228/2008 Sb.
DECREE
of 23 December 2003. June 2008
for registration of medicinal products
Change: 13/2010 Sb.
Change: 171/2010 Sb.
Change: 255/Sb.
The Ministry of health and Ministry of agriculture lays down pursuant to §
paragraph 114. 2 and to implement section 2 (2). 2 (a). (c)), § 8 para. 5, § 26 para.
5 (b). l), § 26 para. 7, section 27 para. 5, 7, 11 and 12, § 28 para. 1 (b).
(c)), § 28 para. 3, § 29 para. 2, § 30 paragraph 2. 3 and 7, § 32 para. 3, § 33
paragraph. 3 (b). g) in point 4, § 34 paragraph 1. 1 and 3, § 35 para. 2, 3 and 12, § 36
paragraph. 1, § 37 para. 1 to 3, 5 and 6, § 38, § 40 paragraph 2. 2 (a). (f)), section 40
paragraph. 3, § 44 para. 3 and 9 (b). (f)), § 45 para. 7 (b). (b)), § 49 para.
5, section 91 paragraph 2. 2 (a). (b)) and § 92 para. 11 and 12 of law No 378/2007 Coll.
pharmaceuticals and on amendments to certain related laws (law on medicinal products):
§ 1
Introductory provisions
(1) this Decree incorporates the relevant provisions of the European
Community ^ 1) and modifies the authorisation of medicinal products, its changes,
extension, transfer the registration to take registration, issuance of permits
for parallel imports, presenting and designing specific treatment
programs with the use of unregistered medicinal products for
the method of notification and assessment of the adverse effects of the
of the product, including the requirements of the psur
security, and the type and extent of the notification of the prescription or use of the
an unauthorised medicinal product, Essentials reporting
the person responsible for pharmacovigilance, information about filing method
non-Interventional study in the Czech Republic and on its completion, more
storage conditions of the documentation including the scope, and lays down the rules
for determining the extent of information provided from the pharmacovigilance
the system.
(2) For the purposes of this Ordinance, means the
a) vaccines, toxins and Sera, of which consist of human
immunological medicinal products pursuant to § 2 (2). 2 (a). (c)) of the
pharmaceuticals:
1. vaccines used to produce active immunity, such as diphtheria,
tetanus and pertussis, against communicable polio, viral hepatitis
And, viral hepatitis B, cholera, tuberculosis (BCG), against smallpox,
2. products used to produce passive immunity, such as diphtheria antitoxin
anti-smallpox globulin, antilymphocytic globulin,
3. products used to verify the State of immunity, in particular tuberculin and
tuberculin PPD, toxins for the Schick and Dick tests, brucellin,
b) allergen product any product for human use that is specified by the
to identify or induce a specific acquired alteration in the immunological response to
an allergizing agent,
(c)) the new active substance, the active substance which is:
1. chemical or biological nature or the nature of radiopharmaceuticals, and is not
not yet included in any of the registered in the framework of the European
Community (hereinafter referred to as "the community"),
2. an isomer, mixtures of isomers, complex, derivative or salt of a chemical
having different characteristics with regard to the safety and efficacy of the
chemical substances contained in the medicinal product is already authorised in the framework of the
The community,
3. biological substance, having different molecular structure, origin of
sources of raw materials or method of manufacture of biological substances that are contained in the
the product already authorised within the community, or
4. the nature of radiopharmaceuticals and radionuclide or carrier is not yet
neobsaženým in any of the product already authorised within the community,
or is a coupling mechanism of the radionuclide in the molecule, which has not yet
has not been used in any of the registered within the community,
d) biological substance a substance that is produced by or extracted from the
biological resources and to whose characterization and determination of its quality is
required a combination of physical, chemical and biological tests and data
about the production process and its control
e) biological medicinal product, the active substance is
a biological substance; as a result, biological medicinal products
especially consider immunological medicinal products, blood products,
medicinal products falling within the scope of the regulation laid down
The community governing the Community procedures for the authorisation and supervision
of medicinal products ^ 2) and preparations for advanced therapy medicinal products as defined in
part IV of the annex 1 of this order.
§ 2
Specific treatment programs utilizing in the Czech Republic
unregistered medicinal products for human
(1) the design of the specific Content of the treatment program (hereinafter referred to as "treatment
the program ") are in addition to the particulars provided for by the law on pharmaceuticals
and) business name and registered office of promoter, in the case of a legal person,
or the name or names, last name and place of business if the
a natural person,
(b)) justification of the treatment program; justification the fact that the subject of the
the treatment program is a treatment, prevention or diagnosis of a rare
disease or other extraordinary need and it is the States
seriously threatening human health; for the State is seriously threatening human
health is seen as a condition that can cause death, endanger the life,
requires inpatient hospitalisation or prolongation of existing hospitalisation, may
result in persistent or significant disability or health restrictions
skills; other procedures shall be given the treatment, prevention or diagnosis
attributable in this case into account,
(c) the name of the product,) to be used in a treatment program,
including an indication of the content of active substances, the size and number of packages and
information about whether the human medicine is registered abroad; If it is in
foreign registered, enter the country, year of registration, the holder of the
of the marketing authorisation and the registration number,
(d)) of the human pharmaceutical particulars of the product in the range
the corresponding registration status; in the case of medicinal products for human use
registered in one State of the community or a State, with which it was
concluded an international agreement ^ 3), the pharmaceutical particulars do not produce,
at the same time, if the content of the proposal summary of the treatment program
product referred to in subparagraph (f)); in other cases, are submitted to the
pharmaceutical particulars in the extent that the application for authorization or
the announcement of the clinical trial under another law ^ 4); or
It is possible to replace the proof of these data quality checks according to § 62
paragraph. 1 of the law on pharmaceuticals,
e) proof that the manufacturer will ensure humane medicine for treatment
the program, if the submitter is not the manufacturer of the treatment program
of the product,
f) preclinical and clinical data on human medicine in the range
corresponding to the IB to be produced for
the application for authorisation of a clinical trial ^ 4); in the case of human
products registered abroad, these data can be used to replace text
Summary of product characteristics amended text approved by the competent
authority of the State in which the product is authorised for human use,
g) plan the treatment program defining the target group of people, indications,
limit for inclusion in the program, how to use humane medicine
including the dosage, the duration of the treatment program,
h) way to distribute, and the identification data of the person providing the ^ 5)
the distribution of a product; These data are a trading company and
the seat of this person, in the case of a legal person, or the name or
name, surname and place of business of such person, in the case of a natural person;
If the submitter of the treatment program is not a distributor, the
proof that the distributor is informed and agrees with the provision
distribution within the treatment program
Even picking the humane) way of preparation,
j) way of monitoring and evaluation of safety and efficacy
humane medicine,
k) information for the patient in the Czech language of the corresponding, mutatis mutandis,
information designated bodies of a clinical trial, where appropriate, the package insert
information of the product,
l) ^ 5) identification data of the person providing control during treatment
the programme and details of the inspection intervals and how the
documentation,
m), whether the start of a treatment program is considered to be
urgent,
n) proof of implementation of the refund of expenditure an assessment. If it is not
the submitter of the proposal of the treatment program the manufacturer, distributor or
the marketing authorisation holder of one of the product and, in the case
about the treatment program, the implementation of which is in the public interest or that may
have significant consequences for the wider group of persons, shall provide to the Department of the
request the petitioner in the Assembly of the data referred to in points (c))
and (d)) to the extent of the information available to him.
(2) the Institute shall formulate an opinion, which shall transmit to the Ministry of health
(hereinafter referred to as "the Ministry"). The Ministry, taking into account this
opinion, shall issue a written consent to the carrying out of the treatment program, or
the proposal shall take account, where appropriate, refuse the need for urgent opening
the treatment program. The result of the assessment, the Ministry shall notify the petitioner
and the Institute, which in the case of the consent shall allocate to human medicine
the code, in the case of humane medicine subject to registration.
(3) treatment program, to which consent has been granted, shall be published
the following information:
and the name of the product), its pharmaceutical form, qualitative and
the quantitative content of the active substances in human medicine, the size of the
packaging, manufacturer, marketing authorisation holder as appropriate in the other country,
Distributor or a person importing human medicine from third countries,
(b)) the name or name, last name and business address of the petitioner,
in the case of a natural person or business name and address, in the case of
the legal entity,
(c)) the objective of the treatment program and the period of validity of the consent.
§ 3
The particulars and documents requests
(1) applications and other documents to be submitted to the Institute, in the case of human
products, or Veterinary Institute, in the case of veterinary medicinal products,
must be submitted in electronic format, if in the Special
cases, not with the Institute, in the case of medicinal products for human use or with
The animal health Institute, in the case of veterinary medicinal products, unless otherwise agreed.
In the processing of applications and other documents in electronic form in
the case of the medicinal products for human use uses the electronic format of the eCTD or
Nees ^ 19) according to the instructions of the Institute; This format is used for information and
report submitted pursuant to this order in electronic form. In
the case of veterinary medicinal products shall apply the electronic format
VNees, unless in special cases with the Veterinary Institute agreed
otherwise.
(2) in the application, in addition to the information provided for by the law on pharmaceuticals presents
and) business name and registered office of the legal person, or the name or names,
last name and place of business of a natural person, if that person request
under the authority of the applicant,
(b) proposal for how to supply the product), in the case of an application for registration or
a variation on how to supply the product,
(c) the registration number of the product), in the case of a request for change, renewal,
transfer or cancellation of the registration.
(3) if the application is lodged by the person authorized by the applicant, this shall be documented
the fact the authorization with the signature of the principal.
(4) applications shall be accompanied by proof of payment of the administrative fee, and
proof of implementation of the refund of expenditure on the examination of the application
a form containing all information enabling the identification of the payment. The applicant is an
an applicant for a reduction or waiver of reimbursement of expenditure, shall describe the facts
that would justify such a procedure.
(5) the completed application form shall be submitted in electronic form in
format detailed by the competent institution in a manner allowing remote
access. If you are part of the design of indications on the packaging also details
the leaflet does not require the presentation of a separate proposal
leaflet. In the case of applications in the context of the mutual recognition of
marketing authorisations by the Member States pursuant to section 41 of the law on pharmaceuticals, the Czech proposals
Summary of product characteristics, the indications on the packaging, package
information and designs all the internal and external packaging in which it is to be
product is placed on the market, including the colorful graphics editing, shall submit to the
not later than 5 days after the conclusion of the procedure pursuant to § 41 para. 4 of the law on
pharmaceuticals.
(6) in the cases referred to in § 38 of the law on medicinal products shall be considered as
and) a registration or request a change in labelling
the product, in which the applicant has expressed interest in placing the information on the package in the
other than the English language, it is a product, the issue is the decision to
registration subject to medical prescription, and
1. the product is intended to treat serious diseases and for use in the
delivery of health care under the supervision of a physician, including treatment for the patient and
outside of a medical facility, if it is a humane medicine
2. the frequency of occurrence of the disease we can deduce that the number of packages on the market
does not exceed 5000 units per year, in the case of humane medicine
3. availability of the product in the Czech Republic is significant with regard to the
the protection of animal health, public health, protection of the environment
or to ensure the well-being of the animals, in the case of veterinary medicinal product placed on the
market in quantities not exceeding 1000 packing per year
4. design of the markings on the outer packaging of the applicant shall submit, in English,
the German or English language and
5. is not registered or is not placed on the market with equivalent
packaging marked in Czech language
6. on the outer packaging or on the immediate packaging, if the outer package
There is, in an appropriate manner followed by the registration number in the United
Republic and in the form of European commodity bar code EAN Code (hereinafter referred to as
"the European code"), in the case of human medicine; in the case of veterinary
products, the European code on the package indicate
(b) allow placing requests) for each batch of the product into circulation,
If the data indicated on the label in a language other than English, if the
1. it is a product, the issue is bound to the terms of the marketing
medical prescription,
2. is not registered or placed on the market the equivalent product with packaging
identified in the Czech language
3. number of packages of the product corresponds to the need for a lot of instant solutions
lack of product characteristics, for which the labelling is in Czech language
4. in the event of unavailability of the product should
immediately serious consequences for public health, or in the case of
veterinary medicinal product for health and welfare, public health, or
for the environment,
5. a lot of the product was released to the market in the State of the community,
6. the basic data, which is the product name, strength, dosage
form, active substance, the marketing authorisation holder, method of preservation
and shelf life, the comply with the conditions of registration in the Czech Republic
and can be from a text in a foreign language to derive or are on the packaging in the Czech
languages added,
7. each container is equipped with an approved a package leaflet in Czech
the language that comes along with each individual packaging of the product. If
in exceptional cases, this information will not be inserted into the outer
the packaging must be inseparably attached externally, or shall be, in the case of
humane medicine, otherwise, to ensure that the information they receive
the patient,
8. on the outer packaging or on the immediate packaging, if the outer package
There is, in an appropriate manner, such as through the band's
or stickers added in the form of a bar code, different from the European code
commodity code applicable to the approved packaging of the product and the registration
the number of the product in the Czech Republic, in the case of human medicine; in
the case of veterinary medicinal products, the European code on the package can be stated and
9. the layout of the cover is similar to the adjustment of the packaging placed on the market in
The Czech Republic.
(7) the conditions referred to in paragraph 6 (b). a) points 2 and 3 demonstrates
the registrant or a variation of the projected balance sheet
annual consumption, consumption of products authorised for the previous years.
In the case of subsequent consumption higher than 5000 pieces of packaging per year, in the case of
humane medicine, or 1000 pieces of packaging per year, in the case of animal health
product, the marketing authorisation holder shall submit a request for change
registration for the purpose of labelling in the Czech language. Changes
the registration referred to in paragraph 6 shall be construed as a change in labelling
of non-summary of product characteristics in accordance with § 35 para.
5 of the law on medicinal products. Compliance with the conditions referred to in paragraph 6 (b). a) points 1,
4 and 5, and pursuant to paragraph 6 (b). (b) the applicant shall be documented in the application) and its
the annexes.
(8) procedures for each type of application or a notice drawn up in accordance with
the guidelines issued by the authorities of the community, including all necessary supporting documentation, and
the forms shall be published by the Institute in a manner allowing remote access and
or even in the State Institute for drug control, and are
provided in the Constitution, as regards requests and notifications relating to human
preparations. In the case of applications and notifications relating to animal health
preparations, the first sentence shall be, mutatis mutandis, and the information is
publish, where appropriate, in the journal of the Institute for State control
Veterinary Biologicals and medicaments and are available in the health
of the Institute.
(9) when compiling and submission of the registration dossier, applicants for
registration of the account of the guidelines, which the Institute issued in accordance with the instructions
issued by the Community authorities.
§ 4
Application for registration of
Range of data submitted in the application for marketing authorisation and the
accompanying documentation shall be determined depending on the specific nature of the
the request; those requests are:
and) request, which is evidenced by a documents in the whole range of requirements
pursuant to section 26 paragraph 1. 5 of the law on pharmaceuticals and annexes 1 to 5 of this order
(hereinafter referred to as "the application"); in this type of requests include requests
registration for additional formulations for more power or additional route of administration
the product is already registered on the basis of a separate application; a separate
applications is also an application for registration of the product based on the well established
the therapeutic use of substances contained in the product under § 27 para.
7 of the law on medicinal products (hereinafter referred to as "literary") and the application for registration
with the consent of the holder of the marketing authorisation with the use of
pharmaceutical, pre-clinical and clinical data already registered
product characteristics pursuant to § 27 para. 9 of the law on medicinal products (hereinafter referred to as "the application shall
consent of the holder "),
(b) the application for registration) product containing active substances, which are
components of authorised medicinal products but not hitherto in
The community used in combination for therapeutic purposes, in accordance with section 27 of the
paragraph. 8 (hereinafter referred to as "request for fixed dose combination"),
(c)) the request using the reference to the results of the pharmacological and
toxicological tests, the results of clinical trials, and in the case of
veterinary medicinal product safety tests on the residue already submitted
in the context of another registration procedures to other holder of
registration
1. in accordance with section 27 para. 1 of the law on pharmaceuticals, provided that it is
Generics under § 25 para. 4 (b). (b)) of the law on pharmaceuticals, or
2. in accordance with section 27 para. 4 of the law on medicinal products, if the product
does not match the definition of generic medicinal products in accordance with § 25 para. 4 (b). (b)) of the
medicines, or if you cannot demonstrate bio-equivalence studies biological
the availability or, in the case of changes to the active substance or substances,
therapeutic indications, strength, pharmaceutical form or route of administration compared with
the reference medicinal product, or
3. in accordance with section 27 para. 5 of the law on pharmaceuticals, provided that it is
similar biological medicinal product; in the case of this application, the time limit must be 8 years of age,
or 6 years under § 27 para. 1 of the law on pharmaceuticals and, in the case of
veterinary medicine, or 13 years of age provided for in § 27 para. 1
the law on pharmaceuticals to pass by the date of submission of the application,
d) application for simplified procedure for the registration of homeopathic medicine, in
which does not require the proof of therapeutic efficacy (hereinafter referred to as "request
simplified registration of homeopathic medicinal product ") under section 28 or 29
the law on pharmaceuticals; This request can be made only for products for which the
a sufficient degree of dilution ensures the safety of the product; medicine
must not contain more than one part per 10000 of the mother tincture tinctures or in 10,
If it is a humane medicine, more than 1/100th of the smallest dose
used in allopathy with regard to active principles whose presence in
an allopathic medicinal product results in the need for submission of medical
Regulation; a homeopathic medicinal product may contain multiple folders,
e) application for registration of traditional herbal medicinal product under
section 30 of the law on pharmaceuticals,
(f) a request for registration of the specific) for a homeopathic medicine
under section 28a of the law on medicinal products.
Documentation submitted with the application for the authorisation of products
§ 5
(1) the content and structure of the data and documentation to be submitted with the application for
the authorisation of a medicinal product are listed in the annexes 1, 3 and 5
of this order. The scope of the documentation to be submitted with the application corresponds to the
knowledge of humane medicine, its nature, therapeutic benefit
It brings, and the risks associated with its use.
(2) an application for the authorisation of a medicinal product must contain all the
information relating to the evaluation of a product, regardless,
product for human use are favourable or unfavourable. They must in particular
be listed all the relevant details of any incomplete or
the abandoned pharmacotoxicological or clinical
reviews relating to human medicine, and completed
the clinical trial, which relates to the therapeutic indications other than those referred to in
request. I shall be a comparative study with other products or other
treatment and non-interventional studies, where available.
(3) if it is a part of the documentation relating to the quality (chemical,
pharmaceutical and biological information), are applicable to all
monographs including General monographs and General chapters of the European
pharmacopoeia under section 11 (b). (c)) of the law on medicinal products. Under the terms of
in annex 1 of this order may be submitted by a certificate of conformity with the European
of suitability issued by the European Directorate for the quality of medicines that
is replaced by the annex set out in this section of the documentation.
(4) a separate application shall be accompanied by complete documentation that sets out
Annex 1 of this order. In the case of literary requests when
proof of a well-established medicinal use shall apply the rules laid down
in annex 1 of this Ordinance, part II, point 1. The application shall be accompanied by (i)
the appropriate professional literature. In the case of an application with the consent of the holder of the
This consent shall be documented with the signing of the Declaration. The holder must have permanent
access to documentation or it must possess. Informed consent is
apply to all modules, so it is only possible for identical human
medicine.
(5) in respect of applications under section 4 (b). (c)) shall be submitted to the data referred to in annex No.
1 of this Decree, modules 1, 2 and 3 and the relevant part of the other
modules, documenting and justifying the failure to present the results of pre-clinical
tests and clinical trials. Furthermore, it shall submit appropriate documentation
to assess those aspects of the safety and efficacy of the product,
that are not included in the documentation to which the reference is made; the similarity of the
for a product for which registration is applied for, because of the human
the product, to which reference is made, for example, the card must be produced
bioequivalence or pharmacodynamic or therapeutic equivalence. In
the case of applications under section 4 (b). (c)) must the proposed summary of product
the product match the current summary of product characteristics, for which the
referenced. Shall be submitted to the final form of the summary of proposal
of the product, so the text is highlighted against the current check-in summary
Summary of product characteristics, for which the reference is made, in both written and electronic
form. Any deviation of the proposed summary of product characteristics from the
the current summary of product characteristics to justify including information
relating to indications or dosage forms which will be at the time of entry
generics on the market covered by patent law.
(6) in the case of similar biological medicinal products
do not meet the conditions of the definition of generic medicinal products in accordance with § 25 para. 4 (b). (b)) of the Act
on pharmaceuticals, for example, due to differences relating to raw materials or differences in
procedures for the production of such a biological medicinal product and the
the reference biological medicinal product, the following must be submitted
results of the appropriate pre-clinical tests or clinical trials
about these terms. Type and quantity of additional information which
to be submitted, shall be in accordance with the relevant criteria
established by other legislation ^ 4) and the relevant guidelines of the European
the Commission (hereinafter referred to as "the Commission"), the European Medicines Agency (hereinafter referred to as
"the Agency") and indicating the directions of the Institute. If there is a suitable reference
product is authorised in the Czech Republic, not to refer to the
the medicinal product authorised in another Member State. European reference
It is used only in the event that suitable reference product
It is not or has not been registered in the Czech Republic. Enter the information about the
the country of origin of the European reference product and in which
the participating States is applied.
(7) with a request for simplified registration of homeopathic
of the summary of product characteristics they do not produce, the clinical summary and
Clinical overview of module 2 and module 5 in part I of the annex No. 1 of this
the Decree. Module 5 is replaced with the documentation justifying the homeopathic
the basic use of the substance or substances on the basis of the relevant
the bibliography. When it comes to modules 3 and 4, shall be submitted
information referred to in part III, section 3 of annex 1 of this order.
(8) an application for authorization of a traditional herbal medicinal product is
submit documentation according to annex No 1 of this order. The draft summary
Summary of product characteristics in accordance with Annex No 3 of this Decree in the case of a traditional
the herbal medicinal product does not contain a point 5-Pharmacology
the properties of the.
(9) The application for authorisation of a specific homeopathic
a medicinal product authorised under section 28a of the law on pharmaceuticals,
submit the documentation referred to in annex 1 to this notice. In module 3
under part I of the annex 1 to this notice shall be submitted to the data referred to in
Part III, section 3 of annex 1 to this notice.
§ 6
(1) include dedicated human medicinal products can be
a) Medicinal teas and medicinal tea mixtures, with the exception of Medicinal teas and
medicinal tea blends that contain strongly or very strongly effective
substance,
(b) preparations for human use, multivitamin) if their recommended daily
the batch does not contain more than 3333 units of vitamin A or more than 400
units of vitamin D; part of such medicinal products for human use may be
mineral substances,
c) adsorption antidiarrhoika containing activated carbon, if one Pack
humane medicine contains the most 20 units of a pharmaceutical form
d) containing teoklan moxastinia in antiemetics the highest quantity of 25
milligrams per unit dosage forms, and if one pack of human
the product contains more than 20 units of a pharmaceutical form
e) human medicines containing paracetamol in the highest quantity of 500
milligrams per unit dosage forms, and if one pack of human
the product contains no more than 12 units of a pharmaceutical form
f) human medicines containing ibuprofen in the highest quantity of 200
milligrams per unit dosage forms, and if one pack of human
the product contains more than 20 units of a pharmaceutical form
g) humane preparations intended for surface disinfection of minor injuries
skin and disinfestation human preparations intended for external use,
h) human drug preparations in the form of a skin patch containing the derivation
the active substances with the local action
I) human smoking cessation preparations containing nicotine.
(2) in assessing the substitutability of names according to § 31 para. 5 (b). and)
section 4 of the law on pharmaceuticals will notably take into account whether the name in print,
handwritten or spoken form is not interchangeable with the name of another
humane medicine. In the assessment taking into account the probability
the likelihood of confusion in the normal course of treatment with the humane treatment and the consequences of the possible
the likelihood of confusion on the patients ' health.
(3) if it is proposed in the context of a request for a product without issue
prescription or non prescription with restrictions, or
the inclusion among the dedicated human medicinal products shall submit, in addition to
the documentation referred to in paragraph 4 or 5 is also the documentation referred to in
Annex No 6 of this Ordinance.
(4) the conclusions of the readability and clarity of the leaflet
pursuant to section 26 paragraph 1. 5 (b). n) of the law on medicinal products shall be presented in the case
for a product with applications for registration and requests for change
registration, which has resulted in a significant change in the leaflet.
The package leaflet is comprehensible, if patients are able to
leaflet find the information necessary for the proper and safe
the use of a product, to understand them and follow them.
The applicant may use previously submitted assessments of readability and
clarity of the package leaflet in the framework of the consideration of other human
the products in respect of which the applicant was either similar to that
of, or relating to the same security issue. In
such a case, the request must be presented in the preamble. The link cannot be
use and assess the readability and clarity of the leaflet is
for example, should be performed for human medicinal products containing a new
the active substance, when changing the method of despatch, if significantly different
new variants of the product, in the case of a new target group
patients, in the case where it is necessary to emphasize some of the guidelines for the
the use of the product. In cases where the request is presented in the
more Member States, it is sufficient to assess readability and
clarity of the package leaflet in one of the official languages of the
of the Member States.
(5) an application for authorization, as appropriate, before issuing a decision on the
the registration shall be submitted to all the internal and external packaging in
to be a human product is placed on the market, including the colorful graphic
editing and one sample of each kind of product from the internal
packaging. The Institute may request the submission of sample dispense medicinal
products regulated by Act No. 167/1998 Coll., on substance abuse
substances and amending some other acts.
§ 7
Documentation submitted with the application for the registration of veterinary medicinal products
(1) an application for authorization of the veterinary medicinal product shall be submitted to the data
and documentation, whose contents and structure are listed in annexes 2 to 5
of this order. This annex shall also apply in the submission and
documentation for the purposes of mutual recognition of registrations pursuant to § 41 para. 1
the law. The scope of the documentation to be submitted with the application corresponds to the knowledge of the
veterinary medicine, its nature, therapeutic benefit
It brings, and the risks associated with its use, and the current level of scientific
the knowledge and technical progress in the field of veterinary medicine.
(2) the request contains all the information relating to the evaluation of the
the veterinary medicinal product, whether they are for veterinary medicine a favourable
or unfavorable. In particular, all relevant details shall be always on
any incomplete or abandoned test or assessment
apply to veterinary medicine.
(3) a separate application shall be accompanied by complete documentation referred to in annex No. 2
of this order. In the case of literary requests shall apply the requirements
set out in annex 2 of this order, as in the case of applications
supporting experimental data.
(4) for applications using the link, they do not produce the reports drawn up by the
Experts pursuant to Title VI of annex 2 of this order for parts
the documentation for which is used by reference to the results of the pharmacological and
toxicological tests, the results of safety tests and residue
clinical trials have already submitted under a different registration procedures
any other marketing authorisation holder. If necessary, requests
pursuant to section 4 (b). (c) shall submit documentation necessary) for the assessment of
the issues of safety and efficacy of the veterinary medicinal product,
they are not included in the documentation to which the reference is made; essential similarity
the veterinary medicinal product in respect of which registration is applied for, due to the
veterinary medicine, to which reference is made, it is necessary to demonstrate the
for example, evidence of bioequivalence, pharmacodynamic or pharmaceutical
or therapeutic equivalence. For applications using the link proposed
Summary of product characteristics corresponds to the usual current of the summary of
of the product to which it is linked; If there are, however, in the proposed text
derogations, shall be in the proposal and the reasons. If there is a suitable reference
the product is registered, you cannot refer to a medicinal product authorised in the
another Member State. European reference product shall be used only in
If suitable reference product is not or has not been registered.
Required information on the country of origin of the European reference product and
about, in which the participating States is applied. For an application
to be submitted with the consent of the original holder of the approval shall be documented.
(5) with a request for simplified registration of veterinary homeopathic
the product documentation is submitted in accordance with title V of annex 2 of this
Decree on the application of simplified registration of veterinary
homeopathic products, they do not produce the reports drawn up by the experts and
a draft summary of the product characteristics.
(6) on the documentation presented by an application for authorization of a veterinary
product characteristics other than immunological veterinary medicinal product shall, for the part of the
registration dossiers affecting quality shall apply all relevant
articles, including general articles and General chapters of the European Pharmacopoeia.
The immunological veterinary medicinal products for the part of the registration
documentation, which may affect the quality, safety and effectiveness, the
all relevant articles, including general articles and General chapters
The European Pharmacopoeia. With regard to the use of colouring substances in veterinary
of the requirements laid down in title VIII of annex 2 of this
the Decree.
(7) the dossier submitted with the application for the registration of veterinary
the product demonstrates that the manufacturing procedures the veterinary medicinal product is
carried out in accordance with the requirements of good manufacturing practice. Documentation
further demonstrates that the pharmacological and toxicological tests, the test
residues and the safety tests have been carried out in accordance with the requirements of
good laboratory practice.
(8) the Documentation submitted with the application for the registration of veterinary
a product containing a genetically modified organism, or
consisting of genetically modified organisms, includes reviews
risk associated with the marketing of a genetically modified organism into the
the environment under another law ^ 9).
(9) the Documentation submitted with the application for the registration of veterinary
product intended for minor species or for minor indications
does not always contain all the information required in annex No. 2, if
so the competent instruction of the Commission or the Agency.
(10) an application for authorization, as appropriate, before issuing a decision on the
the registration shall be submitted one sample of each kind
the inner packaging or in agreement with the Veterinary Institute designs all
the internal and external packaging in which the product is to be health
placed on the market; the sample may also be submitted to the veterinary medicinal product from
development release, whose characteristics correspond to those of the health
the product that is the subject of the request.
Section 7a
Criteria for classification of dedicated veterinary products, for
assessment of veterinary medicines and the interchangeability of the names for
deciding on the classification with regard to the issue for veterinary medicinal products
intended for animals from which the products of animal origin are obtained for
human nutrition
(1) include dedicated veterinary products can be:
and absorption antidiarrhoika),
b) antiseptic preparations intended to treat the surface of the skin of the animal or
available from the outside of the mucous membranes, including cases where the skin or mucous membranes
showing incipient signs of inflammation or are at present minor
injury; It is also a veterinary products intended for the treatment of
pupečních newborn pups and stubs of skin derivatives of animals,
veterinary products intended for the preparation of the operating field and intended to
the application of the milk gland of cattle for the purpose of prevention of mastitis, or
to their treatment,
(c)), dermatologicals
(d)), derivancia
e) insecticidal or acaricidal preparations intended for external submissions,
including veterinary medicines acting on the developmental stages of external
parasites,
(f) the rehydration solutions intended) for oral administration,
g) vitamin and mineral preparations,
h) dietary preparations
I) antitympanika intended for oral use, which achieves the effect
his physico-chemical action.
(2) in assessing the substitutability of names according to § 31 para. 5 (b). and)
section 4 of the Act, particularly taking into account that the name on paper, ink or
spoken form is not interchangeable with the name of another of the veterinary
of the product. In the assessment taking into account the likelihood of the risk
to public health, animal health or to the environment.
(3) the conditions in which the marketing authorisation may provide that
veterinary medicine intended for animals, from which they are obtained
animal products for human nutrition, can be issued without a
Regulation, are laid down in Title VII of annex 2 of this order.
§ 8
Registration changes
In the case of a request for change in the way the issue of preparation of the picking route
prescription for dispensing without prescription or dispensing without
a prescription with a restriction or classification between dedicated healing
products must meet the requirements of the dossier referred to in
Annex No 6 to this Ordinance.
§ 9
Transfer of registration
(1) an application for the transfer of the registration contains in addition to the required
the law on pharmaceuticals, the following information and documentation:
and) product name to which the registration relates his conversion and the pharmaceutical
form, power, and the registration number,
(b) the name or names), surname and place of business of the earlier
the marketing authorisation holder, in the case of a natural person, or
business name and registered office, in the case of a legal person, the name or
name, last name and business address of the person to whom the decision is to be
transferred in the case of a natural person or business name and address, if it is
on the legal person and the date on which the proposal is to transfer registration
take place,
(c)) statement by the marketing authorisation holder and the person to whom it has
to be granted, and that with their signatures, that full and
updated documentation relating to the product, or a copy of this
the documentation has been made available or transmitted to the person to whom it is to be
granted, this documentation corresponds to the documentation
presented by the Institute or the Veterinary Institute under the registration
procedure the procedure for registration of changes,
(d)) the documents submitted pursuant to § 36 odst. 1 of the Act the person to whom it has
to be granted, contain
1. the name or name, last name, address, telephone and
the electronic connection of a qualified person responsible for pharmacovigilance
in accordance with § 91a or § 95 para. 1 of the law on pharmaceuticals,
2. as regards the human medicines, the publicly accessible address for the professional
information services about the preparations in accordance with § 33 para. 3 (b). g) of point 1
the law on pharmaceuticals, including contact details,
(e)) the draft summary of product characteristics, package leaflet,
listed on the packaging, and designs of all external and internal packaging, in
which the product should be placed on the market, including the colorful graphics editing,
containing the name of the person to whom the transfer is to be transferred; In addition to the
affected by the transfer of registration data shall be the summary of proposals
product characteristics, package leaflet and the indications on the packaging of the content
identical with the approved summary of product characteristics and package leaflet
and the details given on the packaging of the product.
(f) transfer of duties) plan in the area of pharmacovigilance under Title V
the law on pharmaceuticals from the previous holder of the marketing authorisation
the person to whom the transfer is to be converted, especially a formalised
How to forward reports on adverse reactions in the period they are on
the market, with the old contact information, plan to ensure the continuity of
Re-evaluation of the risk-benefit balance, and transmission of data on the
pharmacovigilance, and other relevant information.
(2) in the case of a veterinary medicinal product shall be submitted in addition to the data referred to in
paragraph 1 and plan the transfer of responsibilities in the area of pharmacovigilance by
Title V of the law of the existing marketing authorisation holder, the person
on which the decision is to be transferred. Plan the transfer of obligations contains
in particular, a formalized method of passing reports of adverse effects in the
the period when they are on the market, with the old contact information, schedule
ensure continuity in the re-evaluation of the benefit/risk ratio, and the way
the transfer of the data on pharmacovigilance and other pertinent information.
§ 10
(1) for each package size or type of packaging shall be allocated to the holder
the marketing authorisation on the basis of the decision of the registration code (§ 32
paragraph. 5 of the Act). The new code will be allocated in the event of a change of the name of the medicinal
the product, pack sizes and the type of packaging and furthermore in the case of the transfer of
registration, registration and acceptance in the parallel importation.
(2) the Institute or Institute of animal health in the context of assessing the data submitted
fulfilment of the conditions under § 32 para. 3 and 4 of the law on pharmaceuticals and on the basis of
This assessment is reassessing whether the benefit of the use of the product under
the conditions set out summary of product characteristics still exceeds the risks
associated with its use.
(3) if the registrant of the veterinary medicinal product proves that with
regard to the need for availability of a veterinary medicinal product for the purposes of
veterinary care and with regard to the
and prevent the suffering of the animals)
(b)) a rare occurrence of indications, for which the veterinary medicinal product is intended,
(c) the need for the adoption of effective health) measures to protect against
diseases, or
(d)) of the current state of scientific knowledge,
not being able to before completion of registration procedures of the health
product submit complete data concerning the quality, safety or
the effectiveness of the veterinary medicinal product, registration may be granted pursuant to §
32 para. 3 and 4 of the law on medicinal products.
§ 11
Renewal of the authorisation
The application for renewal of the authorisation of the holder shall be presented
the marketing authorisation
and) contact details for person responsible for pharmacovigilance, contact
person to communicate about errors and download the product and contact person
for a publicly accessible information service of technical support of the product,
(b) proof of compliance with conditions) for good manufacturing practice in the production of
preparation, these documents must not be older than 3 years, together with the
the Declaration of a qualified person manufacturer responsible for batch
of the product, in the manufacture are used as starting materials
only the active substances produced in accordance with the principles of good manufacturing practice
in the production of raw materials; for production sites outside the territory of the European
economic area and outside of the States that have with the community
an agreement on the mutual recognition of inspections for good manufacturing praxe3)
the list shall be provided to the inspection of good manufacturing practices carried out in the
the last 5 years, indicating the date of the inspection team and the result
the inspection,
(c)) the draft text of the summary of product characteristics as in its final form, the text
any changes are highlighted against the approved version, and summaries
Summary of product characteristics approved foreign surveillance authorities; in the framework of the
renewal are in addition to the changes to the summary of product characteristics referred to in
the letter f) permissible only text edit summary of product characteristics, without the
content changes
d) the draft text of the leaflet as in its final form, so the text is
highlighting any changes against approved version, where appropriate, a proposal from the
data to be given on the packaging,
e) summary of the pharmacovigilance system, the updated risk management plan
and addendum to the clinical summary and overview neklinickému, and in
the scope of the guidance of the Institute,
f) in the case of medicine, the total of the pharmacovigilance system,
an updated risk management plan and amendment to a clinical overview
neklinickému review, and to the extent provided for under the guidance of the Institute,
g) Appendix to overall quality summary containing an expert statement
about the quality of the product, to the effect that the holder of the marketing authorisation
of introducing the necessary changes to allow the manufacture, inspection
quality and use of the product in accordance with the technical and scientific progress
and with the available scientific knowledge and, further, that all changes in the quality of
medicine is carried out after approval of the request for change of registration and that the
the product complies with the relevant guidelines, the Commission and the Agency; the Declaration
an expert must be signed and attached brief information about education,
training and professional experience of the expert,
h) in the case of veterinary medicinal product
1. statement of the clinical expert that will evaluate the current risk
and the benefits of the product, including an assessment of the consequences of the way issues;
This Declaration will make on the basis of expert of integrated data and documentation
the medicinal product, the information contained in the periodic
updated reports on the safety of the product, and all publicly
the available data; in a statement the expert confirms that there are no
new preclinical or clinical data that could affect the evaluation of the
the current risk-benefit ratio of the product,
2. an expert statement on safety, in which it shall assess the safety
for the user, and if the veterinary product is authorised for animals,
from which they are derived products for human nutrition,
safety for the consumer of foodstuffs obtained from treated animals;
an expert statement summarizes all new relevant information for the period
that is the subject of reviews; in the context of the assessment of the risk
the benefit of the use of the veterinary medicine expert also takes account of the risk
for the environment,
3. an expert statement pursuant to sections 1 and 2 shall include a clear representation to
whether the marketing authorisation may be extended for an unlimited period
or only for the next 5 years, as appropriate, under what conditions, including
justification; If this condition lies in the implementation of changes in the summary
the product information to ensure a favourable benefit
of the product and the risk of its use, can be such a change to take place in the
under the renewal, without being submitted to a separate
application for amendment of registration; the Declaration must be competent expert
signed and attached brief information about education, training and professional
the experience of an expert,
I) and in the case of veterinary medicinal product), periodic safety update report
a report on the safety of the product, to building on the already submitted
periodic safety update reports veterinary medicinal product
to cover the entire period from the issue of the marketing authorisation or
last renewal. If this period is covered in more
periodically updated reports on the safety of the product, the
the Veterinary Institute under the scope of the supplementary report, or
summary the overarching message in accordance with the instructions of the Commission and the agencies to
(j) specification of the active substance) approved or active substances and of the final
of the product,
one sample of the product) in each approved type of container; from
This requirement may, in the case of humane medicine, refrain,
for example, for medicinal products subject to the regulation of the law No.
