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LEGAL ACTS OF THE REPUBLIC OF LATVIA
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The translation of this document is outdated.
Translation validity: 06.09.2013.–12.04.2018.
Amendments not included: 10.04.2018.
Text consolidated by Valsts valodas centrs (State Language Centre) with amending regulations of:

21 August 2007 (No. 563) [shall come into force from 25 August 2007];
28 July 2008 (No. 602)[shall come into force from 1 August 2008];
3 November 2009 (No. 1284) [shall come into force from 11 November 2009];
18 May 2010 (No. 453) [shall come into force from 22 May 2010];
29 June 2010 (No. 589) [shall come into force from 7 July 2010];
1 November 2010 (No. 1019) [shall come into force from 4 November 2010];
24 May 2011 (No. 394) [shall come into force from 27 May 2011];
9 April 2013 (No. 195) [shall come into force from 30 April 2013];
3 September 2013 (No. 710) [shall come into force from 6 September 2013].

If a whole or part of a paragraph has been amended, the date of the amending regulation appears in square brackets at the end of the paragraph. If a whole paragraph or sub-paragraph has been deleted, the date of the deletion appears in square brackets beside the deleted paragraph or sub-paragraph.


Republic of Latvia

Cabinet
Regulation No. 376
Adopted 9 May 2006

Procedures for the Registration of Medicinal Products



  

Issued pursuant to
Section 5, Paragraph three
of the Pharmaceutical Law

I. General Provisions

1. This Regulation prescribes the procedures for the registration of medicinal products (also in accordance with a mutual recognition procedure and decentralised procedure).

2. This Regulation applies to:

2.1. medicinal products for human use manufactured industrially or prepared, using a method, which includes an industrial process;

2.2. herbal medicinal products;

2.3. homeopathic medicinal products and anthroposophic medicinal products;

2.4. biological medicinal products;

2.5. radiopharmaceuticals, kits, radionuclide generators and radionuclide precursors;

2.6. mineral waters if they comply with the definition of the medicinal products and the State Agency of Medicines has recognised them as medicinal products; and

2.7. medicinal gases.

3. This Regulation does not apply to:

3.1. veterinary medicinal products;

3.2. the procedures for registration of such medicinal products, which are registered in accordance with a centralised registration procedure pursuant to Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (hereinafter - Regulation No 726/2004 of the European Parliament and of the Council);

3.3. medicinal products prepared in a pharmacy according to a prescription written out by a medical practitioner to a particular patient or upon the request of a medical practitioner (formula magistralis);

3.4. medicinal products prepared in a pharmacy according to pharmacopoeial monographs and intended for distribution to patients who are served by the relevant pharmacy (formula officinalis);

3.5. medicinal products intended for research and production investigation, and investigational medicinal products, which are referred to in regulatory enactments regarding the procedures for conducting clinical trials and observations on the use of medicinal products;

3.6. intermediate products intended for further processing carried out by a licensed manufacturer of medicinal products;

3.7. radionuclides (radioactive isotopes) in the form of sealed radiation sources;

3.8. radiopharmaceuticals that, according to the instruction of the manufacturer of medicinal product, have been derived in a medical treatment institution (which according to regulatory enactments has a permit to use radiopharmaceutical preparations) from registered generators, kits and any other radionuclide, which is manufactured from another substance for radio-labelling prior to usage and from which the radiopharmaceutical is derived;

3.9. whole blood, plasma or blood cells of human origin, except for industrially prepared plasma; and

3.10. medicinal products complying with the condition referred to in Section 10, Paragraph seven of the Pharmaceutical Law in one of the following cases:

3.10.1. non-registered medicinal products for administration to individual patients, if the registered medicinal products are not suitable for patient use by clinical indications thereof and medicinal products are supplied, in fulfilling an order of a health care specialist who assumes direct legal responsibility (professional responsibility); and

3.10.2. medicinal products intended for the prevention of potential harm of spread of pathogens, toxins, chemical substances or nuclear radiation and usage during catastrophes, natural disasters, epidemics, also during a pandemic.

3.11. any advanced therapy medicinal products as determined in the first subparagraph of Article 28(2) of Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004 (hereinafter - European Parliament and Council Regulation No 1394/2007).

[29 June 2010]

4. For the purpose of this Regulation:

4.1. herbal preparations are preparations derived by subjecting herbal substances to treatments such as extraction, distillation, expression, fractionation, purification, concentration or fermentation. These shall also include comminuted or powdered herbal substances, tinctures, extracts, essential oils, plant juices and processed exudates;

4.2. herbal substances are mainly whole, also crushed or cut plants, plant parts, including algae, fungi and lichen in an unprocessed, usually dried, form, but sometimes fresh. Certain exudates that have not been subjected to a specific treatment shall also be considered as herbal substances. Herbal substances shall be precisely defined by the plant part used and the botanical name of the plant according to the binomial nomenclature system (genus, species, variety and author);

4.3. herbal medicinal products are any medicinal products, exclusively containing as active ingredients one or more herbal substances or one or more herbal preparations, or one or more such herbal substances in combination with one or more such herbal preparations;

4.4. reference medicinal products are products registered in Latvia in accordance with this Regulation or in a Member State of the European Economic Area, or in accordance with a centralised registration procedure pursuant to Regulation No 726/2004 of the European Parliament and of the Council;

4.5. biological medicinal products are:

4.5.1. immunological preparations - any medicinal products consisting of vaccines, toxins, serums or allergen products:

4.5.1.1. vaccines, toxins or serums shall apply to:

4.5.1.1.1. agents used to produce active immunity (for example, cholera vaccine, Calmette-Guérin anti-tuberculosis vaccine BCG, polio vaccines, smallpox vaccine);

4.5.1.1.2. agents used to diagnose the state of immunity, including in particular tuberculin and tuberculin PPD, toxins for the Schick and Dick Tests, brucellin; and

4.5.1.1.3. agents used to produce passive immunity (such as diphtheria antitoxin, anti-smallpox globulin, antilymphocytic globulin); and

4.5.1.2. allergen products - any medicinal products, which are intended to identify or induce a specific acquired change in the immunological response to an allergising agent;

4.5.2. medicinal products derived from human blood and plasma - medicinal products based on blood constituents, which are prepared industrially by public or private establishments, such medicinal products including albumin, coagulating factors and immunoglobulins of human origin;

4.5.3. [29 June 2010];

4.5.4. advanced therapy medicinal products referred to in Article 2 of European Parliament and Council Regulation No 1394/2007;

4.6. generic medicinal product is a medicinal product, which has the same qualitative and quantitative formulation in active substances and the same pharmaceutical form as the reference medicinal product, and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies. The different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of active substances shall be considered to be the same active substance, unless they differ significantly in properties with regard to safety and efficacy (in such cases, additional information providing proof of the safety and efficacy of the various salts, esters or derivatives of an authorised active substance shall be supplied by the applicant of registration application). The various immediate-release oral pharmaceutical forms shall be considered to be one and the same pharmaceutical form;

4.7. the plasma master file is a stand-alone documentation providing detailed information regarding the characteristics of the human plasma, which is used as a starting material or a raw material for the manufacture of subfractions and intermediate fractions and active substance(s) and is a part of medicinal products or medical devices, in which stable derivatives of human blood or human plasma are used;

4.8. radionuclide precursors are any other radionuclides produced for the radioactive labelling of another substance prior to administration;

4.9. a radionuclide generator is any system, from which a radiopharmaceutical product is derived and which incorporates a fixed primary (mother) radioactive isotope, from which a secondary (daughter) radioactive isotope is derived, which is to be obtained by elution or by any other method;

4.10. a radiopharmaceutical is any medicinal product to be used in radiology containing one or more radionuclides in ready-for-use form - radioactive isotopes, except isotopes from sealed sources intended for medical use;

4.11. a kit is any preparation, which is renewable or compatible with radionuclides in the final radiopharmaceutical (usually prior to administration thereof);

4.12. the risk-benefit balance is an evaluation of the positive therapeutic effects of the medicinal product, taking into account the risks relating to the quality, safety or efficacy of the medicinal product as regards patients' health or protection of public health (public health);

4.13. a vaccine antigen master file is a stand-alone part of the documentation of a registration application, which contains all the relevant information regarding the biological, pharmaceutical and chemical nature of each active substance, which are part of this medicinal product. The documentation may apply to one or more monovalent and combined vaccines presented by the same applicant of a registration application or the owner of the registration; and

4.14. the name of the medicinal product may be:

4.14.1. the invented name, which shall not be confused with the general name (the International Non-proprietary Name (INN) recommended by the World Health Organisation or, if such has not been recommended, the name that is widely used); and

4.14.2. the common or scientific name supplemented by the trademark or the name of the holder (owner) of the registration certificate.

[29 June 2010]

5. If a product, taking into account all the properties of the product, in accordance with the opinion of the State Agency of Medicines referred to in Paragraph 6 of this Regulation complies with the definition of a medicinal product, it shall be subject to the registration of medicinal products in accordance with the procedures specified in this Regulation.

[18 May 2010]

6. The State Agency of Medicines is entitled to provide an opinion on the compliance of a product (such as a particular food product, medical device, cosmetic product, biocide) with the definition of a medicinal product specified in the Pharmaceutical Law, upon the initiative of the State Agency of Medicines or a competent authority of another state.

[18 May 2010]

7. The State Agency of Medicines shall assess and register medicinal products in accordance with the Pharmaceutical Law and this Regulation.

8. The fact of the registration (also new or initial registration) and re-registration of medicinal products in the Republic of Latvia shall be confirmed by a valid decision of the State Agency of Medicines on registration and re-registration of medicinal products and the issued registration certificate of medicinal products drawn up in accordance with Annex 1 to this Regulation. The State Agency of Medicines shall take the decision on the basis of an application for the registration and re-registration of medicinal products and documents appended thereto (hereinafter - registration application).

9. A decision of the State Agency of Medicines on registration of a new medicinal product (initial registration) shall be in effect for 5 years after taking of the decision on registration of the medicinal product.

10. After 5 years since the taking of a decision on registration of a medicinal product the State Agency of Medicines is entitled to take a decision on re-registration of the medicinal product on the basis of a repeated evaluation of the risk-benefit balance. If the medicinal product has been re-registered once, the registration of the medicinal product is in effect for an unlimited period of time (which is indicated in the registration certificate of the medicinal product), except for the case where the State Agency of Medicines shall take a decision, on justified grounds relating to pharmacovigilance arising from the laws and regulations on pharmacovigilance (including exposure of an insufficient number of patients to the medicinal product concerned), to re-register medicinal products repeatedly for five years.

[18 May 2010; 9 April 2013]

11. After taking of the decision referred to in Paragraph 8 of this Regulation in respect of any other changes to the application dossier and extension of registration, the State Agency of Medicines shall take one of the following decisions:

11.1. the decision referred to in Sub-paragraph 68.1 of this Regulation on registration of the medicinal product (the case of extension of registration);

11.2. the decision referred to in Sub-paragraph 68.2 of this Regulation on approval of changes (including on new sales packaging, administration mode). Such decision shall be an integral part of the decision referred to in Paragraph 8 of this Regulation;

11.3. a decision on refusal of registration of the medicinal product;

11.4. a decision on non-approval of changes.

[18 May 2010]

11.1 The decision referred to in Paragraphs 9, 10 and 11 of this Regulation shall come into effect at the time of taking thereof.

[18 May 2010]

11.2 If by taking any of the decisions referred to in Sub-paragraph 11.1 or 11.2 of this Regulation the data specified in the registration certificate of a medicinal product (for example, name of the medicinal product, owner of registration, information regarding packaging) change, the State Agency of Medicines shall, within three working days after taking of the decision, ensure issuance of a new registration certificate of the medicinal product (Annex 1).

[18 May 2010]

11.3 Medicinal product shall be deemed as registered in Latvia, if the decision referred to in Paragraphs 9, 10, Sub-paragraph 11.1 and Paragraph 14 of this Regulation is in effect.

[18 May 2010]

11.4 Paragraph 11 of this Regulation shall not be applicable in respect of herbal medicinal products that are registered in accordance with the simplified registration procedure specified in Chapter VII of this Regulation.

[18 May 2010]

12. In taking the decision referred to in Sub-paragraphs 11.1 and 11.2 of this Regulation, the State Agency of Medicines shall take into account all the conditions, also the conditions referred to in Chapter III of this Regulation, in accordance with which the decision referred to in Paragraph 9 of this Regulation has been taken.

[18 May 2010]

13. The legal address of such person on whose name the medicinal product is registered shall be in a Member State of the European Economic Area (a merchant has a registered firm name, central administration or actual place of operation).

14. The fact of the registration and re-registration of medicinal products parallelly imported in the Republic of Latvia shall be confirmed by a valid decision of the State Agency of Medicines on issuance of a permit for the distribution of parallelly imported medicinal products. The State Agency of Medicines shall take the decision in accordance with the regulatory enactments regarding distribution of medicinal products.

15. The State Agency of Medicines shall include the medicinal products registered in the Republic of Latvia, the centrally registered medicinal products and the parallelly imported medicinal products in a register of medicinal products of the Republic of Latvia.

15.1 The State Agency of Medicines shall ensure public access to the following data of the Register of Medicinal Products of the Republic of Latvia on the website of the State Agency of Medicines concurrently with the coming into effect of the decision referred to in Paragraphs 9, 10, 11 and 14 of this Regulation:

15.11. the name of the medicinal product, pharmaceutical form, the strength or concentration in a packaging unit;

15.12. International Non-proprietary Name (INN) of the active ingredient(-s);

15.13. the given name, surname or firm name of the owner of registration, but for medicinal products parallelly imported - the name of the permit holder for the distribution of parallelly imported medicinal products in the Republic of Latvia and the name of the state;

15.14. the name of the manufacturer specifying also the state;

15.15. Anatomical Therapeutic Chemical Code (ATC code);

15.16. registration date and number. For medicinal products parallelly imported - the permit number for the distribution of parallelly imported medicinal products in the Republic of Latvia;

15.17. approved list of medicinal products, package leaflet and mock-up of the labelling;

15.18. designation of the classification group of medicinal products, which has been granted in accordance with the regulatory enactments regarding the procedures for classification of medicinal products.

[18 May 2010; 9 April 2013]

15.2 The State Agency of Medicines shall delete medicinal product from the Register of Medicinal Products of Latvia if:

15.21. the decision referred to in Paragraph 114 of this Regulation has come into effect on cancellation of registration;

15.22. in accordance with Paragraph 125 of this Regulation the decision on registration of medicinal products has become invalid.

[18 May 2010]

II. Criteria for the Registration of Medicinal Products

16. In order to register a medicinal product, a person on whose name it is intended to register the medicinal product (hereinafter - applicant) shall submit to the State Agency of Medicines a registration application, which complies with the sample published in Volume 2 of the collection of documents of the Rules Governing Medicinal Products in the European Community of the European Commission and which is published on the website of the State Agency of Medicines (hereinafter - sample of the European Commission). A registration application for the registration of medicinal products in two or several Member States of the European Economic Area shall be submitted in accordance with Chapter XIII of this Regulation.

[18 May 2010; 9 April 2013]

17. Data pursuant to the sample of the European Commission and Paragraphs 23, 24, 25, 26 and 27 of this Regulation (hereinafter - application dossier) shall be included in the registration application referred to in Paragraph 16 of this Regulation and documents appended thereto. The following information shall be indicated in the application and the application dossier:

17.1. the given name, surname or firm and legal address of the applicant of the registration application and, where necessary, the firm name and legal address of the manufacturer;

17.2. the name of the medicinal product;

17.3. the complete qualitative and quantitative formulation of the medicinal product, including a reference to the International Non-proprietary Name recommended by the World Health Organisation (INN), if the medicinal product has been assigned such, or a reference to the relevant chemical name;

17.4. the assessment regarding potential environmental risk caused by the medicinal product (all risk factors related to adverse effects on the environment). Environmental impact shall be assessed in each individual case and specific procedures for the restriction of risk shall be determined;

17.5. the description of the manufacturing technique;

17.6. the therapeutic indications, contraindications and adverse reactions caused by medicinal products (hereinafter - adverse reactions);

17.7. the doses and route of administration, pharmaceutical form, method and route of administration, anticipated period of storage;

17.8. the justification of the precautionary and safety measures to be complied with in storing the medicinal product, administering the medicinal product to patients and disposing of the medicinal product waste, together with an indication regarding the effects of the potential risk caused by the medicinal product to the environment;

17.9. the description of the control methods used by the manufacturer;

17.10. the results which have been obtained in:

17.10.1. pharmaceutical (physico-chemical, biological or microbiological) tests;

17.10.2. non-clinical (toxicological and pharmacological) tests; or

17.10.3. the clinical trial;

17.11. a summary on pharmacovigilance system of the applicant of the registration in conformity with the laws and regulations regarding pharmacovigilance procedures (hereinafter - pharmacovigilance system). The summary shall include:

17.11.1. a proof that the applicant of the registration has at his disposal a qualified person for pharmacovigilance, as well as indicated a Member State of the European Economic Area in which the referred-to person resides and carries out his or her responsibilities, and the contact details of such person;

17.11.2. a statement signed by the applicant of the registration that the applicant has the necessary means to fulfil the pharmacovigilance tasks;

17.11.3. a reference to the location where the pharmacovigilance system master file conforming to the requirements laid down in the laws and regulations regarding pharmacovigilance (hereinafter - pharmacovigilance system master file) is kept;

17.11.1 the risk management plan which in conformity to the laws and regulation regarding pharmacovigilance procedures describes in detail the risk management system (hereinafter - risk management plan) and which the applicant of the registration will introduce for the medicinal product concerned, as well as a summary of the plan. The risk management system shall be proportionate to the identified risks and the potential risks of the medicinal product, and the need for post-registration safety data of the medicinal product;

17.12. the notification regarding compliance of the clinical trial with the ethical norms referred to in the regulatory enactments regarding the procedures for conducting clinical trials and observations on the use of medicinal products;

17.13. the summary of the product characteristics, which is drawn up in accordance with Paragraph 21 of this Regulation. If a medicinal product is registered in accordance with a mutual recognition or decentralised procedure, the applicant of the registration application shall submit a copy of the summary of the product characteristics, which complies with Paragraph 21 of this Regulation, or - in the case referred to in Sub-paragraph 89.1 of this Regulation - a copy of the summary of the product characteristics approved by a competent authority of the Member States of the European Economic Area. The applicant of a registration application shall regularly update the referred to information;

17.14. the labelling - mock-ups of the secondary and primary packaging containing information specified in the regulatory enactments regarding procedures for the labelling of medicinal products and requirements to be made for the package leaflets of medicinal products as regards secondary and primary packaging;

17.15. the package leaflet, which contains the information specified in the regulatory enactments regarding procedures for the labelling of medicinal products and requirements to be made for package leaflets of medicinal products. If a medicinal product is being registered in accordance with a mutual recognition or decentralised procedure, it shall be necessary to append a copy of a package leaflet of the applicant of the registration application or a copy of the package leaflet approved by a competent authority of the Member States of the European Economic Area;

17.16. a document confirming the rights of the manufacturer to manufacture the relevant medicinal product in the State of manufacture:

17.16.1. if the site of manufacture of the medicinal product is located in the Member State of the European Economic Area, a copy of a special permit (licence) for the manufacture of the medicinal products in accordance with the regulatory enactments regarding licensing of pharmaceutical activity or an indication to the manufacturing licence in the database of the European Union regarding manufacturing and importation licences and certificates of good manufacturing practice. Additionally a certificate of good manufacturing practice (if available) issued by the competent authority of a Member State of the European Economic Area shall be submitted or the number of a certificate of good manufacturing practice in the database of the European Union regarding manufacturing and importation licences and certificates of good manufacturing practice shall be indicated;

17.16.2. if the site of manufacture of the medicinal product is not located in the European Economic Area, a document that is equal to the special permit (licence) for the manufacture of medicinal products referred to in Sub-paragraph 17.16.1 of this Regulation in addition to which a notification (if available) drawn up by the relevant competent authority regarding inspections of good manufacturing practice or the latest certificate of good manufacturing practice shall be submitted if the compliance of the site of manufacture with good manufacturing practice has been inspected by:

17.16.2.1. the competent authority of a Member State of the European Economic Area or the competent authority of the relevant state within the framework of operation of a mutual recognition agreement regarding good manufacturing practice between the European Union and a third country or within the framework of an agreement regulating another measure of the European Union (hereinafter - mutual recognition agreement). In such case a notification regarding inspections of good manufacturing practice shall be not older than three years and the number of a certificate of good manufacturing practice in the database of the European Union regarding manufacturing and importation licences and certificates of good manufacturing practice may be indicated instead of a certificate of good manufacturing practice;

17.16.2.2. another competent authority (other than the authority referred to in Sub-paragraph 17.16.2.1 of this Regulation) to which the mutual recognition agreement referred to in Sub-paragraph 17.16.2.1 of this Regulation applies, and an inspection has been performed within the territory to which the operation of such agreement is not applicable. In such case a summary regarding inspection of good manufacturing practice may be provided instead of a notification;

17.17. the registration certificates (copies) of medicinal products obtained in other Member States of the European Economic Area or in Non-member States of the European Economic Area (hereinafter - third country) together with the list of such Member States of the European Economic Area where the registration applications are examined;

17.17.1 a summary of the safety data including the data contained in the periodic safety update reports, where available, referred to in the laws and regulations regarding pharmacovigilance procedures (hereinafter - safety report) and suspected adverse reactions reports;

17.18. detailed information regarding any decision, with which a refusal regarding granting of a permit has been received in a Member State of the European Economic Area or a third country, and justification of such decision. The applicant of the registration application shall regularly update the referred to information;

17.19. a document (copy) regarding determination of orphan medicinal products in accordance with Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999 on orphan medicinal products, to which a copy of the relevant statement of the European Medicines Agency has been appended;

17.20. [9 April 2013];

17.21. the following information shall be included as regards the additional requirements for radionuclide generators referred to in this Paragraph:

17.21.1. a general description of the system together with a detailed description of such components of the system, which may affect the composition or quality of secondary (daughter) nucleide preparation; and

17.21.2. the qualitative and quantitative data regarding the eluate or sublimate;

17.22. if the formulation of medicinal products contains active substances obtained from specimens that are referred to in Appendices of the Convention on International Trade in Endangered Species of Wild Fauna and Flora, 1973, and Annexes to Council Regulation (EC) No 338/97 of 9 December 1996 on the protection of species of wild fauna and flora by regulating trade therein - a certification of the applicant of registration that obtaining of the relevant specimens in the country of origin has been performed in compliance with the requirements specified in the referred to Convention; and

17. 23. a confirmation that the manufacturer of the medicinal product has verified compliance of the manufacturer of the active substance with principles and guidelines of good manufacturing practice by conducting audits. The written confirmation shall contain a reference to the date of the audit and a declaration that the outcome of the audit confirms that the manufacturing complies with the principles and guidelines of good manufacturing practice.

[21 August 2007; 28 July 2008; 1 November 2010; 9 April 2013; 3 September 2013]

17.1 Additional information on the labelling of outer and immediate packaging for advanced therapy medicinal products shall comply with Article 11 of European Parliament and Council Regulation No 1394/2007. In addition the information on immediate packaging shall be indicated in compliance with Article 12(a) and (b) of European Parliament and Council Regulation No 1394/2007.

[29 June 2010]

17.2 Information in the package leaflet for advanced therapy medicinal products shall comply with Article 13 of European Parliament and Council Regulation No 1394/2007.

[29 June 2010]

17.3 The information referred to in Paragraph 17 of this Regulation shall be updated where it is necessary to make changes.

[9 April 2013]

18. Colouring matters present in the formulation of medicinal products specified in the application dossier shall comply with the colouring matters permitted for use in foodstuffs, and they shall be applied the same specific purity criteria and analyses for verification of the compliance of these criteria that are applied for the colouring matters permitted for use in the foodstuffs in accordance with the regulatory enactments regarding mandatory safety requirements for food additives. Other colouring matters may be added to the medicinal products manufactured for export if the use of such colouring matters is permitted in the state to which the medicinal products are exported.

[18 May 2010]

19. Additionally the applicant of a registration application shall indicate the reference medicinal products, if he or she submits the abridged registration application referred to in Chapter III of this Regulation, and the date when the reference medicinal products have been registered in the European Economic Area for the first time.

20. Detailed summaries shall be appended to documents and information regarding the results of the pharmaceutical, non-clinical tests and clinical trial referred to in Sub-paragraph 17.10 of this Regulation. Summaries shall be drawn up and signed by experts who have the necessary technical or professional qualification (which is indicated in a short description of the course of their education and work (life) (curriculum vitae)). The experts shall substantiate the use of any scientific literature in compliance with Sub-paragraph 28.2 of this Regulation and in accordance with the conditions included in Annex 4 to this Regulation.

[18 May 2010]

21. The description of a medicinal product shall include the following information in the indicated sequence:

21.1. the name of the medicinal product, the pharmaceutical form and strength of the medicinal product;

21.2. the qualitative and quantitative composition of the constituents of the active substances and excipients, the general name or chemical description thereof;

21.3. the pharmaceutical form;

21.4. clinical data:

21.4.1. therapeutic indications;

21.4.2. doses and route of administration to adults and, where necessary, children;

21.4.3. contraindications;

21.4.4. specific warnings and precaution in use. Any specific precautionary measures shall be indicated to immunological preparations to be taken by persons who store such products and administer them to patients, as well as any precautionary measures to be taken by a patient;

21.4.5. interaction with other medicinal products and other forms of interaction;

21.4.6. usage during pregnancy and lactation;

21.4.7. effect on the ability to drive and to service machinery;

21.4.8. undesirable adverse effects;

21.4.9. overdose symptoms, emergency procedures, antidotes;

21.5. pharmacological properties:

21.5.1. pharmacodynamic properties;

21.5.2. pharmacokinetic properties;

21.5.3. pre-clinic data on safety;

21.6. pharmaceutical data:

21.6.1. the list of excipients;

21.6.2. main cases of incompatibility;

21.6.3. the period of storage after the making of the preparation (for example, dilution or mixing) or after the first opening of the primary packaging;

21.6.4. special storage conditions;

21.6.5. the type and content of the packaging; and

21.6.6. specific precautionary measures (where appropriate) regarding the disposal of waste from the medicinal product;

21.7. the owner of the registration;

21.8. the medicinal product registration number(s) (number(s) of the registration certificate of the medicinal product);

21.9. the date of the first registration or re-registration of the medicinal product;

21.10. the date of revision of the medicinal product description; and

21.11. for radiopharmaceuticals:

21.11.1. detailed information regarding the dosimetry of internal radiation; and

21.11.2. additional instructions regarding making of such preparations for immediate use and regarding quality control and, where necessary, the maximum period of storage, during which any preparations made during the interval, such as eluate, or medicinal products prepared for usage comply with specifications thereof.

21.1 The summary of the product characteristics for advanced therapy medicinal products shall contain the information that complies with Article 10 of European Parliament and Council Regulation No 1394/2007.

[29 June 2010]

21.2 In addition to the information referred to in Paragraphs 21 and 21.1 of this Regulation the summary of product characteristics shall contain the following information:

21.21. for medicinal products included on the list referred to in Article 23 of Regulation (EC) No 726/2004, shall include the statement: "This medicinal product is subject to additional monitoring". This statement shall be preceded by the approved black symbol in accordance with Article 23 of Regulation (EC) No 726/2004 and Commission Implementing Regulation (EU) No 198/2013 of 7 March 2013 on the selection of a symbol for the purpose of identifying medicinal products for human use that are subject to additional monitoring (hereinafter - Implementing Regulation No 198/2013) and followed by an appropriate standardised explanatory sentence;

21.22. for all medicinal products - a standard text shall be included expressly asking healthcare professionals - health care practitioner or pharmacists - to report any suspected adverse reaction using spontaneous reporting system, notify the State Agency of Medicines, as well as provide possible ways of reporting in accordance with the laws and regulations regarding pharmacovigilance procedure.

[9 April 2013]

22. If a medicinal product is registered in accordance with the conditions referred to in Chapter III of this Regulation, the summary of the product characteristics shall not include data regarding such indications and doses, to which protection of the patent to reference medicinal products is applicable.

23. Application dossier shall be prepared, taking into account:

23.1. the recommendations (guidelines) of the European Commission referred to in Section 28.1 of the Pharmaceutical Law, which the European Commission has published in Volume 2, Part B "Notice to Applicants, Medicinal Products for Human Use, Presentation and Format of the Dossier, Common Technical Document (CTD)" of the collection of documents of the Rules Governing Medicinal Products in the European Communities and regarding which information is publicly available on the website of the State Agency of Medicines. The Common Technical Document shall be applicable to all types of registration applications regardless of the applicable procedure and products, as well as whether a complete or abridged application for the registration of medicinal products has been submitted;

23.2. scientific guidelines accepted by the the Committee for Medicinal Products for Human Use of the European Medicines Agency (hereinafter - Committee for Medicinal Products) and published by the European Medicines Agency regarding the quality, safety and efficacy of medicinal products for human use, other pharmaceutical guidelines of the European Community, which the European Commission has published in different volumes of the Rules Governing Medicinal Products in the European Community Eudralex, regarding which information is publicly available on the website of the State Agency of Medicines;

23.3. that the manufacturing process complies with good manufacturing practice in accordance with regulatory enactments regarding manufacturing and control of medicinal products and the Guide to Good Manufacturing Practice of Medicinal Products and Investigational Medicinal Products, which the European Commission has published in Volume 4 of the Rules Governing Medicinal Products in the European Community Eudralex, regarding which information is publicly available on the website of the State Agency of Medicines;

23.4. that all information regarding assessment of the particular medicinal product has been submitted regardless of whether it is favourable or unfavourable to the medicinal product. Any details regarding unfinished or discontinued pharmaco-toxicological clinical trials or research on the medicinal product and finished research on the therapeutic indications of the medicinal product, to which the registration application is not applicable, have been provided;

23.5. that the clinical trial conducted in the European Economic Area complies with the requirements specified in the regulatory enactments regarding the procedures for conducting clinical trials and observations regarding the use of medicinal products. A clinical trial conducted outside the European Economic Area to medicinal products, which are intended to be used in the European Economic Area, has been planned, conducted and notified of in accordance with the principles of good manufacturing practice and ethics, which are equal to the principles referred to in the regulatory enactments regarding the procedures for conducting clinical trials and observations regarding the use of medicinal products. The clinical trial is conducted in accordance with the ethical principles specified, for example, in the Helsinki Declaration of the World Medical Association (adopted at the 18th General Assembly of the World Medical Association, published on the website of the State Agency of Medicines);

23.6. that non-clinical trials (pharmaco-toxicological research) are conducted in accordance with the principles of good manufacturing practice included in the regulatory enactments regarding requirements for the quality and inspection of laboratories; and

23.7. that all tests involving animals have taken place in accordance with the regulatory enactments regarding the protection of animals.

[18 May 2010; 9 April 2013]

24. Application dossier shall be drawn up in accordance with Annex 3 to this Regulation. The following shall be indicated in the application dossier:

24.1. administrative information (Module 1);

24.2. summaries (quality, non-clinical and clinical) (Module 2);

24.3. chemical, pharmaceutical and biological information on medicinal products containing chemical and/or biological active substances (Module 3);

24.4. non-clinical reports (Module 4); and

24.5. clinical reports (Module 5).

25. Application dossier pursuant to Annex 4 to this Regulation shall be prepared regarding the following medicinal products:

25.1. well-established medicinal products - medicinal products, the active substance(s) of which is (are) widely used in medicine and which have a recognised efficacy and acceptable level of safety;

25.2. essentially similar medicinal products (generic medicinal products); and

25.3. similar biological medicinal products.

26. Application dossier pursuant to Annex 5 to this Regulation shall be prepared for the following specific medicinal products:

26.1. biological medicinal products;

26.2. radiopharmaceuticals;

26.3. radiopharmaceutical precursors;

26.4. homeopathic medicinal products;

26.5. herbal medicinal products; and

26.6. orphan medicinal products.

27. Application dossier for advanced therapy medicinal products that are referred to in Article 2 of European Parliament and Council Regulation No 1394/2007 shall be prepared according to Annex 6 to this Regulation for submission to the European Medicines Agency, taking into account that:

27.1. gene therapy medicinal product means a biological medicinal product (not vaccines against infectious diseases) which has the following characteristics:

27.1.1. it contains an active substance which contains or consists of a recombinant nucleic acid used in or administered to human beings with a view to regulating, repairing, replacing, adding or deleting a genetic sequence;

27.1.2. its therapeutic, prophylactic or diagnostic effect relates directly to the recombinant nucleic acid sequence it contains, or to the product of genetic expression of this sequence;

27.2. somatic cell therapy medicinal product means a biological medicinal product which has the following characteristics:

27.2.1. it contains or consists of cells or tissues that have been subject to substantial manipulation (not manipulations referred to in Annex I to European Parliament and Council Regulation No 1394/2007) in order to alter biological characteristics, physiological functions or structural properties relevant for the intended clinical use, or of cells or tissues that are not intended to be used for the same essential function in the recipient and the donor;

27.2.2. it is presented as having properties for, or is used in or administered to human beings with a view to treating, preventing or diagnosing a disease through the pharmacological, immunological or metabolic action of its cells or tissues.

[29 June 2010]

27.1 In respect of assessment of the application dossier for advanced therapy medicinal products that includes medical devices or active implantable medical devices, the notified body which has carried out the assessment of the part of the medical device or the part of the active implantable device referred to in Sub-paragraph 13.3.4 of Annex 6 to this Regulation shall make available, upon the request of the competent authority assessing the application, any information related to the results of the part of the medical device or active implantable device. The assessment has been carried out in accordance with the regulatory enactments regarding registration, conformity assessment, distribution, operation and technical supervision of medical devices. This may include information and documents contained in the conformity assessment application concerned, where necessary for the evaluation of the combined advanced therapy medicinal product as a whole.

[29 June 2010]

III. Specific Requirements for an Abridged Application for the Registration of Medicinal Products

28. An applicant of a registration application is entitled not to provide the results of non-clinical trials and clinical studies (notwithstanding the requirements referred to in Sub-paragraph 17.10 of this Regulation, but not violating regulatory enactments applicable to the protection of industrial and commercial property), if he or she is able to prove:

28.1. that the medicinal products are generic medicinal products to the reference medicinal products registered in any of the Member States of the European Economic Area for at least 8 years. In such case the registration of the generic medicinal products shall come into effect not earlier than after 10 years from the registration date of the reference medicinal products in the Member States of the European Economic Area. If the reference medicinal products are not registered in Latvia, the Member State of the European Economic Area, in which the reference medicinal products are or had been registered, shall be indicated in the registration application. If within the first 8 years from the referred to 10 years the owner of the registration has registered one or several new therapeutic indications, which during scientific assessment prior to the registration thereof confirmed a clinically substantial benefit in comparison with the existing therapies, the referred to protection period of 10 years shall be extended for a maximum of one year; and

28.2. that the active substance(s) within the formulation of medicinal products in a Member State of the European Economic Area is (are) widely used in medicine in the formulation of already registered medicinal products for at least 10 years with a recognised efficacy and acceptable safety level in accordance with Annex 4 to this Regulation. In such case the results of trials and studies shall be substituted with a reference to the relevant scientific literature.

29. The State Agency of Medicines shall:

29.1. request a certification of a competent authority of the relevant State regarding the existing or previous registration of the reference medicinal products in any of the Member States of the European Economic Area together with a complete formulation of the reference medicinal products and, where necessary, other appropriate documents; and

29.2. upon the request of a competent authority of another Member State of the European Economic Area, at which the registration application has been submitted, send to the relevant competent authority a certification regarding the existing or previous registration of the reference medicinal products in Latvia together with a complete formulation of the reference medicinal products and, where necessary, other appropriate documents within a time period of one month.

30. Results of non-clinical or clinical trials shall be submitted in one of the following cases:

30.1. the medicinal products do not comply with the generic medicinal products;

30.2. bioequivalence cannot be proved by bioavailability studies;

30.3. active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration thereof change(s) in respect of the reference medicinal products; or

30.4. the biological medicinal products do not comply with the generic medicinal products, but are equal to the reference medicinal products (taking into account the differences as regards starting materials or manufacturing process with the reference medicinal products). The submitted additional type and amount of data shall comply with the criteria specified in Annex 4 to this Regulation. It is allowed not to submit other results of tests or studies referred to in the application dossier for the reference medicinal products.

31. If a registration application is regarding a new indication of a well-established medicinal substance, in addition to the protection period specified in Paragraph 28 of this Regulation a non-cumulative time period of one year shall be assigned in relation to the rights of data protection provided that significant non-clinical or clinical trials regarding the new indication are conducted.

32. Conducting of the necessary research and studies (as regards Paragraphs 28 and 30 of this Regulation) and resultant practical activities shall not be regarded as contradictory to the patent rights and supplementary protection certificates of medicinal products.

33. If formulation of a medicinal product includes active substances, which are used in the formulation of a registered medicinal product, but which have not been previously used in therapy in such composition, new results of non-clinical or clinical studies regarding such composition shall be submitted in accordance with Sub-paragraph 17.10 of this Regulation, but it shall not be required to submit scientific references regarding each active substance separately.

34. After registration of medicinal products the owner of the registration of the medicinal products may allow to use pharmaceutical, non-clinical and clinical documentation included in the application dossier in order to examine subsequent registration applications, which concern other medicinal products with the same qualitative and quantitative formulation of active substances and the same pharmaceutical form.

IV. Specific Requirements for Documentation Regarding Medicinal Products Derived from Human Blood or Plasma

35. Requirements for documentation applicable to medicinal products derived from human blood or plasma, as well as starting materials manufactured from human blood and plasma, shall be determined in a plasma master file approved in accordance with the procedures specified in this Chapter.

36. Each centre or establishment for fractionation and processing of human plasma shall prepare and renew information indicated in the plasma master file. The plasma master file shall contain the following information:

36.1. the origin of the plasma;

36.1.1. information regarding centres or establishments where blood and plasma is collected, also data regarding inspections and certification, as well as epidemiological data regarding infections carried by blood;

36.1.2. information regarding centres or establishments where donor material and the plasma pool are tested, also data regarding inspections and certification;

36.1.3. criteria for the selection and refusal of blood and plasma donors;

36.1.4. the system used, which ensures the traceability of every material transferred by a donor from the collection of blood and plasma until the final product and vice versa;

36.2. the quality and safety of plasma:

36.2.1. compliance with the requirements specified in the European Pharmacopoeia Monographs;

36.2.2. testing of blood and plasma materials and pools as regards infectious agents, also information regarding test methods and as regards the pool of plasma - validation data regarding tests used;

36.2.3. technical characteristics of the bags used for the collection of blood and plasma, also information regarding anticoagulant solutions;

36.2.4. storage and transportation conditions of the plasma;

36.2.5. the inventory procedures performed and the period of quarantine; and

36.2.6. characterisation of the pool of plasma;

36.3. the system determining the conditions and specifications of interaction between fractionator or processor of medicinal products derived from human blood and plasma and centres or establishments of collection and testing of blood and plasma, regarding which an agreement has been reached; and

36.4. a list of such medicinal products, to which the plasma master file applies, regardless of whether the medicinal products have been granted a registration certificate or also registration is in process, also regarding investigational medicinal products in relation to implementation of good clinical practice in conducting clinical studies involving medicinal products for human use.

37. The applicant of the registration application or the owner of the registration shall submit to the State Agency of Medicines the plasma master file. If the applicant of the registration application or the owner of the registration and the owner of the plasma master file are different persons, the plasma master file shall be available to the applicant of the registration application or the owner of the registration so that it could be submitted to the State Agency of Medicines. In any case the applicant of the registration application or the owner of the registration shall assume responsibility regarding the medicinal products.

38. A registration application concerning a constituent derived from human plasma shall include a reference to the plasma master file regarding plasma used as a starting material or a raw material.

39. The State Agency of Medicines shall take a decision on registration after the European Medicines Agency has issued a certificate of the plasma master file.

40. Evaluation and certification of the plasma master file:

40.1. as regards medicinal products not yet registered, an applicant of a registration application shall submit to the State Agency of Medicines complete documentation and an individual plasma master file, if it has not been submitted yet;

40.2. the European Medicines Agency shall perform scientific and technical evaluation of the plasma master file. If evaluation is favourable, a certificate of the plasma master file confirming that it complies with the requirements specified in the legal acts of the European Union and an evaluation report shall be issued. The certificate shall be valid in all Member States of the European Economic Area;

40.3. the plasma master file shall be renewed and re-certified each year; and

40.4. changes to the plasma master file shall be evaluated, taking into account the evaluation conditions specified in Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of a marketing authorisations for medicinal products for human use and veterinary medicinal products (hereinafter - Commission Regulation No 1234/2008).

[18 May 2010]

41. After the evaluation referred to in Paragraph 40 of this Regulation, the State Agency of Medicines, in taking a decision on registration of medicinal products, shall take into account the relevant certification, re-certification or changes to the plasma master file of medicinal products.

42. If the plasma master file applies to medicinal products derived from blood and plasma and registered only in accordance with a national procedure (registration is valid only in the Republic of Latvia), the State Agency of Medicines shall perform the scientific and technical evaluation of the referred to plasma master file.

V. Specific Requirements for Documentation Regarding Vaccines for Human Use

43. As regards vaccines for human use, a system of vaccine antigen master file shall be used, taking into account the following conditions:

43.1. the vaccine may contain one or several different vaccine antigens. The amount of active substances in the vaccine shall be the same as the amount of vaccine antigens;

43.2. a combined vaccine contains at least two different vaccine antigens, which protect against one or several infectious diseases; and

43.3. a monovalent vaccine contains one vaccine antigen, which protects against one infectious disease.

44. Documentation appended to the registration application of a vaccine (except for an influenza vaccine) shall include a master file of each such vaccine antigen, which is the active substance of the vaccine.

45. The following information regarding the quality data of an active substance shall be included in the vaccine antigen master file (Module 3 of Annex 3 to this Regulation):

45.1. general information, also conformity to the requirements specified in the relevant European Pharmacopoeia Monograph;

45.2. information regarding the manufacture of the active substance. This section shall include the description of the manufacturing process, information regarding starting materials and raw materials, specific measures in relation to the safety evaluation and possibilities of TSE and adventitious agents, as well as equipment;

45.3. characteristics of the active substance;

45.4. quality control of the active substance;

45.5. standards used for testing of the finished product (hereinafter - reference standards) and materials;

45.6. packaging and sealing system of the active substance; and

45.7. stability of the active substance.

[28 July 2008]

46. Evaluation and certification:

46.1. as regards new vaccines containing a new vaccine antigen, an applicant of a registration application shall submit to the State Agency of Medicines a complete application dossier, including therein all the vaccine antigen master files regarding each individual vaccine antigen, which is a part of the new vaccine, if such separate vaccine antigen master file has not already been submitted;

46.2. the State Agency of Medicines shall perform scientific and technical evaluation of the vaccine antigen master files. If evaluation is favourable, a certificate for each vaccine antigen master file confirming that it complies with the requirements specified in legal acts of the European Union and an evaluation report shall be issued. The certificate shall be valid in all Member States of the European Economic Area. The European Medicines Agency shall perform the scientific and technical evaluation of changes to the content of the vaccine antigen master file allowed in the European Union in accordance with the procedure specified in Commission Regulation No 1234/2008;

46.3. the conditions referred to in Sub-paragraphs 45.1 and 45.2 of this Regulation shall also apply to all vaccines composed of a new combination of vaccine antigens, regardless of whether one or several such vaccine antigens are a part of the vaccines already permitted in the European Union;

46.4. the State Agency of Medicines, upon taking a decision on registration of medicinal products, shall take into account certification of the vaccine antigen master file of the relevant medicinal products, re-certification thereof or changes to the vaccine antigen master file.

[18 May 2010]

47. If a vaccine antigen master file applies to a vaccine, to which registration has not been granted yet or will not be granted in accordance with Regulation No 726/2004 of the European Parliament and of the Council, as well as if a vaccine contains vaccine antigens, which are not evaluated in accordance with the procedure of the European Union referred to in Sub-paragraph 45.2 of this Regulation, the State Agency of Medicines shall perform scientific and technical evaluation of the vaccine antigen master file and changes arising therefrom.

VI. Specific Registration Criteria of Medicinal Products Applicable to Homeopathic Medicinal Products and Anthroposophic Medicinal Products

48. This Chapter shall apply to homeopathic medicinal products made of substances, which are called homeopathic starting materials in accordance with the process of manufacturing of homeopathic medicinal products described in the European Pharmacopoeia or, where such does not exist, in pharmacopoeias officially used by Member States of the European Economic Area. Formulation of homeopathic medicinal products may also include several substances.

49. In order to register homeopathic medicinal products, a registration application shall be submitted to the State Agency of Medicines. The registration application and documents appended thereto shall be prepared in accordance with the requirements for application dossier specified in this Regulation and the sample of the European Commission.

