13/2010 Coll.
DECREE


Dated January 8, 2010

Amending Decree no. 228/2008 Coll., On the registration of medicinal products


Ministry of Health and Ministry of Agriculture stipulates pursuant to §
114 par. 2 Act no. 378/2007 Coll., On pharmaceuticals and amending some
Related Acts (Pharmaceuticals Act), as amended by Law no. 296 / 2008
Coll., (hereinafter the "Act")

Art. I

Decree no. 228/2008 Coll., On the registration of medicinal products, shall be amended as follows
:

First Footnote. 1 reads:

"1) Directive of the European Parliament and Council Directive 2001/83 / EC of 6
November 2001 on the Community code relating to medicinal products
.

Directive of the European Parliament and Council Directive 2002/98 / EC of 27 January 2003
setting standards of quality and safety for the collection, testing,
processing, storage and distribution of human blood and blood components | || amending Directive 2001/83 / EC.

Commission Directive 2003/63 / EC of 25 June 2003 amending
Directive of the European Parliament and Council Directive 2001/83 / EC on the Community code
relating to medicinal products.

Directive of the European Parliament and Council Directive 2004/24 / EC of 31 March
2004 amending Directive 2001/83 / EC on the Community code relating to
medicines for human use, as regards traditional || | herbal medicines.

Directive of the European Parliament and Council Directive 2004/27 / EC of 31 March
2004 amending Directive 2001/83 / EC on the Community code
relating to medicinal products.

Directive of the European Parliament and Council Directive 2001/82 / EC of 6 November
2001 on the Community code relating to veterinary medicinal products
.

Directive of the European Parliament and Council Directive 2004/28 / EC of 31 March
2004 amending Directive 2001/82 / EC on the Community code
relating to veterinary medicinal products.

Commission Directive 2009/9 / EC of 10 February 2009 amending
Directive of the European Parliament and Council Directive 2001/82 / EC on the Community code
relating to veterinary medicinal products.

Commission Directive 2006/130 / EC of 11 December 2006 implementing Directive
European Parliament and Council Directive 2001/82 / EC as regards the establishment
criteria for exempting certain veterinary medicinal products | || animals intended for food production from the requirement to dispense veterinary prescription
.

Directive of the European Parliament and Council Directive 2009/35 / EC of 23 April 2009
on coloring matters which may be added to medicinal products. ".

Second § 7 including the heading reads:

"§ 7

The documentation submitted with the application for registration of veterinary products

(1) An application for authorization for a veterinary product shall be submitted
data and documents whose content and layout are specified in Annexes no. 2-5
hereof. These annexes apply the submission of data and
documentation for the purpose of mutual recognition of authorizations according to § 41 paragraph. 1
Act. The extent of documentation submitted with the application corresponds
knowledge about veterinary medicine, its nature, its therapeutic benefit, which brings
, and risks associated with its use, and the current level of scientific
knowledge and technical progress in the field of veterinary medicine.

(2) The request contains all information pertaining to the evaluation of the
veterinary medicine, whether for veterinary medicine
favorable or unfavorable. Especially always bring all the important details about
any incomplete or abandoned test or trial that
relating to veterinary medicine.

(3) A separate application shall be evidenced by a full dossier in accordance with Annex no. 2
hereof. In the case of literary application applies
requirements set out in Annex no. 2 of this Order, as in the case of applications
documented experimental data.

(4) For applications using a legacy not report prepared by experts
under Title VI of Annex no. 2 of the Decree for parts
documentation, which is used for reference to the results of pharmacological and toxicological tests
, tests for safety and residues
results of clinical trials already submitted in the context of a registration procedure
another MAH. If necessary, at the request
according to § 4. c) submit further documentation necessary for assessment

Those safety issues and efficacy of veterinary medicine, which
not included in the dossier, to which reference is made; essential similarity
veterinary product for which registration is sought with respect to
veterinary medicine, to which reference is made, it is necessary to demonstrate bioequivalence
example, card or pharmaceutical, pharmacodynamic
or therapeutic equivalence. For applications using a legacy
proposed SPC usually corresponds to the current summary of product
, to which reference is made; there are, however, in the proposed text
variations indicated in the proposal and the reasons for it. If the appropriate reference
product is authorized, you can not refer to the product registered in another Member State
. The reference product is used only
event that a suitable reference product is not or was not registered.
Required information on the country of origin of European reference product and
about where participating countries is applied. For application
submitted with the consent of the original owner, this agreement demonstrates.

(5) An application for a simplified registration of homeopathic veterinary
product documentation is submitted pursuant to Title V of the Annex no. 2 of the Decree
application for simplified registration
veterinary homeopathic products are not report prepared by experts and | || draft summary of product characteristics.

(6) The documentation provided with the application for registration of veterinary medicine
other than immunological veterinary medicine for part
affecting the quality of the dossier apply all relevant
articles, including general articles and general chapters of the European Pharmacopoeia.
For immunological veterinary preparations for the registration of
documentation that affect the quality, safety and efficacy apply
all relevant articles, including general articles and general chapters of the European Pharmacopoeia
. With regard to the use of dyes in veterinary medicine
apply the requirements set out in Title VIII of the Annex no. 2
this decree.

(7) The documentation submitted with the application for registration of veterinary medicine
shows that manufacturing practices veterinary medicine
is carried out in accordance with the requirements of good manufacturing practice.
Documentation also shows that the pharmacological and toxicological tests, tests
residue and safety tests were conducted in accordance with the requirements
good laboratory practice.

(8) The documentation submitted with the application for authorization for a veterinary
product containing genetically modified organisms, or GMOs
consisting includes evaluation
risk associated with the introduction of genetically modified organisms into the environment
under other legislation ^ 9).

(9) The documentation submitted with the application for authorization for a veterinary
product intended for minor species or minor indications
not always include all the information required in Annex no. 2 if
thus provides the instruction of the Commission or agencies.

(10) An application for authorization or before the decision
registration, shall be submitted one sample of each type of
inner packaging or in agreement with the Veterinary Institute
patterns of inner and outer packages, which has a veterinary medicine
marketed; may be submitted to a sample of veterinary medicine
development batches, whose characteristics are
veterinary product which is the subject of the request. ".

Third Under § 7, the following § 7a, including the heading reads:

"§ 7a

Criteria for classification as a dedicated veterinary preparations for
assessing confusion of names and veterinary products for
decisions about classification with respect to dispensing veterinary preparations
for animals, which are obtained from animal products | || human nutrition

(1) Include the reserved veterinary medicines can be:

A) absorption antidiarrhoika,

B) antiseptic preparations for surface treatment of the animal skin or mucous membranes available
outside, including in cases where the skin or mucous membranes
showing incipient signs of inflammation or to present them
minor injuries; it is also a veterinary products intended for the treatment
umbilical cord of newborns and skin derivatives of animals

Veterinary products intended to prepare the surgical field and
intended for application to the mammary gland of cattle for the purpose of prevention of mastitis or
to treat them,

C) dermatologics,

D) derivancia,

E) insecticidal or acaricidal preparations intended for external use,
including veterinary products acting on the developmental stages
external parasites

F) rehydration solutions intended for oral administration,

G), vitamin and mineral preparations

H) dietetic preparations,

I) antitympanika for oral administration to achieve the effect
its physico-chemical action.

(2) When assessing confusion of names under § 31 para. 5 point. a)
section 4 of the Act to specifically take into account whether the name in print, manuscript or
spoken form is not confused with the name of another
veterinary medicine. The assessment shall take into account the likelihood of risks
public health, animal health or the environment.

(3) The conditions, which may be in the marketing authorization to provide that
veterinary medicine intended for animals from which they are derived
animal products for human nutrition, can be issued without medical prescription
are set Title VII of the Annex no. 2 hereto. ".

Fourth In § 10 paragraph 1 reads:

"(1) For each package size and type of packaging will be allocated
holder of the marketing authorization on the basis of a marketing code (§ 32 paragraph
. 5 of the Act). The new code will be allocated in the case of Type I
listed in Annex no. 7, under sections 2, 41 and possibly the 29th new code also assigns
changes in defined paragraphs 41 and 29 and Annex no. 7 that
do not meet the classification as type I and type II and changes, and in the case of transfer
registration, registration and acceptance of the concurrent
imports. ".

Fifth In § 13 par. 3 first sentence, the words "or on its inner packaging
" are deleted.

6th In § 18 par. 1, the words "administered by the attending physician in writing or in electronic form
address" is replaced by "serves physician
electronically or in writing to the address of the Institute".

7th In Annex no. 1 paragraph 3.2.2.4 at the end of subparagraph a), the sentence "
To verify the purity criteria laid down in the applicable method of analysis, which
to verify compliance purity criteria for certain additives used in
foods. ".

8th Annex no. 2, including the heading and footnotes. 13a-13f reads:

"Annex no. 2 to Decree no. 228/2008 Coll.
TITLE
I

REQUIREMENTS FOR VETERINARY PRODUCTS OTHER THAN IMMUNOLOGICAL VETERINARY PRODUCTS


Unless Title III provides otherwise, the provisions of this chapter
veterinary products other than immunological veterinary medicinal products

PART 1: SUMMARY OF THE DOSSIER

A.
ADMINISTRATIVE DATA


Veterinary medicine, which is the subject of an application for registration is
identified by its name and the name of the active substance or active substances together with
strength and dosage form, method and route of administration and a description of the final sales even Leni
product, including packaging, labeling and package leaflet
.

The name and address of the applicant together with the name and address of the manufacturers and
places that are involved in the different stages of production, testing and
layoffs (including the manufacturer of the finished product and the manufacturer of the active substance or
drugs), and, optionally, the name and address
importer.

Applicant shall identify the number and titles of volumes of documentation submitted
applications, and if they are provided and indicate what samples,.

The administrative data shall be copies of the manufacturing authorization for all
production site, which is involved in the production of that product, and a list
countries in which authorization has been granted, copies of all the summaries of product by
§ 3 para. 1 of the Act, as approved by Member States
a list of countries in which an application has been submitted or refused.

B.

SUMMARY OF PRODUCT CHARACTERISTICS AND PACKAGE INSERT

Applicant shall propose a summary of product pursuant to Annex no. 3
this ordinance.

Proposed labeling text for immediate and outer packaging shall be submitted by
Annex no. 5 of this Order, together with a package leaflet in accordance with Annex
no. 4 of the Decree, if this is required by § 37 par. 3 of the Act.

The applicant must also submit one or more specimens or mock sales
packing all inner and outer containers in which to be a veterinary
product is marketed in the Czech language, if warranted, in one of the official languages ​​
European Union. In agreement with the Veterinary Institute may
proposals put forward in the sales package only in black and white and
electronically.

C.

DETAILED AND CRITICAL SUMMARIES

In accordance with § 26 par. 6 of the Act shall submit a detailed and critical summaries
results of pharmaceutical (physico-chemical, biological or microbiological
) tests, safety tests and residue,
clinical and clinical evaluation and testing, which is
evaluate possible risks to the health of the environment.

Each detailed and critical summary shall be prepared for the condition
scientific knowledge at the time of application. Each summary includes such
evaluation of all tests and trials, which constitute documentation
application for registration, and affects any questions they may have
importance to assess the quality, safety and efficacy of veterinary medicine
. SUMMARY always contains the detailed results of the tests and trials and
precise references to published data.

All important data shall be summarized in an appendix,
in tabular or graphic form if possible. Detailed and critical summaries and the appendices
always contain precise cross references to the information contained in the main
documentation.

The detailed and critical summaries are always signed and dated
are and are always connected to them about education, training and professional experience of the author
. The professional relationship of the author with the applicant.

If the drug is contained in human
product authorized in accordance with the requirements of Annex no. 1 hereto, the total sum of
Quality Module 2, section 2.3 of this Annex, if necessary
replace the summary regarding the documentation related to the active substance or preparation
.

If the Veterinary Institute of the Guidelines provides that the chemical, pharmaceutical and
biological / microbiological information for the finished product may be
dossier mentioned only in the format of the Common Technical Document
can be detailed and critical summary results
pharmaceutical tests submitted in the form of a quality overall summary.

In the event that the product is intended for minor species or minor
indication, you can format the quality overall summary
used without prior consent of the Veterinary Institute.

PART 2: PHARMACEUTICAL (PHYSICO-CHEMICAL, BIOLOGICAL OR
MICROBIOLOGICAL INFORMATION (QUALITY)

General principles and requirements

particulars and documents that must accompany applications for marketing authorization
according to § 26 par. 5 point. i) point 1 shall be submitted in accordance with the following requirements
.

Pharmaceutical (physico-chemical, biological or microbiological)
data for the active substance or active substances and finished veterinary
product information on the manufacturing process, characteristics and properties
, procedures and requirements for quality, stability
as well as a description of the composition, the development and presentation of the veterinary medicine.

Apply to all articles, including general articles and general chapters
European Pharmacopoeia, or failing listed
pharmacopoeia of a Member State.

All test procedures shall fulfill the criteria for analysis and control
quality of the starting materials and the finished product and should take into account the
established guidance and requirements. Submit the results of the validation studies
.

All test procedures shall be described in sufficiently precise detail
allow them to be repeated in control tests, carried out at the request
Veterinary Institute; any special apparatus and equipment
which can be used, must be described in sufficient detail
possibly accompanied by a diagram.

Composition of the laboratory reagents shall be supplemented, if necessary
way of preparation. In the case of test procedures included in the European Pharmacopoeia or the pharmacopoeia
Member State, this description may be replaced by a detailed
reference to the relevant pharmacopoeia. Where applicable, also apply to the chemical and biological reference materials
European Pharmacopoeia. When used
other reference preparations and standards must be identified and

Described in detail.

If the drug is contained in human
product authorized in accordance with the requirements of Annex I to Directive 2001/83 / EC, as amended ^ 1)
chemical, pharmaceutical and biological / microbiological information provided by
module 3 of this Directive may replace the documentation
relating to the active substance or finished product.

