The Procedure Of Registration Of Medicinal Products

Original Language Title: Zāļu reģistrēšanas kārtība

Read the untranslated law here: https://www.vestnesis.lv/ta/id/138149

Cabinet of Ministers Regulations No. 376 in Riga 2006 (May 9. No. 26) order of registration of medicinal products issued in accordance with article 5 of the law on Pharmacy (3) i. General questions 1. determines the procedure for the registration of the medicinal product (also the mutual recognition procedure and decentralised procedure).
2. These provisions apply to: 2.1. medicinal products for human use manufactured industrially or manufactured by a method that involves an industrial process;
2.2. herbal medicines;
2.3. homeopathic medicinal products and medicinal products antropozofaj;
2.4. products of biological origin;
2.5. for radiopharmaceuticals, this, kits, radionuclide generators, radionuclide precursors;
2.6. mineral waters, if they meet the definition of a medicinal product and the State Agency of medicines is recognised as medicines;
2.7. for medical gases.
3. These provisions shall not apply to: 3.1. veterinary medicinal products;
3.2. the registration of the medicinal products, which shall be recorded in the centralised registration procedure of the European Parliament and of the Council of 31 March 2004, Regulation (EC) No 726/2004 laying down the procedures for the authorisation and supervision of medicinal products for human and veterinary use Community procedures and establishing a European Medicines Agency (hereinafter referred to as the European Parliament and Council Regulation No 726/2004);
3.3. any medicinal product which is prepared in the Pharmacy at the medical treatment person's prescription for an individual patient or after treatment at the request of the person (the magistral formula);
3.4. for medicinal products which are prepared in a pharmacy in accordance with the pharmacopoeia grāfij and Mono which is intended for distribution to patients served by the pharmacy in question (the officinal formula);
3.5. medicinal products intended for research and development trials and investigational medicinal product referred to in the Act, regulations for clinical trials of the medicinal product and the use of the observation procedure;
3.6. intermediate products intended for further processing by the licensed manufacturer of the medicinal product;
3.7. radionuclides (radioactive ISO top) in the form of sealed sources.
3.8. for radiopharmaceuticals, which are in accordance with the instructions of the manufacturer of the medicinal product for the medical institution (in accordance with the laws and have permission to use a radiopharmaceutical preparations) from generators, kits and any other radionuclide produced another substance to mark before use for radiological and from which is produced a radiopharmaceutical preparations;
3.9. whole human blood, plasma or blood cells, except for plasma which is prepared industrially;
3.10 medicinal products meet the pharmaceutical law article 10 paragraph 7 referred to in condition, in one of the following cases: 3.10.1. unregistered medicinal products for use in certain patients, if the registered product after the clinical indications are not suitable for use on patients and medications delivered using healthcare professional order that assumes direct legal responsibility (professional liability);
3.10.2. medicines for pathogens, toxins, chemical agents or the suspected or confirmed spread of possible prevention and use of disasters, natural disasters, epidemics, also during a pandemic.
4. the meaning of these provisions: 4.1 herbal preparations are preparations obtained by processing vegetable substances such as extraction, distillation, pressing, fractionation, purification, to dispatch or fermentation. They also include chopped or powdered herbal substances, tinctures, extracts, essential oils, plant juices and processed exudates;
4.2. herbal substances are mainly whole, chopped or sliced also plants, parts of plants, including algae, fungi and lichen, unprocessed, usually dried, sometimes too fresh. Herbal substances are to be considered as a separate vegetable secretions, not specifically treated. Herbal substances accurately defines the applicable portion of the plant and the plant's scientific name, binary nomenclature (genus, species, variety and author);
4.3. herbal medicine is medicine that is only active ingredients one or more herbal substances or one or more herbal preparations, or one or more herbal substances, combined with one or more herbal preparations;
4.4. the reference product is a medicinal product which has been registered in Latvia in accordance with these terms or the European economic area country, or in a centralized registration procedure in accordance with European Parliament and Council Regulation No 726/2004;
4.5. biological medicinal products are: 4.5.1 immunologicals: any medicinal product consisting of vaccines, toxins, serums or allergen products: 4.5.1.1. vaccines, toxins and serums shall cover: 4.5.1.1.1. agents used to produce active immunity (such as ram, the cholera vaccine, Used in tuberculosis Kalmet-vaccine BCG, polio vaccines, smallpox mielīt vaccine);
4.5.1.1.2. agents used to diagnose the State of immunity, including tuberculin and tuberculin PPD toxins for the Schick and Dick tests, brucellin;
4.5.1.1.3. agents used to produce passive immunity (such as diphtheria antitoxin, anti-smallpox globulin, antilymphocytic globulin;)
4.5.1.2. allergen-any medicinal product intended to be specific to get change for the creation of the immunological response or to the allergic agent;
4.5.2. from human blood and plasma-derived medicinal product: a public or private company manufacture medicinal products based on blood constituents, including such drugs as human albumin, clotting factors and immunoglobulin;
4.5.3. medications, subject to registration, in accordance with European Parliament and Council Regulation No 726/2004;
4.5.4. advanced therapy medicinal products.
4.6. generic medicines are drugs that have the same qualitative and quantitative composition 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. Different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of an active substance shall be considered to be the same active substance, unless they do not substantially differ in their characteristics, related to the safety or effectiveness (in such cases, the applicant for registration provides additional information that demonstrates the different salts, esters or derivatives of an active substance permitted for safety and effectiveness). Different pharmaceutical form for oral use with immediate disposal of the active substance is considered to be one and the same pharmaceutical form;

4.7 plasma master file is separate from the registration documentation documentation, which contains detailed information about the characteristics of human blood plasma that as raw materials or as raw material used in the apakšfrakcij and starpfrakcij of the excipient (s) and the active substance (s) in production and which is part of the medicinal products or medical devices incorporating stable derivates of human blood or human plasma;
4.8. the pharmaceutical precursors are all other radionuclide produced for radio-labelling of another substance prior to its use;
4.9. radionuclide generator: any system, from the radio pharmaceutical product and that includes a fixed primary ("parent"), from which the radioactive isotope retrieves the secondary ("subsidiary") that the radioactive isotope emits by Elution or by any other method;
4.10. the pharmaceutical preparation is any radiopharmaceutical drugs that use the prepared form contains one or more radionuclides — radioactive isotopes except isotopes from closed sources, intended for medical purposes;
4.11. the kit is any pre by the Town Council, which shall be renewable or joining in the jam with radionuclides in the final radiopharmaceutical (usually prior to its administration);
4.12. the risk-benefit balance of the medicinal product have a beneficial therapeutic effect assessment, taking into account all the risks relating to the quality of the product, safety or effectiveness related to the patient's health or public health (public health);
4.13. the vaccine Antigen master is an application for the registration of certain parts of the dossier, which contains all the relevant information for each medicinal ingredient active substances biological, pharmaceutical and chemical properties. Documentation may relate to one or more Monovalent and combined vaccines presented by one and the same application for registration of the applicant or holder of the registration;
4.14. the name of the medicinal product, which may be: the name given 4.14.1., which should not be confused with the generic name (the World Health Organization recommended international non-proprietary name (INN) or, if such is not recommended, the commonly used name);
4.14.2. General or scientific name accompanied by a trade mark or holder of the registration certificate (the owner's) name.
5. If the product, taking into account all the characteristics of the product correspond to the definition of medicinal products and other products (e.g., food, dietary supplements, cosmetics, medical devices, biocides) definition according to European Union legislation, to products covered by these regulations.
6. the State Agency of medicines has the right to decide on the conformity of pharmaceutical products in the statutory definition of a drug. In this case the product has to be registered in the State Agency of medicines as drugs if it meets at least one of the following criteria: 6.1 product contains: 6.1.1. vitamins and minerals or their compounds, which are included in the law on minimum safety requirements for nutritional supplements and dietary supplements registration procedures, but the quantity or recommended daily intake exceeds the legislation on food labelling of vitamins and minerals specified in the recommended daily dose;
6.1.2. other vitamins and minerals or their compounds, which are not included in the law on minimum safety requirements for nutritional supplements and dietary supplements registration procedures;
6.2. information on primary or secondary packaging (labels), package leaflet, advertising material or other information about the product or use of the expressed medical claims or product advertised for a specific range of patients;
6.3. like product is registered as a drug;
6.4. the product complies with: 6.4.1. homeopathic medicinal products, which shall be recorded in a special, simplified registration procedure;
6.4.2. traditional herbal medicinal products, and products of vitamin and mineral supplements the effect of the herbal active ingredients regarding the specified exposure (s) indication (s).
7. the State Agency of medicines under the pharmaceutical law and these rules shall assess and record the medications.
8. Registration (for new or original registration) and the fact that the renewal of the Republic of Latvia declares valid the State Agency of medicines of the decision on registration or Reregistration and issued a registration certificate for medicinal products, which is designed according to annex 1 of these rules. The State Agency of medicines shall decide, on the basis of registration or re-registration application and the documents annexed thereto (hereinafter registration application).
9. Medicine State agency decision on new registration (initial registration) is valid for a period of five years after the decision on the registration of the adoption.
10. the five years since the decision on the registration of the medicinal product by the national agency of adoption, on the basis of the risk-benefit balance of the reassessment is entitled to take a decision on the registration of the medicinal product. If the product is once re-registered, medicine State agency may adopt a decision on the validity of the registration for an unlimited period of time (specified in the certificate of registration of medicinal products), except that if, on the basis of the monitoring of adverse reactions of the medicinal products (pharmacovigilance) of the evidence obtained, the State Agency of medicines, re-register a product, has taken a decision on the registration of the medicinal product again for five years.
11. after the State Agency of medicines has taken a decision on the registration of the medicinal product in relation to any of the additional strength, pharmaceutical form, route of administration, marketing packages or registration extension (extension of the registration certificate), or changes in the registration dossier shall adopt one of the following decisions: 11.1. registration of medicinal products;
11.2. the inclusion of data in the existing decision on registration.
12. Both of these rules the decision referred to in paragraph 11 shall be included in the initial decision on the registration of medicinal products, in particular as regards the provisions referred to in paragraph 28 of the registration.
13. legal address of the person to whose name the medication record, are members of the European economic area country (trader is a registered firm, the actual Central Administration or place of business).

14. the parallel imported medicinal product registration and re-registration of the Republic of Latvia, the facts presents a valid medicine State agency decision on the parallel imported medicinal product distribution issue. The decision of the State Agency of medicines shall be adopted in accordance with the laws and regulations on the distribution of medicinal products.
15. the State Agency of medicines of the Republic of Latvia registered medicines, centrally registered medicines and parallel imported medicinal product included in the Republic of Latvia register of medicinal products.
II. the criteria for the registration of medicines 16. To register the drug, the person to whose name the intended to register medicines (hereinafter applicant) shall submit a registration to the Agency for medicinal products in the national application of European Commission European Community pharmaceutical legislative framework document published volume 2 of items the specimen and which is also published by the National Agency for Medicines home page on the internet (hereinafter referred to as the model of the European Commission). Registration application for registration of a medicinal product in two or more European economic area countries submitted in accordance with the provisions of chapter XIII.
17. paragraph 16 of these rules of registration referred to in the application and the attached documents contain data relevant to the European Commission and this provision 23, 24, 25, 26 and 27 (hereinafter registration). The application and the registration dossier shall specify the following: 17.1. application for registration of the applicant, the name or business name and registered office and, if necessary, the manufacturer's brand and registered office;
17.2. the name of the medicinal product;
17.3. the full its qualitative and quantitative composition, including the reference to the international non-proprietary name recommended by the World Health Organization (INN) where a medicinal product is granted, or a reference to the relevant chemical name;
17.4. the assessment of the medicinal potential of the environmental risk posed by (all risk factors associated with adverse effects on the environment). Environmental impact in each case assessed individually and determine the specific procedures to limit the risk;
17.5. the description of the manufacturing method;
10.9. therapeutic indications, contra-indications and adverse reactions (side effects);
17.7. the dose and route of administration, pharmaceutical form, the method and the way storage period;
11.1., reasons for any precautionary and safety measures to be followed, the medication storage, medicine using patients and destroying waste of medicinal products, together with an indication of the potential risk of the medicinal effects on the environment; 11.1. Description of the control methods employed by the manufacturer;
17.10. results of: 17.10.1. pharmaceutical (physico-chemical, biological or microbiological in) tests;
17.10.2. non-clinical (toxicological and pharmacological in) tests;
17.10.3. clinical trials.
17.11. detailed description of pharmacovigilance systems description and, where appropriate, a detailed description of the risk control system, which will introduce a registration applicant;
17.12. notification of clinical trial compliance with legislation on clinical trials of medicines and the use of the observation procedure the following ethical norms;
17.13. Summary of product characteristics drawn up in accordance with paragraph 21 of these rules. If the medicinal product is recorded in the mutual recognition or decentralised procedure, the registration of the application, the applicant shall submit a copy of the summary of product characteristics that meet this provision paragraph 21, or — this rule 89.1. in the case referred to in subparagraph — European economic area approved by the competent authority a copy of the summary of product characteristics. The information referred to in the registration application, the applicant regularly;
17.14. Label: secondary and primary packaging mock-ups containing regulations on the labelling of medicinal products and pharmacovigilance procedures manual izvirzāmaj the information specified requirements relating to a secondary and primary mark;
17.15. instructions, which contain regulations on the labelling of medicinal products and pharmacovigilance requirements laid down for izvirzāmaj instructions. If the medicinal product is recorded or mutual recognition in the decentralised procedure, you need to add a registration the applicant providing a gum a copy of the instructions or the European economic area, approved by the competent authority a copy of the instructions for use;
17.16. the document certifying the right of the manufacturer to produce the product in question, the competent authorities of the country report, which is inspicējus in the place of production, or a European economic area country competent authority issued the certificate of good manufacturing practice (no older than three years). That document can replace the reference to good manufacturing practice requirements or the summary of the good manufacturing practice inspections carried out during the last two years;
17.17. registration certificate (copies) obtained in other European economic area countries or countries that are not members of the European economic area (hereinafter third country), together with the countries of the European economic area, in which the appearance of the list of the registration;
17.18. information on any decision that the European economic area country or third country's refusal of granting permission, and such a decision of the Community body. The information referred to in the registration application, the applicant regularly;
17.19. document (copy) on the establishment of the medicinal product as an orphan in accordance with European Parliament and Council of 16 December 1999, Regulation (EC) No 141/2000 on orphan medicinal products of which is connected to the European Medicines Agency, a copy of the opinion;
17.20. proof that services provided to the applicant the application for registration of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any undesirable side effects, for which there is a suspicion that they might be observed in the European economic area or in a third country;
17.21. with regard to the genitals of radionuclides submit comments in addition to the requirements referred to in this paragraph shall contain the following information: 17.21.1. General description of the system together with a detailed description of the system components that may affect the secondary (subsidiary) nucleid preparation, composition or quality;
17.21.2. quality and quantitative data on the eluate or the sublimate.
18. the registration of the medicinal products specified in the documentation contained in the colours correspond to the rules of annex 2.

19. in addition to the registration application, the applicant indicates the reference product when submitted for registration submissions, abbreviated as referred to in chapter III of these regulations and the date when the reference product is first registered in the European economic area.
20. The documents and information on the pharmaceutical, non-clinical and clinical trials of the test results referred to in these rules are added 17.10 detailed summary. Summaries drawn up and signed by experts with the necessary technical or professional qualifications (which is specified in the short their education and work (living) (curriculum vitae)).
21. The summary of the order below includes the following information: 21.1. name of the medicinal product, the strength and the pharmaceutical form;
21.2. the active substances and constituents of the excipient qualitative and quantitative composition in terms of their generic name or chemical description;
21.3. the pharmaceutical form;
21.4. clinical data: 21.4.1. therapeutic indications;
21.4.2. dose and route of Administration for adults and, where necessary, for children;
21.4.3. contraindications;
21.4.4. Special warnings and precautions for use. Immunological preparations indicate any special precautions to be taken by persons following products store and enter the patients, as well as any precautionary measures to be taken to the patient;
21.4.5. interaction with other medicinal products and other forms of interaction;
21.4.6. use during pregnancy and breastfeeding;
21.4.7. effects on ability to drive transport means and use machines;
21.4.8. adverse side 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. preclinical safety data;
21.6. pharmaceutical particulars: 21.6.1. list of excipients;
21.6.2. major incompatibilities,
21.6.3. storage time after preparation (for example, dilution or mixing) or after the primary packaging is opened for the first;
21.6.4. special storage conditions;
21.6.5. type of packaging and contents.
21.6.6. Special protective measures (if necessary) for the destruction of waste derived from medicinal products;
21.7. the holder of the registration;
21.8. the registration number (s) (registration certificate number (s));
13.6. the first registration or re-registration date;
21.10. date of revision of the summary of product characteristics;
21.11. such preparations: 21.11.1. details of internal radiation dosimetry.
21.11.2. additional instructions for the preparation of these preparations for immediate use and quality control and, where appropriate, maximum storage time during which any intermediate preparation preparations, such as an eluate or the ready for use products meet their specifications.
22. Where a medicinal product registered under this chapter III conditions referred to in the summary of product characteristics shall not be included in the data for those indications and dosages covered by patent protection reference product.
23. Registration dossiers shall be prepared taking into account: 23.1. Pharmaceutical law referred to in article 28.1, the European Commission's recommendations (guidelines), which is published by the European Commission European Community pharmaceutical legislative framework document item volume 2, part B "notice to applicants, medicinal products for human use, content and submission of the dossier, common technical document (KTD) and on which the information is made publicly available by the national agency of Medicine home page on the internet. Common technical document is applied to all types of submissions for registration irrespective of the applicable procedures and products, as well as whether it is filed or shorten the registration application;
23.2. the Committee adopted, and of medicinal products of the European Medicines Agency published scientific guidelines on medicinal products for human use, the quality, safety and effectiveness, the other European Community pharmaceutical guidelines which the European Commission has published in different European Community pharmaceutical legislative framework document Eudralex, for which the inventory information is publicly available medicines agency website on the internet;
23.3. the production process comply with the good manufacturing practice for medicinal products in accordance with the laws and regulations on the production and control of medicinal products and the European Commission's guidance on medicinal products and investigational medicinal products good manufacturing practices, the European Commission has published the European Community pharmaceutical legislative framework document item 4. volume for which the information is made publicly available by the national agency of Medicine home page on the internet;
23.4. that is all the information submitted for the evaluation of medicinal products, whether favourable or unfavourable. Provide all details about incomplete or interrupted farmakotoksikoloģisk or clinical tests or studies on medicinal products and completed studies on therapeutic indications not covered by the registration application;
14.6. the European economic area-based clinical trials comply with the legislation on medicinal products for clinical trials and the use of the observation procedure requirements. Outside the European economic area make clinical research medicinal products intended for use in the European economic area is planned, conducted and reported in accordance with good clinical practice and ethical principles equivalent to regulations on clinical trials and observations using procedure above. Clinical trials are carried out in accordance with the ethical principles that are laid down, such as the World Medical Association Helsinki Declaration (adopted by the World Medical Association General Assembly, 18, of medicinal products published by the National Agency's website on the internet);
14.7. the non-clinical studies (farmakotoksikoloģisk studies) is carried out in accordance with the laws and regulations on the requirements to the quality inspection of the laboratory and the principles of good laboratory practice;
23.7. that all tests on animals are performed in accordance with the laws and regulations on the protection of animals.
24. the registration dossier shall be drawn up in accordance with the provisions of annex 3. The registration dossier shall specify: 24.1. administrative data (module 1);
24.2. the summaries (quality, non-clinical and clinical) are (module 2);
24.3. the chemical, pharmaceutical and biological information for medicinal products containing both chemical and biologically active substances (module 3);
15.2. the reports on non-clinical research (module 4);