50. The State Agency of Medicines shall establish a specific, simplified registration procedure for the registration of the homeopathic medicinal products referred to in Paragraph 51 of this Regulation.

51. The State Agency of Medicines is entitled to apply a specific, simplified registration procedure only to the registration of such homeopathic medicinal products, which comply with all of the below-mentioned conditions:

51.1. the medicinal products are intended for oral or external use only;

51.2. no specific therapeutic indications appear on the labelling of the medicinal products or in any information relating thereto; and

51.3. there is a sufficient degree of dilution to guarantee the safety of the medicinal products. Medicinal products shall not contain more than 1/10 000 part of the mother tincture or more than 1/100th of the smallest dose used in allopathic medicinal products to be dispensed on a doctor's prescription.

52. In order to register homeopathic medicinal products, using the specific, simplified registration procedure, homeopathic degrees of dilution derived from the same homeopathic starting material or starting materials shall be included in the registration application of homeopathic medicinal products. In order to prove pharmaceutical quality and batch-to-batch consistency (homogeneity) of the product, the following documents and data shall be included in the registration application:

52.1. the scientific name or another name given in a pharmacopoeia of the homeopathic starting material(s), together with a statement regarding the various routes of administration, pharmaceutical forms and degree of dilution to be registered;

52.2. the documentation describing how the homeopathic starting material(s) is (are) obtained and controlled, and substantiating the homeopathic nature thereof (indicating an adequate bibliography);

52.3. the manufacturing and control documentation for each pharmaceutical form and a description of the method of dilution and potentization;

52.4. a special permit (licence) for the manufacture of the relevant medicinal products;

52.5. any copies of documents issued in other Member States of the European Economic Area, which confirm the registration of the same medicinal products;

52.6. one or more mock-ups of the secondary and primary packaging of the medicinal products to be registered;

52.7. data regarding stability of the medicinal products.

53. Other homeopathic medicinal products (except for the ones referred to in Paragraph 50 of this Regulation) shall be registered in accordance with Chapters II and III of this Regulation.

[18 May 2010]

54. The State Agency of Medicines is entitled to apply exceptions to non-clinical and clinical studies of homeopathic medicinal products in accordance with the principles and characteristics of homeopathy practised in Latvia, on the basis of the opinion of the relevant professional association.

55. Anthroposophic medicinal products, which are described in the officially used pharmacopoeia and which are made using a homeopathic method, shall be registered in accordance with the procedures for the registration of homeopathic medicinal products specified in this Regulation.

VII. Specific Registration Criteria of Medicinal Products Applicable to Traditional Herbal Medicinal Products

56. The simplified registration procedure shall be applied to herbal medicinal products (traditionally used herbal medicinal products), which comply with all of the below-mentioned criteria:

56.1. they have only indications corresponding to traditionally used herbal medicinal products and, taking into account the formulation and purpose of administration thereof, they are intended for usage without direct supervision of a medical practitioner only in the following cases - for the purposes of diagnostics, administration or supervision of a medical treatment process;

56.2. they are intended for administration only in the specified strength and dose;

56.3. they are intended for oral or external use or inhalations;

56.4. they are being used in the period of time specified in Sub-paragraph 61.3 of this Regulation; and

56.5. information regarding the traditional administration of herbal medicinal products is sufficient, particularly if it has been proved that the products are harmless in the specified conditions of administration, and the efficacy or effects of the medicinal products, based on long-term experience of use, are credible.

57. The presence of vitamins or mineral substances in traditionally used herbal medicinal products, if safety evidence thereof is well documented, does not prohibit registration of the products in accordance with Paragraph 56 of this Regulation, using a simplified registration procedure, if the effect of the vitamins or mineral substances supplement specific therapeutic indication(s) of herbal active substances.

58. Herbal medicinal products, to which a simplified registration procedure is applicable, shall be registered in accordance with a mutual recognition procedure or decentralised procedure, if at least one of the following conditions is in effect:

58.1. the monograph referred to in Sub-paragraph 63.2 of this Regulation regarding herbal medicinal products has been drawn up; or

58.2. the herbal medicinal products, preparations or combinations thereof are included on the list of substances, preparations or combinations thereof used in traditional herbal medicinal products (hereinafter - list), which is approved by a decision of the European Commission and where indications, strength and dose, mode of administration of each herbal substance and other information necessary in order to use herbal medicinal products safely as traditional medicinal products is indicated.

59. As regards other herbal medicinal products, to which Paragraphs 56, 57 and 60 of this Regulation apply, the State Agency of Medicines, in evaluating the registration application, shall take into account whether they are registered in a Member State of the European Economic Area in accordance with Chapter XIII of this Regulation.

60. If the State Agency of Medicines recognises that traditionally used herbal medicinal products comply with the conditions referred to in Paragraph 51 or with the registration criteria for medicinal products referred to in Chapter II of this Regulation, or to medicinal products to be registered in accordance with the centralised registration procedure pursuant to Regulation No 726/2004 of the European Parliament and of the Council, the requirements specified for such medicinal products in this Chapter shall not be applicable.

61. In order to register herbal medicinal products in accordance with a simplified registration procedure (or a procedure for the registration of traditionally used herbal medicinal products), a registration application shall be submitted to the State Agency of Medicines. In accordance with the requirements specified in this Regulation and according to the sample of the European Commission, the following shall be appended to the application:

61.1. data and documents (in accordance with Annexes 3 and 5 to this Regulation);

61.1.1. which are referred to in Sub-paragraphs 17.1, 17.2, 17.3, 17.4, 17.5, 17.6, 17.7, 17.8, 17.9, 17.13, 17.14, 17.15 and 17.16 of this Regulation;

61.1.2. the results of pharmaceutical tests, which are referred to in Sub-paragraph 17.10.1 of this Regulation;

61.1.3. summary of the product characteristics, except for the data specified in Sub-paragraph 21.4 of this Regulation; and

61.1.4. if there are combinations referred to in Sub-paragraph 4.3 or Paragraph 57 of this Regulation - information pursuant to the requirements referred to in Sub-paragraph 56.5 of this Regulation. If individual active substances are not sufficiently well known, data regarding such active substances shall also be indicated;

61.2. any permit or document confirming that the applicant has registered medicinal products and received a permit to distribute the medicinal products in some other Member State of the European Economic Area or a third country, as well as detailed information regarding refusal to register in a Member State of the European Economic Area or a third country, indicating any reasons of refusal;

61.3. bibliographic or expert certification regarding the usage of the relevant medicinal products or product in medicine for at least 30 years prior to the application of an application for registration of the medicinal products, including at least 15 years in the European Economic Area; and

61.4. a bibliographic report on safety data together with an expert report.

62. If a registration application applies to a herbal substance, preparation or combination, which is included on the list referred to in Sub-paragraph 58.2 of this Regulation:

62.1. the data referred to in Sub-paragraphs 61.2 and 61.3 of this Regulation shall not be submitted; and

62.2. Sub-paragraphs 94.3 and 94.4 of this Regulation shall not be applied.

63. The State Agency of Medicines:

63.1. in relation to Sub-paragraph 61.3 of this Regulation:

63.1.1. after receipt of a registration application, shall request a statement of the Committee on Herbal Medicinal Products of the European Medicines Agency regarding conformity of evidence of continuous usage of the relevant medicinal product or equal product;

63.1.2. if medicinal products have been used for less than 15 years, but they conform to the criteria of the simplified registration procedure described in this Chapter, the issue shall be given for examination to the Committee on Herbal Medicinal Products of the European Medicines Agency, submitting the relevant justifying documents;

63.1.3. shall evaluate whether the equal product contains the same active substances and regardless of excipients it has the same utilisation, equivalent strength and posology, the same or equal type of administration as to medicinal products, regarding which a registration application has been submitted; and

63.1.4. shall examine whether the request to prove the usage of medicinal products in medical practice for 30 years has been fulfilled also in the case where the medicinal products have not been registered. It shall also be fulfilled if the number or quantity of ingredients of the medicinal products has been reduced during this period of time; and

63.2. in examining a registration application and taking the final decision on registration of medicinal products, a herbal monograph of the European Community drawn up by the Committee on Herbal Medicinal Products of the European Medicines Agency shall be taken into account, where the requirements referred to in Sub-paragraph 25.2 of this Regulation, as well as conformity to traditionally used herbal medicinal products, have been complied with. If a herbal monograph of the European Community has not been developed yet, a reference to other relevant monographs, publications or data may be made.

64. An owner of registration shall:

64.1. evaluate the necessity to make amendments to application dossier if a new monograph of the European Community is being developed; and

64.2. notify the State Agency of Medicines or the competent authority of the relevant Member State of the European Economic Area regarding any changes to the information and documents submitted.

VIII. Variations to Application Dossier and Extension of Registration

65. In order to confirm variations to application dossier, an owner of registration shall submit an application or notification for confirmation of variations, to which data and documents pursuant to the sample of the European Commission shall be appended and which shall be drawn up in accordance with the requirements specified in this Regulation for application dossier:

65.1. to the State Agency of Medicines - in accordance with Commission Regulation No 1234/2008 and Paragraph 142 of this Regulation if medicinal products are registered in accordance with the national registration procedure other than the mutual recognition procedure or decentralised procedure;

65.2. to the State Agency of Medicines and competent authorities of the relevant Member State of the European Economic Area - in accordance with Commission Regulation (EC) No 1234/2008 (if medicinal products are registered in accordance with a mutual recognition procedure or decentralised procedure);

65.3. to the European Medicines Agency - in accordance with Commission Regulation No 1234/2008 if medicinal products are registered in accordance with a centralised registration procedure.

[18 May 2010; 1 November 2010]

65.1 Paragraph 65 of this Regulation shall not apply to those homeopathic (also anthroposophic) medicinal products and traditionally used herbal medicinal products that have been registered in accordance with the simplified registration procedure.

[18 May 2010]

66. The State Agency of Medicines in accordance with competence thereof shall fulfil the duties of a competent supervision authority referred to in Commission Regulation No 1234/2008.

[18 May 2010]

67. In order to take a decision on extension of registration of medicinal products in accordance with the national registration procedure for registered medicinal products (including medicinal products which are registered in accordance with the mutual recognition procedure or decentralised procedure), an owner of registration shall submit to the State Agency of Medicines an application pursuant to the sample of the European Commission, which is published on the website of the State Agency of Medicines. The data and documents indicated in the application shall be included therein and appended thereto.

[18 May 2010; 1 November 2010; 9 April 2013]

68. As regards medicinal products registered in accordance with the national registration procedure, including medicinal products which are registered in accordance with the mutual recognition procedure or decentralised procedure, the State Agency of Medicines shall assess the compliance of the relevant applications or notifications with Sub-paragraphs 65.1 and 65.2 of this Regulation and take a decision:

68.1. on registration of medicinal products (in case of extension of registration) if the submitted data and documents confirm the compliance with Annex 1 to Commission Regulation No 1234/2008 (or in the case referred to in Paragraph 142 of this Regulation - Annex 7 to this Regulation) or on refusal of registration. In case of variations the name of the medicinal product shall comply with the name of the medicinal product in the original decision on registration of the medicinal product;

68.2. on confirmation or non-confirmation (refusal) of the variations if the requirements of this Regulation have not been observed.

[1 November 2010]

68.1 In addition to Articles 2 and 3 and Annex II to Commission Regulation No 1234/2008 Annex 7.1 to this Regulation determines detailed information regarding classification of variations in categories specified by Article 2 of Commission Regulation No 1234/2008 - minor variation of type IA, minor variation of type IB, major variation of type II - and, where relevant, provide additional information regarding scientific data that are to be submitted in respect of these variations, as well as how such data are to be documented.

[1 November 2010]

68.2 Annex 7.1 to this Regulation shall not apply to:

68.21. extension of registration referred to in Sub-paragraph 68.1 of this Regulation;

68.22. the case referred to in Paragraph 42 of this Regulation.

[1 November 2010]

68.3 General documents that are to be appended to all applications regarding performance of variations in application dossier of medicinal product are determined in Annex IV to Commission Regulation No 1234/2008 and in Chapters II, III and IV of the Commission Guideline on Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products (Communication from the Commission (2009/C 323/04)), that is available to the public on the website of the State Agency of Medicines.

[1 November 2010; 9 April 2013]

68.4 Each Chapter of Annex 7.1 to this Regulation (A - administrative changes, B - quality changes, C - safety, efficiency and pharmacovigilance changes, D - Plasma Master File and Vaccine Antigen Master File special changes) provides the list of such variations that:

68.41. are classified as minor variations of type IA or major variations of type II in accordance with the definitions specified in Article 2 and the classification provided for in Annex II to Commission Regulation No 1234/2008 and it is specified regarding the implementation of which minor variations of type IA it shall be immediately notified in accordance with Article 8(1) of Commission Regulation No 1234/2008;

68.42. are considered as sample for minor variations of type IB (that are referred to in Article 3(2) of Commission Regulation No 1234/2008) and such category shall be applied by default as specified in Article 3 of Commission Regulation No 1234/2008 (therefore complete listing of such variations is not specified in Annex 7.1 to this Regulation).

[1 November 2010]

68.5 If a condition referred to in Annex 7.1 to this Regulation or several such conditions are not complied with in respect of minor variations of type IA, the relevant variations may be specified as variations of type IB unless they are specially classified as major variations of type II.

[1 November 2010]

68.6 Special approval data for variations of type IB and type II (Annex 7.1 to this Regulation) shall depend on peculiarities of variations.

[1 November 2010]

68.7 If it results from variations that the description, labelling or package leaflet of a medicinal product (information regarding a medicinal product) should be reviewed, it shall be regarded as part of the referred to variations. In such cases the updated information on the medicinal product shall be submitted as part of the application.

[1 November 2010]

IX. Minor Variations of Type IA and IB in Application Dossier

69. As regards medicinal products registered in accordance with a national registration procedure (which are not registered in accordance with a mutual recognition procedure or decentralised procedure), minor variations of type IA and IB in application dossier are indicated in Annex 8 to this Regulation. The relevant variations shall be evaluated and approved in accordance with this Chapter.

70. For the medicinal products referred to in Paragraph 69 of this Regulation:

70.1. only variations of type I shall be indicated in an application regarding variations of type I;

70.2. one application, indicating therein the relation among all resultant variations, shall be submitted, if:

70.2.1. one or several other variations of type IA result from one variation of type I A; and

70.2.2. variations of type IA or type IB result from one variation of type IB;

70.3. if several variations of Type I are to be made, a separate application shall be submitted for each variation. Each application shall include a reference to other applications, where such exist; and

70.4. if it results from variations of type I that the description, labelling or package leaflet of medicinal products can be amended, it shall be regarded as part of the variations.

71. The State Agency of Medicines shall ascertain whether an application complies with the conditions referred to in Paragraphs 69 and 70 of this Regulation, evaluate the submitted data and documents (perform expert-examination of the documents) and take a decision on approval of variations in the application dossier or non-approval of variations in accordance with the procedures specified in the Administrative Procedure Law in observance that evaluation (expert-examination) of data and documents is being performed:

71.1. for minor variations of type IA - within 14 days after receipt of the application at the State Agency of Medicines; and

71.2. for minor variations of type I B - within 30 days after receipt of the application at the State Agency of Medicines.

72. The State Agency of Medicines is entitled to request the owner of a registration to provide supplementary information. In such case the procedure referred to in Paragraph 71 of this Regulation shall be suspended until the application of the requested supplementary information to the State Agency of Medicines.

73. If after evaluation of an application regarding variations of type IB and data, documents and other information appended thereto the State Agency of Medicines regards that the referred to application is not acceptable, it shall provide a justified statement to the owner of the registration who has submitted the relevant application in accordance with the procedures specified in the Administrative Procedure Law, but not later than within 30 days after receipt of the application referred to in Paragraph 70 of this Regulation at the State Agency of Medicines. The owner of the registration is entitled to make amendments to the application regarding variations of type IB within 30 days after receipt of the statement of the State Agency of Medicines, taking into account the justification referred to in the statement of the State Agency of Medicines. The owner of the registration shall notify the State Agency of Medicines in writing regarding amendments within the above-mentioned 30 days.

74. If an owner of a registration does not make any amendments to an application regarding variations of type IB in accordance with Paragraph 73 of this Regulation, it shall be regarded rejected, and the State Agency of Medicines shall notify the owner of a decision on non-approval of the variations in accordance with the procedures specified in the Administrative Procedure Law, but not later than within 30 days.

75. If the State Agency of Medicines has not notified an owner of a registration of a decision on non-approval of variations in accordance with Paragraph 73 of this Regulation, it shall be regarded that the State Agency of Medicines has approved the variations and the owner of the registration may implement the intended variations.

X. Major Variations of Type II in Application Dossier and Change of the Firm or Address of the Owner of a Registration

76. The following variations shall be regarded major - type II - variations for medicinal products registered in accordance with a national registration procedure (which are not registered in accordance with a mutual recognition procedure or decentralised procedure):

76.1. which do not comply with Annexes 7 and 8 to this Regulation; and

76.2. which are related to the change of the firm of the owner of a registration (the new and the existing owner of a registration is not the same person) or the change of the address thereof.

77. For the medicinal products referred to in Paragraph 76 of this Regulation:

77.1. only one variation of type II shall be indicated in an application regarding variations of type II, except for the case where:

77.1.1. several variations of type II are made to one medicinal product. In such case a separate application shall be submitted for each variation of type II. Each application shall include a reference to other applications, where such exist; and

77.1.2. other variations result from one variation of type II. One application may be submitted for all such variations, and it shall indicate the relation among all the resulting variations; and

77.2. if it results from variations that the description, labelling or package leaflet of medicinal products is to be amended, it shall be regarded as part of the variations.

78. The State Agency of Medicines shall ascertain whether an application complies with the conditions referred to in Paragraphs 76 and 77 of this Regulation, and evaluate the submitted data and documents (perform expert-examination of documents) and take a decision on approval of variations in the application dossier or non-approval of variations in accordance with the procedures specified in the Administrative Procedure Law in observance that evaluation (expert-examination) of data and documents is being performed:

78.1. not longer than within 60 days after receipt of the application at the State Agency of Medicines. The referred to term may be reduced, taking into account the urgency of the issue, particularly if it is related to safety; or

78.2. not longer than within 90 days, if the application is related to variations of therapeutic indications or supplementation of new indications.

79. The State Agency of Medicines is entitled to request the owner of a registration to provide supplementary information. In such case the procedure referred to in Paragraph 78 of this Regulation shall be suspended until the application of the requested supplementary information to the State Agency of Medicines.

80. If there are variations in application dossier of anti-influenza vaccines provided for human use, the following procedure shall be applied:

80.1. the State Agency of Medicines shall prepare an evaluation report and a draft decision in accordance with the procedures specified in the Administrative Procedure Law within 30 days after receipt of the application, on the basis of documents confirming the quality (Module 3 of Annex 3) and send them to the owner of the registration;

80.2. the owner of the registration shall submit to the State Agency of Medicines clinical data and, where necessary, data on the stability of the medicinal product within 12 days after receipt of the documents referred to in Sub-paragraph 80.1 of this Regulation; and

80.3. the State Agency of Medicines:

80.3.1. within 7 days after receipt of the data shall evaluate the data submitted, prepare the final decision and issue it to the owner of the registration; and

80.3.2. issue a package leaflet and a summary of product characteristics to the owner of the registration.

81. Due to a pandemic of human influenza virus (applies also to other pandemic human diseases), which is recognised as such by the World Health Organisation or European Union, the State Agency of Medicines has the right to recognise in exceptional cases variations in the application dossier of an anti-influenza vaccine intended for human use within the time period from the receipt of the application until the end of the procedure specified in Paragraph 80 of this Regulation, if the owner of the registration submits complete data regarding clinical safety and efficacy.

82. If the firm or the address of the owner of the registration changes and the owner of the registration is not the same person, the existing owner of the registration shall submit an application to the State Agency of Medicines. The following documents shall be appended and the following information shall be indicated in the application:

82.1. a document confirming the change of the owner of the registration;

82.2. the name of the medicinal product, the number of the medicinal product registration certificate and the date of the registration of the medicinal product;

82.3. the existing firm and address of the owner of the registration, as well as the name and address of such person to whom the transfer of the medicinal product registration certificate is intended;

82.4. a document certifying availability of a complete and, prior to the moment of transfer, renewed medicinal product registration folder (documentation) or a copy thereof, and the handing over thereof to the person to whom the medicinal product registration certificate is being transferred;

82.5. the date when the person to whom the medicinal product registration certificate is intended to be transferred will be able to take over all the duties of the previous owner of the registration; and

82.6. a document confirming that the person to whom the medicinal product registration certificate is being transferred is able to ensure the duties of the owner of the registration pursuant to the requirements specified in the regulatory enactments regarding the manufacture and control of medicinal products, bringing in, bringing out and distribution of medicinal products, advertising of medicinal products, pharmacovigilance procedure and clinical studies of medicinal products. The document shall indicate:

82.6.1. the person responsible for the activities related to the pharmacovigilance system, the address, telephone number and fax number thereof. A short description of the activities and experience shall be appended;

82.6.2. the service responsible for advertising and distribution of the medicinal products, as well as the address, telephone number and fax number of the relevant service;

82.6.3. a draft of the description, package leaflet and labelling of the medicinal products; and

82.6.4. a document confirming the payment for evaluation in accordance with Paragraph 85 of this Regulation.

[1 November 2010; 9 April 2013]

83. The State Agency of Medicines shall determine the date when the registration certificate will be transferred to a new owner of the registration, and it shall be recorded in an agreement between the present and the new owner of the registration. The validity of the registration of the medicinal products shall not change.

XI. Re-registration

84. In order to re-register medicinal products, an owner of a registration shall submit a re-registration application to the State Agency of Medicines. The re-registration application shall include and it shall have appended data and documents pursuant to the sample of the European Commission published on the website of the State Agency of Medicines and pursuant to the requirements for application dossier specified in this Regulation. The application shall include the following information:

84.1. concerning the quality, safety and efficacy of the medicinal products - the relevant application dossier which has been submitted for taking of the decision referred to in Paragraph 9 or 10 or Sub-paragraph 11.1 of this Regulation and in which all variations implemented after taking of the decision have been included (consolidated version of the application dossier);

84.2. as medicinal products are re-registered, on the basis of repeated evaluation of risk-benefit balance, the application shall have appended:

84.2.1. an evidence and a statement of a clinical expert that the risk-benefit balance remains favourable. The statement of a clinical expert shall be based on the data compiled since registration of re-registration of the medicinal products;

84.2.2. a data assessment provided in a suspected adverse reactions report and a safety report, and, wehere appropriate, a summary regarding all safety reports submitted since registration, as well as the information regarding all changes which have been made sins granting of the registration.

[18 May 2010; 9 April 2013]

84.1 The owner of registration shall lodge the applications referred to in Paragraph 84 of this Regulation to the State Agency of Medicines at least nine months prior to the end of the term of the decision referred to in Paragraph 9 or 10 or Sub-paragraph 11.1. of this Regulation.

[18 May 2010; 9 April 2013]

84.2 If medicinal products have been registered in accordance with the national registration procedure and an application has been lodged prior to the end of the term for lodging of the application referred to in Paragraph 84.1 of this Regulation, the owner of registration is entitled to agree with the State Agency of Medicines on the date of re-registration.

[18 May 2010]

XII. Procedures Related to the Registration of Medicinal Products

85. Expenditure of the evaluation, registration, approval of variations, re-registration and post-registration maintenance (hereinafter - service) of medicinal products (annual expenditure related to registration of medicinal products) shall be covered by the person on whose name it is planned to register the medicinal products (but in respect of the evaluation of the product documentation as regards conformity with the definition of the medicinal product - the applicant of the application) in accordance with the laws and regulations regarding the pricelist of paid public services of the State Agency of Medicines (hereinafter - pricelist of paid public services of the State Agency of Medicines).

[18 May 2010; April 9 2013]

85.1 [April 9 2013].

[18 May 2010]

85.2 [April 9 2013].

[18 May 2010]

85.3 [April 9 2013].

[18 May 2010]

85.4 [April 9 2013].

85.5 [April 9 2013].

[18 May 2010]

85.6 Annual fee for the supervision of re-registration of medicinal products shall be applied in the next calendar year following the date of the decision taken in Paragraph 9 or 10 or Sub-paragraph 11.1 of this Regulation.

[18 May 2010]

85.7 [April 9 2013].

[18 May 2010]

86. In order to examine a registration application, the State Agency of Medicines:

86.1. shall conduct a primary expert-examination, in which conformity of the registration and re-registration application with the requirements of this Regulation is determined (the primary expert-examination need not be conducted when approving variations):

86.1.1. within 30 days after receipt of the registration application at the State Agency of Medicines;

86.1.2. within 14 days after receipt of the application at the State Agency of Medicines, if the medicinal products are registered in accordance with a mutual recognition procedure or decentralised procedure; and

86.1.3. within 10 days after receipt of the re-registration application at the State Agency of Medicines;

86.2. shall examine the conformity of conditions for taking of a decision on registration of medicinal products, and until taking of the decision shall perform all the necessary activities in order to ensure the fulfilment of the procedure. The decision shall be taken in accordance with the procedures specified in the Administrative Procedure Law, ensuring the evaluation of data and documents within 210 days after lodging of the relevant registration application to the State Agency of Medicines (if the medicinal products are registered only in accordance with the national registration procedure, but not registered in accordance with the mutual recognition procedure or decentralised procedure). If the decision is taken in respect of generic medicinal products to be registered in accordance with the national registration procedure, the decision on registration shall be taken in accordance with the procedures specified by the Administrative Procedure Law not exceeding 90 days. The competence of the State Agency of Medicines shall not include examination of information related to patent rights;

86.3. is entitled to subject medicinal products, the starting materials and intermediate products thereof or other materials of components to testing at the laboratory of the State Agency of Medicines or at another laboratory (the referred to laboratory in compliance with the requirements of good manufacturing practice specified in the European Commission guidelines of good manufacturing practice of medicinal products and investigational medicinal products has the right to control medicinal products) in order to ascertain that the control methods, which are used by the manufacturer and which in accordance with Sub-paragraph 17.9 of this Regulation are described in documents appended to the registration application (Paragraph 17), are satisfactory; and

86.4. where necessary, is entitled to request that the applicant of the application adds supplementary data to the application. In such case the time period referred to in Sub-paragraph 86.2 of this Regulation shall be suspended until the application of the requested supplementary information to the State Agency of Medicines. Similarly the aforementioned time period may be suspended for the provision of oral or written explanations.

[28 July 2008; 18 May 2010]

87. The State Agency of Medicines:

87.1. in co-operation with other competent authorities shall confirm that the medicinal products of the manufacturer of medicinal products and the importer of medicinal products (medicinal products are imported from the third countries (by persons who have a special permit (licence) for manufacturing/import of medicinal products)) comply with the data submitted in accordance with Sub-paragraph 17.5 of this Regulation and control thereof has been conducted pursuant to the methods indicated in accordance with Sub-paragraph 17.9 of this Regulation;

87.2. is entitled to take a justified decision to issue a permit to the manufacturers of medicinal products and the importers of medicinal products to perform some manufacturing stages and the control referred to in Sub-paragraph 87.1 of this Regulation to the third parties.

[28 July 2008]

88. The State Agency of Medicines shall take a decision on refusal to examine an application:

88.1. if during the primary expert-examination it has been confirmed that the registration application does not conform to the requirements of this Regulation or the information referred to in Paragraph 19 of this Regulation has not been submitted. The State Agency of Medicines shall inform the applicant of the application about it and is entitled to return the registration application; and

88.2. in accordance with a national registration procedure:

88.2.1. if the State Agency of Medicines has information that another registration application regarding the same medicinal product is already being examined in another Member State of the European Economic Area. In such case the State Agency of Medicines shall inform the applicant of the registration application that the conditions referred to in Chapter XIII of this Regulation are applicable in respect of the application of the registration application unless the registration application has been submitted pursuant to Chapter XIII and the medicinal products are to be registered in accordance with a decentralised procedure; and

88.2.2. if in accordance with Sub-paragraph 17.17 of this Regulation the State Agency of Medicines has been notified that the medicinal products, regarding which an application has been submitted to the State Agency of Medicines, are registered in another Member State of the European Economic Area. In such case the State Agency of Medicines shall inform the applicant of the registration application that the conditions referred to in Chapter XIII of this Regulation are applicable in respect of the application of the registration application unless the registration application has been submitted pursuant to Chapter XIII and the medicinal products are to be registered in accordance with a mutual recognition procedure.

89. The State Agency of Medicines shall:

89.1. notify the owner of the registration regarding approval of the summary of the product characteristics after the taking of a decision on the registration of the medicinal products;

89.2. ensure that the information provided in the summary of the product characteristics complies with the approved information and take a decision on the registration of medicinal products (or accordingly a decision on the re-registration or approval of variations, or extension of the registration);

89.3. draw up an assessment report and make comments on the file as regards the results of the pharmaceutical and pre-clinical tests, the clinical trials, the risk management system and the pharmacovigilance system of the medicinal product concerned, as well as prepare public assessment report.. The assessment report shall be updated whenever new information becomes available which is important for the evaluation of the quality, safety or efficacy of the medicinal product concerned. The drawing up of the assessment report shall not apply to homeopathic, anthroposophic herbal and medicinal products which are registered according to simplified registration procedure;

89.4. make the assessment report publicly accessible without delay on the website of the Agency, after deletion of any information in co-operation with the owner of the registration of the medicinal product which the owner of the registration of the medicinal product has classified as restricted access information and which has a commercially confidential nature. The justification shall be provided separately for each indication. The public assessment report shall include a summary written in a manner that is understandable to the public which containa section relating to the conditions of use of the medicinal product.

89.5. take a decision on belonging of the medicinal products to such group of medicinal products, for the use of which a written indication of a medical practitioner is required (prescription medicinal products), or to a group of medicinal products, which may be used without a written indication of a medical practitioner (non-prescription medicinal products).

[18 May 2010; 9 April 2013]

89.1 In addition to the provisions laid down in Paragraph 86 of this Regulation, the State Agency of Medicines in relation to pharmacovigilance is entitled to register medicial product with a condition determining the following obligation for the owner of registration:

89.1 1. to take certain measures for ensuring the safe use of the medicinal product to be included in the risk management system by the applicant of the registration;

89.1 2. to conduct post-registration safety studies for medicinal products in accordance with regulatory enactments on pharmacovigilance procedure;

89.13. to record or report of suspected adverse reactions, if the obligation is stricter than the requirements laid down in the laws and regulations on pharmacovigilance procedure;

89.1 4. to comply with any other conditions or restrictions with regard to the safe and effective use of the medicinal product;

89.15. to ensure the existence of an adequate pharmacovigilance system;

89.1 6. to conduct post-registration efficacy studies where concerns relating to some aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed; or

89.1 7. to submit a safety report by complying with the frequency and date of submission of the safety report laid down in a decision to register the medicinal product.

[9 April 2013]

89.2 The State Agency of Medicines shall include the obligation referred to in Paragraph 89.1 of this Regulation as the obligation to be fulfilled and lay down deadline for the fulfilment thereof where necessary.

[9 April 2013]

90. In exceptional circumstances and following consultation with the applicant of the registration application the State Agency of Medicines is entitled to register medicinal prduct by indicating in a decision the obligation determined for the owner of the registration, particularly as regards the safety of medicinal product, notification to the State Agency of Medicines regarding any incident related to the use of medicinal product and regarding activities that are to be completed. Under such circumstance the medicinals product may be registered only when the applicant of the application can prove that he is unable to provide comprehensive data on the efficacy and safety of the medicinal product under normal conditions of use, for objective, verifiable reasons and it must be based on one of the following grounds:

90.1. indications, for which the relevant medicinal product is intended, are so rare that it cannot be expected that the applicant of the application would provide comprehensive evidence;

90.2. detailed information cannot be provided due to insufficient scientific experience; and

90.3. compiling of such information would be in contradiction with the generally accepted ethical principles of medicine.

[18 May 2010; 9 April 2013]

90.1 In addition to the provisions laid down in Paragraph 90 of this Regulation, the following requirements may be included:

90.11. the applicant of the application shall end the specified research programme, the results of which will be the basis of repeated risk-benefit evaluation, in the term specified by the State Agency of Medicines;

90.12. the relevant medicinal product will be distributed only with a prescription of a medical practitioner, in some cases it may be used only under strict medical supervision, where appropriate, in an outpatient medical treatment institution and under supervision of an authorised person (in respect of radiopharmaceuticals); and

90.13. the package leaflet and medical information shall draw the medical practitioner's attention to the fact that data available regarding the relevant medicinal product are not yet sufficient.

[9 April 2013]

90.2 If in accordance with Paragraph 90 of this Regulation a medicinal product is registered with a condition, it is an obligation of the owner of the registration to submit safety reports complying with the frequency and dates of submission of safety report laid down in a decision to register medicinal product.

[9 April 2013]

90.3 In relation to term for registration of medicinal product the State Agency of Medicines shall review each year the conditions laid down for the owner of the registration referred to in Paragraph 90 of this Regulation.

[9 April 2013]

90.4 After registration of medicinal product, the State Agency of Medicines in conformity with the laws and regulations on pharmacovigilance procedures is entitled to impose an obligation on the owner of registration:

90.41. to conduct a post-registration safety study if there are concerns about the risks of a registered medicinal product. If the same concerns apply to more than one medicinal product, the State Agency of medicines shall, following consultation with the Pharmacovigilance Risk Assessment Committee of the European Medicines Agency (hereinafter - Pharmacovigilance Risk Assessment Committee), encourage the owners of registration of medicinal product concerned to conduct a joint post-registration safety study;

90.42. to conduct a post-registration efficacy study when the understanding of the disease or the clinical methodology indicate that previous efficacy evaluations might have to be revised significantly.

[9 April 2013]

90.5 If the State Agency of Medicines considers that it is necessary to conduct the efficacy studies referred to in Paragraph 90.4 of this Regulation for medicinal product, it shall duly justify an obligation, notifying in writing the owner of registration thereon, and shall include the objectives and timeframe for submission of the results obtained.

[9 April 2013]

90.6 An owner of registration wihin 30 days after the receipt of the written notification referred to in Paragraph 90.5 of this Regulation is entitled to request the State Agency of Medicines to determine a timeframe for the provision of written explanations in relation to the obligation referred to in Paragraph 90.4 of this Regulation.

[9 April 2013]

90.7 After assessment of written explanations of the owner of the registration, the State Agency of Medicines shall take an appropriate decision -to determine for the owner of the registration to conduct the safety and efficacy studies for medicinal product referred to in Paragraph 90.4 of this Regulation or not to conduct them. If the State Agency of Medicines takes a decision on the obligation of the owner of the registration to conduct the safety and efficacy studies for medicinal product referred to in Paragraph 90.4 of this Regulation, it shall make the relevant amendments to the decision to register medicinal product in order to include the referred-to obligation as a condition of the registration.

[9 April 2013]

90.8 An owner of registration shall include the obligations referred to in Paragraphs 89.1, 90 and 90.1 of this Regulation and determined for him or her in the risk management system and update it accordingly.

[9 April 2013]

90.9 An owner of registration shall maintain a pharmacovigilance system master file and ensure post-registration safety studies in accordance with the laws and regulation on pharmacovigilance procedure.

[9 April 2013]

91. The State Agency of Medicines:

91.1. shall publish the conditions that are determined for the owner of the registration in conformity with Paragraphs 89.1, 90 and 90.1 of this Regulation together with the specified time periods of execution and dates of execution on the website of the Agency without delay;

91.2. in taking a decision on re-registration of medicinal products or in case if the medicinal products have been re-registered once and the registration of the medicinal products is left in effect for an unlimited period of time, shall ensure the annual evaluation of fulfilment of the conditions referred to in Paragraph 90 of this Regulation. The results of execution shall be taken into account when taking the decision referred to in Paragraph 10, 93, 94 or 114 of this Regulation;

91.3. in order to ensure regular evaluation of the risk-benefit balance, is entitled to request the owner of a registration at any time to submit to the State Agency of Medicines data confirming that the risk-benefit balance is still favourable;

91.4. in a decision to register medicinal product shall indicate how often the owner of a registration shall submit a safety report. The timeframe for the submission of the safety report shall be determined taking intoaccount the day of coming into effect of the decision;

91.5. is entitled to request the owner of a registration at any time time submit a copy of the pharmacovigilance system master file;

91.6. is entitled to assign the owner of a registration to ensure the operation of the risk management system in respect of any medicinal products, if there are concerns about risk affecting the risk-benefit balance of registered medicinal products. In such case the State Agency of Medicines shall:

91.6.1. request the owner of a registration to submit a detailed description of risk management system which he intended to introduce for the medicinal product concerned;

91.6.2. notify in writing the owner of a registration the timeframe for submission of the detailed description of the risk management system;

91.6.3. determine the owner of a registration the timeframe for provision of written explanation, if the owner of a registration requests such opportunity within 30 days of receipt of the written notification;

91.6.4. on the basis of the written explanation submitted by the owner of a registration, shall decide whether it is necessary to include risk management system measures as a condition for the registration in conformity with Paragraph 89.11 of this Regulation in the decision to register medicinal product. If the State Agency of Medicines considers that it is necessary to include the referred-to condition for the registration, it shall make the relevant amendment to the decision to register medicinal product.

[18 May 2010; 9 April 2013]

91.1 An owner of a registration shall submit a safety report to the State Agency of medicines immediately justified request or in accordance with the following:

91.1 1. where a medicinal product has not yet been placed on the market - at least every six months following granting of authorisation and until the placing on the market;

91.1 2. where a medicinal product has been placed on the market:

91.1 2.1. at least every six months - during the first two years following the initial placing on the market,

91.1 2.2. once a year for the following two years and at thre - yearly intervals thereafter.

[ 9 April 2013]

91.2 Where medicinal products that are subject to different registration certificates of medicinal products contain the same active substance or the same combination of active substances, the frequency and dates of submission of the periodic safety update reports resulting from the application of Paragraph 91.5 of this Regulation may be amended. In order to enable a single assessment to be made in the context of a safety report work-sharing procedure, to determinē harmonised frequency for the submission of the safety reports and in order to determine the reference date in the European Union according to which the dates fo the submission of the safety reports (hereinafter - European Union reference date), the information on changes in respect of the frequency and dates for the submission of the safety reports shall be submitted to the Committee of Medicinal Products or the Co-ordination Group of the European Medicines Agency (hereinafter - Coordination Group) that has been established for examination of issues related to registration of medicinal products (or marketing authorisation of medicinal products) in two or more Member States of the European Economic Area. European Union reference date is one of the following:

91.21. the date of granting of the first registration certificate in the European Union of a medicinal product containing the referred-to active substance or the referred-to combination active substances;

91.22. if the date referred to in Sub-paragraph 91.21 of this Regulation cannot be ascertained, the earliest of the known dates of the registration certificates for a medicinal product containing the referred-to active substance or the referred-to combination active substances.

[ 9 April 2013]

91.3 Owner of registration shall submit safety reports regarding medicinal products of well-established medicinal use, generic medicinal products, homeopathic medicinal products registered according to a simplified procedure and traditional-use herbal medicinal products in the following cases:

91.31. if in a decision to register medicinal product such obligation is set as a condition for the registration that is referred to in Paragraph 89.1 and 90 of this Registration;

91.32. upon a justified request by the State Agency of Medicines if the problems related to pharmacovigilance data are identified, or the safety reports in relation to active substance are not submitted after the registration. Assessment reports regarding the referred-to safety reports shall be submitted to the Pharmacovigilance Risk Assessment Committee which shall assess whether the single assessment referred to in Paragraph 91.2 of this Regulation in respect of safety reports is necessary and shall inform the Coordination Group or the Committee of Medicinal Products which applies the procedure laid down in Paragraph 91.5 of this Regulation or in the laws and regulations on pharmacovigilance accordingly.

[ 9 April 2013]

91.4 An owner of a registration shall lodge a submission to the State Agency of Medicines regarding approval of changes in the application dosier after the European Medicines Agency has published the information referred-to in Paragraph 91.8 of this Regulation.

[ 9 April 2013]

91.5 The harmonised periodicity of submission of the safety reports and the European Union reference date refered to in Paragraph 91.2 of this Regulation after consultation of the Pharmacovigilance Risk Assessment Committee, may be determined by one of the following institutions:

91.51. the Committee of Medicinal Products where at least one of the marketing authorisations for the medicinal products containing the active substance concerned has been granted in accordance with the centralised procedure provided for in Chapter 1 of Title II of Regulation (EC) No 726/2004;

91.52. the Coordination Group - in other cases than those referred to in Paragraph 91.5 of this Regulation.

[ 9 April 2013]

91.6 An owner of a registration shall be allowed to submit a justifed submission to the Committee for Medicinal Products or the Coordination Group, as appropriate, to determine European Union reference dates or to change the frequency of submission safety reports for reasons relating to public health or in order to avoid a duplication of the assessment, or in order to achieve international harmonisation.

[ 9 April 2013]

91.7 The Committee for Medicinal Products or the Coordination Group after consultation with the Pharmacovigilance Risk Assessment Committee shall approve or refuse the submission referred to in Paragraph 91.6 of this Regulation.

[ 9 April 2013]

91.8 The periodicity of submission of safety report and European Union reference date, as well as changes therein shall be published by the Eruopean Medicines Agency.

[ 9 April 2013]

92. If the State Agency of Medicines takes a decision on registration or re-registration of medicinal products, it shall be assigned a registration or re-registration number, and it shall be indicated in the Drug Register of Latvia and the medicinal product registration certificate.

93. The State Agency of Medicines shall take a decision on refusal to register or re-register medicinal products if:

93.1. after evaluation of data and documents it has been detected that:

93.1.1. the risk-benefit balance is not to be regarded as favourable;

93.1.2. the applicant of the registration application has not sufficiently justified the therapeutic efficacy of the medicinal product. The requirements to justify therapeutic efficacy shall not apply to homeopathic medicinal products, which are registered in accordance with a specific, simplified registration procedure; and

93.1.3. the qualitative and quantitative composition of the medicinal product does not conform to the application dossier;

93.2. the data and documents submitted for the justification of the application dossier do not comply with the requirements of this Regulation;

93.3. the medicinal product is to be registered or is registered in accordance with a centralised registration procedure pursuant to Regulation No 726/2004 of the European Parliament and of the Council;

93.4. the registration requester or owner has not submitted the additionally requested documents or data to the State Agency of Medicines and has not explained the reason for his or her action;

93.5. the requirements referred to in Paragraph 13 of this Regulation are not observed.

[18 May 2010]

94. The State Agency of Medicines shall take a decision on refusal to register herbal medicinal products in accordance with a registration procedure of traditionally used medicinal products, if the registration application regarding herbal medicinal products does not comply with the requirements referred to in Paragraphs 13, 56, 57, 60 and 61 of this Regulation or if one of the following criteria is in effect:

94.1. the quantitative and qualitative composition does not comply with the declared one;

94.2. indications do not comply with the conditions indicated in Paragraphs 56 and 57 of this Regulation;

94.3. the product may be harmful in regular conditions of use; and

94.4. data regarding traditional use are insufficient (do not comply with the requirements of this Regulation) particularly if, on the basis of long-term use and experience, the pharmacological effect or efficacy is not credible; or

94.5. the quality of the medicinal product is insufficiently clearly proved.

XIII. Mutual Recognition Procedure and Decentralised Procedure

95. In order to register medicinal products in more than one Member State of the European Economic Area, a registration application in accordance with the sample of the European Commission, which is published on the website of the State Agency of Medicines, shall be submitted to the competent authority of the relevant Member State of the European Economic Area (in Latvia - to the State Agency of Medicines) (hereinafter - participating Member States). Data and documents indicated in the application shall be appended thereto. Application dossier shall comply with the following requirements:

95.1. it shall be identical to the application dossier submitted in other referred to States;

95.2. it shall include information in accordance with Chapters II, III, IV, V, VI and VII of this Regulation;

95.3. it shall indicate the list of participating Member States, in which the registration application has been submitted or in which the medicinal products are registered during application of the application.

[18 May 2010; 9 April 2013]

96. If medicinal products during the application of registration application in the States referred to in Sub-paragraph 95.3 of this Regulation:

96.1. are registered, the medicinal products shall be registered in accordance with a mutual recognition procedure;

96.2. are not registered, but are in the process of registration, the medicinal products shall be registered in accordance with a decentralised procedure.

97. In order for the State Agency of Medicines to register medicinal products in accordance with a mutual recognition procedure:

97.1. an applicant of a registration application (owner of the registration) shall:

97.1.1. indicate, which of the States referred to in Sub-paragraph 95.3 of this Regulation is the reference Member State and which are participating Member States;

97.1.2. request the competent authority of the reference Member State to prepare or to renew (where appropriate) an evaluation report regarding the relevant medicinal products within 90 days after receipt of a registration application drawn up pursuant to the requirements and shall ask to send it together with an approved description, labelling and package leaflet of medicinal products to the applicant of the registration application and the competent authorities of participating States of the European Economic Area;

97.2. if Latvia is a reference Member State, the State Agency of Medicines shall:

97.2.1. prepare an evaluation report regarding the relevant medicinal products requested by the applicant of the registration application or renew it in accordance with the procedures specified in the Administrative Procedure Law, but not later than within a time period of 90 days after receipt of the registration application (which complies with the specified requirements);

97.2.2. send an evaluation report with the approved description, labelling and package leaflet of medicinal products to the applicant of the registration application and to the participating competent authorities of the Member States of the European Economic Area.

