these regulations).
The name and address of the applicant shall be given, together with the name and
address of the manufacturers and the sites involved in the different stages of the
manufacture, testing and release (including the manufacturer of the finished product
and the manufacturer(s) of the active substance(s)), and where relevant the name and
address of the importer.
The applicant shall identify the number and titles of volumes of documentation
submitted in support of the application and indicate what samples, if any, are also
provided.
Annexed to the administrative information shall be a document showing that the
manufacturer is authorised to produce the veterinary medicinal products concerned,
as defined in regulation 38 hereof, together with a list of countries in which
authorisation has been granted, copies of all the summaries of product characteristics
in accordance with regulation 14 hereof as approved by the territory of Malta and a
list of countries in which an application has been submitted or refused.
B. SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND
PACKAGE LEAFLET
The applicant shall propose a summary of the product characteristics, in accordance
with regulation 14 of these regulations.
A proposed labelling text for the immediate and outer packaging shall be provided in
accordance with Title V of these regulations, together with a package leaflet where
such is required pursuant to regulation 51 of these regulations. In addition the
applicant shall provide one or more specimens or mock-ups of the final
B
presentation(s) of the veterinary medicinal product in at least one of the official
languages of the European Union; the mock-up may be provided in black and white
and electronically where prior agreement from the competent authority has been
obtained.
C. DETAILED AND CRITICAL SUMMARIES
In accordance with regulation 12(3) hereof, detailed and critical summaries shall be
provided on the results of pharmaceutical (physico-chemical, biological or
microbiological) tests, of the safety tests and residue tests, of the pre-clinical and
clinical trials and of the tests assessing the potential risks posed by the veterinary
medicinal product for the environment.
Each detailed and critical summary shall be prepared in the light of the state of
scientific knowledge at the time of submission of the application. It shall contain an
evaluation of the various tests and trials, which constitute the marketing
authorisation dossier, and shall address all points relevant to the assessment of the
quality, safety and efficacy of the veterinary medicinal product. It shall give detailed
results of the tests and trials submitted and precise bibliographic references.
All important data shall be summarised in an appendix, whenever possible in tabular
or graphic form. The detailed and critical summaries and the appendices shall
contain precise cross references to the information contained in the main
documentation.
The detailed and critical summaries shall be signed and dated, and information about
the author's educational background, training and occupational experience shall be
attached. The professional relationship of the author with the applicant shall be
declared.
Where the active substance has been included in a medicinal product for human use
authorised in accordance with the requirements of Annex I to Directive 2001/83/EC
of the European Parliament and of the Council 9 the overall quality summary
provided for in Module 2, section 2.3 of that Annex may replace the summary
OJ L 311, 28.11.2001, p. 67 .
B
regarding the documentation related to the active substance or the product, as
appropriate.
Where the competent authority has publicly announced that the chemical,
pharmaceutical and biological/microbiological information for the finished product
may be included in the dossier in the Common Technical Document (CTD) format
only, the detailed and critical summary on the results of pharmaceutical tests may be
presented in the quality overall summary format.
In the case of application for an animal species or for indications representing
smaller market sectors, the quality overall summary format may be used without
prior agreement of the competent authorities.
PART 2: PHARMACEUTICAL (PHYSICO-CHEMICAL, BIOLOGICAL OR
MICROBIOLOGICAL INFORMATION (QUALITY))
Basic principles and requirements
The particulars and documents which shall accompany the application for marketing
authorisation pursuant to regulation 12 of these regulations shall be submitted in
accordance with the requirements below.
The pharmaceutical (physico-chemical, biological or microbiological) data shall
include for the active substance(s) and for the finished veterinary medicinal product
information on the manufacturing process, the characterisation and properties, the
quality control procedures and requirements, the stability as well as a description of
the composition, the development and presentation of the veterinary medicinal
product.
All monographs, including general monographs and general chapters of the
European Pharmacopoeia, or failing that, of Malta are applicable.
All test procedures shall fulfil the criteria for analysis and control of the quality of
the starting materials and the finished product and should take account of established
guidance and requirements. The results of the validation studies shall be provided.
B
All the test procedure(s) shall be described in sufficiently precise detail so as to be
reproducible in control tests, carried out at the request of the competent authority;
any special apparatus and equipment, which may be used shall be described in
adequate detail, possibly accompanied by a diagram. The formulae of the laboratory
reagents shall be supplemented, if necessary, by the method of preparation. In the
case of test procedures included in the European Pharmacopoeia or the
pharmacopoeia of Malta, this description may be replaced by a detailed reference to
the pharmacopoeia in question.
Where relevant, chemical and biological reference material of the European
Pharmacopoeia shall be used. If other reference preparations and standards are used,
they shall be identified and described in detail.
In cases where the active substance has been included in a medicinal product for
human use authorised in accordance with the requirements of Annex I to Directive
2001/83/EC
the
chemical,
pharmaceutical
and
biological/microbiological
information provided for in Module 3 of that Directive may replace the
documentation related to the active substance or the finished product, as appropriate.
The chemical, pharmaceutical and biological/microbiological information for the
active substance or the finished product may be included in the dossier in CTD
format only where the competent authority has publicly announced this possibility.
In the case of any application for an animal species or for indications representing
smaller market sectors the CTD format may be followed without prior agreement of
the competent authorities.
A.
QUALITATIVE
AND
QUANTITATIVE
PARTICULARS
OF
THE
CONSTITUENTS
1. Qualitative particulars
"Qualitative particulars" of all the constituents of the medicinal product shall mean
the designation or description of
- the active substance(s),
B
- the constituents of the excipients, whatever their nature or the quantity used,
including colouring matter, preservatives, adjuvants, stabilisers, thickeners,
emulsifiers, flavouring and aromatic substances,
- the constituents, intended to be ingested or otherwise administered to animals, of
the outer covering of the veterinary medicinal products, such as capsules, gelatine
capsules.
These particulars shall be supplemented by any relevant data concerning the
immediate packaging and if relevant the secondary packaging and, where
appropriate, its manner of closure, together with details of devices with which the
medicinal product will be used or administered and which will be supplied with the
medicinal product.
2. Usual terminology
The usual terminology to be used in describing the constituents of veterinary
medicinal products means, notwithstanding the application of the other provisions of
regulation 12(3)(c) hereof
- in respect of constituents which appear in the European Pharmacopoeia or, failing
this, in the national pharmacopoeia of one of the Member States, the main title at the
head of the monograph in question, with reference to the pharmacopoeia concerned,
- in respect of other constituents, the international non-proprietary name (INN)
recommended by the World Health Organisation (WHO), which may be
accompanied by another non-proprietary name, or, failing these, the exact scientific
designation; constituents not having an international non-proprietary name or an
exact scientific designation shall be described by a statement of how and from what
they were prepared, supplemented, where appropriate, by any other relevant details,
- in respect of colouring matter, designation by the "E" code assigned to them by
Council Directive 78/25/EEC 10 .
3. Quantitative particulars
OJ L 11, 14.1.1978, p. 18.
B
3.1. In order to give "quantitative particulars" of all the active substances of the
veterinary medicinal products, it is necessary, depending on the pharmaceutical form
concerned, to specify the mass, or the number of units of biological activity, either
per dosage-unit or per unit of mass or volume, of each active substance.
Units of biological activity shall be used for substances, which cannot be defined
chemically. Where an International Unit of biological activity has been defined by
the World Health Organisation, this shall be used. Where no International Unit has
been defined, the units of biological activity shall be expressed in such a way as to
provide unambiguous information on the activity of the substances by using where
applicable the European Pharmacopoeia Units.
Whenever possible, biological activity per units of mass or volume shall be
indicated. This information shall be supplemented
- in respect of single-dose preparations, by the mass or units of biological activity of
each active substance in the unit container, taking into account the usable volume of
the product, after reconstitution, where appropriate,
- in respect of veterinary medicinal products to be administered by drops, by the
mass or units of biological activity of each active substance contained per drop or
contained in the number of drops corresponding to 1 ml or 1 g of the preparation,
- in respect of syrups, emulsions, granular preparations and other pharmaceutical
forms to be administered in measured quantities, by the mass or units of biological
activity of each active substance per measured quantity.
3.2. Active substances present in the form of compounds or derivatives shall be
described quantitatively by their total mass, and if necessary or relevant, by the mass
of the active entity or entities of the molecule.
3.3. For veterinary medicinal products containing an active substance which is the
subject of an application for marketing authorisation in any Member State for the
first time, the quantitative statement of an active substance which is a salt or hydrate
shall be systematically expressed in terms of the mass of the active entity or entities
in the molecule. All subsequently authorised veterinary medicinal products in Malta
B
shall have their quantitative composition stated in the same way for the same active
substance.
4. Development pharmaceutics
An explanation shall be provided with regard to the choice of composition,
constituents, immediate packaging, possible further packaging, outer packaging if
relevant, the intended function of the excipients in the finished product and the
method of manufacture of the finished product. This explanation shall be supported
by scientific data on development pharmaceutics. The overage, with justification
thereof, shall be stated. The microbiological characteristics (microbiological purity
and antimicrobial activity) and usage instructions shall be proven to be appropriate
for the intended use of the veterinary medicinal product as specified in the marketing
authorisation application dossier.
B. DESCRIPTION OF THE MANUFACTURING METHOD
The name, address and responsibility of each manufacturer and each proposed
production site or facility involved in manufacturing and testing shall be indicated.
The description of the manufacturing method accompanying the application for
marketing authorisation pursuant to regulation 12(3)(d) hereof, shall be drafted in
such a way as to give an adequate synopsis of the nature of the operations employed.
For this purpose it shall include at least
- mention of the various stages of manufacture, so that an assessment can be made of
whether the processes employed in producing the pharmaceutical form might have
produced an adverse change in the constituents,
- in the case of continuous manufacture, full details concerning precautions taken to
ensure the homogeneity of the finished product,
- the actual manufacturing formula, with the quantitative particulars of all the
substances used, the quantities of excipients, however, being given in approximate
terms insofar as the pharmaceutical form makes this necessary; mention shall be
B
made of any substances that may disappear in the course of manufacture; any
overage shall be indicated and justified,
- a statement of the stages of manufacture at which sampling is carried out for in-
process control tests and the limits applied, where other data in the documents
supporting the application show such tests to be necessary for the quality control of
the finished product,
- experimental studies validating the manufacturing process and where appropriate a
process validation scheme for production scale batches,
- for sterile products, where non-pharmacopoeial standard sterilisation conditions are
used, details of the sterilisation processes and/or aseptic procedures used.
C. CONTROL OF STARTING MATERIALS
1. General requirements
For the purposes of this paragraph, "starting materials" shall mean all the
constituents of the veterinary medicinal product and, if necessary, of its container
including its closure, as referred to in Section A, point 1, above.
The dossier shall include the specifications and information on the tests to be
conducted for quality control of all batches of starting materials.
The routine tests carried out on each batch of starting materials must be as stated in
the application for marketing authorisation. If tests other than those mentioned in a
pharmacopoeia are used, this shall be justified by providing proof that the starting
materials meet the quality requirements of that pharmacopoeia.
Where a Certificate of Suitability has been issued by the European Directorate for
the Quality of Medicines and HealthCare for a starting material, active substance or
excipient, this Certificate constitutes the reference to the relevant monograph of the
European Pharmacopoeia.
Where a Certificate of Suitability is referred to, the manufacturer shall give an
assurance in writing to the applicant that the manufacturing process has not been
B
modified since the granting of the certificate of suitability by the European
Directorate for the Quality of Medicines and HealthCare.
Certificates of Analysis shall be presented for the starting materials in order to
demonstrate compliance with the defined specification.
1.1. Active substances
The name, address, and responsibility of each manufacturer and each proposed
production site or facility involved in manufacturing and testing of an active
substance shall be indicated.
For a well-defined active substance, the active substance manufacturer or the
applicant may arrange for the following information to be supplied in a separate
document directly to the competent authorities by the manufacturer of the active
substance as an Active Substance Master File
(a) a detailed description of the manufacturing process;
(b) a description of the quality control during manufacture;
(c) a description of the process validation.
In this case, the manufacturer shall however provide the applicant with all the data
which may be necessary for the latter to take responsibility for the veterinary
medicinal product. The manufacturer shall confirm in writing to the applicant that he
shall ensure batch to batch consistency and not modify the manufacturing process or
specifications without informing the applicant. Documents and particulars
supporting the application for such a change shall be supplied to the competent
authorities those documents and particulars shall also be supplied to the applicant
where they concern the applicant’s part of the Active Substance Master File.
Additionally, information on the method of manufacture, on quality control and on
impurities as well as evidence of the molecular structure shall be provided where a
Certificate of Suitability for the active substance is not available
1. Information on the manufacturing process shall include a description of the active
substance manufacturing process that represents the applicant’s commitment for the
manufacture of the active substance. All materials needed in order to manufacture
B
the active substance(s) shall be listed, identifying where each material is used in the
process. Information on the quality and control of those materials shall be provided.