15.2. the reports of the clinical trials (module 5).
25. the registration documentation according to annex 4 to these rules shall be prepared for the following medicinal product: 25.1. medicine widely used medicinal products — medicinal products the active substance (s) (s) widely used in medicine and is recognized and acceptable safety level;
25.2. the essence of similar medicines (generic medicines);
25.3. similar biological medicinal products.
26. the registration documentation according to annex 5 of these rules shall be prepared for the following specific products: 26.1. biological medicinal products;
26.2. radiopharmaceutical preparations;
26.3. for pharmaceutical precursors;
26.4. homeopathic medicinal products;
26.5. herbal medicines;
16.5. an orphan medicinal product.
27. Registration dossiers according to annex 6 of these rules shall be prepared for the following advanced therapy medicinal products (medicinal products, acquired the manufacturing processes for active substances or part of active substances used mainly for various gene transfer-produced bio-molecules, as well as biologically advanced therapeutic modified cells): 27.1. gene (human and xenogeneic) medicinal (therapeutic products derived from the production process as a whole, the purpose of which is to transfer the preventive , diagnostic or therapeutic gene (nucleic acid) on the human or animal cells in vivo or ex vivo with following it expression in vivo. With gene transfer expression systems understands that include transfer system, known as vector, which may or may not be the origin of the virus. The vector can also contain any human or animal cell). Gene therapy medicinal products are diverse: 27.1.1. medicinal products based on allogeneic or xenogeneic cells: 27.1.1.1. before its transfer into the cells of the vector is prepared and stored;
27.1.1.2. the cells are obtained in advance and may be processed as a cell bank (bank collection or bank created from stem cells) with limited viability;
27.1.1.3. cell, which genetically modified with the vector, is the active substance;
27.1.1.4. to obtain the finished product can perform additional steps. In essence, the medicine is intended for use in certain patients;
27.1.2. medications that use autologous human cells: 27.1.2.1. the active substance is a prewritten set of vector before its transfer into the autologous cells are stored;
27.1.2.2. to obtain the finished medicinal product, additional steps may be carried out;
27.1.2.3. these medicines prepared from cells derived from the patient. Later cells are genetically modified, using prepared vector containing the gene, who previously prepared and constitute the active substance. Preparation of injected, and it is for one patient. The whole manufacturing process from the collection of the cells to the patient to consider injecting one intervention;
27.1.3. using vector with insert ready (preventive, diagnostic or therapeutic) genetic material: 27.1.3.1. the active substance is a predefined set of vectors;
27.1.3.2. to get the finished product, you can take additional steps, and such a medicinal product is intended for use on multiple patients;
27.1.3.3. genetic transfer may be prepared directly by injecting the vector recipient;
27.2. somatic cell (human and xenogeneic) medicinal therapy (means of autologous (from the patient himself), allogeneic (coming from another human being) or xenogeneic (from animals) somatic living cells, used by people and that biological characteristics are changed substantially, with the manipulating to get therapeutic, diagnostic or preventive effect with metabolic, pharmacological or immunological means. This manipulation includes the expansion of autologous cell populations ex vivo or activation (for example adoptive immunotherapy), with medical device related allogeneic or xenogeneic cells using ex vivo or in vivo, such as the complex matrix of mikrokapsul, bio-degradable or degradable);
27.3. ksenotransplantācij medicinal products.
III. Summary of the marketing application special requirements 28. the applicant for registration is not entitled to provide a clinical test and clinical trial results (not taking into account this provision 17.10. the requirements referred to in paragraph below, but not in violation of laws and regulations relating to the protection of industrial and commercial property), if he can demonstrate: 28.1. that the medicinal product is a generic medicinal product, the reference medicinal product which has been registered in one of the countries of the European economic area not less than eight years. In this case, the generic registration shall enter into force not earlier than after 10 years from the date of registration of the medicinal product of reference in European economic area countries. If the reference medicinal product has not been registered in Latvia, the registration application shall indicate the countries of the European economic area in which the reference product is registered or have been registered. If the first eight years of this decade has been registered by the owner of the registration of one or more new therapeutic indications which, during the scientific evaluation prior to their registration confirmed clinically significant benefits compared with existing therapies, said the 10-year protection period shall be extended to a maximum of one year;
28.2. the medicinal product (s) of the active substance (s) (s) European economic area country is widely used in medicine (s) if the composition of the medicinal product for at least 10 years, with recognised efficacy and an acceptable level of safety in accordance with the provisions of annex 4. In this case, the test and the results of the research have been replaced with references to the relevant scientific literature.
29. the State Agency of medicines: 29.1. require the competent national authorities evidence that the reference medicinal product is or has been registered in one of the established European economic area countries, together with the full composition of the reference medicinal product and, if necessary, other relevant documents;
29.2. by other countries of the European economic area to request the competent authority to which the application for registration has been filed, the month of the transfer receipt to the competent authority that the reference medicinal product is or has been registered in Latvia, established with the full composition of the reference medicinal product and, if necessary, other relevant documents.
30. non-clinical or clinical trial results shall be submitted in one of the following cases: 30.1. the medicinal product does not meet the generic medicines;
30.2. the bioequivalence cannot be demonstrated through bioavailability studies;
30.3. the change in the active substance (s), therapeutic indications, strength, pharmaceutical form or route of Administration for reference product;

18.9. biological medicinal product does not meet the generic medicines, but is equivalent to the reference product (taking into account the differences in the raw materials or the manufacturing process with the reference product). The additional data type and amount complies with the criteria laid down in annex 4 of these rules. Other results of the tests and studies referred to in the registration dossier, the reference product may not provide.
31. If the application is for registration of medicine widely used substances new indication, in addition to the provisions laid down in paragraph 28 of the protection period granted a one-year cumulative period not related to data protection, provided that the new indication to non-clinical or clinical significance research.
32. the necessary studies and trials (for these rules 28 and 30) and the ensuing practical steps are not considered as being contrary to patent rights or to supplementary protection certificates for medicinal products.
33. If the product contains active substances used in medicinal products authorised, but in this combination therapy have not been applied previously, in accordance with the provisions of paragraph 17.10. submit new non-clinical or clinical trial results for this composition, but the scientific references for each active substance separately do not provide.
34. After registration registration holder may authorise the use of the pharmaceutical, non-clinical and clinical documentation, which is included in the documentation for the information in the register to check future submissions for registration which apply to other drugs with the same active substance, qualitative and quantitative composition and the same pharmaceutical form.
IV. specific documentation requirements for medicinal products derived from human blood or plasma 35. Documentation requirements applicable to medicinal products derived from human blood or plasma, as well as the raw materials produced from human blood and plasma, the plasma master file shall be determined, subject to the approval of the procedure laid down in this chapter.
36. each human plasma fractionation and the processing center or authority shall draw up and update the information that is specified in the plasma master file. The plasma master file shall contain the following information: 36.1. plasma origin: 36.1.1. information on centres or establishments that collect blood and plasma, the data inspection and approval, and epidemiological data on infections transmitted by blood;
36.1.2. information on centres or establishments in which testing of materials and plasma donor Fund, including data on inspection and approval;
36.1.3. blood and plasma donor selection and rejection criteria;
36.1.4. used system that provides every donor in the media path passed to traceability of blood and plasma collection to finished product and vice versa;
36.2. plasma quality and safety: 36.2.1. compliance with European Pharmacopoeia requirements;
36.2.2. blood and plasma for testing of materials and funds for infectious agents, including information on test methods and, in the case of plasma pools, validation data on the tests used;
36.2.3. blood and plasma collection bag used for technical characteristics, including information on anticoagulants solutions;
36.2.4. plasma storage and transport conditions;
36.2.5. counting procedures and made the quarantine period;
36.2.6. plasma characteristics of the Fund;
36.3. the system, which is determined from human blood and plasma-derived medicinal product manufacturer and plasma fractionator of the controller or the processor, on the one hand, and to blood and plasma collection and testing centres or institutions, on the other hand, the interaction terms and specifications, as agreed;
22.6. a list of the medicinal products for which the plasma master file shall apply, irrespective of whether the product is granted a certificate of registration or registration is also in the process of the investigational medicinal product in relation to the implementation of good clinical practice in the conduct of clinical trials with medicinal products for human use.
37. the applicant for registration or the registration of the holder of the national agency of medicinal products plasma master file. If the applicant for registration or the registration holder and holder of the plasma master file is a different person, the plasma master file is available to the applicant for registration or the owner of the registration, to be submitted to the State Agency of medicines. In any case, the registration of the applicant or the owner of the registration shall take responsibility for the medicinal product.
38. the registration application, which refers to the component that is derived from human plasma, the plasma master file is referenced on the plasma used as starting material or raw material.
39. the State Agency of medicines shall adopt a decision on registration after the European Medicines Agency has issued a certificate, the plasma master file.
40. the evaluation of the plasma master file and the certificate: 24.9. for medicinal products not yet recorded on the registration application, the applicant shall submit the State Agency of medicines of the complete dossier and a separate plasma master file, if it has not been submitted;
40.2. the plasma master file shall be scientific and technical assessment of the European Medicines Agency. If the assessment is positive, the plasma master file shall be issued a certificate attesting that it meets European Union statutory requirements and the assessment report. The certificate is valid in all countries of the European economic area;
40.3. the plasma master file shall be restored and re certified each year;
25.1. the changes in the plasma master file shall be assessed, taking into account the evaluation of the conditions laid down in the Commission's June 3, 2003 Regulation (EC) No 1085/2003 concerning the examination of variations of a marketing authorisation for medicinal products for human use and veterinary medicinal products conditions, within the scope of Council Regulation (EEC) No 2309/93 (hereinafter referred to as Commission Regulation No 1085/2003).
41. following the provisions referred to in paragraph 40 of the Medicines Evaluation Agency, deciding on the registration of the medicinal product concerned taken into account the plasma master file certification, re-certification or variation.
42. If the plasma master file shall apply to medicinal products derived from blood and plasma and recorded only the national procedure (registration is only valid in the Republic of Latvia), the plasma master file the scientific and technical evaluation carried out by the national agency of medicine.
V. specific documentation requirements for products for human use vaccines 43. for vaccines for human use the vaccine Antigen master file system, taking into account the following conditions:

43.1. vaccine may contain one or several distinct vaccine antigens. The vaccine is just as active substances as vaccine Antigen;
43.2. the combined vaccine contains at least two distinct vaccine antigens, which protects from one or several infectious diseases;
43.3. the monovalent vaccine contains one vaccine Antigen that is protected from any infectious diseases.
44. Vaccines (except influenza vaccine) attached to the application for registration shall include the documentation of each vaccine Antigen master file, which is the active substance of this vaccine.
45. the vaccine Antigen master file (this provision 3. module 3) concerning the quality of the data includes the following information: 45.1. General information, including compliance with the relevant monograph of the European Pharmacopoeia;
45.2. the information on the active substance production. This section includes a description of the manufacturing process, the raw materials and raw materials, specific measures on TSEs and possible disease agents safety evaluation and facilities, as well as equipment;
45.3. characterisation of the active substance;
28.2. quality control of the active substance;
28.3. reference standards and materials;
45.6. the active substance packaging and sealing system;
28.4. the stability of the active substance.
46. Evaluation and certification: 46.1. about new vaccines that contain new vaccine Antigen, application for the registration of medicinal products, the applicant shall submit a complete national registration documentation, including all of the vaccine Antigen master file for each single vaccine Antigen that is part of the new vaccine, if such a separate vaccine Antigen master file has already been submitted;
46.2. the entire vaccine Antigen master scientific and technical assessment by the European Medicines Agency. If the assessment is positive, for each vaccine Antigen master file shall be issued a certificate attesting that it meets European Union statutory requirements and the assessment report. The certificate is valid in all European economic area countries. The European Union allowed the vaccine Antigen master content changes in the scientific and technical evaluation of the European Medicines Agency in accordance with Commission Regulation No 1085/2003 lays down the procedure;
46.3. the rule 45.1. and 45.2. the conditions referred to in subparagraph also applies to all vaccines consisting of new vaccine Antigen combinations, regardless of whether one or more of these vaccine antigens are already permitted in the European Union part of vaccines;
46.4. the State Agency of medicines, deciding on registration, having regard to the medicinal product concerned vaccine Antigen master certification, re-certification or variation of the vaccine Antigen master file.
47. If the vaccine Antigen master file refers to a vaccine for which registration has not yet been granted or will be granted in accordance with European Parliament and Council Regulation No 726/2004, as well as if the vaccine includes vaccine antigens which have not been valued in accordance with the provisions of 45.2. referred to the procedures of the European Union, the State Agency of medicines shall take the vaccine Antigen master file and its subsequent changes, the scientific and technical evaluation.
Vi. the registration of the medicinal product in particular criteria applicable to homeopathic medicinal products and medicinal products antropozof 48. This chapter relates to the prescribed homeopathic medicinal products prepared from substances called homeopathic stocks in accordance with a homeopathic medicine manufacturing procedure described by the European Pharmacopoeia or, failing this, of the European economic area, the official pharmacopoeias. Homeopathic medicinal products may contain a number of substances.
49. To register homeopathic medicines, national agency of medicines shall submit a registration application. Application for registration and the documents annexed thereto shall be drawn up in accordance with these rules of registration documentation requirements and the European Commission.
50. the State Agency of medicines shall establish a special simplified registration procedure that rule 51. homeopathic medicinal products referred to in paragraph 1.
51. the special, simplified registration procedure for the State Agency of medicines has the right to apply only for registration of homeopathic medicinal products which satisfy all of the following conditions: 51.1. medicines for oral or external use only;
51.2. specific therapeutic LaTeX is not specified in the labelling of the medicinal product or in any information relating thereto;
51.3. the degree of dilution is sufficient to guarantee the safety of the medicinal product. Medicinal product shall not contain more than one part in 10000 of the mother tincture (mother tincture) or one part of a least 100 allopathic medicinal products used in the dose to be issued against the person discharged treatment recipe.
52. To register homeopathic medicines, using special, simplified procedure, the application for registration of homeopathic medicinal products shall include homeopathic dilution, which is derived from the same homeopathic stock or stocks. To prove the pharmaceutical quality and the product series uniformity (homogeneity), the registration application shall contain the following documents and data: 52.1. homeopathic (-o) materials (s) scientific name or other name given in a pharmacopoeia, together with the notice of recorded different route of administration, pharmaceutical forms and degree of dilution;
52.2. dossier describing how the homeopathic raw materials are obtained and controlled, and justifying its/their homeopathic use (including appropriate bibliography);
52.3. each pharmaceutical form and control production documentation and dilution and potencēšan methods;
52.4. the medicinal products in question special permission (license);
52.5. other European economic area countries issued any copies of documents certifying the same registration;
52.6. one or more of the medicinal products to be secondary and primary packaging mock-ups;
52.7. data on the stability of the medicinal product.
53. the other homeopathic medicine (except this rule 48) recorded in accordance with the provisions of chapters II and III.
54. the State Agency of medicines has the right to apply the exceptions of homeopathic medicinal products with non-clinical and appropriate clinical trial in Latvia practiced homeopathy principles and characteristics, on the basis of the relevant professional association.

55. Antropozof Hall, which is described in the official pharmacopoeia and the use which is made using the homeopathic method shall be recorded in accordance with the established in these rules of registration of homeopathic medicinal products.
VII. special medicine registration criteria applicable to traditional herbal medicinal products, 56. Simplified registration procedure applies to herbal medicines (traditionally used in herbal medicine) that meet all of the following criteria: they are only 56.1. traditional herbal medicinal products according to the indications, and having regard to their composition and purpose, are intended for use without direct personal supervision of treatment only in the following cases, for diagnostic purposes , use or treatment process monitoring;
56.2. they are intended for use solely in accordance with a specified strength and dose;
56.3. they are designed for oral or external use or inhalation;
56.4. they have been used in this rule 38.1 in period;
56.5. information on herbal medicines traditional use is sufficient, especially if it is proved that the product is not harmful in specified conditions of use, and drug effectiveness or impact, based on years of experience, is unlikely.
57. The vitamin or mineral present in traditional herbal medicinal products, if their security is well documented in the evidence, there is no prohibition to register the product in accordance with the provisions of paragraph 56. using simplified registration procedure when vitamins or mineral supplements plant exposure active substance exposure (s) to a specific therapeutic indication (s) (s).
58. Herbal Medicine, which is applicable in the simplified registration procedure, register the mutual-recognition procedure or the decentralised procedure, if at least one of the following conditions: 58.1. herbal medicinal product shall be drawn up at the bottom of this rule 39.3. monograph referred to;
58.2. herbal substances, preparations or combinations thereof are included in traditional herbal medicinal products use of substances, preparations and combinations thereof (hereinafter list), which was approved by the European Commission's decision and to each herbal substance the indication, the specified strength and dose, route and other information necessary for the herbal substance can safely be used as traditional medicines.
59. For other herbal medicinal products covered by this provision, 56, 57 and 60, the State Agency of medicines of the registration application, take into account whether they are established in the European economic area in accordance with the provisions of chapter XIII.
60. If the medicine government agency recognises that traditionally applied herbal medicine meets this provision in paragraph 51 above, or medicinal products referred to in chapter II, the registration criteria, or according to the European Parliament and Council Regulation No 726/2004 in the central registration of medicinal products to be registered, the requirements laid down in this chapter, these drugs are not suitable.
61. to register for herbal medicine in the simplified registration procedure (or traditional herbal medicines registration procedure), the State Agency of medicines shall submit a registration application. Application in accordance with the requirements laid down in these provisions and according to the model of the European Commission adds: 61.1. data and documents (according to the rules of annex 3 and 5): 61.1.1. This provision is referred to in 17.1, 17.2, 17.3., 17.4., 17.5., 10.9, 11.0, 11.1.., 17.9.,.,., 17.15 17.14 17.13. and in paragraph 17.16.;
61.1.2. the pharmaceutical tests referred to in section 17.10.1. these provisions;
61.1.3. Description of the medicinal products, with the exception of those rules specified in point 13.3.;
61.1.4. If you have this provision in point 4.3, or referred to in paragraph 57 of the nation's — information combos under this provision in 56.5. If the individual active substances are not well enough known, also provide data on these active substances;
61.2. any permit or document certifying that the applicant has registered and received authorization to distribute medicines on the market in another European economic area country or in a third country, as well as detailed information on refusal of registration of a European economic area country or in a third country, stating any reasons for the refusal;
38.1. bibliographical or expert evidence about the drug or the use of medical products for at least 30 years before the registration of the application, including at least 15 years in the European economic area;
61.4. bibliographic review of safety data together with an expert report.
62. where the registration application relates to a herbal substance, preparation or a combination that is included with this rule 58.2. the list referred to in point: 62.1. these rules 61.2 and 38.1. the data referred to in subparagraph need not be provided;
62.2. this rule 94.3 and 94.4. point does not apply.
63. the State Agency of medicines: 39.2. in connection with this provision: 38.1.63.1.1. after receipt of the registration application requires the European Medicines Agency, a Committee for herbal medicinal products for an opinion on the medicinal product concerned or an equivalent product durable evidence of conformity;
63.1.2. If the product is used in less than 15 years, but they correspond to those described in this chapter in the simplified registration procedure, the matter shall be referred for the European Medicines Agency Committee for herbal medicinal products shall submit the relevant supporting documents;
63.1.3. consider whether equivalent product contains the same active substance and irrespective of the excipients it has the same or a similar use, the equivalent of the strength and posology, the same or similar route of administration as the medicinal products for which an application for registration has been filed;
63.1.4. check whether the requirement to show medicinal medicinal use for 30 years is satisfied even if the medicinal product has not been registered. It is satisfied even if in this period the number of ingredients or quantities are reduced;

39.3. in considering the application for registration and when a final decision on registration has been taken into account in the European Medicines Agency, a Committee for herbal medicinal products drawn up by the European Community herbal monographs, which have complied with this rule 25.2. the requirements referred to in subparagraph as well as compliance with the traditional herbal medicinal products. If the European Community herbal monographs have not yet been developed, may refer to other appropriate monographs, publications or data.
64. the registration owner: 64.1. assess the need for amendment of a registration document in the tation! developed a new monograph of the European Community;
64.2. notify of any changes in the submitted information and documents to the State Agency of medicines or the European economic area to the national competent authority.
VIII. Changes in registration and extension of registration 65. to approve changes to the registration documentation, the registration holder for approval of changes to the application, accompanied by the particulars and documents according to the model of the European Commission and which has been drawn up in accordance with the requirements laid down in these rules of registration dossiers: 65.1. — the State Agency of medicines on prescription are registered only in the national registration procedure (which are not recorded in the mutual recognition procedure or the decentralised procedure);
65.2. the national agency of medicinal products and the European economic area, to the competent authorities, in accordance with the European Commission of 3 June 2003, Regulation (EC) no 1084/2003 concerning the examination of variations to the terms of a marketing authorisation granted by a competent authority of a Member State relating to medicinal products for human use and veterinary medicinal products (hereinafter referred to as Commission Regulation (EC) no 1084/2003) (if the product is registered in the mutual recognition procedure or the decentralised procedure);
65.3. the European Medicines Agency, in accordance with Commission Regulation No 1085/2003, if the product is registered in a centralized registration procedure.
66. the State Agency of medicines according to the competence of the Executive Commission Regulation No. 1084/2003 the competent supervisory authorities.
67. in order to make a decision on the extension of the marketing authorisation procedures established in the national medicinal products (which are not recorded in the mutual recognition procedure or the decentralised procedure), the owner shall submit a registration to the national agency of medicinal products in the application under the European Commission's sample that is published by the National Agency for Medicines home page on the internet. The application is included and present added contains data and documents.
68. the National Agency for medicines in the national registration of the medicinal procedure (which are not recorded in the mutual recognition procedure or the decentralised procedure): 68.1. a decision on the extension of the registration of medicinal products, if any particulars or documents submitted in compliance with this provision confirms 7. the criteria set out in the annex. In this case, the name of the medicinal product matches the name of the medicinal product the original decision on registration;
68.2. assess the application for approval of changes in accordance with the provisions laid down in chapter IX or X of the claims and shall take a decision on the approval or non-approval of the change.
IX. Minor type I A and I B changes in the registration dossier 69. National procedure of registration of the medicinal product (which is not recorded in the mutual recognition procedure or the decentralised procedure) small type I A and I B changes the registration dossier contains the provisions of Annex 8. The changes assessed and approved in accordance with this chapter.
70. in paragraph 69 of these rules in such products: 70.1. application for type I variations indicate only one type I changes;
70.2. one application indicating the connection between all resulting changes, if submitted: from IA 70.2.1. change of type derives one or more other type I A;
70.2.2. from the type of change I B I A clear type or type IB;
70.3. If more than one do I type changes, for each application submitted. Each application contains a reference to the other submissions, if any;
70.4. where type I variations, the summary of product characteristics, labelling or the package leaflet is immutable, it is regarded as part of the change.
71. the State Agency of medicines shall verify that the application complies with this provision in paragraph 69 and 70 above conditions, evaluate the submitted data and documents (the performed inspection of documents) and the Act on administrative procedures in accordance with the procedure laid down in the decision on the approval of changes in registration or approval of the change, noting that data and document evaluation (inspection) is performed: 71.1. small type IA variations — 14 days after receipt of the application to the State Agency of medicines;
71.2. minor changes — type B (I) 30 days following receipt of the application to the State Agency of medicines.
72. the State Agency of medicines has the right to ask the owner of the registration, to provide additional information. In this case, the provisions referred to in paragraph 71 of the procedure shall be suspended until additional information requested for submission to the State Agency of medicines.
73. If after the application of (I) changes in type B and its attached data document and other information for the evaluation of medicinal products the State Agency considers that the application is inadmissible, since the administrative procedure law, but not more than 30 days after this Regulation referred to in paragraph 70 of the due receipt of the application in the State Agency of medicines shall provide the registration owner who has submitted the application, issue a reasoned opinion. The owner of the registration shall be entitled 30 days after receipt of the opinion of the Agency on the State of application of the modifications (I) changes in type B, subject to the opinion of the State Agency of medicines in that basis. On amendments to the registration owner above 30 days written notice to the State Agency of medicines.
74. If the holder of the registration application for change of type I B shall be amended in accordance with this paragraph 73, it is deemed to have been rejected, and the Government agency decision on approval of the change, notify the owner of the registration of the administrative procedure law, but not later than 30 days.