98. In order for the State Agency of Medicines to register medicinal products in accordance with a decentralised procedure:

98.1. the applicant of registration application shall:

98.1.1. indicate, which of the States referred to in Sub-paragraph 95.3 of this Regulation are the participating Member States, and shall request one of them to act as the reference Member State;

98.1.2. request the reference Member State to prepare a draft of the evaluation report, description, labelling and package leaflet of the medicinal products regarding medicinal products to be registered and shall ask to send it to the applicant of the registration application and to the participating competent authorities of the Member States of the European Economic Area;

98.2. if Latvia is the reference Member State, the State Agency of Medicines shall prepare the drafts of the documents referred to in Sub-paragraph 98.1.2 of this Regulation in accordance with the procedures specified in the Administrative Procedure Law, but not later than within 120 days after receipt of the registration application drawn up pursuant to the specified requirements at the State Agency of Medicines and shall send it to the applicant of the registration application and to the participating competent authorities of the Member States of the European Economic Area.

99. If Latvia is a participating Member State, the State Agency of Medicines shall approve the evaluation report, the description, text of the labelling and package leaflet of the medicinal products in accordance with the procedures specified in the Administrative Procedure Law, but not later than within 90 days after receipt of the documents referred to in Sub-paragraphs 97.1.2 and 98.1.2 of this Regulation and shall notify the competent authority of the reference Member State regarding it without delay. The reference Member State shall record agreement of all involved parties in the minutes after receipt of information from participating Member States, shall close the procedure and notify the applicant of the registration application regarding it without delay.

100. The State Agency of Medicines shall take a decision on registration of medicinal products in accordance with the procedures specified in the Administrative Procedure Law, but not later than within 30 days after approval of the agreement referred to in Paragraph 99 of this Regulation pursuant to the approved evaluation report, description, and text of the labelling and package leaflet of the medicinal products.

101. If the State Agency of Medicines is not able to approve the evaluation report, description, text of the labelling and package leaflet of the medicinal products in the period of time specified in Paragraph 100 of this Regulation on the basis of potential serious risk to public health, it shall:

101.1. submit a detailed explanation of the position thereof to the reference Member State, participating Member States and the applicant of the registration application;

101.2. submit issues, regarding which agreement has not been reached, for examination to the Co-ordination Group.

[9 April 2013]

102. If the relevant participating Member States within 60 days after application of issues (in which agreement has not been reached) to the Co-ordination Group:

102.1. reach agreement and Latvia is:

102.1.1. the reference Member State, the State Agency of Medicines shall record the agreement of all the involved parties in the minutes, shall close the procedure and notify regarding it the applicant of the registration application accordingly;

102.1.2. the participating Member State, the State Agency of Medicines shall ensure the fulfilment of Sub-paragraph 102.1.1 of this Regulation;

102.2. do not reach agreement and Latvia is the reference Member State, the State Agency of Medicines shall:

102.2.1. inform the European Medicines Agency about it without delay so that it could commence arbitration procedure in accordance with Paragraph 108 of this Regulation;

102.2.2. submit to the European Medicines Agency a detailed notification, specifying the issues, regarding which the relevant participating Member States have not reached agreement, and the reasons. A copy of the notification shall be issued to the applicant of the registration application.

103. The applicant of the registration application:

103.1. is entitled to address the Co-ordination Group in order to express his or her opinion in oral and written form;

103.2. after receipt of the notification referred to in Sub-paragraph 102.2.2 of this Regulation, shall submit to the European Medicines Agency copies of the documents referred to in Paragraph 95 of this Regulation.

104. If the State Agency of Medicines has approved the draft of the evaluation report, description, text of the labelling and package leaflet of the medicinal products, but participating Member States have not reached an agreement in the Co-ordination Group, the State Agency of Medicines is entitled to register the medicinal products upon the request of the applicant of the registration application, without waiting for a statement of the Committee for Medicinal Products as the result of the procedure referred to in Paragraph 108 of this Regulation. The decision shall not be restricted in relation to the result of the referred to procedure.

[9 April 2013]

105. The State Agency of Medicines (Member States and the European Commission), the applicant of the registration application or the owner of the registration is entitled to submit a case for consideration at the Committee for Medicinal Products so that it could commence the procedure referred to in Paragraph 108 of this Regulation, if the following conditions are in effect concurrently:

105.1. two or more registration applications have been submitted regarding the particular medicinal products in participating Member States; and

105.2. the participating Member States have taken different decisions on the registration of the medicinal products, suspension or cancellation thereof.

106. The State Agency of Medicines (as well as other participating Member States and the European Commission) is entitled to:

106.1. send the Co-ordination Group every year a list of such medicinal products, for which a harmonised summary of product characteristics is needed to be drawn up in order to promote harmonisation of the registration of medicinal products in the European Economic Area; and

106.2. to submit the case for consideration at the Committee for Medicinal Products pursuant to Paragraph 105 of this Regulation after agreement with the European Medicines Agency, taking into account the opinions of concerned parties.

107. Where the interests of the European Union are concerned, prior to any decision to register medicinal product, to suspend registration, to cance registration and any other variations in relation to approval of necessary variations or extension of registration, the State Agency of Medicines, the applicant of the registration application or the owner of the registration is entitled to refer with such matter to the Committee for Medicinal Products:

107.1. the applicant of the registration application or the owner of the registration shall submit to the Committee for Medicinal Products all available information related to the particular issue; and

107.2. in order to commence the procedure referred to in Paragraph 108 of this Regulation, the State Agency of Medicines shall:

107.2.1. submit all available information related to the referred to clearly identified issue for consideration of the case at the Committee for Medicinal Products. If transfer of the case for consideration at the Committee for Medicinal Products applies to a range or groups of medicinal products or therapy, it shall be taken into account that the European Medicines Agency may limit the procedure to a few specific parts of the permit; and

107.2.2. notify the applicant of the registration application or the owner of the registration regarding application of the case to the Committee for Medicinal Products.

[9 April 2013]

107.1 Where the the basis of request is evaluation of data relating to pharmacovigilance of registered medicinal product, the State Agency of Medicines, the applicant of the registration application or the owner of the registration shall refer the matter to the Pharmacovigilance Risk Assessment Committee for examination. Where urgent action is considered necessary the urgent procedure relating to safety of medicinal products shall apply in accordance with the the laws and regulations on pharmacovigilance procedure.

[9 April 2013]

107.2 Where the referral to the Committee for Medicinal Products concerns a range of medicinal products or a therapeutic class, the European Medicines Agency may limit the procedure to certain specific parts of the authorisation. In that event, the norm referred to in Paragraph 109 of this Regulation shall apply to those medicinal products only if they were covered by the authorisation procedures referred to in this Chapter.

[3 September 2013]

107.3 Where the scope of the procedure initiated under this Paragraphs 107 and 1071 of this Regulation concerns a range of medicinal products or a therapeutic class, the medicinal products registered in accordance with European Parliament and Council Regulation No 726/2004 and which belong to that range or class shall also be included in the procedure.

[3 September 2013]

107.4 The State Agency of Medicines may, where urgent action is necessary to protect public health at any stage of the procedure, suspend the registration of medicinal product and prohibit the use of the medicinal product concerned in Latvia until a definitive decision is adopted. After such action the State Agency of Medicines shall inform the European Commission, the European Medicines Agency and competent institutions of the Member States of the European Economic Area, no later than the following working day, of the reasons for its action.

[3 September 2013]

107.5 Where the scope of the procedure initiated under Paragraphs 107, 107.1, 107.2, 107.3 and 107.4 of this Regulation, includes medicinal products registered under centralised registration procedure of medicinal products in accordance with the European Parliament and Council Regulation (EC) No 726/2004, it shall be taken into account that the European Commission may, where urgent action is necessary to protect public health, at any stage of the procedure, suspend the registration certificate and prohibit the use of the medicinal products concerned until a definitive decision is adopted and shall inform the European Medicines Agency and competent institutions of the Member States of the European Economic Area no later than the following working day of the reasons for its action.';

[3 September 2013]

108. The applicant of the registration application or the owner of the registration and the State Agency of Medicines shall take into account that:

108.1. the Committee for Medicinal Products:

108.1.1. shall examine the relevant issue and provide a justified statement within 60 days after receipt of the case. If the case is urgent, the referred to period of time may be extended up to 90 days, taking into account the opinion of the applicant of the registration application or the owner of the registration, as well as an agreement may be reached regarding a shorter term, which is justified by a proposal of the chairperson of the Committee for Medicinal Products;

108.1.2. may appoint a rapporteur (one of members of the Committee for Medicinal Products) and independent experts for examination of the case in order to receive their consultations on specific issues. In appointing experts, the Committee for Medicinal Products shall define their tasks and specify the time period for the completion of such tasks;

108.1.3. prior to provision of an opinion shall give the applicant of the registration application or the owner of the registration an opportunity to provide a written or oral explanation in the period of time specified thereby. A draft of the summary of the summary of the product characteristics, version of the text of labelling and package leaflet thereof shall be appended to the opinion. Where necessary, other persons may also be invited to provide information regarding the relevant issue; and

108.1.4. the period of time referred to in Sub-paragraph 108.1.1 of this Regulation may be suspended, allowing the applicant to prepare explanations;

108.2. the European Medicines Agency:

108.2.1. shall inform the relevant applicant of the registration application or the owner of the registration without delay, if the opinion of the Committee for Medicinal Products contains one of the following conclusions:

108.2.1.1. the application does not comply with the criteria for granting registration;

108.2.1.2. amendments suggested by the applicant must be made to the summary of product characteristics;

108.2.1.3. the medicinal products are registered pursuant to several conditions, taking into account conditions, which are substantial for the safe and efficient use of medicinal products, including pharmacovigilance; and

108.2.1.4. registration must be suspended, changed or cancelled; and

108.2.2. within 15 days after receipt of the final opinion of the Committee for Medicinal Products, the following shall be sent to Member States, the European Commission and the applicant of registration application or the owner of registration:

108.2.2.1. the opinion together with a report, in which the evaluation of the medicinal products is described and justification of the opinion is provided. If the opinion is favourable for the registration (for issuance of a permit for putting on the market) or preservation of the relevant medicinal products, the following documents shall be appended to the opinion:

108.2.2.1.1. the draft of the summary of the product characteristics (Paragraph 21); and

108.2.2.1.2. any conditions affecting the granting of the permit within the meaning of Sub-paragraph 108.2.1.3 of this Regulation;

108.2.2.2. detailed information regarding any conditions or restrictions, which are recommended on the basis of the safe and efficient use of the medicinal products;

108.2.2.3. the suggested revision of the text for the labelling and package leaflet; and

108.2.2.4. a report, in which the evaluation of the medicinal products is described and justification of opinions is provided;

108.3. the applicant of the registration application or the owner of the registration is entitled to notify the European Medicines Agency regarding the intent to request a repeated revision of the statement of the Committee for Medicinal Products in writing within 15 days after receipt of the statement of the Committee for Medicinal Products and send a justified request to the European Medicines Agency within 60 days after receipt of the statement;

108.4. the Committee for Medicinal Products, within 60 days after receipt of a justified request, shall re-evaluate the provided statement in accordance with Article 62(1)(4) of Regulation No 726/2004 of the European Parliament and of the Council and shall append the arguments referred to in the statement to the evaluation report referred to in Sub-paragraph 108.2.2.1 of this Regulation

108.5. the European Commission:

108.5.1. within 15 days after receipt of the statement referred to in Sub-paragraph 108.2.2.1 of this Regulation, shall prepare a draft of such decision, which should be taken in respect of the application, taking into account legal acts of the European Union;

108.5.2. if the draft decision intends registration of the medicinal products (granting of a sales permit), the documents referred to in Sub-paragraph 108.2.2 of this Regulation shall be appended thereto;

108.5.3. if in an exceptional case the draft decision does not comply with the statement of the European Medicines Agency, the European Commission shall append thereto a detailed explanation regarding the reasons of differences;

108.5.4. the draft decision shall be sent to the competent authority of a Member State (in Latvia - to the State Agency of Medicines) and to the applicant of the registration application or the owner of the registration; and

108.5.5. in accordance with the procedure shall take the final decision, the execution of which shall be ensured by the Standing Committee of the European Commission (hereinafter - Standing Committee) within 15 days after termination of the procedure). The procedure of the Standing Committee shall include the following conditions:

108.5.5.1. the statement of the Standing Committee shall be provided in writing, except for the case referred to in Sub-paragraph 108.3.3 of this Regulation;

108.5.5.2. the competent authority (in Latvia - the State Agency of Medicines) shall send to the European Commission written considerations regarding the draft decision of the European Commission within 22 days. If a decision must be taken as a matter of urgency, the referred to considerations shall be sent to the European Commission in a specified shorter period of time, which is not shorter than 5 days, unless it is requested due to exceptional circumstances; and

108.5.5.3. the competent authority (in Latvia - the State Agency of Medicines) is entitled to submit a written request regarding examination of the referred to draft decision in a plenary meeting of the Standing Committee;

108.6. if after the statement of the European Commission the written considerations of the competent authority (in Latvia - the State Agency of Medicines) produce new significant scientific and technological issues, which are not viewed in the statement provided by the European Medicines Agency, the Chairperson of the Standing Committee shall stop the procedure and send the application back to the European Medicines Agency for repeated examination;

108.7. the decision of the European Commission shall be addressed to all Member States and shall be notified to the owner of the registration or the applicant of the registration application for informational purposes; and

108.8. within 30 days after receipt of the decision of the European Commission, the State Agency of Medicines (the relevant Member State) and the competent authority of the reference Member State shall take a decision on registration of the medicinal products or cancellation of the registration or, where necessary, on amendments to the application dossier (conditions) in order to execute the decision of the European Commission, and shall notify the European Commission and the European Medicines Agency regarding it.

108.9. the Coordination Group

108.9.1. shall review the matters related to marketing authorisations of medicinal products in two or several Member States;

108.9.2 the matters related to pharmacovigilance of medicinal products permitted by the Member States;

108.9.3. the matters related to variations to medicinal products registered in the Member States of the European Union;

108.9.4. shall carry out the pharmacovigilance tasks, including approce risk management systems and supervise efficacy thereof on the basis of scientific assessment and guidelines provided by Pharmacovigilance Risk Assessment Committee referred to in Article 56 (1) (aa) of the European Parliament and Council Regulation No 726/2004.

108.10.Where the scope of the procedure initiated under Paragraphs 107, 107.1 and 197.2 of this Regulation includes medicinal products registered in accordance with the European Parliament and Council Regulation (EC) No 726/2004, the Commission shall, where necessary, adopt decisions to vary, suspend or revoke the registration of the medicinal products or to refuse the renewal of the registration of the medicinal products.

[9 April 2013; 3 September 2013]

109. The owner of the registration shall submit all applications regarding variations in application dossier of the medicinal products in relation to medicinal products, which are registered in accordance with this Regulation, to all competent authorities (in Latvia - to the State Agency of Medicines), which have registered the relevant medicinal products pursuant to Commission Regulation No 1234/2008. If an arbitrary claim regarding the alterations made is submitted to the European Commission, the procedure described in Paragraph 108 of this Regulation shall be applied.

[18 May 2010]

110. [9 April 2013]

[9 April 2013]

111. The mutual recognition procedure and decentralised procedure shall not be applied to registration applications regarding:

111.1. homeopathic medicinal products, to which the following shall be applied:

111.1.1. Paragraph 51 of this Regulation;

111.1.2. the norm referred to in Paragraph 54 of this Regulation;

111.2. traditional herbal medicinal products, which are registered in accordance with a simplified registration procedure and regarding which the monograph referred to in Sub-paragraph 63.2 of this Regulation is not drawn up or which are not included on the list referred to in Sub-paragraph 58.2 of this Regulation.

XIV. Supervision and Sanctions

112. The State Agency of Medicines:

112.1. shall carry out activities in order to ensure that the owner of registration and the manufacturer of medicinal products (if the owner of registration is not the manufacturer of medicinal products) provides certification regarding conducted control of the medicinal products, ingredients thereof and control of the intermediate stages of the manufacturing process (Sub-paragraph 17.9 of this Regulation);

112.2. is entitled to request that manufacturers of immunological preparations submit to the State Agency of Medicines copies of all the control reports, which are signed by the qualified person.

[18 May 2010]

112.1 The Ministry of Health after consultations with the State Agency of Medicines shall assign a representative for work in the Coordination Group and his or her substitute (hereinafter - representative). A representative is entitled to invite experts. The State Agency of Medicines shall facilitate, as well as supervise the activity of the representative and experts and the scientific level of the assessment performed.

[9 April 2013]

113. Urgent restrictions related to safety:

113.1. may be specified by the State Agency of Medicines;

113.2. may be specified by the owner of the registration, if risk to public health arises. In such case the owner of the registration shall inform the State Agency of Medicines regarding it without delay. If the State Agency of Medicines has not expressed objections within 24 hours after receipt of the referred to information, the urgent restrictions related to safety shall be regarded as recognised; and

113.3. shall be implemented by the owner of the registration (in order to fulfil the requirements referred to in Sub-paragraphs 113.1 and 113.2 of this Regulation):

113.3.1. within the time period, regarding which the owner of the registration agrees with the State Agency of Medicines; and

113.3.2. shall submit to the State Agency of Medicines an application regarding approval of variations to the application dossier pursuant to the specified urgent restrictions related to safety not later than within 15 days after commencement of the restrictions related to safety.

114. The State Agency of Medicines:

114.1. shall take a decision to suspend or revoke registration or re-registration of medicinal product or to vary registration of medicinal product on the basis of the following considerations:

114.1.1. the view is taken that the medicinal product is harmful ;

114.1.2. the medicinal product lacks therapeutic efficacy (therapeutic results cannot be obtained from the medicinal product) or the risk-benefit balance is not favourable. The requirement of justification of therapeutic efficacy shall not be applicable to homeopathic medicinal products that are registered in accordance with the simplified registration procedure;

114.1.3. the qualitative and quantitative composition of the medicinal product does not comply with that specified in the application dossier;

114.1.4. an application to revoke or suspend registration has been received from the owner of registration;

114.2. is entitled to take a decision to suspend or revoke registration or re-registration of medicinal product or to vary registration of medicinal product taking into account the following reasons:

114.2.1. the data indicated in relation to the registration or re-registration application are incorrect or incomplete or are not amended in accordance with Sub-paragraphs 120.4.1 and 120.4.2 of this Regulation, or the control of medicinal product or ingredients thereof referred to in Paragraph 112.1 of this Regulation is not conducted;

14.2.2. the responsibilities laid down for the owner of registration and which are referred to in Paragraphs 89.1, 90 and 90.5 of this Regulation are not complied with;

14.2.3. the medicinal product has not been manufactured in conformity with the description of manufacture method or control is not carried out in conformity with the description of control methods referred to in Paragraph 17.9 of this Regulation.

[18 May 2010; 9 April 2013; 3 September 2013]

114.1 The decision referred to in Paragraph 114 of this Regulation shall come into effect on the day of taking thereof.

[18 May 2010]

115. The State Agency of Medicines shall take a decision on suspension or cancellation of the registration of medicinal products for a category of preparations or all preparations, if any of the requirements specified in the regulatory enactments regarding the manufacture and control of medicinal products is not being fulfilled or is not in effect in order to obtain a special permit (licence) for the manufacture of medicinal products.

116. If a herbal medicinal product, a preparation or a combination thereof is no longer included on the list referred to in Sub-paragraph 58.2 of this Regulation (deleted from the list), the State Agency of Medicines shall take a decision on cancellation of the registration of the medicinal products for such herbal medicinal products, which contain the referred to substances and preparations unless the data and documents referred to in Sub-paragraph 61.3 of this Regulation are submitted within 3 months.

117. The State Agency of Medicines has the right to take a decision on urgent suspension of the registration of medicinal products on the basis of the results of evaluation of data as regards monitoring of the adverse effects of medicinal products. In such case the State Agency of Medicines shall inform the European Medicines Agency, the European Commission and other Member States not later than on the next working day.

118. The State Agency of Medicines shall take a decision to withdraw the decision referred to in Paragraph 114 of this Regulation on suspension of registration or re-registration of medicinal products, if conditions, which were the basis for taking of the decision, have been eliminated.

[18 May 2010]

119. Registration of medicinal products shall be refused, suspended or cancelled only in accordance with the justification specified in the Pharmaceutical Law and this Regulation.

120. The owner of a registration shall:

120.1. be responsible for promotion of the medicinal products on the market and shall not be released from liabilities. The owner of a registration may appoint a person (local representative of the owner of a registration) so that he or she could represent him or her in the relevant Member State;

120.2. be legally located in the European Economic Area (registered firm, central administration or actual location of operation); and

120.3. pay the State Agency of Medicines the expenditure in accordance with Paragraph 85 of this Regulation; and

120.4. after the State Agency of Medicines has taken a decision on registration of medicinal products:

120.4.1. in respect of the methods of manufacture and control provided for in Sub-paragraphs 17.5 and 17.9 of this Regulation, take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods. The referred-to changes shall be subject to the approval of the State Agency of Medicines;

120.4.2. shall forthwith provide the State Agency of Medicines with any new information which might entail the amendment of the application dosier, as well as notify of any prohibition or restriction imposed by the competent authorities of any country in which the medicinal product is marketed and of any other new information which might influence the evaluation of the benefits and risks of the medicinal product concerned. The information shall include both positive and negative results of clinical trials or other studies in all indications and populations, whether or not included in the application dosier,approved by the State Agency of Medicines, as well as data on the use of the medicinal product where such data is outside the terms of the description of the medicinal product;

120.4.3. if the owner of the registration is not the manufacturer of the medicinal products, he or she shall sign a written agreement with the manufacturer in order to guarantee that manufacturing operations comply with regulatory enactments and the manufacturing conditions indicated in the application dossier;

120.4.4. he or she shall ensure that there is a scientific service, which supervises scientific information regarding the relevant medicinal products;

120.4.5. [21 August 2007].

120.4.6. shall ensure that the medicinal product information is kept up to date with the current scientific knowledge, including the conclusions of the assessment and recommendations made public by means of the European Medicines Agency web-poetal (established in accordance with Article 26 of European Parliament and Council Regulation No 726/2004);

120.4.7. shall provide complete information to the State Agency of Medicines without delay in conformity with Sub-paragraph 91.2 of this Regulation;

120.4.8. shall submit a copy of the pharmacovigilance system master file referred to in Sub-paragraph 91.5 of this Regulation to the State agency of Medicines within seven days after receipt of the request;

120.5. be obliged to notify the State Agency of Medicines forthwith of any action taken by the owner in Latvia to request the withdrawal of a registration of medicinal product or not to apply for the renewal of a registration, whether any of the criteria referred to in Paragraph 114 of this Regulation are the reasons for such action. The owner of the registration shall in particular declare if such action is carried out in a third country and based on any of the criteria set out in Sub-paragraphs 114.1.1, 114.1.2, 114.1.3 or 114.2 of this Regulation. If such action is justified by any of the criteria set out in Sub-paragraphs 114.1.1, 114.1.2, 114.1.3 or 114.2 of this Regulation, the owner of the registration shall notify the European Medicines Agency.

[21 August 2007; 18 May 2010; 9 April 2013; 3 September 2013]

121. An applicant of a registration application or an owner of a registration shall be responsible for the accuracy of the documents and data submitted and veracity of the information provided.

122. The State Agency of Medicines shall:

122.1. place the decision taken on registration (including supplementary application of the registration application), re-registration, approval of variations, cancellation and suspension (also cancellation of the suspension) of registration (re-registration) of medicinal products and the procedures of commissions established by the State Agency of Medicines on the website of the State Agency of Medicines;

122.2. be responsible and fulfil all the possible procedures in order to ensure that officials and employees who are responsible and are involved in the taking of decisions in relation to the registration and monitoring of medicinal products, developers (rapporteurs) of reports and experts are not financially or otherwise interested in the field of pharmacy and their impartiality is not influenced. The referred to persons, in entering into a contract with the State Agency of Medicines regarding the fulfilment of the particular work, shall submit to the State Agency of Medicines an annual declaration, the sample of which shall be appended to the employment contract;

122.3. make public the procedures, including the procedures, agenda and protocols of the meetings of committees (commissions) together with the decisions taken, results of voting and explanation of voting, including also a minority opinion;

122.4. notify the National Health Service and the Health Inspectorate regarding the decisions taken that are referred to in Paragraphs 9, 11, 14, 114 and 118 of this Regulation and decisions that have been become invalid in accordance with Paragraph 125 of this Regulation;

122.5. without delay notify the Health Inspectorate regarding a decision on cancellation or suspension of the registration of medicinal products;

122.6. ensure that:

122.6.1. the European Medicines Agency receives information regarding:

122.6.1.1. decisions on registration (in accordance with a mutual recognition procedure), refusal, cancellation of registration, as well as refusal or withdrawal of a cancellation of medicinal products together with the reasons for justification of the decision; and

122.6.1.2. notifications provided by the owner of the registration of medicinal products to the State Agency of Medicines as regards any activity performed in order to discontinue distribution of medicinal products or withdraw medicinal products from the market, together with a justification of the relevant activity, if it applies to the effect of the medicinal products or protection of public health;

122.6.2. the World Health Organisation receives the relevant information regarding the activity, which is commenced in accordance with Sub-paragraph 122.6.1 of this Regulation and which may influence the protection of public health in the third countries; and

122.6.3. the European Commission and any competent authority receives upon a request information regarding any decision taken as regards refusal of registration of herbal medicinal products in accordance with a simplified registration procedure and the reasons of such a decision;

122.7. publish the sample of the application for the registration (including extension of registration), re-registration or approval of variations of medicinal products (Paragraphs 16, 49, 61, 65, 67 and 84) on the website in Latvian;

122.8. issue a registration certificate of medicinal prducts or a duplicate thereof in a paper form and upon request - in electronic form; and

122.9. carry out tasks inteded for a competent authority in conformity with the requirements laid down in the Implementing Regulation No 198/2013.

[18 May 2010; 9 April 2013; 3 September 2013]

123. Decisions, which are taken by the State Agency of Medicines in accordance with this Regulation, shall not influence the civil legal and criminal law liability of a manufacturer and - accordingly, an owner of a registration and a distributor.

[28 July 2008]

124. Registration owners, manufacturers of medicinal products, medical practitioners (medical treatment institution) and officials and employees of the State Agency of Medicines shall not be subject to civil legal, criminal or administrative liability for any consequences caused by the administration of medicinal products, which is different from the one anticipated for the registered indications of the medicinal products. The referred to specification shall apply both to medicinal products, which are registered in accordance with Regulation No 726/2004 of the European Parliament and of the Council, and to medicinal products, which pursuant to regulatory enactments are registered in accordance with the national registration procedure, including the mutual recognition or decentralised procedure.

125. A decision of the State Agency of Medicines on registration of medicinal products shall cease to be in effect if:

125.1. the medicinal products are not placed on the market of the Republic of Latvia within three years after taking of the decision on registration of the relevant medicinal products. The referred to shall not apply to the case, if at least one sales packaging of pharmaceutical form is in distribution in Latvia;

125.2. the registered medicinal products, which have been previously placed on the market in the Republic of Latvia, are not actually sold for three consecutive years;

125.3. the owner of registration has notified the State Agency of Medicines regarding discontinuation of distribution of the medicinal products in the Republic of Latvia;

125.4. a decision on refusal of re-registration has come into effect.

[18 May 2010]

125.1 The State Agency of Medicines is entitled to take a decision not to apply the norm referred to in Sub-paragraphs 125.1 and 125.2 of this Regulation for a period of time from one year to three years taking into account the application of the owner of registration that is substantiated by considerations of the protection of public health (Annex 9).

[18 May 2010]

125.2 The owner of registration shall submit the application referred to in Paragraph 125.1 of this Regulation to the State Agency of Medicines not later than three months before the end of the term referred to in Sub-paragraphs 125.1 and 125.2 of this Regulation.

[18 May 2010]

125.3 The State Agency of Medicines shall, within 30 days after receipt of the application referred to in Paragraph 125.1 of this Regulation, evaluate the substantiation referred to in the application in accordance with the procedures specified in the Administrative Procedure Law and take a decision on application or non-application of the norm referred to in Sub-paragraph 125.1 or 125.2 of this Regulation and inform the owner of registration thereof. The State Agency of Medicines shall publish information regarding the referred to decision on the website without delay.

[18 May 2010; 9 April 2013]

126. The State Agency of Medicines and the Health Inspectorate according to the competence thereof shall ensure quick mutual exchange of information in order to ensure the fulfilment of the requirements of this Regulation.

[28 July 2008]

127. In order to provide the opinion referred to in Paragraph 6 of this Regulation, the State Agency of Medicines is entitled to request the following data and documents from the manufacturer, the distributor of the product or authorised persons thereof for the evaluation of the product:

127.1. the firm name, registration number in the Register of Enterprises and address of the manufacturer and the distributor (distributors);

127.2. the product name, components and quantity(-ies) thereof in units of mass or volume in one packaging unit;

127.3. the normative technical documentation or description of the product approved by the manufacturer specifying the characteristics, formulation, specific ingredients of the product and the quantity thereof;

127.4. the recommended daily dose;

127.5. the type and size of packaging;

127.6. the text of the labelling;

127.7. a sample of the package leaflet; and

127.8. other informative materials regarding the product to be evaluated.

[18 May 2010]

127.1 When evaluating the characteristics of the product, the State Agency of Medicines shall take into account:

127.11. the qualitative and quantitative composition of the product;

127.12. the pharmacological, immunological and metabolic properties insofar as it may be ascertained in accordance with the latest scientific findings;

127.13. the type of use of the product, as well as the fact whether a product similar by the composition has been registered as the medicinal product;

127.14. information regarding the product (for example, labelling, package leaflet);

127.15. identification of the product by consumers;

127.16. risks that may be caused by use of the product.

[18 May 2010]

127.2 The State Agency of Medicines shall evaluate a product and issue the opinion referred to in Paragraph 6 of this Regulation to the requester ensuring the evaluation of data and documents within two months after receipt of the information referred to in Paragraph 127 of this Regulation.

[18 May 2010]

127.3 The State Agency of Medicines shall, not later than a day following the provision of the opinion referred to in Paragraph 6 of this Regulation, send information regarding the opinion in the form of electronic documents:

127.31. to the Health Inspectorate;

127.32. to the Food and Veterinary Service, if the opinion is provided upon the initiative of the Food and Veterinary Service;

127.33. to the State Environmental Inspection, if the opinion is provided upon the initiative of the State Environmental Inspection.

[18 May 2010]

128. [18 May 2010]

129. [18 May 2010]

XV. Closing Provisions

130. Cabinet Regulation No. 381 of 31 October 2000, Regulations for Registration of Medicinal Products (Latvijas Vēstnesis, 2000, No. 391/393; 2003, No. 116; 2004, No. 69) is repealed.

131. The requirements referred to in Paragraph 53 of this Regulation shall not apply to such homeopathic medicinal products, which are registered in the European Economic Area until 31 December 1993.

132. The requirement referred to in Sub-paragraph 61.3 of this Regulation as regards usage of the product in medicine for at least 15 years in the European Economic Area shall also be applicable to the States, which joined the European Union on 1 May 2004.

133. The requirement referred to in Sub-paragraph 65.2 of this Regulation shall also be applicable to high technology medicinal products, which the Committee for Medicinal Products of the European Medicines Agency has allowed until 1 January 1995.

134. Paragraphs 109 and 110 of this Regulation shall be applied by analogy to medicinal products, which Member States have allowed, taking into account the statement regarding high technology medicinal products, which the Committee for Medicinal Products of the European Agency for the Evaluation of Medicinal Products has issued until 1 January 1995.

135. The safety reports shall be submitted:

135.1. in accordance with the regulatory enactments regarding the procedures for monitoring of adverse effects caused by the administration of medicinal products for medicinal products, which were registered until 30 October 2005;

135.2. together with an application for the next re-registration for the medicinal products, which were re-registered until 30 October 2005; and

135.3. every three years after taking of a decision on re-registration of medicinal products for medicinal products, which were re-registered after 30 October 2005.

[9 April 2013]

135.1 The norm referred to in Paragraph 91.1 of this Regulation for owners of the registration the medicinal products of which have been registered before 21 July 2012, and for which the frequency and dates of submission of the safety reports are not laid down as a condition for the registration, except for the case when another frequency or other dates of submission of the safety reports, or periodicity of submission of the safety reports is harmonised and a European Union date is set from which the dates for submission of the safety reports are calculated in accordance with Paragraph 91.5 of this Regulation.

135.2 The norm referred to in Paragraph 91.1 of this Regulation shall be applied to the medicinal products registered in accordance with the national registration procedure (other than mutual recognition or decentralised procedure) in respect of which the norm referred to in Paragraph 91.2 and 91.5 of this Regulations is not applied.

[9 April 2013]

135.3 Any change to the dates and frequency of submission of the safety reports that are indicated in a decision to register medicinal products, in applying the norm referred to in Paragraphs 91.2, 91.5, 91.6 and 91.7 of this Regulation, shall take effect six motnhs after the date when the European Medicines Agency has made public the harmonised periodicity of submission of the safety reports and the date set by the European Union or the relevant changes.

[9 April 2013]

136. Registration certificates of medicinal products issued by the State Agency of Medicines until the day of coming into force of this Regulation shall be valid until the end of the term of validity indicated therein, except the case referred to in Paragraph 125 of this Regulation.

[18 May 2010]

137. The State Agency of Medicines shall apply the requirements referred to in this Regulation for herbal medicinal products which comply with the criteria referred to in Paragraph 56 of this Regulation and which have already been on the market since 30 April 2004.

[24 May 2011]

138. [3 November 2009]

139. A protection period of 10 years provided for in Paragraph 28 of this Regulation shall not be applied to reference medicinal products in respect of which the registration application has been submitted until 30 October 2005. If the registration application in relation to Chapter III of this Regulation, indicating reference medicinal products, has been submitted until 30 October 2005, the generic medicinal products may not differ significantly from the reference medicinal products, which are registered in a Member State of the European Economic Area for at least six years. As regards the reference medicinal products registered in accordance with centralised registration procedure Regulation (EC) No 726/2004 shall be applied.

[9 April 2013]

140. When lodging the application referred to in Paragraphs 16, 49, 61, 65, 84, 95 and 125.1 of this Regulation and data and documents attached thereto (application dossier) in the form of electronic document, it shall be prepared in compliance with the regulatory enactments regarding drawing up of the electronic documents. If initially the documentation was submitted in the form of electronic document, the application dossier referred to in Paragraphs 16, 49, 61, 65, 84 and 95 of this Regulation may be submitted electronically in accordance with Sub-paragraph 23.1 of this Regulation.

[18 May 2010]

141. Valid notifications that are specified by Article 5 of Commission Regulation No 1084/2003 and applications regarding variations in respect of the medicinal products registered in accordance with the mutual recognition procedure and decentralised procedure, which have been lodged in accordance with Chapter XIII of this Regulation until 1 January 2010, shall be examined in compliance with Article 27(2) of Commission Regulation No 1234/2008.

[18 May 2010]

142. Chapter IX, Paragraphs 76, 77, 78, 79, 80, 81 and Annexes 7 and 8 to this Regulation may be applied in respect of applications regarding variations in medicinal products registered in accordance with the national registration procedure (that are not registered in accordance with the mutual recognition procedure or decentralised procedure) or notifications that have been submitted to the State Agency of Medicines and regarding which the decision referred to in Paragraph 11 of this Regulation has not been taken by 20 January 2011.

[1 November 2010]

143. Owners of registration whose medicinal products have been registered until 21 July 2012 shall not ensure the operation of a risk management system for all registered medicinal products, except for the case referred to in Sub-paragraph 91.6 of this Regulation.

[9 April 2013]

Informative Reference to European Union Directives

This Regulation contain legal norms arising from:

1) Directive 2009/35/EC of the European Parliament and of the Council of 23 April 2009 on the colouring matters which may be added to medicinal products;

2) Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use;

3) Commission Directive 2003/63/EC of 25 July 2003 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use;

4) Directive 2004/24/EC of the European Parliament and of the Council of 31 March 2004 amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use;

5) Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use;

6) Commission Directive 2009/120/EC of 14 September 2009 amending Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use as regards advanced therapy medicinal products; and

7) Directive 2009/53/EC of the European Parliament and of the Council of 18 June 2009 amending Directive 2001/82/EC and Directive 2001/83/EC, as regards variations to the terms of marketing authorisations for medicinal products;

8) Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use;

9) Directive 2011/62/EU of the European Parliament and of the Council of 8 June 2011 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use, as regards the prevention of the entry into the legal supply chain of falsified medicinal products;

10) Directive 2012/26/EU of the European Parliament and of the Council

of 25 October 2012 amending Directive 2001/83/EC as regards pharmacovigilance.

[18 May 2010; 29 June 2010; 1 November 2010; 9 April 2013; 3 September 2013]

Prime Minister A. Kalvītis

Acting for the Minister for Health,
Minister for Culture H. Demakova

 

[18 May 2010; 9 April 2013]

Annex 1
Cabinet Regulation No. 376
9 May 2006

LATVIJAS REPUBLIKA

 

REPUBLIC OF LATVIA

ZĀĻU VALSTS AĢENTŪRA

 

STATE AGENCY OF MEDICINES

 

(adrese, reģistrācijas numurs, tālruņa, faksa numurs)

 

(address, registration number, phone, fax number)

ZĀĻU REĢISTRĀCIJAS APLIECĪBA MARKETING AUTHORIZATION OF THE MEDICINAL PRODUCT

Rīgā/Rīga

Nr./No._____

Zāļu nosaukums, stiprums, zāļu forma
Name of the medicinal product, strength, pharmaceutical form
Aktīvās vielas nosaukums
Name of active substance
Informācija par iepakojumu
Package information
Reģistrācijas apliecības īpašnieks
Marketing authorization holder
Lēmums reģistrēt/pārreģistrēt zāles
Decision on authorization/renewal
Spēkā līdz
Valid until
Lēmums apstiprināt izmaiņas
Decision on variation approval
Zāļu valsts aģentūras atbildīgā amatpersona
Responsible official of the State Agency of Medicines

(paraksts)
(signature)

(amats, vārds, uzvārds)
(position, name, surname)

Z.v.
Seal

Datums___________________
Date

Note. The detail of the document "Signature" shall not be completed if the electronic document has been drafted in compliance with the laws and regulations regarding the drawing up of electronic documents.

Acting for the Minister for Health,
Minister for Culture H. Demakova

 

Annex 2
Cabinet Regulation No. 376
9 May 2006

[18 May 2010]

 

[28 July 2008; 18 May 2010; 9 April 2013]

Annex 3
Cabinet Regulation No. 376
9 May 2006

Basic Requirements for Application Dossier

1. General Provision

1. Basic requirements for the application dossier are specified in this Annex:

1.1. for administrative information - Module 1;

1.2. for quality, non-clinical and clinical summaries - Module 2;

1.3. for chemical, pharmaceutical and biological information for medicinal products containing chemical and/or biological active substances - Module 3;

1.4. for non-clinical reports - Module 4; and

1.5. for clinical reports - Module 5.

2. Module 1. Administrative Information

2. Table of contents of Modules 1, 2, 3, 4 and 5 of application dossier shall be provided.

3. The following shall be indicated in an application form:

3.1. the medicinal product, which is the subject of the registration application (name thereof, the name of the active substance(s), pharmaceutical form, the route of administration, the strength and the final presentation (also packaging));

3.2. the name and address of the applicant, the name and address of the manufacturer of the medicinal products and the sites involved in the different stages of the manufacture, including the manufacturer of the finished product and the manufacturer(s) of the active substance(s)), and where relevant - the name and address of the importer;

3.3. the type of the application and submitted samples, where such exist;

3.4. and the following shall be appended to the Annex:

3.4.1. copies of the manufacturing authorisation (licence) of the medicinal products;

3.4.2. a list of the countries, in which the authorisation referred to in Sub-paragraph 3.4.1 of this Annex has been granted;

3.5. detailed information regarding:

3.5.1. the medicinal products indicated in the registration application;

3.5.2. the legal status of the applicant of the registration application;

3.5.3. the proposed owner of the registration and the manufacturer(s) of the medicinal products;

3.5.4. information on the orphan medicinal product status;

3.5.5. scientific information; and

3.5.6. the paediatric development programme.

4. The summary of the product characteristics shall comply with Paragraph 21 of this Regulation.

5. A proposed labelling text for the primary and secondary packaging, as well as for the package leaflet shall comply with the regulatory enactments regarding procedures for the labelling of medicinal products and requirements to be made for the package leaflets of medicinal products. Samples or mock-ups of the primary and secondary packaging, labelling and package leaflets for the relevant medicinal product shall be submitted.

6. Where appropriate, the following shall be appended to administrative information:

6.1. copies of descriptions of medicinal products already approved in Member States of the European Economic Area; and

6.2. lists of such states, in which a registration application has been submitted.

7. Expert evaluation reports regarding documents and data of application dossier (part of application dossier) shall be developed in detail, in particular on Modules 3, 4 and 5 (chemical, pharmaceutical and biological documentation, non-clinical documentation and clinical documentation, respectively). The referred to reports shall address the critical points related to the quality of the medicinal product and of the investigations carried out on animals and human beings and shall specify all the data relevant for evaluation. These requirements shall be met in Module 2, in providing a quality overall summary, a non-clinical overview (data from studies carried out on animals) and a clinical overview. A declaration signed by the experts (with suitable technical or professional qualifications) together with brief information regarding their educational background, training and occupational experience shall be included in Module 1. The expert shall have an appropriate technical or professional qualification. The professional relationship of the expert and the applicant of the registration request shall be declared.

8. Specific requirements for different types of registration applications are indicated in Annex 4 to this Regulation.

9. Where applicable, the registration application shall include an environmental risk assessment overview (any risks related to adverse effects to the environment). In the overview:

9.1. possible risks to the environment due to the use or disposal of the medicinal product shall be assessed and proposals for appropriate labelling provisions shall be made;

9.2. attention to environmental risk, which is connected with the release of medicinal products containing genetically modified organisms in the environment, shall be paid in accordance with the regulatory enactments of the European Union and the Republic of Latvia regarding the deliberate release of genetically modified organisms into the environment;

9.3. environmental risk shall be indicated in Annex to Module 1 and the following shall be included:

9.3.1. an introduction;

9.3.2. a written consent (copy) to the deliberate release into the environment of the genetically modified organisms (for research and development purposes);

9.3.3. information regarding detection and identification methods and the code of genetically modified organisms;

9.3.4. additional information regarding the genetically modified organisms or the product of relevance to assessing the environmental risk in accordance with the regulatory enactments regarding genetically modified organisms;

9.3.5. an environment risk assessment report prepared in accordance with the regulatory enactments regarding genetically modified organisms;

9.3.6. an opinion (taking into account the referred to information and the environment risk assessment report), which proposes an appropriate risk management or control strategy, including therein, as relevant to the genetically modified organisms and product in question, a post-market monitoring plan and the identification of any special particulars, which need to appear in the description, labelling and package leaflet of the medicinal products;

9.3.7. information regarding measures for informing the public;

9.4. information regarding the author shall be provided:

9.4.1. the dated signature of the author;

9.4.2. education;

9.4.3. training;

9.4.4. occupational experience; and

9.4.5. a statement of the author's relationship with the applicant of the registration application.

3. Module 2. Summaries

3.1. General Provisions

10. Module 2 shall summarise:

10.1. the chemical, pharmaceutical, biological, non-clinical and clinical data provided in Modules 3, 4 and 5; and

10.2. the summaries referred to in Paragraph 20 of this Regulation.

11. Critical points shall be addressed and analysed. Factual summaries (also in tables) shall be provided. The reports shall provide cross-references to the tables or to the information contained in Module 3 (chemical, pharmaceutical and biological documentation), Module 4 (non-clinical documentation) and Module 5 (clinical documentation).

3.2. Summaries

12. Summaries shall contain a common table of contents, which includes the table of contents of the scientific documentation submitted according to Modules 2, 3, 4 and 5.

13. Information regarding the pharmaco-therapeutic class, mode of action and proposed clinical use of the medicinal product to be registered shall be supplied.

14. The quality overall summary shall:

14.1. provide a review of the chemical, pharmaceutical and biological data;

14.2. emphasise the key critical parameters and issues related to quality aspects, as well as provide justification in cases where there is no compliance. This document shall follow the scope and outline of the detailed data presented in Module 3.