The chemical, pharmaceutical and biological / microbiological information for the
active substance or the finished product may be included in the registration
documentation in a format of common technical document only if such
Veterinary Institute provides instruction in the Veterinary Institute.

In the event that the product is intended for minor species or minor
indication, it may be the CTD format
without prior agreement of the Veterinary Institute.

A.

QUALITATIVE AND QUANTITATIVE INFORMATION ON INGREDIENTS

First Qualitative data

"Qualitative particulars" of all the constituents of the medicinal product shall mean the designation or description
:

- The active substance or active substances

- Adjuvants or excipients, whatever their nature or
quantity used, including coloring matter, preservatives, adjuvants,
stabilizers, thickeners, emulsifiers, agents for the treatment of taste and smell,

- The outer covering of the veterinary products intended to be ingested or otherwise administered to animals
- capsules, gelatine capsules.

These data are supplemented by any relevant data concerning the container and
appropriate packaging and, where appropriate, its manner of closure, together with details of
means by which the veterinary
product is used or administered and which they will be delivered.

Second Usual terminology (terminology)

The usual terminology to be used in describing the constituents
veterinary products, notwithstanding the other provisions of § 26 par. 5
point. b) Act means:

- In the case of the components listed in the European Pharmacopoeia or, if it
not listed in the pharmacopoeia of one of the Member States, the main title
relevant article with reference to the pharmacopoeia,

- In the case of other constituents, the international non-proprietary name recommended
World Health Organization (WHO), which may be accompanied by another
proprietary name, or, failing these, the exact scientific designation
; constituents not having an international non-proprietary name or an exact scientific designation
, is described by a statement of how and from what they were prepared, with the possible addition of
any other relevant details,

- In the case of dyes designation "E" code assigned to them by
another legal regulation 13a).

Third Quantitative data

3.1 When placing quantitative data on all active substances
animal products is necessary, depending on the dosage form
state for each active substance, weight or number of units
biological activity, either in unit dosage forms unit or
mass or volume.

Units of biological activity are used for substances which can not be
chemically defined. As has been defined by the World Health Organisation
uses international unit of biological activity.
Has been defined international unit, expressed
units of biological activity, so as to provide unambiguous information on the activity
substances, whenever possible, using units
European Pharmacopoeia.

If possible, indicate biological activity per unit weight or volume
. Such information shall be supplemented:

- In the case of single-dose preparations
mass or units of biological activity of each active substance in the container with
taking into account the usable volume of the product, or after
reconstitution

- In the case of veterinary medicinal products administered by drops
mass or units of biological activity of each active substance contained in one or
drop in the number of drops corresponding to 1 ml or 1 g of product

- In respect of syrups, emulsions, granular preparations and other pharmaceutical forms
administered in measured quantities
mass or units of biological activity of each active substance per measured quantity.

3.2 Active substances present in the form of compounds or derivatives are
quantitatively by their total mass, and if it is

Necessary or relevant, by the mass of active entity or entities of the molecule
.

3.3 For veterinary medicinal products containing an active substance which is in a
a Member State for the first time the subject of an application for registration is
systematically expresses the content of the active ingredient, if it is a salt or hydrate mass of active
or entities of the molecule.
Quantitative composition of veterinary medicines
subsequently authorized in the Member States must be for the same active substance
stated in the same way.

Fourth Pharmaceutical development

Submitted the explanations concerning the choice of composition, constituents, immediate
packaging, possible further packaging or outer packaging
intended function of the excipients in the finished product and the method of manufacture of the finished product
. This explanation is supported by scientific data on the pharmaceutical
development. The overage, with justification. It must be demonstrated that
microbiological characteristics (microbiological purity and antimicrobial
activity) and usage instructions are appropriate for the intended use
veterinary medicine, as specified in the application dossier
registration.

B.


DESCRIPTION OF MANUFACTURING METHOD
The name, address and responsibility of each manufacturer and each proposed
production site or facility involved in manufacturing and testing.

Description of the manufacturing method accompanying the application for marketing authorization pursuant to § 26 par. 5
point. d) of the Act shall be to provide sufficient information about
nature of the operations.

For this purpose the description shall include at least:

- Putting the various stages of production in order to assess whether
processes employed in producing the pharmaceutical form might have produced an adverse change
ingredients

- In the case of continuous manufacture, full details concerning
measures taken to ensure the homogeneity of the finished product,

- The actual manufacturing formula, with the quantitative particulars of all
substances used, the quantities of excipients, however, being given
about if required dosage form; They shall refer to all
substances that may disappear in the course of manufacture;
any overage shall be indicated and justified,

- The stages of manufacture at which sampling is carried out for
control tests during the manufacturing process, and the limits,
if the data in the documents supporting the application show that such tests to be necessary
quality control of the finished product

- Experimental studies validating the manufacturing process and, if necessary
validation scheme for production scale batches,

- For sterile products, where conditions are used
sterilization process specified in the Pharmacopoeia, details of the sterilization processes
or aseptic procedures.

C.


CONTROL OF STARTING MATERIALS
First General requirements

Starting materials shall mean all the constituents of the veterinary medicine
and, where appropriate, of its container including its closure, as stated
in Section A, point 1 above.

The dossier contains specifications and information on the tests
to be conducted for quality control of all batches of starting materials
.

Routine tests carried out on each batch of starting materials must conform
tests specified in the application for registration. If
used tests other than those mentioned in the pharmacopoeia must be
proof that the starting materials meet the quality requirements of that pharmacopoeia
.

When was the starting material, active substance or excipients
issued by the European Directorate for the Quality of Medicines and HealthCare
certificate of conformity, this certificate represents a link to the relevant article
European Pharmacopoeia.

Referring to the certificate of conformity, the manufacturer of the applicant in writing
ensure that the manufacturing process has not been modified since the granting of the certificate of conformity
European Directorate for the Quality of Medicines and HealthCare.

Submitted the results of batch analyzes for the starting materials in order
demonstrate compliance with the defined specification.

1.1 APIs

The name, address and responsibility of each manufacturer and each proposed
production site or facility involved in manufacturing and testing of active substances
.

For a well-defined active substance, the manufacturer of the active substance or the applicant

Take advantage of the manufacturer of the active substance administered directly
Veterinary Institute in a separate document called basic document on
drug substance (Active Substance Master File), the following information:

A) a detailed description of the manufacturing process

B) a description of quality control during manufacture,

C) a description of the process validation.

In this case, the manufacturer shall provide the applicant with all the data that
are necessary for the latter to take responsibility for veterinary medicine
. Producer confirms in writing to the applicant that he shall ensure batch to batch consistency among
and not modify the manufacturing process or specifications without informing the applicant
. Documents and particulars supporting the application for such a change
be submitted to the Veterinary Institute. These documents and data
also provide the applicant when they concern the portion of the document
active substance to the applicant.

If there is no certificate of conformity for the active substance shall be submitted
further details of the production process, quality control and on impurities as well as
evidence of the molecular structure.

First Information on the manufacturing process shall include a description of the manufacturing process
active ingredient, which represents the applicant's commitment to manufacture the drug.
Give a list of all the raw materials needed to manufacture the active substance or active substances
showing at which stage of the process each material is used.
They provide information about the quality and control of these materials. Information demonstrating
that materials meet standards appropriate for their intended use.

Second Information on quality control shall contain information on the tests
(including acceptance criteria) carried out at every critical step,
information on the quality and control of intermediates and process validation or
or evaluation studies. If necessary, it shall also contain
validation data for the analytical methods applied to the active substance
.

Third Information on impurities shall indicate predictable impurities together with
content and nature of observed impurities. If it's important
shall also information on the safety of these impurities.

Fourth For biotechnological veterinary medicinal products, evidence of molecular structure
include the schematic amino acid sequence and relative molecular mass
.

1.1.1 Active substances listed in the Pharmacopoeia

General and specific articles of the European Pharmacopoeia shall be applicable to all
active substances that are listed there.

Constituents in accordance with the requirements of the European Pharmacopoeia or the pharmacopoeia
one of the Member States, consider the provisions of § 26 par. 5 point. h)
law to be fulfilled. In this case the description of analytical methods and procedures
replaced in each relevant section by an appropriate reference to the pharmacopoeia
.

In cases where a specification contained in Article
European Pharmacopoeia or in the pharmacopoeia of a Member State is insufficient to ensure the quality
substance, the competent authorities may require the applicant preferable
specifications, including limits for specific impurities with validated
test procedures.

Competent authorities shall inform the authorities responsible for the pharmacopoeia. Holder
decision to provide the authorities of that pharmacopoeia
details of the alleged insufficiency and the additional specifications
.

In cases where the active substance is described in the article
European Pharmacopoeia, and if this active substance is described in the pharmacopoeia of a Member State
may use such an article.

In cases where the active substance is described neither in the European Pharmacopoeia
nor in the pharmacopoeia of a Member State may be declared compliance with Article
mentioned in the pharmacopoeia of a third country if its suitability is demonstrated;
in such cases, the applicant shall submit a copy of an article, possibly in conjunction with
translation. Must be presented data demonstrating the ability of the article
adequately control the quality of the active substance.

1.1.2 Active substances not in a pharmacopoeia

Ingredients that are not listed in any pharmacopoeia shall be described in the form
article with the following points:

A) the name of the constituent, meeting the requirements of Section A point 2, shall be supplemented
any trade or scientific synonyms;

B) the definition of a substance listed in a form similar to that used in
European Pharmacopoeia, shall be accompanied by any necessary explanatory
evidence, especially concerning the molecular structure. If they can be

Substances described only by their manufacturing method, the description should be sufficiently
detailed to characterize a substance which is constant both in its composition and in its effects
;

C) methods of identification may be described in the form of complete techniques such
as used for production of the substance and form of tests which should be carried out routinely
;

D) purity tests shall be described in relation to each individual
predictable impurity, especially those which may have a harmful effect and
or to those with respect 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
describes, for example, particle size and sterility, and
appropriate methods must be described and validated where relevant;

F) with regard to complex substances of plant or animal origin
it is necessary to distinguish where multiple pharmacological effects render
chemical, physical or biological control of the principal constituents
necessary, and the case of substances containing one or more
groups of constituents with similar activity for which it may be permitted method of setting
total content.

These data demonstrate that the proposed set of test procedures is
sufficient to control the quality of the active substance from the defined source.

1.1.3 Physico-chemical properties that may affect the biological availability


Following information on medicinal substances, whether or not listed in
Pharmacopoeia, shall be provided as part of the general description of the active substances
depends on them if the bioavailability of the veterinary medicine:

- Crystalline form and solubility coefficients,

- Particle size, optionally after pulverization,

- State of hydration,

- Partition coefficient oil / water

- PK / pH.

The first three indents are not applicable to substances used solely in solution.

1.2 Excipients

General and specific articles of the European Pharmacopoeia shall be applicable to all
substances that are listed there.

Excipients shall comply with the requirements of the relevant article of the European Pharmacopoeia.
If such a link exists, it is possible to make a link to the article
pharmacopoeia of a Member State. In the event that such a link exists
is possible to make a link to an article a third country pharmacopoeia. In this case
necessary to demonstrate the appropriateness of such an article. If necessary, it must be
requirements of Article supplemented by additional tests to control parameters such
as particle size, sterility, residual solvents.
In the absence of a pharmacopoeial article suggests and justified
specifications. Comply with the specification requirements set out in section 1.1.2
. a) to e) for the active substance. Submit the proposed methods and
accompanying data validation.

Dyes, which are added to animal health products, meet always
requirements set out in Chapter VIII, except for certain veterinary
products for topical use, eg. Insecticidal collars and ear tags, where the
use other coloring matters is justified.

Dyes must meet the purity criteria laid down in another legal regulation
^ 13b).

For novel excipients, ie. With adjuvants or excipients
used in veterinary medicine for the first time or a new route of administration,
shall be given detailed information on the production, detailed characterization and
detailed information on controls with cross-references to additional information
clinical and non-clinical safety.

1.3 closure systems

1.3.1 Active substance

Information shall be provided on the container-closure system for the active substance
. The level of information required is determined by the physical state
(liquid, solid) of the active substance.

1.3.2 Finished product

Information shall be provided on the container-closure system for the finished product
. The level of information required is determined by the route of administration
veterinary medicine and physical state (liquid, solid)
dosage forms.

Packaging materials meet the requirements of the relevant article of the European Pharmacopoeia
. If such a link exists, it is possible to provide a link to the article
pharmacopoeia of a Member State. In the event that there is no such
article may be made to the article a third country pharmacopoeia. In this

Case must be documented suitability of such article.

If there is no article Pharmacopoeia, it is necessary to propose and justify
for the packaging material.

Give Scientific data on the choice and suitability of the packaging material.

For novel packaging materials in contact with the product,
information on their composition, manufacture and safety.

Specifications and, if necessary, information about functionality for
any device for dispensing or administering veterinary medicinal product.

1.4 Substances of biological origin

If the manufacture of veterinary products such as raw materials used.
Microorganisms, tissues of either plant or animal origin, cells or
fluids (including blood) of human or animal origin or biotechnological cell constructs
must be described
and documented the origin and history of starting materials.

Description feedstock includes manufacturing strategy
purification / inactivation procedures with their validation and all
control procedures during the manufacturing process designed to ensure the quality
safety and batch to batch consistency of the finished product.

When cell banks are used, it must be shown that the properties of the cells in the passage
used for the production and the passage remained unchanged.

Seed materials, cell banks, serum and, if possible, the source materials must
be tested for adventitious agents.

When using starting materials of animal or human origin, shall
a description of measures to ensure the absence of pathogens which can be pathogenic
.

If the presence of foreign agents who might be pathogenic,
inevitable, the material shall be used only when further processing ensures their
removal or inactivation, and this shall be validated
.

Shall be submitted documentation showing that the seed materials, cell seeds, batches
serum and other animal raw materials essential for the transmission of TSE
accordance with the guidelines for minimizing the risk of transmitting agents of animal
spongiform encephalopathy via human and
veterinary products, as well as the corresponding article of the European Pharmacopoeia.
To demonstrate compliance, it is possible to use the certificates of conformity
European Directorate for the Quality of Medicines and HealthCare, with reference to the relevant article
European Pharmacopoeia.