75. If a State Agency of medicines has not announced a decision on registration of the owner change without approval according to paragraph 73 of these regulations, it is considered that a government agency has approved the changes and the applicant for registration may introduce changes.
X. major type II changes to the registration documentation and registration of the company or the owner address change 76. registration procedure For national registered medicinal products (which are not recorded in the mutual recognition procedure or the decentralised procedure) important: the type II — changes are considered changes: 76.1. does not meet these rules 7 and 8 of the annex;
76.2. related to the registration of the owner of the company (the new owner of the registration and the owner are one and the same person) or change of address.
77. in paragraph 76 of these provisions such products: 77.1. the application for type II changes only one type II except where: one medicinal 77.1.1. make a number of changes of type II. Then for each type II variation applications submitted. Each application contains a reference to the other submissions, if any;
77.1.2. from the type II changes follows other changes. For all these changes you can submit one application, and it indicates a relationship between all resulting changes;
77.2. It follows from the changes in the summary of product characteristics, labelling or the package leaflet is immutable, it is regarded as part of the change.
78. the State Agency of medicines shall verify that the application complies with this provision and 77.76. conditions referred to in points and appraise the submitted data and documents (the performed inspection of documents) and the Act on administrative procedures in accordance with the procedure laid down in the decision on the approval of changes in registration or approval, noting that the data and document evaluation (inspection) is performed: 78.1. not more than 60 days after receipt of the application to the State Agency of medicines. This period may be reduced to take account of the urgency of the matter, especially if it is related to security;
78.2. not more than 90 days, if the application associated with the therapeutic indications of changes or a new indication for replenishment.
79. the State Agency of medicines has the right to ask the owner of the registration, to provide additional information. In this case this rule 78 procedures referred to in paragraphs suspended until additional information requested for submission to the State Agency of medicines.
80. If there are changes, for human influenza vaccine registration documentation, the following procedure shall apply: 80.1. the State Agency of medicines of the administrative procedure law within 30 days after receipt of the application, based on the quality of the supporting documents (Appendix 3 module 3), prepare an assessment report and a draft decision and forward it to the owner of the registration;
80.2. the registration owner 12 days after 80.1. these provisions referred to in the bottom of receipt of documents submitted to the State Agency of medicines in the clinical data and, if necessary, the stability of the medicinal product;
49.9. State Agency of medicines: 80.3.1. within seven days after receipt of the data evaluated the submitted data, prepare the final decision and issue the registration holder;
80.3.2. registration shall be issued to the owner of the operating instructions and a description of the medicinal product.
81. In connection with the human influenza virus pandemic (also applies to other pandemic human diseases), which is recognised as such by the World Health Organization or the European Union, the State Agency of medicines of exception, has the right to recognize changes in influenza vaccines for human medicine registration period from receipt of application to this rule 80 procedures laid down in paragraph if a registration submitted complete data about clinical safety and effectiveness.
82. A change in the holder of the registration company (related to the national registration of the medicinal procedure (which are not recorded in the mutual recognition procedure or the decentralised procedure)) or address and the owner are one and the same person, the owner shall submit the registration of the medicinal product in the application to the State Agency. The application shall be accompanied by the following documents and specify the following information: 82.1. the document certifying the registration of the change of owner;
82.2. the name of the medicinal product, registration certificate number and date of registration of the medicinal product;
82.3. existing registration of business name and address of the holder, as well as the name and address of the person that is expected to put the registration certificate;
82.4. a document showing a complete and updated before the transfer of the registration of the case (documentation) or a copy of the transfer and the person transferring the registration certificate;
82.5. date on which the person intended to pass registration, will take over from the previous owner of the registration of all his obligations;
82.6. a document showing that the person who passes the registration, the registration can provide the owner's obligations under the requirements of laws and regulations on the production and control of medicinal products, medicinal products, import, export and distribution, advertising of medicines, unwanted side effects and drug clinical trials. Document: 82.6.1. person responsible for the activities related to the medicine side effects monitoring system, its address, phone and fax numbers. Add a brief description of the action and experience;
82.6.2. staff who is responsible for the promotion and distribution of medicines, as well as the business address, phone and fax numbers;
82.6.3. Summary of product characteristics, labelling and package leaflet;
82.6.4. the document certifying the payment of the assessment in accordance with the provisions of 85.
83. The date when the certificate of registration will be transferred to the new owner of the registration shall be determined by the national agency of medicinal products and it is recorded in the contract between the customer and the new owner of the registration. Registration validity does not change.
XI. Renewal of 84. With a view to re-registering medicines, the owner of the registration of the medicinal product shall be submitted to the National Agency an application for renewal. The renewal application contains data and the corresponding documents and the European Commission, published in the State Agency of medicines of the website on the internet, and the requirements set out in these provisions of the registration dossier. The application includes the following information:

84.1. consolidated version of the registration documentation relating to a medicinal product quality, safety and efficacy, including all changes that have been introduced following the adoption of the decision on registration, at least six months before the decision on the initial registration lapse;
52.3. as the medicine re-registered at the basis of the risk-benefit balance of the reassessment, the application has added: 84.2.1. evidence and clinical expert's claim that the risk-benefit balance remains favourable;
84.2.2. Summary for all since the registration submitted periodically updated safety reports.
XII. the registration of the medicinal product With associated procedures 85. Medicines, registration, re-registration and post-registration monitoring (with an annual registration costs) shall be borne by the person in whose name the registration Hall is planned (but in relation to the product documentation for the assessment of compliance with the definition of medicinal products, the applicant) in accordance with the State Agency of medicines to the public provided by the paid service price list. The State Agency of medicines has the right to health reasons in exceptional cases decide about medicines, registration, re-registration and other registration-related activities to the exemption from fees or fee reductions, if the product is essential to the process of treatment, for treatment of a rare disease or distributed in limited quantities.
86. to verify the registration of the medicinal product, the gum cold state agency: 53.5. primary expertise, which determines the application of the compliance with the registration requirements of this Regulation (the primary inspection is not performed, re-register and affirming changes): 86.1.1.  within 30 days after receipt of the registration application to the State Agency of medicines;
86.1.2.14 days after receipt of the application to the State Agency of medicines, if the medicinal product is recorded in the mutual recognition procedure or the decentralised procedure;
86.2. checks that are appropriate to the circumstances of adoption of the decision on registration, and until a decision shall take all necessary action to ensure the discharge of the procedure. Decision of the administrative procedure law, providing data and document evaluation for 210 days of the submission of the application for registration of the State Agency of medicines (medicines registered only national registration procedure, but not recorded in the mutual recognition procedure or the decentralised procedure). The State Agency of medicines is not the patent rights for the related information;
86.3. is entitled to place the medicinal product, its starting materials and intermediate products or other constituent materials for testing by the national agency of medicinal products in a laboratory or another laboratory, which has the power to control drugs, to ensure that the control methods that are used by the manufacturer and in accordance with this rule 11.1. section are described in the documents supporting the application for registration (paragraph 17), are satisfactory;
86.4. If needed, is entitled to ask the applicant to add additional data to the application. In this case this rule 86.2. period referred to is stopped until the required supplementary information for submission to the State Agency of medicines. Similar to the period might stop oral or written explanation.
87. the State Agency of medicines: 87.1. in cooperation with other competent authorities certifying that the manufacturer and the importer of a medicinal products (medicinal products imported from third countries (people who have a special permit (license) for the manufacture of medicinal products/import)) medicinal product meets the data submitted in accordance with this provision, and 17.5. is the control according to the methods laid down in accordance with the provisions of section 11.1.;
87.2. is entitled to adopt a decision to issue the drug manufacturers and importers of medicinal products authorised in some stages of the production and that rule 87.1. the controls referred to in (a) to make to any third parties. In this case the competent authorities shall carry out the conformity assessment.
88. the State Agency of medicines shall adopt the decision on the application for the examination of exclusion: 88.1. If the primary inspection has confirmed that the application for registration does not meet the requirements of this regulation or, in the absence of this provision, paragraph 19. The State Agency of medicines shall inform the principal applicant and is entitled to check in the application for registration;
88.2. national registration procedures: 88.2.1. If a State Agency of medicines has information that another registration application for the same medicinal product if the look in another European economic area country. In this case, the State Agency of medicines shall inform the applicant for registration in respect of that registration, the application of this provision is applicable to the conditions referred to in chapter XIII, if the registration application is filed pursuant to chapter XIII, and drugs are to be recorded in the decentralised procedure;
88.2.2. If in accordance with the provisions of paragraph 17.17. Medicine State at the bottom, the Agency has been notified that the product for which an application has been submitted to the State Agency of medicines is registered in another European economic area country. In this case, the State Agency of medicines shall inform the applicant for registration in respect of that registration, the application of this provision is applicable to the conditions referred to in chapter XIII, if the registration application is filed pursuant to chapter XIII, and drugs are to be recorded in the mutual recognition procedure.
89. the State Agency of medicines: 89.1. notify the owner of the registration of the medicinal product description approval decision on the registration of the medicinal product;
89.2. ensure that a summary of the information supplied in the information, and approved a decision on registration (or, where appropriate, the decision concerning the renewal or change approval, or the extension of the registration);
89.3. in accordance with the development of the registration dossier assessment report and comments on the pharmaceutical and clinical tests and clinical trials. The assessment report shall be updated when new information becomes known, which is important for the quality of the medicinal product concerned, safety or effectiveness;
89.4. public agencies immediately home page on the internet at: 89.4.1. the fact of registration and the approved summary of product characteristics;

89.4.2. the assessment report and its reasons, stating the information about each indication provided by any confidential commercial information from the message deletion (in cooperation with the registration holder);
89.5. Decides on membership of the medicine group, which requires medical treatment person's written directions (prescription drugs), or to a group of medicines that can be used without a medical person writing instructions (non-prescription drugs).
90. the State Agency of medicines has the right, in exceptional cases, after consultation with the principal applicant for the registration of objective and verifiable reasons to take a decision on the registration of the applicant to comply with the conditions laid down, in particular as regards the safety of the medicinal product, if one of the following circumstances: 90.1. the applicant can demonstrate that it is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because: the indicating 90.1.1. that the product in question is intended are encountered so rarely that can't wait for the applicant provide comprehensive evidence;
90.1.2. comprehensive information cannot be provided so far accumulated scientific knowledge;
90.1.3. collection of such information would be contrary to generally accepted principles of medical ethics;
90.2. the State Agency of medicines within the time specified by the applicant completes a specific research programme, the results of which will be repeated in the benefit and risk assessment;
90.3. the medicinal product in question will only be promoted to medical personal recipe, in some cases, they may be used only under strict medical supervision, if necessary, the fixed medical institution. Radiopharmaceutical preparations of monitoring shall be performed by an authorised person;
90.4. instructions for use and medical information shall draw the attention of the person for treatment to the fact that for the medicinal product concerned, the available data are not yet enough.
91. the State Agency of medicines: 91.1.90. these provisions referred to in paragraph 1, the list of conditions with the specified due dates and due dates immediately to the public agency's website on the internet;
91.2. deciding on the registration of the medicinal product or when the product is re-registered and once registration is left in force for an unlimited period of time, provided that the annual 90. compliance with the conditions referred to in paragraph 1 of the evaluation;
91.3. to ensure that the risk-benefit balance of permanent evaluation is entitled, at any time, request the owner of the registration to send medicines agency data, which shows that the risk-benefit balance is favorable.
92. If the State Agency of medicines shall decide on the registration or renewal of registration, respectively, or re-registration number, and the Latvian register of medicinal products and the registration certificate.
93. the State Agency of medicines shall decide on the registration or renewal refused if: 93.1. after the evaluation of data and documents have been found that: 93.1.1. risk-benefit balance is not considered to be favourable;
93.1.2. the registration application is insufficiently substantiated by the applicant of therapeutic effectiveness. The therapeutic efficacy requirements do not apply to homeopathic medicinal products, which shall be recorded in a special, simplified registration procedure;
93.1.3. its qualitative and quantitative composition is not as described in the registration dossier;
93.2. data submitted and documents do not meet the requirements of this regulation;
93.3. medicine is to register or are registered in a centralized registration procedure in accordance with European Parliament and Council Regulation No 726/2004.94. State Agency of medicines shall take a decision on the registration of herbal medicinal products for traditional-use registration procedure refusal, if the application for registration of herbal medicinal products do not comply with this rule 13, 56, 57, 60 and 61 the requirements referred to in paragraph or if one of the following criteria : 94.1. qualitative and quantitative composition is not as declared;
94.2. the indications do not comply with this provision and paragraph 57 56. in specified circumstances;
58.6. product may be harmful in the normal conditions of use;
94.4. the data on traditional use are insufficient (do not meet the requirements of this Regulation), in particular if, on the basis of long-standing use and experience, pharmacological effects or efficacy are not plausible;
94.5. the quality of medicinal products is not sufficiently demonstrated.
XIII. The mutual recognition procedure and decentralised procedure 95. registered medicinal product in more than one European economic area country, an application for registration in accordance with the model of the European Commission, which is published by the National Agency for Medicines home page on the internet, submit the relevant to the European economic area by the competent national authority (in Latvia — National Agency for medicinal products) (hereinafter the participating Member States). The application shall be accompanied by the particulars and documents specified. Registration dossiers comply with the following requirements: 95.1. it is identical to the registration documentation, which have been made in other countries;
95.2. include information in accordance with the provisions of II, III, IV, V, VI and VII;
95.3. it contains a list of the participating Member States in which application for registration has been filed or for which the product is registered at the time of submission of the application.
96. If these provisions of 95.3. the countries referred to in the registration application submission time: 96.1. are registered, grass records the mutual recognition procedure;
96.2. are registered, but in the process, Hall recorded the decentralised procedure.
97. the National Agency For medicinal products medicinal products registered in the mutual recognition procedure: 60.3. the registration applicant (owner): 97.1.1. indicate which of the provisions referred to in subparagraph 95.3. countries have the reference Member State and the participating Member States;
97.1.2. request the reference to the competent authority of a Member State to prepare an assessment report on the medicinal product concerned or to restore it (if necessary) within 90 days in accordance with the requirements presented in due receipt of the application and registration please send it together with the approved summary of product characteristics, labelling and package leaflet of the applicant for registration and the participating countries of the European economic area to the competent authorities;
97.2. If Latvia is the reference Member State, the State Agency of medicines:

97.2.1. prepare an assessment report on the medicinal product concerned, that the applicant is requested, or restore it to the administrative procedure law, but not later than 90 days after the application for registration (which meets the requirements);
97.2.2. the evaluation report with the approved summary of product characteristics, labelling and package leaflet, sent to the applicant for registration and the participating countries of the European economic area to the competent authorities.
98. to the State Agency of medicines of the medicines registered in the decentralised procedure: 98.1. registration the applicant: 98.1.1. indicate which of the provisions referred to in subparagraph 95.3. countries are participating Member States, and request one of them to act as reference Member State;
98.1.2. request the reference Member State to prepare a draft assessment report, summary of product characteristics, labelling and package leaflet of medicinal products to be registered the project and ask them to send a registration application to the applicant and the participating countries of the European economic area to the competent authorities;
98.2. If Latvia is the reference Member State, the State Agency of medicines shall prepare 98.1.2. these provisions referred to in draft documents during the administrative procedure law, but no later than 120 days after the requirements presented in due receipt of the application for registration to the national agency of medicinal products and send them to the applicant for registration and the participating countries of the European economic area to the competent authorities.
99. If a participating Member State, Latvia is a State Agency of Medicines of the administrative procedure law, but not later than 90 days after the 97.1.2 these rules and 98.1.2. referred to confirm receipt of the assessment report, summary of product characteristics, labelling and package leaflet and shall forthwith notify the reference to the competent authority of the Member State. The reference Member State, following the receipt of the information from the Member States concerned of all the parties involved in the Protocol Agreement, close the procedure and shall forthwith notify the applicant of the registration.
100. the State Agency of medicines of the administrative procedure law, but not later than 30 days after this provision in paragraph 99 of the arrangement of the approval in accordance with the approved assessment report, summary of product characteristics, labelling and package leaflet of the medicinal product, shall adopt a decision on registration.
101. If this provision in paragraph 100 period Medicine State Agency cannot approve the assessment report, summary of product characteristics, labelling and package leaflet of the medicinal product on the basis of potential serious risk to public health, it: 101.1. provided detailed explanations of his position in the reference Member State, the Member States concerned and the applicant for registration;
101.2. the matters on which agreement has been reached, shall be submitted to the European Medicines Agency Coordination Group established by registration (or of marketing authorisations for medicinal products) in two or more European economic area countries related questions (hereinafter referred to as the coordination group). The Secretariat of the coordination group of the European Medicines Agency.
102. If the Member States concerned within 60 days of issue (which is not agreed) submission coordination group: 102.1. reach an agreement and Latvia is: 102.1.1. the reference Member State, the State Agency of medicines shall be recorded in the agreement of all parties involved, close the procedure and inform the applicant of the registration application;
102.1.2. a participating Member State, the State Agency of medicines shall ensure 102.1.1. these provisions of subparagraph;
102.2. Latvia has not reached an agreement and the reference Member State, the State Agency of medicines: 102.2.1. immediately notify the European Medicines Agency to enable it to initiate an arbitration procedure in accordance with the provisions of paragraph 108;
102.2.2. European Medicines Agency submitted a detailed statement, indicating the matters on which the Member States concerned have agreed, and the reasons. A copy of the notice of registration shall be issued to the applicant.
103. the applicant for registration: 103.1. is entitled to take in the coordination group, orally and in writing to present their views;
103.2 102.2.2. these provisions. at the bottom of the notification referred to in paragraph 1 shall be submitted to the European Medicines Agency this rule 95, paragraph, copies of the document.
104. If a State Agency of medicines has approved assessment report, summary of product characteristics, labelling and package leaflet of the project, but the participating Member States in the coordination group has not reached a consensus, the State Agency of medicines shall be entitled upon registration, the applicant's request to register medicines without waiting for the European Medicines Agency Committee for medicinal products for human use (hereinafter referred to as the Committee of medicinal products) as that rule 108. the procedures referred to in paragraph 1. The decision is not controlled in connection with that procedure.
105. the State Agency of medicines (Member States and European Commission), the applicant for registration or the registration holder is entitled to submit for consideration by the Committee for medicinal products so as to be able to launch this rule 108. the procedure referred to in paragraph 1, if the following conditions are met: 105.1. for the medicinal product concerned Member States have submitted two or more registration submissions;
105.2. participating Member States have adopted divergent decisions on the registration, the suspension or cancellation.
106. the National Agency for medicinal products (as in the other participating Member States and the European Commission) is entitled: 106.1. send each year to the coordination group a list of medicinal products, the need to develop harmonised summary of product characteristics, in order to facilitate the harmonisation of medicinal products in the European economic area;
106.2. in agreement with the European Medicines Agency, subject to the views of interested parties, to submit the matter to the Committee for medicinal products in accordance with this provision, paragraph 105.
107. Special cases (if the affected are members of the European economic area national interests) prior to any decision on the application for registration, registration suspension, cancellation of the registration and any other changes in the registration dossier, especially taking into account the data collected in the monitoring system of the side effects of the medicinal product in accordance with the laws and regulations for pharmacovigilance procedures:

107.1. the applicant for registration or the registration of the medicinal product submitted in the Committee all available information relating to the matter in question;
107.2. Medicine State Agency to start this rule 108, paragraph procedure: 107.2.1. submit to the consideration of the Committee for medicinal products all available information related to those clearly identified issues. If the transfer of the case for consideration by the Committee for medicinal products subject to a series of drug or therapeutic class, take into account that the European Medicines Agency may limit the procedure to certain specific parts of the authorisation;
107.2.2. notify the applicant or the owner of the registration of the medicinal product by the Committee for the submission of the case.
108. the applicant for registration or the registration of the owner and the State Agency of medicines shall take into account that: the Committee for medicinal products: 108.1.108.1.1. shall consider the matter concerned and within 60 days of the receipt of the case shall issue a reasoned opinion. If the case is urgent, this period may be extended to 90 days, taking into account the submissions of the applicant for registration or the registration holder's views, and you can agree on a shorter term based on the proposal of the Chairman of the Committee for medicinal products;
108.1.2. case may appoint a Rapporteur (one of the members of the Committee for medicinal products) and external experts to advise it on specific questions. When appointing experts, the Committee for medicinal products define their tasks and specify the time-limit for the completion of these tasks;
108.1.3. before issuing its opinion, the possibility of registration of the applicant or the owner of the registration deadline to provide written or oral explanations. The opinion shall be added to the summary of product characteristics, labelling and package leaflet versions of project. If necessary, it may invite any other person to provide information relating to the matter;
108.1.4. you can stop this rule 108.1.1. the deadline referred to in point, allowing the applicant to prepare explanations;
108.2. European Medicines Agency: 108.2.1. immediately notify the applicant of the registration concerned or the registration of the holder, if the opinion of the Committee for medicinal products contain one of the following conclusions: 108.2.1.1. the application does not meet the criteria for the granting of registration;
108.2.1.2. Summary of amendments should be made thereto, proposed by the applicant;
108.2.1.3. medicinal products registered in accordance with certain conditions, taking into account the conditions that are essential for the safe and effective use of the medicinal product including pharmacovigilance pharmacovigilance;
108.2.1.4. registration be suspended, or to be cancelled;
108.2.2. in the 15 days after the adoption of the final opinion of the Committee shall be sent to the Member States, the European Commission and to the applicant for registration or the registration holder: 108.2.2.1. opinion, together with a report describing the assessment of the medicinal product and stating the reasons for the opinion. If an opinion is favourable to the registration of the medicinal product concerned (marketing authorisation) or save, the following documents shall be annexed to the opinion: 108.2.2.1.1. Summary of the project (paragraph 21);
108.2.2.1.2. any conditions affecting the authorisation of such provisions within the meaning of paragraph 108.2.1.3;
108.2.2.2. details of any recommended conditions or restrictions with regard to the safe and effective use of the medicinal product;
108.2.2.3. the proposed text of the labelling and package leaflet;
108.2.2.4. a report describing the assessment of the medicinal product and stating the reasons for the opinion;
108.3. the registration application, the applicant or the owner of the registration within 15 days after receipt of the opinion of the Committee is entitled to notify the European Medicines Agency of its intention to request the opinion of the Committee for medicinal products for revision and within 60 days after receipt of the opinion of the European Medicines Agency send a reasonable request;
108.4. Medicinal products within 60 days of the receipt of a reasoned request repeatedly evaluated in accordance with the opinion of the European Parliament and Council Regulation No 726/2004, article 62 (1) of the fourth subparagraph and, in the opinion of those arguments added this provision to that in 108.2.2.1 the evaluation report;
108.5. European Commission: 108.5.1.  15 days 108.2.2.1. This provision referred to the receipt of the opinion drawn up a draft decision to be taken in respect of the application, taking into account the European Union legislation;
108.5.2. If the draft decision provided for the registration (marketing authorization), then add that rule 108.2.2. referred to in documents;
108.5.3. If exceptionally ruled for the project not in accordance with the opinion of the European Medicines Agency, the European Commission shall be accompanied by a detailed explanation of the reasons for the differences;
108.5.4. draft decision forwarded to the membership to the national competent authority (Latvia, the National Agency for medicines) and the registration of the applicant or holder of the registration;
108.5.5. in accordance with the procedure adopted the final decision, within 15 days after the completion of the procedure the European Commission by a Standing Committee (hereinafter referred to as the Standing Committee). The procedure of the Standing Committee includes the following conditions: 108.5.5.1. the opinion of the Standing Committee is provided in writing, except that rule 108.3.3. referred to;
108.5.5.2. the competent authority (Latvia-State Agency of medicines) 22 days shall be forwarded to the European Commission written observations on the draft decision of the European Commission. If a decision has to be taken urgently, the above considerations sent the European Commission a specific shorter period of not less than five days, unless exceptional circumstances require;
108.5.5.3. the competent authority (Latvia, the State Agency of medicines) are entitled to submit a written request for consideration of the draft decision referred to the plenary session of the Standing Committee;
108.6. If the European Commission's opinion to the competent authorities (in Latvia — National Agency for medicinal products) in the written observations raise important new scientific and technological issues that are not addressed in the European Medicines Agency, the opinion given by the Standing Committee, the Chairman shall suspend the procedure and refer the application back to the European Medicines Agency for further prosecution;
108.7. European Commission decision is addressed to all Member States and communicated, for information purposes, the owner of the registration or application for registration by the applicant;

108.8. within 30 days after receipt of the decision of the European Commission, the State Agency of medicines (Member State concerned) and the competent authority of the reference Member State shall decide on the registration or cancellation of the registration or, if necessary, the registration documentation (conditional) amendments to comply with the decision of the European Commission, and notify the European Commission and the European Medicines Agency.
109. the owner of the Registration all ie the tubers of changes to DSB registration documentation relating to a medicinal product which has been registered in accordance with these rules shall be submitted to all competent authorities (in Latvia — National Agency for medicinal products), which have registered the product in question in accordance with Commission Regulation (EC) no 1084/2003. If the European Commission shall submit to the arbitration claim for registration of modifications made, applies this provision in paragraph 110 of the procedure.
110. If a State Agency of medicines shall consider that: 110.1. changes in registration or its suspension or withdrawal, is necessary to protect public health, the State Agency of medicines shall immediately forward the matter to the European Medicines Agency to enable it to initiate the procedure under this provision in paragraph 108;
110.2. the health protection of the population require urgent action (in the case of the US withdrawal, without taking into account the provisions of paragraph 107), it may decide to temporarily pending a final decision on the suspension of the registration of medicinal products and to stop the use of the product at the time. The reasons for its action the State Agency of medicines shall inform the European Commission and the other Member States (competent authorities) not later than the next working day after the decision.
111. the mutual recognition procedure and decentralised procedure shall not apply to applications for registration: 111.1. homeopathic medicinal products, the: 111.1.1. This provision, paragraph 51;
111.1.2. This provision, paragraph 54;
111.2. traditional herbal medicinal products, which recorded the simplified registration procedure and for which you have not made this provision in paragraph 39.3 monograph or which are not included in this rule 58.2. above that list.
XIV. Supervision and sanctions 112. State Agency of medicines: 112.1. take steps to ensure that the holder of the registration and, if necessary, also a drug company submits evidence on drug control and production process at an intermediate state of the control (11.1);
112.2. is entitled to require manufacturers of immunological preparation of medicinal product submitted to the national agency in all the copies of the control report which is signed by the qualified person.
113. the urgent safety restrictions: 113.1. is entitled to impose the State Agency of medicines;
113.2. registration is entitled to determine the owner in the event of risk to public health. In this case, the registration holder shall immediately inform the State Agency of medicines. If the State Agency of medicines within 24 hours after receipt of the information referred to is not voiced objections, the urgent safety restrictions shall be deemed accepted;
113.3. implement the registration owner (to comply with this provision and the bottom point 113.1 113.2. the requirements referred to in): 113.3.1. term for which registration owner agreed with the State Agency of medicines;
113.3.2. the State Agency of medicines shall be submitted on application for the approval of changes in the registration dossier accordingly established the urgent safety restrictions not later than 15 days after the urgent safety restrictions.
114. the State Agency of medicines under the pharmaceutical requirements laid down in the law, shall decide on the registration or re-registration or on the suspension or withdrawal of approval of the change, as well as the decision on the revocation or the decision on the registration of the amendment, if one of the following circumstances: 114.1. is of the opinion that the medicinal product is harmful under normal conditions of use;
114.2. the medicinal product is lacking in therapeutic efficacy. Decision on the therapeutic results of drugs cannot be obtained, means that a medicinal product lacks therapeutic efficacy;
114.3. risk-benefit balance is not favourable (positive) under normal conditions of use;
114.4. its qualitative or quantitative composition is not as declared;
114.5. the owner has not paid this rule 85. expenditure referred to in paragraph 1;
114.6. data specified in the registration application or added, are incorrect or have not been amended or has not fulfilled the terms referred to in paragraph 112 of the control;
114.7. information is not provided for the suspension of distribution of medicinal products, or more than three months does not ensure the permanent availability of the medicinal product (the right to suspend the registration).
115. the State Agency of medicines shall decide on the suspension or withdrawal of the registration of preparations or for all preparations for the category, if no longer fulfilled or is one of the requirements laid down in the regulations on the production and control of medicinal products in order to get the special permission (license) for the production of medicinal products.
116. If a herbal substance, preparation or a combination thereof is no longer included in this rule 58.2. the list referred to in subparagraph (deleted from the list), the State Agency of medicines shall take a decision on the cancellation of the registration of the medicinal product for those herbal medicines containing these substances and preparations unless, within three months from the date of these regulations is not produced 38.1. the data referred to in point and documents.
117. the State Agency of medicines has the right to take a decision on the registration of an emergency suspension based on adverse data for monitoring the results of the assessments. In this case, the State Agency of medicines shall inform the European Medicines Agency, the European Commission and the other Member States no later than the next working day.
118. the State Agency of medicines shall cancel the decision on registration of the suspension (restores suspended registration) if the circumstances which were the basis for the suspension of the registration.
119. Registration is refused, suspended or withdrawn only in accordance with the law and these rules of Pharmacy provided justification.
120. the registration owner: 120.1. is responsible for the direction of the market of the medicinal product and will not be released from his obligations. The owner of the registration may designate a person (owner's local representative) to represent him in the Member State concerned;
120.2. the legally located in the European economic area (a registered firm, the actual Central Administration or place of business);

120.3. the National Agency for medicines expenses in accordance with this provision, 85;
120.4. after the State Agency of medicines has taken a decision on the registration of the medicinal product: 120.4.1. follow the scientific and technical progress and introduce any changes that may be required, giving the right to produce the medicine and check with the General approved scientific methods of production and control, for which the information is provided in accordance with this provision and paragraph 17.5.11.1.;
120.4.2. immediately submitted to the State Agency of medicines of any new information that may lead to amendment of the registration dossier reasons;
120.4.3. If the owner of the registration is not a drug manufacturer, signed a written agreement with the manufacturer to ensure that the manufacturing operation to comply with the law and the registration dossier contains the conditions of production;
120.4.4. ensure that the scientific Department, which handles the scientific information for the medicinal product concerned;
120.4.5. notify the State Agency of medicines: 120.4.5.1. on the actual distribution of the medicinal product (sales) start date of the Republic of Latvia pursuant to the various types of packaging of the medicinal product;
120.4.5.2. If the product ceases to be placed on the market in the Republic of Latvia (at the time (transient) or permanently), not later than two months before the end of the distribution of these products (on the market). This condition does not apply to emergencies;
120.4.5.3. at the request of the State Agency of medicines of the data on the sales of the medicinal product and any other property (possession) existing data relating to the volume of prescriptions (mainly apply to data obtained under the supervision of the side-effects of medicines);
120.4.5.4. immediately on any action that it executes in order to stop the distribution of medicinal products, or remove the product from the market (in Latvia or any other country), together with the reasons for the action in question, if it refers to the action of the medicinal product or the protection of public health;
120.4.5.5. immediately of any prohibition or restriction, which is specified by the competent authorities of any country in which the veterinary medicinal product is marketed and of any other new information which might influence the medicinal benefits and risk assessment;
120.4.5.6. any incident relating to the use of the product and satisfied or enforceable actions (in Latvia or in another country).
121. the applicant for registration or the registration is the responsibility of the owner of the documents submitted and the accuracy of the data and the accuracy of the information provided.
122. the State Agency of medicines: 122.1. Insert medicines agencies website online decisions on registration (including the extension of the registration certificate), renewal, change, cancellation of the registration (re-registration) and stop (including the lifting of the suspension) and Drug Commission created the national agency procedures;
122.2. is responsible and perform all possible procedures to ensure that officers and employees who are responsible and are involved in decision-making in connection with the registration and supervision of medicinal products, report preparers (Rapporteur) and experts have no financial or other interests in the pharmaceutical industry and not affected their impartiality. Such persons may, through a contract with the State Agency of medicines for a particular job, the State Agency of medicines shall be submitted in the annual declaration, a specimen of which is attached to the employment contract;
122.3. public procedures, including procedures of committees (commissions), the agenda for meetings and protocols together with the decisions taken and the results of votes and explanations of votes, including minority views;
122.4. after registration, the Commission shall notify the meeting of medicine price in the national agency of the decision taken to drug price public agency permit to assess information on medicinal products that are included in or eligible for inclusion in the list of medicinal products;
122.5. immediately notified in writing to the Ministry of Health and the State Pharmaceutical inspection decision on registration cancellation or suspension;
122.6. ensure that: 122.6.1. European Medicines Agency receives information on: 122.6.1.1. decisions on registration (under the mutual recognition procedure) refusal, cancellation of registration, as well as refusal or cancellation of registration cancellation with reasons in support of the decision;
122.6.1.2. the registration of the holder of the notifications issued by the State Agency of medicines of any activity, which is performed to stop the distribution of medicinal products, or remove the product from the market, together with the reasons for the action in question, if it refers to the action of the medicinal product or the protection of public health;
122.6.2. World Health Organization having relevant information on IAEA activities to begin in accordance with the provisions of paragraph 122.6.1. below and which may affect the protection of public selīb te in third countries;
122.6.3. the European Commission and any competent authority, on request, to receive information on any of the decisions about herbal medicines registration simplified the registration procedure in the reject and the reasons for that decision;
122. home page on the internet language Latvian published application sample registration (including registration extension), renewal or change approval (16, 49, 61, 67 and 65, 84).
123. The decisions taken by the national agency of medicinal products in accordance with these rules shall not affect the manufacturer's and the owner of the registration, and the dealer's civil and criminal liability.
124. the owner of the registration, the manufacturer of medicines, medical treatment (treatment) and the State agency officials and employees shall not be subject to civil, criminal or administrative liability for any consequences which result from the use of the medicinal product, which is different from that provided for the registered drug indications. This applies to medicinal products which have been registered in accordance with European Parliament and Council Regulation No 726/2004, and medicinal products in accordance with the law is a registered national registration procedure, including mutual recognition or decentralised procedure.
125. the State Agency of medicines of the decision on registration or Reregistration shall cease to be valid: 125.1. medication within three years after the adoption of the decision on the registration of the medicinal product concerned is not placed on the market in the Republic of Latvia;

125.2. registered medicines, which has been placed on the market in the Republic of Latvia, is not actually marketed for three consecutive years.
126. the State Agency of medicines and the national pharmaceutical inspection according to the competency provides operational exchange of information to ensure compliance with these provisions.
127. in cases of doubt and suspicion, if information received from customers or the competent supervisory authorities, of the possible product compliance with the pharmaceutical Act the definition of medicinal product given in medicine, a government agency, to evaluate the product in question in accordance with point 6 of these rules, is entitled to request from the product manufacturer, Distributor, or authorized persons the following particulars and documents: producer and distributor of 127.1. (dealer) business name, registration number and address in the register of companies;
127.2. product name, ingredients and their quantity (s) in units of mass or volume in one packing unit;
127.3. manufacturer's approved technical documents or regulations in the product description, which outlines the characteristics of the product, a composition, specific ingredients and their quantity;
127.4. recommended daily intake;
127.5. packaging type and size;
127.6. labelling;
127.7. instructions for use.
128. If a State Agency of medicines, in assessing this Rule 127. data referred to in paragraph 1 and the documentation on the product, provided that the product meets the pharmaceutical law the definition of medicinal product given in, but the product is registered as a food supplement and its distribution is authorised under the Cabinet of Ministers of 20 September 2005, the Regulation No 725 "rules on minimum safety and labelling requirements for dietary supplements and dietary supplements registration order" This product is to be recorded, as the medicine medicine State Agency, in the light of the Cabinet of Ministers of 20 September 2005, the Regulation No 725 "rules on minimum safety and labelling requirements for dietary supplements and dietary supplements registration procedures" set out in paragraph 24 of the transitional period.
129. If the State Agency of medicines shall take a decision on the rules referred to in paragraph 127 of the product meets the definition of a medicinal product and if a similar composition of the product is registered in the State Agency of medicines and the inclusion of Latvia register of medicinal products, the product the status of dietary supplements losing with the date when the State Agency of medicines has adopted the decision on adequacy, and medicinal product withdrawn from the market in accordance with the laws and regulations governing the distribution of medicinal products.
XV. concluding issues 130. Be declared unenforceable in the Cabinet of 31 October 2000, Regulation No 381 "rules of registration of medicinal products" (Latvian journal, 2000, 2003,/393.nr.; 391.116. No; 2004, nr. 69).
131. The provision referred to in paragraph 53 requirements do not apply to the homeopathic medicinal products which are registered in the European economic area in 1993 to December 31.
132. The provisions referred to in paragraph 38.1. requirement for use of the product in medicine for at least 15 years in the European economic area extended to the countries that joined the European Union on 1 May 2004.
133. This rule 65.2. of referred requirement also applies to high-technology medicinal products of the European Medicines Agency's Committee for medicinal products is authorized until January 1, 1995.
134.109. These provisions and 110 above shall apply by analogy to medicinal products authorised by the Member States, subject to the opinion of the high-technology medicinal products of the European Agency for the evaluation of medicinal products, the Committee for medicinal products has delivered up to January 1, 1995.
135. Periodic reports shall be submitted to the restored security: 135.1. in accordance with the laws and regulations for pharmacovigilance of medicinal products, arrangements for which were recorded up to 30 October 2005;
135.2. the application for the renewal of the next product, which was moved to the 30 October 2005;
135.3. every three years after the decision on the registration of the medicinal product making the drug, which was re-registered after 30 October 2005.
136. the registration certificate issued by the State Agency of medicines to the date of entry into force of the provisions, they are valid until the expiry date.
137. A product set out in these provisions of traditional herbal medicinal products: 137.1. and that this provision enters into force is already on the market, including the if product regulations in the order is recognised, such as dietary supplements, cosmetics, this capacity could be on the market no later than 20 May 2011;
137.2. by 20 May 2011 may be placed on the market only if it is in accordance with these rules is registered in the State Agency of medicines as traditionally used in herbal medicine.
138. This provision, paragraph 28 of the protection period shall enter into force 10 years after the entry into force of these regulations. Up to the end of that period: 138.1. medicinal products for which an application for registration, may not differ substantially from the medication, which is at least six years registered (allowed for distribution) European economic area country, but for high-technology medicinal products, the Committee for medicinal products for 1995 1 January is authorised by the Member States, this period is not less than 10 years;
138.2. for medicinal ingredient (s) (s) widely used in medicine, medicine registration application requires the applicant to submit to the State Agency of medicines in non-clinical and clinical trials if he can demonstrate that the medicinal ingredient (s) in use in medicine is a broad (well established), with recognized efficacy and an acceptable level of security, giving references to the scientific literature.
139. If the application for registration in relation to chapter III of these rules is filed until 30 October 2005, medicines (generic medicines) may not differ substantially from the medication, which is at least six years recorded in the European economic area country. For high-technology medicinal products, the Committee for medicinal products for 1995 1 January is authorised by the Member States, this period is not less than 10 years.
Informative reference to European Union directives, the regulations include provisions resulting from: 1) of the Council of 12 December 1977 Directive 78/25/EEC on the approximation of the laws of the Member States relating to the colouring matters which may be added to medicinal products;
2) of the European Parliament and of the Council of 6 November 2001, Directive 2001/83/EC on the Community code relating to medicinal products for human use;

3) of the European Commission in 2003 25 July Directive 2003/63/EC of the European Parliament and the Council amending Directive 2001/83/EC on the Community code relating to medicinal products for human use;
4) of the European Parliament and of the Council of 31 March 2004, Directive 2004/24/EC amending, as regards traditional herbal medicinal products, Directive 2001/83/EC on the Community code relating to medicinal products for human use;
5) of the European Parliament and of the Council of 31 March 2004, Directive 2004/27/EC amending Directive 2001/83/EC on the Community code relating to medicinal products for human use.
Prime Minister a. Halloween health ministers in place cultural Minister h. demakova Editorial Note: the entry into force of the provisions by 23 June 2006.
 