15. In the non-clinical overview:

15.1. the non-clinical evaluation of the medicinal product in animals/in vitro shall be integrated and critically assessed, as well as the testing strategy, allowing also deviations, shall be discussed and justified;

15.2. an assessment of the impurities and degradation products shall be included along with their potential pharmacological and toxicological effects (except for biological medicinal products). The implications of any differences in the chirality, chemical form and impurities between the compound used in the non-clinical studies and the medicinal product to be distributed shall be examined;

15.3. comparability of the material used in non-clinical studies and clinical studies of biological medicinal products and the medicinal product to be registered shall be assessed;

15.4. any new excipients shall be the subject of a specific safety assessment; and

15.5. the characteristics of the medicinal product, as demonstrated by the non-clinical studies shall be defined, as well as the data as regards the safety of the medicinal product for the intended clinical use in humans shall be examined.

16. The clinical overview shall comply with the following conditions:

16.1. provide a critical analysis of the clinical data included in the clinical summary and Module 5. The approach to the clinical development of the medicinal product, including justified study plan and decisions related to and performance of the studies shall be provided;

16.2. provide a brief overview of the clinical findings, including important limitations, as well as an evaluation of the benefits and risks (any risks, which are related to the quality, safety or efficacy of medicinal products in respect of health of patients or protection of public health (public health)) based on the conclusions of the clinical studies. An interpretation of the way the efficacy and safety findings support the proposed dose and target indications, as well as an evaluation of how the summary of the product characteristics and other approaches will optimise the benefits and manage the risks shall be included; and

16.3. explain the efficacy or safety issues encountered in the development of the medicinal products, as well as unresolved issues.

17. Non-clinical summary. The pharmacology, pharmaco-kinetics and toxicology studies carried out on animals/in vitro shall be provided in writing and as tabulated summaries presented in the following order:

17.1. an introduction;

17.2. a pharmacology written summary;

17.3. a pharmacology tabulated summary;

17.4. a pharmaco-kinetics written summary;

17.5. a pharmaco-kinetics tabulated summary;

17.6. a toxicology written summary; and

17.7. a toxicology tabulated summary.

18. In the clinical summary:

18.1. a detailed, factual summary of the clinical information regarding the medicinal product included in Module 5 shall be provided. This shall include the results of all bio-pharmaceutical studies, of clinical pharmacology studies, and of clinical efficacy and safety studies. A synopsis of the individual studies shall be required;

18.2. summarised clinical information shall be presented in the following order:

18.2.1. a summary of the bio-pharmaceutics and associated analytical methods;

18.2.2. a summary of the clinical pharmacology studies;

18.2.3. a summary of clinical efficacy;

18.2.4. a summary of clinical safety; and

18.2.5. a synopsis of the individual studies.

4. Module 3. Chemical, Pharmaceutical and Biological Information for Medicinal Products Containing Chemical and/or Biological Active Substances

4.1. Format and Presentation

19. The general outline of Module 3 shall be as follows:

19.1. a table of contents:

19.1.1. active substance(s);

19.1.2. finished medicinal products;

19.1.3. appendices;

19.1.4. additional information;

19.2. body of data; and

19.3. literature references.

20. The body of data referred to in Sub-paragraph 19.1.1 of this Annex regarding active substance(s) shall include the following information:

20.1. general information:

20.1.1. nomenclature;

20.1.2. structure;

20.1.3. general properties;

20.2. manufacture:

20.2.1. manufacturer(s);

20.2.2. a description of the manufacturing process and process controls;

20.2.3. control of starting materials;

20.2.4. controls of the critical steps and intermediates;

20.2.5. process validation and/or evaluation;

20.2.6. manufacturing process development;

20.3. characterisation:

20.3.1. elucidation of the structure and other characteristics;

20.3.2. impurities;

20.4. control of active substance:

20.4.1. specification;

20.4.2. analytical procedures;

20.4.3. validation of analytical procedures;

20.4.4. batch analyses;

20.4.5. justification of the specification;

20.5. reference standards or materials;

20.6. container closure system;

20.7. stability:

20.7.1. stability summary and conclusions;

20.7.2. stability protocol (post-approval) and stability commitment;

20.7.3. stability data.

21. The body of data referred to in Sub-paragraph 19.1.2 of this Annex regarding finished medicinal products shall include the following information:

21.1. a description and formulation of the medicinal product;

21.2. pharmaceutical development:

21.2.1. components of the medicinal product:

21.2.1.1. active substance(s);

21.2.1.2. excipients;

21.2.2. the medicinal product:

21.2.2.1. development of the pharmaceutical form;

21.2.2.2. overages;

21.2.2.3. physical and chemical properties;

21.2.2.4. biological properties;

21.2.3. manufacturing process development;

21.2.4. container closure system;

21.2.5. microbiological attributes;

21.2.6. compatibility;

21.3. manufacture:

21.3.1. manufacturer(s);

21.3.2. batch formula;

21.3.3. description of the manufacturing process and process controls;

21.3.4. controls of the critical steps and intermediates;

21.3.5. process validation and/or evaluation;

21.4. control of excipients:

21.4.1. specifications;

21.4.2. analytical procedures;

21.4.3. validation of analytical procedures;

21.4.4. justification of specifications;

21.4.5. excipients of human or animal origin;

21.4.6. novel excipients;

21.5. control of the finished medicinal product:

21.5.1. specification(s);

21.5.2. analytical procedures;

21.5.3. validation of the analytical procedures;

21.5.4. batch analyses;

21.5.5. characterisation of the impurities;

21.5.6. justification of the specification(s);

21.6. reference standards or materials;

21.7. container closure system;

21.8. stability:

21.8.1. stability summary and conclusions;

21.8.2. stability protocol (post-approval) and stability commitment;

21.8.3. stability data.

22. The body of data referred to in Sub-paragraph 19.1.3 of this Annex regarding appendices shall include the following information:

22.1. facilities and equipment (for biological medicinal products only);

22.2. adventitious agents safety evaluation; and

22.3. excipients.

23. The body of data referred to in Sub-paragraph 19.1.4 of this Annex regarding additional information shall include the following information:

23.1. the process validation scheme for the medicinal product;

23.2. the medical device;

23.3. the certificate(s) of suitability; and

23.4. medicinal products containing or using starting materials of animal and/or human origin (TSE procedure) in the manufacturing process.

4.2. Content Principles and Requirements

4.2.1. General Provisions

24. The chemical, pharmaceutical and biological data shall include the following information regarding active substance(s) and the finished medicinal products:

24.1. the development;

24.2. the manufacturing process;

24.3. the characterisation and properties;

24.4. the quality control operations and requirements;

24.5. the stability; and

24.6. a description of the formulation and presentation of the finished medicinal product.

25. Information regarding the active substance(s) and regarding the finished medicinal products shall be provided separately.

26. Detailed information regarding the starting and raw materials used during the manufacture of the active substance(s) and regarding the excipients incorporated in the finished medicinal product shall be supplied.

27. The procedures and methods used for manufacturing and controlling the active substance and the finished medicinal product shall be described in sufficient detail to enable them to be repeated in control tests, carried out at the request of the State Agency of Medicines. Test procedures shall correspond to the state of scientific progress at the time and shall be validated. Results of the validation studies shall be provided. In performing test procedures included in the European Pharmacopoeia, this description shall be replaced by the appropriate detailed reference to the monograph(s) and general chapter(s).

28. The monographs of the European Pharmacopoeia shall be applicable to all substances, preparations and pharmaceutical forms appearing in it. In respect of other substances, each Member State of the European Economic Area may require observance of the national pharmacopoeia thereof. In performing analytical procedures included in the European Pharmacopoeia, this description shall be replaced in each relevant section by the appropriate detailed reference to the monograph(s) of the European Pharmacopoeia and general chapter(s). Where a material in the European Pharmacopoeia or in the pharmacopoeia of a Member State of the European Economic Area has been prepared by a method liable to leave impurities not controlled in the pharmacopoeia monograph, such impurities and maximum tolerance limits thereof shall be declared and a suitable test procedure shall be described. If a specification contained in the European Pharmacopoeia or in the national pharmacopoeia of a Member State of the European Economic Area might be insufficient in order to ensure the quality of the substance, the State Agency of Medicines is entitled to request more appropriate specifications from the registration certificate holder (owner) of the medicinal products. The State Agency of Medicines shall inform the authorities responsible for the pharmacopoeia in question. The holder (owner) of the medicinal product registration certificate shall provide the authorities of such pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied.

29. If starting and raw materials, active substance(s) or excipient(s) are described neither in the European Pharmacopoeia nor in the pharmacopoeia of a Member State of the European Economic Area, compliance with the monograph of a third country (a state, which is not a Member State of the European Economic Area) pharmacopoeia may be accepted. In such case a copy of the monograph shall be submitted accompanied by the validation of the analytical procedures contained in the monograph and, where appropriate, by a translation.

30. If the active substance, as well as the raw and starting material(s) or excipient(s) are included in any monograph of the European Pharmacopoeia, a certificate issued by the European Directorate for the Quality of Medicines, which replaces the relevant data described in this Module, may be included in that section of this Module. The manufacturer shall give the assurance in writing to the applicant of the registration request that the manufacturing process has not been modified since the granting of the certificate of suitability by the European Directorate for the Quality of Medicines.

31. The manufacturer of the active substance is entitled to submit information regarding the detailed description of the manufacturing process of well-defined active substances, quality control during manufacture and process validation in a separate document as an active substance master file. The manufacturer shall confirm in writing to the applicant of the registration application that he or she shall ensure batch to batch consistency and not modify the manufacturing process or specifications without informing the registration requester. Documents and particulars shall justify any changes made. The referred to documents and particulars shall also be submitted to the applicant of the registration application, if they concern the open part of the active substance master file.

32. In performing specific measures concerning the prevention of the transmission of animal spongiform encephalopathies, the compliance of the materials used at each step of the manufacturing process with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products and its updates, published by the European Commission in the Official Journal of the European Union, shall be demonstrated. Compliance with the referred to Note for Guidance may be demonstrated by submitting either, a certificate of suitability to the relevant monograph of the European Pharmacopoeia that has been granted by the European Directorate for the Quality of Medicines or by the supply of scientific data to substantiate this compliance.

33. For adventitious agents, information assessing the risk with respect to potential contamination with viral or non-viral agents, as laid down in the relevant guidelines, as well as in the relevant general monograph and general chapter of the European Pharmacopoeia, shall be provided.

34. Stages of the manufacturing process of medicinal products and any special apparatus and equipment used in control operations shall be described in adequate details.

35. Where applicable, a CE marking in accordance with the legal acts of Latvia and the European Union regarding medical devices shall be provided.

4.2.2. Active Substance(s)

36. General information regarding the starting and raw materials shall be supplied:

36.1. the nomenclature of the active substance, including the recommended International Non-proprietary Name (INN), European Pharmacopoeia name and, if relevant, chemical name(s). The structural formula, also the relative and absolute stereo-chemistry, the molecular formula and the relative molecular mass, shall be indicated. For biotechnological medicinal products, the schematic amino acid sequence and relative molecular mass shall be indicated. A list shall be provided of the physical, chemical and other properties of the active substance;

36.2. for biological medicinal products, the biological activity shall be indicated, taking into account that starting materials in a biological product shall mean the materials, from which the active substance is manufactured or extracted:

36.2.1. 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, also primary cells);

36.2.2. a biological substance is a substance that is produced by or extracted from a biological source and that needs for characterisation thereof and the determination of quality thereof a combination of physical, chemical and biological testing, as well as control of the production process. Any other substances used for manufacturing or extracting the active substance(s) but from which this active substance is not directly derived (such as reagents, culture media, foetal calf serum, additives, and buffers involved in chromatography) shall be known as raw materials.

37. Manufacturing process of the active substance(s):

37.1. the description thereof shall specify the commitment of the applicant of the registration request as regards the manufacture of the active substance. In order to adequately describe the manufacturing process and process controls, appropriate information as laid down in the guidelines published by the European Medicines Agency shall be provided;

37.2. materials needed in order to manufacture the active substance(s) shall be listed, identifying where each material is used in the process. Information regarding the quality and control of these materials shall be provided. Information demonstrating that materials meet the reference standards shall be provided. Raw materials shall be listed, as well as their quality and controls shall also be documented. The name, address and responsibility of each manufacturer (also contractors) and each proposed production site or facility involved in manufacturing and testing shall be provided;

37.3. for biological medicinal products, the following additional requirements shall apply:

37.3.1. the origin and history of the starting materials shall be described and documented;

37.3.2. as regards the specific measures for the prevention of the transmission of animal spongiform encephalopathies, the applicant of the registration request shall demonstrate that the active substance complies with the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Medicinal Products and its updates, published by the European Commission in the Official Journal of the European Union;

37.3.3. if cell banks are used, the cell characteristics shall be shown to have remained unchanged at the passage level used for the production and beyond;

37.3.4. seed materials, cell banks, pools of serum or plasma and other materials of biological origin and, whenever possible, the materials, from which they are derived, shall be tested for adventitious agents;

37.3.5. if the presence of potentially pathogenic adventitious agents is inevitable, the corresponding material shall be used only when further processing ensures their elimination and inactivation, and this shall be validated;

37.3.6. whenever possible, vaccine production shall be based on a seed lot system and on established cell banks. For bacterial and viral vaccines, the characteristics of the infectious agent shall be demonstrated on the seed lot. In addition, for live vaccines, the stability of the attenuation characteristics shall be demonstrated on the seed lot. If this proof is not sufficient, the attenuation characteristics shall also be demonstrated at the production stage;

37.3.7. for medicinal products derived from human blood or plasma, the origin and the criteria and procedures for collection, transportation and storage of the starting material shall be described and documented in accordance with Chapter IV of this Annex;

37.3.8. the manufacturing facilities and equipment shall be described;

37.4. tests and acceptance criteria carried out at every critical step, information regarding the quality and control of intermediates, as well as process validation and evaluation studies shall be provided as appropriate;

37.5. if the presence of potentially pathogenic adventitious agents is inevitable, the correspondent material shall be used only when further processing ensures their elimination and inactivation, and this shall be validated in the section dealing with viral safety evaluation;

37.6. the significant changes made to the manufacturing process during development and manufacturing site of the active substance shall be described and discussed.

38. Characteristics of the active substance(s) shall be provided:

38.1. the structure and other characteristics of the active substance(s); and

38.2. confirmation of the structure of the active substance(s) based on any physico-chemical or immuno-chemical, or biological methods, as well as information regarding impurities.

39. Information regarding control of the active substance(s) shall be provided:

39.1. the specifications used for the routine control of active substance(s), justifying the choice of these specifications, as well as methods of analysis and validation thereof; and

39.2. the results of the control carried out on individual batches manufactured during development.

40. Reference preparations and reference standards shall be identified and described in detail. Where relevant, the chemical and biological reference material of the European Pharmacopoeia shall be used.

41. A description of the container and the closure system(s) and specifications thereof shall be provided.

42. Regarding stability of the active substance(s):

42.1. the types of studies conducted, protocols used, and the results of the studies;

42.2. detailed results of the stability studies, including information regarding the analytical procedures used to generate the data and validation of these procedures in an appropriate format; and

42.3. there shall be a stability protocol (post authorisation). Information regarding stability commitment shall be provided.

4.2.3. Finished Medicinal Products

43. In the description of finished medicinal products:

43.1. composition thereof shall be indicated. The information shall include the description of the pharmaceutical form and composition, indicate the constituents of the finished medicinal product, their amount on a per-unit basis and the function of the constituents of:

43.1.1. the active substance(s);

43.1.2. the constituents of the excipients, whatever their nature or the quantity used (such as colouring matter, preservatives, adjuvants, stabilisers, thickeners, emulsifiers, flavouring and aromatic substances);

43.1.3. the constituents, intended to be ingested or otherwise administered to the patient, of the outer covering of the medicinal products (such as hard capsules, soft capsules, suppositories, coated tablets). The referred to particulars shall be supplemented by any relevant data concerning the type of container and, where appropriate, its manner of closure, as well as data concerning devices, with which the medicinal product will be used or administered and which will be delivered with the medicinal product;

43.2. the qualitative and quantitative composition of the medicinal product shall be indicated, using simple terminology and indicating the following information regarding the constituents of the medicinal product:

43.2.1. the main title at the head of the monograph in question, with reference to the pharmacopoeia concerned - in respect of substances, which appear in the European Pharmacopoeia or, failing this, in the national pharmacopoeia of one of the Member States of the European Economic Area;

43.2.2. the international non-proprietary name recommended by the World Health Organisation or, failing this, the exact scientific designation - in respect of other substances. If a substance does not have an international non-proprietary name or an exact scientific designation, it shall be indicated how and from what they were prepared, as well as any other relevant details shall be indicated;

43.2.3. the international "E" code that complies with the colouring matter referred to in the list of food additives regarding mandatory safety requirements for food additives shall be indicated for the colouring matter;

43.3. in order to give the quantitative composition of the active substance(s) of the finished medicinal products, depending on the pharmaceutical form concerned, the mass or the number of units of biological activity (either per dosage-unit or per unit of mass or volume) of each active substance shall be specified;

43.4. active substances present in the form of compounds or derivatives shall be designated quantitatively by their total mass and, if necessary, by the mass of the active entity or entities of the molecule;

43.5. for medicinal products containing an active substance, which is the subject of a registration request in any Member State of the European Economic Area for the first time, the quantitative evaluation of an active substance, which is a salt or hydrate, shall be systematically expressed in terms of the mass of the active entity or entities in the molecule. All subsequently registered medicinal products in the Member States of the European Economic Area shall have their quantitative formulation stated in the same way for the same active substance;

43.6. units of biological activity shall be used for substances, which cannot be defined molecularly. If an international unit of biological activity has been defined by the World Health Organisation, this shall be used. If no international unit has been defined, the units of biological activity shall be expressed in such a way as to provide unambiguous information regarding the activity of the substances by using where applicable the European Pharmacopoeia units.

44. Pharmaceutical development:

44.1. shall provide information regarding the development studies of medicinal products conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes and usage instructions are appropriate for the intended use specified in the application dossier;

44.2. the studies described in this chapter shall be distinct from routine control tests conducted according to specifications. Critical parameters of the formulation and process attributes that can influence batch reproducibility, medicinal product performance and medicinal product quality shall be determined and described. If additional supportive data is necessary, references to the relevant chapters of Module 4 (Non-clinical Study Reports) and Module 5 (Clinical Study Reports) shall be made:

44.2.1. the compatibility of the active substance with excipients, as well as key physical an chemical characteristics of the active substance that can influence the performance of the finished product or the compatibility of different active substances with each other in the case of combination products, shall be documented;

44.2.2. the choice of excipients, in particular relative to their respective functions and concentration shall be documented;

44.2.3. a description of the development of the finished product shall be provided, taking into consideration the proposed route of administration and usage;

44.2.4. superiority of any constituent in the formulation shall be justified;

44.2.5. as far as the physical, chemical and biological properties are concerned, any parameters relevant to the performance of the finished product shall be addressed and documented;

44.2.6. the selection and optimisation of the manufacturing process, as well as differences between the manufacturing process(es) used to produce pivotal clinical batches and the process used for manufacturing the proposed finished medicinal product shall be provided;

44.2.7. the suitability of the container and closure system used for the storage, shipping and use of the finished product shall be documented. Where appropriate, a possible interaction between the medicinal product and container may be considered;

44.2.8. the microbiological attributes of the dosage form in relation to non-sterile and sterile products shall be in accordance with and documented as prescribed in the European Pharmacopoeia;

44.2.9. in order to provide appropriate and supportive information for the labelling, the compatibility of the finished product with diluent(s) or dosage devices shall be documented.

45. Manufacturing process of the finished medicinal product:

45.1. the description of the manufacturing method shall be drafted, and it shall be appended to the request for the registration of medicinal products pursuant to Sub-paragraph 17.5 of this Regulation. The description shall give an adequate synopsis of the nature of the operations employed. It shall include at least:

45.1.1. mention of the various stages of manufacture, including process controls and acceptance criteria, so that an assessment can be made of whether the processes employed in producing the pharmaceutical form might have produced an adverse change in the constituents;

45.1.2. in the case of continuous manufacture, - full details concerning precautions taken to ensure the homogeneity of the finished product;

45.1.3. results of experimental studies validating the manufacturing process, where a non-standard method of manufacture is used or where they are critical for the process of manufacture of the medicinal product;

45.1.4. for sterile medicinal products - information regarding the sterilisation processes, as well as aseptic procedures used;

45.1.5. detailed information regarding the batch formula;

45.2. the name, address and responsibility of each manufacturer (including contractors) and each proposed production site and object involved in manufacturing and testing shall be provided;

45.3. 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 shall be included. The referred to tests are essential for checking the conformity of the medicinal product with the formula when, exceptionally, an applicant for registration request proposes an analytical method for testing the finished product, which does not include the assay of all the active substances (or of all the excipient constituents subject to the same requirements as the active substances). The same shall apply where the quality control of the finished product depends on in-process control tests, particularly if the medicinal product is essentially defined by the method of preparation thereof;

45.4. description, documentation, and results of the validation studies for critical stages used in the manufacturing process shall be provided.

46. Control of excipients:

46.1. materials needed in order to manufacture the excipient(s) shall be listed, identifying where each material is used in the process. Information regarding the quality and control of these materials shall be provided. Information demonstrating that materials meet standards appropriate for their intended use shall be provided. Colouring matters shall comply with the colouring matters included in the list of food additives permitted by the regulatory enactments regarding mandatory safety requirements for food additives. The purity criteria for colouring matters shall comply with the purity criteria for food additives specified in the regulatory enactments regarding mandatory safety requirements for food additives;

46.2. for each excipient, the specifications and their justifications shall be detailed. The analytical procedures shall be described and duly validated;

46.3. specific attention shall be paid to excipients of human or animal origin. In performing specific measures concerning the prevention of the transmission of animal spongiform encephalopathies, the applicant of a registration application shall demonstrate also for the excipients that the medicinal 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 European Commission in the Official Journal of the European Union. Compliance with the referred to Note for Guidance may be demonstrated by submitting either, a certificate of suitability to the relevant monograph of the European Pharmacopoeia that has been granted by the European Directorate for the Quality of Medicines or by the supply of scientific data to substantiate this compliance;

46.4. novel excipients:

46.4.1. according to the active substance format previously described, detailed information regarding characterisation of excipient(s) used for the first time in a medicinal product or by a new route of administration, shall be provided. Information regarding manufacture and controls of excipient(s) shall be provided, with cross references to supporting safety data, both non-clinical and clinical;

46.4.2. a document containing the detailed chemical, pharmaceutical and biological information shall be submitted. This information shall be formatted in the same order as the chapter devoted to active substance(s) of Module 3;

46.4.3. information regarding novel excipient(s) may be presented as a stand-alone document following the previously described format. If the applicant of a registration request is not the novel excipient manufacturer, the referred to stand-alone document shall be made available to the applicant of the registration request in order to submit it to the competent authority (in Latvia - to the State Agency of Medicines);

46.4.4. additional information regarding toxicity studies with the novel excipient shall be provided in Module 4;

46.4.5. information regarding clinical studies shall be provided in Module 5.

47. Control of the finished medicinal product:

47.1. in order to control the finished medicinal product, a batch of a medicinal product shall comprise 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 sterilisation operations or, in the case of a continuous production process, all the units are manufactured in a given period of time;

47.2. unless there is an appropriate justification, the maximum acceptable deviation in the active substance content of the finished product shall not exceed ± 5 % at the time of manufacture;

47.3. detailed information regarding the specifications (at the moment of release and during shelf life) and justification for their choice, methods of analysis and validation thereof shall be provided.

48. Reference preparations and reference standards used for testing of the finished medicinal product shall be identified and described in detail, if such information has not been previously provided in the section related to the active substance.

49. Container and closure of the finished medicinal product:

49.1. shall provide a description of the container and the closure system(s) and their specifications, identifying also each of the primary packaging materials. The specifications shall include the description and identification. Non-pharmacopoeial methods (with validation) shall be included where appropriate;

49.2. shall provide only a brief description for non-functional secondary packaging materials. Additional information shall be provided regarding functional secondary packaging materials.

50. Stability of the finished medicinal product:

50.1. shall summarise the types of studies conducted, protocols used, and the results of the studies;

50.2. shall present in an appropriate format detailed results of the stability studies, including information regarding the analytical procedures used to generate the data and validation of these procedures. Where appropriate, information regarding the cumulative stability of the vaccines shall be provided;

50.3. shall provide the stability protocol (post-approval) and stability commitment.

5. Module 4. Non-clinical Reports

5.1. Format and Presentation

51. The general outline of Module 4 shall be as follows:

51.1. the table of contents;

51.2. study reports;

51.2.1. pharmacology;

51.2.2. pharmaco-kinetics;

51.2.3. toxicity;

51.2.4. other toxicity studies; and

51.3. literature references.

52. The reports on the pharmacology referred to in Sub-paragraph 51.2.1 of this Annex shall include the following information:

52.1. primary pharmaco-dynamics;

52.2. secondary pharmaco-dynamics;

52.3. safety pharmacology;

52.4. pharmaco-dynamic interactions.

53. The reports on the pharmaco-kinetics referred to in Sub-paragraph 51.2.2 of this Annex shall include the following information:

53.1. analytical methods and validation reports;

53.2. absorption;

53.3. distribution;

53.4. metabolism;

53.5. excretion;

53.6. pharmaco-kinetic interactions (non-clinical study); and

53.7. other pharmaco-kinetic studies.

54. The reports on the toxicity referred to in Sub-paragraph 51.2.3 of this Annex shall include the following information:

54.1. single-dose toxicity;

54.2. repeat-dose toxicity;

54.3. genotoxicity:

54.3.1. in vitro;

54.3.2. in vivo (including supportive toxicokinetics evaluations);

54.4. carcinogenicity:

54.4.1. long-term studies;

54.4.2. short- or medium-term studies;

54.4.3. other studies;

54.5. reproduction and developmental toxicity:

54.5.1. fertility and early embryonic development;

54.5.2. embryo (foetal) development;

54.5.3. prenatal and postnatal development;

54.5.4. studies in which the offspring (juvenile animals) are dosed and/or further evaluated; and

54.6. local tolerance.

55. The reports on other toxicity studies referred to in Sub-paragraph 51.2.4 of this Annex shall include the following information:

55.1. antigenicity;

55.2. immuno-toxicity;

55.3. mechanistic studies;

55.4. dependence;

55.5. metabolites;

55.6. impurities; and

55.7. other.

5.2. Basic Principles and Requirements of Content

56. Special attention shall be paid that the following conditions are complied with:

56.1. the pharmacological and toxicological tests:

56.1.1. the potential toxicity of the medicinal product and any dangerous or undesirable toxic effects that may occur under the recommendations of use in human beings. Such effects shall be evaluated in relation to the relevant pathological condition;

56.1.2. the pharmacological properties of the medicinal product, in both qualitative and quantitative relationship to the proposed use in human beings. The results shall be reliable and of general applicability. Where appropriate, mathematical and statistical procedures shall be used in designing the experimental methods and in evaluating the results;

56.1.3. additionally, information regarding the therapeutic and toxicological potential of the product shall be supplied;

56.2. the requirements of Module 4 may be adapted for individual biological medicinal products (such as immunological medicinal products and medicinal products derived from human blood or plasma), therefore the testing program carried out shall be justified by the applicant of the request. In establishing the testing program, the following requirements shall be taken into consideration:

56.2.1. all tests requiring repeated administration of the product shall be designed, taking account of the possible induction and interference of antibodies;

56.2.2. examination of reproductive function, of embryo, as well as foetal and perinatal toxicity, of mutagenic potential and of carcinogenic potential shall be considered. Where constituents other than the active substance(s) are incriminated, validation of the removal of such substances may replace the study;

56.3. the toxicology and pharmaco-kinetics of an excipient used for the first time in the pharmaceutical field shall be demonstrated;

56.4. if there is a possibility of significant degradation during storage of the medicinal product, the toxicology of the degradation products shall be evaluated.

57. Data regarding pharmacology:

57.1. the pharmacology study shall follow two distinct lines of approach:

57.1.1. actions relating to the proposed therapeutic use shall be adequately investigated and described. Where possible, recognised and validated assays, both in vivo and in vitro, shall be used. Novel experimental techniques shall be described in such detail as to allow them to be reproduced. The results shall be expressed in quantitative terms (using, for example, dose-effect curves, time-effect curves). Wherever possible, comparisons shall be made with data relating to a substance or substances with a similar therapeutic action;

57.1.2. the potential undesirable pharmaco-dynamic effects of the substance on physiological functions shall be investigated. Such investigations shall be performed at exposures in the anticipated therapeutic range and above. The experimental techniques, unless they are standard procedures, shall be described in such detail as to allow them to be reproduced, and the investigator shall establish their validity. Any possible modification of responses resulting from repeated administration of the substance shall be investigated;

57.2. for the pharmaco-dynamic medicinal product interaction, tests on combinations of active substances may be prompted either by pharmacological premises or by indications of therapeutic effect:

57.2.1. the pharmaco-dynamic study shall demonstrate such interactions, which might make the combination of value in medical treatment;

57.2.2. where scientific justification for the combination is sought through therapeutic experimentation, the investigation shall determine whether the effects expected from the combination can be demonstrated in animals, and the importance thereof shall be investigated.

58. Data regarding pharmaco-kinetics:

58.1. pharmaco-kinetics shall mean the study of the fate of the active substance, and metabolites thereof, within the organism, and shall cover the study of the absorption, distribution, metabolism (bio-transformation) and excretion of such substances;

58.2. the study referred to in Sub-paragraph 58.1 of this Annex may be carried out mainly by means of physical, chemical or possibly by biological methods, as well as by observation of the actual pharmaco-dynamic activity of the substance itself;

58.3. information regarding distribution and elimination (bio-transformation and excretion) shall be necessary if the referred to data are indispensable in order to determine the dosage for humans, as well as in respect of chemotherapeutic substances (for example, antibiotics) and substances whose use depends on the non-pharmaco-dynamic effects thereof (for example, numerous diagnostic agents);

58.4. in vitro studies also may be carried out, using human material for comparison with animal material (i.e. protein binding, metabolism, drug-drug interaction);

58.5. data of pharmaco-kinetic study of pharmacologically active substances shall be necessary. In deriving new combinations of known substances, which have been investigated in accordance with this Regulation, pharmaco-kinetic studies shall not be required, if the toxicity tests and therapeutic experimentation justify their omission;

58.6. the pharmaco-kinetic study program shall be designed to allow comparison and extrapolation between data regarding animals and humans.

59. Data regarding toxicity:

59.1. the single-dose toxicity test shall be carried out in accordance with the relevant documents published by the European Medicines Agency. A single-dose toxicity test shall mean such toxic reaction, which may result from a single administration of the active substance or substances contained in the medicinal product, in the proportions and physico-chemical state, in which they are present in the actual medicinal product;

59.2. repeated dose toxicity tests:

59.2.1. shall be intended to reveal any physiological and/or anatomical pathological changes induced by the repeated administration of the active substance or combination of active substances under examination, as well as to determine how these changes are related to dosage;

59.2.2. it is desirable to perform two tests - one short-term, lasting from 2 to 4 weeks, and the other long-term, the duration of which shall depend on the conditions of clinical use. The potential adverse effects, to which attention should be paid in clinical studies, shall be described in the test. The duration of the test shall be defined in the relevant guidelines published by the European Medicines Agency;

59.3. genotoxicity: the purpose of the study of mutagenic and clastogenic potential shall be to reveal the changes, which a substance may cause in the genetic material of individuals or cells. Mutagenic substances may present a hazard to health since exposure to a mutagen carries the risk of inducing germ-line mutation, with the possibility of inherited disorders, as well as the risk of somatic mutations (also those leading to cancer). The referred to studies are obligatory for any new substance;

59.4. normally in respect of carcinogenicity tests are necessary to reveal carcinogenic effects. The studies:

59.4.1. shall be performed for any medicinal product whose expected clinical use is for a prolonged period of a patient's life (either continuously or repeatedly in an intermittent manner);

59.4.2. shall be recommended for some medicinal products if there is concern about their carcinogenic potential (for example, from product of the same class or similar structure) or if carcinogenicity is proved in repeated dose toxicity studies;

59.4.3. studies with unequivocally genotoxic compounds shall not be carried out, as they are presumed to be trans-species carcinogens, implying a hazard to humans. If such a medicinal product is intended to be administered chronically to humans, a long-term study may be necessary in order to detect early tumorigenic effects;

59.5. reproduction and developmental toxicity:

59.5.1. possible impairment of male or female reproductive function, as well as harmful effects on progeny shall be investigated by appropriate tests;

59.5.2. the tests shall comprise studies of the effect on adult male or female reproductive function, studies of the toxic and teratogenic effects at all stages of human development from conception to sexual maturity, as well as studies of the latent effects of the relevant medicinal product, if it is being administered to the female during pregnancy;

59.5.3. omission of these tests shall be adequately justified;

59.5.4. depending on the indicated use of the medicinal product, additional studies, for example, addressing the development of an offspring if the medicinal product is administered to the offspring, may be necessary;

59.5.5. embryo, as well as foetal toxicity studies shall normally be conducted on two mammalian species, one of which shall be other than a rodent. Peri- and postnatal studies shall be conducted in at least one species. If the metabolism of a medicinal product in a particular species is known to be similar to that in man, it is desirable to select this species. It is also desirable that one of the species is the same as in the repeated dose toxicity studies;

59.5.6. the state of scientific knowledge at the time when the request of registration is submitted shall be taken into account in planning the study;

59.6. the purpose of local tolerance shall be to ascertain whether the medicinal products (both active substances and excipients) are tolerated at sites in the body, which may come into contact with the medicinal product as a result of its administration in clinical use. The testing strategy shall be such that any mechanical effects of administration or physico-chemical actions of the medicinal product can be distinguished from the toxicological or pharmaco-dynamic effects. Local tolerance studies shall be conducted with the preparation, which is developed for human use, using the vehicle, as well as excipients in treating the control group(s). If necessary, positive control (reference) substances shall be used. The design of local tolerance (choice of species, duration, frequency and route of administration, doses) shall depend upon the problem to be investigated and the proposed conditions of administration in clinical use. Where appropriate, reversibility of local lesions shall be performed. Studies in animals may be substituted by validated in vitro tests provided that the test results are of comparable quality and usefulness for the purpose of safety evaluation. For chemicals applied locally (for example, dermal, rectal, vaginal), the sensitising potential shall be evaluated in at least one of the test systems currently available (the guinea pig assay or the local lymph node assay).

6. Module 5. Clinical Study Reports

6.1. Format and Presentation

60. The general outline of Module 5 shall be as follows:

60.1. the table of contents for clinical study reports;

60.2. the tabular listing of all clinical studies;

60.3. clinical study reports:

60.3.1. of bio-pharmaceutical studies;

60.3.2. of studies pertinent to pharmaco-kinetics using human bio-materials;

60.3.3. of human pharmaco-kinetic studies;

60.3.4. of human pharmaco-dynamic studies;

60.3.5. of efficacy and safety studies;

60.3.6. of medicinal product post-marketing experience;

60.4. literature references.

61. The reports of the bio-pharmaceutical studies referred to in Sub-paragraph 60.3.1 of this Annex shall be:

61.1. the bio-availability study reports;

61.2. the bio-availability and bio-equivalence study reports (comparative reports);

61.3. the in vivo-in vitro correlation study reports; and

61.4. the reports of the bio-analytical and analytical methods.

62. The reports of the studies pertinent to pharmaco-kinetics using human bio-materials referred to in Sub-paragraph 60.3.2 of this Annex shall be:

62.1. the plasma protein binding study reports;

62.2. the reports of hepatic metabolism and interactions studies; and

62.3. the reports of studies using other human bio-materials.

63. The reports of the studies pertinent to pharmaco-kinetics using human bio-materials referred to in Sub-paragraph 60.3.3 of this Annex shall be:

63.1. the healthy subjects pharmaco-kinetics and initial tolerability study report;

63.2. the patient pharmaco-kinetics and initial tolerability study report;

63.3. the intrinsic factor pharmaco-kinetics study report;

63.4. the extrinsic factor pharmaco-kinetics study report; and

63.5. the population pharmaco-kinetics study report.

64. The reports of the human pharmaco-dynamic studies referred to in Sub-paragraph 60.3.4 of this Annex shall be:

64.1. the healthy subject pharmaco-dynamic and pharmaco-kinetics-pharmaco-dynamic study reports; and

64.2. the patient pharmaco-dynamic and pharmaco-kinetics-pharmaco-dynamic study reports.

65. The reports of efficacy and safety studies referred to in Sub-paragraph 60.3.5 of this Annex shall include the following data:

65.1. controlled clinical studies pertinent to the claimed indication;

65.2. uncontrolled clinical studies;

65.3. analyses of data from more than one study, including any formal integrated analyses, meta-analyses and bridging analyses; and

65.4. other studies.

6.2. Basic Principles and Requirements of Content

66. Special attention shall be paid that the following conditions are complied with:

66.1. the clinical particulars provided shall be sufficient in order to provide a well-founded and scientifically valid opinion on whether the medicinal product satisfies the criteria governing the granting of registration. The results of all clinical trials - both favourable and unfavourable - shall be provided;

66.2. clinical trials shall always be preceded by adequate pharmacological and toxicological tests, carried out on animals in accordance with the requirements of Module 4 of this Annex. The investigator shall acquaint himself or herself with the conclusions of the pharmacological and toxicological studies. The applicant of the registration request shall provide him or her at least with the investigator's brochure, consisting of all the substantial information known prior to the onset of a clinical trial (chemical, pharmaceutical and biological data, toxicological, pharmaco-kinetic and pharmaco-dynamic data in animals and the results of earlier clinical trials, as well as adequate data justifying the nature, scale and duration of the proposed trial). The complete pharmacological and toxicological reports shall be provided on request. For materials of human or animal origin, all available means shall be employed in order to ensure safety from transmission of infectious agents prior to the commencement of the trial;

66.3. in respect of clinical trial documents, compliance with the following requirements shall be ensured:

66.3.1. the holder (owner) of the medicinal product registration certificate has ensured that essential clinical trial documents (including case report forms) other than medical documentation, are kept by the owner of the data:

66.3.1.1. for at least 15 years after completion or discontinuation of the trial;

66.3.1.2. for at least 2 years after the granting of the last registration in the Member States of the European Economic Area, if there are no pending or contemplated marketing applications therein;

66.3.1.3. for at least 2 years after the formal discontinuation of the clinical development of the investigational preparation;

66.3.2. medical documentation shall be retained in accordance with applicable legal acts and regulatory enactments in accordance with the maximum period of time permitted by the medical treatment institution, including doctor's practice;

66.3.3. the documents may be retained for a longer period, if it has been specified in regulatory requirements or by agreement with the sponsor. The duty of the sponsor shall be to inform the hospital, institution or practice, if such documents no longer need to be retained;

66.3.4. the sponsor or other owner of the data shall retain documentation, which pertains to the trial as long as the product is authorised and which includes:

66.3.4.1. the protocol including the rationale, objectives, statistical design and methodology of the trial, with the conditions, under which it is performed and managed, as well as detailed information regarding the investigational product, the reference medicinal product and the placebo used;

66.3.4.2. standard operating procedures;

66.3.4.3. all written opinions on the protocol and procedures;

66.3.4.4. the investigator's brochure;

66.3.4.5. case report forms on each trial subject;

66.3.4.6. the final report;

66.3.4.7. audit certificate(s), if available, issued by a competent authority of the relevant Member State of the European Economic Area that performs audit;

66.3.5. the owner of the registration of medicinal products shall make any additional arrangements for archiving of the documentation in accordance with regulatory enactments regarding the clinical trials of medicinal products;

66.3.6. any change of the owner of the data shall be documented;

66.3.7. all data and documents shall be available if requested by the relevant authorities;

66.4. the data of each clinical trial shall contain sufficient detail in order to allow an objective judgement to be made, which includes:

66.4.1. the protocol including the rationale, objectives, statistical design and methodology of the trial, with the conditions, under which it is performed and managed, as well as detailed information regarding the investigational product used;

66.4.2. audit certificate(s), if available, issued by a competent authority of the relevant Member State of the European Economic Area that performs audit;

66.4.3. the list of investigator(s), where the given name, surname, address, appointments, qualifications and clinical duties of each investigator and trial site is indicated. The investigators shall assemble the information regarding each patient individually, including case report forms on each trial subject;

66.4.4. the final report shall be signed by the investigator. For multi-centre trials, it shall be signed by all the investigators or the co-ordinating (principal) investigator;

66.5. the data of clinical trials shall be sent to the State Agency of Medicines. In agreement with the State Agency of Medicines, the applicant of the registration request may omit part of this information, however complete documentation shall be provided forthwith upon request of the State Agency of Medicines. The investigator shall, in his or her conclusions on the experimental evidence, express an opinion on the safety of the medicinal product under normal conditions of use, tolerance thereof, efficacy thereof and any useful information relating to indications and contra-indications, dosage and average duration of treatment, as well as any special precautions to be taken during treatment and the clinical symptoms of over dosage. In reporting the results of a multi-centre study, the principal investigator (co-ordinator) shall, in his or her conclusions, express an opinion on the safety and efficacy of the investigational medicinal product on behalf of all centres;

66.6. the clinical observations shall be summarised. The following information shall be indicated regarding each trial:

66.6.1. the number and sex of the subjects treated;

66.6.2. the selection and age-distribution of the groups of patients being investigated and the comparative tests;

66.6.3. the number of patients withdrawn prematurely from the trials and the reasons for such withdrawal;

66.6.4. if the controlled trials were carried out in accordance with the provisions referred to, it shall be indicated whether the control group:

66.6.4.1. received no treatment;

66.6.4.2. received a placebo;

66.6.4.3. received another medicinal product of known effect;

66.6.4.4. was treated otherwise (not using medicinal products);

66.6.5. the frequency of observed adverse reactions;

66.6.6. information regarding patients of an increased risk group (for example, elderly people, children, women during pregnancy or menstruation), or patients whose physiological or pathological condition requires special consideration;

66.6.7. parameters or evaluation criteria of efficacy and the results (expressed with the referred to parameters);

66.6.8. a statistical evaluation of the results, if this is intended in the design of the trials, and the variable factors involved;

66.7. the investigator shall provide observations regarding:

66.7.1. any signs of habituation or addiction or difficulties in withdrawing patients from the medicinal product;

66.7.2. any interactions with other medicinal products administered concomitantly;

66.7.3. the criteria determining exclusion of certain patients from the trials;

66.7.4. any deaths, which occurred during the trial or within the follow-up period;

66.8. data concerning a new combination of medicinal substances shall be identical to those required for new medicinal products and shall substantiate the safety and efficacy of the combination;

66.9. total or partial omission of data shall be explained. If unexpected results occur during the course of the trials, further pre-clinical, toxicological and pharmacological tests shall be undertaken and reviewed;

66.10. if the medicinal product is intended for long-term administration, particulars shall be given of any modification of the pharmacological action following repeated administration, as well as the establishment of long-term dosage.

67. For bio-pharmaceutical studies bio-availability study reports, comparative bio-availability, bio-equivalence study reports, reports on in vitro and in vivo correlation study, as well as bio-analytical and analytical methods shall be provided. Bio-availability shall be assessed if bio-equivalence of the medicinal products must be demonstrated.

68. For studies pertinent to pharmaco-kinetics using human bio-materials (proteins, cells, tissues and related materials derived from human sources that are used in vitro or ex vivo to assess the pharmaco-kinetics properties of drug substances) reports shall be provided if the studies pertain to plasma protein binding, regarding hepatic metabolism and active substance interaction studies and studies using other human bio-materials.

69. In reports of human pharmaco-kinetic studies:

69.1. the following pharmaco-kinetic characteristics shall be described:

69.1.1. absorption (rate and extent);

69.1.2. distribution;

69.1.3. metabolism;

69.1.4. excretion;

69.2. clinically significant features (including the implication of the kinetic data for the dosage regimen), especially for patients at risk, and differences between man and the animal species used in the pre-clinical studies shall be described;

69.3. for the pharmaco-kinetics studies during the population pharmaco-kinetics analysis based on sparse sampling and during clinical studies may address questions about the contributions of intrinsic and extrinsic factors to the variability in the dose and pharmaco-kinetics response relationship. The following shall be supplied:

69.3.1. reports of pharmaco-kinetic and initial tolerability studies in healthy subjects and in patients;

69.3.2. reports of pharmaco-kinetic studies in order to assess the effects of intrinsic and extrinsic factors;

69.3.3. reports of population pharmaco-kinetic studies;

69.4. if the medicinal product is normally to be administered concomitantly with other medicinal products, particulars shall be given of joint administration tests performed in order to demonstrate possible modification of the pharmacological action;

69.5. pharmaco-kinetic interactions between the active substance and other medicinal products or substances shall be investigated.

