Data Requirements for

Veterinary Medicinal
Products
Pharmaceutical and Immunological

Version 1.0
Data Requirements for Veterinary
Medicinal Products
Pharmaceutical and Immunological

Version 1.0

Central Registration

Please visit the GHC website

for the latest updates

For Inquiries [email protected]

[email protected]

2
Contents

I. Introduction ....................................................................................................................... 6
II. Part 1 (Summary of the dossier) for pharmaceutical and immunological veterinary
medicinal products .................................................................................................................... 9
Part 1 Summary of the dossier ................................................................................................. 10
III. Data Requirements for Veterinary Pharmaceutical Products ................................ 15
Part 2 Quality Documentation ............................................................................................... 17
Part 3 Safety and Residues Tests ........................................................................................... 32
Part 4 Preclinical and clinical trials ...................................................................................... 46
IV. Data Requirements for Veterinary Immunological Products ................................. 54
Part 2 Quality Documentations ............................................................................................. 57
Part 3 Safety Documentation ................................................................................................ 67
Part 4 Efficacy documentation ............................................................................................. 73
V. References ........................................................................................................................ 76

3
 I. Introduction
This guidance published to assist applicant in the preparation of Veterinary medicinal
products submissions for presentation to Gulf Health Council (GHC).

The data requirements for veterinary medicinal product for each application will differ,
based on the type of product pharmaceutical or immunological. However, presentation and
content of part 1 (summary of the dossier) is similar for both types and will differ in Parts
2, 3 and 4:

• For pharmaceutical product; Parts 2, 3 and 4 of the dossier consist of quality, safety
and residues tests and preclinical and clinical respectively.

• For immunological product; Parts 2, 3 and 4 of the dossier consist of quality, safety
and efficacy respectively.

About preparing the dossier for generic and similar biological veterinary medicinal
products, it is acknowledged that certain parts or sections would generally not be
applicable, as explained in the following sections:

• For veterinary generic products

The dossier shall contain the data referred to in Parts 1 and 2 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 bioequivalence with the reference medicinal
product.

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,

4
 - an evaluation of the bioequivalence studies or justification as to why studies were
not performed concerning 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 pharmacodynamics properties of the
therapeutic moiety and/or in toxicity, which could influence the safety/efficacy
profile.

For 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.

• Similar biological veterinary medicinal products

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 the generic
medicinal product, information to be supplied shall not be limited to Parts 1 and 2,
supplemented with bioequivalence 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.

5
 - Due to the diversity of biological veterinary medicinal products, GHC shall
determine the necessary studies foreseen in Parts 3 and 4, taking into account the
specific characteristic of each individual biological veterinary medicinal product.

If the reference biological veterinary medicinal product has more than one indication, the
efficacy and safety of the biological veterinary medicinal product claimed to be similar
shall be justified or, if necessary, demonstrated separately for each of the claimed
indications.

6
II. Part 1 (Summary of the dossier) for pharmaceutical and
immunological veterinary medicinal products
Section Requirements
1a Administrative information
1a1 Cover letter
1a2 Application form
1a3 Pharmacovigilance
1a31 Pharmacovigilance system
1a32 Risk management plan
1a4 Certificates & documents
1a41 GMP certificate
1a42 CPP
1a43 Certificate of analysis – Drug substances & Finished product
1a44 Certificate of analysis - Excipients
1a45 Certificate of suitability
1a46 Patent Information
1a47 Letter of access or acknowledgment to DMF
1a5 Pricing
1a51 Price list
1a52 Other documents related
1a6 Responses to questions
1a7 Additional data
1b SPC and Product Literature
1b1 Summary of Product Characteristics (SPC)
1b2 Package leaflet (PL)
1b21 Arabic leaflet
1b22 English leaflet
1b3 Labeling
1b4 Artwork (Mock-ups)
1b5 Samples
1c Critical Summaries
1c1 Quality
1c2 Safety & residues
1c3 Efficacy

7
 Part 1 Summary of the dossier
1a Administrative information

1a1 Cover letter

The applicant shall include a cover letter for each submission. A template is provided in the GHC
website in (Forms) section.