Information demonstrating that materials meet standards which are appropriate for
their intended use shall be provided.
2. Information on quality control shall contain tests (including acceptance criteria)
carried out at every critical step, information on the quality and control of
intermediates and process validation and/or evaluation studies as appropriate. It shall
also contain validation data for the analytical methods applied to the active
substance, where appropriate.
3. Information on impurities shall indicate predictable impurities together with the
levels and nature of observed impurities. It shall also contain information on the
safety of these impurities where relevant.
4. For biotechnological veterinary medicinal products, evidence of molecular
structure shall include the schematic amino acid sequence and relative molecular
mass.
1.1.1. Active substances listed in pharmacopoeias
The general and specific monographs of the European Pharmacopoeia shall be
applicable to all active substances appearing in it.
Constituents fulfilling the requirements of the European Pharmacopoeia or the
pharmacopoeia of one of the Member States shall be deemed to comply sufficiently
with regulation 12(3) hereof. In this case the description of the analytical methods
and procedures shall be replaced in each relevant section by an appropriate reference
to the pharmacopoeia in question.
In cases where a specification contained in a monograph of the European
Pharmacopoeia or in the national pharmacopoeia of Malta is insufficient to ensure
the quality of the substance, the competent authorities may request more appropriate
specifications from the applicant, including limits for specific impurities with
validated test procedures.
The competent authorities shall inform the authorities responsible for the
pharmacopoeia in question. The marketing authorisation holder shall provide the
B
authorities of that pharmacopoeia with the details of the alleged insufficiency and the
additional specifications applied.
In the absence of a European Pharmacopoeia monograph for an active substance,
and where the active substance is described in the pharmacopoeia of Malta, that
monograph may be applied.
In cases where an active substance is described neither in the European
Pharmacopoeia nor in the pharmacopoeia of Malta, compliance with the monograph
of a third country pharmacopoeia may be accepted if its suitability is demonstrated;
in such cases, the applicant shall submit a copy of the monograph accompanied by a
translation where appropriate. Data to demonstrate the ability of the monograph to
adequately control the quality of the active substance shall be presented.
1.1.2. Active substances not in a pharmacopoeia
Constituents which are not given in any pharmacopoeia shall be described in the
form of a monograph under the following headings
(a) the name of the constituent, meeting the requirements of Section A point 2, shall
be supplemented by any trade or scientific synonyms;
(b) the definition of the substance, set down in a form similar to that used in the
European Pharmacopoeia, shall be accompanied by any necessary explanatory
evidence, especially concerning the molecular structure. Where substances can only
be described by their manufacturing method, the description shall be sufficiently
detailed to characterise a substance which is constant both on its composition and in
its effects;
(c) methods of identification may be described in the form of complete techniques as
used for production of the substance, and in the form of tests which ought to be
carried out as a routine matter;
(d) purity tests shall be described in relation to each individual predictable impurity,
especially those which may have a harmful effect, and, if necessary, those which,
having regard to the combination of substances to which the application refers,
might adversely affect the stability of the medicinal product or distort analytical
results;
B
(e) tests and limits to control parameters relevant to the finished product, such as
particle size and sterility shall be described and methods shall be validated where
relevant;
(f) with regard to complex substances of plant or animal origin, a distinction must be
made between the case where multiple pharmacological effects render chemical,
physical or biological control of the principal components necessary, and the case of
substances containing one or more groups of principles having similar activity, in
respect of which an overall method of assay may be accepted.
Those data shall demonstrate that the proposed set of test procedures is sufficient to
control the quality of the active substance from the defined source.
1.1.3. Physico-chemical characteristics liable to affect bioavailability
The following items of information concerning active substances, whether or not
listed in the pharmacopoeias, shall be provided as part of the general description of
the active substances if the bioavailability of the veterinary medicinal product
depends on them
- crystalline form and solubility coefficients,
- particle size, where appropriate after pulverisation,
- state of hydration,
- oil/water coefficient of partition,
- pK/pH values.
The first three indents are not applicable to substances used solely in solution.
1.2. Excipients
The general and specific monographs of the European Pharmacopoeia shall be
applicable to all substances appearing in it.
Excipients shall comply with the requirements of the appropriate European
Pharmacopoeia monograph. Where such a monograph does not exist reference may
be made to the pharmacopoeia of Malta. In the absence of such a monograph
reference may be made to the pharmacopoeia of a third country. In this case the
suitability of this monograph shall be demonstrated. Where appropriate, additional
B
tests to control parameters such as particle size, sterility, residual solvents shall
supplement the requirements of the monograph. In the absence of a pharmacopoeial
monograph a specification shall be proposed and justified. The requirements for
specifications as set out in section 1.1.2 (a to e) for the active substance shall be
followed. The proposed methods and their supporting validation data shall be
presented.
Colouring matters for inclusion in veterinary medicinal products shall satisfy the
requirements of Directive 78/25/EEC, except for certain veterinary medicinal
products for topical use, such as insecticidal collars and ear tags, where the use of
other colouring matters is justified.
Colouring matters shall meet the purity criteria as laid down in Commission
Directive 95/45/EC 11 .
For novel excipients, that is to say excipient(s) used for the first time in a veterinary
medicinal product or by a new route of administration, details of manufacture,
characterisation, and controls, with cross references to supporting safety data, both
clinical and non-clinical, shall be provided.
1.3. Container-closure systems
1.3.1. Active substance
Information on the container-closure system for the active substance shall be given.
The level of information required shall be determined by the physical state (liquid,
solid) of the active substance.
1.3.2. Finished product
Information on the container-closure system for the finished product shall be given.
The level of information required shall be determined by the route of administration
of the veterinary medicinal product and the physical state (liquid, solid) of the
dosage form.
Packaging materials shall comply with the requirements of the appropriate European
Pharmacopoeia monograph. Where such a monograph does not exist reference may
OJ L 226, 22.9.1995, p. 1.
B
be made to the pharmacopoeia of Malta. In the absence of such a monograph
reference may be made to the Pharmacopoeia of a third country. In this case the
suitability of this monograph shall be demonstrated.
In the absence of a pharmacopoeial monograph, a specification shall be proposed
and justified for the packaging material.
Scientific data on the choice and suitability of the packaging material shall be
presented.
For novel packaging materials in contact with the product, information on their
composition, manufacture and safety shall be presented.
Specifications and, if appropriate, performance data shall be presented for any
dosing or administration device supplied with the veterinary medicinal product.
1.4. Substances of biological origin
Where source materials such as microorganisms, tissues of either plant or animal
origin, cells or fluids (including blood) of human or animal origin or
biotechnological cell constructs are used in the manufacture of veterinary medicinal
products, the origin and history of starting materials shall be described and
documented.
The description of the starting material shall include the manufacturing strategy,
purification/inactivation procedures with their validation and all in-process control
procedures designed to ensure the quality, safety and batch to batch consistency of
the finished product.
When cell banks are used, the cell characteristics shall be shown to have remained
unchanged at the passage level used for the production and beyond.
Seed materials, cell banks and pools of serum and, whenever possible, the source
materials from which they are derived shall be tested for extraneous agents.
When starting materials of animal or human origin are used, the measures used to
ensure freedom from potentially pathogenic agents shall be described.
B
If the presence of potentially pathogenic extraneous agents is inevitable, the material
shall be used only when further processing ensures their elimination and/or
inactivation, and this shall be validated.
Documentation shall be supplied to demonstrate that the seed materials, cell seeds,
batches of serum and other material originating from animal species relevant for the
transmission of TSE comply with the Note for Guidance on minimising the risk of
transmitting animal spongiform encephalopathy agents via human and veterinary
medicinal products 12 , as well as with the corresponding monograph of the European
Pharmacopoeia. Certificates of Suitability issued by the European Directorate for the
Quality of Medicines and HealthCare, with reference to the relevant monograph of
the European Pharmacopoeia, may be used to demonstrate compliance.
D. CONTROL TESTS CARRIED OUT AT INTERMEDIATE STAGES OF THE
MANUFACTURING PROCESS
The dossier shall include particulars relating to the product control tests that may be
carried out at an intermediate stage of the manufacturing process, with a view to
ensuring the consistency of the technical characteristics and the production process.
These tests are essential for checking the conformity of the veterinary medicinal
product with the formula when, exceptionally, an applicant proposes an analytical
method for testing the finished product which does not include the assay of all the
active substances (or of all the excipient components subject to the same
requirements as the active substances).
The same applies where the quality control of the finished product depends on in-
process control tests, particularly if the substance is essentially defined by its
manufacturing method.
Where an intermediate product may be stored prior to further processing or primary
assembly, a shelf life for the intermediate product shall be defined on the basis of the
data resulting from stability studies.
OJ C 24, 28.1.2004, p. 6.
B
E. TESTS ON THE FINISHED PRODUCT
For the control of the finished product, a batch of a finished product comprises all
the units of a pharmaceutical form which are made from the same initial quantity of
material and have undergone the same series of manufacturing and/or sterilisation
operations or, in the case of a continuous production process, all the units
manufactured in a given period of time.
The application for marketing authorisation shall list those tests, which are carried
out routinely on each batch of finished product. The frequency of the tests which are
not carried out routinely shall be stated. Release limits shall be indicated.
The dossier shall include particulars relating to control tests on the finished product
at release. They shall be submitted in accordance with the following requirements.
The provisions of the relevant monographs and general chapters of the European
Pharmacopoeia, or failing that, of Malta, shall be applicable to all products defined
therein.
If test procedures and limits other than those mentioned in the relevant monographs
and general chapters of the European Pharmacopoeia, or failing this, in the
pharmacopoeia of Malta are used, this shall be justified by providing proof that the
finished product would, if tested in accordance with those monographs, meet the
quality requirements of that pharmacopoeia for the pharmaceutical form concerned.
1. General characteristics of the finished product
Certain tests of the general characteristics of a product shall always be included
among the tests on the finished product. These tests shall, wherever applicable, relate
to the control of average masses and maximum deviations, to mechanical, physical
or microbiological tests, organoleptic characteristics, physical characteristics such as
density, pH, refractive index. For each of these characteristics, standards and
tolerance limits shall be specified by the applicant in each particular case.
The conditions of the tests, where appropriate, the equipment/apparatus employed
and the standards shall be described in precise details whenever they are not given in
B
the European Pharmacopoeia or the pharmacopoeia of Malta; the same shall apply in
cases where the methods prescribed by such pharmacopoeias are not applicable.
Furthermore, solid pharmaceutical forms having to be administered orally shall be
subjected to in vitro studies on the liberation and dissolution rate of the active
substance or substances, unless otherwise justified. Those studies shall also be
carried out where administration is by another means if the competent Authority
concerned consider this necessary.
2. Identification and assay of active substance(s)
Identification and assay of the active substance(s) shall be carried out either in a
representative sample from the production batch or in a number of dosage units
analysed individually.
Unless there is appropriate justification, the maximum acceptable deviation in the
active substance content of the finished product shall not exceed ± 5 % at the time of
manufacture.
On the basis of the stability tests, the manufacturer shall propose and justify
maximum acceptable deviation limits in the active substance content of the finished
product up to the end of the proposed shelf life.
In certain cases of particularly complex mixtures, where assay of active substances
which are very numerous or present in very low amounts would necessitate an
intricate investigation difficult to carry out in respect of each production batch, the
assay of one or more active substances in the finished product may be omitted, on
the express condition that such assays are made at intermediate stages in the
production process. This simplified technique may not be extended to the
characterisation of the substances concerned. It shall be supplemented by a method
of quantitative evaluation, enabling the competent authority to have the conformity
of the medicinal product with its specification verified after it has been placed on the
market.
An in vivo or in vitro biological assay shall be obligatory when physico-chemical
methods cannot provide adequate information on the quality of the product. Such an
assay shall, whenever possible, include reference materials and statistical analysis
B
allowing calculation of confidence limits. Where these tests cannot be carried out on
the finished product, they may be performed at an intermediate stage, as late as
possible in the manufacturing process.
Where degradation occurs during manufacture of the finished product, the maximum
acceptable levels of individual and total degradation products immediately following
manufacture shall be indicated.
Where the particulars given in Section B show that a significant overage of an active
substance is employed in the manufacture of the medicinal product or where the
stability data show that the assay of the active substance declines on storage, the
description of the control tests on the finished product shall include, where
appropriate, the chemical and, if necessary, the toxico-pharmacological investigation
of the changes that this substance has undergone, and possibly the characterisation
and/or assay of the degradation products.
3. Identification and assay of excipient components
An identification test and an upper and lower limit test shall be obligatory for each
individual antimicrobiological preservative and for any excipient that is liable to
affect the bioavailability of the active substance, unless the bioavailability is
guaranteed by other appropriate tests. An identification test and an upper limit test
shall be obligatory for any antioxidant and for any excipient liable to adversely
affect physiological functions, with a lower limit test also included for antioxidants
at time of release.
4. Safety tests
Apart from the toxico-pharmacological tests submitted with the application for
marketing authorisation, particulars of safety tests, such as sterility and bacterial
endotoxins, shall be included in the analytical particulars wherever such tests must
be undertaken as a matter of routine in order to verify the quality of the product.