70. In reports of human pharmaco-dynamic studies:

70.1. the pharmaco-dynamic action correlated to the efficacy shall be demonstrated, including dose-response relationship, as well as their changes in time, justification for the dosage and conditions of administration and, if possible, the mode of action. The pharmaco-dynamic action not related to efficacy shall be described. The demonstration of the pharmaco-dynamic effects in human beings shall not in itself be sufficient to justify conclusions regarding any particular potential therapeutic effect;

70.2. if the medicinal product is normally to be administered concomitantly with other medicinal products, particulars shall be given of joint administration tests performed in order to demonstrate possible modification of the pharmacological action. Pharmaco-dynamic interactions between the active substance and other medicinal products or substances shall be investigated.

71. Reports of efficacy and safety studies:

71.1. shall be regarding controlled clinical studies pertinent to the claimed indication:

71.1.1. clinical trials shall be done as controlled clinical trials. If possible, randomisation shall be used, comparing as appropriate versus placebo and versus an established medicinal product of proven therapeutic value. Any other design shall be justified. The treatment of the control groups shall vary from case to case and also shall depend on ethical considerations and therapeutic area. In some cases it may be more pertinent to compare the efficacy of a new medicinal product with that of an established medicinal product of proven therapeutic value rather than with the effect of a placebo:

71.1.1.1. as far as possible, particularly in trials where the effect of the medicinal product cannot be objectively measured, steps shall be taken to avoid bias, - methods of randomisation and blinding shall also be used;

71.1.1.2. The protocol of the trial shall include a thorough description of the statistical methods to be employed, the number and reasons for the inclusion of patients (including calculations of the power of the trial), the significance and a description of the statistical unit. Measures taken to avoid bias (particularly methods of randomisation) shall be documented. Inclusion of a large number of subjects in a trial shall not be regarded as an adequate substitute for a properly controlled trial;

71.1.2. the safety data shall be reviewed with particular attention to events resulting in changes of dose or the need for concomitant medication, serious adverse events, events resulting in withdrawal of the patient or the death thereof. Any patients or patient groups at increased risk shall be identified, paying particular attention to potentially vulnerable patients who may be present in small numbers (for example, children, pregnant women, frail elderly people, people with marked abnormalities of metabolism or excretion). The implication of the safety evaluation for the possible uses of the medicinal product shall be described;

71.2. reports of such uncontrolled clinical studies reports of analyses of data, which concern more than one study, and other clinical study reports shall be submitted.

72. If the medicinal product is already registered in third countries, information regarding adverse reactions observed using medicinal products containing the same active substance(s) and, if possible, data regarding the usage rates in the referred to countries shall be provided in reports of medicinal product post-marketing experience.

73. Case report forms and individual patient listings shall be provided in the same order as the clinical study reports (indexed by study). They shall be submitted in accordance with the relevant guideline published by the European Medicines Agency.

Acting for the Minister for Health,
Minister for Culture H. Demakova

 

[9 April 2013]

Annex 4
Cabinet Regulation No. 376
9 May 2006

Specific Requirements for Application Dossier as Regards Applications for the Registration of Medicinal Products

I. General Provision

1. Specific requirements for application dossier are specified in this Annex to:

1.1. well-established medicinal products;

1.2. essentially similar medicinal products;

1.3. specific cases, if additional data is necessary;

1.4. similar biological medicinal products;

1.5. fixed combinations; and

1.6. mixed marketing applications.

II. Well-established Medicinal Products

2. Requirements of application dossier for well-established medicinal products:

2.1. in Annex 3 to this Regulation:

2.1.1. 1., 2. Modules 1, 2 and 3 - included;

2.1.2. 4. Modules 4 and 5 shall include a detailed non-clinical and clinical characteristics and indicate scientific bibliography;

2.2. the well-established medicinal use of medicinal products shall be demonstrated by the submitted evidence:

2.2.1. factors, which have to be taken into account in order to establish a well-established medicinal use of constituents of medicinal products:

2.2.1.1. the time over which a substance has been used;

2.2.1.2. quantitative aspects of the use of the substance;

2.2.1.3. the degree of scientific interest in the use of the substance (reflected in scientific literature);

2.2.1.4. the coherence of scientific assessments;

2.2.2. the period of time required for establishing a well-established medicinal use of a constituent of a medicinal product (different periods of time may be necessary for establishing well-established use of different substances) shall not be less than 10 years from the first systematic and documented use of that substance as a medicinal product in the Member States of the European Economic Area;

2.2.3. all aspects of the safety and efficacy assessment and included reviews of the relevant literature or references thereto:

2.2.3.1. taking into account pre- and post-marketing studies and published scientific literature dedicated to epidemiological studies (in particular of comparative studies). All documentation shall be submitted (both favourable and unfavourable);

2.2.3.2. it shall be particularly clarified that literature reference to other sources of evidence (for example, post marketing studies, epidemiological studies) and not just data related to tests and trials may serve as a valid proof of the safety and efficacy of a preparation if a registration application justifies the use of such sources of information satisfactorily;

2.2.4. any missing information and justification why demonstration of an acceptable level of safety and efficacy may be supported although some studies are lacking;

2.2.5. the relevance of any data explained in the non-clinical and clinical overviews, which concern a product different from the product intended for distribution. It shall be assessed whether the investigational medicinal product can be considered as similar to the product, for which a registration request has been submitted in spite of the existing differences;

2.2.6. post-marketing experience with other products containing the same constituents, so applicants of a registration shall specifically examine these issues.

III. Essentially Similar Medicinal Products

3. Requirements of application dossier for essentially similar medicinal products (generic medicinal products):

3.1. if the registration request is justified (Chapter III of this Regulation), it shall contain the data described in Modules 1, 2 and 3 of Annex 3 to this Regulation provided that the applicant of the registration application has been granted the consent of the holder of the original registration of the medicinal product to cross refer to the content of Modules 4 and 5 submitted by the holder of the original registration of the medicinal product;

3.2. documents confirming bio-availability and bio-equivalence in comparison with the original medicinal product provided that the original medicinal product is not a biological medicinal product shall be included;

3.3. the non-clinical and clinical study summaries shall particularly focus on the following elements:

3.3.1. the grounds for claiming essential similarity;

3.3.2. a summary of the impurities present in batches of the active substance(s), as well as those of the finished medicinal product (where relevant, decomposition products arising during storage) as proposed for use in the product to be distributed together with an evaluation of these impurities;

3.3.3. an evaluation of the bio-equivalence studies or a justification why studies were not performed, taking into account the guideline on investigation of bio-availability and bio-equivalence;

3.3.4. an update of published literature relevant to the substance and the present registration application. Articles in peer review journals may be annotated for this purpose;

3.3.5. every claim in the summary of medicinal product characteristics not known from or inferred from the properties of the medicinal product or therapeutic group thereof shall be discussed in the non-clinical and clinical study summaries and substantiated by published literature, as well as additional studies;

3.3.6. if the registration application concerns essential similarity, additional data in order to demonstrate evidence on the equivalence of the safety and efficacy properties of different salts, esters or derivatives of an authorised active substance shall be provided.

IV. Additional Data Required in Specific Situations

4. Specific situations when additional data regarding application dossier is required shall be as follows:

4.1. the active substance of an essentially similar medicinal product contains the same therapeutic constituent as the original authorised product associated with a different salt, as well as ester complex and derivative, evidence that there is no change in the pharmaco-kinetics, pharmaco-dynamics, as well as toxicity of the constituent, which could change the safety, as well as efficacy profile shall be demonstrated in the documentation. If there are changes, such association shall be considered as a new active substance;

4.2. a medicinal product is intended for a different therapeutic use or presented in a different pharmaceutical form or a medicinal product is intended to be administered by different routes and in different doses or with a different posology. In such case the results of appropriate toxicological and pharmacological tests, as well as of clinical trials shall be provided.

V. Similar Biological Medicinal Products

5. If, using the information required in the case of essentially similar medicinal products, it is not possible to prove the similar nature of two biological medicinal products, additional data, in particular, the toxicological and clinical profile shall be provided.

6. If an applicant of a registration application submits a registration application for a biological medicinal product specified in this Annex, which refers to an original medicinal product having been granted a registration of medicinal product in Member States of the European Economic Area, after the expiry of data protection period:

6.1. information regarding Modules 1, 2 and 3 (pharmaceutical, chemical and biological data) referred to in Annex 3 to this Regulation shall be supplemented with bio-equivalence and bio-availability data. The type and amount of additional data (toxicological and other non-clinical data, as well as appropriate clinical study data) shall be determined on a case by case basis;

6.2. due to the diversity of biological medicinal products, the requirement of the State Agency of Medicines for intended studies (which are specified in Modules 4 and 5 referred to in Annex 3 to this Regulation) shall be fulfilled, taking into account the specific characteristic of each individual medicinal product;

6.3. the general principles shall be fulfilled, taking into account the characteristics of the concerned biological medicinal product, which are indicated in a guideline published by the European Medicines Agency. If the originally registered medicinal product has more than one indication, to which the registration application applies, the similarity shall be justified or, where appropriate, demonstrated separately for each of the claimed indications.

VI. Fixed Combinations

7. Registration applications for fixed combinations shall relate to such new medicinal products, which consist of at least two active substances, the combination of which has not been previously registered as a fixed combination medicinal product:

7.1. information shall conform to Modules 1, 2, 3, 4 and 5 referred to in Annex 3 to this Regulation;

7.2. where appropriate, information regarding the manufacturing sites and the safety evaluation of adventitious agents shall be provided.

VII. Mixed Marketing Registration Applications

8. In respect of mixed registration applications:

8.1. Modules 4 and 5 referred to in Annex 3 to this Regulation shall consist of reports of limited non-clinical and clinical studies carried out by the applicant of the registration application and of literature references;

8.2. all other modules shall conform to the structure described in Annex 3 to this Regulation.

Acting for the Minister for Health,
Minister for Culture H. Demakova

 

[28 July 2008; 9 April 2013]

Annex 5
Cabinet Regulation No. 376
9 May 2006

Specific Requirements for Application Dossier as Regards Particular Medicinal Products

I. General Provision

1. In this Annex specific requirements are specified for application dossier of the following particular medicinal products:

1.1. biological medicinal products (medicinal products and vaccines derived from human blood or plasma) - for the plasma master file and vaccine antigen master file;

1.2. radiopharmaceuticals;

1.3. radiopharmaceutical precursors (hereinafter - precursor);

1.4. homeopathic medicinal products;

1.5. herbal medicinal products; and

1.6. orphan medicinal products.

II. Radiopharmaceuticals

2. Application dossier for radiopharmaceuticals shall contain the following information:

2.1. in Module 3 referred to in Annex 3 to this Regulation (hereinafter - Module 3) - in accordance with Paragraph 3 of this Annex;

2.2. in Module 4 referred to in Annex 3 to this Regulation (hereinafter - Module 4) - in accordance with Paragraph 4 of this Annex; and

2.3. in Module 5 referred to in Annex 3 to this Regulation (hereinafter - Module 5) - in accordance with Paragraph 5 of this Annex.

3. In Module 3:

3.1. in respect of a radiopharmaceutical kit, which is to be radio-labelled after supply by the manufacturer, the active substance shall be considered to be the part of the formulation, which is intended to carry or bind the radio-nuclide. The description of the manufacturing method of the kit shall include information regarding the manufacture of the kit and information regarding recommended final processing thereof to produce the radiopharmaceutical. If necessary, the specifications of the radio-nuclide shall be described in accordance with the general monograph or specific monograph of the European Pharmacopoeia. Any compounds essential for the radioactive-labelling and the structure of the radioactive-labelled compound shall be described. For radio-nuclides, the nuclear reactions involved shall be described. In a generator, both mother and daughter radio-nuclides shall be considered as active substances;

3.2. the nature of the radio-nuclide, the identity of the isotope, likely impurities, the carrier, the use and the specific activity shall be provided;

3.3. starting materials shall include irradiation target materials;

3.4. considerations on chemical, as well as radiochemical purity and relationship thereof to bio-distribution shall be provided;

3.5. radio-nuclide purity, radiochemical purity and specific activity shall be described;

3.6. for radionuclide generators, information regarding the testing for mother and daughter radionuclides shall be required. For radionuclide generator-eluates, information regarding tests for mother radionuclides and for other constituents of the generator system shall be provided;

3.7. the requirement to express the content of active substances in terms of the mass of active entities shall only apply to radiopharmaceutical kits. For radionuclides, radioactivity shall be expressed in Becquerels at a given date and, if necessary, time with reference to the time zone. The type of radiation shall be indicated;

3.8. for radionuclide kits, the specifications of the finished medicinal product shall include tests on the performance of the medicinal products after radio-labelling. Appropriate controls on the radiochemical and radio-nuclidic purity of the radioactive-labelled compound shall be included. Any materials essential for radioactive-labelling shall be identified and determined;

3.9. information regarding stability shall be given for radio-nuclide generators, radio-nuclide kits and radioactive-labelled products. The stability during the use of radiopharmaceuticals in multi-dose vials shall be documented.

4. It is desirable that toxicity may be associated with a radiation dose in Module 4. In diagnosis, this shall be a consequence of the use of radiopharmaceuticals, but in therapy, it shall be the property desired. The evaluation of the safety and efficacy of radiopharmaceuticals shall include medicinal product and radiation dosimetry aspects. Organ and tissue exposure to radiation shall be documented. Absorbed radiation dose estimates shall be calculated according to a specified, internationally recognised system by a particular route of administration.

5. Where applicable, in Module 5 the results of clinical trials shall be provided and justified in the clinical overviews.

III. Precursors

6. In the application dossier of a radiopharmaceutical precursor intended for radioactive-labelling purposes, the primary objective shall be to present information regarding the possible consequences of poor radioactive-labelling efficacy or in vivo dissociation of the radioactive-labelled conjugate (regarding questions related to the effects produced in the patient by free radionuclide). In addition, the relevant information relating to occupational hazards - radiation exposure to hospital staff and to the environment - shall be included. Where appropriate, the following information shall be provided:

6.1. in Module 3 - in accordance with Paragraph 7 of this Annex;

6.2. in Module 4 - in accordance with Paragraph 8 of this Annex; and

6.3. in Module 5 - in accordance with Paragraph 9 of this Annex.

7. The conditions referred to in Paragraph 3 of this Annex shall be complied with in Module 3.

8. In Module 4 the results of the studies concerning single dose and repeat dose toxicity, which are carried out in accordance with the regulatory enactments regarding good laboratory practice, shall be provided, unless otherwise justified. Mutagenicity studies on the radionuclide shall not considered to be valid. Information regarding the chemical toxicity and disposition of the relevant "cold" nuclide shall be presented.

9. In Module 5 it shall be taken into account that information generated from clinical studies of the precursor itself shall not be considered to be relevant in respect of the particular precursor intended solely for radioactive-labelling purposes. Information demonstrating the utility of the precursor when attached to relevant carrier molecules shall be presented.

IV. Homeopathic Medicinal Products

10. In Module 3:

10.1. the provisions shall apply to application dossier submitted pursuant to the registration of homeopathic medicinal products in accordance with a simplified procedure, as well as to the registration of other homeopathic medicinal products;

10.2. in terminology:

10.2.1. the Latin name of the homeopathic starting material shall comply with the Latin title of the European Pharmacopoeia or, in the absence thereof, - with an official name used in the pharmacopoeia of a Member State of the European Economic Area;

10.2.2. where relevant, the traditional name(s) used in each Member State of the European Economic Area shall be provided;

10.3. in control of starting materials:

10.3.1. the data and documents on the starting materials (all materials, including raw materials and intermediates up to the final dilution to be incorporated into the finished medicinal product) shall be supplemented by data on the homeopathic starting materials;

10.3.2. the general quality requirements shall apply to all starting and raw materials, as well as intermediate steps of the manufacturing process up to the final dilution to be incorporated into the finished medicinal product. The quantitative composition shall be determined as much as possible if toxic components are present and if the quality of the final dilution cannot be controlled because of the high dilution degree. The manufacturing process of a medicinal product shall be fully described from the starting materials up to the final dilution;

10.3.3. if dilutions are included, dilution shall be done in accordance with the homeopathic manufacturing methods specified in the relevant monograph of the European Pharmacopoeia or, in the absence thereof, - by an official pharmacopoeia of a Member State of the European Economic Area;

10.4. in control tests on the finished medicinal product:

10.4.1. the general quality requirements shall apply to the homeopathic finished medicinal products. Any exception shall be duly justified;

10.4.2. all the toxicologically relevant constituents shall be identified and specified. If it can be justified that an identification and/or an assay on all the toxicologically relevant constituents is not possible (for example, due to the dilution degree), the quality shall be demonstrated by complete validation of the manufacturing and dilution process;

10.5. in stability tests:

10.5.1. the stability of the finished medicinal products shall be demonstrated. Stability data of the homeopathic starting materials shall be generally applicable to dilutions, as well as triturations;

10.5.2. if no identification or quantitative assay of the active substance is possible due to the degree of dilution, stability data of the pharmaceutical form may be considered.

11. Module 4 shall apply to the simplified registration of homeopathic medicinal products with additional specifications. Any missing information shall be justified, for example, justification shall be given why demonstration of the safety level is acceptable although some studies are lacking.

V. Herbal Medicinal Products

12. For herbal medicinal products complete documentation shall be provided, in which the provisions of Module 3, including compliance with monograph(s) of the European Pharmacopoeia, shall apply to the registration of herbal medicinal products. The scientific experience accumulated until the date when the registration application is submitted shall be taken into account.

13. The following specific aspects of herbal medicinal products shall be included in application dossier:

13.1. regarding herbal substances and herbal preparations:

13.1.1. terms of herbal substances and preparations in the section "Terms" shall comply with the terms defined in the European Pharmacopoeia;

13.1.2. information regarding herbal substance shall specify the binomial nomenclature name of the plant (genus, species, variety and author), and chemotype (where applicable), the parts of the plant, the definition of the herbal substance, the other names (synonyms referred to in European Pharmacopoeia or other Pharmacopoeias);

13.1.3. information regarding herbal preparation shall specify the binomial nomenclature name of the plant (genus, species, variety and author), and chemotype (where applicable), the parts of the plant, the definition of the herbal preparation, the ratio of the herbal substance to the herbal preparation, the extraction solvent(s), the other names (synonyms referred to in European Pharmacopoeia or other Pharmacopoeias) and the excipients (where appropriate);

13.1.4. in documenting the structure of herbal substance(s) and herbal preparation(s), the physical form shall be indicated, the constituents with known therapeutic activity or markers (molecular formula, relative molecular mass, structural formula, also relative and absolute stereo-chemistry, the molecular formula, and the relative molecular mass), as well as other constituent(s) shall be described;

13.1.5. in the section on the manufacturer of the herbal substance, the name, address, and responsibility of each supplier (also contractors), as well as each site or facility involved in production, collection and testing of the herbal substance shall be provided;

13.1.6. in the section on the manufacturer of the herbal preparation, the name, address, and responsibility of each manufacturer (also contractors), as well as each site or facility involved in the production and testing of the herbal preparation shall be provided;

13.1.7. complete information regarding the plant production and collection, the geographical source, cultivation, harvesting, drying and storage conditions shall be provided in the description of the manufacturing process and process controls for the herbal substance;

13.1.8. complete information regarding the manufacturing process of the herbal preparation (also description of the processing, solvents and reagents, purification stages and standardisation) shall be provided in the description of the manufacturing process and process controls for the herbal preparation;

13.1.9. if the manufacturing process is improved, a brief summary describing the processing of herbal substance(s) and herbal preparation(s) shall be provided, taking into consideration the proposed route of administration and usage. Where appropriate, the phyto-chemical composition of the herbal substance(s) and herbal preparation(s) (according to bibliographic data) and the herbal substance(s) and herbal preparation(s) contained as active substance(s) in the herbal medicinal product applied for shall be compared;

13.1.10. in elucidating the structure and other characteristics of the herbal substance, macroscopical and microscopical description, phyto-chemical characterisation and information regarding biological activity, if necessary, shall be provided;

13.1.11. in elucidating the structure and other characteristics of the herbal preparation, phyto-chemical and physicochemical characterisation and information regarding biological activity, if necessary, shall be provided;

13.1.12. where applicable, the specifications for the herbal substance(s) and herbal preparation(s) shall be provided;

13.1.13. where applicable, analytical procedures for herbal substance(s) and herbal preparation(s) shall be described;

13.1.14. the validation of analytical procedures, including experimental data of testing the herbal substance(s) and herbal preparation(s), shall be provided;

13.1.15. a description of batches and the results of batch analyses for the herbal substance(s) and herbal preparation(s) shall be provided (also regarding substances included in the pharmacopoeia);

13.1.16. where applicable, justification for the specifications of the herbal substance(s) and herbal preparation(s) shall be provided;

13.1.17. where applicable, information regarding the reference standards or materials used for testing of the herbal substance(s) and herbal preparation(s) shall be provided;

13.1.18. if the herbal substance or the herbal preparation is the subject of a monograph, the applicant of the registration application may apply for a certificate of suitability granted by the European Directorate for the Quality of Medicines;

13.2. a brief summary describing the development of the pharmaceutical form of the herbal medicinal product shall be provided, taking into consideration the proposed route of administration and usage. Where appropriate, the phyto-chemical composition of the product (according to bibliographic data) and the herbal medicinal product applied for shall be compared.

VI. Orphan Medicinal Products

14. In the case of orphan medicinal products within the meaning of Regulation (EC) No 141/2000 of the European Parliament and of the Council of 16 December 1999, the conditions referred to in Paragraph 90 of this Regulation may be applied. In such case:

14.1. the non-clinical and clinical summaries shall justify the reasons, for which it is not possible to provide the complete information; and

14.2. the benefit-risk balance for the relevant medicinal product shall be justified, which means favourable evaluation of the therapeutic effects of medicinal products, taking into account any risks related to the quality, safety or efficacy of medicinal products in relation to the health of patients or protection of public health (public health).

15. If a registration application for an orphan medicinal product includes the provisions for well-established medicinal substance, the systematic and documented use of the relevant substance may be applied to the use of the referred to substance, allowing derogation from the provisions of this Annex.

Acting for the Minister for Health,
Minister for Culture H. Demakova

 

[29 June 2010; 9 April 2013]

Annex 6
Cabinet Regulation No. 376
9 May 2006

Specific Requirements for Application Dossier as Regards Advanced Therapy Medicinal Products

1. General Provisions

1. Application dossier for advanced therapy medicinal products, as defined in Annex 3 to this Regulation, shall follow the format requirements for Modules 1, 2, 3, 4 and 5. The technical requirements of Modules 3, 4 and 5 for biological medicinal products, as described in Annex 3 to this Regulation, shall apply.

2. The specific requirements for advanced therapy medicinal products described in sections 3, 4 and 5 of this Annex explain how the requirements of Modules 1, 2, 3, 4 and 5 in Annex 3 to this Regulation apply to advanced therapy medicinal products and, where appropriate and taking into account the specificities of advanced therapy medicinal products, additional requirements have been set.

3. Due to the specific nature of advanced therapy medicinal products, a risk-based approach may be applied for advanced therapy medicinal products to determine the extent of quality, non-clinical and clinical data to be included in the application dossier, taking into account the scientific guidelines relating to the quality, safety and efficacy of medicinal products. The risk analysis may cover the entire development. Risk factors that may be considered include for example the origin of the cells (autologous, allogeneic, xenogeneic), the ability to proliferate and differentiate and to initiate an immune response, the level of cell manipulation, the combination of cells with bioactive molecules or structural materials, the nature of the gene therapy medicinal products, the extent of replication competence of viruses or micro-organisms used in vivo, the level of integration of nucleic acids sequences or genes into the genome, the long time functionality, the risk of oncogenicity and the mode of administration or use. Relevant available non-clinical and clinical data or experience with other, related advanced therapy medicinal products may also be considered in the risk analysis.

4. Any deviation from the requirements of Annex 3 to this Regulation and this Annex shall be scientifically justified in Module 2 of the application dossier. The risk analysis described in Paragraph 3, when applied, shall also be included and described in Module 2, where the methodology followed, the nature of the identified risks and the implications of the risk based approach for the development and evaluation program shall be discussed and any deviations from the requirements of Annex 3 to this Regulation and this Annex resulting from the risk analysis shall be described.

2. Specific Requirements for Drawing up of Module 3 of the Application Dossier

2.1. for all advanced therapy medicinal products

5. A description of the traceability system that is intended to be established and maintained to ensure that the individual product and its starting and raw materials, including all substances coming into contact with the cells or tissues it may contain, can be traced through the sourcing, manufacturing, packaging, storage, transport and delivery to the medical treatment institution where the product is used, shall be provided for in Module 3 of the application dossier for all advanced therapy medicinal products.

6. The traceability system referred to in Paragraph 5 of this Annex shall be compatible with and complementary to, the regulatory enactments regarding the procedures for banking, storage and utilisation of human tissues, as regards human cells and tissues other than blood cells, and the regulatory enactments regarding the quality and safety standards for the collection, testing, processing, storage and distribution of human blood and blood components, as regards human blood cells, and the requirements specified in these regulatory enactments for traceability.

2.2. for gene therapy medicinal products

7. Finished product, active substance and starting materials:

7.1. gene therapy medicinal product containing recombinant nucleic acid sequence(s) or genetically modified microorganism(s) or virus(es):

7.1.1.the finished medicinal product shall consist of nucleic acid sequence(s) or genetically modified microorganism(s) or virus(es) formulated in their final immediate container for the intended medical use. The finished medicinal product may be combined with a medical device or active implantable medical device;

7.1.2. the active substance shall consist of nucleic acid sequence(s) or genetically modified microorganism(s) or virus(es);

7.2. gene therapy medicinal product containing genetically modified cells formulated in the final immediate container for the intended medical use. The finished medicinal product may be combined with a medical device or active implantable medical device. The active substance shall consist of cells genetically modified by one of the products described in Sub-paragraph 7.1.1 of this Annex;

7.3. in the case of products consisting of viruses or viral vectors, the starting materials shall be the components from which the viral vector is obtained, i.e. the master virus vector seed or the plasmids used to transfect the packaging cells and the master cell bank of the packaging cell line;

7.4. in the case of products consisting of plasmids, non-viral vectors and genetically modified microorganism(s) other than viruses or viral vectors, the starting materials shall be the components used to generate the producing cell, i.e. the plasmid, the host bacteria and the master cell bank of recombinant microbial cells;

7.5. in the case of genetically modified cells, the starting materials shall be the components used to obtain the genetically modified cells, i.e. the starting materials to produce the vector, the vector and the human or animal cells. The principles of good manufacturing practice shall apply from the bank system used to produce the vector onwards.

8. In addition to the requirements determined in Sections 4.2.2 and 4.2.3 of Annex 3 to this Regulation, the following requirements shall apply:

8.1. information shall be provided on all the starting materials used for the manufacture of the active substance, including the products necessary for the genetic modification of human or animal cells and, as applicable, subsequent culture and preservation of the genetically modified cells, taking into consideration the possible absence of purification steps;

8.2. for medicinal products containing a microorganism or a virus, data on the genetic modification, sequence analysis, attenuation of virulence, tropism for specific tissues and cell types, cell cycle dependence of the micro organism or virus, pathogenicity and characteristics of the parental strain shall be provided;

8.3. process-related impurities and product-related impurities shall be described in the relevant sections of the application dossier, and in particular replication competent virus contaminants if the vector is designed to be replication incompetent;

8.4. for plasmids, quantification of the different plasmid forms shall be undertaken throughout the shelf life of the product;

8.5. for genetically modified cells, the characteristics of the cells before and after the genetic modification, as well as before and after any subsequent freezing and storage procedures, shall be tested.

9. For genetically modified cells, in addition to the specific requirements for gene therapy medicinal products, the quality requirements for somatic cell therapy medicinal products and tissue engineered products in compliance with the specified in Section 2.3 of this Annex shall apply.

2.3. for somatic cell therapy medicinal products and tissue engineered products

10. Finished medicinal product, active substance and starting materials:

10.1. the finished medicinal product shall consist of the active substance formulated in its immediate container for the intended medical use, and in its final combination for combined advanced therapy medicinal products as defined in Article 2(1)(d) of European Parliament and Council Regulation No 1394/2007;

10.2. the active substance shall be composed of the engineered cells and tissues. Cells and tissues shall be considered as "engineered" if they comply to that specified in Article 2(1)© of European Parliament and Council Regulation No 1394/2007;

10.3. additional substances (for example scaffolds, matrices, devices, biomaterials, biomolecules and other components) which are combined with manipulated cells of which they form an integral part shall be considered as starting materials, even if not of biological origin;

10.4. materials used during the manufacture of the active substance (for example culture media, growth factors) and that are not intended to form part of the active substance shall be considered as raw materials.

11. In addition to the requirements set out in Sections 4.2.2 and 4.2.3 of Annex 3 to this Regulation, the following requirements shall apply:

11.1. starting materials:

11.1.1. summary information shall be provided on donation, procurement and testing of the human tissue and cells used as starting materials and made in accordance with the regulatory enactments regarding the procedures for banking, storage and utilisation of human tissues. If non-healthy cells or tissues (for example cancer tissue) are used as starting materials, their use shall be justified;

11.1.2. if allogeneic cell populations are being pooled, the pooling strategies and measures to ensure traceability shall be described;

11.1.3. the potential variability introduced through the human or animal tissues and cells shall be addressed as part of the validation of the manufacturing process, characterisation of the active substance and the finished product, development of assays, setting of specifications and stability;

11.1.4. for xenogeneic cell-based products, information on the source of animals (such as geographical origin, animal husbandry, age), specific acceptance criteria, measures to prevent and monitor infections in the source (donor) animals, testing of the animals for infectious agents, including vertically transmitted micro-organisms and viruses, and evidence of the suitability of the animal facilities shall be provided;

11.1.5. for cell-based products derived from genetically modified animals, the specific characteristics of the cells related to the genetic modification shall be described. A detailed description of the method of creation and the characterisation of the transgenic animal shall be provided;

11.1.6. for the genetic modification of the cells, the technical requirements specified in Section 2.2 of this Annex shall apply;

11.1.7. the testing regimen of any additional substance (scaffolds, matrices, devices, biomaterials, biomolecules or other components), which are combined with engineered cells of which they form an integral part, shall be described and justified;

11.1.8. for scaffolds, matrices and devices that fall under the definition of a medical device or active implantable medical device, the information required under Section 2.4 of this Annex for the evaluation of the combined advanced therapy medicinal product shall be provided;

11.2. manufacturing process:

11.2.1. the manufacturing process shall be validated to ensure batch and process consistency, functional integrity of the cells throughout manufacturing and transport up to the moment of application or administration, and proper differentiation state;

11.2.2. if cells are grown directly inside or on a matrix, scaffold or device, information shall be provided on the validation of the cell culture process with respect to cell-growth, function and integrity of the combination;

11.3. characterisation and control strategy:

11.3.1. relevant information shall be provided on the characterisation of the cell population or cell mixture in terms of identity, purity (e.g. adventitious microbial agents and cellular contaminants), viability, potency, karyology, tumourigenicity and suitability for the intended medicinal use. The genetic stability of the cells shall be demonstrated;

11.3.2. qualitative and, where possible, quantitative information on product- and process-related impurities, as well as on any material capable of introducing degradation products during production, shall be provided. The extent of the determination of impurities shall be justified;

11.3.2. if certain release tests cannot be performed on the active substance or finished product, but only on key intermediates and as in-process testing, this shall be justified;

11.3.4. where biologically active molecules (such as growth factors, cytokines) are present as components of the cell-based product, their impact and interaction with other components of the active substance shall be characterised;

11.3.5. where a 3-dimensional structure is part of the intended function, the differentiation state, structural and functional organisation of the cells and, where applicable, the extracellular matrix generated shall be part of the characterisation for these cell-based products. Where needed, non-clinical investigations shall complement the physicochemical characterisation;

11.4. for excipients used in cell or tissue-based medicinal products, for example the components of the transport medium, the requirements for novel excipients, as laid down in Annex 3 to this Regulation, shall apply, unless data exists on the interactions between the cells or tissues and the excipients;

11.5. for developmental studies the description of the development program shall address the choice of materials and processes. In particular, the integrity of the cell population as in the final formulation shall be discussed;

11.6. for reference materials a reference standard, relevant and specific for the active substance and the finished product, shall be documented and characterised.

2.4. specific requirements for advanced therapy medicinal products containing devices or active implantable medical devices

12. Advanced therapy medicinal product containing devices as referred to in Article 7 of European Parliament and Council Regulation (EC) No 1394/2007:

12.1. a description of the physical characteristics and performance of the product and a description of the product design methods shall be provided;

12.2. the interaction and compatibility between genes, cells and tissues and the structural components shall be described.

13. Combined advanced therapy medicinal products as defined in Article 2(1)(d) of European Parliament and Council Regulation (EC) No 1394/2007:

13.1. for the cellular or tissue part of the combined advanced therapy medicinal product, the specific requirements for somatic cell therapy medicinal products and tissue engineered products set out in Section 2.3 of this Annex shall apply and, in the case of genetically modified cells, the specific requirements for gene therapy medicinal products set out in Section 2.2 of this Annex shall apply;

13.2. the medical device or the active implantable medical device may be an integral part of the active substance. Where the medical device or active implantable medical device is combined with the cells at the time of the manufacture or application or administration of the finished products, they shall be considered as an integral part of the finished product;

13.3. information related to the medical device or the active implantable medical device (which is an integral part of the active substance or of the finished product) which is relevant for the evaluation of the combined advanced therapy medicinal product shall be provided. This information shall include:

13.3.1. information on the choice and intended function of the medical device or implantable medical device and demonstration of compatibility of the device with other components of the medicinal product;

13.3.2. evidence of conformity of the medical device part with the essential requirements laid down in the regulatory enactments regarding registration, conformity assessment, distribution, operation and technical supervision of medical devices, or conformity of the active implantable device part with the essential requirements laid down in the regulatory enactments regarding registration, conformity assessment, distribution, operation and technical supervision of medical devices;

13.3.3. where applicable, evidence of compliance of the medical device or implantable medical device with the geographic BSE (GBR) and TSE in compliance with the laid down in the regulatory enactments regarding registration, conformity assessment, distribution, operation and technical supervision of medical devices;

13.3.4. the results of any assessment of the medical device part or the active implantable medical device part (if any available) performed by a notified body in accordance with the regulatory enactments regarding registration, conformity assessment, distribution, operation and technical supervision of medical devices.

3. Specific Requirements for Drawing up of Module 4 of the Application Dossier

3.1. for advanced therapy medicinal products

14. The requirements of Module 4 of Annex 3 to this Regulation on the pharmacological and toxicological testing of medicinal products may not always be appropriate due to unique and diverse structural and biological properties of advanced therapy medicinal products. The technical requirements described in Section 3 of this Annex explain how the requirements in Annex 3 to this Regulation apply to advanced therapy medicinal products. Where appropriate and taking into account the specificities of advanced therapy medicinal products, additional requirements have been set.

15. The rationale for the non-clinical development and the criteria used to choose the relevant species and models (in vitro and in vivo) shall be discussed and justified in the non-clinical overview. The chosen animal model may include immuno-compromised, knockout, humanised or transgenic animals. The use of homologous models (for example mouse cells analysed in mice) or disease mimicking models shall be considered, especially for immunogenicity and immunotoxicity studies.

16. In addition to the requirements of Annex 3 to this Regulation, the safety, suitability and biocompatibility of all structural components (such as matrices, scaffolds and devices) and any additional substances (such as cellular products, biomolecules, biomaterials, and chemical substances), which are present in the finished product, shall be provided. Their physical, mechanical, chemical and biological properties shall be taken into account.

3.2. for gene therapy medicinal products

17. In order to determine the extent and type of non-clinical studies necessary to determine the appropriate level of non-clinical safety data, the design and type of the gene therapy medicinal product shall be taken into account.

18. Pharmacology:

18.1. in vitro and in vivo studies of actions relating to the proposed therapeutic use (namely pharmacodynamic "proof of concept" studies) shall be provided using models and relevant animal species designed to show that the nucleic acid sequence reaches its intended target (target organ or cells) and provides its intended function (level of expression and functional activity). The duration of the nucleic acid sequence function and the proposed dosing regimen in the clinical studies shall be provided;

18.2. target selectivity, when the gene therapy medicinal product is intended to have a selective or target-restricted functionality, studies to confirm the specificity and duration of functionality and activity in target cells and tissues shall be provided.

19. Pharmacokinetics:

19.1. biodistribution studies shall include investigations on persistence, clearance and mobilisation. Biodistribution studies shall additionally address the risk of germline transmission;

19.2. investigations of shedding and risk of transmission to third parties shall be provided with the environmental risk assessment, unless otherwise duly justified in the application on the basis of the type of medicinal product concerned.

20. Toxicology:

20.1. toxicity of the finished gene therapy medicinal product shall be assessed. In addition, depending on the type of product, individual testing of active substance and excipients shall be taken into consideration and the in vivo effect of expressed nucleic acid sequence-related products which are not intended for the physiological function shall be evaluated;

20.2. single-dose toxicity studies may be combined with safety pharmacology and pharmacokinetic studies, for example to investigate persistence;

20.3. repeated dose toxicity studies shall be provided when multiple dosing of human subjects is intended. The mode and scheme of administration shall closely reflect the planned clinical dosing. For those cases where single dosing may result in prolonged functionality of the nucleic acid sequence in �ģents, repeated toxicity studies shall be considered. The duration of the studies may be longer than in �ģents�r toxicity studies depending on the persistence of the gene therapy medicinal product and the anticipated potential risks. A justification for the duration shall be provided;

20.4. genotoxicity shall be studied. However, �ģents�r genotoxicity studies shall only be conducted when they are necessary for testing a �ģents�ra impurity or a component of the delivery system;

20.5. carcinogenicity shall be studied. Standard lifetime rodent carcinogenicity studies shall not be required. However, depending on the type of product, the tumourigenic potential shall be evaluated in �ģents�rant vivo/in vitro models;

20.6. reproductive and developmental toxicity. Studies on the effects on fertility and general reproductive function shall be provided. Embryo-foetal and perinatal toxicity studies and germline transmission studies shall be provided, unless otherwise duly justified in the application on the basis of the type of product concerned;

20.7. additional toxicity studies:

20.7.1. integration studies: integration studies shall be provided for any gene therapy medicinal product, unless the lack of these studies is scientifically justified, for example because nucleic acid sequences will not enter into the cell nucleus. For gene therapy medicinal products not expected to be capable of integration, integration studies shall be performed, if biodistribution data indicate a risk for germline transmission;

20.7.2. immunogenicity and immunotoxicity, potential immunogenic and immunotoxic effects shall be studied.

3.3. for somatic cell therapy medicinal products and tissue engineered products

21. Pharmacology:

21.1. the primary pharmacological studies shall be adequate to �ģents�rante the proof of concept. The interaction of the cell-based products with the surrounding tissue shall be studied;

21. 2. the amount of product needed to achieve the desired effect or the effective dose, and, depending on the type of product, the frequency of dosing shall be determined;

21.3. secondary pharmacological studies shall be taken into account to evaluate potential physiological effects that are not related to the desired therapeutic effect of the somatic cell therapy medicinal product and of gene engineered product or of additional substances, as biologically active molecules besides the protein of interest might be secreted or the protein of interest could have unwanted target sites.

22. Pharmacokinetics:

22.1. conventional pharmacokinetic studies to investigate absorption, distribution, metabolism and excretion shall not be required. However, parameters such as viability, longevity, distribution, growth, differentiation and migration shall be investigated, unless otherwise duly justified in the application on the basis of the type of product concerned;

22.2. for somatic cell therapy medicinal products and tissue engineered products, producing systemically active biomolecules, the distribution, duration and amount of expression of these molecules shall be studied.

23. Toxicology:

23.1. the toxicity of the finished product shall be assessed. Individual testing of active substance, excipients, additional substances and any process-related impurities shall be taken into consideration;

23.2. the duration of observations may be longer than in �ģents�r toxicity studies and the anticipated lifespan of the medicinal product, together with its pharmacodynamic and pharmacokinetic profile, shall be taken into consideration. A justification of the duration shall be provided;

23.3. conventional carcinogenicity and genotoxicity studies shall not be required, except with regard to the tumourigenic potential of the product;

23.4. potential immunogenic and immunotoxic effects shall be studied;

23.5. in the case of cell-based products containing animal cells, the associated �ģents�ra safety concerns such as transmission to �ģents of xenogeneic pathogens shall be addressed.

4. Specific Requirements for Drawing up of Module 5 of the Application Dossier

4.1. for advanced therapy medicinal products

24. The �ģents�ra requirements in Section 4.1 of this Annex are additional requirements to those �ģents Module 5 in Annex 3 to this Regulation.

25. Where the clinical application of advanced therapy medicinal products requires �ģents�ra concomitant therapy and involve surgical procedures, the therapeutic procedure as a whole shall be investigated and described. Information on the standardisation and optimisation of those procedures during clinical development shall be provided. Where medical devices used during the surgical procedures for application, implantation or administration of the advanced therapy medicinal product may have an impact on the efficacy or safety of the advanced therapy product, information on these devices shall be provided. Specific expertise required to carry out the application, implantation, administration or follow-up activities shall be defined. Where necessary, the training plan of health care professionals on the use, application, implantation or administration procedures of these products shall be provided.

26. Given that, due to the nature of advanced therapy medicinal products, their manufacturing process may change during clinical development, additional studies to �ģents�rante comparability may be required.

27. During clinical development, risks arising from potential infectious �ģents or the use of material derived from animal sources and measures taken to reduce such risk shall be addressed.

28. Dose selection and schedule of use shall be defined by dose-finding studies.

29. The efficacy of the proposed indications shall be supported by relevant results from clinical studies using clinically meaningful endpoints for the intended use. In certain clinical conditions, evidence of long-term efficacy may be required. The strategy to evaluate long-term efficacy shall be provided.

30. A strategy for the long-term follow-up of safety and efficacy shall be included in the risk management plan.

31. For combined advanced therapy medicinal products, the safety and efficacy studies shall be designed for and performed on the combined product as a whole.

4.2. for gene therapy medicinal products

32. Human pharmacokinetic studies shall include the following aspects:

32.1. shedding studies to address the excretion of the gene therapy medicinal products;

32.2. biodistribution studies;

32.3. pharmacokinetic studies of the medicinal product and the gene expression moieties (for example expressed proteins or genomic signatures).

33. Human pharmacodynamic studies shall address the expression and function of the nucleic acid sequence following administration of the gene therapy medicinal product.

34. Safety studies shall address the following aspects:

34.1. emergence of replication competent vector;

34.2. emergence of new strains;

34.2. reassortment of existing genomic sequences;

34.4. neoplastic proliferation due to insertional mutagenicity.

4.3. for somatic cell therapy medicinal products

35. For somatic cell therapy medicinal products where the mode of action is based on the production of defined active biomolecule, the pharmacokinetic profile (in particular distribution, duration and amount of expression) of those molecules shall be addressed, if feasible.

36. The biodistribution, persistence and long-term engraftment of the somatic cell therapy medicinal product components shall be addressed during the clinical development.

37. Safety studies shall address the following aspects:

37.1. distribution and engrafting following administration;

37.2. ectopic engraftment;

37.3. oncogenic transformation and cell or tissue lineage fidelity.

4.4. for tissue engineered products

38. Where conventional pharmacokinetic studies are not relevant for tissue engineered products, the biodistribution, persistence and degradation of the tissue engineered product components shall be addressed during the clinical development.

39. Pharmacodynamic studies shall be designed and tailored to the specificities of tissue engineered products. The evidence for the "proof of concept" and the kinetics of the product to obtain the intended regeneration, repairing or replacement shall be provided. Suitable pharmacodynamic markers, related to the intended function and

structure shall be taken into account.

40. For safety studies the aspects of safety studies determined in Paragraph 37 of this Annex shall be applied.

 

[9 April 2013]

Annex 7
Cabinet Regulation No. 376
9 May 2006

Extension of Registration of Medicinal Products

Changes to application dossier, regarding which the owner of the registration of medicinal products submits an application for extension of the registration shall be as follows:

1. Changes related to the active substance(s):

1.1. replacement of the active substance(s) by a different salt or ester complex or derivative thereof (with the same therapeutic constituent), where the efficacy and safety characteristics are not significantly different;

1.2. replacement of the active substance(s) with a different isomer or a different mixture of isomers, replacement of a mixture by an isolated isomer (for example, racemate is replaced by a single enantiomer), where the efficacy and safety characteristics are not significantly different;

1.3. replacement of a biological substance or product of biotechnology with a substance of a slightly different molecular structure. Modification of the vector used to produce the antigen, as well as the starting material (also a new master (main) cell bank from a different source), where the efficacy and safety characteristics are not substantially different;

1.4. a new ligand or coupling mechanism for a radiopharmaceutical; or

1.5. change to the extraction solvent or the ratio of the herbal drug to the herbal drug preparation, where the efficacy and safety characteristics are not substantially different.