D.

TESTS CARRIED OUT AT INTERMEDIATE STAGES OF THE MANUFACTURING PROCESS

The dossier contains information relating to the control tests
product, which can be performed while intermediate products
to ensure compliance with the technical characteristics and the production process
.

These tests are essential for checking the conformity of the veterinary
formula when, exceptionally, an applicant proposes an analytical method for
testing the finished product which does not include the assay of all
drugs (or any excipients which are subject to
same requirements as the active ingredients).

The same applies where the quality control of the finished product depends on
control tests during the manufacturing process, particularly if the
substance is essentially defined by its manufacturing method. If it can be
intermediate before further processing or primary formulations stored,
time must be defined for the intermediate
based on data derived from stability studies.

E.
TESTS ON THE FINISHED PRODUCT


For control of the finished product comprises a finished product batch
all unit dosage forms, which are made from the same initial
quantity of material and have undergone the same series of manufacturing or sterilization
operations or, in case of a continuous production process, all | || units manufactured in a given period of time.

The application for registration shall state tests, which are carried out routinely
on each batch of finished product. It must be stated frequency of the tests
which are carried out routinely. Indicate Release limits.

The dossier shall include particulars relating to control
tests on the finished product at release. The data must be submitted
comply with the following requirements. To all products that are
therein, the provisions of relevant articles and general
chapters of the European Pharmacopoeia, or failing that, pharmacopoeia

Member State.

If test procedures and limits other than those listed in
relevant articles and general chapters of the European Pharmacopoeia, or
failing this, in the pharmacopoeia of a Member State shall be
proof, that the finished product would, if tested in accordance with the articles
, meet the quality requirements of that pharmacopoeia for the pharmaceutical form
.

First General characteristics of the finished product

Certain tests of the general characteristics of a product shall always be included among the tests
finished product. Those tests whenever it
possible, relate to the control of average masses and maximum deviations,
mechanical, physical or microbiological tests,
organoleptic characteristics, physical characteristics such as density, pH
index quarry. For each of these characteristics, the applicant must specify
standards and tolerance limits for each individual case.

If they are not given in the European Pharmacopoeia or in the pharmacopoeia of a Member State shall be
test conditions, or use of facilities or equipment and standards
always accurately described; The same applies in cases where the
are the methods prescribed by such pharmacopoeias are applicable.

Must also be solid dosage forms for oral administration
subjected to in vitro studies on the release and dissolution rate of the active substance or substances
unless otherwise justified. These studies should also be carried out
terms of bringing in another way and if the Veterinary Institute shall assess
necessary.

Second Identification and assay of the active substance or substances

Identification and assay of the active substance or active substances
carried out either in a representative sample from the production batch or in a certain number of units
dosage forms analyzed individually.

Unless there is sufficient justification, the maximum acceptable deviation
to the active substance in the final product shall not exceed the time of manufacture
+ - 5%.

On the basis of the stability tests, the manufacturer must propose and justify maximum acceptable deviation
for the content of active substances in the finished product
until the end of the proposed shelf.

In cases of particularly complex mixtures, where assay of active
substances which are very numerous or present in very low amounts
necessitate an intricate, difficult to carry out
each production batch may determine the content one or more active substances in the finished product
omitted, under the condition that such
determination made at an intermediate stage.
This simplified technique may not be extended to the characterization of the substances and
must be supplemented by a method of quantitative evaluation, enabling
Veterinary Institute to verify the conformity of the medicinal product with its specification
after it was launched.

Biological determination of in vivo or in vitro is mandatory if
physico-chemical methods can not provide adequate information about the quality of the product
. Such determination whenever possible, include
reference materials and statistical analysis allowing calculation of confidence limits
. If these tests can not be conducted with the final
product, they may be performed at an intermediate stage, and it
as late as possible in the manufacturing process.

If during manufacture of the finished product degradation occurs, it must be noted
maximum acceptable levels of individual and total
degradation products immediately after production.

If the data referred to in section B show that the production of the medicinal product is used
significant overage of the drug substance, or if
stability data show that the content of the active substance declines
storage, the description of control testing of the finished product
optionally contain chemical and, if necessary
toxico-changes that this substance
passes, and optionally the characterization or determination of the degradation
products.

Third Identification and assay of adjuvants

Identification and determining upper and lower limits are required for each individual antimicrobiological
preservative and for all
excipients which may affect the bioavailability of a drug
substance, unless bioavailability confirmed by other appropriate || | tests. Identifying and an upper limit are required to

Any antioxidant and for any adjuvants that may
adversely affect physiological functions, wherein for antioxidants
determine the lower limit at the time of batch release.

Fourth Safety tests

Apart from the toxico-pharmacological tests submitted with the application for registration must be
particulars of safety tests, such as sterility and bacterial endotoxins
included in the analytical particulars wherever such tests must be undertaken
routinely for verification quality of the product.

F.


STABILITY TESTS
First The active substance or active substances

Must be precisely determined period of examination (retest) and
storage conditions of the active substance except in cases where the active substance is subject to Article
European Pharmacopoeia and the manufacturer of the finished product
performs a complete test retest the active substance immediately prior
its use in the manufacture of the finished product.

To justify retest period and storage conditions to provide data on the stability
type of stability studies conducted, protocols used,
analytical procedures and their validation together with the detailed results and
obligation to monitor the stability in post-marketing
stabilitním with the general protocol.

If not for the active substance from the proposed source is available
certificate of compliance, which specifies a retest period and storage conditions
, stability data for the active substance from that source are not required
.

Second The final preparation

A description of the tests on the basis of the determined time
, the recommended storage conditions and the specifications at the end
shelf life proposed by the applicant.

The type of stability studies conducted, protocols used,
analytical methods and their validation together with the detailed results.

Where a finished product requires reconstitution prior to administration
or diluted, details of the proposed shelf life and
specification for the reconstituted or diluted product
supported by relevant stability data.

In the case of multi-dose vials must be where it is necessary, given
stability data to justify a shelf life for the product
after first opening, and must be defined specifications
preparation during usage.

If there is a possibility that the finished product
rise to degradation products, the applicant shall designate and identification methods and test procedures
.

Conclusions always contain the results of analyzes, justifying the proposed time
application and if necessary shelf life during use
under recommended storage conditions and the specifications of the finished product at
end of the shelf, and if necessary time
usability during use of the finished product under these recommended storage conditions
.

Enter the maximum acceptable level of individual and total
degradation products at the end of the shelf.
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.

Commitment to monitor the stability of post authorization shall be submitted together with a summary
stabilitním protocol.

G.
ADDITIONAL INFORMATION


The dossier may contain information relating to the quality
veterinary medicinal product not covered in the previous sections
.

For medicated premixes (products intended for incorporation into medicated feeds
) to submit information on the added ratios
instructions for incorporation, homogeneity feed, compatibility and suitability
feed stability in the feed, and the proposed the shelf life of the food.
It will also specifications for medicated feed
manufactured using these pre-mixes in accordance with the recommended instructions for use.

PART 3: SAFETY AND RESIDUES TESTS

The particulars and documents accompanying the application for marketing authorization pursuant to § 26 par. 5
point. i) Point 2 and 4 of the Act shall be submitted in accordance with the following requirements
.

A. Safety tests

CHAPTER I: PERFORMANCE OF TESTS

The safety documentation shall show:

A) the potential toxicity of the veterinary medicinal product and any dangerous or
unwanted effects that may occur under the proposed conditions

Use in animals; these should be evaluated in light of the seriousness
relevant pathologies;

B) the possible harmful effects of residues of veterinary medicinal products or substances
food obtained from treated animals and what problems
these residues may create in the industrial processing of foodstuffs;

C) the potential risks which may result from the exposure of people
veterinary medicine, for example during its administration to the animal;

D) the potential risks to the environment resulting from the use
veterinary medicine.

All results must be reliable and valid generally. Whenever
on the spot, shall be used in designing the experimental methods and in evaluating the results
mathematical and statistical procedures. Furthermore
submit information about the therapeutic potential of the product and the risks associated with its use.

In some cases it may be necessary to test the metabolites of the original
compound where these represent the residues of metabolites, which must be taken into account
.

An excipient used in the pharmaceutical field for the first time shall be treated like
with the active ingredient.

First Precise identification of the product and its active substance or active substances

- International Nonproprietary Name (INN)

- Name according to International Union of Pure and Applied Chemistry (IUPAC)

- Number CAS (Chemical Abstract Service)

- 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,

- Vapor pressure,

- Solubility in water and organic solvents expressed in g / l,
indication of temperature,

- Density,

- Refractive index, rotation, etc.,

- Formulation.

Second pharmacology

Pharmacological studies are of fundamental importance in clarifying the mechanisms that
therapeutic effects of veterinary medicine and therefore
pharmacological studies conducted in experimental and target species of animal
submitted under Part 4 of this Annex.

However, pharmacological studies may also assist in the understanding of toxicological phenomena
. If the veterinary medicine
pharmacological effects in the absence of a toxic response, or operate in
doses lower than those required to elicit toxicity must be
these pharmacological effects taken into account when assessing the safety
veterinary medicine.

Safety documentation must therefore always be preceded
details of pharmacological investigations undertaken in laboratory
animals and all relevant information observed during clinical
in the target animal.
2.1 Pharmacodynamics


Shall be provided on the mechanism of action of the active substance or active substances
, together with information on primary and secondary
pharmacodynamic effects in order
understanding of any adverse effects in the animal studies.
2.2 Pharmacokinetics


Shall be provided information about the fate of the active substance and its metabolites in the species
animals used in toxicological studies, covering absorption,
distribution, metabolism and excretion (ADME). These data must
related to the dose / effect findings in the pharmacological and toxicological
studies, to determine adequate exposure.
Comparison with the pharmacokinetic data obtained in studies on the target
animal species, Part 4, Chapter I, Section A.2, shall be provided for in section 4
to determine the significance of the results obtained in the toxicology
toxicity studies in the target species.

Third toxicology

Documentation on toxicology shall be submitted in accordance with guidelines published by the Agency
relating to general rules for testing
and guidance on particular studies. These guidelines include:

1) basic tests required for all new veterinary products
intended for use in animals intended for food production in order
assessing the safety of any residues present in food for human consumption
;

2) Additional tests may be required depending on

Specific toxicological expectations, such as those associated with
structure, class, and mode of action of the active substance or active substances
;

3) special tests which might assist in the interpretation of data
obtained in the basic or additional tests.

These studies must be performed on the active substance or active substances
not with the formulated product. As studies are required to
formulated product are specified below.

03.01 Single dose toxicity

Toxicity tests after single dose may be used to determine:

- The possible effects of acute overdosage in the target species,

- The possible effects of accidental administration to humans,

- Doses that can be used in the tests after repeated administration.

Toxicity tests after single dose should reveal the acute toxic effects
substance and the time course for their onset and remission.
Tests carried out shall be selected with a view to providing information on user safety, eg
. If substantial exposure of the user
veterinary medicine by inhalation or contact with the skin, it should be tested routes
exposure.

3.2 Repeated dose toxicity

Tests repeated dose toxicity are intended to reveal
physiological or pathological changes induced by repeated administration
rated active substances or combinations of active substances and to determine
how these changes are related to dosage.

In the case of pharmacologically active substances or veterinary products
intended solely for use in animals which do not produce food
normally be sufficient test repeated dose toxicity
performed in one laboratory animal species.
This test can be replaced by a study conducted in the target animal. The frequency and route of administration, and duration
tests are always chosen with regard to the proposed
conditions of clinical use. The investigator shall give reasons for the extent and duration
trials and the dosages chosen.

In the case of substances or veterinary medicinal products intended for
use in animals intended for food-producing toxicity study
repeated administration (90 days) carried by rodents and other species of animals
than rodents, to determine the target organs and
toxicological criteria for exclusion (endpoints) and determine appropriate
species and doses to be optionally used, if carried
chronic toxicity tests.

Investigator shall give his reasons for the choice of species, having regard to the available knowledge of the metabolism
product in animals and humans. The test substance is administered orally
. Investigator shall clearly state the reasons for the method and frequency of administration and the length
tests.

The maximum dose should normally be selected so as to take effect
harmful effects. The lowest dose should be chosen so that
did not produce any evidence of toxicity.

Evaluation of the toxic effects is based on observation of behavior, growth,
hematology and physiological tests, especially those that affect
authorities involved in the secretion, and also on autopsy
reports and accompanying histological data. The choice and range of each
group of tests depends on the species of animal used and the state of scientific knowledge
at the time.

In the case of new combinations of known substances which have been investigated in accordance with the provisions of the Act
, the test may be repeated dose toxicity,
if the toxicity tests have shown an increase of toxicity or new
toxic effects, be suitably modified the investigator, who shall submit his
reasons for such changes.

3.3 Tolerance in the target species

Submits a summary of information about any signs of intolerance
which have been observed during studies conducted, usually using
final formulation, in the target species in accordance with
requirements of Part 4, Chapter I, Section B of this Annex.
Indicate relevant tests, the dosages at which the intolerance occurred and the
species and breeds. Further Details of any unexpected physiological changes
. Full reports of these studies
full text are given in Part 4 of this Annex.

3.4 Reproductive toxicity including developmental toxicity

3.4.1 Study of the effects on reproduction


The study aims to determine effects on reproduction
possible impairment of male or female reproductive function or harmful effects on progeny
due administration of the veterinary product or substance.

In the case of pharmacologically active substances or veterinary products
intended for use in animals intended for food production, the study
effects on reproduction carried out in the form of 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 to weaning, || | sexual maturity and the subsequent reproductive function of the offspring as adults.
At least three different doses. The maximum dose is selected so as to
showed harmful effects. The lowest dose level should not produce any evidence of toxicity
.