 
 
1. the annex to Cabinet on May 9, 2006, regulations No 376 health ministers in place cultural Minister h. demakova annex 2 Cabinet may 9 2006, regulations No dyes, 1866 which allowed to add drugs no PO box
(E) number of international name in English name in Latvian Edition 1 2 3 4 1.
E 100 Curcumin Kurkumīn 2.
E 101 Lactoflavin (Riboflavin) riboflavin 3.
E-102 Tartrazin Tartrazīn 4.
E 104 quinoline yellow Quinolin yellow 5.
E 110 orange yellow S sunset yellow FCF Oranždzelten S sunset yellow FCF 6.
E 120 Cochineal Carminic acid by carmines 7 Ponceau 4R.
E-Carmoisin-122 azorubine Azorubin carmoisine 8.
E 123 amaranth, Amaranth 9.
Cochineal Red A, e 124 Košenilsarkan A Kumač of Poncea 4R 4R is 10.
E 127-11 Eritrozīn Erythrosin.
E 131 patent blue V, the V Patentzil 12.
Indigotin e 132 (Indigo Carmine), indigotine (Indigo Carmine) 13.
(E) the 14.140 Chlorophyllum Chlorophyll
E 141 Copper complex of chlorophyll chlorophyllin to chlorophyllum and and hlorofilīn can be complex, 15.
E Acid brilliant green BS 142 (lissamin green) acid brilliant green BS (lizamīnzaļ) the 16.
Caramel caramel e 150 17.
E 151 brilliant Black BN Black brilliant black BN PN PN 18.
E the vegetal 153 Carb medicinalis (charcoal) medical charcoal (charcoal) 19.
E 160 Carotenoid: carotenoids: 19.1.
E 160 a, Alpha-, beta-, gamma-caroten-alpha-, beta-, gammakarotīn 19.2.
E 160 b Bixin Norbixin (Annatt of Rouco) bixin norbixin 19.3.
E 160 c Capsanthin Capsorubin capsanthin Kapsorubīn 19.4.
E 160 d lycopene Lycopen is 19.5.
E 160 e beta-APO-8 ' carotenal (C30) Beta-APO-8-karotināl (C30) 12.2.
E 160 f Ethyl ester of beta-APO-8-carotenoic acid (C30) ' beta-APO-8-carotenic acid (C30) 20.
E 161 Xanthophyll: Ksantofil: 20.1.
E 161 (a) Flavoksantīn Flavoxanthin 20.2.
E 161 Lutein lutein 20.3 (b).
161 Kryptoxanthin c Kriptoksantīn e to 20.4.
E 161 d Rubixanthin Rubiksantīn 20.5.
E 161 e Violoxanthin Violoksantīn 20.6.
(E) (f) of the Rodoksant 161 Rhodoxan 20.7.
E 161 g Canthaxanthin canthaxanthin 21.
(E) the red beet Beetro 162 Betanin red betanin 22.
E 163 anthocyanins in Anthocianin 23.
E 170 calcium carbonate calcium carbonate 24.
E 171 titanium dioxid is titanium dioxide 25.
E 172 Iron oxide and iron oxides and hydroxid hydroxides 26.
E 173 aluminium aluminum 27.
174 e Silver silver 28.
E 175 Gold notes.
1. the General and specific purity criteria for colours that are allowed to add products, as well as methods of analysis used to determine the colours of the compliance with the criteria are identical to those applied to food colours.
2. The export of manufactured products can be added to the other colours if colours are allowed in the importing country.
Health Ministers in place cultural Minister h. demakova annex 3 cabinet may 9 2006, regulations no requirements for the registration dossier 376 1. Generic question 1. essential requirements set out in this Annex: registration 1.1. administrative data – module 1;
1.2. quality, non-clinical and clinical summaries, module 2;
1.3. for chemical, pharmaceutical and biological information for medicinal products containing chemical and biological active substances – module 3;
1.4. non-clinical reports module; 4.
1.5. the clinical trial reports – module 5. 
2. module 1. 2. Administrative data Provide documentation of registration 1., 2., 3., 4. and 5. module table of contents.
3. the application form shall specify: 3.1 medicinal products covered by the application for registration (the name of the active substance (s) name, pharmaceutical form, route of administration, the strength and the final presentation (including packaging);
3.2. the applicant's company name and address, the name and the manufacturer of the medicinal product and plant sites involved in the different stages of production, including the manufacturer of the finished product and the active substance (s) manufacturer (s) and, if necessary, the name and address of the importer;
3.3. the application type and the look presented by gus, if any;
3.4. and annex adds: 3.4.1. production of medicines authorisation (licence);
3.4.2. the list of countries which have granted this Appendix 3.4.1. transactions referred to in the licence;
3.5. detailed information on the registration application 3.5.1: specified medicinal products;
3.5.2. the registration of the applicant's legal status;
3.5.3. the anticipated registration of the owner and the manufacturer (s);
3.5.4. the status of the medicinal product as an orphan;
3.5.5. scientific information;
3.5.6. paediatric development program.
4. Summary of this provision complies with paragraph 21.
5. The proposed text of the labelling and packaging to the primary to the secondary, as well as instructions for use, complies with the laws and regulations on the labelling of medicinal products and pharmacovigilance instruction izvirzāmaj requirements. Submit the relevant veterinary medicinal product on the primary and secondary packaging, labelling and package leaflet of the samples or models.
6. If possible, administrative data include: 6.1. European economic area countries already approved copies of the summary of product characteristics;
6.2. list of countries in which the registration application.

7. the expert evaluation report on registration documents and data (a part of the registration dossier) is detailed, especially on the 3., 4. and 5. module (chemical, pharmaceutical and biological documentation, non-clinical documentation and clinical documentation). These reports focused on critical points related to the quality of the product, and the studies carried out in animals and people, and are indicated in important data for evaluation. These requirements follow 2. module, providing a general overview of the quality, non-clinical study report (data from studies carried out in animals) and the clinical study report. 1. module include expert (with suitable technical or professional qualifications) signed a declaration together with brief information on their education, training and professional experience. Experts have the appropriate technical or professional qualifications. The experts and the applicant's professional relationship is declared.
8. The specific requirements of various applications for registration are listed in annex 4 of these rules.
9. If necessary, the registration application shall include environmental risk (all the risks associated with adverse effects on the environment) the assessment report. Report: assessing the potential 9.1 environmental risk or the use of the medicinal product and stating the reasons for the destruction the proposal for the labelling of medicines;
9.2. the focus on environmental risk associated with product release into the environment of genetically modified organisms and the European Union of the Republic of Latvia Law on the deliberate release into the environment of genetically modified organisms;
9.3. module 1 in the annex indicates the environmental risk and include: 9.3.1. introduction;
9.3.2. writing (copy) as acceptance of genetically modified organisms deliberate release into the environment (research and development);
9.3.3. information about genetically modified organism detection and identification methods and code;
9.3.4. environmental risk assessment for important information about genetically modified organisms or products in accordance with the laws and regulations on genetically modified organisms;
9.3.5. environmental risk assessment report, prepared in accordance with the laws and regulations on genetically modified organisms;
9.3.6. opinion (in the light of that information, and environmental risk assessment report), which recommends that appropriate risk management or control strategy, including plans to sell the genetically modified organism and post marketing surveillance of products in the market and all the specific data to be specified in the summary of product characteristics, labelling and package leaflet;
9.3.7. information on public information activities;
9.4. provide information about the author: 9.4.1 the author's signature and date;
9.4.2. education;
9.4.3. training;
9.4.4. professional experience;
new item 9.4.5. notification on the author's relationship with the applicant.
 3. module 2. 3.1. General summary question 10.  2. the module is compiled: 10.1. chemical, biological, pharmaceutical, not clinical trials and clinical trial data provided 3., 4. and 5. module;
10.2. the provisions referred to in paragraph 20 of the summary.
11. Attention is drawn to the critical points, and they are analyzed. Summary of the facts is provided (including tables). The reports provide cross-references to tables or to the information contained in module 3 (chemical, pharmaceutical and biological documentation), module 4 (non clinical trial documentation) and module 5 (clinical documentation).

3.2. Summary 12. Summaries are provided in the total index according to the inserted, 2., 3., 4. and 5. scientific documentation submitted in module table of contents.
13. key contains information about the farmakoter of the peitisk of the medicinal products to be of the class, the activity and the intended clinical use.
14. overall quality summary: 14.1. Overview of chemical, pharmaceutical and rearing the most rigorous data;
14.2. highlights the main characteristics and critical quality issues, as well as provide justification if there is no match. 3. This document, complied with the module provided detailed data and presentation.
15. the clinical trial report: 15.1 integrated and critical assessment of the medicinal clinical trials in animals/in vitro, as well as set out and reasonable testing strategy, allowing also the deviation;
15.2. includes the impurities and degradation products, and their potential pharmacological and toxicological assessment (except for biological medicinal products). Examine the differences in the meaning of hiralitāt, chemical form and impurity between a connection that is not used in clinical trials, and distribution of medicinal products;
15.3. evaluate a medicinal product not of biological origin in clinical research and the clinical research of the material used and the comparability of the medicinal products to be registered;
15.4. the new adjuvants are specifically evaluated security;
15.5. certain medicinal properties are not clinical studies, as well as examined data on the safety of the medicinal product for use in the clinical subjects.
16. Clinical study report shall meet the following conditions: 16.1. and 5. clinical summary module includes a critical analysis of the clinical data. Provides clinical trials of the medicinal product, including the method of research based plan and related decisions and research activity;
16.2. provide a brief overview of clinical data obtained, including the relevant restrictions, as well as the benefits and risks (all risk relating to the quality of the product, safety or effectiveness as regards patients ' health or public health (public health)) assessment based on clinical findings. Include an explanation of how the data obtained on the basis of efficiency and safety of the proposed dose and target indications, as well as the evaluation of the summary of product characteristics and other techniques will optimise the benefits and manage risks;
16.3. explain the effectiveness and safety issues that have arisen during the development of the medicinal product, as well as unresolved issues.
17. non-clinical summary. In animals/in vitro pharmacological, pharmacokinetic undertaken and toxicological studies is presented in writing and in the form of a table in the following order: 17.1. introduction;
17.2. written summary of Pharmacology;
17.3. summary table of Pharmacology;
17.4. written summary of pharmacokinetics;

17.5. pharmacokinetics table summary;
10.9. written summary of Toxicology;
17.7. Summary of toxicology in the table.
18. The clinical trial summary: 18.1. a summary of the facts provides detailed clinical information about the medicine, which included 5. module. It includes the study of the biofarmaceitisk, the koloģij of clinical research and farm the clinical efficacy and safety studies. You need a separate synopsis of research;
18.2. aggregate information about clinical trials in the following order: 18.2.1. a summary of the studies biofarmaceitisk and related methods of analysis;
18.2.2. Clinical Pharmacology research summary;
18.2.3. Summary of clinical effectiveness;
18.2.4. Summary of clinical safety;
18.2.5. synopsis of the individual studies.

4. module 3. Chemical, pharmaceutical and biological information for medicinal products containing both chemical and biological active substances of 4.1. Form and design 19.  3. outline of the module is the following: 19.1. table of contents: 19.1.1. active substance (s);
19.1.2. finished medicinal product;
19.1.3. additions;
19.1.4. more information;
19.2. data set;
19.3. bibliographical references.
20. This annex referred to in 19.1.1. the bottom set of data on the active substance (s) (s) include the following: 20.1. General information: 20.1.1. nomenclature;
20.1.2. structure;
20.1.3. General characteristics;
20.2. production: 20.2.1. the manufacturer (s);
20.2.2. the manufacturing process and process controls;
20.2.3. raw material control;
20.2.4. critical period and the intermediate examination;
20.2.5. process validation and/or evaluation;
20.2.6. manufacturing process development;
20.3. Description: 20.3.1. the structure and other characteristics of the explanation;
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. series analysis;
20.4.5. justification of specifications;
20.5. (reference) reference standards or materials;
20.6. packaging and sealing system;
20.7. stability: 20.7.1. Summary and conclusions on stability;
20.7.2. stability Protocol (after approval) and stability commitment;
20.7.3. data on stability.
21. This annex 19.1.2. the data referred to in point total of ready-made medicinal products shall contain the following information: 21.1. Description and composition of the medicinal product;
21.2. pharmaceutical development: 21.2.1. medicinal ingredients: 21.2.1.1. the active substance (s);
21.2.1.2. excipients;
21.2.2. medicine: 21.2.2.1. the pharmaceutical form;
21.2.2.2. dose increase;
21.2.2.3. physical and chemical properties;
21.2.2.4. biological properties;
21.2.3. the development of the manufacturing process;
21.2.4. packaging and sealing system;
21.2.5. microbiological characteristics;
21.2.6. compatibility;
21.3. production: 21.3.1. the manufacturer (s);
21.3.2. serial composition;
21.3.3. the manufacturing process and process controls;
21.3.4. the critical period and the intermediate examination;
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. of human or animal origin for excipients;
21.4.6. new adjuvants;
21.5. the control of the finished medicinal product: 21.5.1. specification (s);
21.5.2. analytical procedures;
21.5.3. validation of analytical procedures;
21.5.4. series analysis;
21.5.5. characterisation of impurities;
21.5.6. specification (s) description;
21.6. reference standards or materials;
21.7. the packing and sealing system;
21.8. stability: 21.8.1. Summary and conclusions on stability;
21.8.2. stability Protocol (after approval) and stability commitment;
21.8.3. data on stability.
22. This annex 19.1.3. data referred to in subparagraph for you to add the following information: 22.1. installations and equipment (only the products of biological origin);
22.2. the possible disease agent security assessment;
22.3. excipients.
23. This annex 19.1.4. the data referred to in the supplementary information include the following: 23.1. pharmaceutical process validation scheme;
23.2. a medical device;
23.3. eligibility certificate (s);
23.4. medicinal products containing or using in the manufacturing process of animal and/or human origin (TSE procedure).
4.2. Content principles and requirements 4.2.1 General questions 24. Chemical, pharmaceutical and biological data shall include the following information on the active substance (s) (s) and for ready-made products: 24.1.;
24.2. production process;
24.3. the characteristics and properties;
15.2. the quality control operations and requirements;
15.2. stability;
24.6. the composition of the finished product and design description.
25. Provide separate information on the active substance (s) (s) and for ready-made products.
26. Provide detailed information about raw materials and raw materials used for the active substance (s), and on the excipients incorporated into the finished medicinal product.
27. the procedures and methods used in active substances and the production of the finished product and a detailed description of the control, so that they can repeat the tests, carried out at the request of the State Agency of medicines. Analysis procedures comply with current scientific knowledge and are validated. Are provided to validation studies. Taking the test included in the European Pharmacopoeia, this description shall be replaced by the appropriate detailed reference to the monograph (s) and General Chapter (front) (s).

28. The monographs of the European Pharmacopoeia are applicable to all the substances, preparations and pharmaceutical forms. In respect of other substances, each country of the European economic area may require observance of its own national pharmacopoeia. The European Pharmacopoeia analytical procedures included in its description in each relevant section is replaced with the appropriate detailed reference to the monograph of the European Pharmacopoeia (s) and General Chapter (s) (s). If the material in the European Pharmacopoeia or a European economic area country pharmacopoeia is prepared with the method because it can stay, not covered in the pharmacopoeia monograph, these impurities and their maximum amount is specified and is described in the appropriate analytical procedure. If the European Pharmacopoeia or in the European economic area countries included in the pharmacopoeia of the specification may not be sufficient to ensure the quality of the substance, the State Agency of medicines has the right to request from the registration certificate holder (owner) of the appropriate specifications. The State Agency of medicines shall inform the relevant competent authorities of the pharmacopoeia. Registration certificate holder (owner) shall provide the authorities of that Pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied.
29. If the raw materials and raw materials, active substance (s) or excipient (s) not described in the European Pharmacopoeia or in the European economic area national pharmacopoeia, shall have the right to accept compliance with the monograph of a third country (country, which is not a European economic area country) pharmacopoeia. In this case is filed together with a copy of the monograph a monograph contained in the validation of analytical procedures and, if necessary, translation.
30. If the active substance, the raw material, as well as raw material (s) or excipient (s) include (s) a monograph of the European Pharmacopoeia, this module can be included in the section of the European Directorate for the quality of medicines issued certificate, which replaces the relevant data described in this module. Manufacturer approved registration in writing to the applicant that the manufacturing process has not changed since the European Directorate for the quality of medicines issued a certificate of compliance.
31. Information about a specific active substance for a detailed description of the production process, quality control during manufacture and process validation is the manufacturer of the active substance may submit a separate document as the active substance master file. The manufacturer has confirmed in writing to the applicant for registration that he ensure the homogeneity of the series and without registration requesting not modify the manufacturing process or specifications. Document and justify any changes. The following documents and particulars are filed the registration applicant, if they cover the basics of the active substance in the open part.
32. the special measures related to the transmission of animal spongiform encephalopathies, is demonstrated at each stage of the production process of the materials used in compliance with the instructions of the animal spongiform encephalopathy agent to reduce the risk of proliferation with medicines and their larger editions, published by the European Commission in the official journal of the European Union. Compliance with these instructions, it can be shown, by the European Directorate for the quality of medicines provided by the certificate of conformity to the relevant monograph of the European Pharmacopoeia or to provide scientific data to substantiate this compliance.
33. On the possible disease agent provides information, assessing the possible virus or viral agents risk of impurities, as defined in the relevant guidelines, as well as the relevant European Pharmacopoeia Monographs and General in the General Chapter.
34. Detailed enough description of manufacturing process and testing specialist equipment to be used and the equipment.
35. Where relevant, the CE mark according to the Latvian and European Union legislation on medical devices.

4.2.2. the active substance (s) 36. Provides general information about raw materials and raw materials: 36.1. the nomenclature of the active substance, including recommended international non-proprietary name, title of the European Pharmacopoeia and, if required, a chemical (s) name (s). Structural formula, also indicate the relative and absolute chemistry, the molecular formula and relative molecular mass shall be provided. Biotehnoloģiskaj medicinal product schematic amino sequence and relative molecular mass shall be provided. Provides a list of active substances and other physical, chemical characteristics;
36.2. biological medicines indicate biological activity, given that the products of biological origin with raw materials from understand how manufactured or extracted active substances: 36.2.1. materials are substances of biological origin (such as micro-organisms, plant or animal organs and tissues, human or animal origin, cells or fluids (including blood or plasma)) and cell biotechnology organization (cell substrates, which are recombinant or not the also, stem cells);
36.2.2. the active substance is a substance that is manufactured or extracted from a biological source and characteristics and quality determination must take physical, chemical and biological inspections, as well as to control the production process. Other substances used for the active substance (s) or ekstraģēšan, but from which the active substance does not acquire (such as reagents, culture media, fetal calf serum, additives, chromatography used in buffer), known as raw materials.
37. The active substance (s) in the production process: 37.1. this schedule registration, the applicant's commitment to produce the active substance. To adequately describe the manufacturing process and process controls, provide the appropriate information to determine the of the European Medicines Agency published guidelines;
37.2. the accounts of the active substance (s) materials needed for production, identifying where each material is used in the process. Provides information on the quality of materials and test. Provide information demonstrating that materials meet standards of use envisaged. List unprocessed materials, as well as the quality of the document and checks. Each manufacturer (contractor) and each proposed production site or involved in the production and testing equipment (devices) name, address, and responsibility;

37.3. for biological medicinal products, subject to the following additional requirements: 37.3.1. is described and documented the origin and history of starting materials;
37.3.2. with regard to specific measures of animal spongiform encefal pātij for the prevention of the transmission of the registration request, the applicant must demonstrate that the active substance complies with the guidelines of agents of animal spongiform encephalopathies proliferation risk reduction with drugs and their larger editions, published by the European Commission in the official journal of the European Union;
37.3.3. when cell banks are used, indicating that the cell characteristics remain unchanged before and after the flow used in production;
37.3.4. has been tested, or seed, cell banks, pools of serum or plasma and other materials of biological origin and, whenever possible, the materials from which they are derived, is not possible disease agent;
37.3.5. If the potential pathogens for possible presence of adventitious agents is inevitable, the corresponding material shall be used only when further processing ensures their elimination and inactivation, and it requires validation;
37.3.6. whenever possible, vaccine production shall be based on a seed lot system and on a series of established cell banks. Bacteriological and viral vaccines for infectious agent characteristics demonstrate the inoculum. Live vaccines in addition to prove the inoculum attenuation characteristics. If this proof is not sufficient, the attenuation characteristics shall demonstrate also the production stage;
37.3.7. for medicinal products derived from human blood or plasma, in accordance with chapter IV of this annex describe and document the origin of the raw materials, criteria and collection, transport and storage procedures;
37.3.8. Description of the production facilities and equipment;
23.2. If needed, provide information about each critical phase of the tests carried out and the acceptance criteria, the quality and control of intermediates, as well as the process validation and evaluation;
37.5. If potentially pathogenic potential presence of adventitious agents is inevitable, the corresponding material shall be used only when further processing ensures its destruction and inactivation, and it requires validation section on viral safety evaluation;
23.4. describes and explains the major changes in the development of the active substance during the production process and production site.
38. the active substance (s): 38.1. the description of the active substance (s) and other relevant bodies;
38.2. the approval of the active substance (s) structure, based on physical and chemical or imūnķīmiskaj, or biological methods, as well as information on impurities.
39. Provide information on the active substance (s) control: 24.3. specifications used for the active substance (s) regular control, giving the choice of these specifications, as well as methods of analysis and their validation;
24.4. separate development during a series of tests produced results.
40. the fixed and detailed description of ces (reference) reference preparations and standards of reference. If necessary, use the European Pharmacopoeia chemical and biological reference materials.
41. the active substance Provided the packaging and closure system (s) and their specifications.
42. the active substance (s) stability: 42.1. aggregated study, Protocol and study results;
26.2. in an appropriate form in detail presented in the stability studies, including information on the data used in the preparation of analytical procedures and validation for this procedure;
26.3. the stability Protocol (after approval). Provides information on the obligations relating to stability.