F. STABILITY TEST
1. Active substances(s)
B
A retest period and storage conditions for the active substance shall be specified
except in the case where the active substance is the subject of a monograph in the
European Pharmacopoeia and the manufacturer of the finished product fully retests
the active substance immediately before its use in the manufacture of the finished
product.
Stability data shall be presented to support the defined retest period and storage
conditions. The type of stability studies conducted, protocols used, the analytical
procedures used and their validation together with the detailed results shall be
presented. The stability commitment with a summary of the protocol shall be
provided.
However, where a Certificate of Suitability for the active substance from the
proposed source is available and specifies a retest period and storage conditions,
stability data for the active substance from that source are not required.
2. Finished product
A description shall be given of the investigations by which the shelf life, the
recommended storage conditions and the specifications at the end of the shelf life
proposed by the applicant have been determined.
The type of stability studies conducted, protocols used, the analytical procedures
used and their validation together with the detailed results shall be presented.
Where a finished product requires reconstitution or dilution prior to administration,
details of the proposed shelf life and specification for the reconstituted/diluted
product are required, supported by relevant stability data.
In the case of multi-dose containers, where relevant, stability data shall be presented
to justify a shelf life for the product after it has been broached for the first time and
an in-use specification shall be defined.
Where a finished product is liable to give rise to degradation products, the applicant
shall declare these and indicate the identification methods and test procedures.
The conclusions shall contain the results of analyses, justifying the proposed shelf
life and if appropriate, the in-use shelf life, under the recommended storage
conditions and the specifications of the finished product at the end of the shelf life,
B
and in-use shelf life if appropriate, of the finished product under these recommended
storage conditions.
The maximum acceptable level of individual and total degradation products at the
end of shelf life shall be indicated.
A study of the interaction between product and container shall be submitted
wherever the risk of such interaction is regarded as possible, especially where
injectable preparations are concerned.
The stability commitment with a summary of the protocol shall be provided.
G. OTHER INFORMATION
Information relating to the quality of the veterinary medicinal product not covered in
the previous sections may be included in the dossier.
For medicated premixes (products intended for incorporation into medicated
feedingstuffs), information shall be provided on inclusion rates, instructions for
incorporation, homogeneity in-feed, compatibility/suitable feedingstuffs, stability in-
feed, and the proposed in-feed shelf life. A specification for the medicated
feedingstuffs, manufactured using these pre-mixes in accordance with the
recommended instructions for use shall also be provided.
PART 3: SAFETY AND RESIDUES TESTS
The particulars and documents which shall accompany the application for marketing
authorisation pursuant to the second and fourth indents of regulation 12(3) hereof
shall be submitted in accordance with the requirements below.
A. Safety tests
CHAPTER I: PERFORMANCE OF TESTS
The safety documentation shall show
B
(a) the potential toxicity of the veterinary medicinal product and any dangerous or
undesirable effects which may occur under the proposed conditions of use in
animals; these should be evaluated in relation to the severity of the pathological
condition concerned;
(b) the potential harmful effects to man of residues of the veterinary medicinal
product or substance in foodstuffs obtained from treated animals and what
difficulties these residues may create in the industrial processing of foodstuffs;
(c) the potential risks which may result from the exposure of human beings to the
veterinary medicinal product, for example during its administration to the animal;
(d) the potential risks for the environment resulting from the use of the veterinary
medicinal product.
All results shall be reliable and valid generally. Whenever appropriate, mathematical
and statistical procedures shall be used in designing the experimental methods and in
evaluating the results. Additionally, information shall be provided regarding the
therapeutic potential of the product and about the hazards connected with its use.
In some cases it may be necessary to test the metabolites of the parent compound
where these represent the residues of concern.
An excipient used in the pharmaceutical field for the first time shall be treated like
an active substance.
1. Precise identification of the product and of its active substance(s)
- international non-proprietary name (INN),
- International Union of Pure and Applied Chemistry Name (IUPAC),
- Chemical Abstract Service (CAS) number,
- therapeutic, pharmacological and chemical classification,
- synonyms and abbreviations,
- structural formula,
- molecular formula,
- molecular weight,
B
- degree of impurity,
- qualitative and quantitative composition of impurities,
- description of physical properties,
- melting point,
- boiling point,
- vapour pressure,
- solubility in water and organic solvents expressed in g/l, with indication of
temperature,
- density,
- spectra of refraction, rotation, etc,
- formulation of the product.
2. Pharmacology
Pharmacological studies are of fundamental importance in clarifying the
mechanisms by which the veterinary medicinal product produces its therapeutic
effects and therefore pharmacological studies conducted in experimental and target
species of animal shall be included in Part 4.
However, pharmacological studies may also assist in the understanding of
toxicological phenomena. Moreover, where a veterinary medicinal product produces
pharmacological effects in the absence of a toxic response, or at doses lower than
those required to elicit toxicity, these pharmacological effects shall be taken into
account during the evaluation of the safety of the veterinary medicinal product.
Therefore the safety documentation shall always be preceded by details of
pharmacological investigations undertaken in laboratory animals and all relevant
information observed during clinical studies in the target animal.
2.1. Pharmacodynamics
Information on the mechanism of action of the active substance(s) shall be provided,
together with information on primary and secondary pharmacodynamic effects in
order to assist in the understanding of any adverse effects in the animal studies.
B
2.2. Pharmacokinetics
Data on the fate of the active substance and its metabolites in the species used in the
toxicological studies shall be provided, covering absorption, distribution,
metabolism and excretion (ADME). The data shall be related to the dose/effect
findings in the pharmacological and toxicological studies, to determine adequate
exposure. Comparison with the pharmacokinetic data obtained in the studies on the
target species, Part 4, Chapter I, Section A.2, shall be included in Part 4 in order to
determine the relevance of the results obtained in the toxicology studies for the
toxicity to the target species.
3. Toxicology
The documentation on toxicology shall follow the guidance published by the Agency
on the general approach to testing and guidance on particular studies. This guidance
includes
1. basic tests required for all new veterinary medicinal products for use in food-
producing animals in order to assess the safety of any residues present in food for
human consumption;
2. additional tests that may be required depending on specific toxicological concerns
such as those associated with the structure, class, and mode of action of the active
substance(s);
3. special tests which might assist in the interpretation of data obtained in the basic
or additional tests.
The studies shall be conducted with the active substance(s), not with the formulated
product. Where studies of the formulated product are required, this is specified in the
text below.
3.1. Single-dose toxicity
Single-dose toxicity studies may be used to predict
- the possible effects of acute overdosage in the target species,
- the possible effects of accidental administration to humans,
- the doses which may usefully be employed in the repeat dose studies.
B
Single-dose toxicity studies should reveal the acute toxic effects of the substance and
the time course for their onset and remission.
The studies to be carried out shall be selected with a view to providing information
on user safety, e.g. if substantial exposure by inhalation or dermal contact of the user
of the veterinary medicinal product is anticipated, those routes of exposure shall be
studied.
3.2. Repeat-dose toxicity
Repeat-dose toxicity tests are intended to reveal any physiological and/or
pathological changes induced by repeated administration of the active substance or
combination of active substances under examination, and to determine how these
changes are related to dosage.
In the case of pharmacologically active substances or veterinary medicinal products
intended solely for use in non-food-producing animals, a repeat-dose toxicity study
in one species of experimental animal shall normally be sufficient. This study may
be replaced by a study conducted in the target animal. The frequency and route of
administration, and the duration of the study shall be chosen having regard to the
proposed conditions of clinical use. The investigator shall give his reasons for the
extent and duration of the trials and the dosages chosen.
In the case of substances or veterinary medicinal products intended for use in food-
producing animals, repeat-dose (90 day) toxicity testing shall be performed in a
rodent and a non-rodent species in order to identify target organs and toxicological
endpoints and identify the appropriate species and the dose levels to be used in
chronic toxicity testing, if appropriate.
The investigator shall give his reasons for the choice of species, having regard to the
available knowledge of the metabolism of the product in animals and man. The test
substance shall be administered orally. The investigator shall clearly state and give
his reasons for the method and frequency of administration and the length of the
trials.
The maximum dose should normally be selected so as to bring harmful effects to
light. The lowest dose level should not produce any evidence of toxicity.
B
Evaluation of the toxic effects shall be based on observation of behaviour, growth,
haematology and physiological tests, especially those relating to the excretory
organs, and also on autopsy reports and accompanying histological data. The choice
and range of each group of tests depends on the species of animal used and the state
of scientific knowledge at the time.
In the case of new combinations of known substances which have been investigated
in accordance with the provisions of these regulations, the repeat-dose tests may,
except where toxicity tests have demonstrated potentiation or novel toxic effects, be
suitably modified by the investigator, who shall submit his reasons for such
modifications.
3.3. Tolerance in the target species
A summary shall be provided of any signs of intolerance which have been observed
during studies conducted, usually with the final formulation, in the target species in
accordance with the requirements of Part 4, Chapter I, Section B. The studies
concerned, the dosages at which the intolerance occurred and the species and breeds
concerned shall be identified. Details of any unexpected physiological changes shall
also be provided. The full reports of these studies shall be included in Part 4.
3.4. Reproductive toxicity including developmental toxicity
3.4.1. Study of the effects on reproduction
The purpose of this study is to identify possible impairment of male or female
reproductive function or harmful effects on progeny resulting from the
administration of the veterinary medicinal products or substance under investigation.
In the case of pharmacologically active substances or veterinary medicinal products
intended for use in food-producing animals, the study of the effects on reproduction
shall be performed in the form of a multi-generation reproduction study, designed to
detect any effect on mammalian reproduction. These include effects on male and
female fertility, mating, conception, implantation, ability to maintain pregnancy to
term, parturition, lactation, survival, growth and development of the offspring from
birth through to weaning, sexual maturity and the subsequent reproductive function
of the offspring as adults. At least three dose levels shall be used. The maximum
B
dose should be selected so as to bring harmful effects to light. The lowest dose level
should not produce any evidence of toxicity.
3.4.2. Study of developmental toxicity
In the case of pharmacologically active substances or veterinary medicinal products
intended for use in food-producing animals, tests on developmental toxicity shall be
performed. These tests shall be designed to detect any adverse effects on the
pregnant female and development of the embryo and foetus consequent to exposure
of the female from implantation through gestation to the day before predicted birth.
Such adverse effects include enhanced toxicity relative to that observed in non-
pregnant females, embryo-foetal death, altered foetal growth, and structural changes
to the foetus. A developmental toxicity test in the rat is required. Depending on the
results, a study in a second species may have to be performed, in accordance with
established guidance.
In the case of pharmacologically active substances or veterinary medicinal products
not intended for use in food producing animals, a study of developmental toxicity
shall be performed in at least one species, which may be the target species, if the
product is intended for use in female animals which may be used for breeding.
However, where the use of the veterinary medicinal product would result in
significant exposure to users, standard developmental toxicity studies shall be
performed.
3.5. Genotoxicity
Tests for genotoxic potential shall be performed to reveal changes which a substance
may cause in the genetic material of cells. Any substance intended to be included in
a veterinary medicinal product for the first time must be assessed for genotoxic
properties.
A standard battery of in vitro and in vivo genotoxicity tests in accordance with
established guidance shall usually be carried out on the active substance(s). In some
cases, it may also be necessary to test one or more metabolites that occur as residues
in foodstuffs.
3.6. Carcinogenicity
B
The decision on whether carcinogenicity testing is required shall take into account
the results of genotoxicity tests, structure-activity relationships and the findings in
systemic toxicity tests that may be relevant to neoplastic lesions in longer term
studies.
Any known species specificity of the mechanism of toxicity shall be considered, as
well as any differences in metabolism between the test species, target animal species,
and human beings.
Where carcinogenicity testing is necessary, generally a two-year rat study and an 18-
month mouse study are required. With appropriate scientific justification,
carcinogenicity studies may be carried out in one rodent species, preferably the rat.
3.7. Exceptions
Where a veterinary medicinal product is intended for topical use, systemic
absorption shall be investigated in the target animal species. If it is proved that
systemic absorption is negligible, the repeated dose toxicity tests, the tests for
reproductive toxicity and the carcinogenicity tests may be omitted, unless
- under the intended conditions of use laid down, oral ingestion of the veterinary
medicinal product by the animal is to be expected, or
- under the intended conditions of use laid down, exposure of the user of the
veterinary medicinal product by other routes than the dermal route is to be expected,
or
- the active substance or metabolites may enter foodstuffs obtained from the treated
animal.
4. Other requirements
4.1. Special studies
For particular groups of substances or if the effects observed during repeated dose
studies in animals include changes indicative of e.g. immunotoxicity, neurotoxicity-
or, endocrine dysfunction, further testing shall be required, e.g. sensitisation studies
or delayed neurotoxicity tests. Depending on the nature of the product, it may be
necessary to conduct additional studies to assess the underlying mechanism of the
B
toxic effect or the irritation potential. Such studies shall usually be conducted with
the final formulation.