1a2 Application form

The completed application form printed out from the Taawon system (https://taawon-
ghc.com/esop/ksa-ghc-host/public/web/login.html?_ncp=1593319562575.1635302-1)
should be presented in this section.

1a3 Pharmacovigilance

1a31 Pharmacovigilance system

It shall contain a detailed description of the pharmacovigilance system including the proof
that the applicant has the services of a qualified person responsible for pharmacovigilance
and the necessary means for the notification of any adverse reaction.

1a32 Risk management plan

A detailed description of the risk management system, which the applicant will introduce,
should provide, where appropriate.

1a4 Certificates and documents

1a41 GMP certificate

A valid and legalized GMP Certificate should be submitted.

1a42 Certificate of pharmaceutical product (CPP)

The CPP should be in accordance with WHO guidelines. However, if the CPP is not
available, a marketing authorization (or free sales certificate) from the country of origin
(COO) should be submitted. Marketing authorization (or free sales certificate) should be
legalized and include the following:

10
 1. Product trade name in the COO.

2. Number and date of marketing authorization in the COO.

3. Name of active and inactive substances with their concentrations.

4. A statement that certifies the product is marketed in the COO. If not, please
specify the reasons.

5. Provide official document demonstrating that the product has registered for no
less than one year in the COO.

6. Provide the Summary of Product Characteristics (SPC).

7. Provide a copy of the Package Leaflet (PL).

1a43 Certificate of analysis – drug substance & finished product

- Certificates of analysis for more than one batch of the drug substance should
submitted from the supplier (drug substance manufacturer).
- Certificates of analysis for more than one batch of the drug substance should be
submitted from the finished product manufacturer.
- Certificates of analysis for more than one batch of the finished product should
submitted.

1a44 Certificate of analysis – excipients

Certificates of analysis for more than one batch of the excipients may submitted to support
the application.

1a45 Certificate of suitability for TSE

Data should be provided to confirm that the drug substance, starting materials and reagents
and/ or culture media used to manufacture of the veterinary medicinal products are
submitted according to Note for guidance on minimising the risk of transmitting animal
spongiform encephalopathy agents via human and veterinary medicinal products. When
available, a CEP demonstrating TSE-compliance should be submitted. A complete copy of
the CEP (including any annexes) should be provided.

9
1a46 Patent information

This section should contain a declaration letter on an official company letterhead stating
the patent status of the product.

1a47 Letter of access or acknowledgment to DMF (If applicable)

A letter was written by the DMF Owner or authorized Agent permitting GHC to reference
information in the DMF on behalf of the Applicant.

1a5 Pricing

1a51 Price list

The applicant shall include the price of the product in countries listed in the GHC
Guidance for Submission. A template is provided in the GHC website in (Forms)
section.

1a52 Other documents related

1a6 Responses to questions

The response document should follow the same presentation as the initial dossier. The
applicant should include in this section a document, which lists the questions with the
corresponding narrative text response for each question. This section will not use for
supporting technical documentation, which will be included to the relevant Parts. Each
question should followed by the name of section, page number and a hyperlink where the
answer can be found in the concerned part.

1a7 Additional data

1b SPC and product literature

1b1 Summary of product characteristics (SPC)

Refer to the Guidance for presenting the SPC, PL, and labeling information for veterinary
products.

10
1b2 Package leaflet (PL)

Refer to the Guidance for presenting the SPC, PL, and labeling information for veterinary
products.

1b21 Arabic leaflet

1b22 English leaflet

1b3 Labeling

Refer to the Guidance for presenting the SPC, PL, and labeling information for veterinary
products.

1b4 Artwork (Mock-ups)

A mock-up is a flat artwork design in full color, presented so that, following cutting and
folding, where necessary, it provides a full size replica of both the outer and immediate
packaging so that the two dimensional presentation of the label text is clear. The application
for a marketing authorization must include one or more mock-ups of the outer packaging
and of the immediate packaging of the product. Refer to the Guidance for presenting the
SPC, PL, and labeling information for veterinary products.