4.2.3. Finished medicinal product 43. Description of the finished product: 43.1. indicate the composition. The information includes the pharmaceutical form and a description of the composition, indicates the finished medicinal product components, the unit and the function of these components: 43.1.1. active substance (s) (s);
43.1.2. constituents of the excipients, whatever their nature or the quantity used (such as pigments, preservatives, adjuvants, stabilizers, thickeners, emulsifiers, flavourings and fragrances);
43.1.3. components of the outer covering of the medicinal products intended to be ingested or otherwise administered to the patient use (for example, hard capsules, soft capsules, rectal, film-coated tablets). These particulars shall be supplemented by the relevant data concerning the container and, if necessary, on the way to close it, as well as data on the use of the medicinal product and input devices, which will be delivered with the medicinal product;
43.2. the qualitative and quantitative drug composition using simple terminology and components of the medicinal product: the name 43.2.1. main of the monograph in question with reference to the pharmacopoeia concerned, in respect of substances which appear in the European Pharmacopoeia or, failing this, a European economic area country pharmacopoeia;
43.2.2. International non-proprietary name recommended by the World Health Organization, or, if not, the scientific name for other substances. If the substance has no international non-proprietary name or the scientific name, indicate how and from what they were prepared, as well as other important messages;
43.2.3. legend-E code that has been assigned to the and indicated in annex 2 of these rules as well as regulations governing consumption – permitted colouring agents, colorants;
43.3. in order to define the finished product of the active substance (s) quantitative composition, depending on the pharmaceutical form concerned, to specify the mass of each of the active substances, or the number of units of biological activity (dosage-unit or per unit mass or volume);
43.4. active substances present in the form of compounds or derivatives shall be described quantitatively, taking into account their total mass, and if necessary, active units or unit mass of molecules;
43.5. for medicinal products containing an active substance which is subject to first registration in any European economic area country, quantitative assessment of the active substance, which is a salt or hydrate shall be systematically expressed in terms of the units or unit mass of molecules. All later registered medicinal products of the European economic area countries have their quantitative composition in respect of one and the same point of active substances in the same way;

27.1. the units of biological activity shall be used for substances that can not be defined molecularly. If the World Health Organization has established an international unit of biological activity, then use it. Unless an international unit of biological activity, the units of biological activity shall be expressed in such a way as to provide unambiguous information on the activity of the substances must, if necessary, with the European Pharmacopoeia units.
44. Pharmaceutical Development: 44.1. provide information on the development studies conducted to establish that the dosage, formulation, manufacturing process, sealing system, microbiological attributes and usage instructions corresponds to the intended use specified in the registration dossier;
44.2. these studies differ from regular control tests conducted according to specifications. Define and describe the composition of the medicinal product and process critical parameters that may affect the reproducibility, medicinal product series performance and the quality of the product. If you need additional data, refer to the appropriate module 4 (non clinical study reports) and module 5 (clinical study reports) chapter: 44.2.1. document the active substances of compatibility with excipients, as well as the main active substance in the physical and chemical characteristics that can affect the operation of the finished product or the compatibility of different active substances connections;
44.2.2. document the choice of excipients, in particular with regard to their respective functions and concentration;
44.2.3. provide description of the finished product development, taking into consideration the proposed route of administration and usage.
44.2.4. based on the success of any component of the drug over;
44.2.5. describes and documents the parameters relating to the operation of the finished product, as far as the physical, chemical and biological characteristics;
44.2.6. specify selection and production process optimization, as well as differences between the manufacturing process(es) used the main clinical series in production and process used in the production of the finished product;
44.2.7. document the packaging and sealing systems for finished product suitability for storage, transportation and use. If necessary, consider drug and packaging the potential interaction;
44.2.8. non-sterile and sterile dosage of the products comply with the microbiological characteristics of the European Pharmacopoeia, and document them in the European Pharmacopoeia;
44.2.9. to provide useful information on the label of the finished product, document compatibility with solvent (s) or dosage devices.
45. the production process of the finished product: 45.1. prepare a description of the manufacturing method, and according to this provision shall be added to paragraph 17.5. bottom registration request. Description provides enough statements about the nature of the operations employed. It shall include at least: 45.1.1. mention of the various stages of production, including process controls and acceptance criteria to be assessed, or pharmaceutical forms used in the production process can cause unwanted changes in components;
45.1.2. If the production is not interrupted, the gas in full details concerning precautions taken to ensure the homogeneity of the finished product;
45.1.3. validation of the manufacturing process used for the results of the pilot studies, where a non-standard method of manufacture is used or where they play a decisive role in the process of the manufacture of medicinal products;
45.1.4. for sterile medicinal products, details of the sterilization processes, as well as aseptic procedures;
45.1.5. detailed information on the composition of the series;
45.2. each manufacturer (including contractors) and each proposed production site or production and testing the facility name, address, and responsibility;
45.3. include data about the product control tests that may be carried out at an intermediate stage of the manufacturing process to ensure the conformity of production. These tests are essential for checking the conformity of the medicinal product the formula when, exceptionally, an applicant for registration provides for testing the finished product with the method of analysis, which does not include the determination of the active substance (or check the excipient constituents subject to the same requirements as the active ingredients). It applies where the quality control of the finished product depends on in-process control tests during production, particularly if the medicinal product is fully described by their method of manufacture;
28.2. the validation studies submitted, the documentation and critical points in the manufacturing process of fixing results.
46. control of excipients: 46.1. list the excipient (s) production of materials needed, identifying where each material is used in the process. Provides information on the quality and control of these materials. Certifying that the materials comply with the intended use. Colours correspond to these rules 2. the requirements set out in the annex, as well as the legislation on authorised colouring matters in food. Colours correspond to regulations on the purity criteria applicable to food colours;
46.2. details of each excipient specifications and justify it. Describes and appropriately validated analytical procedures;
46.3. Special attention is paid to the person or the excipients of animal origin. Through specific measures related to the transmission of animal spongiform encephalopathies, the applicant for registration in respect of the excipients must demonstrate that the medicinal product is manufactured in accordance with the instructions of the agents of animal spongiform encephalopathies proliferation risk reduction with drugs and their larger editions, published by the European Commission in the official journal of the European Union. Compliance with these instructions, it can be shown, by the European Directorate for the quality of medicines provided by the certificate of conformity to the relevant monograph of the European Pharmacopoeia or to provide scientific data to substantiate this compliance;
46.4. the new adjuvants: 46.4.1. According to the active substance form provides detailed information about the characteristics of the excipient (s) used by the product for the first time, or if the medicinal product is new. Provides information on excipient (s) production and inspection, including cross-references to the security data obtained in clinical and non clinical trials.
46.4.2. submit the document with detailed chemical, pharmaceutical and biological information. This information is presented in the same way as module 3 section of the active substance (s) (s);

46.4.3. information about the new excipient (s) (s) may be submitted as a separate document under the form described above. If the applicant for registration is not a new excipient manufacturer the said stand-alone document shall be made available to the applicant for registration to be submitted to the competent authority (Latvia-State Agency of medicines);
46.4.4.4. module provides additional information on toxicity studies with the new excipient;
46.4.5. for information on clinical trials provided 5. module.
47. the control of the finished medicinal product: 29.3. to testing the finished product, medicine series includes units of a pharmaceutical form which are made from the same initial quantity of material and have undergone the same production and sterilization operations, or, if the production process is not stopped, all the units manufactured in a given period of time;
47.2. unless there is appropriate justification, the active substance content of the finished product the maximum permitted deviation during production does not exceed ± 5%;
47.3. provide detailed information on the specifications, (release and shelf life) and justification for their choice of methods of analysis and their validation shall be provided.
48. Defines and describes in detail the preparations of reference and reference standards used for testing of the finished medicinal product, if this information is provided in the section on active substance.
49. The finished product packing and sealing system: 30.5. provide packaging and sealing system (s) and their specifications, identifying the primary packaging material. The specifications shall include description and identification. If necessary, include non-Pharmacopoeial methods (with validation);
30.6. non functional secondary packaging material gives only a brief description. For functional secondary packaging materials provide more information.
50. the stability of the finished medicinal product: 50.1. summarizes studies undertaken, the protocols used, and the results of the study;
50.2. in an appropriate form to reflect the detailed results of the stability studies, including information on the data used in the preparation of analytical procedures and validation for this procedure. If necessary, information on vaccine cumulation of stability;
50.3. submit the stability Protocol (after approval) and stability commitment.

5. module 4. Reports on clinical trials 5.1 Form and design, 51.  4. presentation of the module is as follows: 51.1. table of contents;
51.2. reports of studies: 51.2.1. Pharmacology;
51.2.2. pharmacokinetics;
51.2.3. toxicity;
51.2.4. other toxicity studies;
51.3. bibliographical references.
52. This Annex 51.2.1. reports referred to on the pharmacology of include the following: 52.1. primary pharmaco-Dynamics;
52.2. the secondary pharmaco-Dynamics;
52.3. safety pharmacology;
52.4. pharmacodynamic interaction.
53. This Annex 51.2.2. the reports referred to in point on the pharmacokinetics of include the following: 53.1. analytical methods and validation reports;
53.2. absorption;
53.3.;
53.4. metabolism;
13. discharge from the body;
53.6. pharmacokinetic interactions (clinical trials);
53.7. other pharmacokinetic studies.
54.51.2.3. Of this annex referred to reports of toxicity include the following: 54.1. single dose toxicity;
54.2. repeated dose toxicity;
54.3. genotoxicity: 54.3.1. in vitro;
54.3.2. in vivo (including toxicokinetic evaluations);
54.4. carcinogenicity: long-term studies; 54.4.1.
54.4.2. temporarily or medium studies;
54.4.3. other studies;
54.5. reproductive toxicity and developmental toxicity of: 54.5.1. fertility and embryonic development in early;
54.5.2. (fruit) embryo development;
54.5.3. and postnatāl prenatal development;
54.5.4. the study medications given to the offspring (juvenile animals) and/or additional assessed;
54.6. local tolerance.
55.51.2.4. Of this annex referred to reports of other toxicity studies include the following: 55.1. antigenitāt;
55.2. imūntoksicitāt;
55.3. mechanism;
55.4. dependency;
55.5. metabolic products;
57.5. impurities;
55.7. other.

5.2. basic principles and the essential requirements of contents 56. particular attention should be paid to the following conditions: 56.1. pharmacological and toxicological studies: 56.1.1. the potential toxicity of the product and in dangerous or undesirable toxic effects that may occur when people use them in accordance with the recommendations. It assessed in relation to the pathological condition concerned;
56.1.2. pharmacological properties of the medicinal product qualitative and quantitative relationship to the proposed use. The results are reliable and universally applicable. If possible, the experimental techniques in the development and evaluation of the results of the use of mathematics and statistical methods;
56.1.3. in addition to providing information about the product's therapeutic and toxicological potential;
56.2.4. module can be customized to individual requirements for biological medicinal products (such as immunological medicinal products and products derived from human blood or plasma, drugs), the applicant should therefore be based on the testing program. Developing a test program, take into account the following requirements: 56.2.1. plans to test, requiring repeated administration of the product, taking account of the possible induction of antibodies and interaction;
56.2.2. made for reproduction, embryo, and fetus and perinatal toxicity, of mutagenic potential and of carcinogenic potential in check. If the reason for the other components is considered, which is not the active substance (s), the validation of their removal may replace the study;
56.3. displays the first Pharmaceutical Excipients used in the toxicology and pharmacokinetics;
56.4. If storage possible significant degradation of the medicinal product, the toxicology of degradation products assessed.
57. Data on Pharmacology: Pharmacology study of 57.1. using two different approaches: 57.1.1. properly researched and described by the proposed therapeutic use. If possible, use recognized and validated methodology for in vivo and in vitro. New experimental methods are described in detail, so that they can be reused. The results shall be expressed in quantitative terms (using, for example, dose-effect curves, time-effect curves). If possible, compared with data relating to a substance or substances whose effects are similar to therapeutic;

57.1.2. exploring the possible adverse pharmacodynamic effects on physiological functions. These studies are conducted with the intended and more therapeutic dose. Experimental techniques, unless they are standard procedures are described in detail, so that they can be reused, and the investigator is validating them. Exploring the reactions possible changes that might arise, reuse;
57.2. pharmacological or therapeutic effect of precondition indication may be required because of the urgency of the active substance combination for the test drug interactions pharmacodynamic pharmacodynamic study of 57.2.1.: shows the interactions which might make the combination is worth using;
57.2.2. If the combination of scientific grounds looking for therapeutic experimentation, research determines whether the expected combinations of effects can be displayed with animals and what is its significance.
58. Data on pharmacokinetics: 58.1. pharmacokinetics means the active substance and its metabolites in the body exploration and activities apply to this material absorption, distribution, metabolism (biotransformation) and retention studies;
58.2. this annex, 58.1. referred to in research can be carried out primarily by means of physical, chemical or biological methods, as well as observing the same actual pharmacodynamic activity of the substance;
58.3. information on distribution and elimination (biotransformation and excretion) is required, if such data are indispensable to determine the dosage for humans, as well as for ķīmijterapeitisk substances (such as antibiotics) and substances whose use depends on their non-pharmacodynamic effects (e.g. numerous diagnostic products);
58.4. can be made also in vitro studies, in comparison with the animal material using human material (binding of proteins, metabolism, drug interactions);
58.5. need of pharmacologically active substances pharmacokinetic research data. Creating new combinations of known substances which have been investigated in accordance with these rules, farmakokinētisko studies may be omitted if the toxicity tests and therapeutic experimentation justify that they are not necessary;
58.6. pharmacokinetic study program is designed to be able to compare data on the animals and people and can accordingly extrapolate.
59. the data on toxicity: 59.1. single dose toxicity tests shall be carried out in accordance with the relevant provisions of the European Medicines Agency published documents. Single-dose toxicity means the toxic reactions, which may cause the product or active substance within the single use of the substance in the proportions and physico-chemical state in which they are actually present in the halls;
59.2. repeated dose toxicity tests: 59.2.1. designed for the physiological and/or pathological anatomical changes arising from the test for detecting active substance or combination of active substances reuse, as well as to determine how these changes are related to dosage;
59.2.2. make two tests-short term, lasting two to four weeks, and long-term, the duration of which depends on the conditions of clinical use. Test describes the potential harmful effects which the clinical trials requires attention. The test duration is defined in the relevant European Medicines Agency published guidelines;
59.3. genotoxicity: mutagenic and clastogenic potential research aims to discover the changes which a substance may cause in the genetic material of individuals or cells. Mutagenic substances may present a risk to health because of exposure to mutagenic risk that proposes stem cell lines mutated with possible inherited disorders, as well as somatic mutation (one that also causes cancer). All new substances, these studies are mandatory;
59.4. with respect to carcinogenicity usually requires tests that reveal carcinogenic effects. Studies: 59.4.1. with all medicinal products, which the patient clinically to use longer (continuously or repeatedly from time to time);
59.4.2. it is recommended that you perform with the medication, if it can be carcinogenic effects (for example, preparations of the same class or similar structure) or if the carcinogenicity demonstrated repeated dose toxicity studies;
59.4.3. does not perform with clearly genotoxic compounds because they are considered as carcinogens that interspecific endanger persons. If such a medicinal product is intended for people constantly, it may be necessary to carry out long-term research to determine early tumorigenic effects;
59.5. reproductive toxicity and developmental toxicity of: 59.5.1. with the relevant tests are studied the possible men's and women's reproductive function deterioration as well as adverse effects on offspring;
59.5.2. tests include studies on the exposure of adult male and female reproductive function, and teratogenicity of toxic exposure studies in all the stages of human development from conception to sexual maturity, as well as research on the latent effects of the medicinal product concerned, if a woman they used during pregnancy;
59.5.3. If these tests are not carried out, properly justified;
59.5.4. depending on the indication of the use of the product may require additional studies, such as the development of the child, if the medicinal product will be used also for children;
59.5.5. the embryo as well as foetal toxicity studies are typically conducted on two mammalian species, one of which is not a rodent. At least one species taken in the postnatal and perinatal studies. If you know that the metabolism of medicinal products particular species is similar to human metabolism, preferably choose this species. It is also desirable to one species would be the same as that used in the repeated dose toxicity studies;
59.5.6. the design of the study, taking into consideration the accumulated scientific knowledge at the time when the request for registration has been filed;

59.6. local tolerance seeks to establish whether the sites in the body which may come into contact with the medicinal product, its clinical use, tolerate medicinal products (both active substances and excipients). Test strategy shall be such that any mechanical effects of the use of the medicinal product or physico-chemical activities separated from toxic or pharmacodynamic effects. Local tolerance studies are conducted with the preparation, developed for use in humans, the control group (s) of treatment with binders, as well as AIDS. If necessary, use the positive control (reference). Local sustainability plan (choice of species, duration, frequency and type of use, doses) will depend on clinical investigational problems and use conditions. If necessary, prevent local damage. Studies with animals can be substituted by validated in vitro tests, if the quality of the test results and the effectiveness of the safety assessment are comparable. Chemical substances placed on locally (e.g. dermal, rectal, vaginal) the sensitising potential assessment factor in at least one of the test systems currently available (the guinea pigs or locally lymph nodes).
6. Module 5. Reports on clinical trials and design 6.1.60.  5. presentation of the module is as follows: 60.1. clinical study reports table of contents;
60.2. list of all clinical studies table.
60.3. reports of clinical trials: 60.3.1. biofarmaceitisk studies;
60.3.2. research, pharmaco-kinetics using human-Rial biomat;
60.3.3. Human pharmacokinetic studies;
60.3.4. Human pharmacodynamic studies;
60.3.5. efficacy and safety studies;
60.3.6. experience at the commencement of distribution of medicinal products;
60.4. bibliographical references.
61.60.3.1. Of this annex reports referred to the studies is the international biofarmac: 61.1. reports on bioavailability studies;
61.2. reports of bioavailability and bioequivalence studies (comparative reports);
38.1. the reports on the in vivo-in vitro correlation studies;
61.4. reports of bioanalīz and methods of analysis.
62.60.3.2. Of this annex referred to reports of pharmaco-kinetic studies using human bio-materials, are: 62.1. reports on studies relating to binding to plasma proteins;
62.2. reports of hepatic metabolism and interaction studies;
38.7. reports of studies using other human bio-materials.
63.60.3.3. Of this annex reports referred to the kinetics study of the farmak, using human bio-materials, are: a subject's 39.2. pharmaco-kinetics and initial tolerability study reports;
39.3. the pharmacokinetic and initial tolerability study reports;
63.3. internal factor pharmaco-kinetics study reports;
63.4. external factor pharmaco-kinetics study reports;
Population pharmacokinetic study of 63.5. report.
64.60.3.4. Of this annex referred to reports of human pharmacodynamic studies are: 64.1. pharmacodynamic and the whole subject of Pharmacokinetic-dynamic study report the farmak;
64.2. pharmacodynamic and pharmacokinetic patient-pharmacodynamic study reports.
65.60.3.5. Of this annex referred to reports of efficacy and safety studies include the following: 65.1. controlled clinical study on indication subject to registration;
65.2. uncontrolled clinical studies;
65.3. more than one study, data analysis, including all formal integrated analyses, meta-analyses and bridging analyses;
65.4. other studies.

6.2. content principles and essential requirements 66. particular attention should be paid to the following conditions: 66.1. clinical data provided should be enough to give reasonable and scientifically valid opinion as to whether the medicinal product satisfies the criteria governing the granting of the registration. Provides all clinical trial results-both favourable and unfavourable;
66.2. before clinical trials would be conducted and the pharmacological toksik logical tests on animals in accordance with this annex to the requirements of module 4. Researchers will examine the pharmacological and toxicological studies. Registration, the applicant submitted to him at least, the investigator's brochure, which contains all the relevant information known prior to the commencement of the clinical trial (chemical, pharmaceutical and biological data, toxicological, pharmacokinetic and pharmacodynamic data in animals and the previous clinical data, as well as matching data justifying the nature of the proposed research, scale, and duration). Upon request, provide the complete pharmacological and toxicological reports. Human and animal origin materials used every possible means to provide protection against the transmission of the infectious agent before the start of the research;
66.3. in respect of the clinical trial documentation should ensure the achievement of the following requirements: 66.3.1. registration certificate holder (owner) has ensured that essential clinical trial documents (including case report forms) other than medical documentation, data stored by the owner: 66.3.1.1. at least 15 years after completion or discontinuation of the trial;
66.3.1.2. at least two years after the last registration of the award of the European economic area countries, if they are no longer under consideration or projected registration request;
66.3.1.3. at least two years after the preparation under the official termination of the clinical development;
66.3.2. medical records stored in accordance with applicable laws and regulations as long as it allows the medical establishment, including the doctor's practice;
66.3.3. documents may be kept longer if it's a specific law or agreed with the sponsor. Is the responsibility of the sponsor to inform the hospital, institution or practice, if the documents no longer need to be stored;
66.3.4. the sponsor or other owner of the data stored in the documentation pertaining to the trial as long as the product is authorised, and that includes: 66.3.4.1, which contains the Protocol of the rationale, objective research, statistical design, methodology, with conditions under which it is performed and managed, and details of the investigational medicinal product, the reference medicinal product and placebo;
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 any (s);
66.3.5. registration the owner has taken the extra steps to archive research documentation in accordance with the regulations for clinical trials of the medicinal product;
66.3.6. data transfer is documented;
66.3.7. all data and documents are available, if requested by the appropriate authorities;
66.4. of each clinical trial has sufficient information to be able to make an objective assessment, which includes: 66.4.1. a protocol containing the rationale, objectives and statistical design and methodology, with conditions under which it is performed and managed, and details of the investigational medicinal product;
66.4.2. audit certificate (s), if any (s);
66.4.3. the list of researchers that represents each researcher's name, address, job title, qualifications, responsibilities and clinical research sites. The researchers collected information on each patient individually, including case report forms on each trial subject;
66.4.4. final report signed by the investigator. If the research is carried out in several places, it signed by all the investigators or principal investigator, or coordinator;
41.3. clinical trial data should be sent to the State Agency of medicines. By agreement with the State Agency of medicines of the registration, the applicant may not submit part of this information, but if the State Agency of medicines shall immediately submit the request complete documentation. In its conclusions on the evidence obtained in the study, researchers expressed an opinion on the safety of medicinal products, if they are used properly, the effectiveness and sustainability of all useful information relating to indications and contra-indications, dosage and average duration of treatment as well as for special precautions to be taken during treatment and the clinical symptoms of overdosage. If the research is carried out at several locations, principal investigator (Coordinator), reporting on the results of the research, conclusions, express an opinion on the preparations examined the safety and efficacy of all research centres;
66.6. the clinical observations were collected. For each trial indicating: 66.6.1. the number of subjects treated, and gender;
66.6.2. select groups of patients being investigated, a breakdown by age and the comparative tests;
66.6.3. the number of patients in the before time refused participation in the survey, and the reasons for such refusal;
66.6.4. If the controlled trial carried out in accordance with those conditions, indicates whether the control group: 66.6.4.1 not treated;
66.6.4.2. has received a placebo;
66.6.4.3. has received another medicinal product of known effect;
66.6.4.4. are treated differently (than by medicine);
66.6.5. the side effects observed (adverse reactions) frequency;
66.6.6. information about the increased risk to patients (such as the elderly, children, women during pregnancy or menstruation) or those with physiological or pathological condition requires special attention;
66.6.7. efficiency parameters or evaluation criteria and results (expressed with these parameters);
66.6.8. the results of statistical assessment, if it is intended to be a research plan, and associated variables factors;
66.7. provide observations of researchers: 66.7.1. or signs of addiction to addiction or difficulty in weaning patients the use of the medicinal product;
66.7.2. any interaction with other medicinal products, which are used at the same time;
66.7.3. the criteria determining the refusal of certain patients from the trials.
66.7.4. deaths during further research or monitoring;
41.5. data relating to the new combination of medicines, is identical to the data of a new product, and it is based on a combination of safety and effectiveness;
66.9. If the data are not or are only partially, it explained. If research, obtain unexpected results, carry out and report additional prior to clinical, toxicological and pharmacological studies;
66.10. If the medicinal product is intended for long-term use, provides data about all the pharmacological effects change after repeated use, as well as for the determination of the dose for long term usage.
67. the biofarmaceitisk shall submit reports on the studies of bioavailability studies, comparative reports on the bioavailability and bioequivalence study reports, reports on in vitro and in vivo correlation study, as well as bioanalīz and methods of analysis. Bioavailability assessed if it is necessary to demonstrate bioequivalence of medicines.
68. the pharmacokinetic studies using human biomaterials (human proteins, cells, tissues and related materials used in vivo or ex vivo to assess the pharmacokinetic properties of the medicinal product), reports shall be made if the studies relate to the binding with plasma protein on liver metabolism and active substance interaction studies and on research using other human bio-materials.
69. Reports of human pharmaco-kinetic studies: 69.1. description the following pharmaco-kinetic characteristics: 69.1.1. absorption (rate and extent);
69.1.2. spread;
69.1.3. metabolism;
69.1.4. release;
EB 69.2. Description of clinically significant features (including the kinetic data for the dosage), especially for patients at risk, and differences between pre-clinical trials used humans and animal species;
69.3. in addition to the standard pharmacokinetic studies the population pharmacokinetic analysis based on a selection of rare, and clinical trials may include questions about how internal and external factors affect the dose and pharmacokinetics. Provides: 69.3.1. reports of pharmaco-kinetics and initial tolerability studies in healthy people and patients;
69.3.2. messages about pharmacokinetic studies to evaluate the internal and external factors;
69.3.3. messages about population pharmacokinetic studies;
69.4. where medicinal products intended for use in combination with other medicinal products, particulars shall be given of joint administration tests to demonstrate possible modification of the pharmacological effects;
69.5. studied the active substance and other medicinal products or substances pharmacokinetic interactions.
70. Reports of human pharmacodynamic studies: 70.1. pharmacodynamic action of the debt in relation to effectiveness, including dose-response relationship, as well as the changes in time, and conditions of use and, if possible, the type of action. Describes the farmak dynamic action not related to efficiency. Note that in order to justify conclusions regarding any particular potential therapeutic effect, it is not enough to show the pharmacodynamic effects in human beings;