The state of scientific knowledge and established guidance shall be taken into
account when designing such studies and evaluating their results.
4.2. Microbiological properties of residues
4.2.1. Potential effects on the human gut flora
The potential microbiological risk presented by residues of antimicrobial compounds
for the human intestinal flora shall be investigated in accordance with established
guidance.
4.2.2. Potential effects on the microorganisms used for industrial food processing
In certain cases, it may be necessary to carry out tests to determine whether
microbiologically active residues may interfere in technological processes in the
industrial processing of foodstuff.
4.3. Observations in humans
Information shall be provided showing whether the pharmacologically active
substances of the veterinary medicinal product are used as medicinal products in
human therapy; if this is so, a compilation shall be made of all the effects observed
(including adverse reactions) in humans and of their cause, to the extent that they
may be important for the assessment of the safety of the veterinary medicinal
product, where appropriate including results from published studies; where
constituents of the veterinary medicinal products are themselves not used or are no
longer used as medicinal products in human therapy, the reasons shall be stated.
4.4. Development of resistance
Data on the potential emergence of resistant bacteria of relevance for human health
are necessary in the case of veterinary medicinal products. The mechanism of the
development of such resistance is particularly important in this regard. Where
necessary, measures to limit resistance development from the intended use of the
veterinary medicinal product shall be proposed.
B
Resistance relevant for clinical use of the product shall be addressed in accordance
with Part 4. Where relevant, cross reference shall be made to the data set out in Part
4.
5. User safety
This section shall include a discussion of the effects found in the preceding sections
and relate this to the type and extent of human exposure to the product with a view
to formulating appropriate user warnings and other risk management measures.
6. Environmental risk assessment
6.1. Environmental risk assessment of veterinary medicinal products not containing
or consisting of genetically modified organisms
An environmental risk assessment shall be performed to assess the potential harmful
effects, which the use of the veterinary medicinal product may cause to the
environment and to identify the risk of such effects. The assessment shall also
identify any precautionary measures which may be necessary to reduce such risk.
This assessment shall normally be conducted in two phases. The first phase of the
assessment shall always be performed. The details of the assessment shall be
provided in accordance with accepted guidance. It shall indicate the potential
exposure of the environment to the product and the level of risk associated with any
such exposure taking into account in particular the following items
- the target animal species, and the proposed pattern of use,
- the method of administration, in particular the likely extent to which the product
will enter directly into environmental systems,
- the possible excretion of the product, its active substances or relevant metabolites
into the environment by treated animals; persistence in such excreta,
- the disposal of unused veterinary medicinal product or other waste product.
In the second phase, further specific investigation of the fate and effects of the
product on particular ecosystems shall be conducted, in accordance with established
guidance. The extent of exposure of the product to the environment, and the
available information about the physical/chemical, pharmacological and/or
B
toxicological properties of the substance(s) concerned, including metabolites in case
of an identified risk, which has been obtained during the conduct of the other tests
and trials required by these regulations, shall be taken into consideration.
6.2. Environmental risk assessment for veterinary medicinal products containing or
consisting of genetically modified organisms
In the case of a veterinary medicinal product containing or consisting of genetically
modified organisms the application shall also be accompanied by the documents
required under Article 2 and Part C of Directive 2001/18/EC.
CHAPTER II: PRESENTATION OF PARTICULARS AND DOCUMENTS
The dossier of safety tests shall include the following
- an index of all studies included in the dossier,
- a statement confirming that all data known by the applicant at the time of
submission, whether favourable or unfavourable, are included,
- a justification for the omission of any type of study,
- an explanation of the inclusion of an alternative type of study,
- a discussion of the contribution that any study that pre-dates studies performed in
line with good laboratory practice (GLP) according to Directive 2004/10/EC can
make to the overall risk assessment.
Each study report shall include
- a copy of the study plan (protocol),
- a statement of compliance with good laboratory practice, where applicable,
- a description of the methods, apparatus and materials used,
- a description and justification of the test system,
- a description of the results obtained, in sufficient detail to allow the results to be
critically evaluated independently of their interpretation by the author,
- a statistical analysis of the results where appropriate,
B
- a discussion of the results, with comment on observed and no-observed-effect
levels, and on any unusual findings,
- a detailed description and a thorough discussion of the results of the study of the
safety profile of the active substance, and its relevance for the evaluation of potential
risks presented by residues to humans.
B. Residue tests
CHAPTER I: PERFORMANCE OF TESTS
1. Introduction
For the purposes of this Schedule, the definitions of Council Regulation (EEC) No
2377/90 13 shall apply.
The purpose of studying the depletion of residues from the edible tissues or of eggs,
milk and honey derived from treated animals is to determine under what conditions
and to what extent residues may persist in foodstuffs produced from these animals.
In addition, the studies shall enable the determination of a withdrawal period.
In the case of veterinary medicinal products intended for use in food-producing
animals, the residue documentation shall show
1. to what extent, and how long, do residues of the veterinary medicinal product or
its metabolites persist in the edible tissues of the treated animal or in milk, eggs
and/or honey obtained therefrom;
2. that in order to prevent any risk to the health of the consumer of foodstuffs from
treated animals, or difficulties in the industrial processing of foodstuffs, it is possible
to establish realistic withdrawal periods which can be observed under practical
farming conditions;
3. that the analytical method(s) used in the residues depletion study are sufficiently
validated to provide the necessary reassurance that the residues data submitted are
suitable as the basis for a withdrawal period.
2. Metabolism and residue kinetics
2.1. Pharmacokinetics (absorption, distribution, metabolism, excretion)
OJ C 24, 28.1.2004, p. 6.
B
B
The following characteristics shall be described
- specificity,
- accuracy,
- precision,
- limit of detection,
- limit of quantification,
- practicability and applicability under normal laboratory conditions,
- susceptibility to interference,
- stability of incurred residues.
The suitability of the analytical method proposed shall be evaluated in the light of
the state of scientific and technical knowledge at the time the application is
submitted.
The analytical method shall be presented in an internationally agreed format.
CHAPTER II: PRESENTATION OF PARTICULARS AND DOCUMENTS
1. Identification of the product
An identification of the veterinary medicinal product(s) used in the testing shall be
provided, including
- composition,
- the physical and chemical (potency and purity) test results for the relevant
batch(es),
- batch identification,
- relationship to the final product,
- specific activity and radio-purity of labelled substances,
- position of labelled atoms in the molecule.
The dossier of residue tests shall include
- an index of all studies included in the dossier,
B
- a statement confirming that all data known by the applicant at the time of
submission, whether favourable or unfavourable, are included,
- a justification for the omission of any type of study,
- an explanation of the inclusion of an alternative type of study,
- a discussion of the contribution that any study that pre-dates GLP can make to the
overall risk assessment,
- a withdrawal period proposal.
Each study report shall include
- a copy of the study plan (protocol),
- a statement of compliance with good laboratory practice, where applicable,
- a description of the methods, apparatus and materials used,
- a description of the results obtained, in sufficient detail to allow the results to be
critically evaluated independently of their interpretation by the author,
- a statistical analysis of the results where appropriate,
- a discussion of the results,
- an objective discussion of the results obtained, and proposals concerning the
withdrawal periods necessary to ensure that no residues which might constitute a
hazard for consumers are present in foodstuffs obtained from treated animals.
PART 4: PRE-CLINICAL AND CLINICAL TRIAL
The particulars and documents, which shall accompany applications for marketing
authorisations in terms of regulation 12(3)(j) of these regulations shall be submitted
in accordance with the requirements below.
CHAPTER I: PRE-CLINICAL REQUIREMENTS
Pre-clinical studies are required to establish the pharmacological activity and the
tolerance of the product.
A. Pharmacology
B
A.1. Pharmacodynamics
The pharmacodynamic effects of the active substance(s) included in the veterinary
medicinal product shall be characterised.
First, the mechanism of action and the pharmacological effects on which the
recommended application in practice is based shall be adequately described. The
results shall be expressed in quantitative terms (using, for example, dose-effect
curves, time-effect curves, etc.) and, wherever possible, in comparison with a
substance the activity of which is well known. Where a higher efficacy is being
claimed for an active substance, the difference shall be demonstrated and shown to
be statistically significant.
Secondly, an overall pharmacological assessment of the active substance shall be
provided, with special reference to the possibility of secondary pharmacological
effects. In general, the effects on the main body functions shall be investigated.
Any effect of the other characteristics of the products (such as the route of
administration or formulation) on the pharmacological activity of the active
substance shall be investigated.
The investigations shall be intensified where the recommended dose approaches a
dose likely to produce adverse reactions.
The experimental techniques, unless they are standard procedures, shall be described
in such detail as to allow them to be reproduced, and the investigator shall establish
their validity. The experimental results shall be set out clearly and, for certain types
of tests, their statistical significance quoted.
Unless good reasons are given to the contrary, any quantitative modification of
responses resulting from repeated administration of the substance shall also be
investigated.
Fixed combinations may be prompted either on pharmacological grounds or by
clinical indications. In the first case, the pharmacodynamic and/or pharmacokinetic
studies shall demonstrate those interactions, which might make the combination
itself of value in clinical use. In the second case, where scientific justification for the
medicinal combination is sought through clinical experimentation, the investigation
B
shall determine whether the effects expected from the combination can be
demonstrated in animals and, at least, the importance of any adverse reactions shall
be checked. If a combination includes a new active substance, the latter shall have
been previously studied in depth.
A.2. Development of resistance
Where relevant, data on the potential emergence of resistant organisms of clinical
relevance are necessary for veterinary medicinal products. The mechanism of the
development of such resistance is particularly important in this regard. Measures to
limit resistance development from the intended use of the veterinary medicinal
product shall be proposed by the applicant.
Where relevant, cross reference shall be made to data set out in Part 3.
A.3. Pharmacokinetics
Basic pharmacokinetic data concerning a new active substance are required in the
context of assessment of the clinical safety and efficacy of the veterinary medicinal
product.
The objectives of pharmacokinetic studies in the target animal species can be divided
into three main areas
(i) descriptive pharmacokinetics leading to the determination of basic parameters.;
(ii) use of these parameters to investigate the relationships between dosage regimen,
plasma and tissue concentration over time and pharmacological, therapeutic or toxic
effects;
(iii) where appropriate, to compare the kinetics between different target species and
to explore possible species differences having an impact on target animal safety and
efficacy of the veterinary medicinal product.
In the target animal species, pharmacokinetic studies are, as a rule, necessary as a
complement to the pharmacodynamic studies to support the establishment of
effective dosage regimens (route and site of administration, dose, dosing interval,
number of administrations, etc.). Additional pharmacokinetic studies may be
required to establish dosage regimens according to certain population variables.
B
Where pharmacokinetic studies have been submitted under Part 3 cross reference to
such studies may be made.
In the case of new combinations of known substances which have been investigated
in accordance with the provisions of these regulations, pharmacokinetic studies of
the fixed combination are not required if it can be justified that the administration of
the active substances as a fixed combination does not change their pharmacokinetic
properties.
Appropriate bioavailability studies shall be undertaken to establish bioequivalence
- when comparing a reformulated veterinary medicinal product with the existing one,
- where necessary for the comparison of a new method or route of administration
with an established one.
B. Tolerance in the target animal species
The local and systemic tolerance of the veterinary medicinal product shall be
investigated in the target animal species. The purpose of these studies is to
characterise signs of intolerance and to establish an adequate margin of safety using
the recommended route(s) of administration. This may be achieved by increasing the
therapeutic dose and/or the duration of treatment. The report on the trials shall
contain details of all expected pharmacological effects and all adverse reactions.
CHAPTER II: CLINICAL REQUIREMENTS
1. General principles
The purpose of clinical trials is to demonstrate or substantiate the effect of the
veterinary medicinal product after administration at the proposed dosage regimen via
the proposed route of administration and to specify its indications and contra-
indications according to species, age, breed and sex, its directions for use as well as
any adverse reactions which it may have.
Experimental data shall be confirmed by data obtained under normal field
conditions.
Unless justified, clinical trials shall be carried out with control animals (controlled
clinical trials). The efficacy results obtained should be compared with those from the
B
target animal species that have received a veterinary medicinal product authorised in
the Community for the same indications for use in the same target animal species, or
a placebo or no treatment. All the results obtained, whether positive or negative,
shall be reported.
Established statistical principles shall be used in protocol design, analysis and
evaluation of clinical trials, unless justified.
In the case of a veterinary medicinal product intended primarily for use as a
performance enhancer, particular attention shall be given to
1. the yield of animal produce,
2. the quality of animal produce (organoleptic, nutritional, hygienic and
technological qualities),
3. nutritional efficiency and growth of target animal species,
4. general health status of the target animal species.
2. Conduct of clinical trials
All veterinary clinical trials shall be conducted in accordance with a detailed trial
protocol.
Clinical field trials shall be conducted in accordance with established principles of
good clinical practice, unless otherwise justified.