3.4.2 Developmental toxicity studies

In the case of pharmacologically active substances or veterinary products
intended for use in animals intended for food production are carried out
developmental toxicity testing. These tests are designed to detect
any adverse effects on the pregnant female and development of the embryo and fetus
after exposure of the female from implantation during pregnancy until the day before the expected delivery
. Such adverse effects include enhanced
toxicity in comparison with the toxicity in non-pregnant females, the death of the embryo or fetus
, changes in fetal growth and structural changes to the fetus. Always carry
developmental toxicity test in rats. Depending on the results
may be necessary to perform a test on a second species of animals, in accordance with the relevant guidelines
.

In the case of pharmacologically active substances or veterinary products
not intended for use in animals intended for food production, is performed
developmental toxicity study in at least one species,
which may be the target species, if the product is intended for use in
females which can be used for breeding. If, however
use of veterinary medicine has led to significant exposure to users,
carry the standard developmental toxicity studies.
3.5 Genotoxicity


Carry out tests to demonstrate the genotoxic potential
whose purpose is to reveal the changes which a substance may cause in the genetic material of cells
. All substances to be included in veterinary medicine
first, always assess for genotoxic properties.

For the active substance or active substances is usually performed standard set
genotoxicity tests in vitro and in vivo in accordance with established guidelines
. In some cases it may also be necessary to
test one or more metabolites that occur as residues in food
.
3.6 Carcinogenic


The decision on whether carcinogenicity testing is required, always
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.

Taking into account all known species specificity of the mechanism
toxicity, as well as any differences in metabolism between species
used in trials, target animal species and humans.

If carcinogenicity testing is necessary, generally requires
perform a two-year rat study and an eighteen-month study in mice
. With appropriate scientific justification can be carcinogenicity studies
out in one rodent species, preferably the rat.
3.7 Exceptions


If the veterinary medicinal product intended for topical administration,
assess the systemic absorption of the target species. If it is proved that systemic absorption is negligible
need not be present to test
repeated-dose toxicity, reproductive toxicity test and tests for carcinogenicity
except in cases where:

- Under specified conditions of use Veterinary
expect ingestion of animal or

- Under specified conditions of use expected exposure of the user
veterinary medicine in other ways than by contact with skin or

- The active substance or metabolites may enter foodstuffs obtained from treated animals
.

Fourth Other requirements

4.1 Special studies


In the case of certain groups of substances or if the effects observed during
tests after repeated administration in animals include changes indicative
example, immunotoxicity and neurotoxicity and endocrine disorders, it is
necessary to conduct further testing, such as studies sensitization | || or delayed neurotoxicity tests. Depending on the nature of the product
may be necessary to perform additional studies to assess the underlying
mechanism of the toxic effect or the irritation potential. Such studies
are normally conducted for the final formulation.
When designing such studies and evaluating their results
account of current scientific knowledge and valid information.

4.2 Microbiological properties of residues

4.2.1 Potential effects on the human gut flora

Potential microbiological risk presented by residues
antimicrobial compounds for the human intestinal flora
be tested in accordance with established guidelines.

4.2.2 Potential effects on the microorganisms used for industrial food processing


In some 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 foodstuffs.

4.3 Observations in humans

Shall be provided on whether the pharmacologically active substances
veterinary product are used as medicines for humans
; if so, must be drawn
comprehensive report on all the effects observed (including adverse reactions) in humans and
their causes, they can affect the safety assessment
veterinary medicine, possibly including results
published studies; where constituents of the veterinary medicinal products themselves
not used or are no longer used as medicinal products for the treatment
people, indicating the reasons why this is so.
4.4 Development of resistance


Data on potential emergence of resistant bacteria of relevance for human health are
if necessary veterinary products.
Is particularly important in this regard mechanism of the development of such resistance. If
necessary, propose measures to limit resistance development from the intended use
veterinary medicine.

Resistance relevant for clinical use of the product must be specified in accordance with the requirements
Part 4. Where relevant, it should be noted
cross references to the information set out in Section 4

Fifth User Safety

This section provides a discussion of the effects found in the preceding sections
and presents this to the type and extent of human exposure to the product
for the purpose of formulating appropriate warning to the user
and other measures in the field of risk management.

6th Evaluation of environmental risks

6.1 Evaluation of the environmental risk of veterinary products
which do not contain genetically modified organisms or genetically modified organisms
not consist Environmental risk assessment
environment is performed to assess the potential harmful effects
which the use of veterinary medicinal products have on the environment, and
identify the risk of such effects. This evaluation also provides
any precautionary measures which may be necessary to reduce these risks
.

This assessment shall normally be conducted in two phases.
The first phase of the assessment is always performed. Details of the evaluation
submitted in accordance with applicable guidelines. This assessment indicates potential environmental exposure
product and the level of risk associated with any such exposure
having particular regard to the following points:

- The target species and the proposed uses,

- 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
treated animals to the environment;
persistence in poop.

- Removal of unusable veterinary medicinal products or waste
this product.

In the second phase, in accordance with the guidelines established carry out further testing
fate and effects of the various ecosystems. Take into account the range

Environmental exposure, and the available information about the physical
chemical, pharmacological and toxicological properties of the substance or
concerned, including metabolites in case of an identified risk
which were obtained when carrying out further tests and trials | || by law.

6.2 Assessment of the environmental risk of veterinary products
containing genetically modified organisms or genetically modified organisms consist


In the case of a veterinary medicine that contains
genetically modified organisms, or GMOs
is made, the application shall be accompanied also by the other documents required
legal regulation 9).

CHAPTER II: PRESENTATION OF PARTICULARS AND DOCUMENTS

The dossier of safety tests include:

- A list of all studies included in the dossier,

- A statement confirming that all data known by the applicant
at the time of application, whether favorable or unfavorable,

- A justification for the omission of any type of study,

- Explanation for the inclusion of an alternative type of study,

- A discussion of the contribution that any study that time
studies performed in accordance with good laboratory practice
according to another legal předpisu13c), the overall risk assessment.

Each study report contains:

- A copy of the plan (protocol) study

- A statement of compliance with good laboratory practice, where it is
applicable

- Description of the methods, equipment and materials

- A description and justification of the test system

- A sufficiently detailed description of the results obtained, so that the results can be
critically evaluated independently of their interpretation by the author,

- Statistical evaluation of results, where appropriate,

- Discussion of the results, with comment on observed with doses
effect and no-observed effect on any unusual observations
,

- A detailed description and a thorough discussion of the results of the study
safety of active substances and their relevance for the evaluation of potential risks
presented by residues to humans.

B. Residue tests

CHAPTER I: PERFORMANCE OF TESTS

First Introduction

For the purposes of this Annex, the definitions of
European Parliament and Council Regulation (EC) no. 470/2009 of 6 May 2009 laying
down Community procedures for the establishment of residue limits of pharmacologically active
substances in foodstuffs of animal origin,
repealing Council Regulation (EEC) No 2377/90. and amending Directive
European Parliament and Council Directive 2001/82 / EC of the European
Parliament and Council Regulation (EC ) no. 726/2004.

Purpose of studying the depletion of (depletion) residues in edible tissues or
eggs, milk and honey derived from treated animals is to determine under what conditions
and to what extent residues persist in foods derived from these
animals. Furthermore, these studies will allow
set a withdrawal deadline.

In the case of veterinary medicinal products intended for use in animals
food producing documentation concerning residues always proves
:

First to what extent and for how long, do residues of the veterinary
product or its metabolites in edible tissues of treated
animal or in milk, eggs or honey obtained therefrom;

Second that is, in order to prevent any risk to the health of consumers
food derived from treated animals, or difficulties in the industrial
food processing, possible to establish realistic withdrawal periods which can be
under practical farming conditions met;

Third the analytical method and analytical methods used in the study
elimination (depletion) residues are sufficiently validated to
provide the necessary reassurance that the residues data submitted are
suitable as the basis for a withdrawal period.

Second Metabolism and residue kinetics

02.01 Pharmacokinetics (absorption, distribution, metabolism, excretion)

Submits a summary of the pharmacokinetic data with cross references to
pharmacokinetic studies in target species submitted in Part 4 of this Annex
. Report on the full study may not be submitted.

The purpose of pharmacokinetic studies with respect to residues of veterinary

Products is to evaluate the absorption, distribution, metabolism and excretion
product in the target animal species. The final product, or its
formulation, which has comparable characteristics in terms of biological
availability as the final product, the target species
served at the maximum recommended dose.

With regard to the method of administration shall be fully described absorption rate
veterinary medicine. If it is proved that systemic absorption of products for topical
application is negligible, further residue studies will not be required.

A description of the distribution of veterinary product in the target species;
Take into account the possibility of plasma protein binding or passage into milk or eggs and
accumulation of lipophilic compounds.

Describe the route of excretion of the target species.
Down and characterize the major metabolites.

02.02 Elimination (depletion) residues

The purpose of these studies, which measure the rate of excretion of residues from
target animal after the last administration, the determination
withdrawal periods.

After the last dose of the veterinary medicinal product test animal has
validated analytical methods, and that a sufficient number of repetitions
provides for quantities of residues present;
bring the technical procedures and the reliability and sensitivity of the methods used.

Third Analytical method for determining residues

A detailed description of the analytical methods or analytical methods
used in the study (studies) elimination (depletion)
residues and its (their) validation.

Describe the following characteristics:

- Specificity,

- Accuracy,

- Accuracy

- Limit of detection,

- Limit of quantification,

- Practicability and applicability under normal laboratory conditions,

- Susceptibility to interference,

- Stability of residues.

The suitability of the analytical method proposed shall be evaluated in light of the state
scientific and technical knowledge at the time of submission.

The analytical method shall be presented in an internationally agreed format.

CHAPTER II: PRESENTATION OF PARTICULARS AND DOCUMENTS

First Identification of

Veterinary medicine or veterinary products used for testing
determined in detail, including:

- Composition,

- The physical and chemical (potency and purity) test results for the relevant batch or
relevant batch

- Batch identification,

- Relationship to the final product,

- Specific activity and radio-purity of labeled substances

- Position of labeled atoms in the molecule.

The dossier of residue tests shall always include:

- A list of all studies included in the dossier,

- A statement confirming that all data known by the applicant
at the time of application, whether favorable or unfavorable,

- A justification for the omission of any type of study,

- Explanation for the inclusion of an alternative type of study,

- A discussion of the contribution that any study that time
studies performed in accordance with good laboratory practice
(SLP), the overall risk assessment,

- A withdrawal period proposal.

Each study report shall include:

- A copy of the plan (protocol) study

- A statement of compliance with good laboratory practice, where it is
applicable

- Description of the methods, equipment and materials,

- A sufficiently detailed description of the results obtained, so that the results can be
critically evaluated independently of their interpretation by the author,

- A statistical analysis of the results,

- Discussion of the results,

- An objective discussion of the results obtained and suggestions regarding
withdrawal periods necessary to ensure that foodstuffs
obtained from treated animals do not present any residues that could
might pose a risk for consumer.

PART 4: PRE-CLINICAL AND CLINICAL TRIAL

Particulars and documents accompanying applications for marketing authorizations pursuant to § 26 par. 5
point. i) Point 2 and 3 shall be submitted in accordance with the following requirements
.

CHAPTER I: REQUIREMENTS FOR CLINICAL

Clinical studies are required to establish the pharmacological activity and tolerability
.

A. pharmacology
A.1 Pharmacodynamics



Characterize the pharmacodynamic effects of the active substance or medicinal
substances contained in veterinary medicine.

First, it must be adequately described mechanism of action and
pharmacological effects which underlie the recommended application in
practice. Results are expressed quantitatively (using for example curves
affecting the dependence of the effect on the dose effect curves, etc.).
And if possible, in comparison with a substance with known activity. If for a given active substance
indicates greater effectiveness must be demonstrated and the difference must be
shown to be statistically significant.

Second, it must be stated overall pharmacological assessment of the active substance
with special reference to the possibility of secondary pharmacological effects.
Generally, the effects on the main body functions.

Evaluated Any effect of the other characteristics of the products
(eg. The route of administration or formulation) on the pharmacological activity of the active substance
.

Evaluations shall be conducted in greater depth, where the recommended dose approaches
dose likely to produce adverse reactions.

The experimental techniques, unless they are standard procedures, shall be described as
detail to enable them to be reproduced, and the investigator determined their
application (validity). Test results always indicate clearly and in
certain types of tests to indicate statistical significance.

If good reasons are given to the contrary, to evaluate
also any quantitative modification of responses resulting from repeated administration of the substance
.

Fixed-dose combination drugs may be based either on
pharmacological data or clinical indications.
In the first case, the pharmacodynamic and pharmacokinetic studies demonstrate
interactions which might make the combination itself of value in clinical use
. In the second case, where scientific justification for the combination of drugs
looking through clinical experimentation, the investigation
determine whether the effects expected from the combination can be demonstrated in animals, and at least
examine the significance of any adverse reactions.
If a combination includes a novel active substance, the latter must advance
depth.
Development of resistance A.2


Where applicable, a veterinary medicine
submit information on possible occurrence of clinically important resistant organisms.
Particularly important in this respect are data on the mechanism of the development such
resistance. The applicant shall propose measures to limit resistance development
the intended use of the veterinary medicine.

If appropriate, include cross-references to the information set out in Part 3 of this Annex
.
Pharmacokinetics A.3


The evaluation of clinical safety and efficacy of veterinary medicine are required
Basic pharmacokinetic data concerning a new active substance
.

The objectives of pharmacokinetic studies in the target animal species can be divided into three main areas
:

I) descriptive pharmacokinetics leading to the determination of basic
parameters

Ii) use of these parameters to investigate the relationships between dosage regimen
, plasma and tissue concentration over time and
pharmacologic, therapeutic or toxic effects

Iii) when it's in place, compared to the kinetics between different target species
investigation and possible differences between different species of animals
having an impact on the safety and efficacy of veterinary medicine at
target animal.

In target species, pharmacokinetic studies are, in principle
necessary as a complement to the pharmacodynamic studies to support
determine effective dosage regimens (route and site of administration,
dosing interval, number of administrations, etc. ). They may be required
additional pharmacokinetic studies to determine dosage regimens according to certain population
variables.