70.2. If the medicinal product is normally to be administered concomitantly with other medicinal products, particulars shall be given of joint administration tests to show the pharmacological effects of possible change. The active substance and other medicinal products or substances pharmacodynamic interaction.
71. Reports of efficacy and safety studies: 71.1. is about controlled clinical trials for indications on which the registration request: 71.1.1. clinical trials are performed as a controlled clinical trial. If possible, use a random method, respectively, compared with a placebo and with approved products that have proven therapeutic value. All other plans. Control group treatment is different and also depend on ethical considerations and treatment sector. In some cases, new drug effectiveness can be compared not with the placebo effect, but with the effectiveness of approved medicines that have proven therapeutic value: 71.1.1.1. to the extent possible, particularly in trials where the action of the medicinal product cannot be objectively measured, appropriately handled to avoid bias, the use is also a random method and the blind method;
71.1.1.2. the Protocol contains detailed statistical methods used, the number of patients and their involvement (including estimates of the amount of research), and a description of the statistical unit. Measures taken to avoid bias (especially random method). If the research involves many entities may not believe that it can replace the control;
71.1.2. data on safety, with particular attention to cases in which the dose or change was necessary while using other medications, observed serious adverse events, patient is refused participation in the survey or he's dead. Indicate any increased risk patients or patient groups, with particular attention paid to potentially vulnerable patients who may be small (e.g. children, pregnant women, the elderly, people with weak health, people who have expressed metabolic or excretory disorders). Describes the security context of the evaluation of the possible use of a medicinal product;
71.2. submit reports of uncontrolled clinical trial data analysis relating to more than one study and other reports on clinical trials.
72. If the product is registered in third countries, reports on the experience after the commencement of distribution of medicinal products provides information on adverse reactions observed, with the use of the medicinal product (s) (s) (s) of the active substance (s) and, if possible, provide data about usage rates in these countries.
73. the report forms and individual patient listings with the data provided in the same order as the clinical study reports (indexed after studies). It shall be submitted in accordance with the relevant European Medicines Agency published guidelines.
Health Minister-Minister of culture h. demakova annex 4 cabinet may 9 2006, regulations No 376 of the special registration requirements for registration submissions i. General questions set out in this annex 1 specific requirements for registration: 1. medicine widely used drugs;
1.2. in essence similar to the product;
1.3. in special cases, if you need additional data;
1.4. similar biological medicinal products;
1.5. the fixed combinations;
1.6. mixed registration submissions.

II. Medicine widely used medicines 2. documentation requirements registration in medicine widely used medicinal product: 2.1. This provision of the annex 3:2.1.1.  1, 2, and 3. module-included;
2.1.2. module 4 and 5 contain the detailed clinical and non clinical indicators and scientific bibliography;
2.2. the wide use of medicinal products shall certify on the medical evidence: 2.2.1 factors to be considered in order to demonstrate the wide use of medicinal components in medicine: 2.2.1.1. the length of time that a substance has been used;
2.2.1.2. quantitative aspects of the use of the substance;
2.2.1.3. the scientific interest in the use of the substance (reflected in the scientific literature);
2.2.1.4. the coherence of scientific assessments;
2.2.2. the time that proves the wide use of medicinal components in medicine (extensive use of different substances to the showing of need for different periods of time), may not be less than 10 years, starting with the first systematic and documented evidence of such substances as the medicinal product in the European economic area;
2.2.3. all safety and effectiveness assessment and the review of the relevant literature or references to them: 2.2.3.1. in the light of the studies before and after commencement of distribution, epidemiological studies (especially comparative trials) dedicated to scientific literature. Submit all documentation (both favourable and adverse);
2.2.3.2. the specific States that invalid preparations for safety and effectiveness evidence can be not only a test and survey data, but also the bibliographic references to other sources of evidence (such as the study by distribution, the epidemiological studies), if the application for registration of this source of information is justified;
2.2.4. the missing information and justification as to why the degree of efficiency and safety can be considered acceptable for the shortfall of some research;
2.2.5. the non-clinical and clinical overviews explain importance of data relating to another, from the distribution of the product for different products. Assess whether the investigational medicinal products can be considered as similar to those applied for registration, although there is some difference between the two;
2.2.6. the experience gained by the way, the same components, distribution of medicines containing the initiation, enrollment specific applicant therefore examine these issues.

III. Essentially similar medicinal products 3. Registration dossier requirements essentially similar medicinal products (generic medicines): 3.1 if the registration request is based (chapter III of these rules), it shall include this provision 3.1, 2, and 3. the data described in the module, if the original registration holder has agreed that the application for registration, the applicant uses the cross-references to the original registration holder submit modules 4 and 5;

3.2. documents certifying the bioavailability and bioequivalence compared to an original medicinal product if the original product is not biological medicinal products;
3.3. non-clinical and clinical summaries focusing on the following elements: 3.3.1. Why is required to support essential similarity;
3.3.2. Summary of the impurities that are in the active substance (s), as well as a series of finished product (if necessary, decomposition products arising during storage), which are intended to be used in products intended for distribution, and the assessment of impurities;
3.3.3. the assessment of bioequivalence studies or a justification not to carry out studies, taking into account the guidelines for bioavailability and bioequivalence studies;
3.3.4. a renewed published literature relating to the registration of substances and the specific application. For this purpose, you can annotate articles from professional journals;
3.3.5. the summary of any claim that is not known or cannot be inferred from the characteristics of the medicinal product or the therapeutic group, seen in the non-clinical and clinical summaries and substantiated by published literature, as well as additional research;
3.3.6. where the registration application relates to a very great similarity, provides additional data to show the various active substances permitted salts, esters or derivatives of efficiency and safety of the equivalence of the properties.

IV. Special cases when you need additional data 4. special cases require additional data on registration of dock mentācij, are the following: 4.1 essentially similar medicinal products the active substance contains the same medicinal ingredients, allowed by the original product is associated with different salt, as well as the ester derivatives of complex and documentation is evidence that ingredient, pharmacodynamic, pharmacokinetic and toxicity no changes that could change the security as well as performance characteristics. If the changes are, this connection is considered a new active substance;
4.2. the medicinal product is intended for a different therapeutic use or the pharmaceutical form is different, or medicinal products intended for use in other ways and went, or medications are different. In this case, provide the appropriate toxicological and pharmacological tests, as well as the clinical trial results.

V. similar biological medicinal products 5. If using information about the essentially similar medicinal products can prove two biological medicinal products of a similar nature, additional data, in particular toxicological and clinical characteristics.
6. If the registration of an independent applicant after the end of the period of protection shall submit an application for registration laid down in this annex for biological medicinal products, which is a reference to an original medicinal product having the European economic area countries are granted registration: 6.1. information about this rule referred to in annex 1, module 2 and 3 (pharmaceutical, chemical and biological data) is updated with the data of Bioequivalence and bioavailability. Additional data types and volume (toksikol logical and other non-clinical data, as well as the clinical trial data) shall be determined on a case by case basis;
6.2. the diversity of biological medicinal product are satisfied because the State agency requirements for the studies and research provided for (this rule laid down in the said Annex 3 4 and 5 module), taking into consideration each individual medicine special characteristics;
6.3. General principles are met, taking into account the particular biological characteristics of the medicinal products specified in the European Medicines Agency's published guidelines. If the original medicinal product has more than one indication, subject to the application of similarity in the registration or, if necessary, demonstrated separately for each indication, subject to the application for registration.

Vi. The fixed combinations 8. Registration submissions for fixed combinations relate to new medicinal products made of at least two active substances, the combination of which has not been previously registered as drugs with constant composition: 7.1 this information is appropriate for the provisions listed in annex 1., 2., 3., 4. and 5. module;
7.2. If needed, provide information on the place of production and the possible disease agent security assessments.

VII. registration submissions blended 8. Mixed applications of registration: 8.1. This provision in the annex 3 4 and 5 module consists of reports of limited non-clinical and clinical trials carried out by the applicant for registration and of the bibliographic references;
8.2. all other modules comply with these provisions described in annex 3 structure.
Health Minister-Minister of culture h. demakova annex 5 cabinet 9 May 2006 no. 376 of the regulations special requirements for the registration dossier specific medicine i. General issue in this annex 1 specific requirements the following specific registration documentation: 1.1. products of biological origin (from human blood and plasma-derived medicinal products and vaccines)-plasma master file and the vaccine Antigen master file;
1.2. radiopharmaceutical preparations;
1.3. for pharmaceutical precursors (hereinafter referred to as the precursor to);
1.4. homeopathic medicinal products;
1.5. herbal medicines;
1.6. orphan medicinal products.

II. Radiopharmaceuticals 2. Registration dossiers for radiopharmaceuticals, this shall include the following information: 2.1 these rules referred to in annex 3 module 3 (-3. module), in accordance with paragraph 3 of this annex;
2.2. This provision contained in annex 3 module 4 (-4. module) in accordance with point 4 of this annex;
2.3. the provisions referred to in annex 3 Module 5 (-5. module), in accordance with paragraph 5 of this annex.
3. module 3:

3.1. for radiopharmaceutical Kit, which is to be radiolabelled after supply by the manufacturer, the active substance shall be considered as part of the preparation, which is intended to carry or bind the radionuclide. Sets the description of the manufacturing method shall include details of the manufacture of the kit and details of its recommended final processing, in which the radiopharmaceutical. Radionuclide specification description, if necessary, in accordance with the European Pharmacopoeia monograph the General or special. Describe all connections that are important in radiolabelling and radiolabelled compound structure. For a description of the relevant radionuclides in nuclear reaction. Generator for active substances considered as both primary and secondary radionuclides;
3.2. characteristics of radionuclides, the identity of the isotope, likely impurities, the carrier, the use and the specific effects;
3.3. raw materials include irradiation target materials;
3.4. provide observations on the chemical, as well as the radiochemical purity and its relationship to biodistribution.
3.5. Description of the radionuclide purity, radiochemical purity and specific activity;
3.6. radionuclide generators provide information on primary and secondary radionuclide tests. As regards the radionuclide generator eluates provides information about primary and other radionuclides radionuclide generator system component tests;
3.7. the requirement to express the content of active substances with active units of mass to radiopharmaceutical packages. For radionuclides, radioactivity shall be expressed in becquerels at a given date and, if required, indicating the time zone. Specifies the types of radiation;
3.8. as regards the radionuclide kits, the specifications of the finished product shall include tests of efficacy by radioactive tagging. Include the appropriate connection in the radiochemical tests enabling doses radiolabelled and radionuclide purity tests. Identifies and defines all the materials, which are important for the radiolabelling;
3.9. provide information on radionuclide generators, kits and radiolabelled product stability. Document the phials packed radiopharmaceutical dose of more stability during use.
4. the toxicity module link to radiation doses is desirable. Diagnosis it is a radiopharmaceutical use, but it is the preferred therapeutic properties. Radiopharmaceutical evaluation of safety and efficacy of the medicinal product are included and radiation dosimetry aspects. Radiation effects on organs and tissues are indicated in the documents. Absorbed radiation dose estimates shall be calculated according to a specified, internationally recognised system according to the particular use.
5. module, where relevant, the results of clinical trials, based on reports of clinical trials.

III. Precursors 6. documentation for the registration of radioactive tagging precursors for the main purpose is to provide information on potential weak radioactive effects in the markup or in vivo dissociation of the radio-labelled conjugate (for issues related to the exposure, the patient brings free radionuclide). In addition to include relevant information on the arodapdraudējum-radiation exposure to hospital staff and to the environment. If necessary, provide the following information: 6.1.  3. module, in accordance with point 7 of this annex;
6.2.4. module, in accordance with paragraph 8 of this annex;
6.3.5. module, in accordance with paragraph 9 of this annex.
7. follow this module in paragraph 3 of the annex to these conditions.
8. module 4 provides the results of the studies on single-dose and repeated-dose toxicity, conducted in accordance with the laws of good laboratory practice, unless there is no reason to act otherwise. Mutagenicity studies with radionuclide is not considered valid. Provides information about the "cold" nuclide chemical toxicity and disposition.
9. Module 5 takes into account that the precursor to the clinical trial information is not considered to be significant in relation to the specific precursor intended solely for radio-labelling purposes. Provide information that demonstrates the utility of the precursor, if it is not attached to relevant sējmolekul.

IV. Homeopathic Medicine 10.  3. module: 10.1 set to apply to the registration dossier, which shall be in accordance with the simplified registration of homeopathic medicinal products in the procedure, as well as the registration of homeopathic medicinal products;
10.2. terminology: 10.2.1. homeopathic stock described Latin name meets European Pharmacopoeia name used in Latin or, if there is such, the countries of the European economic area is the name used in the official pharmacopoeia;
10.2.2. If necessary, provided in each country of the European economic area (s) used in traditional (s) name (s);
10.3. control of raw materials: 10.3.1. data and documents for raw materials (all materials, including raw materials and intermediates up to the final dilution to be incorporated into the finished medicinal product) is supplemented with data on homeopathic feedstock;
10.3.2. the general quality requirements shall apply to all inputs and raw materials, as well as on the intermediate stages of the manufacturing process up to the final dilution to be included in the finished medicinal product. As determined by the content, if it is made up of toxic components and if the final dilution quality control because of the high dilution factor. A full description of the manufacturing process of the medicinal products from raw materials to the final dilution;
10.3.3. If includes dilution, dilution is carried out in accordance with a homeopathic manufacturing methods laid down in the relevant monograph of the European Pharmacopoeia or, if there is no such,-the European economic area national official pharmacopoeia;
10.4. control tests on the finished product: 10.4.1. General quality requirements are applied to ready-made homeopathic medicinal products. Any exception shall be duly substantiated;
10.4.2 is identified and fixed all the toxicologically relevant constituents. If it can be justified that an important component of all toxicological identification and/or detection is not possible (for example, due to the degree of dilution), the quality is proven in production process of dilution and full validation;
10.5:10.5.1 the stability tests have demonstrated the stability of the finished medicinal product. Stability of homeopathic raw data is usually attributed to the dilutions, as well as to triturācij;

10.5.2. If the active substance identification or quantitative determination is not possible due to the degree of dilution, is entitled to take into account the form of the stability of the medicinal product data.
11.4. module refers to the simplified registration of homeopathic medicinal products with additional specifications. The missing information is justified, for example, justify why the evidence of the level of safety is acceptable, although there is some research.

V. herbal medicine 12. About herbal medicines registration applications shall include a full dossier in which the specified module 3, including compliance with the monograph of the European Pharmacopoeia (s) apply to the registration of herbal medicinal products. Take account of the scientific knowledge that has accumulated up to the date of submission of the registration application.
13. The registration dossier contains the specific herbal medicinal aspects: 13.1 of herbal substances and herbal preparations: 13.1.1. under "terms" herbal substances and preparations in terms of European Pharmacopoeia in terms;
13.1.2. the content of the substances of plant origin indicate the scientific name of the plant according to the binary nomenclature (genus, species, variety and author), and chemotype (where useful), parts of the plants, the definition of the herbal substance, the other names (in the European Pharmacopoeia or in the pharmacopoeia mentioned other synonyms);
13.1.3. the information on herbal preparations indicate the scientific name of the plant according to the binary nomenclature (genus, species, variety and author), and chemotype (where useful), parts of the plants, the definition of the herbal preparation, the ratio of the herbal substance to the herbal preparation, ekstraģent, other names (in the European Pharmacopoeia, or any other such synonyms) and excipients (if necessary);
13.1.4. documenting the herbal substance (s) and herbal preparation (s), specify the physical form, describe the components that the therapeutic effect is unknown, or markers (molecular formula, relative molecular mass, structural formula, including relative and absolute stereoizomēr, molecular formula and relative molecular mass), as well as the other (s) of the component (s);
13.1.5. the section on the manufacturer of the herbal substance shall provide all suppliers (Contracting), as well as the entire production of the herbal substance, the collection and testing of the plant or object names, addresses, and responsibility;
13.1.6. the section on the manufacturer of the herbal preparation shall provide all manufacturer (contractor), as well as all of the herbal preparation for production and testing facilities or involved in object names, addresses, and responsibility;
13.1.7. plant production process and process control description gives full information about the cultivation and harvesting of plants, geographical origin, cultivation, harvesting, drying and storage conditions;
13.1.8. herbal preparations in the manufacturing process and process controls the description provides full information on herbal preparations in the manufacturing process (including the processing, solvents and reagents, purification stages and standardisation of descriptions);
13.1.9. If is an improved production process, provides a synoptic overview of the herbal substance (s) and herbal preparation (s), taking into account the use and intended use. If necessary, compare the herbal substance (s) and herbal preparation (s), the fitoķīmisk (bibliographic data) with the herbal substance (s) and herbal preparation (s) specified as the active substance (s) include the herbal medicinal product applied for registration;
13.1.10. explaining the herbal substance, the structure and other characteristics, if necessary, give the plant a macroscopic and microscopic description of the characteristics of the substance fitoķīmisk and information about the biological activity;
13.1.11. explaining the structure of the herbal preparation, and other nature values, if necessary, provide fitoķīmisk and physico-chemical characteristics and information about the biological activity;
13.1.12. where relevant, the herbal substance (s) and herbal preparation (s) specifications;
13.1.13. If necessary, a description of the herbal substance (s) and herbal preparation (s), analytical procedures;
13.1.14. Add analytical procedure validation, including the herbal substance (s) and herbal preparation (s), testing experimental data;
13.1.15. provides the herbal substance (s) and herbal preparation (s) series and the series results descriptions (also for Pharmacopoeial substances);
13.1.16. where relevant, the herbal substance (s) and herbal preparation (s) specification;
13.1.17. If needed, provide information about the herbal substance (s) and herbal preparation (s) used in the test reference standards or materials;
13.1.18. If a herbal substance or the herbal preparation is developed, the registration application of the monographs, the applicant may request the European Directorate for the quality of medicines issued certificate of conformity;
13.2. provides a synoptic overview of the herbal medicine pharmaceutical form of medicinal products, taking into consideration the proposed route of administration and dose. If necessary, compare the product composition fitoķīmisk (bibliographic data) with herbal medicines for which a registration application.