1b5 Samples

A number of samples should provide to perform complete testing. The required quantities
of samples further described in the GHC Guidance for Submission. The submitted samples
must represent the final finished product to be marketed in Saudi Arabia.

1c Critical summaries (CS)

1c1 Quality

1c2 Safety

1c3 Efficacy

The Quality, Safety, Efficacy Summary is a summary that follows the scope and the outline
of the Body of Data. The CS should not include information, data or justification that was
not already included in each part or other parts of the structure. The CS should
11
include sufficient information from each section to provide the reviewer with an overview
of each part. The CS should include a discussion of key issues that integrates information
from sections in the Quality, Safety, Efficacy part and supporting information from another
part. This CS normally should not exceed 40 pages of text, excluding tables and figures.
For biotech, products and products manufactured using processes that are more complex,
the document could be longer but normally should not exceed 80 pages of text (excluding
tables and figures). The use of tables to summarize the information is encouraged, where
possible.

12
III. Data Requirements for
Veterinary
Pharmaceutical Products

13
 Section Requirements
Part 2 Quality Documentation
2a Qualitative and Quantitative Particulars
2a1 Qualitative Particulars
2a2 Usual Terminology
2a3 Quantitative Particulars
2a4 Development pharmaceutics
2b Description of the Manufacturing Method
2c Control of Starting Materials
2c1 Active substance(s)
2c2 Excipient(s)
2c3 Container / Closure system
2c4 Substances of biological Origin
2d Control Tests at intermediate process stages
2e Tests on the finished Product
2e1 General characteristics of the finished product
2e2 Identification and assay of active substance(s)
2e3 Identification and assay of excipient components
2e4 Safety tests
2f Stability Tests
2f1 Active substances(s)
2f2 Finished product
2g Other Information
Part 3 Safety and residues tests
3a Safety tests
3a1 Precise Identification of the Product and active
3a2 Pharmacology
3a3 Toxicology
3a4 Other requirements
3a5 URA (User safety)
3a6 ERA (Environmental risk assessment)
3b Residue tests
3b1 Identification of product
3b2 Metabolism and residue kinetics
3b3 Residue analytical method
Part 4 Preclinical and clinical trials
4a Preclinical Requirements
4a1 Pharmacology
4a2 Resistance
4a3 Target animal tolerance
4b Clinical Requirements
4b1 Clinical trials

14
Part 2 Quality Documentation
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 characterization 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 test procedures shall fulfill the criteria for analysis and control of the quality of the
starting materials and the finished product. The results of the validation studies shall be
provided.

2a Qualitative and quantitative particulars

2a1 Qualitative particulars
Qualitative particulars of all the constituents of the veterinary medicinal product shall mean
the designation or description of:

- the active substance (s),

- the constituent (s) of the excipients, whatever their nature or the quantity used,
including preservatives, adjuvants, stabilizers, thickeners, emulsifiers, coloring
matter, flavoring, 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, gelatin
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.

2a2 Usual terminology

The usual terminology to be used in describing the constituents of the veterinary medicinal
product:

15
 1. in respect of constituents which appear the Pharmacopoeia
2. in respect of other constituents, the international non-proprietary name (INN)
recommended by the World Health Organization (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,

2a3 Quantitative particulars

In order to give the ‘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
WHO , 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 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

16
 forms to be administered in measured quantities, by the mass or units of
biological activity of each active substance per measured quantity.

- 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.

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.

2a4 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 authorization application dossier.

2b 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.
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

17
 terms insofar as the pharmaceutical form makes this necessary; mention shall be
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.

2c Control of starting materials

• 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
mentioned in section 2a1.
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 authorization. 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.

Certificates of Analysis shall be presented for the starting materials in order to demonstrate
compliance with the defined specification.
If the starting material is of vegetable origin, the monograph of the material should be
summarized (specification with description of the test procedures). Only the substances of
vegetable origin that determine the therapeutic activity of the product should be stated.