167/1998 Coll., on addictive substances and amending some other acts.
In the case of veterinary medicine, veterinary department shall proceed in this matter
by analogy. The sample of the medicine which is being placed into circulation in
The Czech Republic. If the product is put into circulation in the Czech Republic,
the particulars to appear on the package in accordance with annex 5.
§ 12
Acceptance of registration
Request to take charge of registration of a product from another Member
the State contains the following information and documentation:
and the name of that) is taking over the registration refers to its pharmaceutical
form, power, the Member State from which the authorisation is to take,
the registration number of the product in that State and the date of issue of the decision on
his registration,
(b) the name or names), surname and place of business of the applicant, if
a natural person, or the business name and registered office, in the case of legal
person,
(c)) the name or name, last name and the business address of the holder
marketing authorisation in the Member State from which the authorisation is
to take, in the case of a natural person, or the business name and registered office, in the case of
the legal entity,
d) affidavit by the applicant that it is not the holder of a
registration of the product in a Member State or by a person with it
linked,
e) grounds for the request accompanied by the facts substantiating the legal
the conditions for receipt of registration,
(f) the registration document) of the Member State,
g) a list of manufacturers involved in repackaging, relabelling and
any other adjustments to the product and the relevant permit shall be
production or evidence of compliance with good manufacturing practice,
h) reference number and date of the authorization for distribution, which the applicant is
or the person to ensure the distribution of the product from the Member
the State holds, in the case of authorisations issued for distribution
the competent authority of another Member State of the community, the
a copy of this permit,
I) the way in which they will be monitored for changes in registration of the product in
the Member State concerned, or stop its supply or marketing of
on the market,
(j)) the way in which the pharmacovigilance will be ensured,
for a sample of the product in the form), which is intended to be placed on the market in the
The Czech Republic, a draft summary of product characteristics, labelling
and package leaflet. These proposals will be presented in the English language,
If it was not pursuant to § 38 of the law on pharmaceuticals provided otherwise.
section 13 of the
Parallel imports
(1) the applications for authorisation of parallel imports, in addition to the information specified
the law on medicinal products shall indicate:
and business name and registered office) of the applicant, in the case of a legal person, or
name or name, surname and place of business, in the case of physical
person,
(b)) reference number and date of the authorization for distribution, which the applicant is
holder, in the case of authorisations to distribute has been issued by a competent
authority of another Member State of the community, shall provide a copy of this
the authorization,
(c)) the way that will be monitored or placing any stop picking
on the market, changes in registration, suspension or revocation of registration
the reference product in the Czech Republic and of the imported product in the
the Member State of the community,
(d)) the way in which the pharmacovigilance will be ensured,
e) in the case that the product imported in parallel is not its composition or of the
other causes of identical to the reference product for parallel imports,
the data available to the applicant that the differences do not result in the difference
therapeutic effects of parallel imported product from the reference
preparation for the parallel imports and do not pose a risk to public health;
in the event of differences in the composition of excipients, or other relevant
differences, these differences in the package leaflet and shall indicate on the packaging
parallel imported product.
(2) in the case of parallel imports of a product from Estonia, Latvia, Lithuania,
Hungary, Poland, Slovakia or Slovenia, in the case of medicine,
in relation to which the Czech Republic was granted protection by a patent
or supplementary protection certificate in a time when in the State from which
the product is imported, such protection could not be provided, in
accordance with the Treaty of accession of the Czech Republic to the European Union in
the application shall indicate whether the intention to import the product in the United States
the applicant informed at least one month before the submission of the request
the owner of the patent or supplementary protection or of the person authorized
such protection relating to the imported product.
(3) on the outer packaging of the product that is the subject of parallel importation,
appropriate means, such as reprinting or stickers,
Basic data shall be the corresponding authorisation conditions in
The Czech Republic, which cannot be of text in a foreign language easily deduce and
all data that are not listed in the Latin alphabet. For basic data
consider the particular product name, strength, dosage form, active substance,
the marketing authorisation holder of the reference product in the Czech
Republic, the holder of the authorisation the parallel importation, the method of storage and the time
usability. The name of the product on the outer packaging of the Braille
letters shall be specified so as to avoid confusion, if the name is in the
the country of export. Additionally, the outer packaging shall be given in the form of
bar code European code different from the code of the reference product,
in the case of medicinal products for human use, the registration number of the reference product in
The Czech Republic, supplemented by a unique identification referred to in the authorisation
parallel imports. On the outer packaging of veterinary medicinal products can be supplemented with
the European code.
(4) if imported into the repackaging of the product in new external
the package, the data referred to in annex No. 5 to this Decree and
at the same time the information referred to in paragraph 3.
§ 14
cancelled
§ 15
Notification of adverse reactions for the preparation
(1) notification of suspicion or occurrence of the adverse effect of human
the product contains
and details of the person being treated), initials, date of birth, age, and gender with the
It is sufficient that at least one of the communication of such data,
(b)), the identification of the notifier, údaje5)
(c) a description of the side effect),
(d) the name of the product) or active substance administered to the person being treated,
or any other particulars allowing their identification, administered dose and
the method of administration.
(2) the notification form shall be used, that the Institute shall publish in the Gazette
The State Institute for drug control, and a manner allowing remote
access; However, notification can be made to other proven way for
provided that it contains the information referred to in paragraph 1.
(3) the notification of adverse reactions to medicinal products for human use, including
additional information provided for the proper evaluation of the individual
the cases are provided in an anonymous form due to the person treated. About
the treated person shall communicate the information referred to in paragraph 1 (b). and) to use to
the basis of the treated person can only identify the person notifying
for example, the year of birth and the initials. Received information allowing the direct
identify the treated person is processed, and the data is in the data
do not store.
(4) if the notification of suspected serious side effect is
the information is drawn from the scientific literature or electronic
sources of information, the provisions of paragraph 1 shall not apply, and only
the source of the information.
(5) the notified of suspected side effects passes Department of the holder
the decision to register without identification of the person who has made the announcement.
(6) the Completion of the notification of adverse reactions to the Department
or the marketing authorisation holder, depending on which of these notifications
received first. In the case of receipt of reporting compliance time will do so after
mutual agreement.
section 16 of the
More detailed conditions for archiving data relating to pharmacovigilance
products for human use
Archived these documents relating to pharmacovigilance:
and all the original documents), related to the various cases
to report adverse reactions, either in written form or in the form of
by electronic means the captured image (scan) on the archive media
b) records in pharmacovigilance databases in electronic
the form,
(c) the pharmacovigilance database) backups, and in an appropriate retrieval
the data medium,
(d)) made by the documentation or ongoing
postmarketing safety studies,
e) collected data on the volume of supply, sales and prescriptions,
f) correspondence relating to pharmacovigilance activities in writing
or electronic form; the original correspondence in writing
It can be archived in the form of electronic means the captured image,
g) periodic safety update reports in written or
electronic format,
h) plans for risk management and documents of a similar nature that are related
to the implementation of pharmacovigilance activities in paper or
electronic format,
I) credentials of the person or persons responsible for pharmacovigilance, in
the documentary form.
§ 17
Information on starting or their non-Interventional post-authorisation studies
products for human use
(1) the marketing authorisation holder shall notify by electronic means
Institute of non-Interventional post-authorisation of the intention to study with the fact that
provide the following information:
and) the name or name, last name and the business address of the holder
marketing authorisation in the case of a natural person, or the business name and
the marketing authorisation holder, in the case of a legal person,
(b)) identification of the product that is to be the subject of study, the code that
is allocated to the Institute of Medicine (article 32, paragraph 5, of the Act),
(c) the name of the study)
(d) the identification number of the study), under which the documents are kept
the marketing authorisation holder relating to the study,
e) study protocol that contains a minimum of information about the purpose,
the arrangement, blinding, extent, population and the objectives of the study and
the method of data processing, and
(f) the date of the start of the study), the expected date of completion of data collection,
completion of the analysis and transmission of the final report.
(2) the marketing authorisation holder shall notify by electronic means
The Institute about their non-Interventional post-authorisation studies by providing
the following data:
and) identification number of the studies that the notification concerns,
(b)) the name, or name, last name and address including the telephone number
places providing health care to the doctor who was responsible for the
medical decisions at the point of the implementation of the study,
(c)) the manner and amount of reimbursement of the costs of the investigator (section 52, paragraph 2, of the Act)
related to the implementation of the study,
d) final report.
§ 17a
Information on starting or their non-Interventional post-authorisation studies
the safety of medicinal products
(1) the marketing authorisation holder shall inform at least 60 days before the date of
begin study Institute of the intention to electronically non-Interventional
Post-authorisation safety study under § 93j law on pharmaceuticals, and shall communicate
The Institute the following information:
a) name or business name and address of the marketing authorisation holder,
(b)) product identification, which should be the subject of study, the code that
is allocated to the Institute of medicine,
(c) the name of the study)
(d) the identification number of the studies selected) the holder of a
the registration,
e) start date of the collection of data, the estimated date of completion of data collection,
completion of the analysis and transmission of the final report and
f) study protocol.
(2) the marketing authorisation holder shall inform the Institute about electronically
termination of non-Interventional post-authorisation safety studies
characterized by the identification number allocated to the study by the Institute with the
including the date of completion of data collection.
section 18
The method and extent of the notification of the prescription or use of an unauthorised
humane medicine
(1) notice of the prescription or use of an unauthorised human
product characteristics pursuant to § 8 para. 3 of the law on pharmaceuticals administered in physician
electronic form or by writing to the Institute.
(2) the notice of an unauthorised use of a prescription or
the product contains the following information:
and the name of an unauthorised human medicine), qualitative and
the quantitative content of the active substance, its pharmaceutical form, and size
packaging,
(b) the identity of the manufacturer of an unauthorised human) of the product, stating the
the country of manufacture or the identification of the person responsible for the placing on the market in
a country other than in the Czech Republic, with an indication of the country,
(c) the identification of the operator) the unregistered human medicine
He added,
(d) the address of the medical facility) in which the unregistered human
the product is prescribed or used, and the name or names, and last names
the doctor who prescribed or used it,
(e) identify patient for) which the unregistered human
the product is intended, with sufficient initials, date of birth and gender,
(f)) of the disease for which treatment was unregistered human medicine
prescribed or used,
g) estimated number of packaging used for the treatment of diseases of the
the patient,
h) information as to whether the treating physician shall provide information on the results of
the use of an unauthorised medicinal product in the human persons
referred to under point (b)), or their representatives.
§ 19
cancelled
section 20
Regulation (EEC)
Decree No. 288/2004 Coll., laying down details of registration
medicinal products, changes, renewals, the classification of the medicinal
preparations for release, transfer, registration, issuing permits for concurrent
imports, presenting and designing specific treatment programs with
the use of unregistered medicinal products about how to
the notification and assessment of adverse reactions of the medicinal product,
including the terms periodic safety update reports, and
the method and extent of the notification of the use of an unauthorised medicinal product
(Registration Ordinance on medicinal products), is hereby repealed.
section 21
The effectiveness of the
This Decree shall take effect on the first day of the calendar month
following the date of publication.
Minister:
Mudr. Julínek, MBA in r.
Minister:
Mgr. Gandalovič in r.
Annex 1
The content and structure of the complete dossier in case of
of the product
The particulars and documents shall be submitted in the form of 5 modules. Module 1 includes the
administrative data specific to the community, module 2 contains
a summary of the quality, non-clinical and clinical summary, module 3 contains
chemical, pharmaceutical and biological information, module 4 contains
non-clinical reports and module 5 provides clinical study reports.
If it is used in this annex to the Decree of the concept of "preparation", it is understood
This medicinal product.
PART I
THE STANDARDISED MARKETING AUTHORISATION DOSSIER REQUIREMENTS
1. Module 1: ADMINISTRATIVE INFORMATION
1.1 the contents of the
The full contents of modules 1 to 5 of the documentation submitted with the application
about registration.
1.2 application form
A product which is the subject of the application, it is identified by its name and
the name of the active substance or medicinal substances, together with the pharmaceutical form,
route of administration, the strength and the final presentation, including packaging. It must be stated
name or name, surname and place of business of the applicant, in the case of
natural person or business name and registered office, in the case of legal
person, along with the name and address of the manufacturers and the sites involved in the
the various stages of manufacture (including the manufacturer of the finished product and the manufacturer
or producers of active substances), and, where appropriate, the name and address of the importer of
a third of the country. The applicant shall identify the type of request, and if they are provided
indicate what samples,.
To the administrative data shall be copies of the manufacturing authorization for all
production sites participating in the production of the product and the Declaration
the qualified person responsible for batch of manufacturer
of that in the production are used as starting materials only
the active substance produced in accordance with the principles of good manufacturing practice in the
the production of raw materials. Additionally, joins the list of countries in which was awarded
registration, including an indication of the year of registration and registered the name,
If the product is authorised in the Member State of the community, shall also
the legal basis for the registration and the type of procedure, which has been registered
granted, copies of all the summaries of product characteristics, as
approved by Member States. Additionally, the list of countries in which is about
the registration applied for or where an application for registration has been taken by the applicant
back or registration is refused, cancelled or suspended, including
the communication of reasons; If you applied for registration in the Member State
The community, the legal basis and the registration procedure, the type of
that is sought. In the case of an application for mutual recognition of
registration under section 41 the law on pharmaceuticals, and the list shall be provided to the Member
States concerned by the application for registration refers to.
1.3 Summary of product characteristics in accordance with annex 3, labelling
According to annex No 5 and package leaflet in annex No 4
The conclusions of the readability and clarity of the leaflet
submitted pursuant to § 26 para. 5 (b). l) law on medicinal products contain
at least the following particulars and documents:
the characteristics of the product under consideration),
(b) a description of the assessment method used) with an indication of the language in which the assessment of the
took place, and a description of the groups of patients used to assess the grounds
their choice,
c) questions raised by patients, including instructions and forms for
answers,
d) summary of responses of patients with evaluation results,
e) leaflet with highlighted changes that were made on the basis of
of assessment of readability and clarity.
1.4 Information on experts
Pursuant to section 26 paragraph 1. 6 section 27 para. 12 of the law on pharmaceuticals must experts
submit in detailed reports of his comments to the documents and data,
that make up the registration documentation, and in particular to modules 3, 4 and 5
(chemical, pharmaceutical and biological documentation, non-clinical
the documentation and the clinical documentation). It is required that the experts
critically evaluate the quality of the product and of the investigations carried out on animals and
people and spell out all the data relevant for evaluation. These requirements
will be accomplished by producing a quality overall summary, non-clinical overview
(data from studies carried out on animals) and clinical compendium
are contained in module 2 of the registration dossier. In module 1,
a declaration signed by the experts together with brief information
about their education, training and occupational experience. Enter the professional
relationship expert to the applicant.
1.5 specific requirements for different types of applications
Specific requirements for different types of applications are listed in part II of
of this annex.
1.6 environmental risk assessment
Applications for registration shall contain, if necessary, an overview of reviews
risk assessment the potential risks for the environment
resulting from the use and/or disposal of the product, and is designed to be appropriate to
the markings on the packaging. Enter the risk to the environment associated with the
release of products containing genetically modified organisms, or
consisting of (§ 31 para. 6 of the law on medicinal products). Information
regarding the risk for the environment shall be included as an annex to
module 1. Information shall be provided in accordance with the provisions of other
Law ^ 9).
Information includes:
1.6.1. the introduction,
1.6.2. a copy of the written consent or consents to the deliberate release
a genetically modified organism into the environment for the purpose of
research and development in accordance with part B of Directive 2001/18/EC,
1.6.3 information required by annexes II to IV of Directive 2001/18/EC,
including methods for detection and identification, as well as the unique code
genetically modified organism and any other information about
the genetically modified organism or preparation concerning the assessment of
risks to the environment,
1.6.4. report on the evaluation of the risks to the environment for
the basis of the information referred to in annex III and IV to Directive 2001/18/EC and
in accordance with annex II to that directive,
1.6.5 conclusion drawn up taking into account the above information and
the report on the assessment of the risk to the environment in which it is designed
appropriate risk management strategies; This strategy includes having regard to
the genetically modified organism and post-marketing surveillance plan
monitoring and identification of specific details that need to be put in
Summary of product characteristics, the labelling and the package leaflet,
1.6.6 appropriate measures for informing the public.
Enter the date and the signature of the author, information about his education, training and
professional experience, and a statement of the author's relationship to the applicant.
1.7 information about market exclusivity for orphan medicinal product
disease
1.8 the risk management system and a description of the manner of pharmacovigilance
Applications for registration shall contain a summary of the pharmacovigilance system and
a risk management plan that describes the risk management system.
The risk management plan includes:
and Security specification)
(b) the pharmacovigilance plan),
c) plan of the post-efficiency,
d) measures to minimise the risks and
e) a summary of the risk management plan.
1.2 information on clinical trials
1.10 Information on use in the paediatric population
2. Module 2: SUMMARIES
The aim of this module is to summarise the chemical, pharmaceutical and biological
data, non-clinical data and the clinical data presented in modules 3, 4 and 5
the registration dossier and provide reports and the reports drawn up by the
Experts pursuant to section 26 paragraph 1. 6 section 27 para. 12 of the law on medicinal products. In
the reports and summaries compiled by experts, in particular, whether
the product conforms with the stated composition, justification of the control methods
used by the manufacturer, the toxicity of the product, the observed pharmacological
properties that have been identified in people treated with effects
the corresponding data referred to by the applicant in the documentation, whether treated persons
the preparation is well tolerate, what dosage is recommended, and what are the
any contra-indications and side effects. If necessary, indicate the
reasons for using the bibliography under § 27 para. 7 of the law
on pharmaceuticals.
Indicate and dealing with critical points. Benefits in kind shall be provided, including summaries
spreadsheet processing. These reports must contain cross-references to
table or on the information contained in the main documentation presented in the
module 3 (chemical, pharmaceutical and biological documentation), module 4
(non-clinical documentation) and module 5 (clinical documentation). Information
contained in module 2 shall be presented in accordance with the format, content and system
numbering, which are worked out in detail in the guidelines of the Commission. Overviews
and summaries shall be submitted in accordance with the principles and requirements set out
This Decree.
2.1 total content
Module 2 covers the content of the scientific documentation submitted in modules 2 to
5.
2.2 Introduction
Information shall be provided on the pharmacological group, mode of action and
the proposed clinical use of the product for which registration is sought.
2.3 quality overall summary
The form of the quality overall summary shall be submitted for an overview
relating to chemical, pharmaceutical and biological data.
It will highlight the key critical parameters and issues relating to aspects of the
quality, as well as justification in cases where they are not tracked
the relevant guidelines. This document corresponds to the scope and structure of the
detailed data presented in module 3.
2.4 non-clinical overview
Calls for a full and critical reviews of the product in animals/in
vitro. This report contains an analysis and justification of the test strategy and
any deviations from the instructions relating to the neklinickému
reviews. With the exception of biological medicinal products shall include
evaluation of the impurities and degradation products, along with their potential
pharmacological and toxicological effects. Analyse the implications of
any differences in the chirality, chemical form and impurity profile between
compound used in non-clinical studies and medicine, to be
placed on the market. For biological medicinal products is evaluated
comparability of material used in non-clinical studies, clinical
studies and preparation to be placed on the market. Any new
auxiliary substance is subject to a specific safety assessment. Define
the characteristics of the non-clinical studies documented and analysed the implications of
the findings for the safety of the product intended for clinical use
of the people.
2.5 clinical overview
The clinical overview is intended to provide a critical analysis of the clinical data
included in the clinical summary and module 5. Access shall be provided to
the clinical development of the product, including critical studies and decisions
regarding the studies and their implementation. A brief overview of the
clinical findings, including important limitations as well as reviews
the benefits and risks, based on the findings of clinical trials. Requires
the interpretation of how the findings on the efficacy and safety support
the proposed dose and target indication and reviews how the summary of
preparation and additional procedures will optimise the benefits and manage the risks.
Explain the efficacy and safety issues that arose during the development,
and unresolved issues.
2.6 non-clinical summary
In the form of factual written and tabulated summaries of the submitted results
the pharmacological, pharmacokinetic, and toxicological studies
carried out on animals or in vitro, which shall be given in this order:
2.6.1 Introduction,
2.6.2 the pharmacodynamics written summary
2.6.3 the pharmacodynamics tabulated summary
2.6.4 the pharmacokinetics of written summary
2.6.5 the pharmacokinetics of tabulated summary
2.6.6 Toxicology written summary
2.6.7 Toxicology tabulated summary.
2.7 Clinical summary
Detailed subject shall be provided a summary of the clinical information about the medicine
contained in module 5. Must include the results of all bio-pharmaceutics
studies, studies of clinical pharmacology and clinical efficacy studies and
safety. An overview of the individual studies is required. A summary of the
clinical information shall be presented in the following order:
2.7.1 Summary of bio-pharmaceutics studies and the analytical methods used,
2.7.2 clinical pharmacology, study summary
2.7.3 Summary of clinical efficacy,
2.7.4 Summary of clinical safety
2.7.5 overviews for individual studies.
3. Module 3: chemical, pharmaceutical and biological information for
PRODUCTS CONTAINING CHEMICAL AND/OR BIOLOGICAL ACTIVE SUBSTANCES
3.1 Format and edit
Module 3 has the following general structure:
the contents of the
file data
a) the active substance
1. General information
1.1 terminology
1.2 structure of the
1.3 General properties
2. production
2.1 the manufacturer or manufacturers
2.2 description of manufacturing process and process controls
2.3 review materials
2.4 control of critical steps and intermediates
2.5 validation and/or evaluation process
2.6 manufacturing process development
3. characterisation of the
3.1 elucidation of structure and other characteristics
3.2 impurities
4. review of the active substance
4.1 specifications
4.2. analytical methods
4.3 validation of analytical methods
4.4 batch analyses
4.5 justification of specifications
5. reference standards or materials
6. the container and its closure system
7. stability of the
7.1 stability summary and conclusions about
7.2 stability Protocol and stability commitment
postmarketing period
7.3 stability data
b) finished product
1. Description and composition of the
2. pharmaceutical development
2.1 components of
2.1.1. the active substance
2.1.2 excipients
2.2 product
2.2.1 formulation development
2.2.2 overage
2.2.3 the physico-chemical and biological properties
2.3 development of the production process
2.4 container and its closure system
2.5 microbiological attributes
2.6 compatibility
3. production
3.1 the manufacturer or manufacturers
3.2 batch formula
3.3 description of manufacturing process and process controls
3.4 control of critical steps and intermediates
3.5. validation and/or evaluation process
4. control of excipients
4.1 specifications
4.2. analytical methods
4.3 validation of analytical methods
4.4 the preamble specification
4.5 excipients of human or animal origin
4.6 novel excipients
5. review of the finished product
5.1 specifications
5.2. analytical methods
5.3 validation of analytical methods
5.4 batch analyses
5.5 characterisation of impurities
5.6 justification of specifications
6. reference standards or materials
7. container and closure
8. stability
8.1 stability summary and conclusions about
8.2 the stability Protocol and stability commitment
postmarketing period
8.3 stability data
(c)) of the annex
1. production equipment and facilities (only for biological medicinal products)
2. evaluation of the safety of foreign agents
3. processing AIDS
d) additional information within the Community
1. process validation scheme for the product
2. a medical device
3. the certificate or certificates of conformity
4. products containing or using in the manufacturing process materials
animal and/or human origin (TSE procedure)
d) literature references
3.2 content: basic principles and requirements
(1) submitted to the chemical, pharmaceutical and biological data shall
contain all the relevant information on the active substance or medicinal
substances and the final product, i.e. the development, the manufacturing process,
characterization and properties, procedures, and requirements for quality control,
the stability and the description of the composition and the type of packaging and the packing size of the final
of the product.
(2) the two main blocks of information concerning the active substance
or medicinal substances and the final product.
(3) in this module must be additionally supplied detailed information about default
materials and raw materials used in the manufacturing operations for medicinal
substances or medicinal substances and excipients included in the final
of the product.
(4) all the procedures and methods used in the production and control of medicinal substances
and the finished product must be described in sufficient detail to
repeated in control tests, carried out at the request of
Of the Institute. All test methods must correspond to the State
scientific progress and must be validated. The results shall be provided
validation studies. In the case of the control methods referred to in the European
Pharmacopoeia, this description may be replaced with the appropriate link to the
the monograph or monographs and general paper or general topics.
(5) the monographs of the European Pharmacopoeia shall be applicable to all substances,
medicinal products and pharmaceutical forms which are referred to therein. With regard to the
other substances is required to comply with the requirements of the Czech pharmacopoeia. If
However, the material in the European Pharmacopoeia or in the pharmacopoeia
a Member State made in a way that may leave impurities
not controlled in the pharmacopoeia monograph, these impurities and their
the maximum limits are given and must be documented for appropriate control
method. In cases where a specification contained in a monograph of the European
Pharmacopoeia or in the pharmacopoeia of the Czech Republic could be insufficient to ensure
quality of the substance, the Institute may require the marketing authorisation holder
more appropriate specifications. The Institute shall inform the authorities responsible for the
Pharmacopoeia in question. The marketing authorisation holder shall provide the authorities responsible for
the pharmacopoeia concerned details of the alleged insufficiency and the used
additional specifications. In the case of the analytical methods referred to in
The European Pharmacopoeia, this description shall be replaced in each relevant section of the
the appropriate link to a monograph or a monograph and a general article or
General topics.
(6) in cases where they are not the default material and raw materials, active substance
or a medicinal substance or excipient or excipients described even in the
The European Pharmacopoeia nor in the pharmacopoeia of a Member State, it may be recognized
compliance with the monograph of a third country. In such cases, the
the applicant shall submit a copy of the monograph, together with the validation control
methods contained in the monograph and by a translation.
(7) if the active substance or starting material/raw material and
adjuvant or excipient subject of monographs of the European
Pharmacopoeia, the applicant can apply for a certificate of conformity, which is an independent
The European Directorate for the quality of medicines, shall be presented in the appropriate
section of this module. These certificates of conformity with European
the pharmacopoeia is valid as a replacement of the relevant data of the corresponding section
described in this module. The manufacturer shall confirm in writing to the applicant that the production
the process has not been since the release of the European Directorate for the certificate of compliance
the quality of medicines changed.
(8) for a well-defined active substance, the manufacturer of the active substance may or
the applicant shall arrange to
and a detailed description of the manufacturing process),
(b)) quality control during manufacture and
c) process validation
they were supplied in a separate document directly to the Institute by the manufacturer of the active substance
as a basic document for the active substance (drug master file). If they are not
the following information was submitted with the application, the Institute does not consider this application
to be complete.
In this case, however, the manufacturer shall provide the applicant with all the information that
may be necessary for the latter to take responsibility for the product.
The manufacturer shall confirm in writing to the applicant that will ensure consistency between
batches and not modify the manufacturing process or specifications without informing the
of the applicant. Documents and particulars supporting the application for variation, the
give the Institute; These documents and particulars shall also be supplied to the applicant, if
they relate to the open part of the active substance master file.
(9) specific measures regarding the prevention of the transmission of animal
spongiform encephalopathies (materials from ruminant origin): at each
stage of the manufacturing process, the applicant must demonstrate the compliance of the used
material with the guidance to minimize the risk of transmitting animal
spongiform encephalopathy agents via medicinal products and its additions
published by the Commission in the official journal of the European Union. Compliance with the above
Note for guidance can be done by submitting either preferably a certificate of suitability
to the relevant monograph of the European Pharmacopoeia has been granted by the European
Directorate for the quality of medicines, or by the supply of scientific data
to substantiate this compliance.
(10) with regard to the foreign agent information assessing the risk shall be
a potential contamination with adventitious agents, be non viral or viral, as
relevant guidelines as well as relevant General monograph and
the General chapters of the European Pharmacopoeia.
(11) any special apparatus and equipment, which can be used in
any stage of the manufacturing process and control operations of the product,
must be sufficiently detailed.
(12) Or, if necessary, shall be submitted to the CE marking as required by
by Community legislation on medical devices.
Special attention must be paid to these selected elements:
3.2.1 active ingredient
3.2.1.1 General information and information related to the starting materials and
raw materials
and Provide information on) the nomenclature of the active substance, including recommended
international non-proprietary name (INN) or the name of the European
Pharmacopoeia and the chemical name or names.
The structural formula, including relative and absolute
stereochemistry, structure of molecules and relative molecular mass. U
biotechnological medicinal products, where appropriate, shall present a schematic
amino acid sequence and relative molecular mass. Shall also be
physicochemical and other relevant properties of the medicinal
the substance, including biological activity for biological medicinal products.
(b)) for the purposes of this annex, starting materials shall mean all
the materials from which the active substance produced by or extracted.
For biological medicinal products, starting materials shall mean
any substance of biological origin such as micro-organisms, organs and
tissues of either plant or animal origin, cells or fluids
(including blood or plasma) of human or animal origin and
biotechnological cell constructs (cell substrates, whether they are
recombinant or not, including primary cells).
Any other substance used in the production or extraction of substances from the
where, however, the active substance does not come directly, such as reagents, culture
Fetal calf serum, media, additives, buffers used in chromatography
etc. are known as raw materials.
3.2.1.2 manufacturing process of the active substance
and a description of the manufacturing process) of the active substance is the commitment of the applicant with regard
for the manufacture of the active substance. For an adequate description of manufacturing process and process
the checks shall be submitted to the information set out in the guidelines published
by the Agency.
(b)) shall list all the materials needed for the manufacture of the active substance with
an indication of where in the process the material is used. Will provide
information on the quality and control of these materials. Demonstrate that the
materials meet standards appropriate for their intended use. Shall indicate the
the raw materials and evidence of their quality and control.
Enter the name, address, and responsibility of each manufacturer, including contractors
producers and each proposed production site or facility involved in the production
and testing.
(c)) for biological medicinal products shall apply the following additional
requirements:
Must be described and documented the origin and history of starting materials.
Having regard to the specific measures for the prevention of the transmission of animal
spongiform encephalopathies, the applicant must demonstrate the compliance of the active substance
with the note for guidance on minimising the risk of transmitting animal spongiform
encephalopathy agents via medicinal products and its additions
published by the Commission in the official journal of the European Union.
If they are used by the cell banks, it must be shown that the properties of cells
in the passage used for the manufacture and in the passage following remained unchanged.
Seed materials, cell banks, pools of serum or plasma and other materials
of biological origin and, whenever possible, the materials from which they originate,
shall be tested for adventitious agents.
If the presence of potentially pathogenic adventitious agents is inevitable, the
the material can be used only when further processing ensures
their elimination and/or inactivation, and this shall be validated.
Manufacture of vaccines shall be, if possible, based on a system of uniform
inoculation and on established cell banks. For bacterial and viral
vaccine infectious agent properties must be shown in the seed. For
Live vaccines must be further demonstrated the stability of the properties of infectious
agents in the seed in weakening; If this proof is not enough, you must
be property in weakening established also in the production stage.
For medicinal products derived from human blood or plasma must be in accordance
with the provisions of part III of this annex described and documented the origin and criteria
and procedures for collection, transportation and storage of the starting material.
Must be described production equipment and facilities.
(d)) shall submit to the tests and acceptance criteria carried out at every critical
step, where appropriate, information on the quality and control of intermediates and validation
process and/or evaluation studies.
e) if the presence of potentially pathogenic adventitious agents
inevitable, the material can be used only if other
processing ensures their elimination and/or inactivation, and this shall be
validated in the section dedicated to the evaluation of the viral safety.
(f)) a description and explanation of the significant changes made during
development in the manufacturing process and/or manufacturing site of the drug substance.
3.2.1.3 characterization of active substances
The data shall be vyjasňující the structure and other characteristics of the active
the substance.
The confirmation of the structure of the active substance based on the
physico-chemical and/or immunochemical and/or biological methods,
as well as information on impurities.
3.2.1.4. Control of active substance
Provide detailed information on the specifications used for routine
the control of substances justification the choice of these specifications, analytical
methods and their validation. The results of the checks carried out on the
individual batches.
3.2.1.5 reference standards or materials
Shall be described in detail and with the reference standards. Where appropriate, shall apply
chemical and biological material of the European Pharmacopoeia.
3.2.1.6 the inner packaging of the active substance and its closure system
Shall provide a description of the container, the system or the systems of its conclusion and
their specifications.
3.2.1.7 Stability of the active substance
and) shall be summarised the types of studies conducted, protocols used, and results
studies.
(b)) in a suitable format to submit detailed results of stability studies
including information on the analytical methods used to generate the data and
validation of these methods.
(c)) shall be submitted on the stability Protocol and stability commitment
for the post-marketing period.
3.2.2 finished product
3.2.2.1 description and composition of the finished product
A. a description of the finished product and its composition. This information
must include a description of the pharmaceutical form and composition with all the constituents of the final
of the product, their amount in the unit and the function of the components for
a) the active substance or substances
(b)) of the excipients, or excipients, whatever their nature or the
the quantity used, including colouring matter, preservatives, adjuvants,
stabilisers, thickeners, emulsifiers, flavouring and aromatic substances
etc.,
(c) the outer layer) component products intended for internal use or
Another submission to the patient (hard capsules, soft capsules, rectal
capsules, coated tablets, film-coated tablets, etc.),
(d)) the following information shall be supplemented by any relevant data concerning the container and
where appropriate, its manner of closure, together with details of
devices with which the product will be used or administered and which
will be delivered with.
(B). the "usual terminology", to be used in describing the constituents of
the products shall mean the
and) in the case of substances listed in the European Pharmacopoeia or, failing that,
not listed, in the national pharmacopoeia of one of the Member States, the main title
the monograph in question, with reference to the pharmacopoeia concerned,
(b)) in the case of other substances, the international non-proprietary name (INN)
recommended by the World Health Organization, or, if such a name
does not exist, the exact scientific designation; substances not having an international
non-proprietary name or an exact scientific designation describes the details of the
the origin and method of acquisition, with the possible addition of any other
relevant details,
(c)) in the case of colouring matter, designation by the "E" code in another legal
prescription ^ 10).
(C). when placing the "quantitative particulars" of the active substance or medicinal
fabrics finished products always indicate for each active substance
Depending on the pharmaceutical form of weight or number of units of biological
efficiency, either per dosage-unit or per unit of mass
or volume.
(D). Active substances present in the form of compounds or derivatives shall be
be designated quantitatively by their total mass, and if it is
necessary or important, or the mass of the active molecule.
F. for products containing a new active substance [§ 1, paragraph 2 (b), (c))]
is expressed in the content of the active substance, if it is a salt or hydrate shall systematically
mass of the active or active parts of the molecule. Quantitative
the composition of all products presented in the Czech Republic to register after the
their registration in a Member State must be for the same Active
substance referred to as has been stated in the context of such registration.
G. units of biological activity shall be used for substances that cannot
be chemically defined. If it has been defined by the World Health
organisations, the international unit of biological activity.
If the defined international unit, expressed with units
biological activity so as to provide unambiguous information on the
activity of the substances, using units of the European Pharmacopoeia.
3.2.2.2 pharmaceutical development
Information on the development studies conducted to confirm
that the dosage form, formulation, manufacturing process, container and its system
the conclusion, microbiological characteristics and instructions for use are appropriate
for the intended use specified in the marketing authorisation application dossier.
The studies described in this chapter can be different from the routine
control tests conducted according to specifications. Must be
identified and described the critical parameters for the composition and properties of
the process, which may affect the reproducibility of the batches, the effects and the quality of the
of the product. In the event additional supporting data
makes reference to the relevant chapters of module 4 (non clinical
Studies) and module 5 (clinical trials) documentation
the application for registration.
and) shall be compatibility of the active substance with excipients as well
as key physico-chemical properties of the active substance, which can
affect the performance of the finished product or the compatibility of different
the active substances with each other in the case of combination products.
(b)) shall be the choice of excipients, in particular in relation to their function and
concentration.
(c)) shall be the development of the finished product, taking into account the proposed
route of administration and usage.
(d)) shall justify any overages in the formulation or configurations.
(e)) concerning the physico-chemical and biological properties, and
evidence of, any parameter relevant to the effect of the finished product.
f) describe the selection and optimisation of the production process, as well as
differences between the manufacturing process or processes used to produce
pivotal clinical batches and the process used for manufacturing the proposed
of the finished product.
g) suitability of the container and its closure system used
for the storage, transport and use of the finished product. Where applicable, the
taking into account possible interaction between medicinal product and container.
(h)) in relation to non-sterile and sterile products shall be
the microbiological attributes of the dosage form in accordance with the European Pharmacopoeia
and must be accompanied by, as this pharmacopoeia prescribes.
I) to provide appropriate and supportive information for the labelling
must be accompanied by the compatibility of the finished product with solvent
or solvents for reconstitution or with metering device.