Before the commencement of any field trial, the informed consent of the owner of
the animals to be used in the trial shall be obtained and documented. In particular,
the animal owner shall be informed in writing of the consequences of participation in
the trial for the subsequent disposal of treated animals or for the taking of foodstuffs
from treated animals. A copy of this notification, countersigned and dated by the
animal owner, shall be included in the trial documentation.
Unless the field trial is conducted with a blind design, the provisions of regulations
55, 56 and 57 of these regulations shall apply respectively to the labelling of
formulations intended for use in veterinary field trials. In all cases, the words "for
veterinary field trial use only" shall appear prominently and indelibly upon the
labelling.
B
CHAPTER III: PARTICULARS AND DOCUMENTS
The dossier on efficacy shall include all pre-clinical and clinical documentation
and/or results of trials, whether favourable or unfavourable to the veterinary
medicinal products, in order to enable an objective overall assessment of the
risk/benefit balance of the product.
1. Results of pre-clinical trials
Wherever possible, particulars shall be given of the results of
(a) tests demonstrating pharmacological actions;
(b) tests demonstrating the pharmacodynamic mechanisms underlying the
therapeutic effect;
(c) tests demonstrating the main pharmacokinetic profile;
(d) tests demonstrating target animal safety;
(e) tests investigating resistance.
Should unexpected results occur during the course of the tests, these should be
detailed.
Additionally, the following particulars shall be provided in all pre-clinical studies
(a) a summary;
(b) a detailed experimental protocol giving a description of the methods, apparatus
and materials used, details such as species, age, weight, sex, number, breed or strain
of animals, identification of animals, dose, route and schedule of administration;
(c) a statistical analysis of the results, where relevant;
(d) an objective discussion of the results obtained, leading to conclusions on the
efficacy and safety of the veterinary medicinal product.
Total or partial omission of any of these data shall be justified.
2. Results of clinical trials
B
All the particulars shall be supplied by each of the investigators on individual record
sheets in the case of individual treatment and collective record sheets in the case of
collective treatment.
The particulars supplied shall take the following form
(a) name, address, function and qualifications of investigator in charge;
(b) place and date of treatment; name and address of owner of the animals;
(c) details of the clinical trial protocol giving a description of the methods used,
including methods of randomisation and blinding, details such as the route of
administration, schedule of administration, the dose, identification of trial animals,
species, breeds or strains, age, weight, sex, physiological status;
(d) method of animal management and feeding, stating the composition of the feed
and the nature and quantity of any feed additives;
(e) case history (as full as possible), including occurrence and course of any
intercurrent diseases;
(f) diagnosis and means used to make it;
(g) clinical signs, if possible according to conventional criteria;
(h) precise identification of the formulation of the veterinary medicinal product used
in the clinical trial and the physical and chemical test results for the relevant
batch(es);
(i) dosage of the veterinary medicinal product, method, route and frequency of
administration and precautions, if any, taken during administration (duration of
injection, etc.);
(j) duration of treatment and period of subsequent observation;
(k) all details concerning other veterinary medicinal products which have been
administered during the period of examination, either prior to or concurrently with
the test product and, in the latter case, details of any interactions observed;
(l) all results of the clinical trials, fully describing the results based on the efficacy
criteria and end points specified in the clinical trial protocol and including the results
of the statistical analyses, if appropriate;
B
(m) all particulars of any unintended event, whether harmful or not, and of any
measures taken in consequence; the cause-and-effect relationship shall be
investigated if possible;
(n) effect on animals’ performance if appropriate;
(o) effects on the quality of foodstuffs obtained from treated animals, particularly in
the case of veterinary medicinal products intended for use as performance enhancers;
(p) a conclusion on the safety and efficacy in each individual case or, summarised in
terms of frequencies or other appropriate variables where specific mass treatment is
concerned.
Omission of one or more items (a) to (p) shall be justified.
The marketing authorisation holder shall make all necessary arrangements to ensure
that the original documents, which formed the basis of the data supplied, are kept for
at least five years after the veterinary medicinal product is no longer authorised.
In respect of each clinical trial, the clinical observations shall be summarised in a
synopsis of the trials and the results thereof, indicating in particular
(a) the number of control and test animals treated either individually or collectively,
with a breakdown according to species, breed or strain, age and sex;
(b) the number of animals withdrawn prematurely from the trials and the reasons for
such withdrawal;
(c) in the case of control animals, whether they have
- received no treatment, or
- received a placebo, or
- received another veterinary medicinal product authorised in the Community for the
same indication for use in the same target animal species, or
- received the same active substance under investigation in a different formulation or
by a different route;
(d) the frequency of observed adverse reactions;
(e) observations as to the effect on animal performance, if appropriate;
B
(f) details concerning test animals which may be at increased risk owing to their age,
their mode of rearing or feeding, or the purpose for which they are intended, or
animals the physiological or pathological condition of which requires special
consideration;
(g) a statistical evaluation of the results.
Finally, the investigator shall draw general conclusions on the efficacy and safety of
the veterinary medicinal product under the proposed conditions of use, and in
particular any information relating to indications and contraindications, dosage and
average duration of treatment and where, appropriate, any interactions observed with
other veterinary medicinal products or feed additives as well as any special
precautions to be taken during treatment and the clinical symptoms of overdosage,
when observed.
In the case of fixed combination products, the investigator shall also draw
conclusions concerning the safety and the efficacy of the product when compared
with the separate administration of the active substances involved.
TITLE II
REQUIREMENTS FOR IMMUNOLOGICAL VETERINARY MEDICINAL
PRODUCTS
Without prejudice to specific requirements laid down by Community legislation for
the control and eradication of specific infectious animal diseases, the following
requirements shall apply to immunological veterinary medicinal products, except
when the products are intended for use in some species or with specific indications
as defined in Title III and in relevant guidelines.
PART 1: SUMMARY OF THE DOSSIER
A. ADMINISTRATIVE INFORMATION
The immunological veterinary medicinal product, which is the subject of the
application, shall be identified by name and by name of the active substance(s),
B
together with the biological activity, potency or titre, the pharmaceutical form, the
route and method if appropriate of administration and a description of the final
presentation of the product, including packaging, labelling and leaflet. Diluents may
be packed together with the vaccine vials or separately.
Information on diluents needed for making the final vaccine preparation shall be
included in the dossier. An immunological veterinary medicinal product is regarded
as one product even when more than one diluent is required so that different
preparations of the final product can be prepared, which may be for administration
by different routes or methods of administration.
The name and address of the applicant shall be given, together with the name and
address of the manufacturer and the sites involved in the different stages of
manufacture and control (including the manufacturer of the finished product and the
manufacturer(s) of the active substance(s)) and where relevant the name and address
of the importer.
The applicant shall identify the number and titles of volumes of documentation
submitted in support of the application and indicate what samples, if any, are also
provided.
Annexed to the administrative information shall be copies of a document showing
that the manufacturer is authorised to produce immunological veterinary medicinal
products, as defined in regulation 38 of these regulations. Moreover, the list of
organisms handled at the production site shall be given.
The applicant shall submit a list of countries in which authorisation has been
granted, and a list of countries in which an application has been submitted or
refused.
B. SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND
PACKAGE LEAFLET
The applicant shall propose a summary of the product characteristics, in accordance
with regulation 14 hereof.
B
A proposed labelling text for the immediate and outer packaging shall be provided in
accordance with Title V of these regulations, together with a package leaflet where
one is required pursuant to regulation 51 hereof. In addition the applicant shall
provide one or more specimens or mock-ups of the final presentation(s) of the
veterinary medicinal product in at least one of the official languages of the European
Union; the mock-up may be provided in black and white and electronically where
prior agreement from the competent authority has been obtained.
C. DETAILED AND CRITICAL SUMMARIES
Each detailed and critical summary referred to in regulation 12(3)(l) of these
regulations shall be prepared in the light of the state of scientific knowledge at the
time of submission of the application. It shall contain an evaluation of the various
tests and trials, which constitute the marketing authorisation dossier and shall
address all points relevant to the assessment of the quality, safety and efficacy of the
immunological veterinary medicinal product. It shall give the detailed results of the
tests and trials submitted and precise bibliographic references.
All important data shall be summarised in an appendix to the detailed and critical
summaries, whenever possible in tabular or graphic form. The detailed and critical
summaries shall contain precise cross references to the information contained in the
main documentation.
The detailed and critical summaries shall be signed and dated, and information about
the author's educational background, training and occupational experience shall be
attached. The professional relationship of the author with the applicant shall be
declared.
PART
2
CHEMICAL,
PHARMACEUTICAL
AND
BIOLOGICAL/MICROBIOLOGICAL INFORMATION (QUALITY)
All test procedures shall fulfil the necessary criteria for analysis and control of the
quality of the starting materials and the finished product and shall be validated
procedures. The results of the validation studies shall be provided. Any special
B
apparatus and equipment which may be used shall be described in adequate detail,
possibly accompanied by a diagram. The formulae of the laboratory reagents shall be
supplemented, if necessary, by the manufacturing method.
In the case of test procedures included in the European Pharmacopoeia or the
pharmacopoeia of Malta, this description may be replaced by a detailed reference to
the pharmacopoeia in question.
Where available, chemical and biological reference material of the European
Pharmacopoeia shall be used. If other reference preparations and standards are used,
they shall be identified and described in detail.
A.
QUALITATIVE
AND
QUANTITATIVE
PARTICULARS
OF
THE
CONSTITUENTS
1. Qualitative particulars
"Qualitative particulars" of all the constituents of the immunological veterinary
medicinal product shall mean the designation or description of
- the active substance(s),
- the constituents of the adjuvants,
- the constituent(s) of the excipients, whatever their nature or the quantity used,
including preservatives, stabilisers, emulsifiers, colouring matter, flavouring,
aromatic substances, markers, etc.,
- the constituents of the pharmaceutical form administered to animals.
These particulars shall be supplemented by any relevant data concerning the
container and, where appropriate, its manner of closure, together with details of
devices with which the immunological veterinary medicinal product will be used or
administered and which will be delivered with the medicinal product. If the device is
not delivered together with the immunological veterinary medicinal product, relevant
information about the device shall be provided, where necessary for the assessment
of the product.
2. "Usual terminology"
B
The "usual terminology", to be used in describing the constituents of immunological
veterinary medicinal products, shall mean, notwithstanding the application of the
other provisions of regulation 12(3)(c) of these regulations
- in respect of substances which appear in the European Pharmacopoeia or, failing
this, in the pharmacopoeia of one of the Member States, the main title of the
monograph in question, which will be obligatory for all such substances, with
reference to the pharmacopoeia concerned,
- in respect of other substances, the international non-proprietary name
recommended by the World Health Organisation, which may be accompanied by
another non-proprietary name or, failing these, the exact scientific designation;
substances not having an international non-proprietary name or an exact scientific
designation shall be described by a statement of how and from what they were
prepared, supplemented, where appropriate, by any other relevant details,
- in respect of colouring matter, designation by the "E" code assigned to them in
Directive 78/25/EEC.
3. Quantitative particulars
In order to give the "quantitative particulars" of the active substances of an
immunological veterinary medicinal product, it is necessary to specify whenever
possible the number of organisms, the specific protein content, the mass, the number
of International Units (IU) or units of biological activity, either per dosage-unit or
volume, and with regard to the adjuvant and to the constituents of the excipients, the
mass or the volume of each of them, with due allowance for the details provided in
Section B.
Where an international unit of biological activity has been defined, this shall be
used.
The units of biological activity for which no published data exist shall be expressed
in such a way as to provide unambiguous information on the activity of the
ingredients, e.g. by stating the immunological effect on which the method of
determining the dose is based.
4. Product development
B
An explanation shall be provided with regard to the composition, components and
containers, supported by scientific data on product development. The overage, with
justification thereof, shall be stated.
B. DESCRIPTION OF MANUFACTURING METHOD
The description of the manufacturing method accompanying the application for
marketing authorisation pursuant to regulation 12(3) hereof, shall be drafted in such
a way as to give an adequate description of the nature of the operations employed.
For this purpose the description shall include at least
- the various stages of manufacture (including production of the antigen and
purification procedures) so that an assessment can be made of the reproducibility of
the manufacturing procedure and of the risks of adverse effects on the finished
products, such as microbiological contamination; the validation of key stages in the
production process shall be demonstrated and the validation of the production
process as a whole shall be demonstrated with provision of results of three
consecutive batches produced using the method described,
- in the case of continuous manufacture, full details concerning precautions taken to
ensure the homogeneity and consistency of each batch of the finished product,
- listing of all the substances at the appropriate steps where they are used, including
those which cannot be recovered in the course of manufacturing,
- the details of the blending, with the quantitative particulars of all the substances
used,
- a statement of the stages of manufacture at which sampling is carried out for
control tests during production.
C. PRODUCTION AND CONTROL OF STARTING MATERIALS
For the purposes of this paragraph "starting materials" means all components used in
the production of the immunological veterinary medicinal product. Culture media
consisting of several components used for production of the active substance shall be
regarded as one starting material. Nevertheless, the qualitative and quantitative
B
composition of the any culture media shall be presented in so far as the authorities
consider that this information is relevant to the quality of the finished product and
any risks that might be posed. If materials of animal origin are used for preparation
of these culture media, the animal species and the tissue used have to be included.