20
2c1 Active substance(s)
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 may arrange for
the following information:
1. A detailed description of the manufacturing process;
2. A description of the quality control during manufacture;
3. 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 the 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 GHC 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 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
21
 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.
• Active substances listed in pharmacopeia
The general and specific monographs of the Pharmacopoeia shall be applicable to all active
substances appearing in it.

Constituents fulfilling the requirements of the Pharmacopoeia shall be deemed to comply

sufficiently with description of the testing methods employed by the manufacturer. 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 Pharmacopoeia is

insufficient to ensure the quality of the substance, GHC may request more appropriate
specifications from the applicant, including limits for specific impurities with validated test
procedures.

• Active substances not in a pharmacopeia

Specification and routine tests, the scientific data on nomenclature, description,
manufacture, quality control during manufacture, the development chemistry (including
evidence of structure, potential isomerism, physico-chemical characteristics and analytical
validation,) potential and actual impurities and the batch analysis should be submitted.
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 composition section, shall
be supplemented by any trade or scientific synonyms;

22
 b) the definition of the substance, set down in a form similar to that used in
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 characterize 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;
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.
• 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:

23
 - crystalline form and solubility coefficients,
- particle size, where appropriate after pulverisation,
- state of hydration,
- oil/water coefficient of partition,
- pK/pH values.
Note: The first three indents are not applicable to substances used solely in solution.

For active substances of vegetable origin and preparations, Test for the potential
contaminant (micro-organisms, pesticides, fumigants, toxic metals, radioactivity etc.)
should be discussed.

2c2 Excipient(s)
Excipients shall comply with the requirements of the appropriate pharmacopoeia general
and specific monographs. Where appropriate, additional 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 for the active substance not in a
pharmacopeia shall be followed. The proposed methods and their supporting validation
data shall be presented.
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,
characterization, and controls, with cross references to supporting safety data, both clinical
and non-clinical, shall be provided.

2c3 Container closure

• 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.

24
• 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 pharmacopoeia
monograph.
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.

2c4 Substances of biological origin

The origin, including geographical region, 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.
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 minimizing the risk of

25
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, may be used to demonstrate compliance.

2d Control tests at intermediate process stages

The dossier shall include particulars relating to the product control tests that may be carried
out at an intermedia test age 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.

2e 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 sterilization operations or, in the
case of a continuous production process, all the units manufactured in a given period of
time.

26
The test which are carried out routinely on each batch of finished product should be
specified. The frequency of the tests which are not carried out routinely shall be stated.
Release limits shall be indicated.

- Specifications of the medicinal product

Methods and Acceptance Limits
Characteristics of the medicinal of the medicinal product
product up to the end at release
of shelf life
1. Characteristics of the Indicate with an asterisk the specification limits
pharmaceutical form
which may require updating in the light of
experience acquired after the first “n” production
batches
2. Identification and assay of
active substance
3. Purity tests
4. Excipient: Identification for
example of colorants,
preservatives, limit values of
preservatives or antioxidants
etc.

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.
If test procedures and limits other than those mentioned in the relevant monographs and
general chapters of the Pharmacopoeias, 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.

2e1 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

27
 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 the
pharmacopoeia.

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.

2e2 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 analyzed
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.
It shall be supplemented by a method of quantitative evaluation, enabling the GHC 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 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.

28
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 2b 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 characterization and/or assay of the degradation products.

2e3 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.

2e4 Safety tests

Apart from the toxico-pharmacological tests submitted with the application for marketing
authorization, 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.

2f Stability tests
Refer to the VICH stability testing guidelines:
http://www.vichsec.org/guidelines/pharmaceuticals/pharma-quality/pharma-stability.html

2f1 Active substance

Stability data shall be presented to support the defined retest period and storage
conditions. The type of stability studies conducted, protocols used, the analytical
29
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.

2f2 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 and indicate the identification methods and test procedures for degradation
products,
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, 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.