Where pharmacokinetic studies have been submitted under Part 3 of this Annex
may be made to these studies cross-reference.

In the case of new combinations of known substances which have been investigated in accordance
provisions of this Directive, pharmacokinetic studies of the fixed combination
not required if it can be justified that the administration of medicinal substances in
fixed combination does not change their pharmacokinetic properties.


Appropriate bioavailability studies to establish bioequivalence
is done:

- When comparing a veterinary preparation with modified
the existing one veterinary medicine,

- Where it is necessary to compare the new method or route of administration
is an established way or the established route of administration.

B. Tolerance in the target species

Evaluated local and systemic tolerance of the veterinary medicine at
target species. The purpose of these studies is to characterize signs
intolerance and to establish an adequate margin of safety using the recommended route or
recommended route of administration.
This can be achieved by increasing the therapeutic dose or duration of treatment.
The report on the trials shall contain details of all expected
pharmacological effects and all adverse reactions.

CHAPTER II: CLINICAL REQUIREMENTS

First General principles

The purpose of clinical trials is to demonstrate or substantiate the effect
veterinary medicinal product after administration at the proposed dosage regimen
proposed route of administration and to specify its indications and contraindications
according to species, age, breed and sex, its directions for use as well as
any adverse effects that may have.

The experimentally obtained data shall be confirmed by data obtained under normal field conditions
.

If good reasons are given, conducted clinical trials with
control animals (controlled clinical evaluation
). The efficacy results obtained are compared with the results
efficacy in the target animal species that have received a veterinary
product authorized in the Community for the same indications for use
in the same target animal species, or a placebo or efficacy results
the target animal species that have not received any treatment
. Specify the results obtained, whether favorable or unfavorable.

Protocol design, analysis and evaluation of clinical trials
used an established statistical principles, unless justified.

In the case of veterinary medicinal product intended primarily for use as a performance enhancer
special attention to:

1) The yield of animals;

2) the quality of animal produce (organoleptic, nutritional, hygienic and technological qualities
);

3) nutritional efficiency and growth of target animal species;

4) general health status of the target animal species.

Second Conduct of clinical trials

All veterinary clinical trials are always conducted in accordance with
detailed trial protocol.

Clinical field trials shall be conducted in accordance
with established principles of good clinical practice, unless otherwise justified
cases.

Before any assessment carried out in field conditions
must be obtained and documented informed consent of the owner of the animals that
will be included in the evaluation. The owner of the animals must be in writing, especially
informed of the consequences, which is the inclusion of animals in the trial for
subsequent disposal of treated animals or for the taking of foodstuffs from such animals
. A copy of this notification, signed and dated by the owner
animals shall be included in the trial documentation.

Unless the trial is conducted field trials conducted with a blind
shall be used for the labeling of products
intended for use in veterinary field trials
provisions of § 37 of the Act accordingly. In all cases, the packaging must be
prominently and indelibly marked with the words "Only for veterinary evaluation
carried out in field conditions."

CHAPTER III: INFORMATION AND DOCUMENTATION

Dossier on efficacy includes all preclinical and clinical documentation
or results of trials, whether favorable or unfavorable
for veterinary products to enable an objective overall assessment
benefit-risk product.

First Results of preclinical testing

Whenever possible, show the results:

) Tests demonstrating pharmacological actions;

B) tests demonstrating the pharmacodynamic mechanisms that lead to
therapeutic effect;

C) tests demonstrating the main pharmacokinetic profile;

D) tests demonstrating the safety for the target animal;


E) tests investigating resistance.

If during the tests unexpected results occur
be described in detail.

Also all pre-clinical studies indicate the following information:

A) a summary;

B) a detailed experimental protocol, which shall
description of the methods, equipment and materials used, details such as species, age, weight,
sex, number, breed or strain of animals, identification of animals, dose,
route and schedule of administration;

C) a statistical evaluation of results;

D) an objective discussion of the results obtained, leading to conclusions on the efficacy and safety
veterinary medicine.

If any of these data wholly or partly missing, must be filed
explanation.

Second The results of clinical trials

Every examiners shall submit all data in case of individual
treatment on individual record sheets in the case of collective treatment
collective record sheets.

The data submitted the following form:

A) the name, address, function and qualifications of investigator in charge;

B) the place and date of treatment; the name and address of the owner of the animals;

C) details of the clinical trial protocol giving a description of
methods used, including methods of randomization and blinding, details
as the route of administration, schedule of administration, the dose, identification of animals
included in the evaluation, types animals, breeds or strains, age,
weight, sex, physiological status;

D) method of rearing and feeding, stating the composition of the feed and the nature and amount of
additives;

E) case history (as full as possible), including occurrence and course of any intercurrent disease
;

F) diagnosis and means used to make it;

G) clinical signs, if possible according to conventional criteria;

H) precise formulation of the veterinary product used in the clinical
trial and the physical and chemical test results for the relevant batch or
of the batch;

I) dosage of the veterinary product, method, route and frequency of administration
and any measures taken during administration (duration of injection
etc.);

J) duration of treatment with a subsequent observation period;

K) all details concerning other veterinary products
which have been administered during the ongoing clinical trial
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 criteria
efficiency and points to exclude specifically identified in
clinical trial protocol and including the results
appropriate statistical evaluation;

M) all particulars of any unintended effects, whether harmful or not
, and any action taken in consequence;
if possible, examine the causal relationship;

N) effect on animals' performance if such effects occur;

O) effects on the quality of foodstuffs obtained from treated animals, particularly
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.

If one or more items a) to p) must be filed
justification.

MAH shall take all necessary measures to
the original documents, which formed the basis of the data presented,
kept for at least five years from the expiry of the registration
veterinary medicine.

Each clinical trial, the clinical observations summarized in a synopsis
evaluation and the results thereof, indicating in particular:

A) the number of animals in the control groups and the number of 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 exclusion
;

C) in the case of control animals, whether:

- No treatment or

- Received a placebo, or

- Received another veterinary product authorized in

Community for the same indication for use in the same target species or animal


- Received the same active substance tested in the form of
different formulation or by a different route;

D) the frequency of observed adverse reactions;

E) or observation to the effect on animal performance;

F) details concerning test animals which may be
increased risk owing to their age, their mode of rearing or feeding, or
purpose for which they are intended, or animals the physiological or
pathological condition 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
product under the proposed conditions of use
along with all information relating to indications and contraindications, dosage and
average duration of treatment and where appropriate, any observed | || interactions with other veterinary treatment or additives in animal feed
any special precautions to be taken in
during treatment and the clinical symptoms observed or
overdose.

In the case of fixed combination products, the investigator shall also draw
conclusions concerning the safety and efficacy in comparison with
separate administration of the drugs.
TITLE II


REQUIREMENTS FOR IMMUNOLOGICAL VETERINARY MEDICINES

Without prejudice to specific statutory requirements
for the control and eradication of certain infectious animal diseases,
apply to immunological veterinary medicinal products
following requirements, except where products are intended for use in
some species or with specific indications as defined in Title III of this
annex and relevant guidelines.

PART 1: SUMMARY OF THE DOSSIER

A.
ADMINISTRATIVE DATA


Immunological veterinary medicine, which is the subject of the application is
identified by name and name of the active substance or active pharmaceutical ingredients, along with
biological activity, potency or titre, the pharmaceutical form, or
route and method of administration and
description of the final presentation of the product, including packaging, labeling and package leaflet
information. Diluents may be packed together with vials containing
active substance or may be packaged separately.

Information dilution, which are necessary for the reconstitution
product must be included in the dossier.

Immunological veterinary medicinal product is regarded as one product even
if it is to prepare a variety of dosage forms
final product must use more than one diluent, which may be due
different routes or methods of administration.

The name and address of the applicant, together with the name and address of the manufacturer
and the sites involved in the different stages of manufacture and control
(including the manufacturer of the finished product and the manufacturer of the active substance or substances
), or the name and address of the importer.

The applicant shall identify the number and titles of volumes of documentation submitted in support of applications
, and if they are provided as samples, indicating what.

The administrative data shall be copies of a document that proves
that the manufacturer is authorized to produce immunological veterinary medicinal products
according to § 62 of the Act. Furthermore, the list of organisms, with which the production site
treats.

The applicant shall submit a list of countries in which authorization has been granted, and
list of countries in which an application has been submitted or refused.

B.

SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE INFORMATION

Applicant shall propose a summary of product characteristics in accordance with Annex no. 3
this ordinance.

In addition, the applicant must submit proposed labeling text for immediate and outer packaging
in accordance with § 37 of the Act, together with a package leaflet where
is required, pursuant to § 37 par. 3 of the Act. The applicant must also submit
one or more specimens or mock sales presentation for all internal and external
containers in which to be a veterinary product is marketed in
Czech language, if warranted, in one of the official languages ​​
European Union.

Agreement with the Veterinary Institute may submit proposals in the sales package
only in black and white and electronically.


C.

DETAILED AND CRITICAL SUMMARIES

Each detailed and critical summary referred to in § 26 par. 6 of the Act must be drawn
considering the current state of scientific knowledge at the time of filing the application
. Always include evaluation of all tests and trials, which constitute
application dossier for marketing authorization, and will focus on all
issues important to assess the quality, safety and efficacy
immunological veterinary medicinal product. Included in it are detailed
test and trial results and accurate references.

All important data shall be summarized in an appendix to the detailed and critical summaries
in tabular or graphic form, if possible.
Detailed and critical summaries shall contain precise cross references to the information contained in the main
documentation. The detailed and critical summaries shall be
signed and dated and must be accompanied by information on
education, training and occupational experience of the author.
The professional relationship of the author to the applicant.

PART 2: CHEMICAL, PHARMACEUTICAL AND BIOLOGICAL / MICROBIOLOGICAL INFORMATION
(QUALITY)

All test procedures shall fulfill the necessary criteria for analysis and quality control
starting materials and the finished product and shall be validated
. Submit the results of the validation studies. Indicate
sufficiently detailed description of any special apparatus and equipment,
which can be used, where appropriate, be accompanied by a drawing. Composition
laboratory reagents shall be supplemented, if necessary, the method of preparation.

In the case of test procedures included in the European Pharmacopoeia or
pharmacopoeia of a Member State, this description may be replaced by a detailed reference to the pharmacopoeia
.

If possible, use chemical and biological reference material of the European Pharmacopoeia
. If used other reference preparations and
standards must be identified and described in detail.

A.

QUALITATIVE AND QUANTITATIVE INFORMATION ON INGREDIENTS

First Qualitative data

"Qualitative particulars" of all the constituents of the immunological veterinary
product shall mean the designation or description of:

- The active substance or active substances

- Constituents of the adjuvants,

- Constituents adjuvants or excipients, regardless of their nature
or the quantity used, including preservatives, stabilizers, emulsifiers
, dyes, agents for the adjustment of flavor, identifiers etc.,

- The constituents of the dosage form administered to animals.

These data are supplemented by any relevant data concerning the container and, where appropriate
manner of closure, together with details of devices with
which the immunological veterinary medicinal product should be used or administered and
which will be delivered. If the device does not come with
immunological veterinary medicinal product shall be provided
important information about the device, if they are necessary for the evaluation
product.

Second Usual terminology (terminology)

Usual terminology used in describing the constituents
immunological veterinary medicinal product is without prejudice to other
provisions of § 26 par. 5 point. b) Act means:

- In the case of substances listed in the European Pharmacopoeia, or if there
not listed in the pharmacopoeia of one of the Member States, the main title
relevant article ,, which will be obligatory for all such substances, with
reference to the pharmacopoeia,

- In the case of other substances, the international non-proprietary name recommended
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
, is described by a statement of how and training, with the possible addition of
any other relevant details,

- In the case of dyes designation "E" code assigned to them by
another legal regulation 13a).

Third Quantitative data

When the "quantitative particulars" of the active substances
immunological veterinary medicinal product is necessary, whenever possible the number of organisms
content specified protein, weight, number
international units (IU) or units biological activity, either
in unit dosage form / dosage unit or volume, and with regard to the adjuvant and
constituents of the excipients, the mass or volume of each of

Them with due regard to the details provided in Section B. If
been defined international unit of biological activity
used with this unit.

Units of biological activity for which there is no publicly available data
be expressed so as to provide unambiguous information about activity
substances, e.g. stating the immunological effect on established
wherein the method of determining benefits.

Fourth Product development

Submitted the explanations concerning the choice of composition, constituents and
containers, supported by scientific data on product development.
The overage, with justification.

B.


DESCRIPTION OF MANUFACTURING METHOD
Description of the manufacturing method accompanying the application for marketing authorization pursuant to § 26 par. 5
point. d) of the Act shall be to provide sufficient information about
nature of the operations.

For this purpose it shall include at least:

- Various stages of manufacture (including production of the antigen and purification procedures)
order to assess the reproducibility of the manufacturing process and
risk of adverse effects on the finished products, such as microbiological contamination
. Must be proven validation of key stages in the production process
and validation of the production process as a whole with the results of the validation studies
with 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 finished product

- Putting all substances indicating the degree of production in which they are used
, including those not in the course of manufacture or
not contained in the final product

- Details of homogenization (blending)
with the quantitative particulars of all the substances used,

- The stages of manufacture at which sampling is carried out for
control tests during production.

C.

PRODUCTION AND CONTROL OF STARTING MATERIALS

For the purposes of this paragraph, "starting materials" means all components used
production of the immunological veterinary medicinal product.
Culture media consisting of several components used for production
active substance shall be regarded as one starting material. However
qualitative and quantitative composition of the any culture media shall be presented
if the authorities consider that this information is
important for the quality of the finished product and any risks.
If for preparation of these culture media used
raw materials of animal origin must be mentioned used animal species and tissues.

Dossier shall include the specifications, information on
tests to be conducted for the quality control of all
batches of starting materials and results for a batch for all used
ingredients and must be submitted in accordance with following provisions.

First Starting materials listed in Pharmacopoeia

For all feedstocks that are listed in the European Pharmacopoeia
Articles of that pharmacopoeia.

In respect of other substances, each Member State may require observance
its own national pharmacopoeia with regard to products manufactured in its territory
.