3.2.2.3 the manufacturing process of the finished medicinal product
and a description of the manufacturing method accompanying) the application for registration (section 26, paragraph 5,
(a). (d)) of the law on medicinal products) shall be specified so as to provide sufficient
an overview of the nature of the operations carried out. For this purpose they shall contain
at least
1. the information about the various stages of production, including process control and
the corresponding acceptance criteria, in order to assess whether the
processes employed in producing the pharmaceutical form might have produced an adverse change in
folders,
2. in the case of continuous manufacture, full details concerning the
measures taken to ensure the homogeneity of the finished product,
3. experimental studies validating the manufacturing process, if used
a non-standard method of manufacture, or if there is a way for the product
critical,
4. for sterile medicinal products, details of the used processes
sterilization and/or aseptic procedures,
5. the detailed composition of the lot, including the overage. Enter the name, address and
responsibility of each manufacturer, including contractors, and each proposed
production site or facility involved in manufacturing and testing.
b) particulars relating to the product control tests that may be
carried out at an intermediate stage of the manufacturing process in order to ensure
the consistency of the production process. These tests are essential for checking the
conformity of the product with the formula when, exceptionally, an applicant proposes
an analytical method for testing the finished product which does not include
assay of all the active ingredients (or of all the excipient constituents
If you are subject to the same requirements as the active ingredients).
The same applies where the quality control of the finished product depends on the
control tests during the production process, particularly if the
product is essentially defined by its method of production.
c) description, documentation, and results of the validation studies for the
critical steps or critical determination is used in the production
process.
3.2.2.4 Control of excipients
and all) provide materials needed for the manufacture of excipients or
excipients, designating, in which stage of the manufacturing process,
the material is used. Provide information on the quality and control
of these materials. Demonstrate that materials meet standards appropriate for
their intended use. The dye must in any case comply with the
the requirements of other legislation ^ 11). To validate the specified criteria
the purity of the methods of analysis are used, which verifies compliance with the criteria
for the purity of certain additives used in foodstuffs.
(b)) for each of the excipients are set out in detail the specifications and their
justification. Analytical methods must be described and duly validated.
c) particular attention must be paid to excipients of human or
of animal origin.
Having regard to the specific measures for the prevention of the transmission of animal
spongiform encephalopathies, the applicant must demonstrate also for excipients,
that the product is manufactured in accordance with the note for guidance on minimising the risk
of transmitting animal spongiform encephalopathy agents via
medicinal products and its updates, published by the Commission in the official additions
Journal of the European Union.
Compliance with the above note for guidance can be done either as a priority
the presentation of a certificate of suitability to the relevant monograph for portable
animal spongiform encephalopathies of the European Pharmacopoeia or the delivery of the
scientific data to substantiate this compliance.
(d)) the new excipient:
For excipients or inactive ingredients used in the product, or for the first time
a new route of Administration must be submitted complete information on production,
characterisation, and controls, with cross references to supporting data on
safety, both non-clinical and clinical, according to the format described above, the
for the active substance.
A document containing the detailed chemical, pharmaceutical and
biological information in the same structure as the document relating to the
active substance (3.2.1).
Information about the new auxiliary substance may be submitted as a separate
document in pursuit of the preceding paragraph. If the applicant
is not identical with the producer of the new excipients listed a separate document
must be available to the applicant for submission to the Institute.
Additional information on toxicity studies with the new excipient
shall be provided in module 4 of the documentation.
Clinical studies shall be provided in module 5.
3.2.2.5 Review of the finished product
For the control of the finished product includes the lot of all
the units of a pharmaceutical form which are made from the same initial quantity
of material and have undergone the same series of manufacturing and/or sterilization
operations or, in the case of a continuous production process, all the
units manufactured in a given period of time.
Unless there is appropriate justification, the maximum acceptable
deviation of the active substance content of the finished product shall not exceed, at the time
5% has been manufactured.
The detailed information about the specifications (for release and during
shelf life), in the preamble to their choice, methods of analysis and their
validation.
3.2.2.6 reference standards or materials
Indicate and describe in detail the reference standards used for testing
the finished product, unless they were already listed in the section on
the active substances.
3.2.2.7 the inner packaging of the finished product and its closure system
Shall provide a description of the container and the closure system (s),
all materials including the identity of the container and their specifications.
The specifications shall include description and identification. Where appropriate, shall be submitted to
methods that are not listed in the Pharmacopoeia, including validation.
For the materials of the outer packaging, which does not have any functionality, shall be provided only
a brief description. For the materials of the outer packaging, which has a function,
submit additional information.
3.2.2.8 Stability of the finished product
and) shall be summarised the types of studies conducted, protocols used, and results
studies.
(b)) in a suitable format to submit detailed results of stability studies
including information on the analytical methods used to generate the data and
validation of these methods; in the case of vaccines, the information shall be provided, where appropriate,
about the cumulative stability.
(c)) shall be submitted on the stability Protocol and stability commitment
for the post-marketing period.
4. module 4: NON-CLINICAL REPORTS
4.1 Format and edit
Module 4 has the following general structure:
4.1.1 content
4.1.2 the rights trials
4.1.2.1 Pharmacology
primary pharmaco-dynamics)
b) secondary pharmacodynamics
c) safety pharmacology
d) pharmacodynamic interactions
4.1.2.2 the pharmacokinetics of
and analytical methods and messages) on the validation
(b)) absorption
c) distribution
d) metabolism
e) excretion
f) pharmacokinetic interactions (non-clinical)
h) other pharmacokinetic studies
4.1.2.3 toxicology
a) toxicity after single administration
(b) repeated dose toxicity)
c) genotoxicity
1. in vitro
2. in vivo (including supportive toxiko-kinetic reviews)
d) carcinogenicity
1. long-term studies
2. short-term or medium-term studies
3. other studies
e) reproductive and developmental toxicity
1. fertility and early embryonic development
2. embryonic/fetal development
3. prenatal and postnatal development
4. studies in which doses are administered to offspring (juvenile animals) and/or
further evaluated
f local tolerance)
4.1.2.4. other toxicity studies
and antigenicita)
b) immunotoxicity
(c) mechanistic studies)
d) dependency
e) metabolites
f) dirt
g) other
4.1.2.5 literature references
4.2 content: basic principles and requirements
Special attention must be paid to these selected elements.
(1) the pharmacological and toxicological tests must show:
and the potential toxicity of the product and) any dangerous or undesirable
toxic effects that may occur under the proposed conditions of
use in human beings; These effects should be evaluated in relation to
the competent State pathological;
(b)) the pharmacological properties of qualitatively and quantitatively
relationship to the proposed use in human beings. All results must be
plausible and generally applicable. Whenever appropriate, the
mathematical and statistical procedures in designing the experimental methods
and in evaluating the results.
In addition, it is necessary for clinicians to be given information
about the therapeutic and toxicological potential of the product.
(2) for biological medicinal products, such as immunological medicinal
medicinal products and medicinal products derived from human blood or plasma, can be
necessary to adapt the requirements of the individual products;
executed by the test programme, the applicant shall be provided. When you create a program
testing shall be taken into account the following requirements:
and all tests requiring repeated) dosing must be
designed with regard to the possible invocation of and interference with antibody production
them,
(b)) must be considered examination of reproductive function, of embryo/foetal and
perinatal toxicity, of mutagenic potential and of carcinogenic
potential. With regard to the consequences of exposure to constituents other than medicinal
substances, it may replace the removal of their validated study.
(3) must be evaluated toxicological and pharmacokinetic properties
an excipient, which is first used in the pharmaceutical field.
(4) if there is a possibility of significant degradation of the product during its
storage, must be evaluated, the toxicology of degradation
products.
4.2.1 Pharmacology
Pharmacological studies follow two distinct lines of approach.
1. Must be sufficiently considered and describes the effects on
the proposed therapeutic use. If possible, the recognised and
validated tests, both in vivo and in vitro. New experimental
techniques must be described in such detail as to allow them to be reproduced.
The results shall be expressed in quantitative terms, for example. using curves
dose-effect of time-effect. Whenever possible, the comparison with
data relating to a substance or substances with a similar therapeutic action.
2. the applicant shall investigate the possible side effects of the substance on the
physiological function. This examination shall be carried out at exposures
corresponding to the anticipated therapeutic range and above.
Experimental techniques, unless they are standard procedures, you must be
described in such detail as to allow them to be reproduced, and the investigator must
to verify their validity. Must investigate any suspicion of change
response after repeated administration.
In the case of a pharmacodynamic interaction of can be a reason for
tests on combinations of active substances either pharmacological or assumptions
information about the therapeutic effect. In the case of conventional assumptions must
pharmacodynamic study shall demonstrate those interactions which might lead to the
that combination has relevance in therapeutic use. In the case of data on treatment
effect, where scientific justification for the combination relies on clinical
reviews, the tests shall be clarified whether the expected effects of the combination may
be demonstrated in animals, and must be evaluated at least significance
any side effects.
4.2.2 Pharmacokinetics
Pharmacokinetics means the study of the fate of the active substance and its
metabolites in an organism, and covers the study of the absorption, distribution,
metabolism (biotransformation) and excretion of active substance and of its
metabolites.
The study of these different phases shall be carried out in particular by means of physical,
chemical or biological methods and monitoring, as appropriate,
the pharmacodynamic action of the substance itself.
Information on distribution and elimination shall be necessary in all cases
where such data are indispensable to determine the dosage for
people, and in the case of chemotherapeutic substances (antibiotics, etc.) and substances,
the use of which is based on other than their pharmacodynamic
effects (e.g. numerous diagnostic agents).
In vitro studies also can be made with advantage with the use of the human
material for comparison with the animal (protein binding, metabolism,
interaction between medicinal products).
Pharmacokinetic study of all pharmacologically active substances is
necessary. In the case of new combinations of known substances that have been
studied in accordance with the provisions of this Ordinance, may not be
Pharmacokinetic studies required, if the toxicity tests and clinical
reviews shall justify their omission.
The pharmacokinetic program must be designed to allow comparison and
extrapolation between animal and human models used.
4.2.3 Toxicology
a) Toxicity after single administration
A single-dose toxicity test shall mean a qualitative and
quantitative study of the toxic reactions which may result from
a single administration of the active substance or substances contained in the product, and
in the proportions and physico-chemical state in which they are present in the
the actual product. A single-dose toxicity test shall be
carried out in accordance with the relevant guidelines published by the Agency.
(b) repeated dose Toxicity)
Repeated dose toxicity tests are intended to reveal
any physiological and/or anatomo-pathological changes
induced by repeated administration of the active substance or combination
active substances, and to determine how these changes are related to dosage.
Usually the tests shall be performed: one short-term, lasting two to
for four weeks, the other long-term. The duration of long-term tests depends on the
conditions of clinical use. The purpose of this test is to describe
the potential side effects, which should be paid attention to when
clinical trials. Duration of the test set out in relevant guidelines
published by the Agency.
c) Genotoxicity
The purpose of the study of mutagenic and clastogenic potential is to reveal the changes
which a substance may cause in the genetic material of individuals or cells.
Mutagenic substances may present a risk to health caused by
exposure to a mutagen carries the risk of germ cell mutation invoked with
the possibility of hereditary diseases and the risk of somatic mutations including
those leading to cancer. These studies are mandatory for
any new substance.
d) Carcinogenicity
As a rule, are required tests to reveal carcinogenic effects:
1. These studies shall be performed for each product, which is expected to
clinical application of patient's life over a longer period, either continuously
or repeatedly with a break.
2. These studies are recommended for some medicinal products if there is
doubt as to their carcinogenic potential, e.g.. on the basis of
of the same group or similar structure as the product
the known carcinogenic effects or on the basis of evidence from studies
After repeated dosing.
3. Studies with unquestionably genotoxic compounds are not necessary; about these
compounds, it is assumed that this is for all the animal species on the
carcinogens, which means a threat to humans. If there is such a
the product is intended for chronic administration of man may be required
chronic studies that were detected early tumorigenic effects.
e) reproductive and developmental toxicity
Review of possible impairment of male or female reproductive function,
as well as harmful effects on progeny shall be performed by appropriate
tests. These tests comprise studies of effect on reproductive function
adult male or female, studies of the toxic and teratogenic effects in the
all stages of development from conception after sexual maturity, as well as
latent effects of the investigational product is administered to pregnant female.
Omission of these tests must be adequately justified. Depending
the expected use of the product may be needed additional
the study focused on the development, in which the product is given to descendants.
Embryo/foetal toxicity studies shall normally be conducted on two
mammalian species, one of which would not be a rodent. Peri-and postnatal
the study shall be carried out at least one species. If it is known that
the metabolism of a given species is similar to that in man, it is
desirable to include this species. It is also desirable that one of the species was
the same as in the repeated dose toxicity studies. When determining the
the study plan taking into account the State of scientific knowledge at the time of submission of the
request.
f local tolerance)
The purpose of local tolerance studies is to ascertain whether medicinal products (both
healing and excipients) are tolerated at sites in the body, which may come
into contact with as a result of its administration in clinical use.
The testing strategy shall be such that any mechanical effects
Administration or purely physico-chemical actions of the product can be
distinguished from toxic and pharmacodynamic effects.
Local tolerance testing shall be carried out with specially developed for
human use, while in the control group or groups shall be used
vehicle and/or excipients. If needed, include the positive
checks for the use of the reference substances. The test plan local
tolerance (choice of species, duration, frequency and route of administration, doses)
depends on the problem to be investigated and the proposed
conditions of administration in clinical use. If necessary, evaluate the
the reversibility of local damage.
Animal studies can be substituted by validated in vitro tests
provided that the test results are of comparable quality and
usefulness for the purpose of safety evaluation.
The chemicals used on the skin or mucous membranes (e.g., dermal,
rectally, vaginally) evaluates the potential at least for sensibilizační
one of the test systems currently available (a test on Guinea-Pigs
or test the local lymph nodes).
5. Module 5: clinical TRIALS
5.1 Format and edit
Module 5 has the general structure:
5.1.1 the content of messages about clinical trials
5.1.2 table enumeration of clinical studies
5.1.3 messages about clinical trials
and reports of bio-pharmaceutics studies)
1. bio-availability study reports
2. the report on the comparative studies of bioavailability and bioequivalence studies
3. reports of studies of the correlation of in vitro-in vivo
4. reports of Bioanalytical and analytical methods
(b)) reports of studies related to pharmacokinetics using
human biomaterials
1. reports of the plasma protein binding study
2. reports of hepatic metabolism and interaction studies
3. reports of studies using other human biomaterials
(c)) reports on pharmacokinetic studies in humans
1. the reports of pharmaco-kinetic and initial tolerability study
in healthy subjects
2. the reports of pharmaco-kinetic and initial tolerability study
in patients
3. the reports on the studies of the influence of internal factors on the pharmacokinetics of
4. reports of studies of the influence of external factors on the pharmacokinetics of
5. reports of human pharmacokinetic study in a population
d) pharmacodynamic studies in humans
1. study reports farmakodymaniky and pharmacokinetics/farmakodymaniky
in healthy subjects
2. reports of studies farmakodymaniky and pharmacokinetics/farmakodymaniky
in patients
f) reports on the efficacy and safety studies
1. reports of controlled clinical studies relating to
declared indication
2. study reports of uncontrolled clinical studies
3. the reports of analyses of data from more than one study, including any
formally integrated analyses, meta-analyses and bridging analyses
4. other reports of studies
h) reports on postmarketing experience
5.1.4. literature references
5.2 contents: basic principles and requirements
Special attention must be paid to these selected elements:
and clinical data), to be submitted pursuant to section 26 of the law on pharmaceuticals,
must allow the creation of a sufficiently reasoned and scientifically valid
opinion on whether the product meets the criteria for the award
registration. The basic requirement is the submission of the results of all
clinical trials, as favourable as unfavourable.
b) clinical trials must always be preceded by adequate pharmacological
and toxicological tests, carried out on animals in accordance with the requirements of
Module 4 of this annex. Clinical trials shall be carried out in accordance with the
the provisions of the Act and its implementing regulations, which ensure that
the investigator will get acquainted with the conclusions arising from the pharmacological and
toxicological studies, the applicant shall provide at least the file zkoušejícímu
the investigator's brochure, which contains all the important information
known before the commencement of a clinical trial including chemical,
pharmaceutical and biological data, toxicological,
Pharmacokinetic and pharmacodynamic data in animals and the results of
earlier clinical trials, with adequate data to justify the
the nature, extent and duration of the proposed evaluation, taking full
pharmacological and toxicological reports shall provide on request. For
materials of human or animal origin are used all of the available
means to ensure safety with respect to the transmission of infectious agents
prior to the commencement of the trial.
(c)) the marketing authorisation holder must ensure that the basic
clinical trial documents (including case report forms of entities
reviews) in addition to the medical records of the subjects were
stored data owners
-for at least 15 years after completion or discontinuation of the trial,
-or for at least 2 years after the last registration in
The community, if they are not submitted, or no intention to present any
other requests for registration in the community,
-or for at least 2 years after formal discontinuation of clinical development
investigational product.
The medical record of the subjects are kept in accordance with the
the legislation, for the longest time the internal rules
the health care facility. However, the documentation may be retained even after the
longer period of time, where provided for by the agreement with the contracting entity or is it
required by the competent authorities of the Member State of the community.
The contracting authority is responsible for informing the medical equipment that
documentation of the clinical trial may no longer be retained.
The sponsor or other owner of the data shall retain all other documentation
relating to the evaluation, in the meantime, until the product is registered. This
documentation includes: the Protocol including the rationale, objectives and statistical
design and methodology of the trial, with conditions under which it is reviews
performed and managed, and details of the investigational product, the reference
preparation or the placebo used; standard operating procedures; all
written opinions on the Protocol and procedures; file information for the
the investigator's brochure; forms on each trial subject; final
the message; audit certificates, if available. Final report of the
the sponsor or subsequent owner, kept for 5 years after the end of
the validity of the registration of the product.
In addition to the assessments carried out in the community, the holder of the
registration must make additional arrangements for archiving of documentation in the
accordance with the provisions of the law on pharmaceuticals, its implementing regulations and
the guidelines of the Institute, the Commission and the Agency. Any change in the ownership of the data
must be documented. All data and documents must be made available to the
the request of the Institute.
(d)) the particulars of each clinical trial, referred to in the following
the documents must contain sufficient detail to allow an
an objective judgement. Of the following documents:
-the Protocol including the rationale, objectives and statistical design and methodology
the trial, with conditions under which it is performed and managed, and details of
about the investigational medicinal product,
-audit certificates, if available,
-a list of investigators, each of them must be mentioned his
name, address, job title, qualifications and duties of the position held
When the conduct of the trial, where the trial was
done, and a summary of each individual patient, including
case report forms on each trial subject,
-final report signed by the investigator and for multicentre evaluation
by all the investigators or principal investigator.
(e)) the above information about the clinical trials submitted to the Institute. After
the agreement with the Institute, however, the applicant may omit a portion of this information.
The complete dossier shall be submitted immediately upon request.
The investigator shall, in his conclusions on the experimental results
opinion on the safety of the product under normal conditions of use, its
tolerability, efficacy and any useful information relating to the
indications, contra-indications, dosage and average duration of treatment as well
as any special precautions to be taken during treatment
and the clinical symptoms of overdosage. In reporting the results
multicentre study principal investigator expressed on behalf of all
the participating workplaces in its conclusions, opinion on the safety and
the effectiveness of the investigational product.
f) clinical observations shall be summarized for each trial indicating the
1. number and sex of subjects treated
2. the selection and age-distribution of the groups of patients being investigated and the comparative
tests,
3. the number of patients withdrawn prematurely from the trials and the reasons for such
disposal,
4. where controlled trials were carried out under the above
terms and conditions, information about whether the control group:
(2) was not treated,
(3) received a placebo,
(4) received another medicinal product of known effect,
(5) was treated differently than the use of the products,
5. the frequency of observed adverse reactions;
6. details concerning patients who may be at increased
risk, for example. elderly people, children, women during pregnancy or menstruation
or whose physiological or pathological condition requires
Special attention,
7. parameters or evaluation criteria of efficacy and the results in terms
These parameters,
8. the statistical evaluation of the results, if a plan is required
reviews, including variability.
(g)) the investigator shall always indicate his observations on the
1. any signs of habituation, addiction or difficulty in weaning
patients from the product
2. any interactions observed with any simultaneously administrated
preparations,
3. the criteria on the basis of certain patients are excluded from
reviews,
4. any deaths which occurred during the trial or within the period
follow-up.
h) data on the new combination of medicinal substances must be identical to those
required for new medicinal products and must substantiate the safety and
efficacy of the combination.
I) total or partial omission of data must be explained. If you are in the
should unexpected results occur during the evaluation must be carried out and
evaluated further preclinical toxicological and pharmacological tests.
(j)) if the product is intended for long-term administration, shall be
details of any modification of the pharmacological action following repeated administration, and
It also provides long-term dosage.
5.2.1. Reports of bio-pharmaceutics studies
A report on the studies of bioavailability, study reports
comparative bioavailability and bioequivalence study reports
correlation of in vivo-in vitro and bioanalytical and analytical methods.
In addition, the assessment of bioavailability shall be carried out, if it is necessary to
demonstrate bio-equivalence for products referred to in section 27 of the law on medicinal products.
5.2.2. Reports of studies of pharmacokinetics using human
biomaterials
For the purposes of this annex, human bio-materials shall mean all
proteins, cells, tissues and related materials derived from human
the sources that are used in vitro or ex vivo to assess
the pharmacokinetic properties of the drug substance. A report on the
the plasma protein binding study, hepatic metabolism
and the interactions of the active substance and studies using other human
biomaterials.
5.2.3. Reports of human pharmacokinetic studies
and) must be described following pharmacokinetic characteristics:
1. absorption (rate and extent),
2. distribution,
3. metabolism,
4. excretion.
Must be described in a clinically significant features including the implication
of the kinetic data for the dosage regimen especially for patients at risk,
and the differences between man and animal species used in the preclinical
studies.
In addition to standard pharmacokinetic studies with multiple samples
can the issues of the impact of internal and external factors to the variability in relation
the dose-pharmaco-responsive also address analysis
Population pharmacokinetic based on small numbers of samples derived from the
clinical trials. A report on the studies of pharmacokinetics and
the initial tolerability in healthy subjects and in patients, reports on
human pharmacokinetic study to evaluate the impact of internal and external factors
and reports of human pharmacokinetic study in a population.
(b)) if the product is normally co-administered with other
preparations, the data on the tests with combined administration
performed to demonstrate possible modification of the pharmacological action.
Must be considered a pharmacokinetic interaction between the active substance and
other medicinal products or substances.
5.2.4 pharmacodynamic studies in humans
and demonstrating the pharmacodynamic effect) relative to the efficiency, including
1. the relationship of the dose and response, and its time course,
2. justification for the dosage and conditions of administration,
3. mode of action, if possible. Describe the pharmacodynamic
the action, which is not related to efficiency. The demonstration of pharmaco-dynamic
effects in humans is not in itself sufficient to justify conclusions
relating to any particular potential therapeutic effect.
(b)) if the product is normally co-administered with other
preparations, the data on the tests with combined administration
performed to demonstrate possible modification of the pharmacological action.
Must be studied pharmacodynamic interactions between the active substance and
other medicinal products or active substances.
5.2.5. Reports of efficacy and safety studies
5.2.5.1. health reports of controlled clinical studies relating to
declared indication
In General, clinical trials shall be done as "controlled clinical
"and if possible, randomized and or versus placebo and against
established product of proven therapeutic value; any other
the layout must be justified. The control treatment in the evaluation of the
vary from case to case and also will depend on ethical considerations and
therapeutic areas; in some cases, it may be more appropriate
to compare the efficacy of the new product with that of an established product with
proven therapeutic value rather than with the effect of a placebo.
-If possible, and particularly in trials where it cannot be
the effect of objectively measured, steps shall be taken to
avoid bias, including by randomisation and blinding.
-Protocol of the trial must include a thorough description of the
statistical methods, the number of patients and the reasons for their inclusion
(including calculations of the power of the trial), the level of significance to
to be used and a description of the statistical unit. Must be accompanied by the
measures taken to avoid bias, particularly methods of randomisation.
The inclusion of a large number of subjects in the trial may not be considered
sufficient to pay the duly controlled assessment.
The safety data shall be reviewed taking account of the guidance published
The Commission, with particular attention to events resulting in changes of dose
or the need for concomitant administration of other medicines, serious
adverse events, events leading to exclusion and the subject's death.
Must be identified for all patients or groups of patients
higher risk, and special attention must be paid to the potentially
vulnerable patients, for example. children, pregnant women, the weak legacy
the people, the people with the implication or excretion, who
may be present in small numbers. Describe the impact reviews
safety in the use of the product, maybe.
5.2.5.2 study reports of uncontrolled clinical studies reports of
analyses of data from more than one study and other clinical
studies
The said report shall be provided.
5.2.6. Reports of post-marketing experience
If it is already authorised in third countries, the
information regarding the adverse effects of the product in these
countries and products containing the same active substance or active
substance, as far as possible in relation to the amount of consumption.
5.2.7 forms and enumerators of data about individual patients
If you follow the relevant instructions of the Agency shall submit the form
records and data on individual patients, in the same
order as the clinical study reports and messages marked with an identifier
the study.
PART II
SPECIFIC MARKETING AUTHORISATION DOSSIERS AND REQUIREMENTS
Some products show a sufficiently specific properties that need to be
all the requirements of the marketing authorisation application dossier as laid down in
Part I of this annex, to adapt. In these situations must
applicants to follow the appropriate customized a form of documentation.
1. WELL-ESTABLISHED MEDICINAL USE
For products whose active substance or active substance have well
well-established medicinal use, with recognized efficacy and an acceptable level of
safety pursuant to § 27 para. 7 of the law on medicinal products shall apply this
Special rules. The applicant shall submit modules 1, 2 and 3 as described in part I of the
of this annex. In modules 4 and 5, shall be non-clinical and clinical
features a detailed scientific bibliography. Well established
use the following specific rules shall be accompanied:
a) factors which have to be taken into account in order to establish a "well established
medicinal use "of components of medicinal products are:
-the period for which the substance is used,
-quantitative aspects of the use of the substance,
-the degree of scientific interest in the use of the substance (reflected in the published
scientific literature) and
-the coherence of scientific assessments.
To demonstrate the well-established medicinal use of various substances, and
ways to use may be required in different time periods. In each
If, however, the time required to demonstrate the well-established medicinal
the use of components of the product and the method of its use shall be not less than
10 years from the first systematic and documented use of that substance
as in the community. Rules for the well established
use only for the therapeutic use of such substances, which
complies with the principles referred to in this paragraph;
(b)) the documentation submitted by the applicant should cover all aspects of
evaluation of the safety and/or efficacy assessment and must include an overview of the
the relevant literature, including a detailed description of the procedure used in the
retrieval of data, and in the case that are not listed in the overview of all
found source of information, then i the procedure chosen to their selection and
justification for their inclusion. In so doing, consideration shall be given to the studies before
placing on the market and post-marketing studies and published scientific
literature concerning experience in the form of epidemiological studies and
in particular of comparative epidemiological studies. Shall be presented to all
documentation, both favourable and unfavourable. Having regard to the provisions on the
well-established medicinal use is in particular necessary to clarify that, as
a valid proof of safety and efficacy of the product may
bibliographic data from tests and reviews also serve other
bibliographic details (post-marketing studies, epidemiological studies
etc.), where a request satisfactorily explained and justified their
the use of the. Furthermore, it should be accompanied by the relationship of the products
referred to in literary overviews;
c) particular attention must be paid to any missing information and
in the choose overview and clinical justification must be given why you may be
demonstration of an acceptable level of safety and/or efficacy,
Although some studies are lacking.
(d)) in the choose overview and clinical relevance must be explained
any data submitted which concern a product different from the
the product to be placed on the market. It must be decided whether the
the product studied to be regarded as similar to the product, which will be
granted a marketing authorisation in spite of the existing differences;
e) post-marketing experience with other products containing the
the same constituents is of particular importance and applicants should put a
Special emphasis.
2. GENERIC PRODUCTS
Application based on section 27 para. 1 of the law on medicinal products shall contain the information
described in modules 1, 2 and 3 of part I of this annex together with data
proving the bioavailability and bioequivalence with the original
product, provided that the original is not a biological medicinal product
medicinal product (section 4).
For these products are non-clinical and clinical summaries and subtotals
in particular, focus on the following elements:
2.1. justification for the failure to submit to pre-clinical tests and clinical
reviews,
2.2 Summary of impurities present in batches of the drug substance or medicinal
substances, as well as finished product (and possibly relevant
degradation products arising during storage) as proposed
for the preparation on the market, together with the evaluation of these impurities,
2.3 evaluation of bioequivalence studies or a justification, why not study
made with regard to the relevant guidelines of the Agency for the evaluation of
bioavailability and bioequivalence studies,
2.4. the updated list of published literature relating to the substances and
requests submitted. For this purpose, it is acceptable to link to articles
published in journals with peer,
2.5 every claim in the summary of product characteristics, which is not known or
inferred from the properties of the original product and/or its therapeutic
the Group should be discussed in the non-clinical and clinical reports and
summaries and substantiated by published literature and/or additional
studies,
2.6 where applicable, should the applicant to demonstrate the similarities to submit additional
data demonstrating the equivalence of the properties of different salts, esters, isomers
or derivatives of an authorised active substance in relation to the safety and
efficiency.
3. additional DATA REQUIRED in SPECIFIC SITUATIONS
If the active substance in a generic medicinal product contains the same therapeutic
the active ingredients as the original authorised product in conjunction with the
by a different salt/ester complex/derivative/an isomer, must be satisfied
that there is no such change of pharmacokinetics, Pharmacodynamics
and/or toxicity which could change the safety/efficacy profile.
If a change in the safety/efficacy profile occurs shall be deemed
join as a new active substance.
If it is newly registered product is intended for a different therapeutic use
than the original authorised product or is presented in a different drug
the form or should be administered by different routes or in different doses, with
a different posology, the results must be submitted to the respective
toxicological and pharmacological tests or clinical trials.
4. SIMILAR BIOLOGICAL MEDICINAL PRODUCTS
If the information required pursuant to the provisions of § 27 para. 5 of the law on pharmaceuticals
do not allow the evidence of a similar nature of two biological medicinal products,
additional information must be submitted, in particular, the toxicological and clinical
profile.
If the applicant shall provide the data protection period to register
biological medicinal product, as defined in part I, paragraph 3.2 of this
of the annex, by reference to the original medicinal product authorised in the community,
use the following procedure:
3 data to be submitted shall not be limited to modules 1, 2 and 3
(pharmaceutical, chemical, and biological data), supplemented by data on
Bioequivalence and bioavailability. The type and amount of additional
the data to be submitted shall be in accordance with the relevant
the criteria established by other legislation ^ 4) and related instructions
The Commission, the Agency and indicating the directions of the Institute.
General procedures that are to be used, are the subject of the order
published by the Agency, taking into account the characteristics of the biological
medicinal products. In the event that the original authorised product has
more than one indication, efficacy and safety must be the preparation,
declared as similar to, or, where appropriate, demonstrated separately
for each declared indication.
5. Fixed combination MEDICINAL PRODUCTS
Application based on section 27 para. 8 of the law on pharmaceuticals concern new
products that consist of at least two active substances that have not been
previously in the community as a fixed combination medicinal product.
Such applications shall be submitted to a full dossier (modules 1 to 5)
for the fixed combination medicinal product. The emphasis is above all proof
the clinical benefit of fixed combination of monotherapy
individual components. If necessary, it shall submit information on the
production and evaluation of safety with respect to foreign agents.
6. Documentation of APPLICATIONS in EXCEPTIONAL CIRCUMSTANCES
If, in accordance with the provisions of § 32 para. 3 of the law on pharmaceuticals, the applicant
demonstrates that he is unable to provide comprehensive data on the efficacy and
safety under normal conditions of use, because the
-the indications for which the medicinal product is intended are encountered so rarely,
that cannot be reasonably expected from the applicant to provide complete evidence, or
-in the present state of scientific knowledge comprehensive information cannot be
granted, or
-the collection of such information would be contrary to generally accepted
the principles of medical ethics,
authorisation may be granted subject to certain specific conditions.
These conditions may include the following:
-the applicant terminates within the time specified by the Institute identified programme of studies, the
the results will form the basis for a reassessment of the benefit/risk profile,
-the product may be supplied on medical prescription only and may in
certain cases be administered only under strict medical supervision, possibly
in the hospital, and for a radiopharmaceutical, by an authorised person to do so
-the package leaflet and any medical information alert
a medical practitioner to the fact that the information available for the product
are as yet inadequate in certain specified respects.
7. The COMBINED applications for registration
The combined applications for a marketing authorisation "means a marketing authorisation application
presented with the documentation, the module 4 and/or 5 consists of a combination of
reports on non-clinical or clinical studies conducted by the applicant and
of bibliographic references. All other modules are in accordance with the
the structure described in part I of this annex. The appropriateness of the format
shall examine the documentation in individual cases by the Institute.
PART III
SPECIAL PRODUCTS
In this section are laid down specific requirements in relation to the nature of the
certain preparations.
1. BIOLOGICAL MEDICINAL PRODUCTS
1.1 Products derived from plasma
For medicinal products derived from human blood or plasma can be by way of derogation
from the provisions of module 3 documentation requirements for starting materials
derived from human blood or plasma are listed in the "Information relating to the
starting and raw materials "are replaced by the founding document of the plasma
(plasma master file) that can be issued under this certificate
part.
and) policy
For the purposes of this Annex:
-the founding document of the plasma master file shall mean a stand-alone document delimited
from the dossier that provides all the detailed information
about the properties of all the human plasma used as starting material
or raw material for the production of sub-fractions or entry-level, intermediate fractions, constituents
excipients and active ingredients or substances, which are part of the
medicinal products or medical devices;
-each device for fractionation/processing of human plasma shall prepare and
maintains an updated file of the relevant detailed information referred to
in the basic document of the plasma;
-Basic plasma master file shall provide the registrant or the holder of the
the decision of the agency or institution. If the applicant is a
the registration or the marketing authorisation holder identical to the holder of the
the basic document of the plasma, shall ensure that the basic document on the
plasma is made available for the purpose of presentation of the Institute. In the cases referred to in the second
indent of subparagraph (c)), unless the specific case referred to in the last indent of the
in the same letter, the Institute will wait for a decision on the application, the Agency will issue to
the certificate;
-any marketing authorisation dossier containing a folder derived from human
the plasma must refer to the basic document of the corresponding
the plasma used as starting/raw material.
(b)) table of contents
Basic plasma master file shall include information on the plasma used
as starting material/raw material, in particular:
1. Plasma origin
-Information about facilities or establishments in which the collection is carried out
blood/plasma, including inspection and approval, and epidemiological data on
infections transmissible by blood.
-Information about facilities or establishments in which testing is performed
donations and plasma pools, including inspection and approval status.
-The selection criteria and the exclusion of blood/plasma donors.
-System in place which allows you to track the path of each subscription from
equipment for blood/plasma collection through to finished products and vice versa.
2. Plasma quality and safety
-Compliance with European Pharmacopoeia Monographs.
-Testing of blood/plasma donations and pools for infectious agents,
including information on test methods and, in the case of plasma pools data on
the validation of the tests used.
-Technical characteristics of bags for blood and plasma collection, including
information on anticoagulants solutions used.
-Conditions of storage and transport of plasma.
-The procedures for any inventory hold and/or quarantine period.
-Characterisation of the plasma.
3. the system established between the manufacturer of originating in the plasma or
the unit, which handles or frakcionuje plasma, on the one hand, and
centres or establishments, which shall be tested in blood/plasma, the
the other hand, defining the conditions for their cooperation and approved
specification.
Furthermore, the plasma master file must include a list of products, for
that is true whether they are registered or are in the registration procedure,
including investigational products.
c) evaluation and certification
-In the case of unregistered products yet, the Registrant shall submit to the
Complete documentation with the Institute, accompanied by a separate core document about
plasma, if this document does not exist.
-The basic document of the plasma is subject to a scientific and technical
evaluation carried out by the Agency. As a result of a positive evaluation is
certificate of conformity of the plasma master file with the legislation
The community, to which is attached the assessment report. Issued by the
the certificate shall apply throughout the community.
-Basic plasma master file must always be updated and newly
certified.
-Changes in the baseline document subsequently made by the plasma master file shall be
evaluated according to the conditions and procedure laid down by the competent law
^ 12) community concerning the examination of variations to marketing authorisations.
-When the evaluation of the Institute shall take into account to the certificate renewed
the certificate or change the underlying plasma master file for the product
or the products.
-Notwithstanding the provisions of the second indent of this subparagraph in cases where
Basic plasma master file applies only to products derived from blood
or plasma, whose registration is limited to the Czech Republic, scientific
and technical evaluation of the plasma master file does
Institute.
1.2 the vaccine
For vaccines for human use, the system is the basic document on the Antigen
vaccine (vaccine antigen master file), by way of derogation from the provisions for
active substance or active substances in module 3 shall apply to the following
requirements.
The marketing authorisation application dossier of a vaccine, in addition to the vaccine against human
flu, must contain the basic document for each vaccine Antigen master file
vaccine Antigen that is the active substance of this vaccine.
and) policy
For the purposes of this Annex:
-the founding document of a vaccine Antigen master file shall mean a stand-alone part of
the marketing authorisation application dossier of a vaccine, which contains all the
important biological, pharmaceutical and chemical data for each of the medicinal
substances that are part of this vaccine. A separate section can be
common to one or more Monovalent and/or combined vaccines
submitted by the same applicant or marketing authorisation holder;
-vaccine may contain one or more distinct vaccine antigens.
Each antigen in the vaccine is considered to be the active substance;
-a combined vaccine contains at least two distinct vaccine antigens,
to induce protection against one or more infectious diseases;
-monovalent vaccine is a vaccine, which contains one antigen
the vaccine to induce protection against a single infectious disease.
(b)) table of contents
The basic document of the vaccine Antigen master file shall contain the following
information excluded from the appropriate section of the (substance) of module 3 for details about the
quality, as described in part I of this Annex:
The active substance
1. General information, including compliance with the relevant monograph or
monographs of the European Pharmacopoeia.
2. Information on the manufacture of the active substance: there must be included in the production
process, information on the starting and raw materials, specific
measures for the evaluation of the safety against TSEs and adventitious agents, as well as
production equipment and facilities.
3. Characterisation of the active substance.
4. Quality control of the active substance.
5. Reference standards and materials.
6. The inner packaging of the active substance and its closure system.
7. stability of the active substance.
c) evaluation and certification
-For new vaccines that contain the new vaccine antigen, present
the applicant Institute complete documentation of the application for registration, including all
basic documents corresponding to each vaccine Antigen master file
a single vaccine Antigen that is part of the new vaccine, if
already a basic document for each vaccine antigen does not exist.