30
2g Other related documents
This part is intended for a summary of any information relevant to the pharmaceutical
assessment and which has not been covered by any of the previous report. Information
on the analytical test procedures used in the metabolism and bioavailability studies and
their validation, and a summary of the synthesis of radiolabeled active substance used in
metabolic and/or pharmacokinetic studies should be provided.

31
Part 3 Safety and Residues Tests
Part 3 of the dossier is aimed at demonstrating the potential risks for man and the
environment resulting from use of the product. In the context of human safety, it is
necessary to consider possible effects on people using the product, handling treated animals
and consuming food products derived from treated animals. Although a knowledge of
adverse effects in the target species may be useful additional information when assessing
the risk for man and the environment, Part 3 is not primarily concerned with target species
safety, which should be considered in detail in Part 4 of the dossier.
Studies submitted to demonstrate safety of chemicals to man and the environment must be
conducted and reported in accordance with Good Laboratory Practice (GLP).

3a Safety tests
Safety documentation:
Relevant data obtained from the open literature should always be included in the
documentation. Copies of published data should be appended to the proprietary data. All
proprietary data should be discussed in conjunction with the data from the open literature.

Residue Documentation:

Documents should be presented as dated and signed reports from named laboratories.
Summaries not accompanied by the individual data will not be accepted as valid
documentation.
Relevant data obtained from the open literature should always be included in the
documentation. Copies of published data should be appended to the proprietary data. All
proprietary data should be discussed in conjunction with the data from the open literature.

The safety documentation shall show:

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;

32
 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.
3a1 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,
- degree of impurity,
- qualitative and quantitative composition of impurities,
- description of physical properties,
- melting point,
- boiling point,
33
 - 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.

3a2 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.

• Pharmacodynamics
Information on the mechanism of action of the active substance(s) shall be provided,
together with information on primary and secondary pharmacodynamics effects in order to
assist in the understanding of any adverse effects in the animal studies.

• 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
34
with the pharmacokinetic data obtained in the studies on the target species, section 4a2,
shall be included in order to determine the relevance of the results obtained in the
toxicology studies for the toxicity to the target species.

3a3 Toxicology
The documentation on toxicology 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 below
sections:

• Single – dose toxicity

Single-dose toxicity studies may be used to predict:

- the possible effects of acute over dosage in the target species,

- the possible effects of accidental administration to humans,
- the doses which may usefully be employed in the repeat dose studies.
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.

35
• 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.
Evaluation of the toxic effects shall be based on observation of behavior, growth,
hematology 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.

36
In the case of new combinations of known substances which have been investigated in
accordance with r this guidance , 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.

• 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 Section 4a3, 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.

• Reproductive toxicity including developmental toxicity

o 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 dose should be selected so as to bring
harmful effects to light. The lowest dose level should not produce any evidence of toxicity.

37
 o 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 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.

• 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.

• Carcinogenicity
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.

38
• 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.

3a4 Other requirements

• 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. sensitization 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 toxic effect or the irritation
potential. Such studies shall usually be conducted with the final formulation.
The state of scientific knowledge shall be taken into account when designing such studies
and evaluating their results.

• Microbiological properties of residues

o 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.

39
• 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.

• 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.
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.

3.a.5 User safety (URA)

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.

3a6 Environmental risk assessment (ERA)

• 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

40
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. The extent of exposure of the product to the
environment, and the available information about the physical/chemical, pharmacological
and/or 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 this guidance , shall be taken into consideration.

• Environmental risk assessment 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
by international guidance and describes the format in which the particulars relevant to the
environmental risk assessment.

• 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,

41
 - 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).

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,
- 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.

3b Residue Tests
• Introduction
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;
42
 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.

3b1 Identification of 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,
- 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),
43
 - 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.

3b2 Metabolism and residue kinetics

• Pharmacokinetics (absorption, distribution, metabolism, excretion)

A summary of the pharmacokinetic data shall be submitted with cross reference to the
pharmacokinetic studies in target species submitted in Part 4. The full study report does
not need to be submitted.