Constituents in accordance with the requirements of the European Pharmacopoeia or the pharmacopoeia
one of the Member States, consider the provisions of § 26 par. 5 point. h)
law to be fulfilled. In this case, a description of the analytical methods
replaced by a detailed reference to the pharmacopoeia.

Dyes in all cases always meet the requirements set out in Chapter VIII of this Annex
.

Routine tests carried out on each batch of starting materials must
match those that are listed in the application for registration. If
used tests other than those mentioned in the pharmacopoeia must be
proof that the starting materials meet the quality requirements of that pharmacopoeia
.

In cases where a specification or other provisions contained in Article
European Pharmacopoeia or in the pharmacopoeia of a Member State might be
insufficient to ensure the quality of the substance, the competent authorities may
require the registrant to appropriate specifications.
The alleged insufficiency shall be reported to the authorities responsible for the pharmacopoeia in question.

In cases where a starting material is described neither in the European

Pharmacopoeia nor in the pharmacopoeia of a Member State may be declared compliance with Article
third country pharmacopoeia; In such cases, the applicant shall submit a copy of the article
, if necessary by the validation test
procedures contained in the article and, where appropriate, with translation.

When starting materials of animal origin must be in compliance with the relevant
articles including general articles and general chapters of the European Pharmacopoeia
. The tests and checks must be proportionate
to the starting material.

The applicant shall provide documentation to demonstrate that the starting materials and manufacturing
veterinary medicine is in accordance with the Note for Guidance
minimizing the risk of transmitting animal spongiform encephalopathy
via human and veterinary products, as well as
requirements of the corresponding article of the European Pharmacopoeia. To demonstrate compliance
can use certificates of conformity issued by the European Directorate for the Quality of Medicines
and health care, with reference to the relevant article
European Pharmacopoeia.

Second Starting materials not in a pharmacopoeia

2.1 Starting materials of biological origin

Description shall be given in the form of article (monograph).

Vaccine production shall be, whenever possible, based on a system
seed lot and on established cell seeds.
For the production of immunological veterinary medicinal products containing serum must be
the origin, general health and immunological status of animals from which the
and defined mixtures of raw materials used.

Origin, including geographical region, and history of starting
materials shall be described and documented. In the case of genetically modified
starting materials this information shall include details such as
description of the starting cells and strains, the construction of the expression vector (name,
origin, function of the replicon, promoter, other regulatory mechanisms)
control effectively inserted DNA or RNA sequences, oligonucleotide sequences
plasmid vector in cells, plasmid used for cotransfection
, added or deleted genes, biological activity
final construct and expressed genes, number of copies and genetic stability
.

Seed materials, including cell seeds and raw serum for the production of immune sera
must be tested for identity and extraneous agents.

Must be provided on all substances of biological origin
all stages of the production process.

This information includes:

- Details of the source of raw materials,

- Details of any processing, purification and inactivation
, together 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 it is detected or suspected presence
foreign agents corresponding material shall be discarded or
used in very exceptional circumstances only when further processing
product ensures their elimination or inactivation;
removal or inactivation of such extraneous agents shall be demonstrated.

When cell seeds are used, it must be demonstrated that the cell
characteristics remain unchanged up to the highest passage level used for the production
.

For live attenuated vaccines should be proof of the stability of the attenuation
inoculum.

Must be submitted documentation showing that the seed materials, cell
inoculum batches of serum and other material originating from animal species
relevant for the transmission of TSE comply with the Note for Guidance
minimizing the risk of transmitting animal spongiform
encephalopathy via human and veterinary products, as well as
requirements of the relevant article of the European Pharmacopoeia. To demonstrate compliance
it is possible to use the certificates of conformity issued by the European Directorate for the Quality of Medicines
and health care, with reference to the relevant article of the European Pharmacopoeia
.

When required, the competent authority shall submit samples of the biological
starting material or reagents used in the testing procedures that
have the authority to ensure implementation of control tests.

2.2 Starting materials of biological origin

Description shall be given in the form of article (monograph) under the following headings:


- The name of the starting material meeting the requirements of Section A point 2
must be supplemented by any trade or scientific synonyms,

- Description of the starting material, set down in a form similar to that used
in a descriptive item in the European Pharmacopoeia

- Function feedstock

- Methods of identification,

- Any special measures that may be necessary during storage
starting material and, if necessary, its storage life.

D.

CONTROL TESTS DURING PRODUCTION

First The registration dossier always includes information relating to the control
tests, which are performed in the production stage
intermediate to verify the consistency of the production process and the final product
.

Second For inactivated or detoxified vaccines must be
inactivation or detoxification tested during each production run immediately after racing
inactivation or detoxification process and after neutralization if
occurs, but before the next step of production.

E.

TESTS ON THE FINISHED PRODUCT

For all tests for quality assessment shall
sufficiently precise detail description of the analysis of the final product.

The dossier shall include particulars relating to control tests
finished product. If there are relevant monograph
and if test procedures and limits other than those set out in Articles
European Pharmacopoeia or, failing
listed in the pharmacopoeia of a Member State shall be submitted evidence that
final product would meet the quality requirements set by the competent
pharmacopoeia for the pharmaceutical form, if tested by
relevant articles. The application for marketing authorization shall test that
are carried out on representative samples of each batch of finished product
. Must be the frequency of the tests which are carried out on each batch
. Indicate Release limits.

If possible, using chemical and biological reference material
European Pharmacopoeia. If used
other reference preparations and standards shall be identified and described in detail.

First General characteristics of the finished product

Tests of general characteristics shall, whenever possible, relate to the control
average masses and maximum deviations, to mechanical, physical or chemical
tests, physical characteristics such as density, pH, viscosity, etc.
. for each of these characteristics, the applicant must for every individual case
specifications, with appropriate confidence limits
.

Second The identity of the active substance or active substances

If necessary, carry special identification test.

Third Titer or Force batch

Each batch is made quantification of the active substance, demonstrating that
each batch contains adequate strength or titre to ensure its safety and efficacy
.

Fourth Identification and assay of adjuvants

The finished product is verified by the quantity and nature of the adjuvant and its components
the range of available testing procedures.

Fifth Identification and assay of adjuvants

If necessary, the excipient substances are subject to at least
identification tests.

Performing tests for upper and lower limit is mandatory for preserving
substances. Performing the test for the upper limit is obligatory for any
other excipients, which can cause undesirable effects.

6th Safety tests

In addition to the results of tests submitted in accordance with Part 3 of this Title
(Safety Tests) must be submitted test data on the safety
lot. These tests shall preferably be overdosage studies carried
at least one of the most sensitive target species and
least the recommended route of administration posing the greatest risk.
Routine application of the batch safety test may be of interest
welfare waived if was made
sufficient number of consecutive production batches have this
comply with the test.

7th The test for sterility and purity

Performance must be appropriate tests to demonstrate the absence
contamination by extraneous agents or other substances to the nature
immunological veterinary medicinal product, method and manufacturing conditions.

If it is routinely employed for each batch fewer tests than required
relevant European Pharmacopoeia tests carried out shall be critical to
demonstrate compliance with the article. It is necessary to submit evidence that if
immunological veterinary medicinal product has passed all tests in accordance with Article
Pharmacopoeia meet the requirements of that article.

8th Residual moisture

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

9th inactivation

For inactivated vaccines on the product in the final container
perform a test to verify inactivation, where the test was not
conducted at a late stage in the production process.

F.

Batch to batch consistency

In order to ensure that the quality of the product is consistent
same batch and to demonstrate conformity with specifications must be submitted
full protocol of three consecutive batches, which includes the results
all tests performed during production and the finished product
.

G.


STABILITY TESTS
The particulars and documents accompanying the application for registration § 26 par. 5
point. f) and h) of the Act shall be submitted in accordance with the following requirements
.

A description of the tests on the basis of the determined time
proposed by the applicant. These tests shall always be
studies carried out in real time; must be carried out on a sufficient number
batches produced according to the described production process and on products
stored in the final container or final internal packaging;
These tests include biological and physico-chemical stability tests
.

Conclusions shall contain the results of analyzes, justifying the proposed period
under all proposed storage conditions.

In the case of products administered in feed must also be given
information on the shelf life of the different stages of mixing
feed 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
of the product is reconstituted in accordance with the recommendation.
Submits the data supporting the proposed shelf
reconstituted product.

Stability data obtained from combined products may be used
as preliminary data for derivative products containing one or more of the same
components.

Proposed use shelf life shall be justified.

Shall be demonstrated efficacy of any preservative system.

Information on the efficacy of preservatives in other similar immunological veterinary
products from the same manufacturer may be sufficient
.

H.
ADDITIONAL INFORMATION


The dossier may contain information relating to the quality
immunological veterinary medicinal products which are not contained in the previous sections
.

PART 3: SAFETY TESTS

A.

INTRODUCTION AND GENERAL REQUIREMENTS

Safety tests shall show the potential risks
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 product contains living organisms,
especially those which could be shed by vaccinated animals,
evaluate the potential risk to unvaccinated animals of the same or different kind
animals that may be exposed to the product.

Safety studies are conducted in the target species.
The dose used must match the amount of 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
registration dossiers submitted with the application for registration .

Where immunological veterinary medicinal product containing a live organism,
dose to be used in the laboratory tests described in Sections
B.1 and B.2 shall be the quantity of the product containing the maximum titre
. Where necessary, the antigen concentration can 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.

Safety documentation shall be used for assessment of possible
risks which may result from human exposure to the effects
veterinary medicine, for example during its administration to the animal.

B.


LABORATORY TESTS
First Safety of the administration of one dose

Immunological veterinary medicinal product shall be administered at the recommended dose and by each
recommended route of administration to animals of all species and categories for which it is intended
, including the youngest animals, which can be administered.
Animals shall be observed and examined for signs of systemic and local reactions
. These studies include detailed post-mortem or
macroscopic and microscopic examinations of the injection site.
Record with more objective criteria, such as rectal temperature and performance measurements
.

The animals shall be observed and examined until when one can not expect
incidence of reactions, the observation and examination period
animals must be at least 14 days after administration.

This study may be part of a study on repeated administration
dose that is required under section 3, or from such studies
can be waived if the results of studies concerning the overdose
required in paragraph 2 revealed no signs of general or local
reaction.

Second Safety of one administration of an overdose

Tests concerning the overdose was only required for live
immunological veterinary medicinal product.

An overdose of the immunological veterinary medicinal product is administered to all
recommended route of administration to animals of the most sensitive categories of the target
species, unless the reasons for the selection of the most sensitive of
several similar routes. In the case of immunological veterinary
products administered by injection to be dose and route of administration
chosen to take account of the maximum volume that can be passed onto
any one single injection site. Animals should be observed and examined for signs
systemic and local reactions at least 14 days after
administration. Other criteria shall be recorded, such as rectal temperature and performance measurements
.

If necessary, these studies shall include detailed post-mortem
gross and microscopic examination of the injection site if this
been carried out in accordance with point 1.

Third Safety of the repeated administration of one dose

Case of immunological veterinary medicinal products to be administered more than once
, as part of the basic vaccination schedule, requires the submission
study of the repeated administration of one dose, which has
reveal any adverse effects induced by such administration. These tests are carried
most sensitive categories of the target species, such
example, in certain breeds and ages, and using all
recommended route of administration.

Animals shall be observed and examined for signs of systemic and local reactions
at least 14 days after the last administration.
Record additional objective criteria, such as rectal temperature and performance measurements.

Fourth Examination of reproductive performance

Submission of reproductive performance tests may be necessary if
data suggest that the starting material from which the product is derived may be a potential risk factor
. Reproductive performance of males and non-pregnant
and pregnant females recommended dose
most sensitive route of administration. Furthermore, the harmful effects on the offspring, including
teratogenic and abortifacient effects.

These studies may form part of the safety studies described in points 1
2, 3, or in studies conducted in field conditions provided for in Section C.


Fifth Examination of immunological functions

Where the immunological veterinary medicinal product might adversely affect
immune response of the vaccinated animal or its progeny, the
appropriate tests on the immunological functions.

6th Special requirements for live vaccines

Spread of the vaccine strain 6.1

Investigated the spread of the vaccine strain from vaccinated animals to target
unvaccinated, and using the recommended route of administration may
with most likely the spread. It may be necessary

Investigate the spread to non target species which could be highly
susceptible to a live vaccine strain.

6.2 Dissemination in the vaccinated animal

Faeces, urine, milk, eggs, secretions oral, nasal and other secretions
according to the nature of the product tested for the presence of the organism. It may also be necessary to submit
studies the spread of the vaccine strain in the body, with particular attention to
predilection sites for replication of the organism. In the case of live
vaccines for zoonoses within the meaning of another legal předpisu13d)
for use in animals intended for food production must take these studies especially
account the persistence of the organism at the injection site.

6.3 Reversion to virulence of attenuated vaccines

Reversion to virulence shall be investigated with the master seed.
If the master seed is not available in sufficient quantity investigate the inoculum of
lowest passage seed used for production. Use of another passage option shall be justified
. Initial vaccination is carried out using the route of administration
most likely to lead to reversion to virulence.
Carry out the subsequent passage through five groups of target species, if
there is justification to make more passages or the organism
disappears from the test animals sooner. If the organism to replicate
sufficiently performed with many passages can be done in the target
species.

6.4 Biological properties of the vaccine strain

As precisely as possible the determination of intrinsic biological properties of the vaccine strain
(eg. Neurotropism)
may be necessary to conduct further tests.

6.5 Recombination or genomic reassortment of strains

Shall be submitted arguments regarding the likelihood of recombination or
genomic reassortment with field or other strains.

7th Safety for user

This section contains information about the effects found in the preceding sections
and presents this to the type and extent of human exposure to
to the product for the purpose of formulating appropriate warning to the user
and other measures in the field of risk management .

8th Study of residues

For immunological veterinary medicinal products not normally
necessary to carry out a study of residues. However, if the production
immunological veterinary medicinal product used adjuvants or preservatives
, the documentation shall be submitted to assess the possibility
persistence of residues in food. If it is necessary to submit data on
investigation of the effects of such residues.