2. Changes to the strength, pharmaceutical form or route of administration:

2.1. change of bioavailability;

2.2. change of pharmacokinetics (for example, in the rate of release);

2.3. change or addition of a new strength, as well as potency;

2.4. change or addition of a new pharmaceutical form; or

2.5. change or addition of a new route of administration. If the medicinal products are intended for parenteral use, the type of administration (for example, intra-arterial, intravenous, intramuscular, subcutaneous) shall be indicated.

Acting for the Minister for Health,
Minister for Culture H. Demakova

 

[1 November 2010; 9 April 2013]

Annex 7.1
Cabinet Regulation No. 376
9 May 2006

Types of Variations and Classification Thereof
(in accordance with the Commission guidelines referred to in Article 4(1) of Commission Regulation No 1234/2008)

1. A Administrative changes

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

1. A.1. Change in the name or address of the owner of registration (the owner of the registration certificate, the marketing authorisation holder). Condition: 1 Documentation: 1, 2

IAIN

1.1. Condition:
  1. The owner of registration shall remain the same legal entity.
1.2. Documentation:
  1. A formal document from a relevant competent authority (for example, Commercial Register, Chamber of Commerce) in which the new name or new address is mentioned.
  2. Revised information on the medicinal product (description, labelling or package leaflet of the medicinal product).
2. A.2. Change in the invented name of the medicinal product:  
  a) for centrally registered medicinal products; Condition: 1 Documentation: 1, 2

IAIN

  b) for medicinal products registered in the European Union or European Economic Area state.   Documentation: 2

IB

2.1. Condition:
  1. The check by the European Medicines Agency on the acceptability of the new name has been finalised and was positive.
2.2. Documentation:
  1. Copy of the European Medicines Agency letter on the acceptability of the new invented name.
  2. Revised information on the medicinal product.
3. A.3. Change in name of the active substance. Condition: 1 Documentation: 1, 2

IAIN

3.1. Condition:
  1. The active substance shall remain the same.
3.2. Documentation:
  1. Proof of acceptance by the World Health Organisation or copy of the International Nonproprietary Name list. For herbal medicinal product, declaration that the name complies with the instructions regarding quality of herbal medicinal products included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation, and with the guideline on declaration of herbal substances and herbal preparations in (traditional) herbal medicinal products.
  2. Revised information on the medicinal product.
4. A.4. Change in the name and/or address of a manufacturer, including where relevant quality control authorities, or supplier of the active substance, starting material, reagent or intermediate used in the manufacture of the active substance (where specified in the product application dossier) where no European Pharmacopoeial Certificate of Suitability is part of the approved application dossier. Condition: 1 Documentation: 1, 2, 3

IA

4.1. Condition:
  1. The manufacturing site and all manufacturing operations shall remain the same.
4.2. Documentation:
  1. A formal document from a relevant competent authority (for example, Commercial Register, Chamber of Commerce) in which the new name or new address is mentioned.
  2. Amendments to the relevant sections of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
  3. In case of change in the name of the holder of the Active Substance Master File, updated "letter of access".
5. A.5. Change in the name or address of a manufacturer of the finished product, including quality control site:  
  a) manufacturer responsible for batch release; Condition: 1 Documentation: 1, 2

IAIN

  b) other manufacturers. Condition: 1 Documentation: 1, 2

IA

5.1. Condition:
  1. The manufacturing site and all manufacturing operations shall remain the same.
5.2. Documentation:
  1. Copy of the modified special permit (licence) (if available); or a formal document from a relevant competent authority, for example Chamber of Commerce, or if not available, from an agency, in which the new name or address is mentioned.
  2. If applicable, amendments to the relevant sections of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including revised information on the medicinal product as appropriate.
6. A.6. Change in Anatomical Therapeutic Chemical Code (ATC Code). Condition: 1 Documentation: 1, 2

IA

6.1. Condition:
  1. Change following granting of or amendment to ATC Code.
6.2. Documentation:
  1. Proof of acceptance issued by the World Health Organisation or copy of the ATC Code list.
  2. Revised information on the medicinal product.
7. A.7. Deletion of manufacturing sites, including for an active substance, intermediate or finished product, packaging site, manufacturer responsible for batch release, site where batch control takes place, or supplier of a starting material, reagent or excipient, when mentioned in the application dossier. Conditions: 1, 2 Documentation: 1, 2

IA

7.1. Conditions:
1. There should at least remain one site or manufacturer, as previously authorised, performing the same function as the one concerned by the deletion.
  2. The deletion should not be due to critical deficiencies concerning manufacturing.
7.2. Documentation:
  1. The variation application form should clearly outline the present and proposed manufacturer.
  2. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including revised information on medicinal product as appropriate.

2. B Quality changes

2.1. B.I. Active substance

2.1.1. B.I. a) manufacture

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

8. B.I.a.1. Change in the manufacturer of a starting material, reagent and intermediate used in the manufacturing process of the active substance or change in the manufacturer, including where relevant quality control site, of the active substance, where no European Pharmacopoeial Certificate of Suitability is part of the approved application dossier:  
  a) the proposed manufacturer is part of the same pharmaceutical group as the currently approved manufacturer; Conditions: 1, 2, 3 Documentation: 1, 2, 3, 4, 5, 6, 7

IAIN

  b) introduction of a new manufacturer of the active substance that is supported by an Active Substance Master File;    

II

  c) the proposed manufacturer uses a substantially different route of synthesis or manufacturing conditions, which may have a potential to change important quality characteristics of the active substance, such as qualitative and quantitative impurity profile requiring qualification, or physico-chemical properties impacting on bioavailability;    

II

  d) new manufacturer of material for which an assessment is required of viral safety and Transmissible Spongiform Encephalopathy risk (TSE risk) in animals;    

II

  e) the change relates to a biological active substance or a starting material/reagent/intermediate used in the manufacture of a biological/immunological product;    

II

  f) changes to quality control testing arrangements for the active substance-replacement or addition of a site where batch control and testing takes place. Conditions: 2, 4 Documentation: 1, 5

IA

8.1. Conditions:
  1. For starting materials and reagents the specifications, including in process controls and methods of analysis of materials, are identical to those already approved. For intermediates and active substances the specifications, including in process controls and methods of analysis of materials, method of preparation, including batch size and detailed route of synthesis are identical to those already approved.
  2. The active substance is not a biological, including immunological substance or sterile.
  3. Where materials of human or animal origin are used in the process, the manufacturer does not use any new supplier for which assessment is required of viral safety or of compliance with the guidance on minimising the TSE risk referred to in Paragraph 32 of Annex 3 to this Regulation.
  4. Method transfer from the old to the new site has been successfully completed.
8.2. Documentation:
  1. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
  2. A declaration from the owner of the registration or the holder of the Active Substance Master File, where applicable, that the synthetic route (or in case of herbal medicinal products, where appropriate the method of preparation, geographical source, production of herbal drug and manufacturing route) quality control procedures and specifications of the active substance and of the starting material, reagent and intermediate in the manufacturing process of the active substance, if applicable, are the same as those already approved.
  3. Either a TSE European Pharmacopoeial Certificate of Suitability for any new source of material or, where applicable, documentary evidence that the specific source of the TSE risk material has previously been assessed by the competent authority and shown to comply with the guidance on minimising the TSE risk referred to in Paragraph 32 of Annex 3 to this Regulation. The information should include the following: name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, its use and previous acceptance. For the centralised procedure, this information should be included in an updated TSE table A and B, if relevant.
  4. Batch analysis data (in a comparative tabular format) for at least two batches (minimum pilot scale) of the active substance from the current and proposed manufacturers/sites.
  5. The variation application form should clearly outline the present and proposed manufacturers.
  6. A declaration by the Qualified Person of each of the manufacturing authorisation holders listed in the application where the active substance is used as a starting material and a declaration by the Qualified Person responsible for batch release. These declarations should state that the active substance manufacturer referred to in the application operate in compliance with the requirements on good manufacturing practice for starting materials. A single declaration may be acceptable under certain circumstances in accordance with the determined in Sub-paragraph 28.3 of this Annex.
  7. Where relevant, a commitment of the manufacturer of the active substance to inform the owner of the registration of any changes to the manufacturing process, specifications and test (analytical) procedures of the active substance.
9. B.I.a.2. Changes in the manufacturing process of the active substance:  
 

a) minor change in the manufacturing process of the active substance;

Conditions: 1, 2, 3, 4, 5, 6, 7 Documentation: 1, 2, 3

IA

  b) substantial change to the manufacturing process of the active substance which may have a significant impact on the quality, safety or efficacy of the medicinal product;  

II

  c) the change refers to a biological, including immunological, substance or use of a different chemically derived substance in the manufacture of a biological, including immunological, medicinal product and is not related to a protocol;  

II

  d) the change relates to a herbal medicinal product and there is a change to any of the following: geographical source, manufacturing route or production;  

II

  e) minor change to the restricted part of an Active Substance Master File.   Documentation: 1, 2, 3, 4

IB

9.1. Conditions:
  1. No adverse change in qualitative and quantitative impurity profile or in physico-chemical properties.
  2. The synthetic route remains the same, for example intermediates remain the same and there are no new reagents, catalysts or solvents used in the process. In the case of herbal medicinal products, the geographical source, production of the herbal substance and the manufacturing route remain the same.
  3. The specifications of the active substance or intermediates are unchanged.
  4. The change is fully described in the open ("applicant's") part of an Active Substance Master File, if applicable.
  5. The active substance is not a biological, including immunological, substance.
  6. The change does not refer to the geographical source, manufacturing route or production of a herbal medicinal product.
  7. The change does not refer to the restricted part of an Active Substance Master File.
9.2. Documentation:
  1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, as appropriate, and of the approved Active Substance Master File, where applicable, including a direct comparison of the present process and the new process.
  2. Batch analysis data in comparative tabular format of at least two batches (minimum pilot scale) manufactured according to the currently approved and proposed process.
  3. Copy of approved specifications of the active substance.
  4. A declaration from the owner of the registration or the holder of the Active Substance Master File, where applicable, that there is no change in qualitative and quantitative impurity profile or in physico-chemical properties, that the synthetic route remains the same and that the specifications of the active substance or intermediates are unchanged.
9.3. Note:
  1. For chemical active substances, Paragraph 9, Sub-paragraph "b" of this Annex refers to substantial changes to the synthetic route or manufacturing conditions which may have a potential to change important quality characteristics of the active substance, such as qualitative and quantitative impurity profile requiring qualification, or physico-chemical properties impacting on bioavailability.
10. B.I.a.3. Change in batch size, including batch size ranges, of active substance or intermediate:  
  a) up to 10-fold increase compared to the currently approved batch size; Conditions: 1, 2, 3, 4, 6, 7, 8 Documentation: 1, 2, 5

IA

  b) downscaling; Conditions: 1, 2, 3, 4, 5 Documentation: 1, 2, 5

IA

  c) the change requires assessment of the comparability of a biological, including immunological, active substance;  

II

  d) more than 10-fold increase compared to the currently approved batch size;   Documentation: 1, 2, 3, 4

IB

  e) the scale for a biological, including immunological, active substance is increased and decreased without process change.   Documentation: 1, 2, 3, 4

II IB

10.1. Conditions:
  1. Any changes to the manufacturing methods are only those necessitated by scale-up or downscaling, for example use of different-sized equipment.
  2. Test results of at least two batches according to the specifications should be available for the proposed batch size.
  3. The product concerned is not a biological, including immunological, medicinal product.
  4. The change does not adversely affect the reproducibility of the process.
  5. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
  6. The specifications of the active substance and intermediates remain the same.
  7. The active substance is not sterile.
  8. The currently approved batch size was not approved via a Type IA variation.
10.2. Documentation:
  1. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
  2. The batch numbers of the tested batches having the proposed batch size.
  3. Batch analysis data in a comparative tabulated format on a minimum of one production batch of the active substance or intermediate as appropriate, manufactured to both the currently approved and the proposed sizes. Batch data on the next two full production batches should be made available upon request and reported by the owner of the registration if outside specification, with proposed action.
  4. Copy of approved specifications of the active substance and of the intermediate, if applicable.
  5. A declaration from the owner of the registration or the holder of the Active Substance Master File as appropriate that the changes to the manufacturing methods are only those necessitated by scale-up or downscaling, for example use of different-sized equipment, that the change does not adversely affect the reproducibility of the process, that it is not the result of unexpected events arising during manufacture or because of stability concerns and that the specifications of the active substance and intermediates remain the same.
11. B.I.a.4. Change to in-process tests or limits (approval criteria) applied during the manufacture of the active substance:  
  a) tightening of in-process limits; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IA

  b) addition of a new in-process test and limits; Conditions: 1, 2, 5, 6 Documentation: 1, 2, 3, 4, 6

IA

  c) deletion of a non-significant in-process test; Conditions: 1, 2 Documentation: 1, 2, 5

IA

  d) widening of the approved in-process test limits, which may have a significant effect on the overall quality of the active substance;  

II

  e) deletion of an in-process test which may have a significant effect on the overall quality of the active substance;  

II

  f) addition or replacement of an in-process test as a result of a safety or quality issue.   Documentation: 1, 2, 3, 4, 6

IB

11.1. Conditions:
  1. The change is not a consequence of any commitment from previous assessments to review specification limits, for example made during the procedure for the application dossier assessment or a type II variation procedure.
  2. The change does not result from unexpected events arising during manufacture, for example new unqualified impurity, change in total impurity limits.
  3. Any change should be within the range of currently approved limits.
  4. The test procedure remains the same, or changes in the test procedure are minor.
  5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
  6. The new test method is not a biological, immunological and immunochemical method or a method using a biological reagent for a biological active substance (does not include standard pharmacopoeial microbiological methods).
11.2. Documentation:
  1. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
  2. Comparative table of current and proposed in-process tests.
  3. Details of any new non-pharmacopoeial analytical method and validation data, where relevant.
  4. Batch analysis data on two production batches of the active substance, but three production batches for biologicals, unless otherwise justified, for all specification parameters.
  5. Justification and risk-assessment from the owner of the registration or the holder of the Active Substance Master File as appropriate showing that the parameter is non-significant.
  6. Justification from the owner of the registration or the holder of the Active Substance Master File as appropriate for the new in-process test and limits.
12. B.I.a.5. Changes to the active substance of a seasonal, prepandemic or pandemic vaccine against human influenza:  
  a) replacement of the strain in a seasonal, prepandemic or a pandemic vaccine against human influenza.  

II

2.1.2. B.I. b) Control of active substance

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

13. B.I.b.1. Change in the specification parameters and limits of an active substance, starting material, intermediate and reagent used in the manufacturing process of the active substance:  
  a) tightening of specification limits for medicinal products subject to Official Batch Release; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IAIN

  b) tightening of specification limits; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IA

  c) addition of a new specification parameter to the specification with its corresponding test method; Conditions: 1, 2, 5, 6, 7 Documentation: 1, 2, 3, 4, 7

IA

  d) deletion of a non-significant specification parameter, for example deletion of an obsolete parameter; Conditions: 1, 2 Documentation: 1, 2, 6

IA

  e) deletion of a specification parameter which may have a significant effect on the overall quality of the active substance and the finished product;  

II

  f) change outside the approved specifications limits range for the active substance;  

II

g) widening of the approved specifications limits for starting materials and intermediates, which may have a significant effect on the overall quality of the active substance and the finished product;

II

  h) addition or replacement (excluding biological or immunological active substance) of a specification parameter as a result of a safety or quality issue.   Documentation: 1, 2, 3, 4, 5, 7

IB

13.1. Conditions:
  1. The change is not a consequence of any commitment from previous assessments to review specification limits, for example made during the procedure for the application dossier assessment or a type II variation procedure.
  2. The change does not result from unexpected events arising during manufacture e.g. new unqualified impurity, change in total impurity limits.
  3. Any change should be within the range of currently approved limits.
  4. The test procedure remains the same, or changes in the test procedure are minor.
  5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
  6. The test method is not a biological, immunological and immunochemical method or a method using a biological reagent for a biological active substance. Standard pharmacopoeia microbiological method is not included.
  7. The change does not concern a genotoxic impurity.
13.2. Documentation:
  1. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
  2. Comparative table of current and proposed specifications.
  3. Details of any new analytical method and validation data, where relevant.
  4. Batch analysis data on two production batches of the active substance, but three production batches for biologicals, unless otherwise justified, for all specification parameters.
  5. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch containing the active substance complying with the current and proposed specification. For herbal medicinal products, comparative disintegration data may be acceptable.
  6. Justification and risk-assessment from the owner of the registration and the holder Active Substance Master File as appropriate showing that the parameter is non-significant.
 

7. Justification from the owner of the registration and the holder Active Substance Master File as appropriate of the new specification parameter and the limits.

14. B.I.b.2. Change in test procedure for active substance or starting material, reagent, intermediate used in the manufacturing process of the active substance:  
  a) minor changes to an approved test procedure; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IA

  b) deletion of a test procedure for the active substance or a starting material, reagent and intermediate, if an alternative test procedure is already authorised; Conditions: 7 Documentation: 1

IA

  c) other changes to a test procedure, including replacement or addition, for a reagent, which does not have a significant effect on the overall quality of the active substance; Conditions: 1, 2, 3, 5, 6 Documentation: 1, 2

IA

  d) change (replacement) to a biological, immunological and immunochemical test method or a method using a biological reagent for a biological active substance, for example peptide map, glyco-map, etc.;  

II

  e) other changes to a test procedure, including replacement or addition, for the active substance or a starting material and intermediate.   Documentation: 1, 2

IB

14.1. Conditions:
  1. Appropriate validation studies have been performed in accordance with the relevant guidelines and show that the updated test procedure is at least equivalent to the former test procedure.
  2. There have been no changes of the total impurity limits no new unqualified impurities are detected.
  3. The method of analysis should remain the same, for example a change in column length or temperature, but not a different type of column or method.
  4. The test method is not a biological, immunological and immunochemical method, or a method using a biological reagent for a biological active substance. Standard pharmacopoeial microbiological method is not included.
  5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
  6. The active substance is not biological, including immunological.
  7. An alternative test procedure is already authorised for the specification parameter and this procedure has not been added through notification regarding IA and IAIN type variations.
14.2. Documentation:
  1. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including a description of the analytical methodology, a summary of validation data, revised specifications for impurities, if applicable.
  2. Comparative validation results, or if justified comparative analysis results showing that the current test and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new test procedure.

2.1.3. B.I. c) Container closure system

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

15. B.I.c.1. Change in immediate packaging of the active substance:  
  a) qualitative and quantitative composition; Conditions: 1, 2, 3 Documentation: 1, 2, 3, 4, 6

IA

  b) qualitative and quantitative composition for sterile and non-frozen biological, including immunological, active substances;  

II

  c) liquid active substances (non sterile).   Documentation: 1, 2, 3, 5, 6

IB

15.1. Conditions:
  1. The proposed packaging material must be at least equivalent to the approved material in respect of its relevant properties.
  2. Relevant stability studies have been started under ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation and relevant stability parameters have been assessed in at least two pilot scale or industrial scale batches and at least three months satisfactory stability data are at the disposal of the applicant at time of implementation. However, if the proposed packaging is more resistant than the existing packaging, the three months' stability data do not yet have to be available. These studies must be finalised and the data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the shelf-life period (with proposed action).
  3. Sterile, liquid and biological, including immunological, active substances are excluded.
15.2. Documentation:
  1. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
  2. Appropriate data on the new packaging, for example comparative data on permeability, for example for O2, CO2 moisture, including a confirmation that the material complies with relevant pharmacopoeial requirements or legislation of the European Union on plastic materials and objects in contact with foodstuffs.
  3. Where appropriate, proof must be provided that no interaction between the content and the packaging material occurs, for example no migration of components of the proposed material into the content and no loss of components of the product into the pack, including confirmation that the material complies with relevant pharmacopoeia requirements or legislation of the European Union on plastic material and objects in contact with foodstuffs.
  4. A declaration from the owner of the registration or the holder of the Active Substance Master File as appropriate that the required stability studies have been started under ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation with indication of the batch numbers concerned and that, as relevant, the required minimum satisfactory stability data were at the disposal of the applicant at time of implementation and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
  5. The results of stability studies that have been carried out under ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation, on the relevant stability parameters, on at least two pilot or industrial scale batches, covering a minimum period of three months, and an assurance is given that these studies will be finalised, and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved retest period (with proposed action).
  6. Comparison of the current and proposed immediate packaging specifications, if applicable.
16. B.I.c.2. Change in the specification parameters and limits of the immediate packaging of the active substance:  
  a) tightening of specification limits; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IA

  b) addition of a new specification parameter to the specification with its corresponding test method; Conditions: 1, 2, 5 Documentation: 1, 2, 3, 4, 6

IA

  c) deletion of a non-significant specification parameter, for example deletion of an obsolete parameter; Conditions: 1, 2 Documentation: 1, 2, 5

IA

  d) addition or replacement of a specification parameter as a result of a safety or quality issue.   Documentation: 1, 2, 3, 4, 6

IB

16.1. Conditions:
  1. The change is not a consequence of any commitment from previous assessments to review specification limits, for example made during the procedure for the application dossier application or a type II variation procedure, unless it has been previously assessed and agreed as part of a follow-up measure.
  2. The change does not result from unexpected events arising during manufacture of the packaging material or during storage of the active substance.
  3. Any change should be within the range of currently approved limits.
  4. The test procedure remains the same, or changes in the test procedure are minor.
  5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
16.2. Documentation:
  1. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
  2. Comparative table of current and proposed specifications.
  3. Details of any new analytical method and validation data, where relevant.
  4. Batch analysis data on two batches of the immediate packaging for all specification parameters.
  5. Justification and risk-assessment from the owner of the registration or the holder of the Active Substance Master File, as appropriate, showing that the parameter is non-significant.
  6. Justification from the owner of the registration or the holder of the Active Substance Master File, as appropriate, of the new specification parameter and the limits.
17. B.I.c.3. Change in test procedure for the immediate packaging of the active substance  
  a) minor changes to an approved test procedure; Conditions: 1, 2, 3 Documentation: 1, 2

IA

  b) other changes to a test procedure (including replacement or addition); Conditions: 1, 3, 4 Documentation: 1, 2

IA

  c) deletion of a test procedure if an alternative test procedure is already authorised. Conditions: 5 Documentation: 1

IA

17.1. Conditions:
  1. Appropriate validation studies have been performed in accordance with the relevant guidelines and show that the updated test procedure is at least equivalent to the former test procedure.
  2. The method of analysis should remain the same, for example a change in column length or temperature, but not a different type of column or method.
  3. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
  4. The active substance and finished product is not biological, including immunological.
5.There is still a test procedure registered for the specification parameter and this procedure has not been added through notification regarding IA and IAIN type variations.
17.2. Documentation:
  1. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including a description of the analytical methodology, a summary of validation data.
2. Comparative validation results or if justified comparative analysis results showing that the current test and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new test procedure.

2.1.4. B.I. d) Stability

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

18. B.I.d.1. Change in the re-test period and storage period or storage conditions of the active substance where no European Pharmacopoeia Certificate of Suitability covering the retest period is part of the approved application dossier:  
  a) re-test period and storage period:  
  1. Reduction. Condition: 1 Documentation: 1, 2, 3

IA

  2. Extension of the retest period based on extrapolation of stability data not in accordance with ICH guidelines included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation. Not applicable for biological, including immunological active substance.  

II

  3. Extension of storage period of a biological, including immunological active substance not in accordance with an approved stability protocol.  

II

  4. Extension or introduction of a re-test period and storage period supported by real time data.   Documentation: 1, 2, 3

IB

  b) Storage conditions:  
  1. Change to more restrictive storage conditions of the active substance. Condition: 1 Documentation: 1, 2, 3

IA

  2. Change in storage conditions of biological, including immunological, active substances, when the stability studies have not been performed in accordance with a currently approved stability protocol.  

II

  3. Change in storage conditions of the active substance.   Documentation: 1, 2, 3

IB

18.1. Condition:
  1. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
18.2. Documentation:
  1. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation that contains results of appropriate real time stability studies, conducted in accordance with the relevant stability guidelines on at least two, but three for biological medicinal products, pilot or production scale batches of the active substance in the authorised packaging material and covering the duration of the requested re-test period or requested storage conditions.
  2. Confirmation that stability studies have been done to the currently approved protocol. The studies must show that the agreed relevant specifications are still met.
  3. Copy of approved specifications of the active substance.

2.1.4. B.I. e) Design Space

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

19. B.I.e.1. Introduction of a new design space or extension of an approved design space for the active substance, concerning:  
  a) one unit operation in the manufacturing process of the active substance including the resulting inprocess controls and test procedures;   Documentation: 1, 2, 3

II

  b) test procedures for starting materials, reagents, intermediates and the active substance.   Documentation: 1, 2, 3

II

19.1. Documentation:
  1. The design space has been developed in accordance with the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation. Results from product, process and analytical development studies, for example interaction of the different parameters forming the design space have to be studied, including risk assessment and multivariate studies, as appropriate, demonstrating where relevant that a systematic mechanistic understanding of material attributes and process parameters to the critical quality attributes of the active substance has been achieved.
  2. Description of the Design space in tabular format, including the variables , including material attributes and process parameters, as appropriate, and their proposed ranges.
  3. Amendment of the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
20. B.I.e.2. Introduction of a post approval change management protocol related to the active substance   Documentation: 1, 2

II

20.1. Documentation:
  1. Detailed description for the proposed change.
  2. Change management protocol related to the active substance.
21. B.I.e.3. Deletion of an approved change management protocol related to the active substance. Condition: 1 Documentation: 1

IAIN

21.1. Condition:
  1. The deletion of the approved change management protocol related to the active substance is not a result of unexpected events or out of specification results during the implementation of the change described in the protocol.
21.2. Documentation:
1. Justification for the proposed deletion.

2.2. B.II. Finished product

2.2.1. B.II. a) Description and composition

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

22. B.II.a.1. Change or addition of imprints, bossing or other markings including replacement, or addition of colouring matter (ink) used for product marking:  
  a) changes in imprints, bossing or other markings; Conditions: 1, 2, 3 Documentation: 1, 2

IAIN

  b) changes in scoring and break lines intended to divide into equal doses.   Documentation: 1, 2, 3

IB

22.1. Conditions:
  1. Finished product release and end of shelf life specifications have not been changed, except for appearance.
2. Any colouring matters (ink) must comply with the relevant pharmaceutical legislation regulating the permitted colouring matters for foodstuffs.
  3. The scoring and break lines are not intended to divide into equal doses.
22.2. Documentation:
1. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including a detailed drawing or written description of the current and new appearance, and including revised product information as appropriate.
2. Sample of the finished product where applicable in accordance with the requirements for samples collected in the Member States that are included in the recommendations of the European Commission on documentation referred to in Section 28.1 of the Pharmaceutical Law.
3. Results of the appropriate European Pharmacopoeia tests demonstrating equivalence in characteristics and correct dosing.
23. B.II.a.2. Change in the shape or dimensions of the pharmaceutical form
  a) immediate release tablets, capsules, suppositories and pessaries; Conditions: 1, 2, 3, 4 Documentation: 1, 4

IAIN

  b) gastro-resistant, modified or prolonged release pharmaceutical forms and scored tablets intended to be divided into equal doses.   Documentation: 1, 2, 3, 4, 5

IB

23.1. Conditions:
  1. If appropriate, the dissolution profile of the reformulated product is comparable to the old one. For herbal medicinal products, where dissolution testing may not be feasible, the disintegration time of the new product compared to the old one.
  2. Release and end of shelf-life specifications of the product have not been changed, except for dimensions.
  3. The qualitative or quantitative composition and mean mass remain unchanged.
  4. The change does not relate to a scored tablet that is intended to be divided into equal doses.
23.2. Documentation:
1. Amendment of the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including a detailed drawing of the current and proposed situation, and including revised product information as appropriate.
2. Comparative dissolution data on at least one pilot batch of the current and proposed dimensions (no significant differences regarding comparability see the relevant guidance on bioavailability and bioequivalence included in the guidelines referred to in Sub-paragraph 23.1 of this Regulation). For herbal medicinal product comparative disintegration data may be acceptable.
3. Justification for not submitting a new bioequivalence study according to the relevant guidance on bioavailability and bioequivalence included in the guidelines referred to in Sub-paragraph 23.1 of this Regulation.
4. Sample of the finished product where applicable in accordance with the requirements for samples collected in the Member States that are determined in the recommendations of the European Commission on documentation referred to in Section 28.1 of the Pharmaceutical Law.
5. Results of the appropriate European Pharmacopoeia tests demonstrating equivalence in characteristics and correct dosing.
24. B.II.a.3. Changes in the composition (excipients) of the finished product:  
  a) changes in components of the flavouring or colouring system:  
  1. Addition, deletion or replacement. Conditions: 1, 2, 3, 4, 5, 6, 7, 9 Documentation: 1, 2, 4, 5, 6

IAIN

  2. Increase or reduction. Conditions: 1, 2, 3, 4 Documentation: 1, 2, 4

IA

  b) other excipients:  
  1. Any minor adjustment of the quantitative composition of the finished product with respect to excipients. Conditions: 1, 2, 4, 8, 9, 10 Documentation: 1, 2, 7

IA

  2. Qualitative or quantitative changes in one or more excipients that may have a significant impact on the safety, quality or efficacy of the medicinal product.  

II

  3. Change that relates to a biological including immunological medicinal product.  

II

  4. Any new excipient that includes the use of materials of human or animal origin for which assessment is required of viral safety data or TSE risk.  

II

  5. Change that is supported by a bioequivalence study.  

II

  6. Replacement of a single excipient with a comparable excipient with the same functional characteristics and at a similar level.   Documentation: 1, 3, 4, 5, 6, 7, 8, 9, 10

IB

24.1. Conditions:
  1. No change in functional characteristics of the pharmaceutical form, for example disintegration time, dissolution profile.
  2. Any minor adjustment to the formulation to maintain the total weight should be made by an excipient which currently makes up a major part of the finished product formulation.
  3. The finished product specification has only been updated in respect of appearance, odour, taste and if relevant, deletion of an identification test.
  4. Stability studies have been started under the ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation with indication of batch numbers, and relevant stability parameters have been assessed in at least two pilot scale or industrial scale batches and at least three months satisfactory stability data are at the disposal of the applicant at time of implementation for Type IA variation procedure and at time of notification for Type IB variation and that the stability profile is similar to the currently registered situation. Assurance is given that these studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specification at the end of the approved shelf life (with proposed action). In addition, where relevant, photo-stability testing should be performed.
  5. Any new proposed components must comply with the relevant regulatory enactments regarding mandatory safety requirements for food additives (for flavourings and colouring matters).
  6. Any new component does not include the use of materials of human or animal origin for which assessment is required of viral safety data or compliance with the guidance on minimising the TSE risk referred to in Paragraph 32 of Annex 3 to this Regulation for medicinal products for human use.
  7. Where applicable, the change does not affect the differentiation between strengths and does not have a negative impact on taste acceptability for paediatric formulations.
  8. The dissolution profile of the new product determined on a minimum of two pilot scale batches is comparable to the old one, and no significant differences regarding comparability, see the guidance on bioavailability and bioequivalence included in the guidelines referred to in Sub-paragraph 23.1 of this Regulation). For herbal medicinal products where dissolution testing may not be feasible, the disintegration time of the new product is comparable to the old one.
  9. The change is not the result of stability issues and should not result in potential safety concerns, for example differentiation between strengths of medicinal products.
  10. The product concerned is not a biological, including immunological, medicinal product.
24.2. Documentation:
1. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including identification method for any new colorant, where relevant, and including revised product information on the medicinal product as appropriate.
2. A declaration that the required stability studies have been started under ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation with indication of the batch numbers concerned and that, as relevant, the required minimum satisfactory stability data were at the disposal of the applicant at time of implementation and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
3. The results of stability studies that have been carried out under ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation, on the relevant stability parameters, on at least two pilot or industrial scale batches, covering a minimum period of three months, and an assurance is given that these studies will be finalised, and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
4. Sample of the new product, where applicable, in accordance with the requirements for samples collected in the Member States that are included in the recommendations of the European Commission on documentation referred to in Section 28.1 of the Pharmaceutical Law.
5. Either a European Pharmacopoeial Certificate of Suitability for any new component of animal susceptible to TSE risk or where applicable, documentary evidence that the specific source of the TSE risk material has been previously assessed by the competent authority and shown to comply with the scope of the current guidance referred to in Paragraph 32 of Annex 3 to this Regulation on minimising the TSE risk via human medicinal products. The following information should be included for each such material: name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals and its use. For the Centralised Procedure, this information should be included in an updated TSE table A (and B, if relevant).
6. Data to demonstrate that the new excipient does not interfere with the finished product specification test methods, if appropriate.
7. Justification for the change and choice of excipients, for example must be given by appropriate development pharmaceutics, including stability aspects and antimicrobial preservation where appropriate.
8. For solid dosage forms, comparative dissolution profile data of at least two pilot scale batches of the finished product in the new and old composition. For herbal medicinal products, comparative disintegration data may be acceptable.
9. Justification for not submitting a new bioequivalence study in accordance with the guidance on bioavailability and bioequivalence included in the guidelines referred to in Sub-paragraph 23.1 of this Regulation.
25. B.II.a.4. Change in coating weight of oral dosage forms or change in weight of capsule shells:  
  a) solid oral pharmaceutical forms; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IA

  b) gastro-resistant, modified or prolonged release pharmaceutical forms where the coating is a critical factor for the release mechanism.  

II

25.1. Conditions:
  1. The dissolution profile of the new product determined on a minimum of two pilot scale batches is comparable to the old one. For herbal medicinal products where dissolution testing may not be feasible, the disintegration time of the new product is comparable to the old one.
  2. The coating is not a critical factor for the release mechanism.
  3. The finished product specification has only been updated in respect of weight and dimensions, if applicable.
  4. Stability studies in accordance with ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation have been started with at least two pilot scale or industrial scale batches and at least three months satisfactory stability data are at the disposal of the applicant at the time of implementation and assurance that these studies will be finalised. Data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
25.2. Documentation:
1. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
2. A declaration that the required stability studies have been started under ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation with indication of the batch numbers concerned and that, as relevant, the required minimum satisfactory stability data were at the disposal of the applicant at time of implementation and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action). In addition, where relevant, photo-stability testing should be performed.
26. B.II.a.5. Change in concentration of a single-dose, total use parenteral product, where the amount of active substance per unit dose (i.e. the strength) remains the same.  

II

27. B.II.a.6. Deletion of the solvent/diluent container from the pack.   Documentation: 1, 2

IB

27.1. Documentation:
  1. Justification for the deletion, including a statement regarding alternative means to obtain the solvent and diluent as required for the safe and effective use of the medicinal product.
  2. Revised medicinal product information.

2.2.2. B.II. b) Manufacture

28. B.II.b.1. Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product:
  a) secondary packaging site; Conditions: 1, 2 Documentation: 1, 3, 8

IAIN

  b) primary packaging site; Conditions: 1, 2, 3, 4, 5 Documentation: 1, 2, 3, 4, 8, 9

IAIN

  c) site where any manufacturing operation take place, except batch release, batch control, and secondary packaging, for biological, including immunological, medicinal products;  

II

  d) site which requires an initial or product specific inspection;  

II

  e) site where any manufacturing operation take place, except batch-release, batch control, primary and secondary packaging, for nonsterile medicinal products;   Documentation: 1, 2, 3, 4, 5, 6, 7, 8, 9

IB

  f) site where any manufacturing operation take place, except batch release, batch control, and secondary packaging, for sterile medicinal products manufactured using an aseptic method excluding biological, including immunological, medicinal products.   Documentation: 1, 2, 3, 4, 5, 7, 8

IB

28.1. Conditions:
1. Satisfactory inspection in the last three years by an inspection service of one of the Member States of the European Economic Area or of a country where an operational Good Manufacturing Practice mutual recognition agreement exists between the country concerned and the European Union.
2. Site appropriately authorised to manufacture the pharmaceutical form or product concerned.
3. Product concerned is not a sterile product.
4. Where relevant, for instance for suspensions and emulsions, validation scheme is available or validation of the manufacture at the new site has been successfully carried out according to the current protocol with at least three production scale batches.
5. Product concerned is not a biological, including immunological, medicinal product.
28.2. Documentation:
1. Proof that the proposed site is appropriately authorised for the pharmaceutical form or product concerned:

1.1. for a manufacturing site within the Member State of the European Economic Area a copy of the current special permit (licence). A reference to the European Union database on manufacturing and import authorisations and Good Manufacturing Practice certificates (EudraGMP database) will suffice once the public version is operational;

1.2. for a manufacturing site outside the Member State of the European Economic Area where an operational Good Manufacturing Practice mutual recognition agreement exists between the country concerned and the European Union: a Good Manufacturing Practice certificate issued within the last three years by the relevant competent authority. A reference to the EudraGMP database will suffice once the public version is operational;

1.3. for a manufacturing site outside the Member State of the European Economic Area where no operational Good Manufacturing Practice mutual recognition agreement exists between the country concerned and the European Union: a Good Manufacturing Practice certificate issued within the last three years by the relevant competent authority. A reference to the EudraGMP database will suffice once the public version is operational.

2. Where relevant, the batch numbers, corresponding batch size and the manufacturing date of batches (≥ 33) used in the validation study should be indicated and the validation data presented, or validation protocol (scheme) to be submitted.
3. The variation application form should clearly outline the "present" and "proposed" finished product manufacturers.
4. Copy of approved release and end-of-shelf life specifications if relevant.
5. Batch analysis data on one production batch and two pilot-scale batches or two production batches simulating the production process and comparative data on the last three batches from the previous site. Batch data on the next two production batches should be available on request or reported if outside specifications (with proposed action).
6. For semisolid and liquid formulations in which the active substance is present in non-dissolved form, appropriate validation data including microscopic imaging of particle size distribution and morphology.
7. If the new manufacturing site uses the active substance as a starting material, a declaration by the Qualified Person at the site responsible for batch release that the active substance is manufactured in accordance with the detailed guidelines on good manufacturing practice of medicinal products and medicinal products to be studied for starting materials referred to in regulatory enactments regarding procedures for manufacture and control of medicinal products. In addition to the determined in Sub-paragraph 28.2.7.1 of this Regulation, if the new manufacturing site is located within the Member State of European Economic Area and uses the active substance as a starting material, a declaration by the Qualified Person of the new manufacturing site that the active substance used is manufactured in accordance with the guidelines of the European Commission on good manufacturing practice of medicinal products and medicinal products to be studied for starting materials that is referred to in regulatory enactments regarding the procedures for manufacture and control of medicinal products.
8. Amendments to the relevant section of the application dossier presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
9. If the manufacturing site and the primary packaging site are different, conditions of transport and bulk storage should be specified and validated.
28.3. Notes:
1. In case of a change in or a new manufacturing site in a country outside the European Economic Area without an operational good manufacturing practice mutual recognition agreement with the European Union, owners of the registration are advised to consult the relevant competent authorities first before making the submission of the notification and to provide information about any previous inspection by a competent authority of the European Economic Area state in the last two to three years and any planned inspection including inspection dates, product category inspected, Supervisory Authority and other relevant information. This will facilitate the arrangement for a good manufacturing practice inspection by an inspection service of one of the Member States if needed.
2. The following conditions are to be met in relation to Qualified Person's declaration in respect of active substances:

2.1. owners of the registration are obliged to only use as starting materials active substances that have been manufactured in accordance with good manufacturing practice so a declaration is expected from each of the owners of the registration that use the active substance as a starting material. As the Qualified Person responsible for batch certification takes overall responsibility for each batch, a further declaration from the Qualified Person responsible for batch certification is expected when the batch release site is a different site from the above;

2.2. in many cases only one manufacturer is involved and therefore only one declaration may be submitted. However, when several manufacturers are involved rather than provide multiple declarations it may be acceptable to provide a single declaration signed by one Qualified Person. This will be accepted provided that:

2.2.1. the declaration makes it clear that it is signed on behalf of all the involved Qualified Persons;

2.2.2. there is an agreement in which a Qualified Person providing the declaration is the one identified in the agreement as taking specific responsibility for the compliance of the active substance manufacturer with the Good Manufacturing Practice. The agreement is described in the guidelines of the European Commission regarding good manufacturing practice of medicinal products and medicinal products to be studied for starting materials referred to in regulatory enactments regarding the procedures for manufacture and control of medicinal products;

2.3. a Qualified Person is at the disposal of the owner of a special permit (licence) for manufacturing of medicinal products and located in the European Economic Area. Therefore declarations from personnel employed by manufacturers not located in the European Economic Area (third countries), including those located within countries with which good manufacturing practice mutual recognition agreement has been entered into with the European Union, are not acceptable;

2.4. it is observed that manufacture includes complete or partial manufacture, import, dividing up, packaging or presentation prior to its incorporation into a medicinal product, including repackaging or re-labelling as carried out by a distributor;

2.5. a declaration is not required for blood or blood components.

29. B.II.b.2. Change to batch release arrangements and quality control testing of the finished product:  
  a) replacement or addition of a site where batch control and testing takes place; Conditions: 2, 3, 4 Documentation: 1, 2, 5

IA

  b) replacement or addition of a manufacturer responsible for batch release:  
  1. Not including batch control and testing. Conditions: 1, 2 Documentation: 1, 2, 3, 4, 5

IAIN

  2. Including batch control and testing. Conditions: 1, 2, 3, 4 Documentation: 1, 2, 3, 4, 5

IAIN

  3. Including batch control and testing for a biological, including immunological, product and one of the test methods performed at that site is a biological, immunological or immunochemical method.  

II

29.1. Conditions:
  1. The manufacturer responsible for batch release must be located within the European Economic Area state.
  2. The site is appropriately authorised.
  3. The product is not a biological, including immunological, medicinal product.
  4. Method transfer from the old to the new site or new test laboratory has been successfully completed.
29.2. Documentation:
1. For a site :

1.1. within the European Economic Area, a copy of a special permit (licence) or where no special permit exists a certificate of good manufacturing practice compliance issued within the last three years by the relevant competent authority;

1.2. for a manufacturing site outside the European Economic Area where an operational good manufacturing practice mutual recognition agreement exists between the country concerned and the European Union: a good manufacturing practice certificate, issued within the last three years by the relevant competent authority. Where no such agreement exists a good manufacturing practice certificate issued within the last three years by a competent authority of the European Economic Area.

2. The variation application form should clearly outline the "present" and "proposed" finished product manufacturers.
3. Contact details of new contact person in the European Economic Area for product defects and recalls, if applicable, (for centralised procedure only).
4. A declaration by the Qualified Person responsible for batch certification stating that the active substance manufacturer referred to in the application dossier operate in compliance with the guidelines of the European Commission on good manufacturing practice of medicinal products and medicinal products to be studied for starting materials referred to in regulatory enactments regarding procedures for manufacturing and control of medicinal products. A single declaration may be acceptable under certain circumstance referred to in Sub-paragraph 28.3.2.2 of this Annex.
5. Amendment of the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including revised medicinal product information as appropriate.
30. B.II.b.3. Change in the manufacturing process of the finished product:  
  a) minor change in the manufacturing process of an immediate release solid oral dosage form or oral solutions; Conditions: 1, 2, 3, 4, 5, 6, 7 Documentation: 1, 3, 4, 6, 7, 8

IA

  b) substantial changes to a manufacturing process that may have a significant impact on the quality, safety and efficacy of the medicinal product;  

II

c) the product is a biological, including immunological, medicinal product and the change requires an assessment of comparability;

II

d) introduction of a non-standard terminal sterilisation method;

II

e) introduction or increase in the overage that is used for the active substance;

II

f) minor change in the manufacturing process of an aqueous oral solution (suspension). Documentation: 1, 2, 4, 6, 7, 8

IB

30.1. Conditions:
1. No change in qualitative and quantitative impurity profile or in physico-chemical properties.
2. The product concerned is not a biological, including immunological, or herbal medicinal product.
3. The manufacturing principle including the single manufacturing steps remain the same, for example processing intermediates. There are no changes to any manufacturing solvent used in the process.
4. The currently registered process has to be controlled by relevant in-process controls and no changes widening or deletion of limits are required to these controls.
5. The specifications of the finished product or intermediates are unchanged.
6. As a result of new process an identical product regarding all aspects of quality, safety and efficacy shall be obtained.
7. Relevant stability studies in accordance with the ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation have been started with at least one pilot scale or industrial scale batch and at least three months stability data are at the disposal of the applicant. Assurance is given that these studies will be finalised and that the data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
30.2. Documentation:
1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including a direct comparison of the present process and the new process.
2. For semi-solid and liquid products in which the active substance is present in non-dissolved form: appropriate validation of the change including microscopic imaging of particles to check for visible changes in morphology and comparative size distribution data by an appropriate method.
3. For solid dosage forms: dissolution profile data of one representative production batch and comparative data of the last three batches from the previous process. Data on the next two full production batches should be available on request or reported if outside specification (with proposed action). For herbal medicinal products, comparative disintegration data may be acceptable.
4. Justification for not submitting a new bioequivalence study according to the guidance on bioavailability and bioequivalence included in the guidelines referred to in Sub-paragraph 23.1 of this Regulation.
5. In case of a change to the sterilisation process, validation data should be provided.
6. Copy of approved release and end-of-shelf life specifications.
7. Batch analysis data in a comparative tabulated format on a minimum of one batch manufactured to both the currently approved and the proposed process. Batch data on the next two full production batches should be made available upon request and reported by the owner of the registration if outside specification (with proposed action).
8. Declaration that relevant stability studies have been started under ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation with indication of the batch numbers concerned and relevant stability parameters have been assessed in at least one pilot scale or industrial scale batch and at least three months satisfactory stability data are at the disposal of the applicant at time of notification and that the stability profile is similar to the currently registered situation. Assurance is given that these studies will be finalised and that the data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
31.