The purpose of pharmacokinetic studies with respect to residues of veterinary medicinal

products is to evaluate the absorption, distribution, metabolism and excretion of the product
in the target species.

The final product, or a formulation, which has comparable characteristics in terms of

bioavailability as the final product, shall be administered to the target animal species at the
maximum recommended dose.

Having regard to the method of administration, the extent of absorption of the veterinary
medicinal product shall be fully described. If it is demonstrated that systemic absorption of
products for topical application is negligible, further residue studies will not be required.

The distribution of the veterinary medicinal product in the target animal shall be described;
the possibility of plasma protein binding or passage into milk or eggs and of

44
the accumulation of lipophilic compounds shall be considered.

The pathways for the excretion of the product from the target animal shall be described.
The major metabolites shall be identified and characterized.

• Depletion of residues
The purpose of these studies, which measure the rate at which residues deplete in the target
animal after the last administration of the medicinal product, is to permit the determination
of withdrawal periods.

At a sufficient number of times after the test animal has received the final dose of the
veterinary medicinal product, the quantities of residues present shall be determined by
validated analytical methods; the technical procedures and the reliability and sensitivity of
the methods employed shall be specified.

3b3 Residue analytical method

The analytical method(s) used in the residues depletion study (studies) and its (their)
validation shall be described in detail.

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.

45
Part 4 Preclinical and clinical trials

A written summary is essential for large, complex clinical documentation. Such

documentation may be contained in numerous volumes, and a 1-2 page summary at the
beginning of each volume, which details its contents and includes an index of that volume,
is particularly helpful. These short summaries can then form the basis for the overall
summary.

4a Pre-clinical requirements
Pre-clinical studies are required to establish the pharmacological activity and the tolerance
of the product.

4a1 Pharmacology
• Pharmacodynamics
The pharmacodynamics effects of the active substance(s) included in the veterinary
medicinal product shall be characterized.

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.
46
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 pharmacodynamics 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 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.

4a2 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.

• 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:

1. descriptive pharmacokinetics leading to the determination of basic parameters;

47
 2. use of these parameters to investigate the relationships between dosage regimen,
plasma and tissue concentration over time and pharmacological, therapeutic or
toxic effects;
3. 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 pharmacodynamics 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.

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 this guidance, 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.

4a3 Target animal tolerance

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 characterize 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

48
duration of treatment. The report on the trials shall contain details of all expected
pharmacological effects and all adverse reactions.

4b Clinical requirements
4b1 Clinical trials
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 target animal
species that have received a veterinary medicinal product authorized in the GHC 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.

• 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.

49
• Particulars and documents
The dossier on efficacy shall include all pre-clinical and clinical documentation and/or
results of trials, whether favorable or unfavorable to the veterinary medicinal products, in
order to enable an objective overall assessment of the risk/benefit balance of the product.

o Results of pre-clinical trials

Wherever possible, particulars shall be given of the results of:
a) Tests demonstrating pharmacological actions;
b) Tests demonstrating the pharmacodynamics mechanisms underlying the
therapeutic effect;
c) Tests demonstrating the main pharmacokinetic profile;
d) Tests demonstrating target animal safety;
e) Tests investigating resistance.
f) 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;
a) 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;
b) a statistical analysis of the results, where relevant;
c) 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.

o Results of clinical trials

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.

50
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;
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;

51
 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, summarized 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.

In respect of each clinical trial, the clinical observations shall be summarized 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 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;
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
52
medicinal products or feed additives as well as any special precautions to be taken during
treatment and the clinical symptoms of over dosage, 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.