Scientific and technical evaluation of each of the basic document on the Antigen
the vaccine carries out the Agency. As a result of a positive evaluation of the certificate is
compliance with the Community legislation for each of the basic document on the
vaccine Antigen master file, which shall be accompanied by the evaluation report.
The certificate shall apply throughout the community.
-The provisions of the first indent shall also apply to every vaccine, which
It consists of a new combination of vaccine antigens, irrespective of whether it is
or not one or more of these vaccine antigens part of vaccines already
registered in the community.
-Changes to the content of the vaccine Antigen master file, registered in the
The community are subject to a scientific and technical evaluation carried out by the
the Agency, pursuant to the procedure established by the relevant regulation
Community ^ 2). In the case of a positive evaluation the Agency shall issue
certificate of conformity of the vaccine Antigen master file with the legal
Community legislation. The certificate shall apply throughout the community.
-By derogation from the provisions of the first and third indents of the present point (evaluation
and certification) in cases where the vaccine Antigen master file shall
refers only to the vaccine, which has not been or will not be granted a registration procedure
Community, and provided that the vaccine contains
the vaccine antigens which have not been evaluated by the scientific community procedure
and technical evaluation of the vaccine Antigen master file and
his subsequent changes, the Institute performs.
-When the evaluation of the Institute shall take into account to the certificate renewed
the certificate or change the underlying vaccine Antigen master file for the
product or the products.
2. RADIOPHARMACEUTICALS and precursors
2.1 Radiopharmaceuticals
For the purposes of this chapter, with requests pursuant to § 25 para. 3 of the law on
pharmaceuticals will submit the full documentation, which must contain the following
specific details:
Module 3
and) in connection with a radio-pharmaceutical Kit, which is to be radiolabelled
marked after supply by the manufacturer, the active substance is considered to be the folder,
that is intended to carry or the radio-nuclide. Description of the method
production of the kit for radiopharmaceutical also includes details about the manufacture of the kit and
details of its recommended final processing to produce the radioactive
medicine. The necessary specifications of the radionuclide shall be described in accordance with
General or specific monographs of the European Pharmacopoeia. Additionally, they shall indicate the
all compounds essential for radiolabelling. Also shall be
the structure of the radiolabelled compounds.
For radionuclides to explain appropriate nuclear reaction.
The generator shall be construed as medicinal substances both mother and child
radionuclide. Enter a general description of the system together with a detailed description of the
components, which may affect the composition or quality of the product with the subsidiaries
radionuclide, and the further qualitative and quantitative particulars of the eluate or
the sublimate.
(b)) details about the nature of the radionuclide, the identity of the isotope,
likely impurities, the carrier, the use and the specific activity.
(c)) between the starting materials include irradiation target.
d) considerations on chemical/radiochemical purity and its relationship to the
biodistribution.
(e) radio-nuclide shall be described) purity, radiochemical purity and specific
activity.
(f)) for generators, details on the testing are required of the parent and
combinations of the radionuclide. For generator-eluates, must be submitted to the
tests for mother radio-nuclides and for other constituents of the generator
the system.
g) the requirement that the content of active substances in terms of the mass of
active parts, only applies to kits for the radiopharmaceutical. For radionuclides
is expressed in units of becquerel radioactivity to date and
Alternatively, time with reference to time zone. Enter the type of radiation.
h) for kits, the specifications of the finished product shall include tests
verification of labelling. Include appropriate controls
radiochemical and radionuclide purity of the radiolabelled compounds.
Shall determine the content of any material relevant for the
radioactive signs.
I) information on stability shall be given for radionuclide generators, radionuclide kits
for radionuclides and radio-labelled products. Shall be
stability of radiopharmaceuticals in multidose vials during use.
Module 4
Take into account that toxicity may be associated with a radiation dose. In
the diagnosis as to the effect of the use of radio-pharmaceuticals; in the treatment of desirable
property. Evaluation of the safety and efficacy of radiopharmaceuticals must take into account
requirements for the preparation and biodistribution. Shall be
organ/tissue exposure to radiation. Absorbed radiation dose estimates shall
be calculated according to a specified, internationally recognised system by a
the route of administration.
Module 5
The results of clinical trials shall be provided, if applicable;
If the results are not submitted, the reasoning in clinical
the summaries.
2.2 precursor radiopharmaceuticals for labelling purposes
In the specific case of a radio-pharmaceutical precursor intended solely for
labelling purposes is the primary goal to submit information,
which take into account the possible consequences of low efficiency-labelling
or in vivo degradation of radiolabelled product, IE. questions
concerning the effect of the free radio-nuclide in the patient. Additionally, always
the relevant information relating to safety at work, IE.
exposure/exposure of the hospital staff and the
environment. In particular, the following information shall be provided, if they are
applicable:
Module 3
The establishment of module 3 applies when the registration of radio-pharmaceutical precursor, as
mentioned above [paragraph 2.1 (a) to (i)))], if applicable.
Module 4
In terms of toxicity after single administration and after repeated administration,
the results of studies conducted in compliance with the requirements of the correct
laboratory practice, unless otherwise justified.
Study on mutagenicity of a radionuclide not in this particular case
considered useful.
Shall submit the information relating to the chemical toxicity and disposition of the
the relevant "cold" nuclide.
Module 5
Clinical information derived from studies using on the precursor itself
are not considered in the specific case of a radio-pharmaceutical precursor
intended solely for radio-labelling purposes.
However, information demonstrating the clinical usefulness of the precursor
After connecting to the appropriate radiopharmaceuticals molecule carrier.
3. homeopathic MEDICINAL PRODUCTS
This section sets out specific provisions for the use of modules 3 and 4 to
homeopathic preparations, as defined in section 2 (2). 2 (a). (g))
the law on pharmaceuticals.
Module 3
The provisions of module 3 shall apply to the documents submitted in
a simplified procedure of registration of homeopathic products and
the registration of specific homeopathic products with the following
modifications.
and) Terminology
The Latin name of the homeopathic stock described in the documentation
submitted with the application for registration must be in accordance with the Latin name
in the European Pharmacopoeia; If there is no in it this name in Pharmacopoeia
of a Member State. Where appropriate, provide the name of the traditional or traditional
the names used in other Member States.
(b)) control of starting materials
Data and documentation for starting materials, i.e. all the materials used
including raw materials and intermediates up to the final dilution, processed into
the finished product shall be submitted with the application, must be
supplemented by additional data on the homeopathic underlying substance.
The general quality requirements shall apply to all source materials and
raw materials, as well as intermediate stages of the manufacturing process up to the final
dilution to be incorporated into the finished product. If it is possible,
the inclusion of the determination, if the present toxic
substance and if you cannot control the quality in the final dilution due to its
high degree. Each step of the manufacturing process from raw materials after
the final dilution to be incorporated into the finished medicinal product must be
fully described.
In the case that's included dilutions, dilution of these steps must be performed
According to the homeopathic manufacturing practices set out in the relevant
a monograph of the European Pharmacopoeia or, in the absence of a Member
State
.
c) control tests on the finished product
The general quality requirements shall apply to homeopathic final
products, any exception needs to be duly justified by the applicant.
Identity must be established and the contents of all the toxicologically relevant
folders. If it can be justified that an identification and/or determination of the content of all
the toxicologically relevant constituents is not possible, for example. due to their
dilution in the finished product, proof of the quality of the complete validation
the production process and the process of dilution.
d) stability tests
Must be accompanied by the stability of the finished product. Stability data
homeopathic stocks are generally transferable to
dilution/triturace of them obtained. If identification is not possible or
determination of the content of the active substance for a high degree of dilution may be taken
into account the data on the stability of the formulation.
Module 4
The provisions of module 4 shall apply to the simplified registration procedure
homeopathic products with the following specification. Any missing
information must be justified, e.g.,. justification must be given why you may be
demonstration of an acceptable level of safety, although some studies
missing.
4. HERBAL MEDICINAL PRODUCTS
With applications for herbal medicinal products shall be submitted to the full
documentation, which must be included the following specific
details:
Module 3
When you register the herbal medicinal product shall apply the provisions of
module 3, including compliance with monograph (s) or the European
Pharmacopoeia. Taking into account the State of scientific knowledge at the time when the
request is submitted. Consider the following aspects specific to
herbal medicinal products:
1. Herbal substances and herbal preparations
For the purposes of this annex, the terms "herbal substances and herbal preparations"
considered to be equivalent to the terms "herbal drugs and preparations
herbal drug ", as defined in the European Pharmacopoeia.
With respect to the nomenclature of the herbal substance, the binomial scientific
the name of plant (genus, species, variety and author), and chemotype, parts of
the plants, the definition of the herbal substance, the other names (synonyms mentioned in
other pharmacopoeias) and the laboratory code. With regard to the terminology
the herbal preparation, the binomial scientific name of plant (genus,
species, variety and author), and chemotype, parts of plants, the definition of
the herbal preparation, the ratio of herbal drug to herbal drug preparation
solvent or solvent for extraction, the other names (synonyms
mentioned in other pharmacopoeias) and the laboratory code.
To document the section on the structure of the herbal substance or the herbal substances
and herbal medicine or herbal preparations shall bear the
physical form, a description of the components with known therapeutic efficacy or markers
(molecular formula, relative molecular mass, structural formula,
including relative and absolute stereo-chemistry), as well as other folders.
To document the section on the manufacturer of the herbal substance, the name, address and
responsibility of each supplier, including contractors, and each proposed
production site or facility involved in the cultivation/collection and testing
herbal substances, where appropriate.
To document the section about the production of the herbal preparation, the name,
address, and responsibility of each manufacturer, including contractors, and each
the proposed production site or facility involved in manufacturing and testing
the herbal preparation, comes into consideration.
With regard to the description of manufacturing process and process controls for the herbal
substance information shall be provided to adequately describe the growing and harvesting
the plant, including the geographical sources of medicinal plants and cultivation,
harvesting, drying and storage conditions.
With regard to the description of manufacturing process and process controls for the herbal
product information shall be provided to adequately describe the manufacturing process
the herbal preparation, including a description of the processing, solvents and
reagents, purification stages and standardisation.
With regard to the development of the manufacturing process shall be provided a brief summary of
describing the development of the herbal substance or the herbal substances and, where appropriate,
the herbal preparation or vegetable preparations with regard to the
proposed route of administration and usage. Alternatively, the results shall be
a comparison of the phyto-chemical composition of the herbal substance or the herbal substances
and herbal medicine or herbal products used in
supporting bibliographic data and the herbal substance or
herbal substances and herbal preparation or plant
products contained as active substance or active substances in plant
medicinal product which is the subject of the request.
With respect to the elucidation of structure and other characteristics of the herbal substance
shall be given information about the botanical, macroscopical, microscopical, and
Phyto-chemical characterisation, and biological activity if necessary.
With respect to the elucidation of structure and other characteristics of plant
the product shall be given information about the phytochemical and physico-chemical
characterisation, and biological activity if necessary.
The specifications for the herbal substance or the herbal substances and
herbal medicine or herbal medicines. Shall submit to the
the analytical methods used for testing the herbal substance or plant
and herbal medicine or herbal products.
With regard to the validation of the analytical methods shall be provided information about the
analytical validation, including experimental data for the analytical
the methods used for testing the herbal substance or the herbal substances and
herbal medicine or herbal products.
With respect to batch analyses a description of batches and shall submit the results of the analyses
the lots for the herbal substance or the herbal substances and herbal
medicine or herbal medicines, including substances listed in the pharmacopoeia.
It shall be indicated in the preamble to the specifications of the herbal substance or the herbal substances
and herbal medicine or herbal products.
Information shall be provided on the reference standards or reference
materials used for testing the herbal substance or plant
and herbal medicine or herbal products.
If the herbal substance or the herbal product subject of a monograph,
the applicant may apply for a certificate of compliance granted by the European
Directorate for the quality of medicines.
2. Herbal Medicinal products
With regard to the development of the composition shall be submitted to a brief summary describing the development of
the herbal medicinal product, taking into consideration the proposed route of
Administration and usage. Where appropriate, the results of the comparison shall be
Phyto-chemical composition of products used in supporting
bibliographic data and the herbal medicinal product,
that is the subject of the request.
5. ORPHAN MEDICINAL PRODUCTS
-In the case of an orphan medicinal product pursuant to Regulation
Community ^ 13) may use the General provisions of part II, section 6
(exceptional circumstances). The applicant shall then justify in the non-clinical and
Clinical summaries the reasons for which it is not possible to provide full
information, and provide justification for the benefit/risk ratio of the
medicine for rare diseases.
-If an applicant for a marketing authorisation for an orphan
referring to the provisions of § 27 para. 7 of the law on pharmaceuticals, and part II, point 1
of this annex (well-established medicinal use), the systematic and
the documented use of that substance, exceptionally, to refer to the use of this
substances according to § 8 para. 3 of the law on medicinal products.
PART IV
ADVANCED THERAPY MEDICINAL PRODUCTS
1. advanced therapy medicinal products are defined in article 2. 2 (2). 1 (b).
and) Regulation (EC) no 1394/2007. Applications for registration must be in the
accordance with the format requirements as described in part I of this annex.
For modules 3, 4 and 5 shall apply the technical requirements on biological active
products set out in part I of this annex. Special requirements for
advanced therapy medicinal products, as described in sections 3, 4 and 5 of this
part of the annex governing how the requirements set out in part I of this
the annex apply to advanced therapy medicinal products. In addition, the
were in appropriate cases and taking into account the specific characteristics
advanced therapy medicinal products in this part of the annex set out
additional requirements for these products.
Due to the specific nature of advanced therapy medicinal products is
possible to determine the level of quality and non-clinical and clinical data that have
be listed in the application for registration, on the basis of a risk analysis and in the
accordance with the scientific guidelines relating to the quality, safety and
efficacy of medicinal products.
The risk analysis may also be taken into account the following risk
factors: the origin of the cell, IE. autologous, allogeneic, xenogeneic, ability to
proliferation and differentiation and initiation of the immune response, the level of cellular
manipulation, the combination of cells with bioactive molecules or
structural character of the medicinal products for gene
therapy, the rate of replication capabilities for viruses or micro-organisms
used in vivo, the level of integration of nucleic acids or
the genes into the genome, long term exposure, the risk of oncogenicity and the way
Administration or use.
The risk analysis may also be taken of the relevant available
non-clinical and clinical data or experience with other related
advanced therapy medicinal products. Any derogations from the requirements of
of this annex must be scientifically justified in module 2 documentation
request. The above analysis of the risks in the case of use also
listed and described in module 2. In this case, it is necessary to indicate the used
the methodology, the nature of the identified risks and the consequences resulting from access
based on a risk analysis for the program development and evaluation, and is
needed to describe any deviations from the requirements of this annex
resulting from the risk analysis.
2. definitions
For the purposes of this annex, in addition to the definitions laid down in Regulation (EC) No.
1394/2007, the following definitions shall apply
2.1. medicinal products for gene therapy ^ 18), which means
biological medicinal products, with the exception of vaccines against infectious
diseases that have the following properties:
and) contain the active substance that contains recombinant nucleic
acid that is used in or administered to people to control, correct,
replacing, adding or deleting a genetic sequence, or of such
recombinant nucleic acid,
(b)) their therapeutic, shown or diagnostic effect
apply directly to the recombinant nucleic acid sequence, which
contain, or the product of genetic expression of this sequence,
2.2. somatic cell therapy medicinal products ^ 18)
means a biological medicinal products that have the following
properties:
and) contain cells or tissues that have been subject to substantial manipulation,
thereby leading to an amendment of the biological characteristics, physiological functions
or structural properties relevant for the intended clinical
the use of, or the cells or tissues that are not intended to be used for
the same basic function in the recipient and the donor, or of such cells, or
tissues consist of essential handling, in particular, shall not be considered
the manipulations listed in annex No. 1 directly applicable regulation
Union ^ 19), and
(b)) are presented in a way that have properties for the treatment, prevention or
the diagnosis in the case of the disease on the basis of pharmacological,
immunological or metabolic action of its cells or tissues, or
for this purpose are used in or administered to people.
3. specific requirements regarding module 3
3.1. the specific requirements for all advanced therapy medicinal products
The application for a marketing authorisation for an advanced therapy medicinal product shall be entered
description of the system of traceability, which intends to the holder of the
create and maintain a registration in order to ensure the possibility of tracking
the individual product and its starting and raw materials, including
all substances coming into contact with the cells or tissues that may
include, from the source, through production, packaging, storage, transport, to
delivery within the health care facility where the product is used.
The traceability system should be complementary and compatible with the requirements of
laid down in Act No 297/2008 Coll. on human tissues and cells, in the
as amended, and Regulation No. 422/2008 Coll., laying down
detailed requirements to ensure the quality and safety of human tissues and
cells intended for human applications, in respect of human tissues and cells with
other than blood cells, and in Act No. 378/2007 Coll. on pharmaceuticals, in
as amended, and its implementing provisions as regards
human blood cells.
3.2. Specific requirements for gene therapy medicinal products
3.2.1. the final product, the active substance and source materials
3.2.1.1. the gene therapy medicinal product containing a sequence
recombinant nucleic acid or a genetically modified
the micro-organism or virus.
The finished medicinal product shall consist of nucleic acid sequence or
the genetically modified micro-organism or virus in the final internal
container for the intended medical use. The finished medicinal product
can be combined with the medical device or the active
implantable medical device.
The active substance shall consist of nucleic acid sequence or genetically
modified micro-organism or virus.
3.2.1.2. the gene therapy medicinal product containing genetically
the modified cells
The finished medicinal product consisting of a genetically modified cells in the
final immediate container for the intended medical use.
Finished medicinal product can be combined with the medical
device or the active implantable medical device.
The active substance is composed of cells genetically modified one of the
the products described in paragraph 3.2.1.1.
3.2.1.3.
In the case of products consisting of viruses or viral vectors are
source materials of the folder from which the viral vector is obtained, this means
the mother seed virus or viral vector or plasmids used to
transfekci host cells and cells from these basic bank
host cells.
3.2.1.4.
In the case of products consisting of plasmids, non-viral vectors and
genetically modified micro-organisms except viruses or viral
vectors are starting materials components used to generate the
production cells, plasmid, it means the host bacteria and the Bank
the basic cells of recombinant microbial cells.
3.2.1.5.
In the case of genetically modified cells are the source materials
folder that is used to obtain the genetically modified cells, which are
source materials for the production of vector, the vector and the human or
animal cells. From the system of the Bank used to manufacture the vector is
apply the principles of good manufacturing practice.
3.2.2. specific requirements
In addition to meeting the requirements set out in section 3.2.1. and 3.2.2. Part I
This annex documentation submitted for application for marketing authorisation of the medicinal
a gene therapy medicinal product contains
and) information on all the starting materials used in the manufacture of the active
substances, including those necessary for the genetic modification of human
or animal cells and if necessary subsequent cultivation and preservation
genetically modified cells, having regard to the possible absence of
purification steps,
(b) information on the genetic modification), sequential analysis, weakening of virulence,
tropism for specific tissues and cell types, dependencies of the micro-organism
or virus on cell cycle, pathogenicity and characteristics of the parent
the strain in the case of preparations containing the micro-organism or virus
(c)) in the relevant sections of documentation description of impurities from manufacturing
process and product-related impurities, especially viral
contaminants capable of replication, if the vector does not have to be able to
replication,
(d)) for medicinal products consisting of plasmids, the quantification of data
various forms of plasmids for the entire shelf life of the medicinal product,
e) in the case of genetically modified cells, the evaluation of the results of tests on
the properties of the cells before and after genetic modification, and before any
freezing and storage procedures and post them.
In the case of genetically modified cells, in addition to the specific requirements
the gene therapy medicinal products shall apply to the quality requirements
somatic cell therapy medicinal products, and tissue preparations
Engineering referred to in section 3.
3.3. Special requirements for somatic cell therapy medicinal products
and on human tissue engineered products
3.3.1. the final product, the active substance and source materials
The finished medicinal product shall be composed of the active substances in the inner packaging in
for the intended medical use and in the final combined in the case of
combined advanced therapy medicinal products.
The active substance is composed of modified cells or tissues.
For source materials for the finished medicinal product shall be regarded as additional
substances, in particular, the support structure, the matrix, medical devices,
biomaterials, biomolecules and other components, in combination with the manipulated
the cells, which are an integral part of, and may not be
of biological origin.
The materials used in the manufacture of active substances, in particular, culture media,
the growth factors that should not be part of the active substance shall be considered as
the raw materials.
3.3.2. specific requirements
The registration dossier for somatic cell therapy medicinal products
and tissue engineered products in addition to the requirements laid down,
in sections 3.2.1. and 3.2.2. part I of this annex, requirements for:
3.3.2.1. source materials consisting
and) of summary information about the donation, procurement and testing of human
tissues and cells, in accordance with the provisions of Act No. 297/2008 Coll., as amended by
amended, and the regulations No 422/2008 Coll., used as the default
materials; If they are used as starting materials other than healthy
cells or tissues, in particular the cancerous tissue, you need to use them
justify,
(b)) in the case of allogeneic cell populations, from the description of the way
creating mixtures and measures to ensure their traceability;
(c)) in the context of the validation of the manufacturing process of the active substance and characterization
the finished product, the development of the tests, the determination of specifications and stability,
where it is necessary to take into account the potential variability caused by human or
animal tissues and cells,
(d) in the case of xenogeneic) medicinal products from animal cells from
provide information about the origin of the animals, in particular the geographical origin, breeding
animals, their age, specific acceptance criteria, measures
aiming to prevent and monitor infections in the animal donors, about
animal testing for infectious agents including vertically
transmitted micro-organisms and viruses, and evidence of the suitability of information
breeding equipment
(e)) for products derived from genetically modified animals, cells from
the description of the special properties of the cells related to the genetic modification
where they provide a detailed description of the methodology of creation and characterization
transgenic animal
f) in the case of genetic modification of cells from the technical requirements
referred to in section 3.2.
g) from the description and justification in the case of the testing of some other substances, in particular
load-bearing structure, the matrix, medical devices, bio-materials,
biomolecules or other ingredients that are in combination with modified
the cells, which are an integral part of,
h) in the case of load-bearing structures, matrices and devices
covered by the definition of a medical device or the active
implantable medical device, of the information required in
under section 3.4. for the evaluation of the combination of the medicinal product for
advanced therapy medicinal products.
3.3.2.2. the production process consisting
and process validation) to ensure the compliance of the batch consistency and
compliance processes, functional integrity of the cells during the whole production and transport to
to the moment of the application or of the filing and proper state of differentiation, and
(b) cultured cells) directly inside the matrix, the supporting structure, or
medical device or on the load-bearing structure of the matrix, or
medical device, information about the validation process of cultivation
cells in terms of growing cells, the function and integrity of the combination.
3.3.2.3. characterisation and control strategy consisting of a
and) relevant information about the characterization of cell population or a mixture
cells with regard to identity, purity, especially foreign microbial agents and
cellular contaminants, viability, potency, karyology, and
tumourigenicity and suitability for the intended medicinal use, including
demonstrate the genetic stability of the cells,
b) qualitative and, where possible, quantitative data about the impurities
associated with the product and impurities from the production process and of any
the materials, which could invoke the presence during production
rozkládaných products, including the preamble to the extent the determination of impurities,
(c)) in the preamble, if certain tests for the release cannot be performed on the
of the active substance or the final product, but only on the key
intermediates or as tests during the production process,
(d)) characterization of the impact of biologically active molecules such as growth
factors and Cytokines and their interactions with other components of the active substances,
If these bioactive molecules form part of the product originating in
cells,
e) information about the State of differentiation, structural and functional arrangement
the cells and the extracellular matrix, or created if it is part of the
the intended function of three-dimensional structure; the information is part of the
characterization for those products originating in cells; where appropriate, the
physico-chemical characterization make up the non-clinical evaluations.
3.3.2.4. excipients
In the case of auxiliary substances used in cell or tissue
medicinal products, in particular transport, media folders are used
new requirements for the other ingredients laid down in part I of this annex, if
There are no data on the interactions between the cells or tissues and the other
substances.
3.3.2.5. developmental studies
Description of the development programme must relate to the materials and processes, and
in particular, with regard to the integrity of the cell population in the final composition.
3.3.2.6. reference materials
For the active substance and the finished product is documented and
characterized by a reference standard, which is for them a substantial and
specific.
3.4. Specific requirements for advanced therapy medicinal products
containing medical devices
3.4.1. an advanced therapy medicinal product containing medical
the resources referred to in article 7 of Regulation (EC) no 1394/2007.
Part of the documentation to be submitted for application for marketing authorisation of the medicinal
an advanced therapy medicinal product containing medical devices is
and a description of the physical characteristics and) the effect of the product,
(b) a description of the methods of product development), a description of the interaction and compatibility between the
genes, cells or tissues, and structural components.
3.4.2. The combined advanced therapy medicinal products referred to in article. 2
paragraph. 1 (b). (d)) of Regulation (EC) no 1394/2007
For cellular or tissue part combination medicinal product for
advanced therapy medicinal products shall apply to the special requirements of medicinal products for
somatic cell therapy and tissue engineering products referred to in
section 3.3. and in the case of genetically modified cells will be used
specific requirements for gene therapy medicinal products, as referred to in
section 3.2.
Medical device or the active implantable medical
a resource can be an integral part of the active substance. In the case that it is
medical device or the active implantable medical
resource at the time of manufacture, application or administration of the finished product
combined with the relevant cells, it is considered an integral part of the
of the finished product.
Part of the documentation to be submitted for application for registration of a combined
an advanced therapy medicinal product-related information is
the medical device or active implantable medical
a resource that is an integral part of the active substance or the final
the product, which are essential for the evaluation of combined medicine
product characteristics for advanced therapy medicinal products. This information includes:
and information about choosing and) the intended function of the medical device or
implantable medical device with other ingredients,
(b) the demonstration of conformity of the medical device), which is part of the
the whole, with the essential requirements laid down in annex 1 of regulation
Government No 336/2004 Coll., laying down technical requirements for
medical devices, as amended, or the conformity of the
active implantable medical device which is part of the
of the whole, with the essential requirements laid down in annex No. 1.
Government Regulation No. 154/2004 Coll., laying down requirements on the active
implantable medical devices, as amended,
(c)), where appropriate, demonstrate the conformity of the medical device or
implantable medical device with the requirements relating to TSES
laid down in Act No. 22/1997 Coll., on technical requirements for
products and amending and supplementing certain acts, as amended by Act No.
205/2002 Coll. and regulation of the Government No. 251/2003 Coll., amending certain
Government regulations issued in implementation of law No. 22/1997 Coll., on technical
requirements for products and amending and supplementing certain acts, as amended by
amended, as amended by Decree-Law No 336/2004 Coll.
(d)) where available, the results of any assessment of the medical
a resource that is part of the whole, or the active
implantable medical device that is part of the
a whole, carried out by the operator in accordance with the law No. 121/2000 Coll. on
medical devices, as amended, and its
the implementing rules.
The body, which carried out the examination referred to in point (d) of this section,)
shall provide on request of the competent authority, which shall examine the request,
all information related to the results of the assessment in accordance with the law
No 123/2000 Coll., as amended, and its implementing
regulations. This can be the information and documents contained in the
the application for assessment of conformity, essential for the evaluation of a combined
an advanced therapy medicinal product, as a whole.
4. specific requirements regarding module 4
4.1. specific requirements for all advanced therapy medicinal products
Because of the unique and diverse structural and biological
characteristics of advanced therapy medicinal products may not be
Part I, module 4 of this annex in respect of pharmacological and
toxicological tests of medicines always appropriate. Technical
the requirements in sections 4.1., 4.2. and 4.3. below explains how to
the requirements referred to in part I of this annex shall apply to medicinal products
for advanced therapy medicinal products. Where appropriate, and taking into account the
the specific characteristics of advanced therapy medicinal products have been
set additional requirements.
In the Choose list must be explained and justified in the preamble
non-clinical development and the criteria used for selection of the relevant species and
modules in vitro and in vivo. The selected animal model/models may include
the animals are immunocompromised animals targeted include knock-out
gene, or animals or transgenic humanised. Consider the use of
homologous models, in particular cells analyzed in mice or mouse models
simulating illness, primarily for safety and immunogenicity studies and
immunotoxicity.
In addition to the requirements listed in part I is the content of the documentation to be submitted
the application for the registration of prove the safety, suitability and
biocompatibility of all structural components such as the matrix, the carrier
structure and medical devices and any other substances such as
are cellular products, bio-molecules, bio-materials and chemicals
that are present in the final product. Taking into account their physical,
mechanical, chemical, and biological properties.
4.2. Specific requirements for gene therapy medicinal products
In order to determine the extent and type of non-clinical studies necessary to
the determination of the appropriate level of non-clinical data on the safety of taking account of the
the nature and type of the gene therapy medicinal product.
4.2.1. Pharmacology
Part of the documentation to be submitted to the application for the registration of medicinal products
medicinal products for gene therapy is
study on the operation) in vitro and in vivo, relating to the proposed
medicinal use of pharmacodynamic studies for the proof of concept, with
using models and relevant animal species, which have shown that the
nucleic acid sequence reaches its intended target, IE. the target
organ or cells and its intended function, IE. the level of
expression and functional activity. In the context of the study shall provide data on the duration of the
the effect of nucleic acid sequence and on the proposed dosage in schemas
clinical trials,
(b) study to confirm the specificity), and duration of the operation and effectiveness of the
the target cells and tissues in the case that has the medicinal product for
gene therapy Act selectively or specifically.
4.2.2. The pharmacokinetics of
and disposition of the Study includes an assessment of) the persistence, clearance and
mobilization. Also included in the study is proof of disposition of data on
the risk of germline transmission.
(b)), together with an assessment of the risks to the environment are listed
details on the evaluation of excretion and the risk of transmission to third parties, unless
their failure to duly justified in the application on the basis of the
the type of the product.
4.2.3. Toxicology
and for the finished medicinal product) for gene therapy to assess its
toxicity. In addition, depending on the type of account of
individual testing of active substances and Excipients, and assess the effect of
in vivo for substances derived from expressed sequences, nucleic acid
which are not intended for physiological function.
b) single dose toxicity studies can be combined with
pharmacological and pharmacokinetic studies of safety, for example, to
assessment of persistence.
c) repeated-dose toxicity Studies are provided in cases where they
It is intended to repeat the dosage for humans. The method and schedule of Administration must
exactly match the scheduled clinical dosage. In cases where the
a single dosage can cause prolonged exposure in humans
nucleic acid sequence, shall consider the repeated-dose toxicity studies
doses. Study duration may be longer than in the case of the standard studies
Depending on the persistence of the medicinal product gene
therapy and expected potential risks. In this case, it is
given the duration of the study.
(d)) part of the toxicity study is proof of the evaluation tests of the medicinal
of the gene therapy on genotoxicity. However, the standard
genotoxicity studies shall be carried out only in cases where they are necessary
for the testing of certain impurities or transporter folder.
(e)) part of the toxicity study is proof of the evaluation tests of the medicinal
of the gene therapy on carcinogenicity. Standard lifetime
carcinogenicity studies in rodents is not required. However, it must be in the
Depending on the type of assessed in relevant in vivo or in
vitro models in vivo/in vitro tumorigenic.
f) reproductive and developmental toxicity: is supported by studies of the effects on
fertility and reproductive function, studies of the embryonic or fetal and
perinatal toxicity studies and germline transmission is not
their failure to duly justified in the application on the basis of the
the type of the product.
(g)) the additional toxicity studies
1. Study the integration:
For each medicinal product gene therapy will provide study
integration, if it is not scientifically justified by the absence of such studies,
for example, because a sequence of nucleic acids cannot penetrate into the cell
the kernel. Integration studies shall be carried out in the case of medicinal products for
gene therapy, in which not expected, although the ability to integrate, but
biodistribution data suggest risk of germline transmission.
2. Immunogenicity and immunotoxicity:
Part of the study on toxicity is proof of the research potential
prepare and imunotoxických effects.
4.3. Specific requirements for somatic cell therapy medicinal products
and on human tissue engineered products
4.3.1. Pharmacology
and the primary pharmacological studies) is illustrated by the concept of the card.
Examines the interaction of cells with products derived from the surrounding tissues.
(b) the quantity of the product) needed to achieve the envisaged
effect, it is the effective dose and depending on the type of
the frequency of administration.
(c)) shall take into account the secondary pharmacological studies to evaluate the
the potential physiological effects, which is not related to the expected
therapeutic effect of the medicinal product somatic cell therapy, and
a tissue engineered product or other substances, as in addition to the
monitoring protein may lead to the exclusion of the biologically active
molecules, or screened protein can have unintended destinations.
4.3.2. The pharmacokinetics of
and Conventional pharmacokinetic studies) to evaluate the absorption, distribution,
metabolism and excretion is not required when they are evaluated
parameters such as viability, life expectancy, distribution, growth,
differentiation and migration, unless they are duly justified in the nehodnocení
the request based on the type of the product concerned,
(b)) in the case of medicinal products and somatic cell therapy medicinal products
tissue engineering, which produce biomolecules,
to evaluate the distribution, duration and level of expression of these molecules.
4.3.3. Toxicology
and) for the finished medicinal product shall be assessed by its toxicity. Take into account the
the individual testing of active substances, excipients, other substances and
any impurities from the production process.
(b)) in the case that is longer than the duration of the observations in the case of standard
studies of toxicity, account shall be taken also expected lifetime of the medicinal
the product, according to pharmacodynamic and pharmacokinetic together
profile. In this case, it is stated in the preamble to the duration of the study.
(c)) the conventional studies of carcinogenicity and genotoxicity are required only in
connection with the potential of the product except.
(d)) shall be research on potential immunogenic and immunotoxic effects
of the medicinal product.
e) in the case of products originating in the cells and tagged animal
the cell is the need to resolve the related specific issues related to
security, as is the transmission of xenogeneic pathogens to humans.
5. specific requirements regarding module 5
5.1. Special requirements for all advanced therapy medicinal products
5.1.1. The specific requirements in this section of part IV are additional
requirements to the requirements of module 5 in part I of this annex.
5.1.2. If clinical applications of advanced therapy medicinal products
requires specific concomitant treatment includes surgical procedures, and
a medical procedure to assess and describe as a whole, including information about
standardize and optimize these processes during clinical development.
If the medical devices used during surgical procedures to
application, implantation or administration of an advanced therapy medicinal product
could have an impact on the efficacy or safety of the medicinal product for
advanced therapy medicinal products, it is necessary to provide information about these medical
resources.
Specific expertise required for the implementation of the application,
implantation, administration or follow-up measures. As appropriate, shall be
plan training of health care workers regarding procedures to use,
application, implantation or administration of these preparations.
5.1.3. If due to the nature of the medicinal products for modern
therapy of their manufacturing process during clinical development, changes may
be requested supplementary studies to demonstrate comparability.
5.1.4. During clinical development, it is necessary to evaluate the risks
arising from potential infectious agents or the use of material
of animal origin and to take measures to reduce such risks.
5.1.5. the choice of doses and schedule of use are established on the basis of studies
the dosage.
5.1.6. the effectiveness of the proposed indication is based on the relevant results of the
clinical studies using clinically relevant parameters for
the intended use. In certain clinical conditions may be required
evidence of long term effectiveness and provide a long-term strategy
efficiency.
5.1.7. the risk management plan is given a fixed monitoring strategy
safety and efficacy.
5.1.8. in the case of combined advanced therapy medicinal products
safety and efficacy studies are designed and conducted for the
combination product as a whole.
5.2. Specific requirements for gene therapy medicinal products
5.2.1. Human pharmacokinetic studies
Pharmacokinetic studies in humans include the following aspects:
and excretion studies) to address the excretion of the medicinal products for
gene therapy;
(b) disposition of the study);
c) pharmacokinetic studies of the medicinal product and functional groups
responsible for the expression of genes in particular expressed proteins or
representative "signature" genomic sequence.
5.2.2. Pharmacodynamic studies in humans
Pharmacodynamic studies in humans must deal with the expression and functions of
nucleic acid sequence after administration of the medicinal product gene
therapy.
5.2.3. Safety studies should address the following aspects:
and the appearance of the vector capable of replication);
(b)) the appearance of new strains;
(c)) by regrouping existing genomic sequences;
d the neoplastic proliferation caused by insertional) mutagenicity.
5.3. Special requirements for somatic cell therapy medicinal products
5.3.1. a somatic cell therapy medicinal products, which is a way of
the effect is based on the production of defined active molecules.
In the case of a somatic cell therapy medicinal products, which is
the mode of action is based on the production of defined active molecules, it is
to be addressed, in particular, the pharmacokinetic profile, distributions,
duration and level of expression of these molecules, if possible.
5.3.2. Biodistribution, persistence and long-term engraftment of folders
a somatic cell therapy medicinal product.
During clinical development, it is necessary to deal with the biodistribucí,
persistence and long-term přihojením of ingredients of the medicinal product for
somatic cell therapy.
5.3.3. Safety studies
Safety studies should address the following aspects:
and distribution and přihojením) after administration;
(b)) ektopickým přihojením;
(c) the oncogenic transformation and fidelity) cells or tissues to the appropriate line.
5.4. requirements specific to tissue engineered products
5.4.1. Pharmacokinetic studies
If for tissue engineered products are not relevant to the conventional
Pharmacokinetic studies, it is necessary in the course of clinical development
address biodistribucí, persistence and degradation components in preparations
tissue engineering.
5.4.2. Pharmacodynamic studies
Pharmacodynamic studies are designed and adapted with regard to the
properties specific to tissue engineered products, which are
supported by data on the card and the kinetics of product concepts to achieve
the intended regeneration, repair or replacement. Appropriate pharmacodynamic
markers related to the intended functions and structure into account.
5.4.3. Safety studies
Section 5.3.3 shall apply.
Annex 2
Marketing authorisation dossier requirements for veterinary medicinal products
TITLE I OF THE
REQUIREMENTS FOR VETERINARY MEDICINAL PRODUCTS OTHER THAN IMMUNOLOGICAL VETERINARY
PREPARATIONS
Unless otherwise provided for in title III, the provisions of this title
for veterinary medicinal products other than immunological veterinary medicinal products
Part 1: SUMMARY of the DOSSIER
And.