The dossier shall include the specifications, information on the tests to be conducted
for the quality control of all batches of starting materials and results for a batch for
all components used and shall be submitted in accordance with the following
provisions.
1. Starting materials listed in pharmacopoeias
The monographs of the European Pharmacopoeia shall be applicable to all starting
materials appearing in it.
In respect of other substances, each Member State may require observance of its own
national pharmacopoeia with regard to products manufactured in its territory.
Constituents fulfilling the requirements of the European Pharmacopoeia or the
pharmacopoeia of one of the Member States shall be deemed to comply sufficiently
with regulation 12(3) hereof. In this case the description of the analytical methods
may be replaced by a detailed reference to the pharmacopoeia in question.
Colouring matter shall, in all cases, satisfy the requirements of Directive 78/25/EEC.
The routine tests carried out on each batch of starting materials must be as stated in
the application for marketing authorisation. If tests other than those mentioned in the
pharmacopoeia are used, proof must be supplied that the starting materials meet the
quality requirements of that pharmacopoeia.
In cases where a specification or other provisions contained in a monograph of the
European Pharmacopoeia or in the pharmacopoeia of Malta might be insufficient to
ensure the quality of the substance, the competent authorities may request more
appropriate specifications from the applicant for marketing authorisation. The
alleged insufficiency shall be reported to the authorities responsible for the
pharmacopoeia in question.
In cases where a starting material is described neither in the European
Pharmacopoeia nor in the pharmacopoeia of Malta, compliance with the monograph
B
of a third country pharmacopoeia can be accepted; in such cases, the applicant shall
submit a copy of the monograph accompanied where necessary by the validation of
the test procedures contained in the monograph and by a translation where
appropriate.
When starting materials of animal origin are used, they shall comply with the
relevant monographs including general monographs and general chapters of the
European Pharmacopoeia. The tests and controls conducted shall be appropriate to
the starting material.
The applicant shall supply documentation to demonstrate that the starting materials
and the manufacturing of the veterinary medical product is in comply with the
requirements of the Note for Guidance on minimising the risk of transmitting animal
spongiform encephalopathy agents via human and veterinary medicinal products, as
well as with the requirements of the corresponding monograph of the European
Pharmacopoeia. Certificates of Suitability issued by the European Directorate for the
Quality of Medicines and HealthCare, with reference to the relevant monograph of
the European Pharmacopoeia, may be used to demonstrate compliance.
2. Starting materials not listed in a pharmacopoeia
2.1. Starting materials of biological origin
The description shall be given in the form of a monograph.
Whenever possible, vaccine production shall be based on a seed lot system and on
established cell seeds. For the production of immunological veterinary medicinal
products consisting of serums, the origin, general health and immunological status of
the producing animals shall be indicated and defined pools of source materials shall
be used.
The origin, including geographical region, and history of starting materials shall be
described and documented. For genetically engineered starting materials this
information shall include details such as the description of the starting cells or
strains, the construction of the expression vector (name, origin, function of the
replicon, promoter enhancer and other regulator elements), control of the sequence
of DNA or RNA effectively inserted, oligonucleotidic sequences of plasmid vector
B
in cells, plasmid used for cotransfection, added or deleted genes, biological
properties of the final construct and the genes expressed, copy number and genetic
stability.
Seed materials, including cell seeds and raw serum for anti-serum production shall
be tested for identity and extraneous agents.
Information shall be provided on all substances of biological origin used at any stage
in the manufacturing procedure. The information shall include
- details of the source of the materials,
- details of any processing, purification and inactivation applied, with data on the
validation of these process and controls during production,
- details of any tests for contamination carried out on each batch of the substance.
If the presence of extraneous agents is detected or suspected, the corresponding
material shall be discarded or used in very exceptional circumstances only when
further processing of the product ensures their elimination and/or inactivation;
elimination and/or inactivation of such extraneous agents shall be demonstrated.
When cell seeds are used, the cell characteristics shall be shown to have remained
unchanged up to the highest passage level used for the production.
For live attenuated vaccines, proof of the stability of the attenuation characteristics
of the seed has to be given.
Documentation shall be supplied to demonstrate that the seed materials, cell seeds,
batches of serum and other material originating from animal species relevant for the
transmission of TSE comply with the Note for Guidance on minimising the risk of
transmitting animal spongiform encephalopathy agents via human and veterinary
medicinal products, as well as with the corresponding monograph of the European
Pharmacopoeia. Certificates of Suitability issued by the European Directorate for the
Quality of Medicines and HealthCare, with reference to the relevant monograph of
the European Pharmacopoeia, can be used to demonstrate compliance.
B
When required, samples of the biological starting material or reagents used in the
testing procedures shall be provided to enable the competent authority to arrange for
check tests to be carried out.
2.2. Starting materials of non-biological origin
The description shall be given in the form of a monograph under the following
headings
- the name of the starting material meeting the requirements of point 2 of Section A
shall be supplemented by any trade or scientific synonyms,
- the description of the starting material, set down in a form similar to that used in a
descriptive item in the European Pharmacopoeia,
- the function of the starting material,
- methods of identification,
- any special precautions which may be necessary during storage of the starting
material and, if necessary, its storage life shall be given.
D. CONTROL TESTS DURING THE MANUFACTURING PROCESS
1. The dossier shall include particulars relating to the control tests, which are carried
out on intermediate products with a view to verifying the consistency of the
manufacturing process and the final product.
2. For inactivated or detoxified vaccines, inactivation or detoxification shall be
tested during each production run as soon as possible after the end of the inactivation
or detoxification process and after neutralisation if this occurs, but before the next
step of production.
E. CONTROL TESTS ON THE FINISHED PRODUCT
For all tests, the description of the techniques for analysing the finished product shall
be set out in sufficiently precise detail for quality assessment.
B
The dossier shall include particulars relating to control tests on the finished product.
Where appropriate monographs exist, if test procedures and limits other than those
mentioned in the monographs of the European Pharmacopoeia, or failing this, in the
pharmacopoeia of Malta, are used, proof must be supplied that the finished product
would, if tested in accordance with those monographs, meet the quality requirements
of that pharmacopoeia for the pharmaceutical form concerned. The application for
marketing authorisation shall list those tests, which are carried out on representative
samples of each batch of finished product. The frequency of the tests, which are not
carried out on each batch, shall be stated. Release limits shall be indicated.
Where available, chemical and biological reference material of the European
Pharmacopoeia shall be used. If other reference preparations and standards are used,
they shall be identified and described in detail.
1. General characteristics of the finished product
The tests of general characteristics shall, wherever applicable, relate to the control of
average masses and maximum deviations, to mechanical, physical or chemical tests,
physical characteristics such as density, pH, viscosity, etc. For each of these
characteristics, specifications, with appropriate confidence limits, shall be
established by the applicant in each particular case.
2. Identification of active substance(s)
Where necessary, a specific test for identification shall be carried out.
3. Batch titre or potency
A quantification of the active substance shall be carried out on each batch to show
that each batch will contain the appropriate potency or titre to ensure its safety and
efficacy.
4. Identification and assay of adjuvants
Insofar as testing procedures are available, the quantity and nature of the adjuvant
and its components shall be verified on the finished product.
5. Identification and assay of excipient components
Insofar as is necessary, the excipient(s) shall be subject at least to identification tests.
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An upper and lower limit test shall be obligatory in respect of preserving agents. An
upper limit test for any other excipient components liable to give rise to an adverse
reaction shall be obligatory.
6. Safety tests
Apart from the results of tests submitted in accordance with Part 3 of this Title
(Safety Tests), particulars of the batch safety tests shall be submitted. These tests
shall preferably be overdosage studies carried out in at least one of the most sensitive
target species and by at least the recommended route of administration posing the
greatest risk. Routine application of the batch safety test may be waived in the
interests of animal welfare when a sufficient number of consecutive production
batches have been produced and been found to comply with the test.
7. Sterility and purity test
Appropriate tests to demonstrate the absence of contamination by extraneous agents
or other substances shall be carried out according to the nature of the immunological
veterinary medicinal product, the method and the conditions of manufacture. If
fewer tests than required by the relevant European Pharmacopoeia are routinely
employed for each batch, the tests carried out shall be critical to the compliance with
the monograph. Proof must be supplied that the immunological veterinary medicinal
product would meet the requirements, if fully tested according to the monograph.
8. Residual humidity
Each batch of lyophilised product shall be tested for residual humidity.
9. Inactivation
For inactivated vaccines, a test to verify inactivation shall be carried out on the
product in the final container unless it has been conducted at a late stage in-process.
F. BATCH-TO-BATCH CONSISTENCY
In order to ensure that quality of the product is consistent from batch to batch and to
demonstrate conformity with specifications a full protocol of three consecutive
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batches giving the results for all tests performed during production and on the
finished product shall be provided.
G. STABILITY TESTS
The particulars and documents accompanying the application for marketing
authorisation pursuant to regulation 12(3) hereof shall be submitted in accordance
with the following requirements.
A description shall be given of the tests undertaken to support the shelf life proposed
by the applicant. These tests shall always be real-time studies; they shall be carried
out on a sufficient number of batches produced according to the described
production process and on products stored in the final container(s); these tests
include biological and physico-chemical stability tests.
The conclusions shall contain the results of analyses, justifying the proposed shelf
life under all proposed storage conditions.
In the case of products administered in feed, information shall also be given as
necessary on the shelf life of the product, at the different stages of mixing, when
mixed in accordance with the recommended instructions.
Where a finished product requires reconstitution prior to administration or is
administered in drinking water, details of the proposed shelf life are required for the
product reconstituted as recommended. Data in support of the proposed shelf life for
the reconstituted product shall be submitted.
Stability data obtained from combined products may be used as preliminary data for
derivative products containing one or more of the same components.
The proposed in-use shelf life shall be justified.
The efficacy of any preservative system shall be demonstrated.
Information on the efficacy of preservatives in other similar immunological
veterinary medicinal products from the same manufacturer may be sufficient.
H. OTHER INFORMATION
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Information relating to the quality of the immunological veterinary medicinal
product not covered by the previous sections may be included in the dossier.
PART 3: SAFETY TESTS
A. INTRODUCTION AND GENERAL REQUIREMENTS
The safety tests shall show the potential risks from the immunological veterinary
medicinal product, which may occur under the proposed conditions of use in
animals: these shall be evaluated in relation to the potential benefits of the product.
Where immunological veterinary medicinal products consist of live organisms,
especially those, which could be shed by vaccinated animals, the potential risk to
unvaccinated animals of the same or of any other potentially exposed species shall
be evaluated.
The safety studies shall be carried out in the target species. The dose to be used shall
be the quantity of the product to be recommended for use and the batch used for
safety testing shall be taken from a batch or batches produced according to the
manufacturing process described in Part 2 of the application.
In the case of an immunological veterinary medicinal products containing a live
organism, the dose to be used in the laboratory tests described in Sections B.1 and
B.2 shall be the quantity of the product containing the maximum titre. If necessary
the concentration of the antigen may be adjusted to achieve the required dose. For
inactivated vaccines the dose to be used shall be that quantity recommended for use
containing the maximum antigen content unless justified.
The safety documentation shall be used for assessment of the potential risks which
may result from the exposure of human beings to the veterinary medicinal product,
for example during its administration to the animal.
B. LABORATORY TESTS
1. Safety of the administration of one dose
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The immunological veterinary medicinal product shall be administered at the
recommended dose and by each recommended route of administration to animals of
each species and category in which it is intended for use, including animals of the
minimum age of administration. The animals shall be observed and examined for
signs of systemic and local reactions. Where appropriate, these studies shall include
detailed post-mortem macroscopic and microscopic examinations of the injection
site. Other objective criteria shall be recorded, such as rectal temperature and
performance measurements.
The animals shall be observed and examined until reactions may no longer be
expected, but in all cases, the observation and examination period shall be at least 14
days after administration.
This study may be part of the repeated dose study required under point 3 or omitted
if the results of the overdose study required under point 2 have revealed no signs of
systemic or local reactions.
2. Safety of one administration of an overdose
Only live immunological veterinary medicinal products require overdose testing.
An overdose of the immunological veterinary medicinal product shall be
administered by each recommended route(s) of administration to animals of the most
sensitive categories of the target species, unless the selection of the most sensitive of
several similar routes is justified. In the case of immunological veterinary medicinal
products administered by injection, the doses and route(s) of administration shall be
chosen to take account of the maximum volume, which can be administered at any
one single injection site. The animals shall be observed and examined for at least 14
days after administration for signs of systemic and local reactions. Other criteria
shall be recorded, such as rectal temperature and performance measurements.
Where appropriate, these studies shall include detailed post-mortem macroscopic
and microscopic examinations of the injection site if this has not been done under
point 1.