53
IV. Data Requirements for
Veterinary
Immunological Products

54
 Section Requirements

Part 2 Quality Documentation

2a Quantitative and Qualitative Particulars
2a1 Qualitative Particulars
2a2 Usual terminology
2a3 Quantitative particulars
2a4 Product development
2b Description of the Manufacturing Method
2c Production and Control of Starting Materials
2c1 Starting Materials listed in Pharmacopeias
2c2 Starting Materials not listed in Pharmacopeias
2d Control tests during the manufacture process
2e Control tests on the finished product
2.1 General Characteristics
2e2 Identification of active substance(s)
2e3 Batch titre or potency
2e4 Identification and assay of adjuvants
2e5 Identification and assay of excipients components
2e6 Safety tests
2e7 Sterility and purity test
2e8 Residual humidity
2e9 Inactivation
2f Batch to Batch Consistency
2g Stability tests
2h Other information

Part 3 Safety Documentation

3a General Requirements
3b Laboratory Tests
3b1 Safety of one dose
3b2 Safety of an overdose
3b3 Safety of the repeated administration of one dose
3b4 Examination of reproductive performance
3b5 Examination of immunological functions
3b6 Special requirements for live vaccines

55
 3b7 User safety (URA)
3b8 Study of residues
3b9 Interactions
3c Field Studies
3d ERA (Environmental Risk Assessment)
3e Assessment of products containing or consisting of GMOs

Part 4 Efficacy Documentation

4a General Requirements
4b Laboratory Trials
4c Field Trials

56
Part 2 Quality Documentations
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 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 Pharmacopoeias, this description may be
replaced by a detailed reference to the pharmacopoeia in question.

Where available, chemical and biological reference material of the Pharmacopoeia shall be
used. If other reference preparations and standards are used, they shall be identified and
described in detail.

2a Qualitative and quantitative particulars

2a1 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

57
the immunological veterinary medicinal product, relevant information about the device
shall be provided, where necessary for the assessment of the product.

2a2 Usual terminology

The usual terminology, to be used in describing the constituents of immunological
veterinary medicinal products:
- In respect of substances which appear in the pharmacopoeia, 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 Organization, 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.

2a3 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 2b.

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.

58
2a4 Product development:
An explanation shall be provided with regard to the composition, and components,
supported by scientific data on product development. The overage, with justification
thereof, shall be stated.

2b Description of the manufacture method

The name, address and responsibility of each manufacturer and each proposed production
site or facility involved in manufacturing and testing shall be indicated.

For this purpose the description it shall include:

- 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.

2c Production and control of the 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 composition of the
59
any culture media shall be presented in so far as GHC 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.

2c1 Starting materials listed in pharmacopoeias

The monographs of the pharmacopoeia shall be applicable to all substances appearing in
it.
The routine tests carried out on each batch of starting materials must be as stated in the
application for marketing authorization. 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 contained in a monograph of the pharmacopoeia might be
insufficient to ensure the quality of the substance, GHC may request more appropriate
specifications from the applicant for marketing authorization.

When starting materials of animal origin are used, they shall comply with the relevant
monographs including general monographs and general chapters of the 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 Pharmacopoeia.
Certificates of Suitability issued by the European Directorate for the Quality of Medicines
and Health Care, with reference to the relevant monograph of the Pharmacopoeia, may be
used to demonstrate compliance.
60
2c2 Starting materials not listed in pharmacopoeias
• 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 in cells, plasmid used for co-transfection, 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.
61
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, Culture media and other material originating from animal species relevant for
the transmission of TSE comply with the Note for Guidance on minimizing the risk of
transmitting animal spongiform encephalopathy agents via human and veterinary
medicinal products, as well as with the corresponding monograph of the 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.

• Starting materials of non - biological origin

The description shall be given in the form of a monograph under the following headings:
1. The name(s) of the starting material meeting the requirements of 2.a.2 shall be
supplemented by (any trade-name or scientific synonyms),
2. Description of starting material (set down in a form similar to that used in a
descriptive item in the Pharmacopoeia),
3. the function of the starting material,
4. methods of identification,
5. any special precautions which may be necessary during storage of the starting
material and, if necessary, its storage life shall be given.

2d Control tests during the manufacturing process

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. 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.

62
2e Control tests on the finished product
For all tests, the description of the techniques for analyzing the finished product shall be
set out in sufficiently precise detail for quality assessment.

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 Pharmacopoeia, 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
authorization 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 Pharmacopoeia shall be
used. If other reference preparations and standards are used, they shall be identified and
described in detail.