ADMINISTRATIVE DATA
Veterinary medicinal product which is the subject of the request for registration, you
identified by its name and the name of the active substance or substances, together with the
the strength and pharmaceutical form, the method and route of administration and a description of the final
ba communication from product sales, including packaging, labelling and
leaflet.
Enter 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 the manufacture, testing and
dismissal (including the manufacturer of the finished product and the manufacturer or manufacturers
of the active substance or substances), and, where appropriate, the name and address
the importer.
The applicant shall indicate the number and designation of the volumes of documentation submitted with the
applications, and if are provided and indicate what samples,.
To the administrative data shall be copies of the manufacturing authorization for all
the place of manufacture, which is involved in the production of the product, and a list of
of countries in which authorization has been granted, copies of all the summaries of
product characteristics pursuant to § 3 (2). 1 of the Act, as approved by Member States,
and a list of countries in which an application has been submitted or rejected.
(B).
SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET
The applicant shall propose a summary of the product characteristics referred to in annex 3 to this
the Decree.
The proposed text of the labelling on the inner or outer packaging shall be submitted in accordance with
Annex No 5 of this order, together with a package leaflet in accordance with annex
# 4 of this order, if this is required in accordance with § 37 para. 3 of the Act.
Furthermore, the applicant shall provide one or more specimens or mock-ups of the sales
the packaging of all internal and external packaging in which the veterinary
product is placed on the market in any language, in a substantiated case in one
of the official languages of the European Union. In agreement with the Health Department can be
draft the sales package to present only in black and white and in the
electronic form.
(C).
A DETAILED AND CRITICAL SUMMARIES
In accordance with § 26 para. 6 of the Act shall provide a detailed and critical summaries
the results of the pharmaceutical (physico-chemical, biological or
microbiological) tests, safety tests and residue tests,
pre-clinical testing and clinical trials and tests, which
assess the potential risks of the veterinary medicinal product for the environment.
Each detailed and critical summary must be drawn up with regard to the status
scientific knowledge at the time of application. Each such summary contains
evaluation of all the tests and trials that make up the documentation for the
the application for registration, and affects all questions that you may have
relevant for the assessment of quality, safety and efficacy of the veterinary
of the product. A summary contains detailed results of tests and trials and the
precise references to published data.
All important data shall be summarized in an appendix, including modifications to tables
or charts if possible. A detailed and critical summaries and appendices
always contain precise cross references to information contained in the main
the documentation.
A detailed and critical summaries are always provided with a signature and are dated
and they are always attached to them information about the education, training and professional
the experience of the author. Enter the professional relationship of the author to the applicant.
If the active substance contained in human medicine authorised in the
accordance with the requirements of annex 1 of this order may total about
quality according to module 2 of section 2.3 of this annex, if necessary
replace the summary relating to the documentation relating to the active substance
or preparation.
If the Health Department guideline States that chemical, pharmaceutical and
biological/microbiological information on the finished product can be in
registration documentation listed only in the format of the joint technical
the document can be detailed and critical summary of the results of the pharmaceutical
testing is done in the form of a quality overall summary.
In the event that the product is intended for minor animal species or for the
minor indications, you can format a quality overall summary use without
the prior consent of the Veterinary Institute.
Part 2: PHARMACEUTICAL (physico-chemical, biological or
MICROBIOLOGICAL INFORMATION (QUALITY)
The General principles and requirements of
The particulars and documents which must accompany applications for marketing authorization
pursuant to section 26 paragraph 1. 5 (b). 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 substance and for ultimate health
does contain information about the manufacturing process, the characteristics, and
properties, procedures, and quality control requirements, stability,
as well as the description of the composition, development and editing of the veterinary medicinal product.
All articles shall apply, including the General articles and General chapters
The European Pharmacopoeia, or failing this, Pharmacopoeia
of a Member State.
All test procedures shall comply with the criteria for analysis and control
the quality of starting materials and the finished product and should take into account the
established guidelines and requirements. The results of the validation
studies.
All test procedures shall be described in a sufficiently precise and detailed,
to be repeated in control tests, carried out at the
the application of the animal health Institute; any special apparatus and equipment,
that can be used, it must be sufficiently detailed,
or with the enclosed diagram.
The composition of the laboratory reagents shall, if necessary, make up to volume in a manner
preparation. In the case of test procedures included in the European Pharmacopoeia
or of a Member State may be replaced with an exact description
reference to the pharmacopoeia in question. Where appropriate, the chemical and
biological reference material of the European Pharmacopoeia. If used
reference preparations and standards must be identified and
described in detail.
If the active substance contained in human medicine authorised in the
accordance with the requirements of annex I to Directive 2001/83/EC as amended ^ 1)
can chemical, pharmaceutical and biological/microbiological information
According to module 3 of the directive, if necessary, replace the documentation
relating to the active substance or of the finished product.
Chemical, pharmaceutical and biological/microbiological information for
the active substance or the final product may be included in the registration
documentation of the common technical document format only
If so, the animal health Institute provides in the instruction of the Veterinary Institute.
In the event that the product is intended for minor animal species or for the
a minor indication may be the common technical document format
used without the prior consent of the Veterinary Institute.
And.
QUALITATIVE AND QUANTITATIVE PARTICULARS OF THE CONSTITUENTS
1. Qualitative information
"Qualitative particulars" of all the constituents of the medicinal product shall mean the
designation or description of:
-a medicinal substances or medicinal substances,
-the other ingredients or excipients, whatever their nature or the
the quantity used, including colouring matter, preservatives, adjuvants,
stabilisers, thickeners, emulsifiers, flavouring and aromatic substances,
-immunological veterinary medicinal products intended for ingestion or
another administration to animals-capsules, gelatine capsules.
These particulars shall be supplemented by any relevant data concerning the container and
where appropriate, the outer package, and, where appropriate, its manner of closure, together
with details of devices with which the veterinary
product is used or administered and which will be delivered with.
2. The usual terminology (terminology)
The usual terminology to be used in describing the constituents of
veterinary medicinal products, shall mean, notwithstanding the other provisions of § 26 para.
5 (b). (b)) of the Act means:
-in the case of folders included in the European Pharmacopoeia or, failing that,
not listed in the pharmacopoeia of one of the Member States, the main title
the relevant article with reference to the pharmacopoeia concerned,
-in the case of the other components of international non-proprietary name recommended by the
The World Health Organization (WHO), which may be accompanied by other
non-proprietary name, or, failing these, the exact scientific
the designation; folders that do not have international non-proprietary name or an exact
scientific designation shall be described by a statement of how and from what is prepared,
with the addition of any other relevant details,
-in the case of colouring matter, designation "E" code assigned to them in accordance with
another law ^ 13a).
3. Quantitative data
3.1 placing of quantitative data on all active substances
veterinary medicines is necessary depending on the particular drug
the form noted for each active substance weight or number of units
of biological activity, either per unit dosage form or per unit
mass or volume.
Units of biological activity shall be used for substances that cannot be
chemically defined. If it has been defined by the World Health
organisations, the international unit of biological activity.
If the defined international unit, expressed with units
biological activity so as to provide unambiguous information on the
the activity of the substances, whenever possible, using units of the European
Pharmacopoeia.
If possible, the biological activity per unit of weight or
volume. This information shall be supplemented:
-in the case of single-dose preparations mass or units of
the biological activity of each active substance in the same outer packaging with
taking into account the usable volume of the product, where appropriate, after
reconstitution,
-in the case of veterinary medicinal products administered drop by drop weight
or units of biological activity of each active substance contained in a single
a drop in the number of drops or corresponding to 1 ml or 1 g of product,
-in the case of syrups, emulsions, granular preparations and other pharmaceutical
forms to be administered in measured quantities of mass or units of
biological activity of each active substance in the measured quantity.
3.2. Active substances present in the form of compounds or derivatives shall be
be designated quantitatively by their total mass, and if it is
necessary or important, the mass of the active or active parts of the
of the molecule.
3.3 for veterinary medicinal products containing the active substance, which is in the
a Member State for the first time the subject of an application for marketing authorisation, the
systematically expresses the content of active substance, if it is a salt or hydrate shall
mass of the active or active parts of the molecule. Quantitative
the composition of all veterinary medicinal products subsequently registered in the
the Member States must be for the same active substance referred to in the same
way.
4. Pharmaceutical Development
The explanations regarding the choice of composition, constituents, internal
packaging the potential of packaging, or the outer packaging, the intended
function of the excipients in the finished product and method of manufacture of the finished
of the product. This explanation shall be scientific data about the pharmaceutical
the development of. The overage, with its justification. Must be demonstrated that the
microbiological characteristics microbiological purity (and antimicrobial
activity) and instructions for use are appropriate for the intended use
the veterinary medicinal product, as provided in the documentation for the application for
registration.
(B).
THE DESCRIPTION OF THE MANUFACTURING METHOD
Enter the name, address, and responsibility of each manufacturer and each proposed
production site or facility involved in manufacturing and testing.
The description of the manufacturing method accompanying the application for marketing authorization pursuant to section 26 paragraph 1.
5 (b). (d)) of the Act shall be disclosed so as to provide a sufficient overview of the
the nature of the operations carried out.
For this purpose the description shall contain at least:
-indication of the individual stages of the construction, in order to assess whether the
processes employed in producing the pharmaceutical form might have produced an adverse change in
folders,
-in the case of continuous manufacture, full details concerning precautions
taken to ensure the homogeneity of the finished product,
-the actual manufacturing formula, with the quantitative particulars of all the
the substances used, the quantities of excipients, however, can be expressed as
approximately, if required by the pharmaceutical form; all the mentioned must be
substances that may disappear in the course of manufacture; any overage
shall be indicated and justified,
-indication of the stages of manufacture at which sampling is carried out for the
the control tests during the production process, and the prescribed limits
If the data in the dossier accompanying the application, it is apparent that such
the studies necessary for the quality control of the finished product,
-experimental studies validating the manufacturing process, and if necessary
plan the validation procedure for the production batch,
-for sterile products if they are used the conditions of sterilization
process not specified in Pharmacopoeia, details about the processes
sterilization or aseptic procedures.
(C).
CONTROL OF STARTING MATERIALS
1. General requirements
Starting materials shall mean all the constituents of the veterinary medicinal product
and, where necessary, of its container, including the closure, as shown
in section A, point 1, above.
The dossier contains specifications and information about tests
to be performed in order to check the quality of all lots
starting materials.
The routine tests to be carried out on each batch of starting materials must
correspond to the tests referred to in the application for registration. If you are
used by other tests than those that are listed in the Pharmacopoeia, shall be
proof that the starting materials meet the quality requirements according to the
of that pharmacopoeia.
If it was for a starting material, the active substance or an excipient issued
The European Directorate for the quality of medicines and healthcare's certificate
conformity certificate, this is the link to the article
The European Pharmacopoeia.
If reference is made to the certificate of conformity, the manufacturer shall give the applicant written
ensure that the manufacturing process has not been modified since the granting of a certificate
the conformity of the European Directorate for the quality of medicines and health care.
Results of the analyses shall be provided for the batches used for the purpose of
demonstration of conformity with the agreed specifications.
1.1 active substances
Enter the name, address, and responsibility of each manufacturer and each proposed
production site or facility involved in the manufacture and testing of medicinal products
the substance.
For well defined active substances, the manufacturer of the active substance or the applicant
use the option that the manufacturer of the active substance provided directly to the veterinary
the Institute in the form of a separate document called a basic document on the
the active substance (Active Substance Master File) with the following information:
and a detailed description of the manufacturing process),
(b)) a description of quality control during manufacture,
(c) description of process validation).
In this case, however, the manufacturer shall provide the applicant with all the information that
are necessary for the latter to take responsibility for animal health
medicine. The manufacturer shall confirm in writing to the applicant that will ensure a match between the
batch consistency and not modify the manufacturing process or specifications without
informing the applicant. Documents and particulars supporting the application for such
the change shall be submitted to the Veterinary Institute. These documents and particulars are
the applicant shall also provide, if they relate to part of the basic document on the
the active substance concerning the applicant.
If you do not have the certificate of conformity for the active substance,
further details of the manufacturing method, quality control and impurities, as well as
evidence of molecular structure.
1. information on the manufacturing process include a description of the manufacturing process of the active
the substance, which represents the applicant's commitment for the manufacture of the active substance. Shall indicate the
to enumerate all of the raw materials needed to produce medicinal substances or medicinal
substances with an indication, in which the process the raw material used.
Information shall be provided on the quality and control of these materials. , Shall be
that the raw materials meet standards appropriate for their intended use.
2. information on quality control must 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
where appropriate, the evaluation studies. If necessary, it must also contain
validation data for analytical methods used in the context of the active
substance.
3. The information on impurities shall be expected debris together with the
the content and characteristics of the observed contamination. If it's important,
shall also be provided information about the safety of these impurities.
4. For biotechnological health products must document the molecular
structures contain the amino acid sequence and relative schematics
the molecular weight.
1.1.1. The active substances listed in the pharmacopoeia
General and specific articles of the European Pharmacopoeia shall be applicable to all
active substances, which are listed therein.
If the folders are in accordance with the requirements of the European Pharmacopoeia or the pharmacopoeia of
one of the Member States, shall consider the provisions of § 26 para. 5 (b). (h))
the law met. In this case, a description of the analytical methods and
the procedures will replace in each relevant section of the appropriate link to the
the pharmacopoeia in question.
In cases where the specifications referred to in article of the European Pharmacopoeia
or in the pharmacopoeia of a Member State to be insufficient to ensure the quality
the substance, the competent authorities may require from the applicant a more appropriate
specifications, including limits for specific contaminants with a validated
the test procedures.
The competent authorities shall inform the authorities responsible for the pharmacopoeia in question. The holder of the
the marketing authorisation shall provide the authorities of that Pharmacopoeia
details of the alleged insufficiency and the additional used
the specifications.
In cases where it is not the active substance described in the European
Pharmacopoeia, and if this is the active substance described in the pharmacopoeia of a Member
the 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, it may be recognized by the compliance with article
listed in the pharmacopoeia of a third country, if there is a demonstrated its suitability; in
such cases, the applicant shall submit a copy of the article, where appropriate, together with the
translation. Listed must be data demonstrating the ability of the article
appropriately control the quality of the active substance.
1.1.2 Active substances not listed in a pharmacopoeia
Folders that are not listed in any Pharmacopoeia shall be described in the form
the article with the following points:
and the name of the folder) meeting the requirements of section A point 2, shall be supplemented by
any trade or scientific synonyms;
(b) substances referred to in the form definition) similar to that used in the
The European Pharmacopoeia, shall be accompanied by all the necessary explanatory
the evidence, especially concerning the molecular structure. If they can be
the substance of their production only in the manner described, the description should be sufficiently
detailed to characterize a substance which is constant both in its composition,
and in its effects;
(c)) method of identification may be described in the form of complete techniques as
how they are used for production of the substance and the form of tests which ought to be
carried out as a routine matter;
d) purity tests shall be described in relation to each individual
the expected dirt, in particular to those which may have a harmful effect, and
where appropriate, those which, having regard to the combination of substances to which the application
refers, might adversely affect the stability of the medicinal product
or distort analytical results;
e) tests and limits to control the parameters relevant to the ultimate
medicine, describes, for example, the particle size and sterility, and
the methods must be described and, where applicable, validated;
(f)) if it is a 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 principles having
a similar activity, which may be permitted by the method of assay
the total content.
These data demonstrate that the proposed set of testing procedures is
sufficient for the quality control of the active substance from a specified source.
1.1.3 physico-chemical characteristics liable to affect bioavailability
the availability of
The following information concerning active substances, whether or not listed in
Pharmacopoeia, shall be submitted as part of the General description of the active substances,
If it depends on them the bioavailability of veterinary medicinal product:
-crystalline form and solubility coefficients,
-particle size, where appropriate after pulverization,
-the degree of solvatace,
-oil/water partition coefficient,
-value pK/pH.
The first three indents shall not apply to substances used only in the solution.
1.2 other ingredients
General and specific articles of the European Pharmacopoeia shall be applicable to all
the substances which are listed therein.
Auxiliary substances meet the requirements of the relevant article of the European Pharmacopoeia.
If such an article does not exist, it is possible to make a link to the article
the pharmacopoeia of a Member State. In the case that such an article does not exist, it is
possible to make a link to a third-country national pharmacopoeia. In this case, it is
must include the appropriateness of such an article. If necessary, must be
the requirements of article supplemented with other tests to check for parameters such as
for example, particle size, sterility, residual solvents. In
When there is no Pharmacopoeial article will propose and justify
specification. Shall comply with the requirements of the specifications set out in section
1.1.2 (c). a) to (e)) for the active substance. Shall submit the proposed methods and
the accompanying data on their validation.
Dyes that are added to the veterinary medicines, always meet
the requirements laid down in title VIII, with the exception of certain veterinary
preparations for topical use, eg. insecticidal collars and ear marks
where use of other dyes is justified.
Colouring matter shall meet purity criteria as laid down in other legal
prescription ^ 13b).
For new adjuvants, IE. for the intermediate substances or excipients
used in veterinary medicine for the first time, or a new route of administration,
shall specify the detailed production information, a detailed description and
for detailed information on the checks with cross-references to additional information
on both clinical and non-clinical safety.
1.3 the container closure Systems
1.3.1. The active substance
Information shall be provided on the container closure system for the active
substance. The level of information required shall be determined according to 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 final
medicine. The level of information required shall be determined by the route of administration
veterinary medicine and physical state (liquid, solid) drug
Forms.
Packaging materials meet the requirements of the relevant article of the European
Pharmacopoeia. If such an article does not exist, it is possible to include a link to
Article pharmacopoeia of a Member State. In the case that there is no such
Article it is possible to include a link to the article of the pharmacopoeia of the third country. In this
the case must be demonstrated the suitability of such article.
If there is no article of the Pharmacopoeia, it is necessary to propose and justify
specification for packing material.
Indicate the scientific data on the choice and suitability of the packaging material.
For new packaging materials, which are in contact with the product,
information about their composition, production and safety.
Specification and shall, if necessary, details of the functionality for
any device for dispensing or administering the veterinary medicinal product.
1.4 Substances of biological origin
If you are in the manufacture of veterinary medicines apply materials such as.
micro-organisms, tissues of either plant or animal origin, cells or
fluids (including blood) of human or animal origin or
biotechnological cell constructs, shall be described and documented
the origin and history of starting materials.
The description of the starting material shall include the manufacturing strategy,
purification/inactivation procedures with their validation and all control
how in the course of the manufacturing process designed to ensure the quality,
Security and compliance to batch consistency of the finished product.
If they are used by the cell banks, it must be shown that the properties of cells
in the passage used for the manufacture and in the passage following remained unchanged.
Seed materials, cell banks, and, if possible, the source materials must
be tested for adventitious agents.
When using starting materials of animal or human origin, shall be
a description of the measures to ensure the absence of pathogens, which can be
pathogenic.
If the presence of foreign pathogens, which may be pathogenic,
inevitable, the appropriate raw material used only when other
processing ensures their elimination and/or inactivation, and this shall be
validated.
Submit documentation stating that the seed materials, cell inoculum, batch
serum and other raw materials of animal origin are important for the transmission of TSE in
accordance with the note for guidance on minimising the risk of transmitting animal
spongiform encephalopathy agents via human and veterinary
products, as well as with the corresponding article of the European Pharmacopoeia. To
demonstrate compliance, you can 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.
(D).
THE CONTROL TESTS CARRIED OUT AT INTERMEDIATE STAGES OF THE MANUFACTURING PROCESS
The dossier contains the data relating to the control tests
the product, which may be carried out at an intermediate stage of production
in order to ensure the consistency of the technical characteristics and the production
process.
These tests are essential for checking the conformity of the veterinary medicinal product is
the formula when, exceptionally, an applicant proposes an analytical method for
testing the finished product which does not include the assay of all the
the active ingredients (or of all the excipient constituents subject to the same
requirements as the active ingredients).
The same applies where the quality control of the finished product depends on the
control tests during the production process, particularly if the
the substance is essentially defined by its manner of production. If it can be
intermediate before further processing or formulation, primary storage
the expiry date must be defined on the basis of the data of the intermediate
derived from stability studies.
(E).
THE TESTS ON THE FINISHED PRODUCT
For the control of the finished product includes a batch of finished product
all the units of a pharmaceutical form which are made from the same initial
quantity of material and have undergone the same series of manufacturing and/or sterilization
operations or, in the case of a continuous production process, all the
units manufactured in a given period of time.
In the application for marketing authorization shall list the tests that are routinely performed
for each batch of the finished product. Frequency of the tests must be reported,
which are not carried out routinely. Shall specify the limits for the layoffs.
The registration dossier shall contain the information relating to inspection
the tests on the finished product when the layoffs. Data must be submitted
in accordance with the following requirements. On all products that are in the
It shall apply the provisions of the relevant articles and General
chapters of the European Pharmacopoeia, or, if these do not exist, Pharmacopoeia
of a Member State.
If used test procedures and limits other than those listed in
the relevant articles and General chapters of the European Pharmacopoeia, or
If it is not listed in the pharmacopoeia of a Member State, must be
proof that the finished product would, if tested in accordance with
the articles, meet the quality requirements of that Pharmacopoeia for the
the pharmaceutical form concerned.
1. General characteristics of the finished product
Certain tests of the General characteristics of the product must always be included
among the tests on the finished product. These tests are always when it is
possible, relate to the control of average masses and maximum deviations,
mechanical, physical or microbiological tests,
organoleptic characteristics, physical properties, such as density,
pH, refractive index. For each of these characteristics, the applicant must specify the
standards and the tolerance limits for each individual case.
If not specified in the European Pharmacopoeia or in the pharmacopoeia of a Member
the State must be the testing conditions, or used equipment or
instruments and standards always accurately described; the same applies in cases where the
are not these pharmacopoeias prescribed method to use.
Additionally, you must be a solid dosage form for oral administration subjected to in
vitro studies release and dissolution rate of the active substance or substances
If it is not otherwise justified. These studies should also be carried out,
When it comes to filing by other means and, if the animal health Institute will assess the
as necessary.
2. Identification and assay of the active substance or substances
Identification and assay of the active substance or substances with
carried out either in a representative sample from the production batch or in a
the number of units of a pharmaceutical form analysed individually.
Unless there is appropriate justification, the maximum acceptable
deviation of the active substance content of the finished product, exceed, at the time
+-5% has been manufactured.
On the basis of the stability tests, the manufacturer must propose and justify
the maximum acceptable deviations for the content of the active substances in the final
of the end of the proposed shelf-life.
In cases of particularly complex mixtures, where assay of active
substances, which are very numerous or present in very low
amounts would necessitate an intricate investigation difficult to carry in respect of each
the production batch, the assay can be one or more of the active substances
the finished product is omitted, on condition that such
assays are made at intermediate stages of production. This
the simplified procedure shall not be extended to the characterization of the substances concerned, and
must be supplemented by a method of quantitative evaluation, enabling the
The Veterinary Institute, check the conformity of the medicinal product with its specifications
After being placed on the market.
Biological determination of in vivo or in vitro is required if
physico-chemical methods cannot provide adequate information on the
quality of the product. Such a determination shall include, if possible,
reference materials and statistical analysis allowing calculation of limits
reliability. If these trials cannot be carried out with the ultimate
the product can be made in the manufacture of an intermediate stage, and it
as late as possible in the manufacturing process.
If, during the production of the finished product degradation occurs, it must be
stated maximum permissible quantities of individual and total
breakdown products immediately after manufacture.
If the information listed in section B show that in the manufacture of the medicinal
the product is applied to a significant overage of an active ingredient, or if
stability data show that the content of the active substance falls during
storage, the description of the control tests on the finished product
where appropriate, contain the chemical and, if necessary,
Toxico-pharmacological evaluation of the changes that this substance
passes, and, where appropriate, the characterization or assay of the degradation
products.
3. Identification and assay of excipient constituents
Identification and determination of upper and lower limit are required for each
individual antimikrobiologickou preservative, and for all
auxiliary substances which may affect the bioavailability of the active
substances, unless it is corroborated by other appropriate bioavailability
tests. Identification and determination of the upper limit are required for
all antioxidants, and for all the other ingredients, which may
adversely affect physiological functions, while for antioxidants
determine (i) the lower limit of the lot at the time of dismissal.
4. 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 carried out routinely to verify the quality of the product.
(F).
STABILITY TESTS
1. The active substance or active substances
There must be exactly determined by the time of the examination (need to retest) and terms and conditions
the retention of the active substance except for the case where an active substance
the subject of the article of the European Pharmacopoeia and the manufacturer of the finished product
Performs complete testing of the drug substance need to retest immediately before the
its use in the manufacture of the finished product.
To justify the retest period and storage conditions shall be submitted to the data on the
stability, stability studies carried out, the type of used protocols
analytical procedures and validation together with detailed results and
commitment to tracking post-approval stability with a comprehensive
serious Protocol.
If, however, for any given active substance from the proposed resource available
the certificate of conformity specifying the need to retest period and conditions
storage, stability data for a given active substance from this source
is not required.
2. Finished product
Enter the description of the tests, on the basis of time have been fixed
shelf life, the recommended storage conditions and the specifications at the end of
the shelf life proposed by the applicant.
Enter the type of studies conducted, protocols used, stability,
the analytical procedures and validation together with detailed results.
Where a finished product requires that the reconstituted
or diluted, shall submit details of the proposed time of usability and
specifications for reconstituted or diluted product, supported by
relevant stability data.
In the case of a multidose containers must be where necessary, listed
stability data, which justify the shelf life for
medicine after his first open, and specifications must be defined
in the course of using the product.
If there is a possibility that the final product is destructive
products, the applicant shall indicate and identify ways to identify and test
procedures.
The conclusions contain the results of analyses, justifying the proposed always time
usability and, if necessary, in the course of the period of application
use under recommended conditions of storage and the specifications of the finished
at the end of the shelf-life of the product and, if necessary, the period of
the applicability of the use of the finished product under these
the recommended storage condition.
Enter the maximum acceptable level of individual and total
degradation products at the end of the shelf life. The study of the interaction between
product and container shall be submitted, if the risk of such
the interaction can be considered as possible, especially as regards the injectable products.
Commitment to tracking post-approval stability shall be submitted
along with a comprehensive serious Protocol.
(G).
FOR MORE INFORMATION
The dossier may contain information relating to the quality
veterinary medicinal product that is not included in the previous
sections.
In the case of medicated pre-mixes (products intended for inclusion in the
medicated feedingstuffs) shall be added, information
guidelines for the inclusion level, homogeneity in the feed, the suitability and compatibility
feed, stability in the feed and the proposed time of usability in the feed.
Shall also be the specifications for the medicated feedingstuffs manufactured using
These pre-mixes in accordance with the recommended instructions for use.
Part 3: safety and residue TESTS
The particulars and documents to accompany the application for marketing authorization pursuant to section 26 paragraph 1.
5 (b). I) point 2 and 4 of the law shall be submitted in accordance with the following
requirements.
A. safety testing
CHAPTER I: THE CONDUCT OF TESTS
Documentation regarding the safety has to demonstrate:
and the potential toxicity of the veterinary medicinal product), and any dangerous or
unwanted effects that may occur under the proposed conditions of
use in animals; These effects should be evaluated with regard to the
the severity of the respective pathological States;
b) possible harmful effects of residues of the veterinary medicinal product or substance in the
foodstuffs obtained from treated animals for humans and the problems that
these residues can act in the industrial processing of foodstuffs;
(c)) the potential risks which may result from the exposure of human
veterinary medicine, for example during its administration to the animal;
(d)) the potential risks for the environment resulting from the use
the veterinary medicinal product.
All results must be reliable and generally valid. At any time it is on the
the place is applied when designing the test methods and evaluation of results
mathematical and statistical procedures. Additionally, submit information on the
the therapeutic potential of the product and on the risks associated with its use.
In some cases it may be necessary to test the metabolites of the original
the substance, if these metabolites residues that must be taken into
account.
With the other ingredient used in the area of pharmaceuticals for the first time must be treated as
with the active substance.
1. Precise identification of the product and its medicinal substances or medicinal substances
-international non-proprietary name (INN),
-name according to the International Union of pure and applied chemistry (IUPAC),
-CAS No (Chemical Abstract Service),
-medical, pharmacological and chemical classification,
-synonyms and abbreviations,
-structural formula,
-molecular formula,
-molecular weight,
-the degree of dirt,
-qualitative and quantitative composition of impurities,
-a description of the physical characteristics,
-melting point,
-boiling point,
-vapour pressure,
-solubility in water and organic solvents expressed in g/l, with
indication of temperature,
-density,
-index of refraction, rotation, etc.
-the composition of the product.
2. Pharmacology
Pharmacological studies are essential for clearing mechanisms,
that produce therapeutic effects of the veterinary medicinal product, and therefore are
pharmacological studies on experimental and target species
submitted in accordance with section 4 of this annex.
However, pharmacological studies may also assist in understanding
toxicological phenomena. If the veterinary medicine Pharmacology
effects that are not accompanied by a toxic response, or is operating in
doses lower than those required to elicit the answers must
In addition, these pharmacological effects to be considered in the assessment
the safety of the veterinary medicinal product.
Documentation relating to safety must therefore always be preceded by a
details of the pharmacological tests, carried out on laboratory
animals and all relevant information observed in clinical
trials in the target animal.
2.1 Pharmacodynamics
Information shall be provided on the mechanism of action of medicinal substances or medicinal
substances, together with information about the primary and secondary
pharmacodynamic effects for the purpose of better understanding of any
side effects in animal studies.
2.2 Pharmacokinetics
The information shall be provided on the fate of the active substance and its metabolites for the species
animals used in toxicological studies involving the absorption,
distribution, metabolism and excretion (ADME). These data must be in the
relation to the dose/effect ratio, as were detected in safety pharmacology
and toxicological studies in order to determine the appropriate exposure.
Compared with the pharmacokinetic data obtained in studies on target
animal species, part 4, chapter I, section 2, shall be presented in section 4 for
the purpose of the determination of the significance of the results obtained in toxicological
toxicity studies in the target species.
3. Toxicology
Documentation regarding the Toxicology is presented in accordance with the instructions
published by the Agency relating to the General rules for the testing of
and guidelines to specific studies. These guidelines include:
1) basic tests required for all new veterinary products
intended for use in food-producing animals in order to
assessment of the safety of any residues present in foods for
human consumption;
2) additional tests that may be required depending on the
specific toxicological expectations, such as those that are
associated with the structure, class, and the mode of action of the active substance or
medicinal substances;
3) special tests, which can be beneficial when interpreting the data
obtained from the Basic or supplementary tests.
These studies must be carried out on the active substance or active substances,
not on the test formulated product. If the studies are required on
test formulated product, are concretized later in the text.
3.1. single dose toxicity
Single dose toxicity tests may be used to establish:
-the possible effects of acute overdosage in the target species,
-the possible effects of accidental administration of people,
-benefits that can be used in the tests after repeated administration.
Single dose toxicity tests should reveal the acute toxic effects
the substance and timing of the onset and aftermath. The tests shall be carried out
be prepared to provide information about the safety of the user,
for example. where it is expected to be significant exposure of the user of the veterinary
of inhalation or contact with the skin, these paths should be
the exposure tested.
3.2 repeated dose Toxicity
Repeated dose toxicity tests are intended to reveal
physiological or pathological changes induced by repeated administration of the
investigational substance or combination of active substances, and to determine
how these changes are related to dosage.
In the case of pharmacological active substances or veterinary products
exclusively intended for use in animals which are not intended for the production of
the food is usually sufficient in repeated dose toxicity test
made in one species of laboratory animals. This test can be
replace the test carried out in the target species of animal. The frequency, and the path
Administration, and the duration of the test are always chosen with regard to the proposed
the conditions of clinical use. The investigator shall give reasons for the extent and
the duration of the trials and the dosages chosen.
In the case of substances or medicinal products intended for
use in food-producing animals, toxicity test
Repeat-dose (90 days) does in rodents and in another animal species,
than are rodents, for the purpose of determining the target organs and
toxicological criteria for disposal (endpoints) and the determination of appropriate
animal species and the benefits which will be used, where appropriate, if they are
chronic toxicity tests are carried out.
The examiner shall state the reasons for the selection of species, having regard to the available knowledge
of the metabolism in animals and in humans. The test substance is administered
orally. The investigator clearly stating the reasons for the choice of method, the frequency of
Administration and the length of the trials.
The highest dose is normally chosen so as to reflect the
harmful effects. The lowest dose is chosen so that it did not produce any
signs of toxic action.
Evaluation of the toxic effects shall be based on observation of behaviour, growth,
haematology and physiological tests, especially those that
affect the authorities involved in excretion, 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 tested in accordance
with the provisions of the Act, may be repeated dose toxicity tests,
If the toxicity tests have shown no increase in toxic action or new
toxic effects, suitably modified by the investigator who shall submit his
the reasons for such changes.
3.3 tolerance in the target species of animal
A summary of the information of any signs of intolerance,
that were observed during studies conducted, usually for use
the final composition of the product in the target species in accordance with the
the requirements of section 4 of chapter I, section B of this annex. Indicate relevant
exams, benefits, in which intolerance showed itself, and the relevant
the animal species and breeds. Furthermore, it shall give details of any
unexpected physiological changes. Full reports of these studies in the
the full wording are listed in part 4 of this annex.
3.4 reproductive toxicity, developmental toxicity, including
3.4.1. A study of the effects on reproduction
The purpose of the study of the effect on the determination of the possible deterioration of the reprodukcije male
or female reproductive function or harmful effects on progeny in
as a result of the administration of the veterinary medicinal product or substance to be tested.
In the case of pharmacologically active substances or veterinary products
intended for use in food-producing animals, studies
the effects on reproduction by multigenerational study reproduction,
the aim is to establish all the effects on mammalian reproduction. These
effects include effects on male and female fertility, mating, parturition,
implantation, ability to carry the fetus up to the date of childbirth, childbirth,
lactation, survival, growth and development of the offspring from birth to weaning,
sexual maturity and the subsequent reproductive function of adult offspring.
Shall be used at least three different doses. The highest dose is chosen so that
showed harmful effects. The lowest dose level should not produce any
signs of toxic action.
3.4.2. Developmental toxicity studies
In the case of pharmacologically active substances or veterinary products
intended for use in food-producing animals shall be carried out
developmental toxicity testing. These tests are designed to
detect any adverse effects on the pregnant female and development of the embryo and
the fetus after the exposure of the female from implantation, during pregnancy until the day
before the expected confinement. Such side effects include increased
toxicity in comparison with the toxicity in non-pregnant females, embryo or death
the fetus, changes in fetal growth and structural changes in the fetus. Always carry out a
developmental toxicity test in rats. Depending on the results of may
be necessary to carry out the test with the other species of animals, in accordance with the
the relevant guidelines.
In the case of pharmacologically active substances or veterinary products,
which are not intended for use in food-producing animals,
developmental toxicity study shall be carried out on at least one animal species,
that can be the target species, if the product is intended for use in
females, which can be used for further breeding. If, however, the
the use of the veterinary medicinal product has led to significant exposure of users
carry out the standard developmental toxicity study.
3.5 Genotoxicity
Tests shall be carried out to demonstrate genotoxic potential, in order to
is to reveal the changes which a substance may cause in the genetic material
cells. All substances that are to be included in the veterinary medicine
for the first time, always assess in terms of genotoxic properties.
For the active substance or substances is usually carried out standard file
tests for genotoxicity in vitro and in vivo in accordance with established
instructions. In some cases, it may also be necessary to submit
testing one or more metabolites that occur as residues in the
foods.
3.6 Carcinogenicity
In deciding whether it is necessary for testing carcinogenicity, is always
taking into account the results of genotoxicity tests, relationships and the effect of structure and
the findings of the tests for systemic toxicity, which may be important
for neoplastic lesions in longer-term studies.
Account shall be taken of all the known species of the particularities of the mechanism
toxicity, as well as any differences in metabolism between animals
used in the tests, target animal species and humans.
If necessary, carcinogenicity testing are required in General
the implementation of a two-year study in rats, and the 18-month study on the
mice. In the case of sound scientific justification can be studies
carcinogenicity in one species of rodent made, preferably in rats.
2.3 Exceptions
If there is a veterinary product intended for the local administration,
systemic absorption in the target species. If it is established that it is
systemic absorption is negligible, the test may not be present
repeated-dose toxicity, reproductive toxicity tests and exams
carcinogenicity, except when:
-You can expect under the specified conditions of use, ingestion, veterinary
of an animal, or
-You can expect under the specified conditions of use, exposure of the user
veterinary medicine in other ways than by contact with the skin, or
-the active substance or metabolites may get into the food derived from the
the treated animal.
4. Other requirements
4.1 special studies
In the case of certain groups of substances, or if the effects observed during the
After repeated administration of tests in animals include changes, indicating
for example, neurotoxicity or immunotoxicity and endocrine disorders, is
necessary to carry out further testing, such as studies of sensitising
or delayed neurotoxicity tests. Depending on the nature of the product
may be necessary to perform additional studies to assess the basic
the mechanism of toxic effect or the potential for irritation. Such studies
is typically carried out using the final composition of the product. When
the design of these studies and the evaluation of their results, taking into account the status of the
scientific knowledge and the valid guidelines.
4.2 microbiological properties of residues
4.2.1. Potential effects on the human gut flora
Potential microbiological risk, residues
antimikrobních substances for the human gut flora will be tested in
accordance with the established guidelines.
4.2.2. Potential effects on the microorganisms used for industrial
food processing
In some cases, it may be necessary to perform tests to determine
whether the microbiologically active residues may interfere with technological
procedures for the industrial processing of foodstuffs.
4.3 Observations in humans
Information shall be provided on whether they are pharmacologically active substances
veterinary medicinal product are used as medicinal products for the treatment of
man; If this is the case, the summary report shall be drawn up on the
all of the observed effects (including adverse effects) in humans and on
their causes, if it may affect the evaluation of the safety
the veterinary medicinal product, including where appropriate the results referred to in
published studies; If a folder of veterinary medicinal products themselves
are not used or are no longer used as medicinal products in
in human therapy, the reasons why this is so.