3. Safety of the repeated administration of one dose
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In the case of immunological veterinary medicinal products to be administered more
than once, as part of the basic vaccination scheme, a study of the repeated
administration of one dose shall be required to reveal any adverse effects induced by
such administration. These tests shall be carried out on the most sensitive categories
of the target species (such as certain breeds, age groups), using each recommended
route of administration.
The animals shall be observed and examined for at least 14 days after the last
administration for signs of systemic and local reactions. Other objective criteria shall
be recorded, such as rectal temperature and performance measurements.
4. Examination of reproductive performance
Examination of reproductive performance shall be considered when data suggest that
the starting material from which the product is derived may be a potential risk factor.
Reproductive performance of males and non-pregnant and pregnant females shall be
investigated with the recommended dose and by the most sensitive route of
administration. In addition, harmful effects on the progeny, as well as teratogenic
and abortifacient effects, shall be investigated.
These studies may form part of the safety studies described in points 1, 2, 3 or of the
field studies provided for in Section C.
5. Examination of immunological functions
Where the immunological veterinary medicinal product might adversely affect the
immune response of the vaccinated animal or of its progeny, suitable tests on the
immunological functions shall be carried out.
6. Special requirements for live vaccines
6.1. Spread of the vaccine strain
Spread of the vaccine strain from vaccinated to unvaccinated target animals shall be
investigated, using the recommended route of administration most likely to result in
the spread. Moreover, it may be necessary to investigate the spread to non-target
animal species which could be highly susceptible to a live vaccine strain.
6.2. Dissemination in the vaccinated animal
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Faeces, urine, milk, eggs, oral, nasal and other secretions shall be tested for the
presence of the organism as appropriate. Moreover, studies may be required of the
dissemination of the vaccine strain in the body, with particular attention being paid
to the predilection sites for replication of the organism. In the case of live vaccines
for zoonoses within the meaning of Directive 2003/99/EC of the European
Parliament and of the Council 14 to be used for food producing animals, these studies
must shall take particularly into account the persistence of the organism at the
injection site.
6.3. Reversion to virulence of attenuated vaccines
Reversion to virulence shall be investigated with the master seed. If the master seed
is not available in sufficient quantity the lowest passage seed used for the production
shall be examined. Use of another passage option shall be justified. The initial
vaccination shall be carried out using the route of administration most likely to lead
to reversion to virulence. Serial passages shall be made in target animals through
five groups of animals, unless there is justification to make more passages or the
organism disappears from the test animals sooner. Where the organism fails to
replicate adequately, as many passages as possible shall be carried out in the target
species.
6.4. Biological properties of the vaccine strain
Other tests may be necessary to determine as precisely as possible the intrinsic
biological properties of the vaccine strain (e.g. neurotropism).
6.5. Recombination or genomic reassortment of strains
The probability of recombination or genomic reassortment with field or other strains
shall be discussed.
7. User safety
This section shall include a discussion of the effects found in the preceding sections,
which shall relate those effects to the type and extent of human exposure to the
OJ L 325, 12.12.2003, p. 31.
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product with a view to formulating appropriate user warnings and other risk
management measures.
8. Study of residues
For immunological veterinary medicinal products, it will normally not be necessary
to undertake a study of residues. However, where adjuvants and/or preservatives are
used in the manufacture of immunological veterinary medicinal products,
consideration shall be given to the possibility of any residue remaining in the
foodstuffs. If necessary, the effects of such residues shall be investigated.
A proposal for a withdrawal period shall be made and its adequacy shall be
discussed in relation to any residue studies which have been undertaken.
9. Interactions
If there is a compatibility statement with other veterinary immunological products in
the summary of product characteristics the safety of the association shall be
investigated. Any other known interactions with veterinary medicinal products shall
be described.
C. FIELD STUDIES
Unless justified, results from laboratory studies shall be supplemented with data
from field studies, using batches according to the manufacturing process described in
the marketing authorisation application. Both safety and efficacy may be
investigated in the same field studies.
D. ENVIRONMENTAL RISK ASSESSMENT
The purpose of the environmental risk assessment is to assess the potential harmful
effects, which the use of the product may cause to the environment and to identify
any precautionary measures, which may be necessary to reduce such risks.
This assessment shall normally be conducted in two phases. The first phase of the
assessment shall always be performed. The details of the assessment shall be
provided in accordance with established guidance. It shall indicate the potential
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exposure of the environment to the product and the level of risk associated with any
such exposure, taking into account in particular the following items
- the target animal species and the proposed pattern of use,
- the method of administration, in particular the likely extent to which the product
will enter directly into the environmental system,
- the possible excretion of the product, its active substances into the environment by
treated animals, persistence in such excreta,
- the disposal of unused or waste product.
In the case of live vaccine strains which may be zoonotic, the risk to humans shall be
assessed.
Where the conclusions of the first phase indicate potential exposure of the
environment to the product, the applicant shall proceed to the second phase and
evaluate the potential risk(s) that the veterinary medicinal product might pose to the
environment. Where necessary, further investigations on the impact of the product
(soil, water, air, aquatic systems, non-target organisms) shall be carried out.
E. ASSESSMENT REQUIRED FOR VETERINARY MEDICINAL PRODUCTS
CONTAINING OR CONSISTING OF GENETICALLY MODIFIED ORGANISMS
In the case of veterinary medicinal products containing or consisting of genetically
modified organisms the application shall also be accompanied by the documents
required under Article 2 and Part C of Directive 2001/18/EC.
PART 4: EFFICACY TESTS
CHAPTER I
1. General principles
The purpose of the trials described in this Part is to demonstrate or to confirm the
efficacy of the immunological veterinary medicinal product. All claims made by the
applicant with regard to the properties, effects and use of the product, shall be fully
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supported by results of specific trials contained in the application for marketing
authorisation.
2. Performance of trials
All efficacy trials shall be conducted in accordance with a fully considered detailed
protocol, which shall be recorded in writing prior to commencement of the trial. The
welfare of the trial animals shall be subject to veterinary supervision and shall be
taken fully into consideration during the elaboration of any trial protocol and
throughout the conduct of the trial.
Pre-established systematic written procedures for the organisation, conduct, data
collection, documentation and verification of efficacy trials shall be required.
Field trials shall be conducted in accordance with established principles of good
clinical practice, unless otherwise justified.
Before the commencement of any field trial, the informed consent of the owner of
the animals to be used in the trial shall be obtained and documented. In particular,
the animal owner shall be informed in writing of the consequences of participation in
the trial for the subsequent disposal of treated animals or for the taking of foodstuffs
from treated animals. A copy of this notification, countersigned and dated by the
animal owner, shall be included in the trial documentation.
Unless the field trial is conducted with a blind design, the provisions of regulations
55, 56 and 57 of these regulations shall apply by analogy to the labelling of
formulations intended for use in veterinary field trials. In all cases, the words "for
veterinary field trial use only" shall appear prominently and indelibly upon the
labelling.
CHAPTER II
A. General requirements
1. The choice of antigens or vaccine strains shall be justified on the basis of
epizoological data.
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2. Efficacy trials carried out in the laboratory shall be controlled trials, including
untreated control animals unless this is not justified for animal welfare reasons and
efficacy can be otherwise demonstrated.
In general, these laboratory trials shall be supported by trials carried out in field
conditions, including untreated control animals.
All trials shall be described in sufficiently precise details so as to be reproducible in
controlled trials, carried out at the request of the competent authorities. The
investigator shall demonstrate the validity of all the techniques involved.
All results obtained, whether favourable or unfavourable, shall be reported.
3. The efficacy of an immunological veterinary medicinal product shall be
demonstrated for each category of target animal species recommended for
vaccination, by each recommended route of administration and using the proposed
schedule of administration. The influence of passively acquired and maternally
derived antibodies on the efficacy of a vaccine shall be adequately evaluated, if
appropriate. Unless justified, the onset and duration of immunity shall be established
and supported by data from trials.
4. The efficacy of each of the components of multivalent and combined
immunological veterinary medicinal products shall be demonstrated. If the product is
recommended for administration in combination with or at the same time as another
veterinary medicinal product, they shall be shown to be compatible.
5. Whenever a product forms part of a vaccination scheme recommended by the
applicant, the priming or booster effect or the contribution of the veterinary
immunological product to the efficacy of the scheme as a whole shall be
demonstrated.
6. The dose to be used shall be the quantity of the product to be recommended for
use and the batch used for efficacy testing shall be taken from a batch or batches
produced according to the manufacturing process described in Part 2 of the
application.
7. If there is a compatibility statement with other immunological products in the
summary of product characteristics, the efficacy of the association shall be
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investigated. Any other known interactions with any other veterinary medicinal
products shall be described. Concurrent or simultaneous use may be allowed if
supported by appropriate studies.
8. For diagnostic immunological veterinary medicinal products administered to
animals, the applicant shall indicate how reactions to the product are to be
interpreted.
9. For vaccines intended to allow a distinction between vaccinated and infected
animals (marker vaccines), where the efficacy claim is reliant on in vitro diagnostic
tests, sufficient data on the diagnostic tests shall be provided to allow adequate
assessment of the claims related to the marker properties.
B. Laboratory trials
1. In principle, demonstration of efficacy shall be undertaken under well-controlled
laboratory conditions by challenge after administration of the immunological
veterinary medicinal product to the target animal under the recommended conditions
of use. Insofar as possible, the conditions under which the challenge is carried out
shall mimic the natural conditions for infection. Details of the challenge strain and
its relevance shall be provided.
For live vaccines, batches containing the minimum titre or potency shall be used
unless justified. For other products, batches containing the minimum active content
shall be used unless otherwise justified.
2. If possible, the immune mechanism (cell-mediated/humoral, local/general classes
of immunoglobulin) which is initiated after the administration of the immunological
veterinary medicinal product to target animals by the recommended route of
administration shall be specified and documented.
C. Field trials
1. Unless justified, results from laboratory trials shall be supplemented with data
from field trials, using batches representative of the manufacturing process described
in the marketing authorisation application. Both safety and efficacy may be
investigated in the same field study.
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2. Where laboratory trials cannot be supportive of efficacy, the performance of field
trials alone may be acceptable.
PART 5: PARTICULARS AND DOCUMENTS
A. INTRODUCTION
The dossier of the safety and efficacy studies shall include an introduction defining
the subject and indicating the tests which have been carried out in compliance with
Parts 3 and 4 as well as a summary, with detailed references to the published
literature. This summary shall contain an objective discussion of all the results
obtained and lead to a conclusion on the safety and efficacy of the immunological
veterinary medicinal product. Omission of any tests or trials listed shall be indicated
and discussed.
B. LABORATORY STUDIES
The following shall be provided for all studies
1. a summary;
2. the name of the body having carried out the studies;
3. a detailed experimental protocol giving a description of the methods, apparatus
and materials used, details such as species or breed of animals, categories of animals,
where they were obtained, their identification and number, the conditions under
which they were housed and fed (stating, inter alia, whether they were free from any
specified pathogens and/or specified antibodies, the nature and quantity of any
additives contained in the feed), dose, route, schedule and dates of administration, a
description and a justification of the statistical methods used;
4. in the case of control animals, whether they received a placebo or no treatment;
5. in the case of treated animals and where appropriate, whether they received the
test product or another product authorised in the Community
6. all general and individual observations and results obtained (with averages and
standard deviations), whether favourable or unfavourable. The data shall be
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described in sufficient detail to allow the results to be critically evaluated
independently of their interpretation by the author. The raw data shall be presented
in tabular form. By way of explanation and illustration, the results may be
accompanied by reproductions of recordings, photomicrographs, etc;
7. the nature, frequency and duration of observed adverse reactions;
8. the number of animals withdrawn prematurely from the studies and reasons for
such withdrawal;
9. a statistical analysis of the results, where such is called for by the test programme,
and variance within the data;
10. occurrence and course of any intercurrent disease;
all details concerning veterinary medicinal products (other than the product
under study), the administration of which was necessary during the course of the
study;
an objective discussion of the results obtained, leading to conclusions on the
safety and efficacy of the product.
C. FIELD STUDIES
Particulars concerning field studies shall be sufficiently detailed to enable an
objective judgement to be made. They shall include the following
1. a summary;
2. name, address, function and qualifications of the investigator in charge;
3. place and date of administration, identity code that can be linked to the name and
address of the owner of the animal(s);
4. details of the trial protocol, giving a description of the methods, apparatus and
materials used, details such as the route of administration, the schedule of
administration, the dose, the categories of animals, the duration of observation, the
serological response and other investigations carried out on the animals after
administration;
5. in the case of control animals, whether they received a placebo or no treatment;
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6. identification of the treated and control animals (collective or individual, as
appropriate), such as species, breeds or strains, age, weight, sex, physiological
status;
7. a brief description of the method of rearing and feeding, stating the nature and
quantity of any additives contained in the feed;
8. all the particulars on observations, performances and results (with averages and
standard deviation); individual data shall be indicated when tests and measurements
on individuals have been carried out;
9. all observations and results of the studies, whether favourable or unfavourable,
with a full statement of the observations and the results of the objective tests of
activity required to evaluate the product; the techniques used must be specified and
the significance of any variations in the results explained;
10. effects on the animals’ performance;
11. the number of animals withdrawn prematurely from the studies and reasons for
such withdrawal;
12. the nature, frequency and duration of observed adverse reactions;
occurrence and course of any intercurrent disease;
all details concerning veterinary medicinal products (other than the product
under study) which have been administered either prior to or concurrently with the
test product or during the observation period; details of any interactions observed;
an objective discussion of the results obtained, leading to conclusions on the
safety and efficacy of the product.