2e1 General characteristics

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.

2e2 Identification the active substance(s)

Where necessary, a specific test for identification shall also be carried out.

2e3 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.

63
2e4 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.

2e5 Identification and assay of excipient components

Insofar as is necessary, the excipient(s) shall be subject at least to identification tests.
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.

2e6 Safety tests

Apart from the results of tests submitted in accordance with Part 3 particulars of safety tests
shall be submitted. These tests shall preferably be over dosage 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.

2e7 Sterility and purity test

Appropriate tests to demonstrate the absence of contamination by adventitious 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.

2e8 Residual humidity

Each batch of lyophilised product shall be tested for residual humidity.

2e9 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.

2f 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 batches
giving the results for all tests performed during production and on the finished product
shall be provided.

64
2g Stability
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
physicochemical 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.

Refer to the VICH stability testing guidelines:

http://www.vichsec.org/guidelines/biologicals/bio-quality/stability.html

65
2h Other information
Information relating to the quality of the immunological veterinary medicinal product not
covered by the previous sections may be included in the dossier.

66
Part 3 Safety Documentation
3a 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 product containing a live organism,

the dose to be used in the laboratory tests described in sections 3b1 and 3b2 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.

3b Laboratory tests
3b1 Safety of one dose
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
67
administration.
This study may be part of the repeated dose study required under section 3b3 or omitted if
the results of the overdose study required section 3b2 have revealed no signs of systemic
or local reactions.

3b2 Safety 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 section 3b1.

3b3 Safety of the repeated administration of one dose

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.

3b4 Examination of reproductive performance

Examination of reproductive performance shall be considered when data suggest that the

68
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 sections 3b1, 3b2 and 3b3
or of the field studies provided for in section 3c.
3b5 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.

3b6 Special requirements for live vaccines

• 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.

• Dissemination in the vaccinated animal

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 to be used for food
producing animals, these studies must shall take particularly into account the persistence
of the organism at the injection site.

• 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
69
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.

• 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).

• Recombination or genomic reassortment of strains

The probability of recombination or genomic reassortment with field or other strains shall
be discussed.

3b7 User safety (URA)

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 product with a
view to formulating appropriate user warnings and other risk management measures.

3b8 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.

3b9 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.

70
3c 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
authorization application. Both safety and efficacy may be investigated in the same field
studies.

3d ERA (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.

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 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.

71
3e Assessment of products containing or consisting of GMO (Genetically Modified
Organisms)
In this section the applicant should describes the format in which the particulars relevant
to the environmental risk assessment.

In the case of veterinary medicinal products containing or consisting of genetically

modified organisms the application shall also be accompanied by the documents required
by international guidance and describes the format in which the particulars relevant to the
environmental risk assessment.

72
Part 4 Efficacy documentation
• 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 supported by results
of specific trials contained in the application for marketing authorization.

• 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.

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

4a General requirements
The choice of antigens or vaccine strains shall be justified on the basis of epizoological
data.

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
73
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 GHC. The investigator shall demonstrate
the validity of all the techniques involved. All results obtained, whether favorable or
unfavorable, shall be reported.
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.

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.

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.

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.

If there is a compatibility statement with other immunological products in the summary of

product characteristics, the efficacy of the association shall be 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.

For diagnostic immunological veterinary medicinal products administered to animals, the

applicant shall indicate how reactions to the product are to be interpreted.

For vaccines intended to allow a distinction between vaccinated and infected animals
74
(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.

4b Laboratory trials
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.

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.

4c Field trials
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
authorization application. Both safety and efficacy may be investigated in the same field
study.

Where laboratory trials cannot be supportive of efficacy, the performance of field trials
alone may be acceptable.

75
V. References
- Notice to applicants of veterinary medicinal products (Presentation and
content of the dossier), Directorate – General for Health and Food safety,
European Commission, 2015.
- Regulations (law) of veterinary products in Gulf Cooperation Council
(GCC).
- VICH stability guidelines.

76