Proposal for a withdrawal period and its adequacy shall be discussed in relation to all the tests carried out
residues.

9th interaction

If the SPC contained
statement on compatibility with other veterinary immunological products
indicate the information relating to the safety of such a connection. Must be described
any known interactions with veterinary preparations.

C.

STUDY FIELD

Unless justified, results from laboratory studies shall be supplemented
data from studies carried out in field conditions, for these studies are used
batch manufactured in accordance with the manufacturing process described in the application for registration
. These studies carried out in field conditions may
while exploring the safety and efficacy.

D.

RISK ASSESSMENT FOR THE ENVIRONMENT

The purpose of the risk assessment for the environment is to assess the potential
harmful effects which may cause the use of environmentally
environment and to identify any precautionary measures which may be
necessary to reduce such risks.

Such assessment shall normally be conducted in two phases.
The first phase of the assessment shall always be performed. Evaluation is carried out in accordance with the Commission's guidelines and
agencies. This evaluation provides potential exposure
environmental product and the level of risk associated with any such exposure
having particular regard to the following points:

- The target species and the anticipated use

- The method of administration, in particular the likely extent to which the
product will enter directly into environmental

- The possible excretion of the product and its active substances into the environment
environment from treated animals, persistence in such excreta,

- Removal of unusable product or waste product.


In the case of live vaccine strains which may be zoonotic, the
also assess the risk to humans.

If 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 or risks that the veterinary medicinal product might pose to the environment
. If necessary, further investigations
impact of the product (soil, water, air, aquatic systems, non-target organisms
).

E.

ASSESSMENT REQUIRED FOR VETERINARY
products containing genetically modified organisms or GMO CONSISTING


In the case of veterinary medicinal products containing genetically modified organisms
or consisting of genetically modified organisms
must accompany the request documents required under another legal provision
^ 9).

PART 4: EFFICACY TESTS
CHAPTER
I

First General principles

Purpose of the trials described in this Part is to demonstrate or to confirm
efficacy of the immunological veterinary medicinal product.
All claims made by the applicant with regard to the properties, effects and use of
must be fully supported by results of trials contained in the application for registration
.

Second Implementation evaluation

All efficacy trials shall be conducted in accordance with
fully considered detailed protocol, which is recorded in writing prior to commencement of the trial
. The welfare of animals in the assessment
subject to veterinary supervision and be fully taken into account when preparing
any trial protocol and throughout the trial.

Evaluation is carried out according to pre-established systematic written procedures governing
organization, conduct, data collection, documentation and verification of efficacy trials
.

Unless justified assessment must be carried out in field conditions
conducted in accordance with established principles of good clinical practice
,.

Before any field trials
conditions must be obtained and documented informed consent of the owner of the animals that
will be included in the evaluation. The owner of the animals must be in writing, especially
informed of the consequences, which is the inclusion of animals in the trial for the subsequent
between treated animals and for obtaining food from them
. A copy of this notification, signed and dated by the animal owner, shall
be included in the trial documentation.

Unless the trial is conducted field trials conducted with a blind
will be used for the labeling of products
intended for use in veterinary field trials
terms of § 37 of the Act accordingly. In all cases, the packaging must be
prominently and indelibly marked with the words "Only for veterinary evaluation
carried out in field conditions."
CHAPTER II


A. General requirements

First The choice of antigens or vaccine strains shall be justified on the basis of epidemiological data
.

Second Efficacy trials carried out in the laboratory shall be conducted by
controlled trials, including untreated control animals
groups, except in cases where it is not possible for reasons of ensuring
animal welfare, and where possible efficiency
prove otherwise.

General, these laboratory by trials carried out in
field conditions, including untreated control animals
groups.

All trials shall be described in sufficient detail to enable them to be
reproducible in controlled trials conducted at the request
competent authorities. The investigator shall demonstrate that all techniques used
correspond to the purpose for which they are used.

Shall submit a report on all the results obtained, whether favorable or unfavorable
.

Third Efficacy of the immunological veterinary medicinal product shall be demonstrated for all categories
target species for which vaccination is recommended
, each recommended route of administration and using the proposed schedule of administration
. Where necessary, accordingly
evaluate the influence of passively acquired maternal antibodies and efficiency
vaccine. Unless justified, the onset and duration of immunity

Determined having regard to information obtained under evaluation and show the
such data.

Fourth The effectiveness of each component of multivalent (multicomponent) and
combined immunological veterinary medicinal products must be demonstrated
. If the product is recommended for administration in combination with another medicine or veterinary
the same time as another veterinary
preparations must be shown that these products are compatible.

Fifth If the product is included in the vaccination schedule recommended
applicant must demonstrate the effect of the primary vaccination or revaccination or
contribution of the veterinary immunological product to the efficacy of the entire
program.

6th The dose used must match the amount of 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
application for registration.

7th If the SPC stated
claim of compatibility with other immunological products must be investigated
efficiency associated with such connections. Describe the
Any other known interactions with any other veterinary products. Concurrent or simultaneous use
may be allowed if supported by appropriate studies
.

8th For diagnostic immunological veterinary medicinal products
administered to animals, the applicant shall be evaluated as a reaction to medicine
.

9th In the case of vaccines intended to distinguish between vaccinated and infected animals
[marked (marker) vaccine], where the efficacy claim
reliant on in vitro diagnostic tests, to submit sufficient data on the diagnostic tests
allow adequate
assessment of these claims related to the marker properties.

B. Laboratory trials

First Demonstration of efficacy shall be undertaken under well-controlled laboratory conditions
challenge after administration of the immunological veterinary
product to the target animal under the recommended conditions of use.
If possible, the conditions under which the challenge is carried out shall mimic the natural conditions for infection
. Details of the challenge strain and
its suitability for the challenge test. For live vaccines, except
substantiated cases apply batches containing the minimum titre or
effectiveness For other products, unless justified apply
batch with a minimum content of active substance.

Second Whenever possible, they are determined and documented immune
mechanism (cell-mediated / humoral, local / general classes of immunoglobulins
), which is caused due to administration of the immunological veterinary
product to target animals by the recommended route administration.

C. Field trials condition

First Unless justified, results from laboratory trials
complement evaluation data from field trials, with
using batches representative of the manufacturing process described in the application for registration
. The same study carried out in field conditions may
examine safety and efficacy.

Second Where laboratory trials can not be supportive
efficacy, it is possible to recognize only
evaluations carried out in field conditions.

PART 5: PARTICULARS AND DOCUMENTS

A.

Introduction

Documentation regarding the safety and efficacy studies
must include an introduction defining the subject and where they are given tests that were performed
in parts 3 and 4, as well as a summary, along with detailed
The bibliographical references. This summary shall contain an objective discussion
All the results obtained and lead to a conclusion on the safety and efficacy
immunological veterinary medicinal product.
Omission of any tests or trials listed shall be indicated and discussed.

B.
LABORATORY STUDIES


For all studies must include the following information:

First summary,

Second the name of the operator who carried out the studies,

Third a detailed experimental protocol giving a description of
methods, equipment and materials used, details such as species or breed of animals,
categories of animals, where they were obtained, their identification and number,
conditions under which they were housed and fed (stating, inter alia, that

Were free from specific pathogens or specified antibodies,
type and quantity of any additives contained in the feed), dose,
route, schedule and dates of administration, a description and justification of the statistical methods
,

Fourth in the case of control animals, whether they received a
placebo or no treatment,

Fifth in the case of treated animals and where appropriate, whether they received
received the test product or another product authorized in
Community

6th all general and individual observations and results obtained (with
averages and standard deviations), whether favorable or unfavorable.
Data shall be described in sufficient detail to allow the results
critically evaluated independently of their interpretation by the author.
Primary data is presented in tabular form. The explanation and illustration, the results may be
accompanied by reproductions of recordings, photomicrographs, or other appropriate means,

7th the nature, frequency and duration of observed adverse reactions

8th the number of animals withdrawn prematurely from the studies stating the reason or
reasons for their exclusion,

9th Statistical evaluation of the results, if required by the test program, and variance within
acquired data,

10th occurrence and course of any intercurrent disease

11th all details concerning veterinary medicinal products (other than
the product under study), the administration of which was necessary during the study,

12th an objective discussion of the results obtained, leading to conclusions about
safety and efficacy.

C.

STUDY FIELD

Data relating to studies carried out in field conditions must be
sufficiently detailed to enable an objective opinion.
Shall include the following:

First summary,

Second name, address, function and qualifications of the investigator in charge,

Third place and date of administration, identity code that can refer to
name and address of the owner of the animal,

Fourth details of the trial protocol, giving a description of
methods, equipment and materials used, details such as the route of administration, schedule
administration, the dose, the categories of animals, the duration of observation, the serological
response and other investigations carried out on the animals after administration ,

Fifth in the case of control animals, whether they received a
placebo or no treatment,

6th identification of the treated animals and the control animals
(collective or individual), such as species, breeds or
strains, age, weight, sex, physiological status,

7th a brief description of the method of rearing and feeding, stating the nature and quantity
any additives contained in the feed

8th all the particulars on observations, performances and
results (with averages and standard deviation);
if they were carried out tests and measurements on individual animals, shall be
individual data

9th all observations and results of the studies, whether favorable or unfavorable, with a full statement
observations and the results of objective performance tests
required to evaluate the product; shall be used
techniques and explain the significance of any variations in the results,

10th effects on the animals,

11th the number of animals withdrawn prematurely from the studies and reasons for their exclusion
,

12th the nature, frequency and duration of observed adverse reactions

13th occurrence and course of any intercurrent disease

14th all details concerning veterinary medicinal products (other than
the product under study) which have been administered prior to or simultaneously with
test product or during the observation period; details of any interactions observed
,

15th an objective discussion of the results obtained, leading to conclusions on
safety and efficacy.

PART 6: scientific references

A detailed scientific references cited in the summary
mentioned under Part 1 and copies shall be provided.
TITLE III


REQUIREMENTS FOR SPECIFIC APPLICATIONS FOR REGISTRATION

First Generic veterinary preparations

Applications for registration pursuant to § 27 para. 1 of the Act (generic veterinary products
) always contain the information listed in Parts 1 and 2
Title I of this Annex, together with the assessment of risks to the environment and

Data showing that the product has the same qualitative and quantitative composition
active substances and the same pharmaceutical form as the reference medicinal product
, and the data that prove that the product is
bioequivalent to the reference medicine . If
reference veterinary medicine biological medicinal product, demonstrates
to meet the documentation requirements set out in Section 2 for similar biological veterinary products
.

For generic veterinary products the detailed and critical summaries
regarding the safety and efficacy focus in particular on the following requirements
:

- Justification for essential similarity,

- A summary of impurities present in batches of the active substance or active pharmaceutical ingredients, as well as
finished medicinal product (and where relevant
decomposition products arising during storage) as proposed
for use in the product to be on the market, together with an evaluation of these impurities
,

- Evaluation of bio-equivalence studies or a justification why studies were not performed
, with reference to the applicable guidelines

- The applicant should, where appropriate, to demonstrate the equivalence of certain properties
salts, esters or derivatives of an authorized active substance in relation to the safety and efficacy
provide additional details;
these figures include evidence that there is no change in the pharmacokinetic or pharmacodynamic properties of the drug
folder or in toxicity, which could influence
safety and efficacy profile;

Every claim in the summary of product characteristics not known from or inferred from the properties
medicine or therapeutic
groups are discussed in detail in nonclinical or clinical overviews
summaries and demonstrate the links to professional
literature or additional studies.

For generic veterinary products intended for administration
intramuscular, subcutaneous or transdermal routes to submit
following additional information:

- Evidence to demonstrate equivalent or differing depletion of residues from the
administration, which may be demonstrated by appropriate studies depletion
residues

- Evidence to demonstrate target animal tolerance at the administration site, which may be substantiated
corresponding tolerance studies in the target animal
.

Second Similar biological veterinary products

In accordance with § 27 para. 5 of the Act, if a biological veterinary
product which is similar to a reference biological veterinary
product does not meet the conditions in the definition of generic medicinal product
, not information that should be provided, restrict
only parts 1 and 2 (pharmaceutical, chemical and biological data)
supplemented with bio-equivalence and bioavailability.
In such cases, submit supplementary information, in particular on the safety and efficacy
. The nature and amount of additional data (ie.
Toxicological and other safety studies and appropriate clinical studies)
down in each case in accordance with relevant scientific guidelines
.

Because of the diversity of biological veterinary products
Veterinary Institute provides the necessary studies foreseen in Parts 3 and 4
, taking into account the specific characteristics of each individual
biological veterinary medicine.

The general principles to be applied shall be addressed in guideline which receives
agency, taking into account the characteristics of the concerned biological veterinary medicine
. If the reference biological
veterinary product more than one indication, the contention
similar efficacy and safety of the biological veterinary medicine properly
reasons or, if necessary, demonstrated separately for each
indication to which the claim relates.

Third Well-established veterinary use

In the case of veterinary products with the active ingredient or active substances
which have well-established medicinal use, as specified in § 27 para.
7 of the Act, with recognized efficacy and an acceptable level of safety,
the following special rules.

The applicant shall submit Parts 1 and 2 as described in Title I of this Annex.

Parts 3 and 4 of detailed references to scientific literature
affects all aspects of safety and efficacy.


To demonstrate the well-established veterinary use shall
following specific rules:

03.01 To establish a well-established veterinary medicinal use of constituents of veterinary medicines
into account the following factors:

A) the period for which the drug is used;

B) quantitative aspects of the use of the active substance;

C) the degree of scientific interest in the use of the active substance (reflected in the published scientific
scientific literature);

D) the coherence of scientific assessments.

For establishing well-established use may be different for different substances needed
different time period. In all cases, however
time required for establishing well-established veterinary medicinal use of constituents
medicinal product must not be less than ten years since the first
systematic and documented use of that substance as a veterinary
product in the Community.