PART 6: BIBLIOGRAPHICAL REFERENCES
The bibliographical references cited in the summary mentioned under Part 1 shall be
listed in detail and copies shall be provided.
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TITLE III
REQUIREMENTS
FOR
SPECIFIC
MARKETING
AUTHORISATION
APPLICATIONS
1. Generic veterinary medicinal products
Applications based on regulation 13 hereof (generic veterinary medicinal products)
shall contain the data referred to in Parts 1 and 2 of Title I of this Schedule together
with an environmental risk assessment and data demonstrating that the product has
the same qualitative and quantitative composition in active substances and the same
pharmaceutical form as the reference medicinal product and data showing bio-
equivalence with the reference medicinal product. If the reference veterinary
medicinal product is a biological medicinal product, the documentation requirements
in Section 2 for similar biological veterinary medicinal products shall be fulfilled.
For generic veterinary medicinal products the detailed and critical summaries on
safety and efficacy shall particularly focus on the following elements
- the grounds for claiming essential similarity,
- a summary of impurities present in batches of the active substance(s) as well as
those of the finished medicinal product (and where relevant decomposition products
arising during storage) as proposed for use in the product to be marketed together
with an evaluation of these impurities,
- an evaluation of the bio-equivalence studies or a justification as to why studies
were not performed with reference to established guidance,
- if applicable, additional data in order to demonstrate the equivalence of safety and
efficacy properties of different salts, esters or derivatives of an authorised active
substance shall be provided by the applicant; those data shall include evidence that
there is no change in the pharmacokinetic or pharmacodynamic properties of the
therapeutic moiety and/or in toxicity, which could influence the safety/efficacy
profile.
Every claim in the summary of product characteristics not known from or inferred
from the properties of the medicinal product and/or its therapeutic group should be
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discussed in the non-clinical/clinical overviews/summaries and substantiated by
published literature and/or additional studies.
For generic veterinary medicinal products intended to be administered by
intramuscular, subcutaneous or transdermal routes, the following additional data
shall be provided
- evidence to demonstrate equivalent or differing depletion of residues from the
administration site, which may be substantiated by appropriate residue depletion
studies,
- evidence to demonstrate target animal tolerance at the administration site, which
may be substantiated by appropriate target animal tolerance studies.
2. Similar biological veterinary medicinal products
In accordance with regulation 13(4) hereof, where a biological veterinary medicinal
product which is similar to a reference biological veterinary medicinal product does
not meet the conditions in the definition of generic medicinal product, information to
be supplied shall not be limited to Parts 1 and 2 (pharmaceutical, chemical and
biological data), supplemented with bio-equivalence and bioavailability data. In such
cases, additional data shall be provided, in particular on the safety and efficacy of the
product.
- The type and amount of additional data (i.e. toxicological and other safety studies
and appropriate clinical studies) shall be determined on a case-by-case basis in
accordance with relevant scientific guidelines.
- Due to the diversity of biological veterinary medicinal products, the competent
authority shall determine the necessary studies foreseen in Parts 3 and 4, taking into
account the specific characteristic of each individual biological veterinary medicinal
product.
The general principles to be applied shall be addressed in guideline which shall be
adopted by the Agency, taking into account the characteristics of the concerned
biological veterinary medicinal product. If the reference biological veterinary
medicinal product has more than one indication, the efficacy and safety of the
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biological veterinary medicinal product claimed to be similar shall be justified or, if
necessary, demonstrated separately for each of the claimed indications.
3. Well-established veterinary use
For veterinary medicinal products the active substance(s) of which has/have been in
"well-established veterinary use" as referred to in regulation 13A(1) of these
regulations, with recognised efficacy and an acceptable level of safety, the following
specific rules shall apply.
The applicant shall submit Parts 1 and 2 as described in Title I of this Schedule.
For Parts 3 and 4, a detailed scientific bibliography shall address all aspects of the
safety and efficacy.
The following specific rules shall apply in order to demonstrate the well-established
veterinary use
3.1. The following factors shall be taken into account in order to establish a well-
established veterinary medicinal use of constituents of veterinary medicinal
products
(a) the time over which an active substance has been used;
(b) quantitative aspects of the use of the active substance;
(c) the degree of scientific interest in the use of the active substance (reflected in the
published scientific literature);
(d) the coherence of scientific assessments.
Different periods of time may be necessary for establishing well-established use of
different substances. In any case, however, the period of time required for
establishing a well-established veterinary use of a constituent of a medicinal product
shall not be less than ten years from the first systematic and documented use of that
substance as a veterinary medicinal product in the Community.
3.2. The documentation submitted by the applicant shall cover all aspects of the
safety and/or efficacy assessment of the product for the proposed indication in the
target species using the proposed route of administration and dosage regimen. It
must include or refer to a review of the relevant literature, taking into account pre-
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and post-marketing studies and published scientific literature concerning experience
in the form of epidemiological studies and in particular of comparative
epidemiological studies. All documentation, both favourable and unfavourable, shall
be communicated. With respect to the provisions on well-established veterinary use,
it is in particular necessary to clarify that bibliographic reference to other sources of
evidence (post-marketing studies, epidemiological studies etc.) and not just data
related to tests and trials may serve as a valid proof of safety and efficacy of a
product if an application explains and justifies the use of these sources of
information satisfactorily.
3.3. Particular attention must be paid to any missing information and justification
must be given as to why demonstration of an acceptable level of safety and/or
efficacy can be supported although some studies are lacking.
3.4. The detailed and critical summaries regarding safety and efficacy must explain
the relevance of any data submitted which concern a product different from the
product intended for marketing. A judgement must be made whether or not the
product studied can be considered as similar to the product, for which application for
a marketing authorisation has been made in spite of the existing differences.
3.5. Post-marketing experience with other products containing the same constituents
is of particular importance and applicants shall put a special emphasis on this issue.
4. Combination veterinary medicinal products
For applications based on regulation 13B of these regulations, a dossier containing
Parts 1, 2, 3 and 4 shall be provided for the combination veterinary medicinal
product. It shall not be necessary to provide studies on the safety and efficacy of
each active substance. It shall nevertheless be possible to include information on the
individual substances in the application for a fixed combination. The submission of
data on each individual active substance, in conjunction with the required user safety
studies, residues depletion studies and clinical studies on the fixed combination
product, may be considered a suitable justification for omitting data on the
combination product, based on animal welfare grounds and unnecessary testing on
animals, unless there is suspected interaction leading to added toxicity. Where
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applicable, information regarding the manufacturing sites and the safety evaluation
of adventitious agents shall be provided.
5. Informed consent applications
Applications based on regulation 13C hereof shall contain the data described in Part
1 of Title 1 of this Schedule, provided that the marketing authorisation holder for the
original veterinary medicinal product has given the applicant his consent to refer to
the content of Parts 2, 3 and 4 of the dossier of that product. In this case, there is no
need to submit quality, safety and efficacy detailed and critical summaries.
6. Documentation for applications in exceptional circumstances
A marketing authorisation may be granted subject to certain specific obligations
requiring the applicant to introduce specific procedures, in particular concerning the
safety and efficacy of the veterinary medicinal product, when, as provided for in
regulation 26(2) of these regulations, the applicant can show that he is unable to
provide comprehensive data on the efficacy and safety under normal conditions of
use.
The identification of essential requirements for all applications mentioned in this
section should be subject to guidelines which shall be adopted by the Agency.
7. Mixed marketing authorisation applications
Mixed marketing authorisation applications are applications where Part(s) 3 and/or 4
of the dossier consist of safety and efficacy studies carried out by the applicant as
well as bibliographical references. All other part(s) are in accordance with the
structure described in Part I of Title I of this Schedule. The competent authority shall
accept the proposed format presented by the applicant on a case-by-case basis.
TITLE IV
REQUIREMENTS FOR MARKETING AUTHORISATION APPLICATIONS
FOR PARTICULAR VETERINARY MEDICINAL PRODUCTS
This part lays down specific requirements for identified veterinary medicinal
products related to the nature of the active substances contained therein.
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1. IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS
A. VACCINE ANTIGEN MASTER FILE
For particular immunological veterinary medicinal products and by derogation from
the provisions of Title II, Part 2 Section C on active substances, the concept of a
Vaccine Antigen Master File is introduced.
For the purpose of this Schedule, a Vaccine Antigen Master File means a stand-alone
part of the marketing authorisation application dossier for a vaccine, which contains
all relevant information on quality concerning each of the active substances, which
are part of this veterinary medicinal product. The stand-alone part may be common
to one or more monovalent and/or combined vaccines presented by the same
applicant or marketing authorisation holder.
Scientific guidelines for the submission and evaluation of a vaccine antigen master
file shall be adopted by the Agency. The procedure for the submission and
evaluation of a vaccine antigen master file shall follow the guidance published by
the Commission in The rules governing medicinal products in the European Union,
Volume 6B, Notice to Applicants.
B. MULTI-STRAIN DOSSIER
For certain immunological veterinary medicinal products (foot-and-mouth disease,
avian influenza and bluetongue) and by derogation from the provisions of Title II,
Part 2 Section C on active substances the concept of the use of a multi-strain dossier
is introduced.
A multi-strain dossier means a single dossier containing the relevant data for a
unique and thorough scientific assessment of the different options of
strains/combinations of strains permitting the authorisation of vaccines against
antigenically variable viruses.
Scientific guidelines for the submission and evaluation of multi-strain dossiers shall
be adopted by the Agency. The procedure for the submission and evaluation of
multi-strain dossiers shall follow the guidance published by the Commission in The
B
rules governing medicinal products in the European Union, Volume 6B, Notice to
Applicants.
2. HOMEOPATHIC VETERINARY MEDICINAL PRODUCTS
This section sets out specific provisions on the application of Title I, Parts 2 and 3 to
homeopathic veterinary medicinal products as defined in regulation 2(8) of these
regulations.
Part 2
The provisions of Part 2 shall apply to the documents submitted in accordance with
regulation 18 of these regulations in the simplified registration of homeopathic
veterinary medicinal products referred to in regulation 17(1) of these regulations as
well as to the documents for authorisation of other homeopathic veterinary medicinal
products referred to in regulation 19(1) hereof with the following modifications.
(a) Terminology
The Latin name of the homeopathic stock described in the marketing authorisation
application dossier shall be in accordance with the Latin title of the European
Pharmacopoeia or, in absence thereof, of an official pharmacopoeia of Malta. Where
relevant the traditional name(s) used in each Member State shall be provided.
(b) Control of starting materials
The particulars and documents on the starting materials, i.e. all of the materials used
including raw materials and intermediates up to the final dilution to be incorporated
into the finished homeopathic veterinary medicinal product, accompanying the
application shall be supplemented by additional data on the homeopathic stock.
The general quality requirements shall apply to all of the starting and raw materials
as well as intermediate steps of the manufacturing process up to the final dilution to
be incorporated into the finished homeopathic product. Where a toxic component is
present, this should be controlled if possible in the final dilution. However, if this is
not possible because of the high dilution, the toxic component shall normally be
B
controlled at an earlier stage. Every step of the manufacturing process from the
starting materials up to the final dilution to be incorporated into the finished product
must be fully described.
In case dilutions are involved, these dilution steps shall be done in accordance with
the homeopathic manufacturing methods laid down in the relevant monograph of the
European Pharmacopoeia or, in absence thereof, in an official pharmacopoeia of
Malta.
(c) Control tests on the finished medicinal product
The general quality requirements shall apply to the homeopathic finished veterinary
medicinal products. Any exception shall be duly justified by the applicant.
Identification and assay of all the toxicologically relevant constituents shall be
carried out. If it can be justified that identification and/or an assay on all the
toxicologically relevant constituents is not possible e.g. due to their dilution in the
finished medicinal product the quality shall be demonstrated by complete validation
of the manufacturing and dilution process.
(d) Stability tests
The stability of the finished product shall be demonstrated. Stability data from the
homeopathic stocks are generally transferable to dilutions/potentisations obtained
thereof. If no identification or assay of the active substance is possible due to the
degree of dilution, stability data of the pharmaceutical form may be considered.
Part 3
The provisions of Part 3 shall apply to the simplified registration of homeopathic
veterinary medicinal products referred to in regulation 17(1) of these regulations
with the following specification, without prejudice to the provisions of Regulation
(EEC) No 2377/90 for substances included in the homeopathic stocks intended for
administration to food-producing animal species.
Any missing information must be justified, e.g. justification must be given why
demonstration of an acceptable level of safety can be supported although some studies are
lacking.”.
€8.01