B.II.b.4. Change in the batch size, including batch size ranges, of the finished product:

 
  a) up to 10-fold compared to the currently approved batch size; Conditions: 1, 2, 3, 4, 5, 7 Documentation: 1, 4

IA

  b) downscaling down to 10-fold; Conditions: 1, 2, 3, 4, 5, 6 Documentation: 1, 4

IA

c) the change requires assessment of the comparability of a biological, including immunological, medicinal product;

II

d) the change relates to all other pharmaceutical forms manufactured by complex manufacturing processes;

II

e) more than 10-fold increase compared to the currently approved batch size for immediate release of active substance; Documentation: 1, 2, 3, 4, 5, 6

IB

f) the scale for a biological, including immunological medicinal product is increased and decreased without process change, for example duplication of line. Documentation: 1, 2, 3, 4, 5, 6

IB

31.1. Conditions:
1. The change does not affect reproducibility and consistency of the product.
2. The change relates to standard immediate release oral pharmaceutical forms or to non-sterile liquid based pharmaceutical forms.
3. Any changes to the manufacturing method and to the in-process controls are only those necessitated by the change in batch-size, for example use of different sized equipment.
4. Validation scheme is available or validation of the manufacture has been successfully carried out according to the current protocol with at least three batches at the proposed new batch size in accordance with the relevant guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation.
5. The product concerned is not a biological, including immunological, medicinal product.
6. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
7. The currently approved batch size was not approved via a Type IA variation procedure.
31.2. Documentation:
1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
2. Batch analysis data in a comparative tabulated format on a minimum of one production batch manufactured to both the currently approved and the proposed sizes. Batch data on the next two full production batches should be made available upon request and reported by the owner of the registration if outside specifications (with proposed action).
3. Copy of approved release and end-of-shelf life specifications.
4. Where relevant the batch numbers, corresponding batch size and the manufacturing date of batches (≥3) used in the validation study should be indicated or validation protocol (scheme) be submitted.
5. The validation results should be provided.
6. The results of stability studies that have been carried out under ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation, on the relevant stability parameters, on at least one pilot or industrial scale batch, covering a minimum period of three months. An assurance is given that these studies will be finalised, and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action). For biologicals, including immunologicals, a declaration that an assessment of comparability is not required.
32. B.II.b.5. Change to in-process tests or limits applied during the manufacture of the finished product:  
  a) tightening of in-process limits; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IA

b) addition of a new tests and limits; Conditions: 1, 2, 5, 6 Documentation: 1, 2, 3, 4, 5, 7

IA

c) deletion of a non-significant in-process test; Conditions: 1., 2. Documentation: 1, 2, 6

IA

d) deletion of an in-process test which may have a significant effect on the overall quality of the finished product;

II

e) widening of the approved in-process limits, which may have a significant effect on overall quality of the finished product;

II

f) addition or replacement of an in-process test as a result of a safety or quality issue. Documentation: 1, 2, 3, 4, 5, 7

IB

32.1. Conditions:
1. The change is not a consequence of any commitment from previous assessments to review specification limits, for example made during the procedure for the registration application or a type II variation procedure.
2. The change does not result from unexpected events arising during manufacture, for example new unqualified impurity.
3. Any change should be within the range of currently approved limits.
4. The test procedure remains the same, or changes in the test procedure are minor.
5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
6. The new test method is not a biological, immunological and immunochemical method or a method using a biological reagent for a biological active substance and it does not include Standard pharmacopoeial microbiological methods.
32.2. Documentation:
1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
2. Comparative table of current and proposed in-process tests and limits.
3. Details of any new analytical method and validation data, where relevant.
4. Batch analysis data on two production batches, but three production batches for biologicals, unless otherwise justified, of the finished product for all specification parameters.
5. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch manufactured using the current and new in-process tests. For herbal medicinal products, comparative disintegration data may be acceptable.
6. Justification and risk-assessment showing that the parameter is non-significant.
7. Justification of the new in-process test and limits.

2.2.3. B.II. c) Control of excipients

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

33. B.II.c.1. Change in the specification parameters and limits of an excipient:  
  a) tightening of specification limits; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IA

b) addition of a new specification parameter to the specification with its corresponding test method; Conditions: 1, 2, 5, 6, 7 Documentation: 1, 2, 3, 4, 6, 8

IA

c) deletion of a non-significant specification parameter, for example deletion of an obsolete parameter; Conditions: 1, 2 Documentation: 1, 2, 7

IA

d) change outside the approved specifications limits range;

II

e) deletion of a specification parameter which may have a significant effect on the overall quality of the finished product;

II

f) Addition or replacement (excluding biological, including immunological, medicinal product) of a specification parameter as a result of a safety or quality issue. Documentation: 1, 2, 3, 4, 5, 6, 8

IB

33.1. Conditions:
1. The change is not a consequence of any commitment from previous assessments to review specification limits, for example made during the procedure for the registration application or a type II variation procedure.
2. The change does not result from unexpected events arising during manufacture, for example new unqualified impurity and change in total impurity limits.
3. Any change should be within the range of currently approved limits.
4. The test procedure remains the same, or changes in the test procedure are minor.
5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
6. The test method is not a biological, immunological and immunochemical method, or a method using a biological reagent, and does not include standard pharmacopoeial microbiological methods.
7. The change does not concern a genotoxic impurity.
33.2. Documentation:
1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
2. Comparative table of current and proposed test and limits of the manufacturing process.
3. Details of any new analytical method and validation data, where relevant.
4. Batch analysis data on two production batches, but three production batches for biological excipients, of the excipient for all specification parameters.
5. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch produced using the current and new test in the manufacturing process. For herbal medicinal products comparative disintegration data may be acceptable.
6. Justification for not submitting a new bioequivalence study in accordance with the guidance on bioavailability and bioequivalence included in the guidelines referred to in Sub-paragraph 23.1 of this Regulation, if appropriate.
7. Justification and risk-assessment showing that the parameter is non-significant.
8. Justification of the new test and the limits in the manufacturing process.
34. B.II.c.2 Change in test procedure for an excipient:  
  a) minor changes to an approved test procedure; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IA

b) deletion of a test procedure if an alternative test procedure is already authorised; Documentation: 5. Documentation: 1

IA

c) replacement of a biological, immunological and immunochemical test method or a method using a biological reagent;

II

d) other changes to a test procedure, including replacement or addition. Documentation: 1, 2

IB

34.1. Conditions:
1. Appropriate validation studies have been performed in accordance with the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation and show that the updated test procedure is at least equivalent to the former test procedure.
2. There have been no changes of the total impurity limits; no new unqualified impurities are detected.
3. The method of analysis should remain the same, for example a change in column length or temperature, but not a different type of column or method.
4. The test method is not a biological, immunological and immunochemical method or a method using a biological reagent, and it does not include standard pharmacopoeial microbiological method.
5. An alternative test procedure is already authorised for the specification parameter and this procedure has not been added by notifying regarding IA and IAIN type variation .
34.2. Documentation:
1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including a description of the analytical methodology, a summary of validation data, revised specifications for impurities, if applicable.
2. Comparative validation results or if justified comparative analysis results showing that the current test and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new test procedure.
35. B.II.c.3 Change in source of an excipient or reagent with TSE risk:  
  a) from TSE risk material to vegetable or synthetic origin:      
1. For excipients or reagents not used in the manufacture of a biological, including immunological, active substance or medicinal product; Condition: 1 Documentation: 1

IA

2. For excipients or reagents used in the manufacture of a biological, including immunological, active substance or medicinal product; Documentation: 1, 2

IB

b) change or introduction of a TSE risk material or replacement of a TSE risk material from a different TSE risk material, not covered by a TSE certificate of suitability.

II

35.1. Condition:
1. Excipient and finished product release and end of shelf life specifications remain the same.
35.2. Documentation:
1. Declaration from the manufacturer or the owner of the registration of the material that it is purely of vegetable or synthetic origin.
2. Study of equivalence of the materials and the impact on production of the final material and impact on behaviour (for example, dissolution characteristics) of the finished product.
36. B.II.c.4 Change in synthesis or recovery (extraction) of a nonpharmacopoeial excipient, when described in the application dossier:      
  a) minor change in synthesis or recovery (extraction) of a nonpharmacopoeial excipient; Conditions: 1, 2 Documentation: 1, 2, 3, 4

IA

b) the specifications are affected or there is a change in physico-chemical properties of the excipient which may affect the quality of the finished product;

II

c) the excipient is a biological, including immunological, substance.

II

36.1. Conditions:
1. The synthetic route and specifications are identical and there is no change in qualitative and quantitative impurity profile (excluding residual solvents, provided they are controlled in accordance with ICH limits included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph . of this Regulation), or in physico-chemical properties.
2. Adjuvants are excluded.
36.2. Documentation:
1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
2. Batch analysis data in a comparative tabulated format of at least two batches (minimum pilot scale) of the excipient manufactured according to the old and the new process.
3. Where appropriate, comparative dissolution profile data for the finished product of at least two batches (minimum pilot scale). For herbal medicinal products, comparative disintegration data may be acceptable.
4. Copy of approved and new (if applicable) specifications of the excipient.

2.2.4. B.II. d) Control of finished product

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

37. B.II.d.1 Change in the specification parameters and limits of the finished product:  
  a) tightening of specification limits; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IA

b) tightening of specification limits for medicinal products subject to Official Batch Release; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IAIN

c) addition of a new specification parameter to the specification with its corresponding test method; Conditions: 1, 2, 5, 6, 7 Documentation: 1, 2, 3, 4, 5, 7

IA

d) deletion of a non-significant specification parameter, for example deletion of an obsolete parameter; Conditions: 1, 2 Documentation: 1, 2, 6

IA

e) change outside the approved specifications limits range;

II

f) deletion of a specification parameter which may have a significant effect on the overall quality of the finished product;

II

g) addition or replacement (excluding biological, including immunological product) of a specification parameter as a result of a safety or quality issue.

1,2,3,4,5,7

IB

37.1. Conditions:
1. The change is not a consequence of any commitment from previous assessments to review specification limits, for example made during the procedure for the registration application or a type II variation procedure.
2. The change does not result from unexpected events arising during manufacture, for example new unqualified impurity and change in total impurity limits.
3. Any change should be within the range of currently approved limits.
4. The test procedure remains the same, or changes in the test procedure are minor.
5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
6. The test method is not a biological, immunological and immunochemical method or a method using a biological reagent for a biological active substance.
7. The change does not concern a genotoxic impurity.
37.2. Documentation:
1. Amendment of the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
2. Comparative table of current and proposed specifications.
3. Details of any new analytical method and validation data, where relevant.
4. Batch analysis data on two production batches, but three production batches for biologicals, unless otherwise justified, of the finished product for all specification parameters.
5. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch complying with the current and proposed test in the manufacturing process. For herbal medicinal products, comparative disintegration data may be acceptable.
6. Justification and risk-assessment showing that the parameter is non-significant.
7. Justification of the new specification parameter and the limits.
38. B.II.d.2 Change in test procedure for the finished product:  
  a) minor changes to an approved test procedure; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IA

b) deletion of a test procedure if an alternative method is already authorised; Conditions: 4 Documentation: 1

IA

c) replacement of a biological, immunological and immunochemical test method or a method using a biological reagent;

II

d) other changes to a test procedure, including replacement or addition. Documentation: 1, 2

IB

38.1. Conditions:
1. Appropriate validation studies have been performed in accordance with the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation and show that the updated test procedure is at least equivalent to the former test procedure.
2. There have been no changes of the total impurity limits. No new unqualified impurities are detected.
3. The method of analysis should remain the same, for example a change in column length or temperature, but not a different type of column or method.
4. The test method is not a biological, immunological and immunochemical method or a method using a biological reagent and it does not include standard pharmacopoeial microbiological methods.
38.2. Documentation:
1. Amendment of the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including a description of the analytical methodology, a summary of validation data, revised specifications for impurities, if applicable.
2. Comparative validation results or if justified comparative analysis results showing that the current test and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new test procedure.
39. B.II.d.3 Variations related to the introduction of real-time release or parametric release in the manufacture of the finished product.  

II

2.2.5. B.II. e) Container closure system

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

40. B.II.e.1 Change in immediate packaging of the finished product:  
  a) qualitative and quantitative composition:  
  1. Solid pharmaceutical forms. Conditions: 1, 2, 3 Documentation: 1, 2, 3, 4, 6

IA

  2. Semi-solid and non-sterile liquid pharmaceutical forms.   Documentation: 1, 2, 3, 5, 6

IB

  3. Sterile medicinal products and biological, including immunological medicinal products.  

II

  4. The change relates to a less protective pack where there are associated changes in storage conditions and reduction in shelf life.  

II

  b) type of container:  
  1. Solid, semi-solid and non-sterile liquid pharmaceutical forms.   Documentation: 1, 2, 3, 5, 6, 7

IB

  2. Sterile medicinal products and biological, including immunological, medicinal products.    

II

40.1. Conditions:
  1. The change only concerns the same packaging type, for example blister to blister.
  2. The proposed packaging material must be at least equivalent to the approved material in respect of its relevant properties.
  3. Relevant stability studies have been started under ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation and relevant stability parameters have been assessed in at least two pilot scale or industrial scale batches and at least three months satisfactory stability data are at the disposal of the applicant at time of implementation. However, if the proposed packaging is more resistant than the existing packaging, for example thicker blister packaging, the three months' stability data do not yet have to be available. These studies must be finalised and the data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
40.2. Documentation:
  1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including revised medicinal product information as appropriate.
  2. Appropriate data on the new packaging (comparative data on permeability, for example for O2, CO2 moisture).
  3. Where appropriate, proof must be provided that no interaction between the content and the packaging material occurs, for example no migration of components of the proposed material into the content and no loss of components of the product into the pack, including confirmation that the material complies with relevant pharmacopoeial requirements or regulatory enactments on materials (plastic) and objects in contact with foodstuffs.
  4. A declaration that the required stability studies have been started under ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation with indication of the batch numbers concerned and that, as relevant, the required minimum satisfactory stability data were at the disposal of the applicant at time of implementation and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
  5. The results of stability studies that have been carried out under ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation, on the relevant stability parameters, on at least two pilot or industrial scale batches, covering a minimum period of three months, and an assurance is given that these studies will be finalised, and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
  6. Comparative table of the current and proposed immediate packaging specifications for the test and limits of the manufacturing process, if applicable.
  7. Samples of the new container and closure where applicable in accordance with the requirements in respect of the samples collected in the Member States that are included in the recommendations of the European Commission on documentation referred to in Section 28.1 of the Pharmaceutical Law.
40.3. Note.
  For applicants or variation application referred to in Sub-paragraph 40. b) of this Annex are reminded that any change which results in a "new pharmaceutical form" requires the submission of an Extension application.
41. B.II.e.2 Change in the specification parameters and limits of the immediate packaging of the finished product:  
  a) tightening of specification limits; Conditions: 1, 2, 3, 4 Documentation: 1, 2

IA

  b) addition of a new specification parameter to the specification with its corresponding test method; Conditions: 1, 2, 5 Documentation: 1, 2, 3, 4, 6

IA

  c) deletion of a non-significant specification parameter, for example deletion of an obsolete parameter; Conditions: 1, 2 Documentation: 1, 2, 5

IA

  d) addition or replacement of a specification parameter as a result of a safety or quality issue.   Documentation: 1, 2, 3, 4, 6

IB

41.1. Conditions:
  1. The change is not a consequence of any commitment from previous assessments to review specification limits, for example made during the procedure for the registration application or a type II variation procedure.
  2. The change does not result from unexpected events arising during manufacture.
  3. Any change should be within the range of currently approved limits.
  4. The test procedure remains the same, or changes in the test procedure are minor.
  5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
41.2. Documentation:
  1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
  2. Comparative table of current and proposed specifications.
  3. Details of any new analytical method and validation data, where relevant.
  4. Batch analysis data on two batches of the immediate packaging for all specification parameters.
  5. Justification and risk-assessment showing that the parameter is non-significant.
  6. Justification of the new specification parameter and the limits.
42. B.II.e.3 Change in test procedure for the immediate packaging of the finished product:  
  a) minor changes to an approved test procedure; Conditions: 1, 2, 3 Documentation: 1, 2

IA

  b) other changes to a test procedure, including replacement or addition; Conditions: 1, 3, 4 Documentation: 1, 2

IA

  c) deletion of a test procedure if an alternative test procedure is already authorised. Condition: 5 Documentation: 1

IA

42.1. Conditions:
  1. Appropriate validation studies have been performed in accordance with the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation and validation studies show that the updated test procedure is at least equivalent to the former test procedure.
  2. The method of analysis should remain the same, for example a change in column length or temperature, but not a different type of column or method.
  3. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
  4. The active substance and finished product is not biological, including immunological.
  5. An alternative test procedure is already authorised for the specification parameter and this procedure has not been added through notification regarding IA and IAIN type variations.
42.2. Documentation:
  1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including a description of the analytical methodology and a summary of validation data.
  2. Comparative validation results or if justified comparative analysis results showing that the current test and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new test procedure.
43. B.II.e.4 Change in shape or dimensions of the container or closure (immediate packaging):  
  a) non-sterile medicinal products; Conditions: 1, 2, 3 Documentation: 1, 2, 4

IA

  b) the change in shape or dimensions concerns a fundamental part of the packaging material, which may have a significant impact on the delivery, use, safety or stability of the finished product;  

II

  c) sterile medicinal products.   Documentation: 1, 2, 3, 4

IB

43.1. Conditions:
  1. No change in the qualitative or quantitative composition of the container.
  2. The change does not concern a fundamental part of the packaging material, which affects the delivery, use, safety or stability of the finished product.
  3. In case of a change in the headspace or a change in the surface and volume ratio, stability studies in accordance with the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation have been started and relevant stability parameters have been assessed in at least two pilot scale (three for biological, including immunological medicinal products) or industrial scale batches and at least three months, but six months for biological, including immunological, medicinal products, stability data are at the disposal of the applicant. Assurance is given that these studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
43.2. Documentation:
  1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including description and detailed drawing of the container or closure material, and including revised medicinal product information as appropriate.
  2. Samples of the new container/closure where applicable in accordance with the requirements for samples collected in the Member States that are determined in the recommendations of the European Commission on documentation referred to in Section 28.1 of the Pharmaceutical Law.
  3. Re-validation studies have been performed in case of sterile products terminally sterilised. The batch numbers of the batches used in the re-validation studies should be indicated, where applicable.
  4. In case of a change in the headspace or a change in the surface and volume ratio, a declaration that the required stability studies have been started under ICH conditions included in the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation with indication of the batch numbers concerned and that, as relevant, the required minimum satisfactory stability data were at the disposal of the applicant at time of implementation for a Type IA notification and time of submission of a Type IB notification, and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
44. B.II.e.5 Change in pack size of the finished product:  
  a) change in the number of units, for example tablets, ampoules, in a pack:  
  1. Change within the range of the currently approved pack sizes. Conditions:1, 2 Documentation: 1, 3

IAIN

  2. Change outside the range of the currently approved pack sizes.   Documentation: 1, 2, 3

IB

  b) deletion of a pack size; Conditions: 3 Documentation: 1, 2

IA

  c) change in the fill weight-fill volume of sterile multidose (or single-dose, partial use) parenteral medicinal products, and biological, including immunological, multidose parenteral medicinal products;  

II

  d) change in the fill weight-fill volume of nonparenteral multi-dose (or single-dose, partial use) products.   Documentation: 1, 2, 3

IB

44.1. Conditions:
  1. New pack size should be consistent with the posology and treatment duration as approved in the Summary of Product Characteristics.
  2. The primary packaging material remains the same.
  3. The remaining product presentation must be adequate for the dosing instructions and treatment duration as mentioned in the Summary of Product Characteristics.
44.2. Documentation:
  1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation including revised medicinal product information as appropriate.
  2. Justification for the new and remaining pack-size, showing that the new and remaining size is/are consistent with the dosage regimen and duration of use as approved in the summary of product characteristics.
  3. Declaration that stability studies will be conducted in accordance with the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation for products where stability parameters could be affected. Data to be reported only if outside specifications (with proposed action).
44.3. Note.
  For Paragraph 44, Sub-paragraphs c) and d) of this Annex, applicants are reminded that any changes to the 'strength' of the medicinal product require the submission of an Extension application.
45. B.II.e.6 Change in any part of the (primary) packaging material not in contact with the finished product formulation, such as colour of flip-off caps, colour code rings on ampoules, change of needle shield (different plastic used):  
  a) change that affects the product information; Conditions: 1 Documentation: 1

IAIN

  b) change that does not affect the product information. Conditions: 1 Documentation: 1

IA

45.1. Condition:
  1. The change does not concern a part of the packaging material, which affects the delivery, use, safety or stability of the finished product.
45.2. Documentation:
  1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including revised product information as appropriate.
46. B.II.e.7 Change in supplier of packaging components or devices (when mentioned in the application dossier):  
  a) deletion of a supplier; Conditions:1 Documentation: 1

IA

  b) replacement or addition of a supplier; Conditions: 1, 2, 3, 4 Documentation: 1, 2, 3

IA

  c) any change to suppliers of spacer devices for metered dose inhalers.  

II

46.1. Conditions:
  1. No deletion of packaging component or device.
  2. The qualitative and quantitative composition of the packaging components and device remain the same.
  3. The specifications and quality control method are at least equivalent.
  4. The sterilisation method and conditions remain the same, if applicable.
46.2. Documentation:
  1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
  2. Proof of CE marking.
  3. Comparative table of current and proposed specifications, if applicable.

2.2.6. B.II. f) Stability

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

47. B.II.f.1 Change in the shelf-life or storage conditions of the finished product:  
  a) reduction of the shelf life of the finished product:  
1. As packaged for sale. Condition: 1 Documentation: 1, 2, 3

IAIN

2. After first opening. Condition: 1 Documentation: 1, 2, 3

IAIN

3. After dilution or reconstitution (other type preparation for use). Condition: 1 Documentation: 1, 2, 3

IAIN

b) extension of the shelf life of the finished product:
1. As packaged for sale (supported by real time data). Documentation: 1, 2, 3

IB

2. After first opening (supported by real time data). Documentation: 1, 2, 3

IB

3. After dilution or reconstitution (supported by real time data). Documentation: 1, 2, 3

IB

4. Extension of the shelf-life based on extrapolation of stability data not in accordance with the scientific guidelines on the quality, safety and efficacy of medicinal products for human use referred to in Sub-paragraph 23.2 of this Regulation.

II

5. Extension of storage period of a biological, including immunological, medicinal product in accordance with an approved stability protocol. Documentation: 1, 2, 3

IB

c) change in storage conditions for biological medicinal products, when the stability studies have not been performed in accordance with an approved stability protocol;

II

d) change in storage conditions of the finished product or the diluted and reconstituted (other type preparation for use) product. Documentation: 1, 2, 3

IB

47.1. Condition:
1. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
47.2. Documentation:
1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation. This must contain results of appropriate real time stability studies, covering the entire shelf life, and conducted in accordance with the scientific guidelines on stability referred to in Sub-paragraph 23.2 of this Regulation on at least two pilot scale batches of the finished product in the authorised packaging material after first opening or reconstitution (other type preparation for use), as appropriate, and, where applicable, results of appropriate microbiological testing should be included. Pilot scale batches can be accepted with a commitment to verify the shelf life on production scale batches.
2. Revised medicinal product information.
3. Copy of approved end of shelf life finished product specification and where applicable, specifications after dilution, reconstitution (other type preparation for use) or first opening.
47.3. Note:
1. Extrapolation referred to in Paragraph 47, Sub-paragraph b), Clause 4 of this Annex is not applicable for biological, including immunological, medicinal product.

2.2.7. B.II.g) Design Space

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

48. B.II.g.1 Introduction of a new design space or extension of an approved design space for the finished product (excluding biologicals) concerning:  
a) one or more unit operations in the manufacturing process of the finished product including the resulting in-process controls and test procedures; Documentation: 1, 2, 3

II

b) test procedures for excipients, intermediates and the finished product. Documentation: 1, 2, 3

II

48.1. Documentation:
1. Results from product and process development studies, including risk assessment and multivariate studies, as appropriate, demonstrating that a systematic mechanistic understanding of material attributes and process parameters to the critical quality attributes of the finished product has been achieved.
2. Description of the design space in tabular format, including the variables, material attributes and process parameters, as appropriate, and their proposed ranges.
3. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
49. B.II.g.2 Introduction of a post approval change management protocol related to the finished product.   Documentation: 1, 2

II

49.1. Documentation:
1. Detailed description for the proposed change.
2. Change management protocol related to the finished product.
50. B.II.g.3 Deletion of an approved change management protocol related to the finish product. Condition: 1 Documentation: 1

IAIN

50.1. Condition:
1. The deletion of the approved change management protocol related to the finish product is not a result of unexpected events or out of specification results during the implementation of the changes described in the protocol.
50.2. Documentation:
1. Justification for the proposed deletion.

2.3. B.III. European Pharmacopoeial Certificate of Suitability, TSE Certificate of Suitability and Pharmacopoeial Monographs

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

51. B.III.1. Submission of a new or updated European Pharmacopoeial Certificate of Suitability for an active substance, for a starting material, reagent and intermediate used in the manufacturing process of the active substance, and for an excipient:  
  a) European Pharmacopoeial Certificate of Suitability to the relevant European Pharmacopoeial Monograph:  
  1. New certificate from an already approved manufacturer. Conditions: 1, 2, 3, 4, 5, 8 Documentation: 1, 2, 3, 4, 5

IAIN

  2. Updated certificate from an already approved manufacturer. Conditions: 1, 2, 3, 4, 8 Documentation: 1, 2, 3, 4, 5

IA

  3. New certificate from a new manufacturer (replacement or addition). Conditions: 1, 2, 3, 4, 5, 8 Documentation: 1, 2, 3, 4, 5

IAIN

  b) European Pharmacopoeial TSE Certificate of suitability for an active substance, starting material, reagent, intermediate and excipient;  
  1. New certificate for an active substance from a new or an already approved manufacturer. Conditions: 3, 6 Documentation: 1, 2, 3, 4, 5

IAIN

  2. New certificate for a new or an already approved manufacturer. Conditions: 3, 6 Documentation: 1, 2, 3, 4, 5

IA

  3. Updated certificate from an already approved manufacturer. Conditions: 7 Documentation: 1, 2, 3, 4, 5

IA

51.1. Conditions:
  1. The finished product release and end of shelf life specifications remain the same.
  2. Unchanged (excluding tightening) additional (to European Pharmacopoeia) specifications for impurities (excluding residual solvents, provided they are in compliance with scientific guidelines referred to in Sub-paragraph 23.2 of this Regulation) and product specific requirements (for example particle size profiles, polymorphic form), if applicable.
  3. The manufacturing process of the active substance, starting material, reagent and intermediate does not include the use of materials of human or animal origin for which an assessment of viral safety data is required.
  4. For active substance only, it will be tested immediately prior to use if no retest period is included in the European Pharmacopoeial Certificate of Suitability or if data to support a retest period is not already provided in the application dossier.
5. The active substance, starting material, reagent, intermediate and excipient is not sterile.
  6. For herbal active substances the manufacturing route, physical form, extraction solvent and drug extract ratio should remain the same.
51.2. Documentation:
  1. Copy of the current European Pharmacopoeial Certificate of Suitability, and if the Certificate is updated, the copy thereof.
2. In case of an addition of a manufacturing site, the variation application form should clearly outline the present and proposed manufacturers.
  3. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
  4. Where applicable, a document providing information of any materials falling within the scope of the guidance referred to in Paragraph 32 of Annex 3 to this Regulation on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products including materials which are used in the manufacture of the active substance and excipient. The following information should be included for each such material: Name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals and its use. For the Centralised Procedure, this information should be included in an updated TSE table A (and B, if relevant).
  5. For active substance - declarations by the Qualified Persons determined by the manufacturing authorisation holders listed in the application where the active substance is used as a starting material and declarations by the Qualified Persons by the manufacturing authorisation holders listed in the application as responsible for batch release. These declarations should state that the active substance manufacturer referred to in the application operate in compliance with the requirements on good manufacturing practice for starting materials in accordance with the determined in the legislation of the European Union and regulatory enactments regarding procedure for manufacture and control of medicinal products. A single declaration may be acceptable under certain circumstances as referred to in Paragraph 29 of this Regulation. The manufacture of intermediates also require a Qualified Person declaration, while as far as any updates to certificates for active substances and intermediates are concerned, a Qualified Person declaration is only required if, compared to the previously registered version of the certificate, there is a change to the actual listed manufacturing sites.
52. B.III.2. Change to comply with European Pharmacopoeia or with a national pharmacopoeia of a Member State:
  a) change of specification of a former non Pharmacopoeial substance to comply with the European Pharmacopoeia or with a national pharmacopoeia of a Member State:  
  1. Active substance. Conditions: 1, 2, 3, 4, 5 Documentation: 1, 2, 3, 4, 5

IAIN

  2. Excipient and active substance starting material. Conditions: 1, 2, 4 Documentation: 1, 2, 3, 4, 5

IA

  b) change to comply with an update of the relevant monograph of the European Pharmacopoeia or national pharmacopoeia of a Member State; Conditions: 1, 2, 4, 5 Documentation: 1, 2, 3, 4

IA

c) change in specifications from a national pharmacopoeia of a Member State to the European Pharmacopoeia. Conditions: 1, 4, 5 Documentation: 1, 2, 3, 4

IA

52.1. Conditions:
  1. The change is made exclusively to comply with the pharmacopoeia.
  2. Additional specifications (in addition to Pharmacopoeia) to the pharmacopoeia for product specific properties are unchanged (for example, particle size profiles, polymorphic form or bioassays, aggregates).
  3. No significant changes in qualitative and quantitative impurities profile unless the specifications are tightened.
  4. Additional validation of a new or changed pharmacopoeial method is not required.
  5. For herbal active substances: the manufacturing route, physical form, extraction solvent and drug extract ratio should remain the same.
52.2. Documentation:
  1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
2. Comparative table of current and proposed specifications.
  3. Batch analysis data on two production batches of the relevant substance for all tests in the new specification.
  4. Data to demonstrate the suitability of the monograph to control the substance, for example a comparison of the potential impurities with the transparency note of the monograph.
  5. Where appropriate, batch analysis data (in a comparative tabulated format) on two production batches of the finished product containing the substance complying with the current and proposed specification and additionally, where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch. For herbal medicinal products, comparative disintegration data may be acceptable.
52.3. Note:
  There is no need to notify the competent authorities of an updated monograph of the European Pharmacopoeia or a national pharmacopoeia of a Member State in the case that compliance with the updated monograph is implemented within six months of its publication and reference is made to the 'current edition' in the application dossier of an authorised medicinal product.

2.4. B.IV Medical Devices

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

53. B.IV.1. Change of a measuring or administration device:  
  a) addition or replacement of a device which is not an integrated part of the primary packaging:  
  1. Device with CE marking. Conditions: 1, 2, 3 Documentation: 1, 2, 4

IAIN

  2. Spacer device for metered dose inhalers.  

II

  b) deletion of a device; Conditions: 4, 5 Documentation: 1, 5

IAIN

  c) addition or replacement of a device which is an integrated part of the primary packaging.  

II

53.1. Conditions:
  1. The proposed measuring device must accurately deliver the required dose for the product concerned in line with the approved posology and results of such studies should be available.
  2. The new device is compatible with the medicinal product.
  3. The change should not lead to substantial amendments of the medicinal product information.
  4. The medicinal product can still be accurately delivered.
53.2. Documentation:
  1. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation, including description, detailed drawing and composition of the device material and supplier where appropriate, and including revised medicinal product information as appropriate.
2. Proof of presence of CE conformity marking.
  3. Data to demonstrate accuracy, precision and compatibility of the device
  4. Samples of the new device where applicable in accordance with the requirements for samples collected in the Member States that are determined in the recommendations of the European Commission on documentation referred to in Section 28.1 of the Pharmaceutical Law.
  5. Justification for the deletion of the device.
53.3. Note.
  For the variations referred to in Paragraph 53, Sub-paragraph c) of this Annex, applicants are reminded that any change which results in a "new pharmaceutical form" requires the submission of an Extension application.

2.5. B V Changes to application dossier resulting from other regulatory procedures

2.5.1. B.V. a) Plasma Master File (PMF) and Vaccine Antigen Master File (VAMF)

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

54. B.V.a.1. Inclusion of a new, updated or amended Plasma Master File (PMF) in the application dossier (PMF 2nd step procedure):  
  a) first-time inclusion of a new Plasma Master File affecting the properties of the finished product;  

II

  b) first-time inclusion of a new PMF not affecting the properties of the finished product;   Documentation: 1, 2, 3, 4

IB

  c) inclusion of an updated or amended PMF when changes affect the properties of the finished product;   Documentation: 1, 2, 3, 4

IB

  d) inclusion of an updated or amended PMF when changes do not affect the properties of the finished product; Conditions: 1 Documentation: 1, 2, 3, 4

IAIN

54.1. Conditions:
  1. The updated or amended PMF has been granted a certificate referred to in Sub-paragraph 40.2 of this Regulation of compliance with the requirements determined in the legislation of the European Union.
54.2. Documentation:
  1. Declaration that the PMF Certificate and Evaluation Report are fully applicable for the authorised product, PMF holder has provided the PMF Certificate, Evaluation report and PMF application dossier to the owner of the registration (where the owner of the registration is different to the PMF holder), the PMF Certificate and Evaluation Report replace the previous PMF documentation for this application dossier.
2. PMF Certificate and Evaluation Report.
  3. An expert statement outlining all the changes introduced with the certified PMF and evaluating their potential impact on the finished products including product specific risk assessments.
  4. The variation application form should clearly outline the "present" and "proposed" PMF Certificate issued by the European Medicines Agency, specifying the code number included in the application dossier. When applicable, the variation application form should clearly list also all the other PMFs to which the medicinal product refers even if they are not the subject of the application.
55. B.V.a.2 Inclusion of a new, updated or amended Vaccine Antigen Master File in the marketing authorisation application dossier of a medicinal product. (VAMF 2nd step procedure):  
  a) first-time inclusion of a new Vaccine Antigen Master File;  

II

b) inclusion of an updated or amended Vaccine Antigen Master File, when changes affect the properties of the finished product; Documentation: 1, 2, 3, 4

IB

c) inclusion of an updated or amended Vaccine Antigen Master File, when changes do not affect the properties of the finished product. Conditions: 1 Documentation: 1, 2, 3, 4

IAIN

55.1. Conditions:
1. The updated or amended Vaccine Antigen Master File has been granted a certificate referred to in Sub-paragraph 40.2 of this Regulation of compliance with the requirements determined in the legislation of the European Union.
55.2. Documentation:
1. Declaration that the VAMF Certificate and Evaluation Report are fully applicable for the authorised product, VAMF holder has submitted the VAMF Certificate, Evaluation report and VAMF application dossier to the owner of the registration (where the owner of the registration is different to the VAMF holder), the VAMF Certificate and Evaluation Report replace the previous VAMF documentation for this application dossier.
2. VAMF Certificate and Evaluation Report.
3. An expert statement outlining all the changes introduced with the certified VAMF and evaluating their potential impact on the finished products including product specific risk assessments.
4. The variation application form should clearly outline the "present" and "proposed" VAMF Certificate issued by the European Medicines Agency, specifying the code number included in the application dossier. When applicable, the variation application form should clearly list also all the other VAMFs to which the medicinal product refers even if they are not the subject of the application.

2.5.2. B.V. b) Referral

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

56. B.V.b.1 Update of the quality application dossier in accordance with the referral regarding which a Commission Decision has been taken that is referred to in Sub-paragraphs 108.7 and 108.8 of this Regulation:  
  a) the change implements the outcome of the referral;   Documentation: 1

IAIN

b) the harmonisation of the quality application dossier was not part of the referral and the update is intended to harmonise it.

II

56.1. Documentation:
1. The variation application is attached by the cover letter in which a reference to the Commission Decision concerned is specified.
56.2. Note.
Variations referred to in Paragraph 58, Sub-paragraph a) of this Annex applies in cases where the owner of the registration need to take steps to allow the Member States to comply with the Commission decision within 30 days after its notification in accordance with Sub-paragraph 108.8 of this Regulation.

2.5.3. B.V. c) Change management protocol

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

57. B.V.c.1. Update of the quality application dossier to implement changes, requested by the competent authority of the Member State, following assessment of a change management protocol:  
  a) the implementation of the change requires no further supportive data; Conditions: 1 Documentation: 1, 2, 4

IAIN

  b) the implementation of the change requires further supportive data;   Documentation: 1, 2, 3, 4

IB

  c) implementation of a change for a biological, including immunological, medicinal product.   Documentation: 1, 2, 3, 4, 5

IB

57.1. Conditions:
  1. The proposed change has been performed fully in line with the approved change management protocol, which requires its immediate notification following implementation.
57.2. Documentation:
  1. Reference to the approved change management protocol.
2. Declaration that the change is in accordance with the approved change management and that the study results meet the acceptance criteria specified in the protocol. In addition, declaration that an assessment of comparability is not required for biological, including immunological, medicinal products.
  3. Results of the studies performed in accordance with the approved change management protocol.
  4. Amendments to the relevant section of the application dossier, presented in the Common Technical Document format referred to in Sub-paragraph 23.1 of this Regulation.
  5. Copy of approved specifications of the active substance or the finished product.

3. C. Safety and efficiency changes and changes related to pharmacovigilance

3.1. C.I. Human medicinal products

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

58. C.I.1 Change in the Summary of Product Characteristics, Labelling or Package Leaflet following a referral procedure in accordance with Sub-paragraph 108.8 of this Regulation:  
  a) the medicinal product is covered by the defined scope of the referral;   Documentation: 1, 2, 3

IAIN

  b) the medicinal product is not covered by the defined scope of the referral but the change implements the outcome of the referral and no new additional data are submitted by the owner of the registration;   Documentation: 1, 2, 3

IB

  c) the medicinal product is not covered by the defined scope of the referral but the change implements the outcome of the referral with new additional data submitted by the owner of the registration.   Documentation: 1, 3

II

58.1. Documentation:
  1. The variation application is attached by the cover letter in which a reference to the Commission Decision concerned with the annexed Summary of Product Characteristics, Labelling or Package Leaflet is specified.
  2. A declaration that the proposed Summary of Product Characteristics, Labelling and Package Leaflet is identical for the concerned sections to that annexed to the Commission Decision on the referral procedure for the reference medicinal product.
  3. Revised medicinal product information.
58.2. Note:
  Paragraph 58, Sub-paragraph a) of this Annex applies in cases where the owner of the registration need to take steps to allow the Member States of the European Economic Area to ensure the compliance with the European Commission decision on the referral procedure within 30 days after its notification in accordance with Sub-paragraph 108.8 of this Regulation.
59. C.I.2. Change in the Summary of Product Characteristics, Labelling or Package Leaflet of a Generic, hybrid and biosimilar medicinal products following assessment of the same change for the reference product:  
  a) implementation of changes for which no new additional data are submitted by the owner of the registration;   Documentation: 1, 2

IB

  b) implementation of change which require to be further substantiated by new additional data to be submitted by the owner of the registration (for example comparability).    

II

59.1. Documentation:
  1. Attached to the cover letter of the variation application: European Medicines Agency or competent authority request, if applicable.
  2. Revised medicinal product information.
60. C.I.3. Implementation of changes requested by the European Medicines Agency or competent authority following the assessment of an Urgent Safety Restriction, class labelling, a Periodic Safety Update report, Risk Management Plan, Follow Up Measure and Specific Obligation, data submitted under Article 45 and 46 of Regulation (EC) No 1901/2006 of the European Parliament and of the Council of 12 December 2006 on medicinal products for paediatric use and amending Regulation (EEC) No 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No726/2004, or amendments to reflect a competent authority core requirements of a supplementary protection certificate:  
  a) implementation of agreed wording changes for which no new additional data are submitted by the owner of the registration;   Documentation: 1, 2

IB

  b) implementation of changes which require to be further substantiated by new additional data to be submitted by the owner of the registration.  

II

60.1. Documentation:
  1. Attached to the cover letter of the variation application: European Medicines Agency or competent authority request, if available.
  2. Revised medicinal product information.
60.2. Notes.
  The owners of the registration are reminded that once new information becomes available which might entail the variation of the application dossier, this should be submitted forthwith as a variation to the competent authorities, rather than awaiting the assessment of those data through one of the procedures mentioned above.
61. C.I.4. Variations related to significant modifications of the Summary of Product Characteristics due in particular to new quality, pre-clinical, clinical or pharmacovigilance data.  

II

62. C.I.5. Change in the legal status of a medicinal product for centrally authorised products:    
  a) for generic, hybrid, biosimilar medicinal products following an approved legal status change of the reference medicinal product;   Documentation: 1, 2

IB

  b) all other legal status changes.  

II

62.1. Documentation:
  1. Attached to the cover letter of the variation application: proof of authorisation of the legal status change (for example reference to the Commission Decision concerned).
  2. Revised medicinal product information.
62.2. Note.
  For nationally authorised products approved via mutual recognition procedure and decentralised procedure, the change of the legal status is to be handled at national level (not via a mutual recognition procedure variation).
63. C.I.6. Changes to therapeutic indications:  
  a) addition of a new therapeutic indication or modification of an approved one;  

II

  b) deletion of a therapeutic indication.  

IB

63.1. Notes.
  Where the addition or modification of a therapeutic indication takes place in the context of the implementation of the outcome of a referral procedure or of changes to the product information of a generic, hybrid and biosimilar product following assessment of the same change for the reference product, variations referred to in Paragraphs 58 and 59 of this Annex apply, respectively.
64. C.I.7. Deletion of:  
  a) a pharmaceutical form;   Documentation: 1, 2

IB

  b) a strength.   Documentation: 1, 2

IB

64.1. Documentation:
  1. Declaration that the remaining product presentation are adequate for the dosing instructions and treatment duration as mentioned in the summary of product characteristics.
  2. Revised medicinal product information.
64.2. Note:
  Where a given pharmaceutical form or strength has received a marketing authorization which is separate to the marketing authorization for other pharmaceutical forms or strengths, the deletion of the former will not be a variation but the withdrawal of the marketing authorization.
65. C.I.8. Introduction of a new pharmacovigilance system:  
  a) which has not been assessed by the competent authority or European Medicines Agency for another product of the same owner of the registration;  

II

  b) which has been assessed by the competent authority or European Medicines Agency for another product of the same owner of the registration.   Documentation: 1

IB

65.1. Documentation:
  1. The detailed description of the new pharmacovigilance system.
65.2. Note:
  The variations referred to in Paragraph 65, Sub-paragraph b) of this Annex covers the situation where the applicability of an already assessed pharmacovigilance system will have to be assessed for the new marketing authorisations concerned (at time of transfer of a marketing authorisation).
66. C.I.9. Changes to an existing pharmacovigilance system for as described in the detailed description of the pharmacovigilance system:  
  a) change in the appropriately qualified person responsible for the pharmacovigilance; Conditions: 1 Documentation: 1

IAIN

  b) change in the contact details of the appropriately qualified person responsible for the pharmacovigilance; Conditions: 1 Documentation: 2

IAIN

  c) change of the back-up procedure of the appropriately qualified person responsible for the pharmacovigilance; Conditions: 1 Documentation: 2

IAIN

  d) change in the safety database (for example introduction of a new safety database including safety data collection and analysis and reporting to the new system); Conditions: 1, 2, 3 Documentation: 2

IAIN

  e) changes in the major contractual arrangements with other persons or institutions and authorities involved in the fulfilment of obligations described in the pharmacovigilance system, in particular where the electronic reporting of adverse effects caused by use of particular medicinal products, the main databases, signal detection, or periodic safety update reports is subcontracted; Conditions: 1 Documentation: 2

IAIN

  f) deletion of topics covered by written procedure describing the activities of the pharmacovigilance system; Conditions: 1 Documentation: 2

IAIN

  g) change of the site undertaking the activities of the pharmacovigilance system; Conditions: 1 Documentation: 2

IAIN

  h) other changes to the pharmacovigilance system that does not impact on the operation thereof (for example change of the major storage and archiving location, administrative changes, update of acronyms, naming changes of functions and procedures). Conditions: 1 Documentation: 2

IA

  i) changes to the pharmacovigilance system following the assessment of the same pharmacovigilance system in relation to another medicinal product of the same owner of the registration. Conditions: 4 Documentation: 2, 3

IAIN

66.1. Conditions:
  1. The pharmacovigilance system itself remains unchanged.
  2. The database system has been validated (approved).
  3. Transfer of data from other database systems has been validated (approved).
  4. The same changes to the pharmacovigilance system are introduced for all medicinal products of the same owner of the registration. The same final version of the pharmacovigilance system.
66.2. Documentation:
  Latest version of the pharmacovigilance system, including

a) summary (curriculum vitae) of work experience (life) of the new appropriately qualified person responsible for pharmacovigilance;

b) proof that an appropriately qualified person responsible for the pharmacovigilance is registered in EudraVigilance database;

c) a new statement signed by the owner of the registration and the appropriately qualified person responsible for the pharmacovigilance regarding their availability and the means for notification of adverse reactions, and reflecting any other consequential changes, for example to the organisation chart.