03.02 The documentation submitted by the applicant always affects all aspects
evaluation of the safety and efficacy of the product for the proposed indication in
target species using the proposed route of administration and dosage regime
. It must include or refer to a review of the relevant literature
, taking into account pre- and post-marketing studies and published scientific literature
experience in the form
epidemiological studies and in particular of comparative epidemiological studies
. Must be submitted all documentation, both favorable and unfavorable.
With regard to the provisions on well-established veterinary use, it is
particular necessary to clarify that bibliographic reference to other sources
evidence (post-marketing studies, epidemiological studies etc.) and not just
data related to tests and trials they can serve as a valid proof
safety and efficacy of a product if an application satisfactorily
explains and justifies the use of these sources of information.

03.03 Special attention is always devoted to any missing information
and justify why demonstration of an acceptable level of safety or efficacy
although some studies are lacking.

3.4 detailed and critical summaries on safety and efficacy
must clarify the meaning of any data submitted which relate to
product different from the product intended for marketing.
Must be examined whether the product studied can be considered as similar
product, or not, for which it has been prepared an application for registration
spite of the existing differences.

3.5 Particularly important are post-marketing experience with other products containing the same constituents
. On this question applicants shall put a special emphasis
.

Fourth Veterinary products with a fixed combination drugs

For applications based on § 27 para. 8 of the Act for veterinary preparations
fixed combination products submitted registration dossiers
containing Parts 1, 2, 3 and 4. It is not necessary to provide studies on the
safety and effectiveness of each active substance. However, it is possible
include information on individual substances in the application for a fixed combination
. The submission of data on each individual active substance, in conjunction with
required user safety studies, residue depletion studies and
clinical studies on the fixed combination product may be
considered a suitable justification for omitting data on the combination
product, due to animal welfare and
unnecessary testing on animals, unless there is suspected interaction leading to added toxicity
. Where appropriate, submit the information
regarding the manufacturing sites and the safety evaluation of adventitious agents.

Fifth Informed consent applications

Applications based on § 27 para. 9 of the Act shall always include details
listed in Part 1 of Title I of this Annex, provided that the marketing authorization holder for the original veterinary
product has given the applicant his consent to make a link
the content of parts 2, 3 and 4 of the dossier of that product
. In this case, they do not provide a detailed and critical summaries
relating to quality, safety and efficacy.

6th Documentation for applications in exceptional circumstances

Marketing authorization may be granted subject to certain specific obligations
requiring the applicant to introduce specific procedures, particularly with

Respect to safety and efficacy of the veterinary product, when, as
specified in § 32 par. 3 of the Act, the applicant can show that he is unable
provide comprehensive data on the efficacy and safety under normal circumstances
usage.

The essential requirements for all applications mentioned in this section are
set out in the Commission's guidelines and agencies.

7th Mixed marketing authorization applications

Mixed marketing authorization applications are applications where Part 3 or 4
dossier consist of safety and efficacy studies
made by the applicant as well as bibliographical references.

All other parts are in accordance with the structure described in Part I
Title I of this Annex. Veterinary Institute will examine separately for each
submitted a registration dossier whether the format presented by the applicant
considered sufficient for evaluation.
TITLE IV


REQUIREMENTS FOR REGISTRATION APPLICATIONS FOR PARTICULAR VETERINARY PRODUCTS

This part lays down specific requirements for identified veterinary
products related to the nature of the active substances contained in them.

First
Immunological veterinary products


A.

BASIC files and vaccine antigen

For certain immunological veterinary medicinal products and by derogation from the provisions
Title II, Part 2 Section C on active substances introduced the concept
basic document of vaccine antigen.

For the purposes of this Annex, a Vaccine Antigen Master File
means a separate part of the application dossier for registration
vaccine ingredient, which contains all relevant information on quality concerning each of
drugs that are part of the relevant
veterinary medicine. A separate part may be common to one or more
monovalent or multivalent vaccines presented by the same applicant
authorization.

Scientific guidelines for the submission and evaluation of a vaccine antigen
agency receives. The submission and evaluation
a vaccine antigen master is performed according to guidelines published by the Commission in
rules governing medicinal products in the European Union, Volume 6B,
Guidelines for Applicants.

B.
MULTI-STRAIN DOSSIER


For certain immunological veterinary medicinal products (foot-and-mouth disease,
avian influenza and bluetongue) and
derogation from the provisions of Title II, Part 2 Section C on active substances introduced the concept of the use
registration dossier for more strains. A multi-strain
registration dossier means a single dossier containing the relevant data for
unique and thorough scientific assessment of different options of strains
or a combination thereof, based on permitting the authorization of vaccines
agents against antigenically variable viruses.

Scientific guidelines for the submission and evaluation documentation for more
tribes adopted by the Agency. Submission and evaluation
multi-strain dossiers is done according to guidelines published by the Commission in
rules governing medicinal products in the European Union, Volume 6B, Notice to Applicants
.

Second


HOMEOPATHIC VETERINARY PRODUCTS
This section sets out specific provisions for the use of Title I, Parts 2 and 3
for homeopathic veterinary products as defined in § 2 para. 2
point. g) of the Act.

To Part 2

The documentation submitted in accordance with § 29 para. 2 of the Act when
simplified registration of homeopathic veterinary products
mentioned in § 29 para. 1 of the Act as well as documentation for
authorization of other homeopathic veterinary products,
which are not subject to the simplified registration procedure pursuant to § 29 para. 1
provisions of part 2 with the following modifications.

A) Terminology (terminology)

Latin name of the homeopathic stock described in the documentation
application for registration shall be in accordance with the Latin title of the European
Pharmacopoeia or, failing this, an official pharmacopoeia of a Member State.
Optionally provides a traditional name or names used in traditional
each Member State.

B) Control of starting materials

Data and documents on the starting materials, ie.
All the materials used including raw materials and intermediates up to the final dilution to be incorporated into
finished homeopathic veterinary medicine, which are
submitted with the application, shall be supplemented by additional data on the homeopathic substance
.


For all starting materials that are incorporated into the finished homeopathic product
apply general quality requirements, as well as
for the intermediate steps of the manufacturing process up to the final dilution. If
toxic component is present, this should be checked at
component of the final dilution. If this is not possible because of the high
dilution, the toxic component shall normally be controlled at an earlier stage
. Every step of the manufacturing process from raw materials to final
dilutions, which are processed into the finished product is accurate description.

In case dilutions are involved, the steps performed by diluting always
homeopathic manufacturing methods laid down in the relevant article
European Pharmacopoeia or, failing this, in an official pharmacopoeia of a Member State
.

C) Control tests on the finished medicinal product

The homeopathic finished veterinary products are subject to general
quality requirements. Any exception shall be duly substantiated
.

It is always the identification and assay of all the toxicologically relevant constituents
. If it can be justified that an identification or determination
all the toxicologically relevant constituents is not possible, for example
due to their dilution in the finished medicinal product the quality shall be demonstrated
complete validation of the manufacturing process and the process of dilution.

D) Stability tests

Always demonstrate the stability of the finished product.
Stability data from the homeopathic stocks are generally transferable to
dilution / potentiation derived therefrom. If no identification or
determination of the active substance for the degree of dilution, may be taken into account
stability data of the pharmaceutical form.

A Part 3

The provisions of Part 3 shall apply to the simplified registration
homeopathic veterinary products referred to in § 29 para. 1 of the Act with
following specification, without prejudice to the provisions of Regulation
European Parliament and Council Regulation (EC) No. 470/2009 laying down
Community procedures for the establishment of residue limits of pharmacologically
active substances in foodstuffs of animal origin, repealing
Council Regulation (EEC) No 2377/90. and amending Directive of the European | || Parliament and Council Directive 2001/82 / EC of the European Parliament and the Council.
726/2004, for substances included in the homeopathic stocks intended for administration
animal species destined for food production.

Any missing information will always justify such a justification as to why
may be recognized as evidence of an acceptable level of safety, even though
some studies are lacking.
TITLE V


REQUIREMENTS FOR CONTENT AND DIVISION OF DATA AND DOCUMENTATION TO REQUEST
layup for simplified registration veterinary homeopathic products

The application for a simplified registration of homeopathic veterinary
products shall be accompanied by the information and documents proving particularly
pharmaceutical quality and homogeneity of the batches of the product concerned.

Shall be accompanied always at least:

First Administrative data, which include:

- Preparation,

- Marking basic substance or substances indicating the name or scientific name
monograph basic substance

- Degree or degree of dilution

- The method and route of administration

- Target species,

- Pack size, type of packaging,

- Business name and address of the registrant, if it is a legal
person, or name, surname and place of business of the applicant for registration
in the case of a natural person, and the same data
manufacturers or products do not conform if a person is a registrant

- The number and names of the individual volumes of documentation, characterization
submitted samples

- Putting all production sites and for each production site stating
manufacturing operations, which are conducted as proof that the manufacturer is
holds a valid permit to manufacture veterinary medicines in
relevant scope || |
- The list of countries where the product is registered or where his
registration is requested, including copies of all marketing authorizations or other permits
marketing, and a list of countries where the application was
Marketing Authorisation is refused or withdrawn for safety reasons
product

- One or more specimens or design of internal and external sales
product packaging.


Second Documentation containing information about the method of manufacture and control basic
substance or substances and documenting data on the homeopathic nature of the basic
substance or substances with reference to scientific literature; if
immunological homeopathic veterinary medicinal products containing biological substances
Furthermore, a description of measures to ensure
absence of pathogenic organisms in the product.

Third Manufacturing and control file for each pharmaceutical form and a description
method of dilution and potentiation.

Fourth Data demonstrating the stability of the product.

Fifth Proposed withdrawal period
TITLE VI


LIABILITY professionals involved in the compilation of DOCUMENTATION


Particulars and documents accompanying applications for marketing authorizations are
before submitting Veterinary Institute drafted by experts with the necessary
technical or professional qualifications.

According to their particular qualifications, the role of experts:

A) carry out such activity that falls within their specialty
(analytical activity, pharmacology and similar experimental sciences,
clinical trials) and to describe objectively the results obtained
qualitative and quantitative manner;

B) to describe their observations in accordance with this Annex and put

First in the case of analysts, whether the veterinary medicinal product conforms with the stated
composition, giving any substantiation of the control methods employed by the manufacturer

Second in the case of pharmacologists and appropriately qualified specialists
toxicity of the veterinary medicinal product and the pharmacological properties observed
and whether, after administration of the veterinary medicinal product under normal conditions
use and observance of the recommended withdrawal period, foodstuffs obtained from
treated animals contain residues which might constitute
risk to consumer health

Third in the case of clinicians, whether in animals treated with veterinary
product effects corresponding to the information furnished by the manufacturer
according to § 27 of the Act, veterinary medicine seem to be well tolerated, what dosage
proposed and what are the contraindications and possible side effects;

C) to provide justification for the possible use of references to published data
according to § 27 para. 12 of the Act.
TITLE VII


CONDITIONS UNDER WHICH CAN DETERMINE THE VETERINARY product is intended for
animals from which are derived ANIMAL PRODUCTS FOR HUMAN NUTRITION
, may be dispensed without a prescription

(1) for the medicinal product intended for animals from which they are derived
animal products for human nutrition, can decide that it
may be dispensed without a prescription, if all
following conditions:

A) administering veterinary medicinal product does not require any special knowledge or skills
,

B) veterinary product does not constitute a direct or indirect risk
animal or animals treated, to the person administering the product or to the environment
environment, even when used incorrectly;

C) the summary of the veterinary product does not contain warnings about possible
serious side effects that may arise as a result of his
proper use

D) present veterinary medicine or other
veterinary product containing the same active ingredient has not been the subject of frequent
submission of reports on serious adverse events

E) the summary of product characteristics does not contraindications related to other
commonly used veterinary medicinal products whose dispensing is not tied to
prescription

F) no specific conditions for storage
veterinary medicine,

G) veterinary product does not present a risk to the safety of consumer
regarding medicinal residues or excipients contained in the formulation
in foods derived from animals which were
such a product is used, even in the event of improper use

H) veterinary products pose a risk to public health or animal health
with regard to the development of resistance to antimicrobial agents
or anthelmintic, even in the event of improper use.
TITLE VIII


REQUIREMENTS coloring agents used in veterinary preparations

First In veterinary preparations can only use dyes that are
allowed in foods which are included in another legal regulation
^ 13e).


Second The applicant shall demonstrate that the dye used in veterinary preparations
meet the requirements for the identity and purity in accordance with another legal regulation
^ 13b).

Third For testing the identity and purity of dyes used in veterinary preparations
applicant uses methods and procedures specified in another legal regulation
^ 13f). ".

13a) Decree no. 4/2008 Coll., Laying down the types and conditions of use
additives and extraction solvents in food production.

13b) Annex no. 1 of Decree no. 54/2002 Coll., Laying down
health requirements for the identity and purity of additives, as amended
regulations.

13c) Decree no. 86/2008 Coll., On the principles of good laboratory practice
in pharmaceuticals.

13d) Decree no. 356/2004 Coll., On monitoring (monitoring)
zoonoses and zoonotic agents and amending Decree no. 299/2003 Coll., On measures for
prevention and control of diseases and communicable diseases from animals to humans.

13e) Annex no. 4 of Decree no. 4/2008 Coll., Laying down the types and conditions of use
additives and extraction solvents in the manufacture
food.

13f) Decree no. 211/2004 Coll., On methods of analysis and sampling and preparation
control samples, as amended.

9th In Annex no. 5, Part A, Section 7 reads:

'7. The outer packaging include information on the method of dispensing or sale
product, and these words: "Medicinal product subject to medical prescription
" or "Medicinal product not subject to medical prescription
" or "Medicinal preparation possible without a medical prescription
restricted "or" medicine is classified as reserved
medicines ".".

Art. II


Transitional provisions
Administrative proceedings commenced before the effective date of this Decree
completed under the current legislation.

Art. III
Efficiency


This Decree shall take effect on the 15th day after its publication.
Health Minister
:

Mgr. Jurásková, Ph.D., MBA vr
Agriculture Minister
:

Ing. Sebesta vr