For Registration Of Medicinal Products

Original Language Title: o registraci léčivých přípravků

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Read the untranslated law here: https://portal.gov.cz/app/zakony/download?idBiblio=67168&nr=228~2F2008~20Sb.&ft=txt

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.