4.4 development of resistance
Information on the possible occurrence of resistant bacteria that are important for human
in the case of veterinary health products are necessary. Particularly important is the
in this respect, the mechanism of the development of such resistance. If it is a
necessary, propose measures to limit the development of resistance of
provided for the use of the veterinary medicinal product.
Significant resistance for clinical use of the product must be listed in the
accordance with the requirements of part 4. If it's important, it should be noted
cross references to the information set out in part 4.
5. Safety of the user
This section contains a discussion of the effects observed in the preceding
sections and lists associated with the type and extent of human exposure
the product in order to formulate appropriate warnings for
user and other measures in the area of risk management.
6. Assessment of the risks for the environment
6.1 environmental risk assessment for veterinary medicinal products,
that do not contain genetically modified organisms or genetically
modified organisms for the risk assessment to consist
the environment is carried out in order to assess the possible harmful effects,
the use of the veterinary medicinal product may have on the environment, and
determining the level of risk of such effects. This evaluation also provides
all the safety measures that may be necessary to limit the
These risks.
This assessment shall normally be carried out in two stages. The first
This assessment phase is always done. Details of the evaluation
submit in accordance with the applicable guidelines. This evaluation shows a possible
the exposure of the environment to the product and the level of risk associated with
any such exposure taking into account in particular the following points:
-the target species and the proposed pattern of use,
-the method of administration, in particular the likely extent to which the
medicine enter directly into environmental systems,
-the possible excretion of the product, its active substances or relevant
metabolites of ošetřovanými animals into the environment; persistence in
výměšcích.
-deleting unusable veterinary medicinal product or waste from the
of this product.
In the second phase, in accordance with the established guidelines for testing
fate and effects of individual ecosystems. Taking into account the scope of the
environmental exposure to the product and the available information about the physical
chemical, pharmacological and/or toxicological properties of the concerned
substance or substances concerned, including the metabolites in the case laid down
the risks that have been obtained in the implementation of other tests and trials
According to the law.
6.2 environmental risk assessment for veterinary medicinal products,
that contain genetically modified organisms or genetically
modified organisms shall consist of:
In the case of a veterinary medicinal product contains genetically
modified organisms or genetically modified organisms
It consists, the application shall be accompanied by documents required by another
Law ^ 9).
CHAPTER II: A FORM OF PRESENTATION OF PARTICULARS AND DOCUMENTS
The dossier of safety tests related contains:
-a list of all studies contained in the registration dossier,
-a declaration that listed all the details are known to the applicant
at the time of application for a marketing authorisation, whether favourable or unfavourable,
-justification for the abandonment of the design of any type of study,
-explanation for the inclusion of an alternate type of study,
-a discussion of the benefits that may have any study time
preceded by studies carried out in accordance with good laboratory practice
According to another rule of předpisu13c), to the overall risk assessment.
Each study report contains:
-a copy of the study plan (Protocol),
-Declaration of compliance with good laboratory practice, where it is
applicable,
-a description of the methods used, equipment and substances,
-Description and justification of the test system,
-a sufficiently detailed description of the results achieved to results
critically evaluate independently of their interpretation by the author,
-statistical evaluation of results, where appropriate,
-a discussion of the results with comments about the value of benefits with the observed
effect and no observed effect level, and any unusual
observations,
-a detailed description and a thorough discussion of study results
the safety of active substances and their importance for the evaluation of the potential risks,
that represent the residues to humans.
(B) residues.
CHAPTER I: THE CONDUCT OF TESTS
1. introduction
For the purposes of this annex, the definitions of the European
Parliament and of the Council (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, which
Council Regulation (EEC) No 2377/90 and amending Directive
European Parliament and Council Directive 2001/82/EC of the European
Parliament and of the Council (EC) No 726/2004.
The purpose of reducing the content of studies (depletion) residues in edible tissues
or eggs, milk and honey obtained from treated animals is to establish, for
what conditions and to what extent persist residues in food
obtained from such animals. In addition, these studies will allow to lay down a protective
the time limit.
In the case of veterinary medicinal products intended for use in animals
intended for the production of food residue documentation always
proves that:
1. to what extent and for how long remain residues of veterinary
product or its metabolites in edible tissues of treated
animals or in milk, eggs or honey derived from such animals;
2. in order to prevent all risks to consumer health
foodstuffs obtained from treated animals, or difficulties in the industrial
food processing, possible to determine the real withdrawal period, which can be
under practical conditions of animal husbandry.
3. that the analytical method and analytical methods used in the study
depletion of residues elimination are sufficiently validated to
providing the necessary assurance that submitted data on residues are
suitable as the basis for the withdrawal period.
2. Metabolism and residue kinetics
2.1. Pharmacokinetics (absorption, distribution, metabolism, excretion)
Summary of pharmacokinetic data, shall be provided with a cross-reference to the
Pharmacokinetic studies in the target species, presented in section 4 of the
of this annex. The study report in full may not be submitted.
The purpose of pharmacokinetic studies in relation to residues of veterinary
products reviews the absorption, distribution, metabolism and excretion
of the product in the target animal. Finished product, or its
a composition that is comparable in terms of biological characteristics
availability as a final product to the target species of animals served in
the maximum recommended dose.
With regard to the method of administration shall fully describe the absorption rate of the veterinary
of the product. If it is proved that systemic absorption of products for local
Administration is negligible, further residue studies is required.
Distribution of the veterinary medicinal product shall be described in the target species;
take into account the possibility of binding to plasma proteins, or passage into milk or
eggs and the accumulation of Lipophilic substances.
Describe the path of excretion of the product of the target animal. Provides for the
and characterize the major metabolites.
2.2. depletion of residues Elimination
The purpose of these studies, which measure the rate of excretion of residues of
target animal after the last administration of the product, is the determination of the
withdrawal periods.
After the last dose of the veterinary medicinal product to protect animal
validated analytical methods repeatedly, in sufficient number
repetition, fixes the amount of residue is present; give technical
procedures and the reliability and sensitivity of the methods used.
3. Analytical method for the determination of residues
Enter a detailed description of the analytical methods and analytical methods
used in the study (studies) depletion of residues elimination and its
(their) validation.
Describe the following characteristics:
-the specificity,
-the accuracy,
-accuracy,
-the limit of detection,
-limit of determination,
-practicability and applicability under normal laboratory conditions,
-susceptibility to interference,
-stability of residues present.
Appropriateness of the proposed analytical methods shall be evaluated with regard to the status
Scientific and technical knowledge at the time of submission of the application.
The analytical method shall be provided in an internationally agreed format.
CHAPTER II: PRESENTATION OF PARTICULARS AND DOCUMENTS
1. identification of the preparation
Veterinary medicine or veterinary products used in testing
Specifies in detail, including:
-the composition,
-the results of the physical and chemical (efficiency and cleanliness) of the tests for
the batch or the batch concerned,
-identification of the batch,
-relationship to the final product,
-specific activity and radio-purity of labelled substances,
-position of labelled atoms in the molecule.
The registration dossier for residue testing always includes:
-a list of all studies contained in the registration dossier,
-a declaration that listed all the details are known to the applicant
at the time of application for a marketing authorisation, whether favourable or unfavourable,
-justification for the abandonment of the design of any type of study,
-explanation for the inclusion of an alternate type of study,
-a discussion of the benefits that may have any study time
preceded by studies carried out in accordance with good laboratory practice
(SLP) to the overall assessment of the risks
-proposal on withdrawal period.
Each study report must include:
-a copy of the study plan (Protocol),
-Declaration of compliance with good laboratory practice, where it is
applicable,
-a description of the methods used, equipment and raw materials,
-a sufficiently detailed description of the results achieved to results
critically evaluate independently of their interpretation by the author,
-statistical evaluation of the results
-a discussion of the results,
-an objective discussion of the results obtained and the proposals concerning the
withdrawal periods necessary to ensure that foodstuffs
obtained from treated animals do not present any residues which might
could pose a risk to the consumer.
Part 4: PRE-CLINICAL and clinical trials
The particulars and documents to accompany applications for marketing authorization, pursuant to section 26 paragraph 1. 5
(a). I) (2). and (3). shall be submitted in accordance with the following
requirements.
CHAPTER I: REQUIREMENTS FOR PRE-CLINICAL TESTING
Preclinical investigation are necessary to establish the pharmacological activity
and the tolerance of the product.
A. Pharmacology
A.1. Pharmacodynamics
Characterize the pharmacodynamic effects of the drug substance or medicinal
substances contained in veterinary medicine.
First, it must be adequately described the mechanism of action and
pharmacological effects, on which it is based featured the use of in
practice. The results shall be expressed in quantitative terms (for example, using curves
affecting the effect of dose, the effect on time, etc.) and if the
can be compared to the substance with a known effect. If, for a given
the active substance of greater efficiency, the difference must be established and must be
shown to be statistically significant.
Second, it must be noted a general pharmacological assessment of the active substance,
with particular reference to possible secondary pharmacological effects. In General, the
effects shall be assessed on the main functions of the body.
Evaluated must be any effect of the other characteristics of the products
(e.g., route of administration or formulation) to the pharmacological activity
the active substances.
The evaluation shall be carried out in greater depth, if the recommended dose approaches
dose that is likely to cause side effects.
Trial techniques, unless they are standard procedures, shall be described in so
in detail, so that they can be repeated, and the investigator shall determine their
the applicability of the (validity). The test results are always clearly indicate and
for certain types of tests, stating their statistical significance.
If not submitted proper reasons for the reverse procedure, shall evaluate the
also, any quantitative modification of responses resulting from repeated
administration of the substance.
Fixed dose combinations of active substances may be based either on the
pharmacological data or clinical indications. In the first
case, the pharmacodynamic or pharmacokinetic studies demonstrate
interactions that can make itself a combination of convenient for clinical
the use of the. In the second case, where scientific justification for the combination
active substances is looking for using clinical monitoring, testing must
to determine whether the effects expected from the combination can be demonstrated in animals, and
examine at least the significance of any adverse effects. If
the combination includes a new active substance, the substance must be in advance
evaluated in detail.
And 2 the development of resistance
Where applicable, for the veterinary product shall submit to the
information on the possible occurrence of clinically relevant resistant organisms.
Particularly important in this regard are data on the mechanism of the development of such
resistance. The applicant shall propose measures to limit the development of resistance to
the basis of the intended use of the veterinary medicinal product.
If appropriate, include cross-references to the particulars set out in part 3 of the
of this annex.
And 3 the pharmacokinetics of
In the context of the evaluation of the clinical safety and efficacy of the veterinary
of the basic pharmacokinetic data are required on the new
the active substances.
The objectives of the pharmacokinetic studies in the target species can be divided into
the three main areas:
I) descriptive pharmacokinetics leading to the adoption of the basic
parameters,
(ii)), the use of these parameters to track relationships between
dosing, plasma and tissue concentrations over time and
pharmacologic, therapeutic or toxic effects,
III) always when it is in place, the comparison of the kinetics between the various target
the animal species and the investigation of possible differences between the various types of animals,
that have an impact on the safety and efficacy of the veterinary medicinal product in
the destination of the animal.
In the target species is the implementation of pharmacokinetic studies, in principle,
necessary as a supplement to the pharmacodynamic studies in order to help
determination of the effective dosage regimens (route and site of administration, the dose,
dosing interval, the number of submissions, etc.). Required may be complementary
Pharmacokinetic studies, in order to determine dosage regimens in accordance
with some population variables.
If they have been submitted in pharmacokinetic studies of part 3 of this annex,
These studies may be made to cross-reference.
In the case of new combinations of known substances which have been investigated by
the provisions of this directive, pharmacokinetic studies, fixed-dose 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
shall be carried out:
-in the case when comparing the veterinary product with a modified
composition with the existing veterinary medicine
-where it is necessary to compare the new method or route of administration
with the way the established route of administration.
B. tolerance in the target species of animal
Assess the local and systemic tolerability of the veterinary medicinal product in
target species. The purpose of these studies is to characterize the symptoms
intolerance and to establish sufficient limits of safety in use
featured or recommended route of administration. This can be achieved
by increasing the therapeutic dose or duration of treatment. Report on these
evaluations shall include details of all the expected
pharmacological effects and about all of the side effects.
CHAPTER II: REQUIREMENTS FOR CLINICAL TRIALS
1. General principles
The purpose of clinical trials is to prove or substantiate the effect
veterinary medicinal product after administration in the proposed dosing regimen
the proposed route of administration and to establish its indications and contraindications
According to species, age, breed and gender, instructions for its use, as well as
all the side effects that can have.
Experimentally obtained data must be confirmed by data obtained under
normal field conditions.
If proper reasons are submitted, the clinical trials with
using the control animals (controlled clinical
reviews). The results obtained are compared with the results of the effectiveness
efficacy in the target species of animal, which was submitted to the veterinary
the medicinal product authorised in the community for the same indication for use
of the same target species, or a placebo, or with the results
efficacy in the target species of animal, which has not been granted any
treatment. All the obtained results, favourable or unfavourable.
In the draft Protocol, in the analysis and assessment of clinical trials is
apply established statistical principles, except in justified cases.
In the case of a veterinary medicinal product intended primarily for use as
performance Stimulator with special attention to:
1) yield of animals;
2) the quality of animal production (organoleptic, nutritional, hygienic and
technological characteristics);
3) conversion of nutrients and the growth of the target species;
4) General State of health of the target species of animal.
2. The implementation of clinical trials
All veterinary clinical trials shall always be carried out in accordance with the
a detailed research protocol reviews.
Clinical trials in the field trials must be conducted in accordance
He laid out the principles of good clinical practice, with the exception of justified
cases.
Before any reviews carried out in field conditions
must be obtained and recorded in the informed consent of the owner of animals
will be included in the evaluation. The owner of the animal must be in writing
informed of the consequences, that has the inclusion of animals in the evaluation for
the subsequent disposal of treated animals or to obtain food from
such animals. A copy of this notice, signed and dated by the owner
animals shall be included in the documentation of the assessment.
Unless the trial carried out in field trials carried out with
a blind design, the provisions for the labelling of medicines
intended for use in veterinary studies in field conditions
the provisions of section 37 of the Act apply mutatis mutandis. In all cases, the packaging must be
dramatically and indelibly marked with the words "for veterinary only reviews
carried out in field conditions ".
CHAPTER III: INFORMATION AND DOCUMENTATION
Documentation regarding the effectiveness of předklinickou and includes all
clinical documentation or the results of the reviews, positive and negative
for veterinary medicinal products, in order to allow an objective overall rating
benefit/risk profile of the product.
1. the results of pre-clinical testing
Whenever possible, the results:
a) tests demonstrating pharmacological action;
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 evaluation resistance.
If during the tests should unexpected results occur, must be
described in detail.
Additionally, for all preclinical studies indicate the following data:
and) a summary;
(b) a detailed experimental protocol), which presents a description of the
methods, apparatus and materials used, details such as species, age, weight,
gender, number, breed or strain of animals, identification of animals, dose,
route and schedule of administration;
(c) a statistical evaluation of the results);
(d)) to discuss the results obtained, leading to conclusions on the
efficacy and safety of the veterinary medicinal product.
If any of these are missing all or part of the data, must be submitted
the explanation.
2. the results of clinical trials
Each investigator shall submit all data in the case of an individual
treatment on the individual record-sheets and, in the case of mass
treatment of the bulk of the recording sheets.
The data presented have the following form:
a) name, address, function and qualifications of investigator in charge;
(b)) the place and date of treatment; name and address of the owner of the animals;
(c) of the Protocol) details of the clinical trial, giving a description
of the 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, species, breeds or strains, age,
weight, sex, physiological status;
(d)) method of rearing and feeding of the animals, indicating the composition of the feed and the nature and
the quantities of all additives;
e) history (as full as possible), including the occurrence and course of any
intercurrent disease;
f) diagnosis and means used for its determination;
g) clinical symptoms, if possible according to conventional criteria;
(h)) to determine exactly the composition of the veterinary medicinal product used in the clinical
reviews and the results of physical and chemical tests for the
the batch or the batch concerned;
I) dosage of the veterinary medicinal product, method, route and frequency of
Administration and any measures taken during administration (duration of injection
etc.);
j) duration of treatment and period of subsequent observation;
k) all details concerning other veterinary medicinal products,
which have been administered during the period an ongoing clinical trial before
to or concurrently with the test product and, in the case of the current administration
details of any interactions observed;
l) all results of the clinical trials with full description of the results of the
basis of the criteria of efficiency and points for the decommissioning of the specifically listed in
clinical trial protocol and, where applicable, including the results of
statistical evaluation;
m) for full details of any unintended effects, whether harmful
or not, and of any measures taken in consequence; If there is a
possible, will investigate the causal relationship;
n) effect of animals ' performance, if such an effect;
about) the effects on the quality of foodstuffs obtained from treated animals, in particular
in the case of veterinary medicinal products intended for use as
the performance;
p) conclusion regarding the safety and efficacy of each individual
the case or a summary of the conclusions in terms of frequency or other appropriate
variables in the case of a specific mass treatment.
If one or more items and) up to p) is missing, must be submitted
justification.
The marketing authorisation holder shall take all necessary measures to ensure that
the original documents, which formed the basis of the data submitted,
kept for at least five years from the expiry of the registration
the veterinary medicinal product.
For each clinical trial, the clinical observations shall be summarised in the overview
reviews and the results thereof, indicating in particular:
and) number of control animals and the number of experimental animals
treated individually or in bulk, with a resolution by type,
breed or strain, age and sex;
(b)) the number of animals withdrawn prematurely from the trials and the reasons for such
withdrawal;
c) in the case of control animals, whether:
-was not treated or
-jim received placebo or
-jim was given another veterinary medicinal product authorised in the
The community for the same indication for use of the same target species
animals or
-jim was administered the same test substance in the form of
a different composition or by different routes;
(d)) the frequency of observed adverse reactions;
(e)) where appropriate, observations relating to the effect of animals ' performance;
f) details concerning test animals which may be
an increased risk as a result of their age, rearing or feeding, or
the purpose for which they are intended, or animals the physiological or
a pathological condition requires special consideration;
(g) statistical evaluation of results).
The investigator shall draw up on the conclusion of the General conclusions regarding the effectiveness and
the safety of the veterinary medicinal product under the proposed conditions of use,
together with all information relating to indications and contra-indications,
the dosage and the average length of treatment and, where appropriate, any observed
interactions with other health products or additives
in feedingstuffs and any specific measures to be adopted in
the course of treatment, and, where appropriate, of the observed clinical signs
overdose.
In the case of fixed combination of active substances, the investigator shall draw up further
conclusions regarding the safety and efficacy of the product in comparison with the
separate administration of the active substances concerned.
TITLE II
REQUIREMENTS FOR IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS
Without prejudice to the specific requirements laid down by the legislation of
Community concerning the control and eradication of certain contagious animal diseases,
apply to immunological veterinary medicinal products, the following
requirements, with the exception of cases, when the products are intended for use in
some species or for a specific indication within the meaning of title III of the
the annex and the relevant instructions.
Part 1: SUMMARY of the DOSSIER
And.
ADMINISTRATIVE DATA
The immunological veterinary medicinal product which is the subject of the application, it is
identified by name and by name of the active substance or substances, together with the
biological activities, efficiency or showing, the pharmaceutical form,
where appropriate, the means and route of administration and a description of the final sales
packaging of the product, including packaging, labelling and package insert
information. Zřeďovače may be packed together with lékovkami containing
active substance or may be packaged separately.
Information about the zřeďovačích, which are necessary for the reconstitution of the
the product must be included in the registration dossier.
The immunological veterinary medicinal product shall be considered as one product and
If it is to prepare different application forms of the final
the product must use more than one zřeďovač, which may be due to
different routes or routes of administration.
Enter 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 the manufacture and control of
(including the manufacturer of the finished product and the manufacturer or manufacturers of the active substance
or substances), where appropriate, the name and address of the importer.
The applicant shall indicate the number and designation of the volumes of documentation submitted with the
requests, and if the samples are also provided, indicating what.
To the administrative data shall be copies of a document that shows
that the manufacturer is authorized to produce immunological veterinary medicinal products
pursuant to section 62 of the Act. Additionally, the list of organisms which in
the place of production.
The applicant shall provide a list of countries in which authorization has been granted, and
list of countries in which an application has been submitted or rejected.
(B).
SUMMARY OF PRODUCT CHARACTERISTICS, LABELLING AND PACKAGE LEAFLET
The applicant shall propose a summary of product characteristics in accordance with Annex No 3 of this
the Decree.
In addition the applicant shall submit the draft text for the markings on the inner and outer
packaging in accordance with section 37 of the Act, together with a package leaflet, if
is required, in accordance with § 37 para. 3 of the Act. Furthermore, the applicant shall submit a
or more specimens or mock-ups of the sales presentation of all internal and
the external packaging in which the veterinary product is to be marketed in the
the Czech language, in a substantiated case in one of the official languages of the
Of the European Union.
In agreement with the Veterinary Institute can submit proposals for sales packaging
only in black and white and in electronic form.
(C).
A DETAILED AND CRITICAL SUMMARIES
Each detailed and critical summary pursuant to section 26 paragraph 1. 6 of the Act must be
drawn up in the light of the current state of scientific knowledge at the time of
request. Always include the evaluation of all the tests and trials that
make up the documentation for the application for registration, and will focus on all
issues important to assess the quality, safety and efficacy
the immunological veterinary medicinal product. Included in it are detailed
the results of the tests and trials and accurate references to the literature.
All important data shall be summarized in an appendix to a detailed and critical
summaries, in the form of tables or graphs, if possible. Detailed and
critical summaries shall contain precise cross references to information
contained in the main documentation. A detailed and critical summaries must be
signed and dated, and they must be accompanied by information about the
education, training and professional experience of the author. Enter the professional
the author's relationship to the applicant.
Part 2: chemical, pharmaceutical and biological/MICROBIOLOGICAL INFORMATION
(Quality)
All test procedures shall meet the necessary criteria for the analysis and
quality control of starting materials and the finished product and must be
validated. The results of the validation studies shall be provided. Enter the
in sufficient detail the description of any special devices and equipment,
that can be used, where appropriate, shall be accompanied by a sketch. The composition of the
laboratory reagents shall, if necessary, supplement the way of preparation.
In the case of test procedures included in the European Pharmacopoeia or
pharmacopoeia of a Member State may be replaced by the description of the exact link
to the pharmacopoeia in question.
If possible, use the chemical and biological reference material
The European Pharmacopoeia. If other reference products are used and
standards, shall be listed and described in detail.
And.
QUALITATIVE AND QUANTITATIVE PARTICULARS OF THE CONSTITUENTS
1. Qualitative information
"Qualitative particulars" of all the constituents of the immunological veterinary
of the medicinal product shall mean the designation or description of:
-a medicinal substances or medicinal substances,
-components of adjuvants,
-the constituents of the excipients, auxiliary substances, regardless of their nature
or the quantity used, including preservatives, stabilisers,
emulsifiers, colouring matter, flavouring and aromatic substances, identifiers, etc.,
-components of the pharmaceutical form administered to animals.
These particulars shall be supplemented by any relevant data concerning the container and, where appropriate,
its manner of closure, together with details of devices with
where immunological veterinary product will be used or administered and
that will be delivered with. If the resource is not supplied with the
immunological veterinary medicinal product shall be provided to the important
information about this resource, if they are necessary for the evaluation of
of the product.
2. The usual terminology (terminology)
The usual terminology to be used in describing the constituents of
immunological veterinary medicinal products, shall mean, notwithstanding the other
the provisions of § 26 para. 5 (b). (b)) of the Act means:
-in the case of the substances referred to in the European Pharmacopoeia, or failing that,
not listed in the pharmacopoeia of one of the Member States, the main title
the respective article, that will be binding for all such substances, with
reference to the pharmacopoeia concerned,
-in the case of other substances, the international non-proprietary name recommended by the
The World Health Organization, which may be accompanied by other
non-proprietary name, or, failing these, the exact scientific
the designation; substances not having an international non-proprietary name or an exact
scientific designation shall be described by a statement of the origin and method of preparation, with
any addition of any other relevant details,
-in the case of colouring matter, designation "E" code assigned to them in accordance with
another law ^ 13a).
3. Quantitative data
When the "quantitative particulars" of the active substances of an immunological
the veterinary medicinal product, it is essential, wherever possible, indicate the number of
organisms, the contents of the specified proteins, weight, number of
international units (IU) or units of biological activity, either
in unit dosage forms/benefits, or per volume, and with regard to the
Adjuvant and adjuvants folder indicate the weight or the volume of each of the
them with due regard to the details set out in section (B).
If you have defined an international unit of biological activity, it
with this unit.
Units of biological activity, for which there are no publicly
the available data, is expressed to provide unambiguous
information about the activity of substances, for example. stating the immunological effect on
which is based the method for the determination of benefits.
4. development of
The explanations regarding the choice of composition, constituents and internal
the package, supported by scientific data on development of the product. The overage
with its justification.
(B).
THE DESCRIPTION OF THE MANUFACTURING METHOD
The description of the manufacturing method accompanying the application for marketing authorization pursuant to section 26 paragraph 1.
5 (b). (d)) of the Act shall be disclosed so as to provide a sufficient overview of the
the nature of the operations carried out.
For this purpose it shall include at least:
-the various stages of manufacture (including purification procedures and production of Antigen),
in order to assess the repeatability of the production process and risks
adverse effect on finished products, such as microbiological
contamination. Must be demonstrated for the validation of the key stages of the
procedure and validation of the manufacturing process as a whole, with the results of the validation
studies in three consecutive batches produced using
the described method of manufacture,
-in the case of continuous manufacture, full details concerning
the security measures taken to ensure the homogeneity and conformity between
-batch consistency of the finished product,
-the placing of all substances, indicating the stages of production, which are
used, including those which cannot be obtained during manufacture or which
they are not included in the finished product,
-details of the homogenization (blendování), with an indication of the quantitative
details of all the substances used,
-indication of the stages of manufacture at which sampling is carried out for the
the control tests during production.
(C).
PRODUCTION AND CONTROL OF STARTING MATERIALS
For the purposes of this paragraph, "starting materials" shall mean all
the components used for the production of the immunological veterinary medicinal product.
Cultivation media consisting of several components used for the production of
the active substance is considered to be one of the starting material. However,
qualitative and quantitative composition of any culture medium must
be submitted, if the authorities consider that this information is
important for the quality of the finished product and any potential risks.
If they are for the preparation of the culture media used raw materials
of animal origin must be listed used animal species and tissues.
The dossier must include the specification, information about
the tests, to be carried out in order to check the quality of all
batch of starting material, and the results for the lot for all used
folder and must be presented in accordance with the following provisions.
1. Starting materials listed in the pharmacopoeia
For all of the starting material, which are specified in the European Pharmacopoeia
articles of that pharmacopoeia.
In respect of other substances, each Member State may require observance of
of its own national pharmacopoeia with regard to products manufactured in the
its territory.
If the folders are in accordance with the requirements of the European Pharmacopoeia or the pharmacopoeia of
one of the Member States, shall consider the provisions of § 26 para. 5 (b). (h))
the law met. In this case, a description of the analytical methods may be
replaced by a detailed reference to the pharmacopoeia in question.
Dyes in all cases meet the requirements set out in title always
(VIII) of this annex.
The routine tests to be carried out on each batch of starting materials must
correspond to those that are listed in the application for registration. If you are
used by other tests than those that are listed in the Pharmacopoeia, shall be
proof that the starting materials meet the quality requirements according to the
of that pharmacopoeia.
In cases where a specification or other provisions referred to in article
The European Pharmacopoeia or in the pharmacopoeia of a Member State might be
insufficient to ensure the quality of the substance, the competent authorities may
request by the applicant for the registration of more appropriate specifications. The alleged
the deficiency must be notified to the authorities responsible for the pharmacopoeia in question.
In cases where there is no starting material is described neither in the European
Pharmacopoeia or in the pharmacopoeia of a Member State, it may be recognized by the compliance with
Article pharmacopoeia of a third country; in such cases, the applicant shall submit
a copy of such article, if necessary, together with the validation of the test
procedures contained in the article and, if appropriate, with translation.
If they are used by the default raw materials of animal origin, must be in
accordance with the relevant articles, including general articles and General chapters
The European Pharmacopoeia. Carried out tests and checks must be proportionate to the
regard to the starting material.
The applicant shall provide documentation to prove that the starting material
and manufacture of the veterinary medicinal product are in accordance with the requirements of the guideline on
minimising the risk of transmitting animal spongiform encephalopathy
via human and veterinary medicines, as well as with the
requirements of the corresponding article of the European Pharmacopoeia. To demonstrate the
line you can use the certificates of conformity issued by the European Directorate
for the quality of medicines and health care, with a link to the article
The European Pharmacopoeia.
2. Starting materials not listed in the pharmacopoeia
2.1 starting materials of biological origin
Description shall be given in the form of the article (a monograph).
The production of the vaccines must be always, when possible, based on a system
seed and on established cell inokulech. For the production of
immunological veterinary medicinal products containing the serum must be
the origin, general health and immunological status of the animals, of which
is collected, used and defined mixtures of raw materials.
Origin, including geographic region, and all actions carried out with default
raw materials shall be described and documented. In the case of genetically modified
starting materials must contain details such as the
a description of the default cells and expression vector construction of strains (name,
the origin, function replikonu, the promoter, other regulatory mechanisms),
control of active advertising sequence of DNA or RNA, a mismatched
the sequence of plasmid vector in cells, plasmid used for
kotransfekci, added or deletované genes, biological activity
the final construct of expressed genes, the number of copies and genetic
stability.
Seed materials, including cell inokul and raw serum for the production of immune
sera, shall be tested for identity, and the presence of adventitious agents.
Information shall be provided regarding all of the substances
biological origin in all stages of the production process.
This information includes:
-details of the source of the raw materials,
-details of any modifications, purification and
inactivation, together with data on the validation of these procedures and controls
carried out in the course of manufacture,
-details of any tests for contamination carried out on each
a batch of substances.
If the system detects the presence or suspected presence of
adventitious agents, must be removed from the relevant raw material production or
used in very exceptional circumstances only when further processing
the product ensures their elimination and/or inactivation; delete
where appropriate, the inactivation of these foreign agents must be demonstrated.
If they are used, the cell must be seed demonstrated that cell
the characteristics remain unchanged up to the highest passage used for
the production.
In the case of live attenuated vaccines must be proof of stability
achieved by the weakening of the inoculum.
Documentation must be submitted to demonstrate that the seed materials, cell
Spore batch of serum and other raw materials originating from animal species
relevant to the transmission of TSES are in accordance with the requirements of the guideline on
minimising the risk of transmitting animal spongiform encephalopathy
via human and veterinary medicines, as well as with the
requirements of the relevant article of the European Pharmacopoeia. To demonstrate compliance
You can use the certificates of conformity issued by the European Directorate for the
the quality of medicines and health care, with reference to the relevant article of the European
Pharmacopoeia.
If requested by a competent authority, it shall submit the samples of the biological
the default material or reagents used in the testing procedures, to
could this body to ensure the implementation of control tests.
2.2 starting materials that do not have a biological origin
Description shall be given in the form of the article (a monograph), with the following particulars:
-the name of the starting material meeting the requirements of section A point 2, shall be
supplemented by any trade or scientific synonyms,
-description of the starting materials referred to in the form similar to the one that is used by
in the descriptive part of the substances in the European Pharmacopoeia,
-the function of the starting material,
-the method of identification,
-any special precautions that may be necessary during storage
the starting material and, if necessary, the maximum period of storage.
(D).
THE CONTROL TESTS CARRIED OUT DURING THE PRODUCTION PROCESS
1. The dossier contains the data relating to the control
the tests which are carried out in the production stage
an intermediate product in order to verify compliance of the manufacturing process and the finished
of the product.
2. for inactivated or detoxified vaccines must be
inactivation or detoxification tested in every production cycle immediately
After the execution of the process of inactivation or detoxification and after neutralization, if
occurs, but before the next stage of production.
(E).
CONTROL TESTS ON THE FINISHED PRODUCT
For all of the tests for the purposes of evaluation of the quality shall be sufficiently
precise detail description of the analysis of the finished product.
The registration dossier shall contain the information relating to inspection
the tests on the finished product. If there are relevant Pharmacopoeial articles
and if used test procedures and limits other than those that are
listed in the articles of the European Pharmacopoeia or, if there are
listed in the pharmacopoeia of a Member State, proof must be provided that the
the final product would meet the quality requirements laid down by the competent
Pharmacopoeia for the pharmaceutical form concerned, if tested in accordance with
the relevant articles. In the application for marketing authorization shall list the tests that
are carried out on representative samples of each batch of finished
of the product. The frequency must be given tests which are not carried out in
each batch. Shall specify the limits for the layoffs.
If possible, use the chemical and biological reference material
The European Pharmacopoeia. If they are used by other reference products
and standards must be listed and described in detail.
1. General characteristics of the finished product
Tests of the General characteristics, whenever possible, relate to the control of
average masses and maximum deviations, to mechanical, physical
or chemical testing, physical characteristics such as density, pH,
viscosity, etc. For each of these characteristics, the applicant must, for each
individual case to determine the specifications with the corresponding limits
reliability.
2. identity of the active substance or substances
If necessary, carry out a special examination of identity.
3. Titre or strength of the lot
For each batch of the quantification of the active substance shall be carried out, which shows that
each batch contains the corresponding strength or titre to ensure
safety and efficacy.
4. Identification and assay of adjuvants
In the finished product, verifies the quantity and nature of the adjuvant and its components
in the range of available testing procedures.
5. Identification and assay of excipient constituents
If necessary, the excipient/excipients are subject to at least
tests of identity.
Perform the test for the upper and the lower limit is required for preservation
the substance. Perform the test for the upper limit is required for any
a different excipient that may be the cause of the side effect.
6. Safety tests
In addition to the results of the tests submitted in accordance with section 3 of this title
(the safety tests) must be accompanied by the particulars of safety tests
the lot. These tests are best in studies overdose
carried out at least one of the most sensitive target species and
at least the recommended route of Administration posing the greatest risk.
From the routine use of the safety tests of the lot can be in the interest of
welfare of animals abandoned, if it was made
a sufficient number of consecutive production lots that
meet the test.
7. Test for sterility and purity
Appropriate tests must be carried out to demonstrate the absence of
contamination with adventitious agents or other substances according to the nature of the
the immunological veterinary medicinal product, the manner and conditions of production.
If you routinely on each batch of used less than required by the tests
the European Pharmacopoeia, carried out the tests must be essential to the
demonstrate the conformity with article. You must furnish proof that, if
the immunological veterinary medicinal product has been subject to all tests in accordance
with article would meet the requirements of that Pharmacopoeia for the article.
8. residual humidity
Each batch of Lyophilised product shall be tested for content
residual moisture.
9. Inactivation
With inactivated vaccines are on the product in the final container
performs a test to verify inactivation, if this test was not
carried out at the advanced stage of the manufacturing process.
(F).
THE MATCH BETWEEN BATCHES
In order to ensure that the quality of the product is
batches are identical, and in order to demonstrate compliance with the specifications, must be
the full protocol presented three consecutive batches, which
contains the results of all the tests carried out during production and at final
of the product.
(G).
STABILITY TESTS
The particulars and documents to accompany the application for marketing authorization § 26 para. 5
(a). f) and h) of the Act shall be submitted in accordance with the following
requirements.
Enter the description of the tests, on the basis of the time has been set
shelf life proposed by the applicant. These tests shall always be studies
carried out in real time; must be made at a sufficient number of
batches produced in accordance with the described production process and products
stored in the final immediate packaging and the final internal packaging;
These tests include biological and physico-chemical tests
stability.
The conclusions shall contain the results of analyses, justifying the proposed period
usability for all proposed storage conditions.
In the case of products administered in the feed must also be provided
information on the period of application of the product in various stages of incorporation
to the feed, if mixed in accordance with the recommended instructions.
If the final product must be reconstituted,
or is administered in the drinking water, shall submit details of the proposed time
applicability of the reconstituted in accordance with the recommendation.
The data shall be provided showing the proposed expiry date
the reconstituted product.
Stability data obtained for combination products can be used
as preliminary data for derivatives containing one or more of the same
folders.
The proposed shelf life when you use must be justified.
Demonstrated the effectiveness of any system must be conservation.
Information on the effectiveness of preservatives with other similar
immunological veterinary medicinal products from the same manufacturer can be
pleasant.
(H).
FOR MORE INFORMATION
The dossier may contain information relating to the quality
the immunological veterinary medicinal product that is not contained in the
the preceding sections.
Part 3: SAFETY TESTS
And.
INTRODUCTION AND GENERAL REQUIREMENTS
The safety tests shall show the potential risks from the immunological
veterinary medicinal product which may occur under the proposed
conditions of use in animals: this risk is evaluated in relation to the potential
the benefits of the product.
If the immunological veterinary medicinal product contains living organisms,
in particular, such that they can be disseminated, vaccinated animals,
the possible risk to unvaccinated animals of the same or of a different kind
animals that may be exposed to the product.
Safety studies are carried out in the target species. The dose
must correspond to the quantity of product to be recommended for use and lot
used for safety testing shall be taken from a batch or batches
produced according to the manufacturing process described in part 2 of the registration
the documentation submitted with the application for registration.
If the immunological veterinary medicinal product contains a living organism,
the dose to be used in laboratory tests described in
sections B 1 and B 2 must correspond to the quantity of a product containing
the maximum titre. If necessary, the concentration of the Antigen can be
adjusted to required dose was obtained. For inactivated
vaccines must correspond to the quantity of the dose recommended for use
containing the maximum level of Antigen, except in justified cases.
Documentation relating to security will be used to evaluate possible
the risks which may arise from human exposure to the action of the veterinary
of, for example, during the administration of the animal.
(B).
LABORATORY TESTS
1. The safety of the administration of one dose
The immunological veterinary medicinal product shall be submitted at the recommended dose, and all
recommended route of Administration to animals of all species and categories for which
It is intended, and that includes the youngest animal to which it may be administered.
The animals shall be observed and examined for signs of systemic and local
reactions. These studies shall include, where appropriate, detailed post-mortem
macroscopic and microscopic examination of injection sites. They shall be registered
For more objective criteria, such as rectal temperature and measurement
a performance Enhancer.
The animals shall be observed and examined up to the time when I cannot be expected to
the occurrence of reactions, with the observation period and the examination must, however,
always take at least 14 days after administration.