2. Latest version of the pharmacovigilance system description and/or latest version of product specific addendum.

For variation referred to in Paragraph 66, Sub-paragraph b) of this Annex if the contact details of the appropriately qualified person responsible for pharmacovigilance were not initially included in the pharmacovigilance system, submission of a revised version of the pharmacovigilance system description is not required, only variation application form or notification to be provided.

  3. Reference of the application and procedure and medicinal product in which the changes were accepted.
66.3. Note:
  For the assessment of a pharmacovigilance system referred to in Paragraph 66, Sub-paragraph i) of this Annex and submitted as part of a new medicinal product registration or extension or variation application may give rise to changes at the request of the national competent authority or European Medicines Agency in this pharmacovigilance system description. Where this occurs, the same changes can be introduced to the pharmacovigilance system in other marketing authorisations of the same owner of the registration by submitting a (grouped) Type IAIN variation.

4. D. Plasma Master File (PMF) and Vaccine Antigen Master File (VAMF)

No

Title of the variation. Conditions to be fulfilled. Documentation to be supplied.

Conditions to be fulfilled

Documentation to be supplied

Procedure type

67. D.1 Change in the name and address of the vaccine antigen master file (VAMF) certificate holder. Conditions: 1 Documentation: 1

IAIN

67.1. Conditions:
1. The VAMF certificate holder shall remain the same legal entity.
67.2. Documentation:
1. A formal document from a relevant official body, for example Commercial Register, Chamber of Commerce, in which the new name or new address is mentioned.
68. D.2 Change in the name and address of the Plasma Master File (PMF) certificate holder Conditions: 1 Documentation: 1

IAIN

68.1. Conditions:
1. The PMF certificate holder shall remain the same legal entity.
68.2. Documentation:
1. A formal document from a relevant official body, for example Commercial Register, Chamber of Commerce, in which the new name or new address is mentioned.
69. D.3 Change or transfer of the current PMF certificate holder to a new PMF certificate holder, namely different legal entity.   Documentation: 1, 2, 3, 4, 5, 6

IAIN

69.1. Documentation:
1. A document including the identification (name and address) of the current PMF Holder (transferor of PMF) and the identification (name and address) of the person to whom the transfer is to be granted (transferee of PMF) together with the proposed implementation date. The document shall be signed by a transferor of PMF and transferee of PMF.
2. Copy of the latest PMF Certificate page 'European Medicines Agency Plasma Master File (PMF) Certificate of compliance with European Union legislation'.
3. Proof of establishment of the new holder (Excerpt of the commercial register and the English translation thereof, if necessary) signed by a transferor of PMF and transferee of PMF.
4. Confirmation of the transfer of the complete PMF documentation since the initial PMF certification to the transferee signed by a transferor of PMF and transferee of PMF.
5. Letter of Authorisation including contact details of the person responsible for communication between the competent authority and the PMF holder signed by the transferee.
6. Letter of Undertaking to fulfil all open and remaining commitments (if any) signed by the transferee.
70. D.4 Change in the name and address of a blood centre including centre and establishment (structural unit thereof) responsible for collection of blood and plasma Conditions: 1, 2 Documentation: 1, 2, 3

IA

70.1. Conditions:
1. The relevant centre and establishment shall remain the same legal entity.
2. The change shall be administrative, for example merger, take over. Change in the name of the relevant centre or establishment provided the relevant centre and establishment shall remain the same.
70.2. Documentation:
1. Signed declaration that the change does not involve a change of the quality system within the relevant centre and establishment.
2. Signed declaration that there is no change in the list of the blood and plasma collection centres.
3. Updated relevant sections and annexes of the PMF application dossier.
71. D.5 Replacement or addition of a structural unit of blood and plasma collection within a blood centre and establishment already included in the PMF. Documentation: 1, 2, 3

IB

71.1. Documentation:
1. Epidemiological data for viral markers related to the blood and plasma collection centres and establishments (structural units thereof) covering the last 3 years. For newly opened establishment (structural unit thereof) or in case no data are yet available, a declaration that epidemiological data will be provided at the time of the next annual updates.
2. Statement that the blood and plasma collection centre and establishment (structural unit thereof) is working under the same conditions as the other centres and establishments (structural units thereof) belonging to the same centre and establishment (structural unit thereof), as specified in the standard contract between such centre and establishment (structural unit thereof) and PMF holder.
3. Updated relevant sections and annexes of the PMF application dossier.
72. D.6 Deletion or change of status (operational, nonoperational) of establishment (structural unit thereof) and centre used for blood and plasma collection or in the testing of donations and plasma pools. Conditions: 1, 2 Documentation: 1

IA

72.1. Conditions:
1. The reason for deletion or change of status should not be related to a good manufacturing practice issue.
2. If non-operational establishment (structural unit thereof) and centre becomes as operational establishment (structural unit thereof) and centre, the establishment (structural unit thereof) and centre should comply with the legislation in terms of inspections determined in the regulatory enactment regarding collection, testing, treatment, storage and distribution of human blood and blood components in case of change of status.
72.2. Documentation:
1. Updated relevant sections and annexes of the PMF application dossier.
73. D.7 Addition of a new blood establishment (structural unit thereof) and centre for the collection of blood and plasma not included in the PMF.

II

74. D.8 Replacement or addition of a blood establishment (structural unit thereof) and centre for testing of donations and plasma pools already included in the PMF. Documentation: 1, 2

IB

74.1. Documentation:
1. Statement that the testing is performed following the same Standard procedures and test methods as already accepted.
2. Updated relevant sections and annexes of the PMF application dossier.
75. D.9 Addition of a new blood establishment (Structural unit thereof) and centre for testing of donations and plasma pool not included in the PMF.

II

76. D.10 Replacement or addition of a new blood Establishment (structural unit thereof) or centre in which storage, replacement or addition of plasma is carried out. Documentation: 1, 2

IB

76.1. Documentation:
1. Statement that the storage centre is working following the same standard procedures as the already accepted establishment.
2. Updated relevant sections and annexes of the PMF application dossier.
77. D.11 Deletion of a blood centre or establishment (structural unit thereof) in which storage of plasma is carried out. Conditions: 1 Documentation: 1

IA

77.1. Conditions:
1. The reason for deletion should not be related to a good manufacturing practice issues.
77.2. Documentation:
1. Updated relevant sections and annexes of the PMF application dossier.
78. D.12 Replacement or addition of an organisation involved in the transport of plasma. Documentation: 1

IB

78.1. Documentation:
1. Updated relevant sections and annexes of the PMF application dossier, including a list of all the blood centres and establishments using this transport organisation, a summary of the system in place to ensure that the transport is performed under appropriate conditions (time, temperature and good manufacturing practice compliance) and confirmation that transport conditions are validated.
79. D.13 Deletion of an organisation involved in the transport of plasma. Conditions: 1 Documentation: 1

IA

79.1. Conditions:
1. The reason for deletion should not be related to good manufacturing practice issues.
79.2. Documentation:
2. Updated relevant sections and annexes of the PMF application dossier.
80. D.14 Addition of a CE-marked test kit to test individual donations as a new test kit or as a replacement of an existing test kit. Conditions: 1 Documentation: 1, 2

IA

80.1. Conditions:
1. The new test kit is CE-marked. .
80.2. Documentation:
1. List of testing sites where the kit is used.
2. Updated relevant sections and annexes of the PMF application dossier, including updated information on testing in accordance with the guidance regarding requirements in respect of the scientific data for a plasma master file included in the guidelines referred to in Sub-paragraph 23.1 of this Regulation.
81. D.15 Addition of a non-CE marked test kit to test individual donations as a new test kit or as a replacement of an existing test kit:
a) the new test kit has not previously been approved in the PMF for any blood or establishment centre for testing of donations;

II

b) the new test kit has been approved in the PMF for other blood centre and establishment for testing of donations. Documentation: 1, 2

IA

81.1. Documentation:
1. List of testing centres where the kit is currently used and a list of testing centres where the kit will be used.
2. Updated relevant sections and annexes of the PMF application dossier, including updated information on testing on testing in accordance with the guidance regarding requirements in respect of the scientific data for a plasma master file included in the guidelines referred to in Sub-paragraph 23.1 of this Regulation.
82. D.16 Change of kit and method used to test pools (antibody or antigen or NAT test).

II

83. D.17 Introduction or extension of inventory hold procedure. Conditions: 1 Documentation: 1

IA

83.1. Conditions:
1. The inventory hold procedure is a more stringent procedure (for example release only after retesting of donors).
83.2. Documentation:
1 Updated relevant sections of the PMF application dossier, including the rationale for introduction or extension of inventory hold period, the sites where the inventory hold takes place and for changes to procedure, a decision tree including new conditions.
84. D.18 Removal of inventory hold period or reduction in its length. Documentation: 1

IB

84.1. Documentation:
1 Updated relevant sections of the PMF application dossier.
85. D.19 Replacement or addition of blood containers, for example, bags, bottles:
a) the new blood containers are CE-marked; Conditions: 1, 2 Documentation: 1

IA

b) the new blood containers are not CE-marked

II

85.1. Conditions:
1.The container is CE-marked.
2. The quality criteria of the blood in the container remain unchanged.
85.2. Documentation:
1. Updated relevant sections and annexes of the PMF application dossier, including the name of container, manufacturer, anticoagulant solution specification, confirmation of CE-mark and the name of the blood establishments where the container is used.
86. D.20 Change in storage and transport:  
  a) storage and transport conditions; Condition: 1 Documentation: 1

IA

  b) maximum storage time for the plasma. Conditions: 1, 2 Documentation: 1

IA

86.1. Conditions:
  1. The change should tighten the conditions and be in compliance with European Pharmacopoeia requirements for human plasma for fractionation.
  2. The maximum storage time is shorter than previously.
86.2. Documentation:
  1. Updated relevant sections and annexes of the PMF application dossier, including detailed description of the new conditions, confirmation of validation of storage and transport conditions and the name of the blood centre and establishment where the change takes place, if relevant.
87. D.21. Introduction of test for viral markers when this introduction will have significant impact on the viral risk assessment.  

II

88. D.22. Change in the plasma pool preparation, for example manufacturing method, pool size, storage of plasma pool samples.   Documentation: 1

IB

88.1. Documentation:
  1. Updated relevant sections of the PMF application dossier.
89. D.23. Change in the steps that would be taken if it is found retrospectively that donation should have been excluded from processing ("look-back" procedure).  

II

Notes.

1. "Information on medicinal product" referred to in this Annex means a description, labelling or package leaflet of medicinal product.

2. "Test procedure" referred to in this Annex means the same as "analytical procedure", and "restrictions" means the same as "approval criteria".

3. "Specification parameter" referred to in this Annex means a quality value for which a test procedure and restrictions are determined, for example assay, identity, water content. Addition or deletion of a specification parameter shall include the relevant test method and restrictions thereof.

4. "Amendments of the relevant section of the application dossier" referred to in this Annex means addition, replacement or deletion of data and documents unless provided otherwise. If the amendments of the relevant section of the application dossier apply only to editorial amendments, such amendments shall not be provided as separate amendments, but they may be included in amendments that apply to a particular section of the application dossier. In such cases a person who notifies regarding amendments shall attest that the content of the relevant section of the application dossier has not been changed as a result of amendments of editorial nature, and that it does not exceed the essence of the content of the submitted amendments.

 

[28 July 2008; 18 May 2010; 9 April 2013]

Annex 8
Cabinet Regulation No. 376
9 May 2006

Minor Variations of Type IA and IB

Minor variations of type I A and I B for medicinal products registered in accordance with a national registration procedure (shall not apply to medicinal products registered in accordance with a mutual recognition procedure and decentralised procedure) shall be as follows:

No.

Title of the variation. Conditions to be fulfilled

Type

1.

Change in the name or address of the owner of the medicinal product registration certificate

IA

Condition: the owner of the medicinal product registration certificate shall remain the same legal person  

2.

Change in the name of the medicinal product

IB

Condition: there can be no confusion with the names of existing medicinal products or with the international non-proprietary name  

3.

Change in the name of the active substance

IA

Condition: the active substance shall remain the same  

4.

Change in the name and/or address of a manufacturer of the active substance where no European Pharmacopoeial certificate of suitability is available

IA

Condition: the manufacturing site shall remain the same  

5.

Change in the name and/or address of a manufacturer of the finished product

IA

Condition: the manufacturing site shall remain the same  

6.

Change in the ATC Code

IA

Condition: change following granting of or amendment to the ATC code by the World Health Organisation

7.

Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product:
7.1. secondary packaging for all types of pharmaceutical forms Conditions: 1, 2 (see below)

IA

7.2. primary packaging site
7.2.1. solid pharmaceutical forms (for example, tablets and capsules) Conditions: 1, 2, 3, 5

IA

7.2.2. soft (semi-liquid or liquid pharmaceutical forms Conditions: 1, 2, 3, 5

IB

7.2.3. liquid pharmaceutical forms (suspensions, emulsions) Conditions: 1, 2, 3, 4, 5

IB

7.3. all other manufacturing operations except batch release Conditions: 1, 2, 4, 5

IB

Conditions:

1. The relevant state competent authority of one of the Member States of the European Economic Area or a country, which has a mutual recognition agreement with the European Communities regarding good manufacturing practice, has carried out a satisfactory inspection in the last 3 years.

2. The site of manufacture has an appropriate licence (a permit to manufacture the pharmaceutical form of the relevant product).

3. The relevant product is not a sterile product.

4. A validation scheme is available or validation of the manufacture at the new site has been successfully carried out according to the current protocol with at least 3 production scale batches.

5. The relevant product is not a biological medicinal product.

8.

Changes in the batch release arrangements and quality control testing of the finished product
8.1. replacement or addition of a site where the batch control (testing) takes place Conditions: 2, 3, 4 (see below)

IA

8.2. replacement or addition of a manufacturer responsible for the batch release
8.2.1. not including batch control Conditions: 1, 2

IA

8.2.2. including batch control Conditions: 1, 2, 3, 4

IA

Conditions:

1. The manufacturer responsible for batch release shall be located within the Member State.

2. The site of manufacture has been granted the appropriate licence (permit).

3. The relevant product is not a biological medicinal product.

4. The transfer of control methods from the old to the new site or new laboratory for quality control of medicinal products has been successfully completed.

9.

Deletion of any manufacturing site (including an active substance, intermediate or finished product, packaging site, manufacturer responsible for the batch release, site where batch control takes place)

IA

No conditions

10.

Minor change in the manufacturing process of the active substance

IB

Conditions:

1. No change in the qualitative and quantitative impurity profile or in the physico-chemical properties.

2. The active substance is not a biological substance.

3. The synthetic route remains the same, i.e., intermediates remain the same. If the medicinal product is a herbal medicinal product, the geographical source, production of the herbal substance and the manufacturing route shall remain the same

11.

Changes in the batch size of the active substance or intermediate
11.1. scale-up up to 10-fold compared to the original batch size approved at the grant of registration Conditions: 1, 2, 3, 4 (see below)

IA

11.2. downscaling Conditions: 1, 2, 3, 4, 5

IA

11.3 scale-up up to 10-fold compared to the original batch size approved at the grant of registration Conditions: 1, 2, 3, 4

IB

Conditions:

1. Any changes to the manufacturing methods are only those necessitated by a scale-up (for example, use of different sized equipment).

2. Test results of at least two batches according to the specifications shall be available for the proposed batch size.

3. The active substance is not a biological substance.

4. The change does not affect the reproducibility of the process.

5. The change shall not be the result of unexpected events arising during manufacture or because of stability concerns.

12.

Change in the specification of an active substance or a starting material/intermediate/reagent used in the manufacturing process of the active substance
12.1. tightening of specification limits Conditions: 1, 2, 3 (see below)

IA

Conditions: 2, 3

IB

12.2. addition of a new test parameter to the specification of the following substances
12.2.1. an active substance Conditions: 2, 4, 5

IB

12.2.2. a starting material/intermediate/reagent used in the manufacturing process of the active substance Conditions: 2, 4

IB

Conditions:

1. The change is not a consequence of any commitment from previous assessments to review specification limits (for example, made during the procedure for registration application or a Type II variation procedure).

2. The change shall not be the result of unexpected events arising during manufacture.

3. Any change shall be within the range of currently approved limits.

4. Any new test method does not concern a non-approved technique or a technique used in a novel way.

5. The active substance is not a biological substance.

13.

Change in the test procedure for the active substance or starting material, intermediate or reagent used in the manufacturing process of the active substance
13.1. minor change to an approved test procedure Conditions: 1, 2, 3, 5 (see below)

IA

13.2. other changes to a test procedure, also replacement or addition of a test procedure Conditions: 2, 3, 4, 5

IB

Conditions:

1. The method of analysis shall remain the same (for example, change in the column length or temperature shall be permissible, but not a different type of the column or method). No new impurities are detected.

2. Appropriate (re-)validation studies have been performed in accordance with the relevant guidelines.

3. Results of method validation show the new test method to be at least equivalent to the former procedure.

4. Any new test method does not concern a non-approved technique or a technique used in a novel way.

5. The active substance, starting material, intermediate or reagent is not a biological substance.

14.

Change in the manufacture of the active substance or starting material/reagent/intermediate in the manufacturing process of the active substance where no European Pharmacopoeial certificate of suitability is available
14.1. change in the site of the already approved manufacturer (replacement or addition of a new site) Conditions: 1, 2, 4 (see below)

IB

14.2. new manufacturer (replacement or addition of a new manufacturer) Conditions: 1, 2, 3, 4

IB

Conditions:

1. The specifications (also in-process controls, methods of analysis of all materials), method of preparation (also batch size) and detailed route of synthesis are identical to those already approved.

2. Where materials of human or animal origin are used in the process, the manufacturer does not use any new supplier, for which assessment is required of the viral safety or of compliance with the European Commission Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (to the last revision).

3. The current or new active substance manufacturer does not use a Drug Master File.

4. The change does not concern a medicinal product containing a biological active substance.

15.

Application of a new or updated European Pharmacopoeial certificate of suitability for an active substance or starting material, reagent or intermediate in the manufacturing process of the active substance
15.1. from a manufacturer currently approved Conditions: 1, 2, 4 (see below)

IA

15.2. from a new manufacturer (replacement or addition of a new manufacturer)
15.2.1. sterile substance Conditions: 1, 2, 3, 4

IB

15.2.2. other substances Conditions: 1, 2, 3, 4

IA

Conditions:

1. The finished product release and end of shelf life specifications remain the same.

2. Unchanged additional (to European Pharmacopoeia) specifications for impurities and product specific requirements (for example, particle size profiles, polymorphic form).

3. The active substance shall be tested immediately prior to use if no retest period is included in the European Pharmacopoeial certificate of suitability, or if data to support a retest period is not provided.

4. The manufacturing process of the active substance, starting material/reagent/intermediate does not include the use of materials of human or animal origin, for which an assessment of viral safety data is required.

16.

Application of a new or updated TSE European Pharmacopoeial certificate of suitability for an active substance or starting material, reagent or intermediate in the manufacturing process of the active substance for a currently approved manufacturer and currently approved manufacturing process
16.1. substances No conditions.

IA

17.

Change in:
17.1. the re-test period of the active substance Conditions: 1, 2, 3 (see below)

IB

17.2. the storage conditions for the active substance Conditions: 1, 2

IB

Conditions:

1. Stability studies have been done according to the currently approved protocol. The studies shall show that the agreed relevant specifications are still met.

2. The change shall not be the result of unexpected events arising during manufacture or because of stability concerns.

3. The active substance is not a biological substance.

18.

Replacement of an excipient with a comparable excipient.

IB

Conditions:

1. The excipient has the same functional characteristics.

2. The dissolution profile of the new product determined on a minimum of two pilot scale batches is comparable to the old one (no significant differences regarding comparability, see Note for Guidance on bioavailability and bioequivalence (Annex II); the principles contained in this note for guidance for medicinal products for human use shall still be taken into account for veterinary medicinal products if relevant). For herbal medicinal products where dissolution testing may not be feasible, the disintegration time of the new product is comparable to the old one.

3. Any new excipient does not include the use of materials of human or animal origin, for which assessment is required of the viral safety data.

4. It does not concern a medicinal product containing a biological active substance.

5. Stability studies in accordance with the relevant guidelines have been started with at least 2 pilot scale or industrial scale batches and at least 3 months satisfactory stability data are at the disposal of the applicant, as well as the assurance that these studies will be finalised. Data shall be provided immediately to the competent authorities if they do not comply, or possibly do not comply with the specifications at the end of the approved shelf life (with the proposed action).

19.

Change in the specification of an excipient
19.1. tightening of specification limits Conditions: 1, 2, 3 (see below)

IA

Conditions: 2, 3

IB

19.2. addition of a new test parameter to the specification Conditions: 2, 4, 5

IB

Conditions:

1. The change is not a consequence of any commitment from previous assessments (for example, made during the procedure for the registration application or a Type II variation procedure).

2. The change shall not be the result of unexpected events arising during manufacture.

3. Any change shall be within the range of currently approved limits.

4. Any new test method does not concern a non-approved technique or a technique used in a novel way.

5. The change does not concern an adjuvant for vaccines or a biological excipient.

20.

Change in the test procedure for an excipient
20.1. minor change to an approved test procedure Conditions: 1, 2, 3, 5 (see below)

IA

20.2. minor change to an approved test procedure for a biological excipient Conditions: 1, 2, 3

IB

20.3. other changes to a test procedure, including replacement of an approved test procedure by a new test procedure Conditions: 2, 3, 4, 5

IB

Conditions:

1. The method of analysis shall remain the same (for example, change in column length or temperature shall be permissible, but not a different type of column or method). No new impurities are detected.

2. Appropriate (re-)validation studies have been performed in accordance with the relevant guidelines.

3. Results of method validation show the new test method to be at least equivalent to the former procedure.

4. Any new test method does not concern a non-approved technique or a technique used in a novel way.

5. The substance is not a biological excipient.

21.

Application of a new or updated European Pharmacopoeial certificate of suitability for an excipient
21.1. from a manufacturer currently approved Conditions: 1, 2, 3 (see below)

IA

21.2. from a new manufacturer (replacement or addition of a new manufacturer)
21.2.1. sterile substance Conditions: 1, 2, 3

IB

21.2.2. other substances Conditions: 1, 2, 3

IA

Conditions:

1. The finished product release and end of shelf life specifications remain the same.

2. Unchanged additional (to European Pharmacopoeia) specifications for product specific requirements (for example, particle size profiles, polymorphic form).

3. The manufacturing process of the excipient does not include the use of materials of human or animal origin, for which assessment of viral safety data is required.

22.

Application of a new or updated TSE European Pharmacopoeial certificate of suitability for an excipient
22.1. from a manufacturer currently approved or a new manufacturer (replacement or addition) No conditions

IA

23.

Change in source of an excipient or reagent: replacement of such product, which may result in TSE risk, by a vegetable or synthetic material  
23.1. excipient or reagent used in the manufacture of a biological active substance or manufacture of a finished product containing a biological active substance Conditions: (see below)

IB

23.2. other cases Conditions: (see below)

IA

Conditions: excipient and finished product release and end of shelf life specifications remain the same.

24.

Change in synthesis or recovery or a non-pharmacopoeial excipient (when described in the documentation)

IB

Conditions:

1. Specifications are not adversely affected; no change in the qualitative and quantitative impurity profile or in physico-chemical properties.

2. The excipient is not a biological substance.

25.

Change to comply with European Pharmacopoeia or with the national pharmacopoeia of a Member State
25.1. change to specification(s) of a former non-European pharmacopoeial substance to comply with the European Pharmacopoeia or with the national pharmacopoeia of a Member State
25.1.1. active substance Conditions: 1, 2 (see below)

IB

25.1.2. excipient Conditions: 1, 2

IB

25.2. change to comply with an update of the relevant monograph of the European Pharmacopoeia or national pharmacopoeia of a Member State
25.2.1. active substance Conditions: 1, 2

IA

25.2.2. excipient Conditions: 1, 2

IA

Conditions:

1. The change is made exclusively to comply with the pharmacopoeia.

2. Unchanged specifications (additional to the pharmacopoeia) for product specific properties (for example, particle size profiles, polymorphic form).

26.

Change in the specifications of the primary packaging of the finished product
26.1. tightening of specification limits Conditions: 1, 2, 3 (see below)

IA

Conditions: 2, 3

IB

26.2. addition of a new test parameter Conditions: 2, 4

IB

Conditions:

1. The change is not a consequence of any commitment from previous assessments - to review specification limits (for example, made during the procedure for registration application or a type II variation procedure).

2. The change shall not be the result of unexpected events arising during manufacture.

3. Any change shall be within the range of currently approved limits.

4. Any new test method does not concern a non-approved technique or a technique used in a novel way.

27.

Change to a test procedure of the primary packaging of the finished product
27.1. minor change to an approved test procedure Conditions: 1, 2, 3 (see below)

IA

27.2. other changes to a test procedure, including replacement or addition of a test procedure Conditions: 2, 3, 4

IB

Conditions:

1. The method of analysis shall remain the same (for example, change in column length or temperature shall be permissible, but not a different type of column or method).

2. Appropriate (re-)validation studies were performed in accordance with the relevant guidelines.

3. Results of method validation show the new test method to be at least equivalent to the former procedure.

4. Any new test method does not concern a non-approved technique or a technique used in a novel way.

28.

Change in any part of the (primary) packaging material not in contact with the finished product formulation (such as the colour of flip-off caps, colour code rings on ampoules, change of needle shield (different plastic used)).

IA

Condition: the change does not concern a fundamental part of the packaging material, which affects the delivery, use, safety or stability of the finished product.

29.

Change in the qualitative and/or quantitative composition of the immediate packaging material
29.1. soft (semi-liquid) or liquid pharmaceutical forms Conditions: 1, 2, 3, 4 (see below)

IB

29.2. all other pharmaceutical forms Conditions: 1, 2, 3, 4

IA

Conditions: 1, 3, 4

IB

Conditions:

1. The product concerned is not a biological or sterile product.

2. The change concerns only the same packaging type and material (for example, blister to blister).

3. The proposed packaging material shall be at least equivalent to the approved material in respect of the relevant properties thereof.

4. Relevant stability studies in accordance with the relevant guidelines have been started with at least 2 pilot scale or industrial scale batches and at least 3 months stability data are at the disposal of the applicant of the request. Assurance is given that these studies will be finalised and that the data will be provided immediately to the competent authorities if they do not comply, or possibly do not comply with the specifications at the end of the approved shelf life (with the proposed action).

30.

Change (replacement, addition or deletion) in the supplier of packaging components or devices (when mentioned in the documentation), except spacer devices for metered dose inhalers
30.1. deletion of a supplier Conditions: 1 (see below)

IA

30.2. replacement or addition of a supplier Conditions: 1, 2, 3, 4

IB

Conditions:

1. No deletion of the packaging component or device.

2. The qualitative and quantitative composition of the packaging components or device remains the same.

3. The specifications and quality control method are at least equivalent.

4. The sterilisation method and conditions remain the same (if applicable).

31.

Change to in-process tests or limits applied during the manufacture of the medicinal product
31.1. tightening of in-process limits Conditions: 1, 2, 3 (see below)

IA

31.2. addition of new tests and limits Conditions: 2, 3

IB

Conditions: 2, 4

IB

Conditions:

1. The change is not a consequence of any commitment from previous assessments (for example, made during the procedure for registration request or a type II variation procedure).

2. The change shall not be the result of unexpected events arising during manufacture or because of stability concerns.

3. Any change shall be within the range of currently approved limits.

4. Any new test method does not concern a non-approved technique or a technique used in a novel way.

32.

Change in the batch size of the finished product
32.1. scale-up up to 10-fold compared to the original batch size approved at the grant of registration Conditions: 1, 2, 3, 4, 5 (see below)

IA

32.2. downscaling down to 10-fold Conditions: 1, 2, 3, 4, 5, 6

IA

32.3. other cases Conditions: 1, 2, 3, 4, 5, 6, 7

IB

Conditions:

1. The change does not affect the reproducibility and/or consistency of the product.

2. The change relates only to standard immediate release oral pharmaceutical forms and to non-sterile liquid forms.

3. Any changes to the manufacturing method, as well as to the in-process controls are only those necessitated by the change in batch-size (for example, different sized equipment).

4. A validation scheme is available or validation of the manufacture has been successfully carried out according to the current protocol with at least 3 batches at the proposed new batch size in accordance with the relevant guidelines.

5. It does not concern a medicinal product containing a biological active substance.

6. The change shall not be the result of unexpected events arisen during manufacture or because of stability concerns.

7. Relevant stability studies in accordance with the relevant guidelines have been started with at least 2 pilot scale or industrial scale batches and at least 3 months stability data are at the disposal of the applicant. Assurance is given that these studies will be finalised and that the data will be provided immediately to the competent authorities if they do not comply, or possibly do not comply with the specifications at the end of the approved shelf life (with the proposed action).

33.

Minor changes in the manufacture of the finished product

IB

Conditions:

1. The overall manufacturing principle remains the same.

2. The new process shall lead to an identical product regarding all aspects of quality, safety and efficacy.

3. The medicinal product does not contain a biological active substance.

4. In case of a change in the sterilisation process, the change is to a pharmacopoeial cycle only.

5. Relevant stability studies in accordance with the relevant guidelines have been started with at least 2 pilot scale or industrial scale batches and at least 3 months stability data are at the disposal of the applicant. Assurance is given that these studies will be finalised and that the data will be provided immediately to the competent authorities if they do not comply, or possibly do not comply with the specifications the end of the approved shelf life (with proposed action).

34.

Change in the colouring system or the flavouring system currently used in the finished product
34.1. reduction or deletion of one or more components    
34.1.1. the colouring system Conditions: 1, 2, 3, 4, 7 (see below)

IA

34.1.2. the flavouring system Conditions: 1, 2, 3, 4, 7

IA

34.2. increase, addition or replacement of one or more components    
34.2.1. the colouring system Conditions: 1, 2, 3, 4, 5, 6, 7

IB

34.2.2. the flavouring system Conditions: 1, 2, 3, 4, 5, 6, 7

IB

Conditions:

1. No change in the functional characteristics of the pharmaceutical form (for example, disintegration time, dissolution profile).

2. Any minor adjustment to the formulation to maintain the total weight shall be made by an excipient, which currently makes up a major part of the finished product formulation.

3. The finished product specification has only been updated in respect of appearance, odour, taste and, if relevant, - deletion or addition of an identification test.

4. Stability studies (long-term and accelerated) in accordance with the relevant guidelines have been started with at least 2 pilot scale or industrial scale batches and at least 3 months satisfactory stability data are at the disposal of the applicant, as well as the assurance that these studies will be finalised. Data shall be provided immediately to the competent authorities if they do not comply, or possibly do not comply with the specifications the end of the approved shelf life (with the proposed action). In addition, where relevant, photostability testing shall be performed.

5. Any new component shall comply with the colouring matters specified in the list of food additives permitted by the regulatory enactments regarding mandatory safety requirements for food additives.

6. Any new component does not include the use of materials of human or animal origin, for which assessment is required of viral safety data or compliance with the Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (with the last revision).

35.

Change in the coating weight or tablets or change in weight of the capsule shells
35.1. immediate release oral pharmaceutical forms Conditions: 1, 3, 4 (see below)

IA

35.2. modified or prolonged release pharmaceutical forms that dissolve in the intestines Conditions: 1, 2, 3, 4

IB

Conditions:

1. The dissolution profile of the new product determined on a minimum of 2 pilot scale batches is comparable to the old one. For herbal medicinal products where dissolution testing may not be feasible, the disintegration time of the new product is comparable to the old one.

2. The coating is not a critical factor for the release mechanism.

3. The finished product specification has only been updated in respect of weight and dimensions.

4. Stability studies in accordance with the relevant guidelines have been started with at least 2 pilot scale or industrial scale batches and at least 3 months satisfactory stability data are at the disposal of the applicant, as well as the assurance that these studies will be finalised. Data shall be provided immediately to the competent authorities if they do not comply, or possibly do not comply with the specifications at the end of the approved shelf life (with the proposed action).

36.

Change in shape or dimensions of the container or closure
36.1. sterile pharmaceutical forms and biological medicinal products Conditions: 1, 2, 3 (see below)

IB

36.2. other pharmaceutical forms Conditions: 1, 2, 3

IA

Conditions:

1. No change in the qualitative or quantitative composition of the container.

2. The change does not concern a fundamental part of the packaging material, which affects the delivery, use, safety or stability of the finished product.

3. If change is related to the head space or a change in the surface/volume ratio, stability studies in accordance with the relevant guidelines have been started with at least 2 pilot scale (in respect of biological medicinal products - 3) or industrial scale batches and at least 3 months (in respect of biological medicinal products - 6 months) stability data are at the disposal of the applicant of the request. Assurance is given that these studies will be finalised and that the data will be provided immediately to the competent authorities if they do not comply, or possibly do not comply with the specifications at the end of the approved shelf life (with the proposed action).

37.

Change in the specification of the finished product  
37.1. tightening of specification limits Conditions: 1, 2, 3 (see below)

IA

Conditions: 2, 3

IB

37.2. addition of a new test parameter Conditions: 2, 4, 5

IB

  Conditions:

1. The change is not a consequence of any commitment from previous assessments to review specification limits (for example, made during the procedure for registration application or a Type II variation procedure).

2. The change shall not be the result of unexpected events arising during manufacture.

3. Any change shall be within the range of currently approved limits.

4. Any new test method does not concern a non-approved technique or a technique used in a novel way.

5. The test procedure does not apply to a biological active substance or biological excipient in the medicinal product.

38.

Change in test procedure of the finished product
38.1. minor change to an approved test procedure Conditions: 1, 2, 3, 4, 5 (see below)

IA

38.2. minor change to an approved test procedure for biological active substance or biological excipient Conditions: 1, 2, 3, 4

IB

38.3. other changes to a test procedure, including replacement or addition of a test procedure Conditions: 2, 3, 4, 5

IB

Conditions:

1. The method of analysis shall remain the same (for example, change in column length or temperature shall be permissible, but not a different type of column or method).

2. Appropriate (re-)validation studies have been performed in accordance with the relevant guidelines.

3. Results of method validation show the new test procedure to be at least equivalent to the former procedure.

4. Any new test method does not concern a non-approved technique or a technique used in a novel way.

5. The test procedure does not apply to a biological active substance or biological excipient in the medicinal product.

39.

Change or addition of the imprints, bossing or other markings (except scoring) on tablets or printing on capsules, including replacement, or addition of inks used for product marking

IA

Conditions:

1. The finished product release and end of shelf life specifications have not been changed (except for the appearance).

2. Any new ink shall comply with the relevant pharmaceutical legislation.

40.

Change of dimensions of tablets, capsules, suppositories or pessaries without change in the qualitative or quantitative composition and mean mass
40.1. modified or prolonged release pharmaceutical forms and scored tablets that dissolve in the intestines Conditions: 1, 2 (see below)

IB

40.2. any other tablets, capsules, suppositories and pessaries Conditions: 1, 2

IA

Conditions:

1. The dissolution profile of the reformulated product is comparable to the old one. For herbal medicinal products, where dissolution testing may not be feasible, the disintegration time of the new product is comparable to the old one.

2. Release and end of shelf life specifications of the medicinal product have not been changed (except for dimensions).

41.

Change in pack size of the finished product
41.1. change in the number of units (for example, tablets, ampoules) in a pack
41.1.1. change within the range of the currently approved pack sizes Conditions: 1, 2 (see below)

IA

41.1.2. change outside the range of the currently approved pack sizes Conditions: 1, 2

IB

41.2. change in the fill-weight and fill volume of the non-parental multi-dose products Conditions: 1, 2

IB

Conditions:

1. New pack size shall be consistent with the posology and treatment duration as approved in the summary of the product characteristics.

2. The primary packaging material remains the same.

42.

Change in:
42.1. the shelf-life of the finished product
42.1.1. as packaged for sale Conditions: 1, 2, 3 (see below)

IB

42.1.2. after first opening Conditions: 1, 2

IB

42.1.3. after dilution or reconstitution Conditions: 1, 2

IB

42.2. the storage conditions of the finished product or the diluted/reconstituted product Conditions: 1, 2, 4

IB

Conditions:

1. Stability studies have been done according to the currently approved protocol. The studies shall show that the agreed relevant specifications are still met.

2. The change shall not be the result of unexpected events arisen during manufacture or because of stability concerns.

3. The shelf life does not exceed 5 years.

4. The relevant product is not a biological medicinal product.

43.

Addition, replacement or deletion of a measuring or administration device which is not an integrated part of the primary packaging (except spacer devices for metered dose inhalers)
43.1. medicinal products for human use
43.1.1. addition or replacement Conditions: 1, 2 (see below)

IA

43.1.2. deletion Condition: 3

IB

Conditions:

1. The proposed measuring device shall accurately deliver the required dose for the product concerned in line with the approved posology, and the results of such studies shall be available.

2. The new device is compatible with the medicinal product.

3. The medicinal product can still be accurately delivered.

Notes.

1. The conditions necessary for a given variation to follow either a type IA or a type IB procedure shall be outlined for each subcategory and listed below each variation.

2. To cover any other changes, it shall be necessary to submit applications for any consequential or parallel variations, which may be linked to the change applied for, and to clearly describe the relation between these variations.

3. For notifications, including a certificate of suitability from the European Pharmacopoeia, and when the variation concerns the documentation submitted for the certificate, the documents required for such change shall be submitted to the European Directorate for the Quality of Medicines (EDQM). If the certificate is revised following evaluation of such change, any relevant registration certificates (application dossier) shall be updated. In many cases this may be done through a type I A notification.

4. A biological medicinal product is a product, the active substance of which is a biological substance. A biological substance is produced by or extracted from a biological source, and a combination of physical, chemical and biological testing must be performed for characterisation and the determination of quality thereof, as well as the production process must be controlled. Immunological preparations and medicinal products derived from human blood and human plasma shall be regarded as biological medicinal products.

5. A change in the manufacturing process of a non-proteinaceous component due to a subsequent introduction of a biotechnology step may be made in accordance with the provisions of variations type I No. 15 or No. 20. This specific variation is without prejudice to other variations listed in this Annex, which can be applied in the particular context. The referred to shall not apply to the introduction of a proteinaceous component obtained through a biotechnology process in the formulation of a medicinal product to a medicinal product subject to centralised registration, to which Commission Regulation No 1234/2008 applies.

6. There is no need to notify the State Agency of Medicines of an updated monograph of the European Pharmacopoeia or a national pharmacopoeia of a Member State, if the compliance with the updated monograph is implemented within a time period of 6 months of the publication thereof and reference is made to the current edition in the documentation of the registered medicinal product.

7. The test procedure referred to in this Annex shall have the same meaning as analytical procedure, and the limits shall have the same meaning as acceptance criteria.

Acting for the Minister for Health,
Minister for Culture H. Demakova

 

[18 May 2010; 3 September 2013]

Annex 9
Cabinet Regulation No. 376
9 May 2006

Iesniegums

saskaņā ar Ministru kabineta 2006.gada 9.maija noteikumu Nr.376 "Zāļu reģistrēšanas kārtība" 125.1punktu*

Application in Accordance with Clause 1251 of the Cabinet of Minister's Regulation No.376 "Medicinal Product Registration Procedure"*

Reģistrācijas apliecības īpašnieks/Marketing authorization holder
Nosaukums/Name
Adrese/Address Pasta indekss/Postal code Pilsēta/City
Kontaktpersona/Contact person Valsts/Country
Tālruņa numurs/Phone Elektroniskā pasta adrese/E-mail address

Zāles, kuras trīs gadus nav bijušas Latvijas tirgū ar vismaz vienu iepakojumu

The medicinal product that has not been placed on the Latvian market within three years with at least one packaging

Informācija par zālēm/Information on medicinal product

Zāļu nosaukums/

Medicinal product name

Zāļu stiprums, forma/

Strenght, form

Reģistrācijas Nr./ Marketing authorization No.

     

Izņēmuma tiesību pamatojums

(saskaņā ar Ministru kabineta 2006.gada 9.maija noteikumu Nr.376 "Zāļu reģistrēšanas kārtība" 125.3.apakšpunktu)/

Justification for exemption/(in accordance with sub-clause 125.3 of the Cabinet of Minister's Regulation No.376 "Medicinal Product Registration Procedure"

Pagarinājuma termiņš/

Possible extension

[ ] Izņēmuma tiesības var piemērot zālēm, kuru neesība var radīt risku sabiedrības veselībai un kurām Latvijas zāļu reģistrā ir divi vai mazāk analogi (ņemot vērā ATĶ kodus, indikācijas, ievadīšanas veidu)

There is lack of suitable alternative medicinal products which means that there is a potential for adverse impact on public health and the medicinal product has two or fewer analogues in the Register of Medicinal Products of the Republic of Latvia (in view of ATC codes, indication, route of administration

3 gadi/ 3 years

[ ] Izņēmuma tiesības var piemērot zālēm, kas ir daļa no valsts materiālo rezervju medikamentiem saskaņā ar normatīvajiem aktiem par neatliekamās medicīniskās palīdzības nodrošināšanu un pretepidēmijas pasākumiem, medikamentu nodrošinājuma sistēmas sagatavošanu un darbu valsts apdraudējuma gadījumā

The medicinal product is a part of national reserves of medicinal products in accordance with regulatory enactments on ensuring emergency medicinal aid and anti-epidemic measures, development of medicinal product provision system and work in case of threat to state security

3 gadi/ 3 years

[ ] Izņēmuma tiesības var piemērot zālēm, kas paredzētas tiesiskam eksportam uz trešajām valstīm

The medicinal product is intended for certified export to non-EEA countries (third countries)

3 gadi/ 3 years

[ ] Izņēmuma tiesības var piemērot zālēm, kas reģistrētas savstarpējās atzīšanas (MR) vai decentralizētajā (DC) reģistrācijas procedūrā ar Latviju kā atsauces valsti (zāļu izplatīšanas iespējas nodrošināšanai iesaistītajās dalībvalstīs)

The medicinal product has been mutually recognised through the mutual recognition (MR) or decentralized(DC) procedure with Latvia as RMS (to ensure supply of medicinal products in participating Member States)

3 gadi/ 3 years

[ ] Izņēmuma tiesības var piemērot zālēm gadījumos, ja tiek plānotas ražošanas vietas vai procesa izmaiņas, un spēkā esoša zāļu reģistrācijas apliecība ir nepieciešama, lai pacientus nodrošinātu ar zālēm

The medicinal product for which there is an on-going planned change in manufacturing site or process and valid marketing authorization is required to ensure patients with the medicinal product

1 gads/ 1 year

Iesnieguma iesniedzējs apliecina, ka iesniegumā norādītā informācija ir pareiza un to apstiprinošs pamatojums tiks iesniegts nedēļas laikā pēc Zāļu valsts aģentūras pieprasījuma.

The applicant declares that the above information is correct and that evidence justifying the above claims will be provided within one week of any request by the State Agency of Medicines

Paraksts/Signature Vārds, uzvārds/Name, surname Datums/Date

Piezīmes.

1. * Atbilst Eiropas Parlamenta un Padomes 2001.gada 6.novembra direktīvas 2001/83/EK 24.panta 4., 5. un 6.punktam (In accordance with Clause 4, 5 and 6 of Article 24 of Directive 2001/83/EC of the European Parliament and the Council as of 6 November 2001).

2. The details of the document "signature" and "date" shall not be completed if the electronic document has been drawn up in conformity with the laws and regulations regarding drawing up of electronic documents.

 


Translation © 2014 Valsts valodas centrs (State Language Centre)

 
Document information
Title: Zāļu reģistrēšanas kārtība Status:
In force
in force
Issuer: Cabinet of Ministers Type: regulation Document number: 376Adoption: 09.05.2006.Entry into force: 23.06.2006.Publication: Latvijas Vēstnesis, 97, 22.06.2006.
Language:
LVEN
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