This study may be part of a study on repeated administration of
the levy, which is required in accordance with point 3, or from such studies can be
If the results of the study concerning the administration of the increased benefits
required in paragraph 2 did not reveal any signs of General or local
reaction.
2. safety of one administration increased benefits
Tests concerning the administration of the increased benefits are required only for live
immunological veterinary medicinal products.
An increased dose of the immunological veterinary medicinal product shall be submitted to all
recommended route of Administration to animals most sensitive categories of the target
species, unless there are reasons for the selection of the most sensitive paths from
several similar routes of administration. In the case of immunological veterinary
injectable preparations must be dose and route or routes of administration
chosen taking into account to the maximum volume that can be filed on
any single point injection. The animals shall be observed and examined for
symptoms of systemic and local reactions for at least 14 days after the
Administration. The additional criteria, such as rectal temperature and
the measurement of performance.
Where necessary, these studies a detailed post-mortem
macroscopic and microscopic examination of injection sites, if this
was not carried out in accordance with point 1.
3. safety after repeated administration of one dose
If the immunological veterinary medicinal products to be administered to more than
Once, as a part of the base schema, the vaccine is required
presentation of a study by the repeated administration of one dose, to reveal
any side effects from such submissions. These tests are
be carried out at the most sensitive categories of target species, such as
for example, for certain breeds, and ages, and using all the
the recommended routes of administration.
The animals shall be observed and examined for signs of systemic and local
the reaction of at least 14 days after the last administration. Record more
objective criteria, such as rectal temperature and measuring performance.
4. Examination of reproductive performance
Submission of reproductive performance tests may be necessary if the data
suggest that the default raw material from which it is derived, may be
a potential risk factor. Reproductive indicators of male
and non-pregnant and pregnant females after administration of recommended doses to the most sensitive
route of administration. Furthermore, the harmful effects on the progeny, including
teratogenic and abortifacient effects.
These studies may form part of the safety studies described in paragraphs 1,
2, 3 or in studies carried out in the conditions laid down in
section (C).
5. Examination of immunological functions
If the immunological veterinary medicinal product could adversely affect the
immune response vaccinated animal or its offspring, the
appropriate tests of immunological functions.
6. Special requirements for live vaccines
6.1 dissemination of the vaccine strain
Examined the spread of vaccine strain from vaccinated to target animals
nevakcinovaná, using the recommended route of administration that can with
most likely to cause spreading. It may also be necessary
to investigate the spread of non-target species, which could be highly
susceptible to a live vakcinačnímu tribe.
6.2 the spread in animal vakcinovaném
Faeces, urine, milk, eggs, secretions of the mouth and nose, and other secretions
According to the nature of the product being tested for the presence of the organism. It may also be
required submission of studies the spread of the vaccine strain in the body, with particular
attention to predilekčním sites of replication of the organism. In the case of live
vaccines for zoonotic disease in the meaning of the other legal předpisu13d) for use in
food-producing animals must take these studies especially
account of the persistence of the organism at the injection site.
6.3. Reversion to virulence of attenuated vaccines
Reversion to virulence shall be investigated with master seed. If the master
seed is not available in sufficient quantities, examined seed from
the lowest passage used for production. The use of other passages must be
justified. The initial vaccination shall be carried out using the routes of administration,
most likely to lead to reversion to virulence. They shall be
subsequent passages on five groups of target species, if
There are no grounds for performing multiple passages or if the body
of the tested animals disappear earlier. If the organism does not replicate
enough, as many passages can be performed on the target
species of animals.
6.4. Biological properties of the vaccine strain
For the best possible determination of the biological
the properties of the vaccine strain (e.g. neurotropism) it may be necessary
to perform additional tests.
6.5. Recombination or genomic reassortment of strains
The arguments regarding the likelihood of recombination or
the transmission of the genome with terrain or other strains.
7. Security for the users
This section contains data on the effects observed in the preceding
sections and lists associated with the type and extent of human exposure to
the product in order to formulate appropriate warnings for
user and other measures in the area of risk management.
8. testing of residues
For immunological veterinary medicines is not in normal circumstances
necessary to perform the test. However, in the manufacture of
the immunological veterinary medicinal product used adjuvant or
preservatives, in the documentation submitted to the assessment of options
persistence of residues in food. If it is necessary to submit the data on the
investigation of the effects of such residues.
The withdrawal period is suggested and its adequacy is discussed in relation to the
all the residue.
9. interaction
If the summary of product characteristics included a declaration of
compatibility with other immunological veterinary medicinal products, the
the data regarding the safety of such a connection. Described must be
any known interactions with veterinary medicines.
(C).
A STUDY CARRIED OUT IN FIELD CONDITIONS
Except where justified, the results of laboratory studies will complement
data from studies carried out in field conditions, for these studies
apply a batch manufactured in accordance with the manufacturing process described in the application
about registration. These studies carried out in field conditions can
at the same time to examine the safety and effectiveness.
(D).
ASSESSMENT OF THE RISKS FOR THE ENVIRONMENT
The purpose of the risk assessment for the environment is to assess possible
harmful effects which the use of the environment can cause
environment, and to provide all the safety measures that may be
necessary to reduce such risks.
Such evaluations usually performed in two stages. The first phase of
the evaluation must always be carried out. The evaluation shall be carried out in accordance with the
the Commission's guidelines and the Agency. This review provides potential exposure
the environment of the product and the level of risk associated with any
such exposure taking into account in particular the following points:
-the target species and the anticipated use,
-the method of administration, in particular the likely extent to which the
medicine to enter directly into the environment,
-the possible excretion of the product and its medicinal substances into the
environment of treated animals, persistence in such excretia, and
-deleting unusable product or waste from this product.
In the case of live vaccine strains that may be zoonotic agents,
It shall also assess the risk to humans.
If the conclusions of the first phase of the potential exposure of the
environment to the product, the applicant shall proceed to the second phase and to evaluate the possible
the risk or risks that the veterinary medicine may pose for
the environment. If necessary, additional tests shall be carried out
influence of the product (soil, water, air, aquatic systems, non-target
organisms).
(E).
REVIEWS REQUIRED FOR VETERINARY MEDICINAL PRODUCTS CONTAINING GENETICALLY
MODIFIED ORGANISMS OR GENETICALLY MODIFIED ORGANISMS
CONSISTING
In the case of veterinary medicinal products containing genetically modified
organisms or products consisting of genetically modified organisms must
be accompanied by the documents required under other legal
prescription ^ 9).
Part 4: TEST the EFFECTIVENESS
CHAPTER I
1. General principles
The purpose of the evaluation described in this section is to demonstrate, or confirm
the efficacy of the immunological veterinary medicinal product. All claims
referred to by the applicant with regard to the properties, effects and use of the product
in its entirety must be supported by the results of the assessment, contained in the
the application for registration.
2. implementation of evaluation
All efficacy trials shall be conducted in accordance with a fully
posouzeným a detailed research protocol that is recorded in writing before the
commencement of the trial. Animal welfare included in
reviews are subject to veterinary supervision and fully taken into account when
the preparation of each protocol reviews and during the reviews.
Reviews the pre-formulated systematic written
the procedures governing the Organization, conduct, data collection, documentation and
evaluating the effectiveness of authentication.
Unless justified, must be carried out in the evaluation
field studies carried out in accordance with the established principles of
of good clinical practice.
Before the start of all the reviews carried out in field conditions must
be obtained and recorded the informed consent of the owner of the animals
will be included in the evaluation. The owner of the animal must be in writing
informed of the consequences, that has the inclusion of animals in the evaluation for
subsequent treatment with treated animals and obtaining food from
them. A copy of this notice, signed and dated by the owner of the animals,
be included in the documentation of the assessment.
Unless the trial carried out in field trials carried out with
a blind design, the provisions for the labelling of medicines
intended for use in veterinary trials carried out in the field
the terms of section 37 of the Act apply mutatis mutandis. In all cases, the packaging must be
dramatically and indelibly marked with the words "for veterinary only reviews
carried out in field conditions ".
CHAPTER II
A. General requirements
1. the choice of the Antigen or vaccine strains shall be justified on the
According to epidemiological data.
2. Evaluation of the effectiveness carried out in the laboratory must be carried out in the form of
controlled trials using animals in the untreated control
groups, except in cases where it is not possible to ensure
animal welfare, and cases where you can demonstrate the effectiveness
otherwise.
Generally, this laboratory evaluation will complement the assessments carried out in
field trials, including untreated control animals
groups.
All reviews shall be described in sufficient detail to enable them to be
repeat in controlled studies, carried out at the request of the
of the competent authorities. The investigator must demonstrate that all used
techniques correspond to the purpose for which they are used.
The reports of all the results obtained, whether favourable or
adverse.
3. the efficacy of the immunological veterinary medicinal product shall be demonstrated for
all categories of target species, for which vaccination is
recommended all recommended route of administration and using the proposed
Timesheet submission. If necessary, in an appropriate manner
evaluates the influence of passively acquired maternal antibodies on the efficacy and
the vaccine. With the exception of substantiated cases, onset and duration of immunity
determined with regard to information obtained in the context of the evaluation and shall be
such data.
4. the effectiveness of each ingredient (multi-component) and polyvalentních
combined immunological veterinary products must be
demonstrated. If the product is recommended for use in combination with another
veterinary medicinal product or the current administration with other health
with, it must be demonstrated that these products are compatible.
5. If the product is included in the vaccine recommended schema
by the applicant, must be shown the effect of revaccination or primovakcinace or
the contribution of the immunological veterinary medicinal product to the effectiveness of the entire
program.
6. The dose must correspond to the quantity of product to be recommended for
the use of the lot used for testing and effectiveness must be obtained from the batch
or batches produced according to the manufacturing process described in part 2
the application for registration.
7. If the summary of product characteristics referred to allegations of
compatibility with other immunological preparations, must be investigated
the efficiency associated with such connection. Describe any other known
interaction with any other veterinary medicines. Concurrent or
simultaneous use may be permitted if it is supported by the relevant
studies.
8. in the case of diagnostic immunological veterinary products
administered to animals, the applicant shall indicate how they are to be evaluated responses to
medicine.
9. in the case of vaccines intended to distinguish vaccinated and infected
animals [marked (marker) vaccines], when the claims of efficacy
It relies on in vitro diagnostic tests, shall provide sufficient details
about diagnostic tests that will allow an appropriate assessment of these
claims on marker properties.
(B) the assessments carried out in the laboratory.
1. Demonstration of efficacy shall be carried out subject to a properly controlled
laboratory conditions by challenge after administration of the immunological veterinary
of the target animal under the recommended conditions of use. If there is a
possible, the conditions under which it is carried out, to mimic the challenge
the natural conditions of infection. Details of the čelenžním tribe and
his fitness for a challenge exam. For live vaccines, with the exception
justified cases, apply the batch containing the minimum titre or
efficiency, for other products, except in justified cases, they shall apply
of the lot, with a minimum content of active substance.
2. always, when possible, to determine and document the immune mechanism
(cell/humoral, local/generalized response class
immunoglobulins) that is invoked as a result of administration of the immunological
the veterinary medicinal product to target animals recommended route of administration.
C. the assessments carried out in field conditions
1. With the exception of substantiated cases, laboratory testing and reviews
make up data on trials carried out in field conditions, with
the use of representative batches of the procedure that is described in the application
about registration. The same study carried out in field conditions can
to examine the safety and effectiveness.
2. where laboratory reviews provide the basis for
evaluation of the effectiveness, it is possible to recognise only evaluations carried out in
field conditions.
Part 5: data and documents
And.
INTRODUCTION
Documentation regarding the safety and efficacy studies must include
an introduction defining the subject and which lists the tests that
have been made under sections 3 and 4, as well as the Executive summary, together with the details
bibliographical references. This summary must contain an objective discussion
of all the results obtained and must lead to conclusions on the safety and
the efficacy of the immunological veterinary medicinal product. The deletion of any
tests or reviews of the list must be noted and discussed.
(B).
LABORATORY STUDIES
For all studies, the following information must be provided:
1. summary,
2. the name of the operator who carried out the study,
3. a detailed test report, in which it is given a description of the
methods, apparatus and materials used, details such as species or breed of animals,
categories of animals, where they were obtained, their identification and number,
the conditions under which they were housed and fed (stating inter alia whether
they were free from specific pathogens or specific antibodies
the type and quantity of any additives contained in the feed), dose,
the way, the schedule and the date of filing, a description and justification of the statistical
methods,
4. in the case of control animals, whether they received
placebo or not treated,
5. in the case of treated animals and, where appropriate, of whether these
animals administered the product under study or other product registered in
The community,
6. all General and individual observations and results obtained (with the
averages and standard deviations), whether favourable or unfavourable.
The data shall be described in sufficient detail to permit the results critically
to evaluate independently of their interpretation by the author. The primary data shall be
refer to it in the form of tables. To explain and demonstrate the results may be
accompanied by reproductions of recordings, photomicrographs, or other appropriate means,
7. the nature, frequency and duration of observed adverse reactions;
8. the number of animals withdrawn prematurely from the studies indicating the reason or
the reasons for their disposal,
9. a statistical evaluation of the results when this is called for by the test programme,
and the variance in the data obtained,
10. occurrence and course of any intercurrent disease,
11. all details concerning veterinary preparations (other than
is the product under study), the administration of which was necessary in the course of the study,
12. an objective discussion of the results obtained, leading to conclusions on the
the safety and efficacy of the product.
(C).
A STUDY CARRIED OUT IN FIELD CONDITIONS
Information relating to studies carried out in field conditions must be
sufficiently detailed to be able to take an objective opinion.
Must contain the following particulars:
1. summary,
2. the name, address, function and qualifications of investigator in charge,
3. place and date of identification code that can refer to
name and address of the owner of the animal or animals,
4. the details of the trial protocol, giving a description of the used
methods, apparatus and materials used, details such as the route of administration, schedule
Administration, the dose, the categories of animals, the length of the observation, the serological
response and other investigations carried out on animals after administration,
5. in the case of control animals, whether they received
placebo or not treated,
6. identification of the animals treated and control animals
(according to the situation of the mass or individual), such as species, breeds or
strains, age, weight, sex, physiological status,
7. a short description of the method of rearing and feeding, stating the type and amount of
any additives contained in the feed,
8. all information concerning sightings, parameters, performance and
the results (with averages and standard deviations); If they have been
performed tests and measurements on each animal, the
the individual data,
9. all observations and results of the studies, positive and negative, with
exhaustive observations and the results of the objective tests
required for the evaluation of the product; the techniques used and shall
explain the significance of any variations in the results,
10. the effects on the animals ' performance,
11. the number of animals withdrawn prematurely from the studies and reasons for their
disposal,
12. the nature, frequency and duration of observed adverse reactions;
13. occurrence and course of any intercurrent disease,
14. all details concerning veterinary preparations (other than
is the product under study) which have been filed before or at the same time
the test product or during the period of observation; details of all the
the interactions observed,
15. an objective discussion of the results obtained, leading to conclusions on the
the safety and efficacy of the product.
Part 6: links to PROFESSIONAL LITERATURE
Indicate in detail the links to scholarly literature cited in the summary
referred to in the context of part 1 and a copy shall be provided.
TITLE III
REQUIREMENTS FOR SPECIFIC APPLICATIONS FOR REGISTRATION
1. the Generic veterinary products
Applications for registration on the basis of section 27 para. 1 of the law (generic
veterinary products) always contain the information referred to in sections 1 and 2
Title I of this annex together with an assessment of the risks to the environment and
data showing that the product has the same qualitative and
quantitative composition in active substances and the same pharmaceutical form as the
the reference medicinal product, and the data to prove that the product is
Bioequivalent with the reference medicinal product. If there is a
reference biological veterinary medicinal product shall
to meet the requirements of the documentation referred to in section 2 for a similar
biological veterinary medicinal products.
For generic veterinary products with detailed and critical summaries
regarding the safety and effectiveness of focus particularly on the following
requirements:
-the relevance of essential similarity,
-a summary of impurities present in batches of the active substance or substances,
as well as the finished medicinal product (and where appropriate, the relevant
degradation products arising during storage) as proposed
for use in the product to be placed on the market, together with the evaluation of
these impurities,
-the assessment of bioequivalence studies or a justification why such studies
have been performed, with reference to the applicable guidelines,
-the applicant should, where appropriate, to demonstrate equivalence properties of some
salts, esters or derivatives of an authorised active substance in relation to the
safety and efficacy to provide additional information; These data
include evidence that there has been a change in the pharmacokinetic or
pharmacodynamic properties of the medicinal ingredient or the toxicity, which would
may affect the safety and efficacy profile;
Every claim in the summary of product characteristics, which is not known or
inferred from the properties of the medicinal product and/or its therapeutic
the Group discussed in detail in the non-clinical/clinical overviews
and summaries and links to the professional literature or
additional studies.
For generic veterinary medicines intended for use
intramuscular, subcutaneous or transdermal route shall be submitted
the following additional information:
-evidence showing the same or different residue depletion from space
submissions, which may be accompanied by the corresponding studies of the depletion
residues,
-evidence proving the compatibility of the target animal at the place of filing, which
may be accompanied by the corresponding studies of the tolerance in the target
animals.
2. Similar biological veterinary products
In accordance with § 27 para. 5 of the Act, where a biological veterinary
the product, which is similar to a reference biological veterinary
the product does not meet the conditions in the definition of a generic medicinal product
of the product, the information to be provided, restrict
only parts 1 and 2 (pharmaceutical, chemical, and biological data),
supplemented by information on Bioequivalence and bioavailability. In such
cases, additional information shall be provided, in particular on security and
the effectiveness of the product. The nature and extent of additional data (i.e..
toxicological and other safety studies and clinical studies)
shall be determined for each individual case in accordance with the relevant
scientific guidelines.
Due to the diversity of biological veterinary medicines
The animal health Institute provides the necessary studies anticipated in parts 3 and
4, taking into account the specific characteristic of each individual
the biological veterinary medicinal product.
The General principles to be applied, shall be determined in the order that
the Agency shall adopt, taking into account the characteristics of the
the biological veterinary medicinal product. If the reference has a biological
veterinary product more than one indication, the claim of a similar
the efficacy and safety of a biological veterinary medicinal product shall be properly
justified or, if necessary, demonstrated separately for each
indication to which the claim relates.
3. the well-established veterinary use
In the case of veterinary medicinal products the active ingredient or active substances,
they have a well established medicinal use, as specified in section 27 para.
7 of the Act, with recognised efficacy and an acceptable level of safety, with
the following specific rules shall apply.
The applicant shall provide parts 1 and 2, as described in title I of this annex.
In parts 3 and 4 detailed references to scholarly literature affect
all aspects of security and efficiency.
To demonstrate the well-established veterinary use shall apply
the following specific rules:
3.1. To demonstrate a well-established veterinary medicinal use of constituents
veterinary medicinal products shall take into account the following factors:
and) the period during which the active substance is used;
(b) quantitative terms of use) of the active substance;
(c)) the level of scientific interest in the use of the active substance (reflected in the
the published scientific literature);
d) coherence of scientific assessments.
As evidence of a well-established use of different substances may be needed
different period of time. In all cases, however, the period required for the
evidence of a well-established veterinary medicinal use of folder
a medicinal product must not be less than ten years from the first
systematic and documented use of that substance as a veterinary
of the product in the community.
3.2. The documentation submitted by the applicant always affects all aspects of the
evaluation of the safety and efficacy of the product for the proposed indication for
target species for the use of the proposed route of administration and mode
the dosage. Must include or refer to a review of the relevant
literature, to refer to the předregistračním and post marketing studies and
published scientific literature presenting the experience in the form of
epidemiological studies and in particular of comparative epidemiological
studies. All documentation must be submitted, favorable and unfavorable.
Having regard to the provisions on the well-established veterinary use is
in particular necessary to clarify that the bibliographic references to other resources
evidence (postmarketing studies, epidemiological studies, etc.) and not only
data relating to tests and trials may serve as a valid proof of
safety and efficacy of the product when it is in the application sufficiently
explains and justifies the use of these sources of information.
3.3. Special attention is always dedicated to any missing information
and the reasons why it is possible to demonstrate proof of an acceptable degree of
safety or efficacy, although some studies are lacking.
3.4 detailed and critical summaries of safety and effectiveness
must clarify the meaning of any of the submitted data, that relate to the
other than the product is intended to be placed on the market. Must be
assessed whether the product under study can be considered as similar to the
product, or not, for which an application for registration has been drawn up,
and this despite the existing differences.
3.5 are particularly important post-marketing experience with other products
that contain the same ingredients. This question must ask applicants special
the emphasis.
4. veterinary medicinal products fixed combination medicinal products
For claims based on section 27 para. 8 of the Act on veterinary products
fixed combination medicinal substances shall submit a registration dossier
containing parts 1, 2, 3 and 4. It is not necessary to submit studies on the
safety and efficacy for each active substance. However, it is possible to
include information on individual substances to requests concerning a fixed
combination. Submission of data about each individual active substance, together with
the required safety studies residue depletion studies and
clinical studies concerning the fixed combination medicinal product can be
considered appropriate justification for the failure to submit data about mixed
the product due to animal welfare and undue
animal testing, if there is no suspicion on the interaction Manager
the higher the toxicity. Where appropriate, the information shall be provided
relating to the production sites and the adventitious agents safety evaluation.
5. applications with informed consent
The application on the basis of section 27 para. 9 of law always contain the information referred to in
Part 1 of title I of this annex, provided that the holder of the registration
the original veterinary medicinal product granted the applicant agree to
He made reference to the contents of parts 2, 3 and 4 of the registration documentation of such
of the product. In this case, they do not produce detailed and critical summaries
regarding the quality, safety and efficacy.
6. Documentation of applications in exceptional circumstances
Authorisation may be granted subject to certain specific obligations
requesting the applicant to introduce specific procedures, in particular with
regard to the safety and efficacy of the veterinary medicinal product, if, as is
provided for in § 32 para. 3 of the Act, the applicant can show that he is able to
present comprehensive data on the efficacy and safety under normal circumstances
the use of.
The essential requirements for all of the requests referred to in this section are
laid down in Commission guidance and the Agency.
7. mixed applications for registration
Mixed marketing authorisation application are applications for which part 3 or 4
the registration dossier shall contain the study of safety and efficacy
made by the applicant, as well as bibliographic references.
All other parts are in accordance with the structure described in part I of the
Title I of this annex. The animal health Institute will examine separately for each
a registration dossier submitted, whether the format submitted by the
by the applicant, be considered sufficient for the evaluation.
TITLE IV
REQUIREMENTS FOR APPLICATIONS FOR MARKETING AUTHORISATION FOR CERTAIN VETERINARY MEDICINAL PRODUCTS
This section sets out the special requirements for specific veterinary
preparations in relation to the nature of the active substances contained in them.
1.
IMMUNOLOGICAL VETERINARY MEDICINAL PRODUCTS
And.
THE BASIC DOCUMENT OF THE VACCINE ANTIGEN MASTER FILE
For some of the immunological veterinary medicinal products, and by way of derogation from the provisions of
Title II, part 2, section C of medicinal substances, introduces the concept of
the basic vaccine Antigen master file.
For the purposes of this annex, the founding document of a vaccine Antigen master file
means a single part of the marketing authorisation application dossier for vaccine
a substance that contains all the important information on the quality of each of the
active substances, which are part of the relevant veterinary
of the product. The stand-alone part may be common to one or more
monovalent or vícevalentních vaccines submitted by the applicant
about registration.
Scientific guidelines for the submission and evaluation of the basic document on the
vaccine Antigen master file shall take the Agency. The submission and evaluation of the basic
vaccine Antigen master file shall be carried out according to the instructions published
By the Commission in the rules governing medicinal products in the European Union, volume 6B,
Instructions for applicant.
(B).
VÍCEKMENOVÁ OF THE REGISTRATION DOSSIER
For certain immunological veterinary medicinal products (foot and mouth disease,
Avian influenza and Bluetongue) and by derogation from the provisions of
Title II, part 2, section C of medicinal substances, introduces the concept of the use of
the registration dossier for more strains. Vícekmenovou registration
documentation means one dossier containing relevant data for the
the only and complete scientific evaluation of various options for the use of the tribes or
combination thereof, on the basis of which you can enable registration of vaccines
antigenně variable of viruses.
Scientific guidelines for the submission and evaluation of registration dossiers for
the Agency shall adopt more strains. The submission and evaluation of registration
documentation for multiple strains shall be carried out according to the guidelines published by the Commission
in the rules governing medicinal products in the European Union, volume 6B
for the applicant.
2.
HOMEOPATHIC VETERINARY MEDICINAL PRODUCTS
This section lays down special provisions for the application of title I of part 2 and 3
for the homeopathic veterinary medicinal products, as defined in section 2 (2).
2 (a). g) of the Act.
To part 2
The documentation submitted in accordance with section 29 para. 2 of the Act when
a simplified registration procedure for homeopathic veterinary medicinal products
referred to in section 29 para. 1 of the act as well as the documentation for the
the registration of other homeopathic veterinary preparations
are not subject to a simplified registration procedure pursuant to § 29 para. 1, the
the provisions of part 2 shall apply with the following modifications.
and) Terminology (terminology)
The Latin name of the homeopathic stock described in the documentation for
applications for registration shall be in accordance with the Latin title of the European
Pharmacopoeia or in the pharmacopoeia of a Member State, the official.
Where appropriate, provide the name of the traditional or traditional names used in
each Member State.
(b)) control of starting materials
Data and documentation for starting materials, i.e. all the materials used
including raw materials and intermediates up to the final dilution, processed into
the final homeopathic veterinary medicinal product, that are
submitted with the application, shall be supplemented by additional data on basic homeopathic
the substance.
For all the starting materials that are processed into a final
a homeopathic medicinal product shall apply the general quality requirements, as well
as for the intermediate stages of the manufacturing process up to the final dilution. If there is a
present a toxic ingredient, this folder should be checked in
the final dilution. However, if this is not possible because of the high degree of
dilution, toxic folder must be checked by default in the ranějším
stage. Each step of the manufacturing process from the starting materials after the final
dilution, which are processed into the finished product, describe exactly.
In the case that's included dilutions, dilution steps is carried out according to the
homeopathic manufacturing practices set out in the relevant article
The European Pharmacopoeia or, in the absence, in the official pharmacopoeia of a Member
State.
c) control tests on the finished medicinal product
The final homeopathic veterinary medicinal products is subject to the General
the quality requirements. Any exceptions must be the applicant, duly
justified.
Always performs identification and assay of all the toxicologically
major components. If it can be justified that the identification or establishment of
the contents of all the toxicologically relevant constituents is not possible, for example, from
due to their dilution in the finished medicinal product, proof of quality
the complete validation of the manufacturing process and the process of dilution
.
d) stability tests
Always showing the stability of the finished product. Stability data
Basic homeopathic substances are generally portable to
dilution/potentiation of them obtained. If identification is not possible or
determination of the content of the active substance for a high degree of dilution may be taken
into account the data on the stability of the formulation.
To part 3
The provisions of section 3 shall apply to the simplified registration procedure
homeopathic veterinary medicinal products referred to in section 29 para. 1 of the law with
the following specifications, without prejudice to the provisions of the regulation
The European Parliament and of the Council (EC) no 470/2009 laying down
Community procedures for 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 of the Council No.
726/2004 for substances contained in basic homeopathic substances
intended for Administration to food-producing animals.
Any missing information will be always justified, for example, are the reasons
Why may be the demonstration of an acceptable level of safety, even though
Some studies are lacking.
TITLE V OF THE
REQUIREMENTS FOR THE CONTENT AND STRUCTURE OF THE DATA AND DOCUMENTATION ACCOMPANYING THE APPLICATION
A SIMPLIFIED REGISTRATION OF VETERINARY HOMEOPATHIC PRODUCTS
The application for simplified registration of veterinary homeopathic
the products shall be accompanied by the particulars and documents stating, in particular,
pharmaceutical quality and homogeneity of the batches of the relevant product.
The application shall be accompanied by at least:
1. Administrative information, which include:
-the name of the product,
-indication of the basic substances or substances with an indication of the scientific name, or
lékopisného the name of the basic substance,
-degree or degrees of dilution,
-the method and route of administration,
-the target species,
-packing size, type of packaging,
-business name and address of the registrant, if the legal
the person, or the name or names, last name and place of business of the applicant
on the registration, in the case of a natural person, the same information about the manufacturer or
products to match with the person of the registrant,
-number and designation of the individual volumes of documentation, the characteristics
submitted samples,
-putting all the production sites and for each place of production, indicating the
manufacturing operations that are carried out, and with proof that the manufacturer is
possession of a valid permit for the manufacture of veterinary medicinal products in
to the extent
-the list of countries where the product is registered or where is his
the registration applied for, including copies of any marketing authorisation or
other authorizations for marketing, and the list of countries in which the application for
the registration of rejected or withdrawn for reasons of safety
of the product,
-one or more specimens or design of internal and external sales
the packaging of the product.
2. the dossier containing data on method of production and control of the basic
substance or substances and documenting data about the homeopathic nature of the basic
substance or substances with reference to professional literature; in the case of
homeopathic immunological veterinary medicinal products containing
substances of biological origin, further describing measures to ensure
the absence of pathogenic organisms in the product.
3. Manufacturing and control file for each pharmaceutical form and a description of the
the method of dilution and potentization.
4. Data demonstrating the stability of the product.
5. the proposal of the withdrawal period
TITLE VI OF THE
THE LIABILITY OF PROFESSIONALS INVOLVED IN THE ASSEMBLY REGISTRATION
DOCUMENTATION
The particulars and documents to accompany applications for marketing authorization before
the presentation of a Veterinary Institute compiled by experts with the necessary
technical or professional qualifications.
According to their particular qualifications, the role of the experts:
and to carry out such activity) that falls within their specialization
(analytical activities, 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 shall state
1. in the case of analysts, whether the veterinary product conforms with the stated
composition, providing justification for the control testing methods employed by the manufacturer,
2. in the case of pharmacologists and appropriately qualified specialists:
the toxicity of the veterinary medicinal product and the pharmacological properties observed,
and whether, after administration of the veterinary medicinal product under normal conditions of
use and in compliance with the recommended withdrawal period, foodstuffs
obtained from the treated animal residues which might constitute a
risk to the health of the consumer,
3. in the case of clinicians, whether in animals treated with the veterinary
product effects corresponding to the information submitted by found by the manufacturer
According to section 27 of the Act, the indicator of veterinary product well tolerated, what
dose of design and what are the contra-indications and adverse reactions;
(c)) to submit justification for the possible use of references to published
information pursuant to § 27 para. 12 of the Act.
TITLE VII
THE CONDITIONS UNDER WHICH IT MAY BE ESTABLISHED THAT THE VETERINARY MEDICINAL PRODUCT INTENDED FOR
THE ANIMALS, FROM WHICH ARE DERIVED THE FOOD PRODUCTS OF ANIMAL ORIGIN
A MAN CAN BE ISSUED WITHOUT A PRESCRIPTION
(1) of the veterinary medicinal product intended for animals, from which they are
collected animal products for human nutrition, it may be decided that it
can be issued without a prescription, if all are true
the following terms and conditions:
and administration of the veterinary medicinal product) does not require any special knowledge
or abilities
(b)) is not a veterinary product direct or indirect risk to
the treated animal or animals, the person administering the product, nor for the
environment, even when its improper use;
(c)) the summary of a health product does not include a warning of the possible
serious side effects, that may arise as a result of his
the right to use,
(d)) the veterinary medicine or other health product
containing the same active substance has not been the subject of frequent submission
reports of serious adverse events
(e)) the summary of product characteristics does not refer to the contraindications associated with other
commonly used veterinary preparations, the issue is not bound to
medical prescription,
(f)) are not laid down the special conditions for storage of veterinary
of the product,
g) veterinary product does not pose a risk to the safety of
the consumer as regards the residues of medicinal or excipients
contained in foodstuffs obtained from animals to which was
such a product is used, even in the event of improper use,
h) veterinary medicinal products does not represent a risk for public health
or animal health with respect to the development of resistance to the indicated substances
or to antihelmintikům, and even if its incorrect use.
TITLE VIII
REQUIREMENTS ON COLOURING AGENTS USED IN VETERINARY MEDICINAL PRODUCTS
1. in the veterinary medicinal products can only use dyes that are
allowed in food and which are mentioned in the other legal
^ Regulation 13e).
2. the applicant shall demonstrate that the colouring agents used in veterinary medicinal products
meet the requirements for identity and purity in accordance with other legal
^ Regulation 13b).
3. For testing the identity and purity of colouring agents used in veterinary
products the applicant uses methods and procedures laid down in other legal
^ Regulation 13f).
Annex 3
The content and structure of the SPC
And in the case of medicinal products for human use. in the summary of product characteristics shall be shown
the following data, which are further specified in the regular
updated templates on the Web site of the Agency. Summary
the product must in the case of medicinal products on the list
According to article 23 of the regulation of the European Parliament and of the Council (EC) No 726/2004
of 31 March 2004. March 2004 laying down Community procedures for the
authorisation and supervision of medicinal products and veterinary medicinal products and laying
European Medicines Agency, as amended by regulation of the European
Parliament and of the Council (EC) no 1901/2006, contain the sentence: "this product
product is subject to further monitoring. " This sentence must be preceded by a black
a symbol referred to in article 23 of Regulation (EC) No 726/2004 and shall
follow the appropriate explanation.
1. Product name
Enter the name of the medicinal product followed by the strength and the pharmaceutical form.
2. Qualitative and quantitative composition
The active substance shall be provided, using their common names in
the Latin version; in the case that these names are not fixed, shall apply
commonly used names. Excipient shall be given only if the
are relevant to the properties of the product and knowledge of them is essential
for the correct use of the product. In the case of specific homeopathic
products authorised under section 28a of the law on pharmaceuticals, provides the scientific
name of the stock or stocks followed by the degree
dilute, using the expression of this level, it's the symbol of the pharmacopoeia.
For a complete list of excipients shall be indicated in section 6.1.
3. pharmaceutical form
Pharmaceutical form means the resulting appearance of the product, which is determined by the
pharmaceutical form of the medicinal product, its administration, or even the
the type of packaging. It is further noted the description of the product, and if the score line,
justified, why is introduced.
4. clinical particulars
4.1 therapeutic indications
Indications relate as closely as possible the results of the clinical
reviews. It is characterized by the use of: treatment, prevention, or diagnosis. In
case of specific homeopathic medicinal products registered in accordance with section
28 the law on pharmaceuticals, together with an indication of the relevant indication shows the sentence
"Homeopathic medicine used traditionally in homeopathy to
mitigation ", or" homeopathic medicine used traditionally in
Homeopathy to treat ".
4.2 Posology and method of administration
It is reported
-dosage for each indication for each age category, and
dosage in hepatic failure or when ledvinném or dialysis; dosage
description of the size of the dose, the interval between doses and duration
treatment,
-possibility of use in children,
-the highest daily dose and the highest dose for the entire treatment,
-recommendations for the monitoring of plasma levels of the drug or other
indicators of its effects.
4.3 Contraindications
4.4 Special warnings and precautions for use
Shall be shown
-warning side effects pharmacodynamic group to which it is
the product ordered or the product under normal use,
-notification of adverse effects that occur in specific
cases, especially in the elderly and ledvinném, liver or
heart failure,
-description of how to use of the product at risk patient groups,
-the procedures, how to avoid side effects,
-specific measures to be taken by the patient or person with
with treats, if it is a imunobiologický product.
4.5 interaction with other medicinal products and other forms of interaction
Shall be shown only clinically significant interactions with medicines that are used to
the same indication, interaction with the preparations for other indications and interactions
related to the way of life, for example. interaction with food.
For each interaction States mechanism, if known; effect on blood
the active substance in plasma and in laboratory and clinical parameters; warning
the current administration of the contraindication with other drugs and any measures
When used in combination with other drugs, in particular adjustment of the dose.
4.6 pregnancy and lactation
Shall be shown
-the results of reproductive and fertility studies on animals; experience
with the medicine in humans and risk assessment at different periods
pregnancy,
-the possibility of use of the product in pregnant women and in women of childbearing potential
-a recommendation whether to continue breastfeeding with an indication of the probability and the
the severity of side effects for the child; the following information shall be given,
If the active substance or its metabolites are excreted in human
milk.
From the perspective of the impact on the fetus is the need to assess all components of the product,
not only the active substance.
4.7. effects on ability to drive and use machines
The indication of the influence of attention. On the basis of the pharmacodynamic
the profile reported adverse reactions and affecting the attention while driving
motor vehicles and machinery products are divided into 3 groups
affecting the attention
-safe or with the improbable by influencing,
-with the probability of a moderate influence,
-with the probability of significant influence, potentially dangerous.
In cases in the probable slight or significant effect on attention
shall bear the warnings.
4.8. undesirable effects
Adverse reactions are classified according to systemically-organ
the MedDRA terminology. In each class are undesirable effects are presented
in descending order according to the expected frequency of occurrence. Give knowledge about
specific product and knowledge of its individual components. It is reported
whether or not the possibility of addiction. Standardized text shall explicitly
the requesting health care professionals are asked to report any suspected
side effect in accordance with the national reporting system.
4.9. overdose
Reported experience with overdose in animals; experience with
overdose in humans; treatment of overdose in humans.
5. Pharmacological properties
5.1. pharmacodynamic properties indicate the
-the pharmaco-therapeutic group ATC code,
-mechanism of action, if known,
-pharmacodynamic properties, if they relate to use of the product.
5.2. pharmacokinetic properties
Shall be shown
-the relevant information about the properties of the active substance, and in particular its
absorption and bioavailability of the product formulation, including the impact
food, are given information on the distribution in the organism,
biotransformation and elimination,
-data obtained in patients, in particular, any known relationships between
the plasma or blood concentrations and therapeutic or adverse
the effects and the effects of age, metabolism and pathological States takes on
the pharmacokinetics of the pointer.
5.3 preclinical safety data safety
Must be reported with any and all information that is important for the doctor in terms of
safety of the product when used in approved indications and
are not listed in other parts of the summary of product characteristics.
6. Pharmaceutical particulars
6.1 list of excipients
Quality shall be provided in Czech nomenclature all excipients
contained in the product.
6.2 Incompatibilities
Shall be shown
-physical or chemical incompatibilities, which come into consideration when
mixing of products or when administering,
-significant problems on the sorption of the syringe.
6.3 shelf life
The expiry date is given as packaged for sale and, if it is
necessary, also after dilution, after preparation according to instructions or first
Open
hits.
6.4 special precautions for storage
Indicate the specific measures required for the storage of the product, on
in particular, temperature, lighting conditions and moisture, or shall indicate that the
storage of special measures required. If it is a
necessary, special measures for the prior
dilution, after preparation according to the instructions, or after first opening.
6.5 nature and contents of container
6.6 special precautions for disposal
Shall be shown
-the procedures for the disposal of or reference to the legal provisions for wastes
-information on the adjustment of the product if the product is not intended for direct
use and is needed to edit prior to administration,
-Special instructions in the case of the special manner of use or type
packaging,
-the need to use a special device to the application of the product.
7. the holder of the marketing authorisation
Lists the business name and seat of the marketing authorisation holder,
in the case of a legal person, or the name or name, surname and
place of business, in the case of a natural person.
8. Registration number
9. Date of first authorisation/renewal of the authorisation
10. date of revision of the text
11. The dosimetry
In the case of radiopharmaceuticals shall specify the details of internal radiation
dosimetry.
12. Instructions for the preparation of radiopharmaceuticals
Detailed instructions for the preparation in time of need, including quality control
the prepared radiopharmaceutical, and, where appropriate, maximum storage time
which will be any intermediate or radiopharmaceutical prepared to
use comply with the relevant specifications.
B. in the case of veterinary medicines in the summary of product characteristics
State the following information:
1. Product name
Enter the name of the medicinal product followed by the strength and the pharmaceutical form.
2. qualitative and quantitative Composition
In the case of active substances shall be indicated, i.e. for complete details. qualitative and
quantitative composition. In the case of substances of the auxiliary is given only the composition of the
qualitative, additional information shall be given in the event that this is necessary from the
because of the correct use of the product.
The names of the substances shall be indicated, using the common names; in the case that these
the names are not provided, the technical names.
3. pharmaceutical form
Is described in accordance with the European Pharmacopoeia or the Czech pharmacopoeia. If
Pharmacopeia and the appropriate dosage form does not indicate, may be a combination of the standard
dosage forms listed in the pharmacopoeia of such pharmaceutical form is created.
4. clinical particulars
4.1. Target species
Indicate the species and category of animals.
4.2 Indications, indicating the target species shall be shown in detail
all the indications for which the veterinary product is intended. Additionally,
indicate whether the product is designed for prophylactic, therapeutic or
diagnostic purposes.
4.3. Contraindications
Absolute contraindications are given when the veterinary product must not
be administered.
Contra-indications are given, in particular in relation to the target species and
categories of animals, the way, and the route of administration or the current administration
other products, including other veterinary medicines. Contraindications
can also represent a specific clinical diagnosis, intercurrent
disease, age or gender. If the product contains active substances,
for which maximum residue limits have been fixed for milk or eggs,
This section contains relevant information and a reference to section 5.11 of the trade
the time limits.
4.4. Special warnings for each target species
Shall be detailed, clear and accurate information about all physical and
the chemical, pharmacological, toxicological and clinical data,
knowledge of which is necessary to ensure the safe and effective use of
the veterinary medicinal product.
4.5 special warnings, including special measures designed for persons
serving veterinary medicine animals must be reported with any and all
the information associated with the change of the safety and efficacy of the medicinal product in
specific situations, such as in the case of ledvinného, liver,
heart failure, juvenile or older animals.
In General, the first shows the relative contraindications, followed by a special
a warning message.
It is reported on the risks arising from the nature of the product, in preparing it
and use.
Shall be shown protective equipment, first-aid measures when in contact with
veterinary medicine, warning of a possible hypersensitivity and more.
4.6. Adverse reactions
Are given comprehensive information on any side, especially the
side effects induced by administration of the competent veterinary
of the product.
At this point, it is stated in particular:
-General description
-measures are taken to prevent the formation of undesirable
effect-with reference to section 4.5,
-adverse reactions occurring with very low frequencies or with
delayed onset of clinical signs, or which may not have been so far
observed in connection with the use of the relevant product, but that
It is generally found in other active substances in the group. The fact
that these are the effects related to the entire group must be listed.
4.7. Use during pregnancy, lactation or lay
Is provided, the information necessary for the safe use of veterinary
the preparation in the period of pregnancy and lactation, and in the case of laying hens in the period
lay.
If the product is in the period of lactation or lay contraindicated, must be
This information is provided in section 4.3. Information regarding the impact on the
fertility in both sexes are given in points 4.3, 4.4, 4.6, or
4.8. interaction with other medicinal products and other forms of interaction
Shall be shown clinically relevant interactions with other medicines and
veterinary medicinal products.
Indicate the information on the nature, mechanism and the effects of these
interactions and corrective measures.
4.9 amounts (dosage), and route of administration
Dosage for the various target species or age
category, description of the size of the dose, the interval between the submission of
single-dose and duration of treatment.
The dose is expressed in the amount of active substance per kg of live weight. In addition, the
States and other ways to the dose, maximum dose at site of administration,
the maximum daily dose, etc.
It is reported the method of administration, including the path and Space Administration including instructions
for correct use (e.g., fasting, aseptically, etc.). Additionally, they shall indicate the
any special tools required for the administration of the veterinary medicinal product. U
veterinary medicinal products that are administered in the feed or in the water
specify any dose adjustments for animals suffering from anorexia.
4.10. overdose (symptoms, first aid, antidotes)
The following information shall be indicated:
-clinical symptoms, their nature, severity, onset, duration,
-first aid,
-antidotes
-symptomatic treatment available.
4.11. Withdrawal period for individual products, including those for which the
no withdrawal period does not provide.
Shows the time since the end of the administration of the veterinary medicinal product, the
It could be adversely affected by the health of the animal
products.
The withdrawal period is expressed in days, in the case of milk may be expressed in
hours, fish stated in stupňodnech.
5. Pharmacological properties
5.1. pharmacodynamic properties
5.2. pharmacokinetic properties
6. pharmaceutical properties
6.1 list of excipients
6.2 Incompatibilities
Lists information about the physical/chemical incompatibilities
of the product with other products, with which the product will be
likely to be diluted, mixed or administered simultaneously with the
product.
In the case of products diluted before intravenous shows
adsorption of a syringe, or high-volume
Parenteral packaging.
In the case of medicated pre-mixes shows any restrictions on
the type of feed, for which the premixture is intended.
6.3 shelf life
The expiry date is given as packaged for sale, after dilution or
reconstitution according to the instructions for use and or after first opening of the internal
packaging. This information shall be given in the case of multiple
veterinary preparations, medicated pre-mixes and medicated feedingstuffs.
6.4 Retention
It is reported the information necessary for proper storage of the product, in particular
temperature, exposure to sunlight and humidity. If the range of storage
temperature 15-25 ° C, and if the environment is dry, then in terms of
retention of State that are not required by the special conditions for
retention; If necessary, the only special requirements for
access light.
6.5 nature and contents of container
6.6 special precautions for disposal of unusable veterinary
of the product, where appropriate, of the waste arising as a result of the use of
Is provided, the information necessary for the safe removal of unusable
the veterinary medicinal product and the funds used for the administration of this
of animals and, where appropriate, of the waste originating from the use of
the competent veterinary medicine. Additionally, lists all of the restrictions in the
waste management originating from treated animals.
7. the holder of the registration decision
8. Registration number
9. Date of first registration and renewal of registration
10. date of revision of the text
Annex 4
The content and structure of the package leaflet
A. requirements for the content and structure of the leaflet on medicinal products
are further specified in the regularly updated templates
the Agency's website.
In the case of medicinal products included on the list referred to in article 23 of the
Regulation (EC) No 726/2004 shall be additionally included the sentence: "this product
product is subject to further monitoring. " This sentence must be preceded by a black
a symbol referred to in article 23 of Regulation (EC) No 726/2004 and shall
follow the appropriate standardized explanations.
1. the data referred to in the leaflet must be in accordance with the summary
the product information.
2. The package leaflet shall state the following particulars:
and the name of the medicinal product), followed by its strength and pharmaceutical
form and, if appropriate, whether it is intended to be used for infants, children, or
adults; If the product contains up to three active substances, the
international non-proprietary name (in the Latin version of the INN) or, if
does not exist, the common name; in the case of specific homeopathic
products authorised under section 28a of the law on pharmaceuticals, in addition to
the clear mention of the words "homeopathic medicinal product" package
the information shall indicate the name of the product consisting of the scientific name of the base
substance or substances, followed by the degree of dilution, while
the expression of this level, it's a symbol according to the pharmacopoeia and pharmaceutical
form; in the case that the name of the product is invented, in addition to
formulation of the scientific name of the stock or stocks
followed by the degree of dilution,
b) pharmaceutical form and contents identified by weight, volume or number of
doses of the product,
(c)) expressed qualitatively and quantitatively the contents of all the active substances
expressed the common name in the Latin version and the quality and the content of
the excipients in the Czech chemical nomenclature, and each presentation
of the product; in the case of specific homeopathic products
registered under section 28a of the law on pharmaceuticals scientific name base
substance or substances, followed by the degree of dilution, while
the expression of this level, it's a symbol according to the pharmacopoeia and
quality and the content of the excipients in the Czech chemical nomenclature,
for each presentation of the product,
d) pharmaco-therapeutic group or type of activity in terms easily
comprehensible for the patient,
(e) the name and registered office) the marketing authorisation holder, in the case of
a legal person, or the name or names, surname and place of
business of the marketing authorisation holder, in the case of a natural person, and
the same information about the manufacturers, if not with the person of the holder of
registration, and where appropriate, the name of the representative appointed by the holder
concerning the registration,
(f)) the therapeutic indications; in the case of specific homeopathic
products authorised under section 28a of the law on medicinal products, together with the
indicating the relevant indication shows the sentence "homeopathic medicinal product
used traditionally in homeopathy to relieve ", or" homeopathic medicinal product
medicine traditionally in homeopathy to treat "
g) contraindications,
h) Special warnings aimed at safe use of the product, in particular
possibility to influence the ability to drive vehicles or to operate
machines,
I) interactions with other medicines and other interactions relating to
a way of life, especially the interaction with food, alcohol, and smoking,
(j) special conditions of use) for certain categories of users (e.g..
children, pregnant or breastfeeding women, the elderly, persons with specific
pathological conditions),
k) information about the excipients, knowledge of which is important for the
the safe and effective use of the medicinal product and included in the guidelines
published by the Commission,
l) dosage, especially the batch size,
m) the method of administration and, if necessary, route of administration, frequency of administration,
the time when you want or need to be administered and the duration of treatment,
If should be limited, if appropriate, shall in the case of measures
overdose, the way to proceed, if it has not been taken, or
more benefits, or a voucher to the risk impacts interruption,
n) explicit recommendations, when necessary, the physician has been consulted.
or pharmacist,
about) a description of the adverse reactions that may occur with an approved
use of the product, and, if necessary, measures in the
their occurrence shall be carried out; Enter the challenge that the patient has announced its
doctor or pharmacist any adverse event that is not listed in the
leaflet or that there is serious; Enter the
standardized text explicitly requesting patients to healthcare
workers, or directly to the national reporting system to report each
suspected adverse reaction in accordance with the national system
reports,
p) reference to the indication of expiry indicated on the packaging and warnings
on the prohibition of the use of the product after the expiry date, if applicable
certain visible signs of deterioration;
q) special storage precautions, warning that the medicinal product must be
kept out of the sight and reach of children, and how to
disposal,
r) if the product is authorised according to § 41 of the law on pharmaceuticals
the Member States concerned under different names, state the names list
registered by individual Member States,
with the date of the last revision of the text) leaflet.
3. in the case of radiopharmaceuticals, radionuclide generators, radionuclide kits
radiopharmaceuticals or radionuclide precursors to the Pack attaches to the
the detailed package insert, while the text of this information is in accordance
with the provisions of paragraph 2. In addition, the information includes all measures in
compliance with other legislation ^ 14) that you want the user and the patient
taken during the preparation and administration of the product, and special measures for the
disposal of the packaging and its unused contents.
4. in the case of homeopathic medicinal products registered according to §
28 the law on pharmaceuticals, in addition to the clear mention of the words "homeopathic
medicinal product "in the package leaflet shall contain:
a) product name consisting of the scientific name of the stock
followed by the degree of dilution, using the expression of this degree
It's the symbol of the pharmacopoeia and pharmaceutical form; in the case that the name of the
the product is invented, in addition to the formulation of the scientific name
the basic substance, followed by the degree of dilution,
b) pharmaceutical form and contents identified by weight, volume or number of
doses of the product,
(c) the scientific name of the stock) or basic substances for which
followed by the degree of dilution, using the expression of this level, it's
the symbol of the Pharmacopoeia, quality and the content of the excipients in the Czech
the nomenclature, for each presentation of the product,
(d) the name and registered office) the marketing authorisation holder, in the case of
a legal person, or the name or names, surname and place of
business of the marketing authorisation holder, in the case of a natural person, and
the same information about the manufacturers, if not with the person of the holder of
registration, and where appropriate, the name of the representative appointed by the holder
concerning the registration,
e) Special warnings aimed at safe use of the product, in particular
possibility to influence the ability to drive vehicles or to operate
machines,
f) information about the excipients, knowledge of which is important for the
the safe and effective use of the medicinal product and included in the guidelines
published by the Commission,
g) dosage, especially the batch size,
h) route of administration, and in the case that the route of Administration is not apparent, also a way
Administration,
I) explicit recommendations, when necessary, the physician has been consulted.
or pharmacist,
j) reference to the indication of expiry indicated on the packaging and warnings
on the prohibition of the use of the product after the expiry date, if applicable
certain visible signs of deterioration;
k) if necessary, special precautions for storage, warning that
the product must be stored out of the reach and sight of children, and
the procedure for disposal,
l) if the product is authorised according to § 41 of the law on pharmaceuticals
the Member States concerned under different names, state the names list
registered by individual Member States,
m) warning "use the following advice from the expert on homeopathy" or other
a special warning, if this is necessary for the product,
n) date of the last revision of the text of the leaflet,
information about) "homeopathic medicine without approved therapeutic
the indication ".
5. the package leaflet may include symbols or pictograms
intended to explain certain information indicated on the packaging of the product, or in the
leaflet, or other data that are useful for
of the patient. These data are consistent with the summary of product characteristics and
elements do not contain the advertising character.
B. requirements for the content and structure of the package leaflet for veterinary
products
1. the data referred to in the leaflet must be in accordance with the particulars and
the documentation accompanying the application for marketing authorisation, and summary information on the
of the product.
2. The package leaflet shall be given, in particular, the following information:
and business name and registered office) the marketing authorisation holder, in the case of
a legal person, or the name or names, surname and place of
business of the marketing authorisation holder, in the case of a natural person, and
the same information about the manufacturer, presents data on the representatives of the holder of the
marketing authorisation if the holder of such a representative has
(b) name of the veterinary medicinal product followed by) the strength and the pharmaceutical form.
If the product contains only one active substance and if its name is
invented, says its name is always current; in the case of product
registered pursuant to section 41 of the law on pharmaceuticals under various names in the
the individual Member States, the list of names by the Member
States,
c) indications;
d) contra-indications and adverse reactions,
(e)) the type or species of animal for which the veterinary medicinal product is intended,
the dosage for each species, the method and route of administration and information about
correct administration,
f) the withdrawal period, even if that is a veterinary medicine without
withdrawal periods, in the case of veterinary medicinal products intended for Administration
animals from which foods are derived to the nutrition of man,
g) storage conditions,
h) Special warnings,
I) special precautions for disposal of unused product or
the waste that comes from this product in accordance with other legal
regulations ^ 17),
3. in the case of veterinary homeopathic products, that are not
registered according to § 29 of the law on pharmaceuticals, in the package insert
the information shall be in addition to the data referred to in point 2, the words "homeopathic clearly
veterinary medicinal product ".
4. in the case of veterinary homeopathic medicinal products registered
the procedure pursuant to § 29 of the law on pharmaceuticals, in the package leaflet shall be
the following data:
and) the scientific name of the basic substance or substances for which
followed by the degree of dilution, using the symbols of the pharmacopoeia used in accordance
with section 2 (2). 2 (a). (g)) of the law on pharmaceuticals; If the product contains more
than one basic substance can be on the packaging and the package leaflet
given in addition to the scientific name of the stock or stocks
listed on product name,
(b) the name and registered office) the marketing authorisation holder, in the case of
a legal person, or the name or names, surname and place of
business of the marketing authorisation holder, in the case of a natural person, and
the same information about the manufacturers, if not with the person of the holder of
the registration,
(c)) method of in the event that the route of Administration is not apparent, also a way
Administration,
d) pharmaceutical form,
e) pack size, given as the weight or volume of the product, or
the number of doses or how many units of a pharmaceutical form
(f)) method of preservation,
(g)) of the target species of animal
h) Special warnings,
I) distinct information ' veterinary homeopathic medicinal product without
approved therapeutic indications ".
5. the package leaflet may include symbols or pictograms
intended to explain certain information indicated on the packaging of the product, or in the
leaflet, or other data that are useful for
the proper use of the veterinary medicinal product. These data are in accordance with the
Summary of product characteristics.
Annex 5
Particulars to appear on the packaging of the product
A. particulars to appear on the cover of the Agency's Web site humánníwebových
the Agency's website.
1. On the outer packaging of the product, or on the immediate packaging, if
There is no outer packaging, shall state the following particulars:
and the name of the medicinal product), followed by its strength and pharmaceutical
form and, if appropriate, whether it is intended to be used for infants, children, or
adults; If the product contains up to three active substances, the
international non-proprietary name (in the Latin version of the INN) or, if
does not exist, the common name; in the case of specific homeopathic
products authorised under section 28a of the law on pharmaceuticals, in addition to
the clear mention of the words "homeopathic medicinal product" package
the information shall indicate the name of the product consisting of the scientific name of the base
the substance, followed by the degree of dilution, using the expression of this
to the degree it's the symbol of the pharmacopoeia and pharmaceutical form; in the case that the name of the
the product is invented, in addition to the formulation of the scientific name
basic substances or basic substances, followed by the degree of dilution,
b) qualitatively and quantitatively, and the content of the active substances in
per dosage unit or according to the form in a given volume or weight,
using their common names in the Latin version; in the case of
specific homeopathic medicinal products registered in accordance with section 28 of the Act
on the scientific name of the stock or stocks for
by the degree of dilution, using the expression of this degree
It's the symbol of the Pharmacopoeia,
c) pharmaceutical form and contents identified by weight, volume or number of
doses of the product,
(d)) the list of excipients which have proven effects on the body
and included in the guidelines issued by the Commission; If it is a
Parenteral, topical or eye preparations, all auxiliary
of the substance; the names of auxiliary substances shall be given in any language,
(e) the method of Administration); in the event that the route of Administration is not apparent, also a way
of administration; leave space for the prescribed dosage,
f) warning that the medicinal product must be stored out of sight and reach of
children,
g) a special warning, in particular the possibility of affecting the ability to drive
motor vehicles or operate machinery if it is for the
the preparation is needed,
h) indication of the expiry (month, year)
I) special precautions for storage,
j) special precautions for disposal of unused product or
waste materials derived from such product, if required by the need to
to limit the adverse effects on the environment, in
compliance with other legislation), ^ ^
the name and registered office) the marketing authorisation holder, in the case of
a legal person, or the name or names, surname and place of
business of the marketing authorisation holder, in the case of a natural person, and
or the name of his appointed representatives,
l) registration number of the product,
m) lot number,
n) in the case of dispensing without prescription instructions for use of the product.
2. The packaging shall show the information referred to in paragraph 1; the exception are
and) blisters located on external packages marked in accordance with point 1,
on which it is placed
1. name of the medicinal product followed by its strength and pharmaceutical
form and, if appropriate, whether it is intended to be used for infants, children, or
adults; If the product contains up to three active substances, the
international non-proprietary name (in the Latin version of the INN) or, if
does not exist, the common name; in the case of specific homeopathic
products authorised under section 28a of the law on pharmaceuticals product name
consisting of the scientific name of the stock, followed by the
the degree of dilution, using the expression of this level, it's the symbol of the
Pharmacopoeia and pharmaceutical form; in the case that the name of the product is invented,
make up in addition to the formulation of the scientific name of the stock or
stocks followed by the degree of dilution,
2. the trade name or name of the holder of the marketing authorisation
of the product,
3. the indication of their applicability,
4. the batch number;
(b) the inner packaging), which does not allow to read all the data location
required in paragraph 1, on which it is placed
1. name of the medicinal product, where appropriate, the strength and the route of administration,
2. the method of administration,
3. the indication of their applicability,
4. the lot number,
5. the size of the package identified by the weight, volume or number of doses
of the product.
3. In the case of medicinal products containing radionuclides with external and internal
In addition, the packaging indicates the symbol of radioactivity. Label on the shielding
containing the information listed in point 1. In addition, the label on the shielding
fully explains the encoding used on the bottle and it is stated there, where is it
necessary, to the time and date, the amount of activity or on
the bottle and the number of capsules or liquid ml in the internal
packaging. The bottle is marked with the following information:
and the name or code of the product), including the name or chemical symbol
the radionuclide,
(b) identification of the lot) the expiry date,
(c)) the international symbol for radioactivity
d) name and address of the marketing authorisation holder,
(e) the quantity of activity, where) it is necessary, to a given time and date
the amount of activity on the dose or per vial and the number of capsules, or, for
number of millilitres of liquid in the container.
4. in the case of homeopathic medicinal products registered according to §
28 the law on pharmaceuticals, in addition to the clear mention of the words "homeopathic
medicinal product "on the label, only the following shall be
information:
a) product name consisting of the scientific name of the stock
followed by the degree of dilution and the pharmaceutical form. in the case that the name of the
the product is invented, make up the scientific name of the stock
followed by the degree of dilution,
(b)) the scientific name of the basic substance or substances, followed by the degree
dilution,
c) pharmaceutical form and contents identified by weight, volume or number of
doses of the product,
(d)) the list of excipients which have proven effects on the body
and included in the guidelines issued by the Commission; If it is a
topical or eye preparations, all excipients; the names of the
excipients are given in Czech language
e) method of in the event that the route of Administration is not apparent, also a way
of administration; leave space for the prescribed dosage,
f) warning that the medicinal product must be stored out of sight and reach of
children,
g) a special warning, in particular the possibility of affecting the ability to drive
motor vehicles or operate machinery if it is for the
the preparation is needed,
h) indication of the expiry (month, year)
I) special precautions for storage,
j) special precautions for disposal of unused product or
waste materials derived from such product, if required by the need to
to limit the adverse effects on the environment, in
compliance with other legislation), ^ ^
the name and registered office) the marketing authorisation holder, in the case of
a legal person, or the name or names, surname and place of
business of the marketing authorisation holder, in the case of a natural person, and
or the name of his appointed representatives,
l) registration number of the product,
m) lot number,
n) in the case of dispensing without prescription instructions for use,
p) information "homeopathic medicinal product without approved therapeutic
the indication ".
5. in the case of advanced therapy medicinal products which are to be
used within the allowed the hospital exemption, in addition to the clear
putting the words "use within the hospital exemption" in the labelling
stating the following:
and) name,
b) lot number,
(c)) the expiration date,
(d)) how to use,
(e) the manufacturer's name and)
f) storage conditions.
6. Part of the markings on the outer packaging of the product may include symbols or
pictograms intended to explain certain information indicated on the package
product characteristics and the package leaflet, or other data that are
helpful for the patient. These data are consistent with the summary of
of the product and do not contain the elements of advertising character.
7. On the outer packaging of the code assigned by the Institute pursuant to § 32
paragraph. 5 of the law on medicinal products and in the form of bar code European code.
8. On the outer packaging can provide information about how to supply or sales
of the product, and these words: "medicinal product subject to
prescription "or" medicinal product available without a
prescription "or" medicinal product possible and without a
Regulation with the restriction "or" medicine is included among the dedicated
the drug ".
9. If the product package does not contain a separate leaflet,
the entire text is indicated on the packaging.
10. The name of the product is indicated on the outer packaging as well as in Braille,
If the marketing authorisation unless otherwise stated.
B. particulars to appear on the packaging of veterinary medicinal products
1. the particulars to appear on the outer and inner packaging shall be in accordance with the
the particulars and documents accompanying the application for marketing authorisation and with the summary
the product information.
2. on the outer and inner packaging shall indicate in particular the following information:
and the name of the product), supplemented by the common name of the drug substance in the case that
the product contains only one active substance and the name of the product is
invented; After the name of the product shall show the strength and pharmaceutical form,
b) qualitatively and quantitatively, and the content of the active substances in
unit or dosage forms according to the form of Administration for a particular volume or
weight, using the common names of medicinal substances,
(c) manufacturer's batch number),
(d)) the registration number,
(e) the name and registered office) the marketing authorisation holder, in the case of
a legal person, or the name or names, surname and place of
business of the marketing authorisation holder, in the case of a natural person, and
the same information about representatives of the marketing authorisation holder, if the holder of
such a representative has
(f)) kind of or types of animal for which the veterinary medicinal product
designed and, where appropriate, the method and route of administration; There is room for
the designation of the prescribed dosage,
g) the withdrawal period, if the product used for animals from which
are derived products for human nutrition; the withdrawal period is
lists for all kinds of animals, for which it is registered, and
for each of the types of tissues and animal products (meat and offal, eggs,
milk, honey); the withdrawal period shall be specified, even if it is not necessary
withdrawal period may provide
h) clearly stated the expiry date;
I) method of preservation;
j) special precautions for disposal of unused product or
the waste that comes from this product in accordance with other legal
regulations ^ 17),
k) Special warnings,
l) the words "for animal treatment only", and in the case of products where the issue is
pursuant to § 40 of the prescription, the words "for animal treatment only-
bound on prescription medicine ";
the pharmaceutical form and the contents by weight, volume, number of units
pharmaceutical form or by number of doses may be given only on the outer
packaging. As regards the expression of the content of the active substances referred to in subparagraph (b)),
the requirements shall apply to the expression of active substances set out in annex
No. 2.
3. In the case of ampoules can give the particulars referred to in section 2 only on the outer
packaging. On the inner packaging, however, must always be reported the following
details:
name of the veterinary medicinal product),
(b)) the amount of active substances or medicinal substances,
(c)) route of administration,
(d) the manufacturer's batch number),
(e) the expiry date),
f), the words "for animal treatment only".
4. In the case of small single-dose containers, other than ampoules internal,
that it is not possible to place the information referred to in paragraph 3, the information referred to in
point 2 appear only on the outer packaging.
5. If there is no outer package, all the particulars must be referred to in points 2 to
4 listed on the container.
6. in the case of veterinary homeopathic products, that are not
registered according to § 29 of the law on pharmaceuticals, the outer and the
the immediate packaging shall in addition to the data referred to in points 2 to 4 below clearly words
' Homeopathic veterinary medicinal product ".
7. in the case of veterinary homeopathic medicinal products registered
procedure referred to in section 29 of the Act, the following information shall appear on the packaging:
and) the scientific name of the basic substance or substances for which
followed by the degree of dilution, using the symbols of the pharmacopoeia used in accordance
with section 2 (2). 2 (a). (g)) of the law on pharmaceuticals; If the product contains more
than one basic substance can be on the packaging and the package leaflet
given in addition to the scientific name of the stock or stocks
listed on product name,
(b) the name and registered office) the marketing authorisation holder, in the case of
a legal person, or the name or names, surname and place of
business of the marketing authorisation holder, in the case of a natural person, and
the same information about the manufacturers, if not with the person of the holder of
the registration,
(c)) method of in the event that the route of Administration is not apparent, also a way
Administration,
(d)) clearly stated the expiry date (month, year)
e) pharmaceutical form,
f) pack size, given as the weight or volume of the product, or
the number of doses or how many units of a pharmaceutical form
g) method of preservation,
h) target species,
I) Special warnings,
(j) the manufacturer's batch number),
k) registration number
l) distinct information ' veterinary homeopathic medicinal product without
approved therapeutic indications ".
Annex 6
The contents of the documentation to be submitted with the application for marketing authorisation or variation
registration for a product designed for dispensing without prescription
prescription or for classification of dedicated medicinal products
1. A critical evaluation of the consequences of the availability of a product without a
prescription.
2. data relating to the safety of
a) proving the low toxicity and the fact that the product has not been
found clinically relevant reproductive toxicity, genotoxicity and
evidence of carcinogenicity,
(b) the scope and length) experience with the application of preparations containing the
the active substance, especially with regard to the method of administration and dosage form
product characteristics proposed for dispensing without a prescription; shall be
a list of States in which the product can be issued without a
Regulation, indicating the date on which the supply in individual
States approved,
c) information about the adverse effects of the active substance, including any
adverse reactions recorded on the issue without a prescription, and
in relation to the extent and the way of its use,
(d) report on the updated periodically) the safety of the product under
Annex No. 8, including the grounds for the usability of the data which have been obtained
under the conditions to prescription,
(e)) the likelihood of interactions with other medicinal products and food, and their
the possible consequences,
(f)) the possible consequences failure to follow instructions for use,
(g)) the possible consequences of the use of, if a patient incorrectly identified
your medical condition or symptoms of the disease,
h) possible consequences of improper or delayed recognition of the patient's
health condition or symptoms of the disease as a result of self-medication, in
the case of veterinary medicinal products the possible consequences of improper or
belated recognition of the State of health of the animal, or symptoms
disease due to treatment carried out by the keeper,
I) proving that the medicine can be issued without a
Regulation, because it contains a substance which, when used incorrectly
present a substantial risk of abuse of medicines, to lead to addiction or to
diversion for illegal purposes.
3. Justification for dispensing without a prescription may not be limited;
demonstrate that the medicinal product cannot constitute a danger to health
people or for the correct use of the product is not necessary a previous
professional consultation with a pharmacist, and especially a special warning on
contraindications, interactions, side effects, need for medical
checks.
4. justification for the recommended lengths of treatment in the proposed indications, the relationship
the recommended duration of treatment to the size of the package.
5. the proposal of the package leaflet in the scale and structure set out in annex No.
4 and the design data to be given on the packaging of the extent and the structure set out in the
Annex No 5. The design of the leaflet contains, in particular, the definition of
and) conditions where it is possible to use the product without consulting your doctor,
(b)) the time during which it is possible to use the product without consulting
doctor
c) circumstances in the course of treatment, under which it is necessary to consult a physician.
6. The preamble to the suitability of the packaging for dispensing without a prescription.
7. in the case of a request for the inclusion of medicinal products
issued without a prescription with a restriction shall be grounds for the
the proposed method of picking and restrictive measures (e.g. proposal.
review of age, limiting the number of recommendations issued by the packaging, as a pharmacist,
Register of persons, the evidence issued by the package).
8. in the change request register relating to changes to the way issues
of the information in paragraphs 1 to 7 shall use reasonably.
9. the requirements referred to in point 2 shall apply to homeopathic medicinal products
adequately.
10. in the case of a request for the inclusion of drugs between the reserved
This requirement alone justify, using points 1 to 5
adequately.
Annex 7
cancelled
Annex 8
cancelled
Selected provisions of the novel
Article. (II) Act No. 13/2010 Sb.
Transitional provision
The administrative proceedings initiated before the date of entry into force of this order, the
completes in accordance with the existing legislation.
Article. (II) Decree No. 255/Sb.
Transitional provisions
1. To produce medicinal products not satisfying the requirements for the placing of the information
on the packaging in accordance with annex 5 of Decree No. 228/2008 Coll., in the version in force
After the effective date of this order, for a maximum period of 6 months after the
the effective date of this Ordinance.
2. medicinal products manufactured in a design that does not meet the
the information on the package in accordance with annex 5 of Decree No. 228/2008 Coll.,
in the version in force after the date of entry into force of this Decree, may continue to be
to market, distribute, supply and use in the provision of
health services for the period of their application.
3. the holder of the marketing authorisation of a medicinal product referred to in
list referred to in article 23 of the regulation of the European Parliament and of the Council (EC) No.
No 726/2004 of 31 March 2004. March 2004 laying down Community procedures
for the authorisation and supervision of medicinal products and veterinary medicinal products and laying
European Medicines Agency, as amended by regulation of the European
Parliament and of the Council (EC) no 1901/2006 shall ensure that the information in the summary
of product characteristics and package leaflet comply with the requirements of Decree No.
228/2008 Coll., in the version in force after the date of entry into force of this order
not later than 31 December 2006. December 2013.
4. the holder of the marketing authorisation of a medicinal product not covered by the
list referred to in article 23 of the regulation of the European Parliament and of the Council (EC) No.
No 726/2004 of 31 March 2004. March 2004 laying down Community procedures
for the authorisation and supervision of medicinal products and veterinary medicinal products and laying
European Medicines Agency, as amended by regulation of the European
Parliament and of the Council (EC) no 1901/2006 shall ensure that the information in the summary
of product characteristics and package leaflet comply with the requirements of Decree No.
228/2008 Coll., in the version in force after the date of entry into force of this order
by 1. April 2016.
1) European Parliament and Council Directive 2001/83/EC of 6 May 1999. November
2001 on the Community code relating to medicinal products for human use.
Directive of the European Parliament and of the Council 2002/98/EC of 27 June 2002. January 2003,
setting standards of quality and safety for the collection, testing,
processing, storage and distribution of human blood and blood components and
amending Directive 2001/83/EC.
Commission Directive 2003/63/EC of 25 March 2002. June 2003, amending
European Parliament and Council Directive 2001/83/EC on the Community code
relating to medicinal products for human use.
European Parliament and Council Directive 2004/24/EC of 31 October. March
2004 amending Directive 2001/83/EC on the Community code
relating to medicinal products, as regards traditional
herbal medicinal products.
European Parliament and Council Directive 2004/27/EC of 31 October. March
2004 amending Directive 2001/83/EC on the Community code
relating to medicinal products for human use.
European Parliament and Council Directive 2001/82/EC of 6 May 1999. November
2001 on the Community code relating to veterinary medicinal products
preparations.
European Parliament and Council Directive 2004/28/EC of 31 October. March
2004 amending Directive 2001/82/EC on the Community code
relating to veterinary medicinal products.
Commission directive 2009/9/EC of 10 June 1999. February 2009 amending
European Parliament and Council Directive 2001/82/EC on the Community code
relating to veterinary medicinal products.
Commission Directive 2006/132/EC of 11 December 1997. in December 2006, which shall be carried out
European Parliament and Council Directive 2001/82/EC, as regards the determination of the
the criteria for the exclusion of certain veterinary medicinal products for
food-producing animals from the requirement to issue on animal health
prescription.
European Parliament and Council directive 2009/35/EC of 23 December 2003. April 2009
of colouring agents that may be added to medicinal products.
Commission directive 2009/120/EC of 14 July 1999. September 2009 amending
European Parliament and Council Directive 2001/83//EC on a code of
Of the community regarding medicines for human use, as regards the
advanced therapy medicinal products.
2) Annex European Parliament and Council Regulation (EC) No 726/2004 of the
on 31 December 2004. March 2004 laying down Community procedures for the
authorisation and supervision of medicinal products and veterinary medicinal products and
establishing a European Medicines Agency.
3) such as agreement on mutual recognition in relation to conformity assessment,
certificates and designations between the European Community and Australia (OJ l.
p. 1. L 229, 17.8.1998, p. 3), the agreement on mutual recognition in relation to the
conformity assessment between the European Community and New Zealand (OJ l.
p. 1. L 229, 17. 8.1998, p. 62), the agreement on mutual recognition between the
The European Community and Canada (OJ. L 280, 16.10.1998, p. 3),
the agreement on mutual recognition between the European Community and Japan
(OJ l. p. 1. L 284, 29.10.2001, p. 3), the agreement between the European
community and the Swiss Confederation on mutual recognition in relation to the
conformity assessment (OJ. L 114, 30.4.2002, p. 368).
4) Decree No 226/2008 Coll., on good clinical practice and detailed
the conditions of the clinical evaluation of drugs.
5) § 19 and 19b of the civil code.
§ 8 to 12 of the commercial code.
6) the agreement between the Member States of the community for the exchange of information
regarding the electronic registration documentation, version 1.0 in February
2006.
7) European Parliament and Council Regulation (EC) No 258/97, which relates to the
novel foods and novel food ingredients.
8) for example, European Parliament and Council Regulation (EC) No 258/97.
9) Act No. 78/2004 Coll., on the use of genetically modified
organisms and genetic products, as amended.
10) Decree No. 446/2004 Coll., laying down the requirements for Add-ons
diet and food supplements for the enrichment of Canada.
11) Decree No. 446/2004 Sb.
Decree No. 54/2002 Coll., laying down the health requirements for the
the identity and purity of additives, as amended.
12) Commission Regulation (EC) No 1085/2003 concerning the examination of variations to
marketing authorisation falling within the scope of Council Regulation (EEC) No.
2309/93
13) European Parliament and Council Regulation (EC) No 141/2000 of 16 December 1999.
December 1999 on orphan medicinal products.
13A) Decree No. 4/2008 Coll., laying down the types and terms of use
additives and extraction solvents in food production.
13B) the annex No. 1 of the Decree No 54/2002 Coll., laying down the health
requirements for the identity and purity of additives, as amended
regulations.
13E) Annex 4 Regulation No. 4/2008 Coll., laying down the types and
the use of additives and the conditions of extraction solvents in the manufacture of
food.
13F) Decree No 207/2004 Coll., on the methods of testing, and the collection and
preparation of control samples, as amended.
14) Act No. 18/1997 Coll. on peaceful uses of nuclear energy and
ionizing radiation (the Atomic Act), and amending and supplementing certain
laws, as amended.
17) for example, Act No. 185/2001 Coll., on waste and amending certain
other acts, as amended.
Act No. 477/2001 SB., on packaging and on amendments to certain acts (the Act on
packages), as amended.
18) Commission directive 2009/120/EC of 14 July 1999. September 2009 amending
European Parliament and Council Directive 2001/83/EC on the Community code
relating to medicinal products for human use, as regards medicinal products
for advanced therapy medicinal products.
19) Annex No. 1 of European Parliament and Council Directive 2001/83/EC of
January 6. November 2001 on the Community code relating to human
medicinal products.