Vi. Orphan Medicinal products for the treatment of 14 for orphan medicinal products of the European Parliament and of the Council of 16 December 1999, Regulation (EC) No 141/2000 of the meaning of this provision can be applied 90. conditions referred to in paragraph 1. In this case: 14.1. non-clinical and clinical summaries points justifiable reasons why it is not possible to provide a complete information;
14.2. the basic benefits of the medicinal products in question and the risk to understand the drug therapeutic effect of the favourable assessment, taking into account all the risks relating to the quality of the product, safety or effectiveness as regards patients ' health or public health (public health).
15. If a registration application, relating to orphan medicinal products, the conditions include the medicine widely used substance, systematic and documented use of the concerned substance can refer to the use of these substances, of a derogation from the provisions of this annex.
Health Minister-Minister of culture h. demakova annex 6 cabinet may 9 2006, regulations No 376 special requirements for the registration dossier on advanced therapy medicinal products 1. General questions

1. this annex defines the special requirements for the registration of such advanced therapy medicinal products: 1.1. gene (human and xenogeneic) therapy medicinal products;
1.2. a somatic cell (human and xenogeneic) therapy medicinal products;
1.3. ksenotransplantācij medicinal products.
2. in drawing up the dossier of registration apply these rules referred to in annex 1., 2., 3., 4. and 5. module (1., 2., 3., 4. and 5. module).
3. in the case of genetically modified organisms deliberate release into the environment focus on genetically modified organisms to the recipient in sustainability and replication of genetically modified organisms, as well as modifications to those entering the environment. Information about the environmental risk is reflected in the annex to module 1.

2. Specific requirements for gene therapy medicinal products (module) 4. Gene therapy medicinal product contains: 4.1 naked nukleīnskāb;
4.2 the bundled nukleīnskāb or non viral vector vectors;
4.3. viral vectors;
4.4. the genetically modified cells.
5. Distinguish between three key factors: the manufacturing process the raw material – 5.1 materials from which the active substance is manufactured (for example, the gene expression plasmids, cell banks and virus or vectors that are not viral vectors);
5.2. the active substance – the vector of recombinant, virus, naked or complex plasmids, virus producing cells, in vitro genetically modified cells;
5.3. the finished product – the active ingredient in the final primary packaging provides the body for use in medicine. Depending on the gene therapy drug types, usage and conditions may require treatment of the patient's cells ex vivo.
6. Special focus on the following issues: 6.1 provides information about gene therapy medicinal products, the relevant indicators, including the expression of the target cell population, as well as information about the source of the kodējoš gene sequence, structure, characteristics and verification, including its integrity and stability. In addition to the therapeutic gene, the gene was also the full sequence, control elements and the basic design of the vector;
6.2. provides information about vector, used in gene transfer and admission. This information includes the vector of the physical and chemical characteristics or biological and immunological characteristics. Gene transfer medicinal products used for the micro-organisms, such as bacteria or viruses (biological gene transfer), provides data on the output of the strain on its pathogenesis and tropism for specific tissues and cell types of the interaction cycle dependence on cell. Gene transfer medicinal products does not use biological means, indicates some component and a combination of physical and chemical properties;
6.3. cell bank or establishment of the seed lot series principles and characteristics necessary to apply gene therapy medicinal products;
6.4. in the cells of recombinant vector source. Document the human age, sex, microbiological and viral results, exclusion criteria and country of origin. Animal cells contain detailed information: 6.4.1. animal origin;
6.4.2. livestock production and care;
6.4.3. transgenic animals (methods of creation, characterisation of transgenic cells, nature of the inserted gene);
6.4.4. measures origin (donor) of animal infection prevention and supervision;
6.4.5. testing for infectious agents;
6.4.6. equipment;
6.4.7. raw materials and raw material control;
6.5. document the cell collection methods description, location, type of tissue, processing, transport, storage and traceability as well as during the picking process checks;
6.6 indicate viral safety evaluation, product traceability from the donor to the finished medicinal product, for example, by preventing the viruses unable to replicate in the presence of the virus unable to replicate vector banks.

3. The specific requirements for somatic cell therapy medicinal products (module 3) 7. Somatic cell (human and xenogeneic) medicinal therapy include: 7.1 cells manipulated to qualitatively or quantitatively transformed their immunological, metabolic or other functional characteristics;
7.2. cells sorted, selected and manipulated later in the production process to obtain the finished medicinal product;
7.3. cells manipulated and which combine with non-cellular components (for example, biological or inert matrixes or medical devices), and that shows the action of the substance in the finished medicinal product;
7.4. autologous cell derivatives in the form of in vitro specific culture conditions;
7.5. genetically modified or otherwise treated cells to those terms previously unexpressed homologous or non-homologous functional properties.
8. The whole manufacturing process from the collection of the cells (autologous situation) up for repetitive injection to the patient shall be considered as one intervention.
9. Similarly, as regards other medicinal products distinguish between three key factors: the manufacturing process the raw-materials 9.1, the manufacture of the active substance (organs, tissues, body fluids or cells);
9.2. active substance-treated cells, lizāt cells, growing cell cultures and cell to be used in conjunction with inert matrixes or other medical devices;
9.3. the finished product – the active ingredient in the final primary packaging provides the body for use in medicine.
10. a somatic cell therapy medicinal products the active substance consists of cells which after overworking in vitro show a prophylactic, diagnostic or therapeutic properties different from their original physiological or biological one. For the active substances shall contain the following information: 10.1. description the corresponding cell and culture;
10.2. document the tissues, organs or biological fluids, as obtained from the cell, as well as donor allogeneic autologous material, or xenogeneic nature and their geographical origin;
10.3. a detailed description of cell collection, sampling and storage prior further processing;
10.4. in respect of the cells essentially paying particular attention to the first stages of the process, including donor selection;
10.5. indicates the type and the manipulation of the active substances used in the cell physiological function;
10.6. indicates the active substance (s) raw materials, human and animal somatic cells.

3.1. Human somatic cells

11. Human somatic cell therapy medicinal products from a limited number of viable cells (cell Fund) obtained in the production process, starting from the human organs or tissue for a level or a specific cell bank system, where the level of the cell based on the Foundation of continuous cell lines. The active substance of substances, which is understood in human cell culture Fund, but the finished product-a human cell culture Fund, intended use the medicine.
12. Fully documented and all stages of the production process, as well as viral safety aspects: 12.1 human organs, tissues, body fluids and cells. Document: 12.1.1. a person's age, sex, microbiological status, exclusion criteria and country of origin;
12.1.2. sample selection description, location, type, operating process, funds, transportation, storage and traceability as well as selected samples taken;
12.2. cell banking systems. 3. These provisions shall be subject to the relevant requirements of the cell bank system and quality control. It can apply to essentially or xenogeneic cells;
12.3. consumables or medical devices. Provides information about: 12.3.1. all raw materials (such as cytokine, growth factor, feed);
12.3.2. possible ancillary products and medical devices, for example, cell sorting devices, bio-compatible polymers, matrix, fibres, beads and their biological compatibility, functionality, as well as the risk of infectious agents.

3.2. Animal (xenogeneic) somatic cells Of 13 animal somatic cells provide the following detailed information: 13.1. animal origin;
13.2. livestock farming and animal care;
13.3. creating method, transgenic cells, nature of the inserted or cut gene properties, if the cells are derived from genetically modified animals;
13.4. measures, as well as of origin of the donor animal infection prevention and supervision;
13.5. testing for infectious agents, including vertically transmitted micro-organisms, including the endogenous retrovīrus;
13.6 equipment;
8.5. the cell banking system;
13.8. raw materials and raw material control.
14. Specify information: 14.1 of active substance (s) and finished product manufacturing process. The different stages of the production process, for example, organ (tissue) dissociation, the selection of a population of cells in vitro cell culture, cell transformation by physical or chemical agents or gene transfer is documented;
14.2. the active substance. Provide all the information about the identity of the population of cells (the cells of origin, banding cytogenetics, morphological commitment analysis), purity (microbial and cell accidentally contaminants), potency (defined biological activity) and compliance (karyology and tumorigenicity tests) intended use in medicine;
14.3. the pharmaceutical development of the finished product. In addition to the specific methods used (intravenous infusion, local injection, transplantation surgery) also provides information on the possible medical use of accessories (biologically compatible polymers, matrix, fibres, beads) and their biological compatibility and durability;
14.4. for traceability. Provide a detailed scheme that ensures product traceability from the donor to the finished medicinal product.
 4. The specific requirements for gene and somatic cell (human and xenogeneic) medicinal therapy (module 4 and 5) 4.1.  4. Module 15.  4. module takes into account that its requirements for medicines not clinical examination is not always suitable for gene and somatic cell therapy medicinal products, their unique and diverse structures and biological characteristics, including strong specificity of species, subject specificity, immunological barriers and because of the different plejotropisk the answer.
16. Themes that justify a clinical trial, and the criteria used in relation to the species concerned and for the selection of the model describes the module 2.
17. May establish or develop new research models in animals to drug studies, in vivo (on the operation of the human body) help to extrapolate data to target specific functional characteristics and toxicity. Provide the scientific justification for the use of animal models of the disease, to justify the concept of safety and effectiveness.

4.2. Module 5.18. efficacy of advanced therapy medicinal products show as described in module 5. Note that some products and some therapeutic indications may not be able to take conventional clinical trials. Deviations from the existing basic framework based module 2.
19. Whereas the medicine clinical research has some special features (in active substances is complex and labile properties), specify additional observations on cell viability, proliferation, migration, and differentiation (somatic cell therapy), for specific clinical circumstances in which the products are used, or on the gene expression of the specific types of activity (somatic gene therapy).
20. points to the products in the associated risks that can cause infectious agents as possible impurities. Particular emphasis on the early stages of development, including the choice of the donor cell therapy medicinal products, the entire therapeutic intervention in General, proper treatment and medicinal use.
21. include relevant data on the measures taken to monitor and control the living cell function and the development of the recipient, to prevent the transmission of infectious agents to recipients and to minimize the possible risk to public health.
22. On the Pharmacology and efficacy studies with people: 22.1. provide information on the expected mode of action and effectiveness, provided a reasoned basis for the target characteristics, biosadalījum, appropriate dose, timing and usage method, or any desired efficacy trials;
22.2. takes note that the pharmacokinetic studies may not be relevant to some of the advanced therapy medicinal products. If studies with healthy volunteers not possible and define the dose and kinetics in clinical studies is difficult to appear: 22.2.1. studies on the spread of the product and activity in vivo, including cell proliferation and activity of long preparation, as well as the amount of the gene, and the desired duration of gene expression;

22.2.2. that have been taken and, if necessary, develop appropriate tests to trace cell or cells preparations that people gets the desired gene, as well as to monitor or transfected cells used;
22.3. advanced therapy medicinal product efficacy and safety assessment, which includes a description of the procedure and the therapeutic evaluation in General for special applications (e.g., cell transfekcij ex vivo, in vitro manipulation or intervention techniques), as well as the related mode checks (including immunosuppressive, antiviral, cytotoxic treatment);
22.4. the procedure has been tested in clinical trials and is described in the summary of product characteristics.
23. Security: 23.1. included in the considerations arising from: 23.1.1. immune response to medicinal products;
23.1.2. immune response to the protein ekspresēt;
23.1.3. immune rejection;
23.1.4. immunosuppression;
23.1.5. imūnizolācij mechanism for collapsing;
23.2. whereas certain advanced gene therapy medicinal products and somatic cell therapy medicinal products (e.g. xenogeneic cell therapy and certain gene transfer medicinal products) can contain particles that can replicate, and infectious agents, are included in the observations or patient may develop infections, as well as pathological complications pre-registration as well as post-registration phase. If necessary, this monitoring is extended to people who have contact with the patient, as well as to health care workers;
23.3. using certain somatic cell therapy medicinal products and certain gene transfer medicinal products cannot be excluded entirely, potentially transmissible substances of risk that can be reduced to 3. module described the measures concerned;
23.4. in the production process described included measures that complement your testing methods, quality control processes and appropriate monitoring methods;
14.6. is satisfied that some of the somatic cell therapy medicinal product to be temporarily or permanently may be authorized institutions which have only documented expertise and facilities to provide special monitoring of patient safety. A similar approach is possible for certain gene therapy medicinal products, by linking with a potential risk of infectious agents that can replicate;
14.7. long-term monitoring is indicated on the late complications of aspects of development;
14.7. If necessary, has filed detailed risk monitoring plan, including the clinical and laboratory data on the potential of patients, epidemiological data and, where relevant, the data from the donor and recipient tissue sample of archives, which ensures traceability and rapid response to suspicious adverse events.

5. Special messages about drugs 24. ksenotransplantācij With ksenotransplantācij to understand the procedure that involves animals get a live tissue or organ, or with live animal cells, tissues or organs ex vivo contact unprecedented human body fluids, cells, tissues or organs for transplantation, implantation or infusion of the recipient person.
25. Particular attention is drawn to the raw materials. Provides detailed information about: 25.1. animal origin;
25.2. livestock production and care;
25.3. the genetically modified animals-creation methods, transgenic cell characteristics, inserted, or removed the gene;
25.4. the measures of the donor animal of origin of infection prevention and supervision;
25.5. test for infectious agents;
6. equipment;
25.7. raw materials and raw material control;
25.8. traceability.
Health Minister-Minister of culture h. demakova annex 7 cabinet may 9 2006, regulations No 376 registration changes the extension of the registration dossier, for which a registration application shall be submitted by the owner of the registration of extension are as follows: 1. changes relating to the active substance (s) (s): 1.1. active substance (s) by a different salt or ester complex or derivatives thereof (with the same therapeutic ingredients) If the exposure and safety characteristics are not significantly different;
1.2. the replacement of the active substance with another isomer or a different mixture of isomers, of a mixture by an isolated isomer (e.g. racemate, replaced with a single enantiomer) where the efficacy and safety characteristics are not significantly different;
1.3. biological substance or product substitution with biotechnological substances that have a slightly different molecular structure. Modification of the vector used, as well as the raw material of the Antigen in the manufacture (including new exit (main) cell bank from a different source) if exposure and safety characteristics are not significantly different;
1.4. a new ligand or coupling mechanism for a radiopharmaceutical to prep for the town;
1.5. changes of solvent or ekstraģent herbal medicine plant for if exposure and safety characteristics are not significantly different.
2. changes in the strength, pharmaceutical form or route of Administration: 2.1 changes bioavailability;
2.2. changes in pharmacokinetics (e.g., release speed);
2.3. changes or new strength, as well as adding effects;
2.4. changes or the addition of a new pharmaceutical form;
2.5. usage changes or add new types. If the product enters a parenteral route of Administration indicates (for example, intraarteriāl, intravenous, intramuscular, subcutaneous).
Health Minister-Minister of culture h. demakova Annex 8 Cabinet 9 May 2006 regulations No 376 small type I A and I B changes in the national registration of the medicinal product (does not apply to products that are recorded in the mutual recognition procedure and decentralised procedure) small type I A and I B changes are the following: no PO box
The change of name. Conditions to be complied with by type 1.
Changes related to the registration of the licence holder's name or change of address condition: I A registration certificate holder remains the same legal person 2.
Drug name changes (I) (B) condition: the name cannot be confused with the names of existing medicinal products or international non-proprietary name 3.
The name of the active substance changes I A condition: the active substance remains the same 4.
The name of the manufacturer of the active substance and/or address change, if there is no European Pharmacopoeia certificate of conformity condition: production I A place remains the same 5.
Finished product manufacturer's name and/or address change (I) condition: the place of manufacture remains the same 6.
ATC code change (I)

Condition: changes after the World Health Organization's ATC code assignment or amendment 7.
The finished product of the manufacturing site of replacement or new sites into the entire manufacturing process, or part of it: 7.1 the place of secondary packaging all types of pharmaceutical forms conditions: 1, 2 (see below) I (A) 7.2. primary packaging site 7.2.1. solid pharmaceutical forms (such as tablets and capsules) conditions are met: 1., 2., 3., 5.7.2.2. I A soft or liquid (slurry) pharmaceutical form: 1., 2., 3., 5.7.2.3. I B a liquid pharmaceutical form (suspension , emulsion) conditions: 1., 2., 3., 4., 5. I B 7.3. all other manufacturing operations except the serial output: 1., 2., 4., 5. I B conditions: 1. The last three years, the country in question, the competent institution of the European economic area or a country which has with the European Community, the agreement on mutual recognition of good manufacturing practices, has made the inspection, the results of which have been satisfactory.
2. Place the appropriate license (authorization to manufacture a pharmaceutical form or product concerned).
3. The product is not sterile.
4. the new production site there is a validation schema or validation of the manufacture has been successful under the current protocol for at least three production series.
5. The product concerned is not a biological medicinal product.
8. changes to the terms of the output of the series and finished product quality control 8.1. serial testing (testing) of replacement or new terms of engagement: 2, 3, 4 (see below) I A 8.2. manufacturer's responsible for serial output, replace or add 8.2.1. without serial test conditions: 1, 2 I (A) 8.2.2. with serial test conditions: 1., 2., 3., 4. (I) the conditions: 1. the serial output of the responsible manufacturer should be located in a Member State.
2. the assigned production site licence (permit).
3. the product is not a biological medicinal product.
4. Test methods of transfer from the old to the new site or new control laboratory has successfully completed.
9. the deletion of any manufacturing site (including for an active substance, intermediate or finished product, packaging site, manufacturer responsible for the series of output, production sites, where the series check) I A condition not 10.
Small changes in the manufacturing process of the active substance in annex I B conditions: 1. No change in qualitative or quantitative impurity composition or in physical and chemical properties.
2. The active substance is not a biological substance.
3. the synthesis path is the same, this means the intermediate products are the same. If the product is herbal, not changing geographical origin, substances of plant origin and manufacturing process 11.
Changes to the active substance or intermediate series volume increasing to 11.1 10 times compared to the original series volume confirmed by giving the registration conditions: 1, 2, 3, 4 (see below) I A reduction conditions 11.2:1., 2., 3., 4., 5. I A 11.3 increase more than 10 times compared to the original series volume confirmed by giving the registration conditions: 1., 2., 3., 4., the conditions I B : 1. changes of the production steps are only necessary if the increase (such as different sizes, the use of equipment).
2. The preferred series volume must be available at least two series of results which match your specifications.
3. the active substance is not a biological substance.
4. The changes do not affect process repeatability.
5. changes have led to unexpected events during production or the reason is stability.
12. changes to the specifications of the active substance or active substances used in the production of the raw material/intermediate/reagent specification 12.1. more stringent restrictions on the specification conditions: 1, 2, 3 (see below) (I) (A): (I) (B) 2., 3.12.2. Add a new test parameter to the specification of such substances 12.2.1. active substance: 2., 4., 5. I B/intermediate 12.2.2. raw material/reagent used in the manufacturing process of the active substance of conditions: 2. 4.
(I) (B) the conditions: 1. No changes have occurred, what other resulting from previous assessments to review specification of obligations, restrictions (for example, they do not make the registration procedure or type II variation procedure).
2. changes have led to unexpected events during production.
3. Any changes to comply with the approved limits.
4. new test method does not apply to the new non-standard technique or a standard technique used in a novel way.
5. the active substance is not a biological substance.
13. changes to the active substance or method of active substances used in the production of the raw material, intermediate, or reagent test methods 13.1. minor changes to the approved test method: 1., 2., 3., 5. (see below) I A 13.2. other changes in the method of testing, including the test methods, the introduction of replacement or new conditions: 2., 3., 4., 5. I B conditions: 1. The method of analysis should remain the same (for example, the column length or temperature changes but not the other column or method). No new impurities are established.
2. In accordance with the relevant guidelines is made in accordance with the (re) validation studies.
3. the results of the validation method to prove that a new inspection method is at least equivalent to the previous one.
4. new test methods do not apply to the new non-standard technique or a standard technique used in a novel way.
5. The active substance, starting material, intermediate or reagent is not a biological substance.
14. the changes associated with the manufacturer of the active substance or active substances used in the production process of the raw material/reagent/intermediate manufacturer, if there is no European Pharmacopoeia certificate of conformity 14.1. changes associated with the location of the manufacturer (replacement or new sites included) conditions: 1, 2, 4 (see below) (I) (B) 14.2. new manufacturer (replacement or a new manufacturer's inclusion): 1., 2., 3., 4., the conditions I B : 1. Specification (also in-process inspections, all material analysis method), the method of production (also in the volume of the series) and a detailed synthesis is identical to already approved.

2. If the process is used on a human or animal material, the producer did not cooperate with new suppliers, which must be checked for safety or conformity with the virus, the European Commission's guidance on how to reduce the risk of carry agents of animal spongiform encephalopathies with medicinal products for human or veterinary medicinal products (the last version).
3. the current or the new active substance manufacturer does not use of the active substance master file.
4. the change does not apply to products containing biological active substance.
15. a new or updated European Pharmacopoeia certificate of compliance of the submission of the active substance or starting material, intermediate, or reagent used in the manufacturing process of the active substance in 15.1. from the currently approved manufacturer conditions: 1, 2, 4 (see below) I A new producer 15.2 (replacement or the inclusion of new producer) 15.2.1. sterile substance: 1., 2., 3., 4.15.2.2. I B other substances: 1., 2. , 3., 4.
(I) the conditions: 1. the quality of the finished product specifications, the finished product release and shelf life specifications have not changed.
2. Unchanged additional specification (in addition to the European Pharmacopoeia) impurities and product specific requirements (e.g. particle size, polymorphic form).
3. If the European Pharmacopoeia, a certificate of conformity do not include repetitive tests or is not being provided data supporting the retest period, active substance tested immediately before use.
4. active substances, raw materials, reagents, intermediates in the production process is not used for human or animal material, which must verify the data on viral safety.
16. a new or updated TSE European Pharmacopoeia certificate of conformity to the approved manufacturer and the submission of approved manufacturing process of the active substance or starting material, intermediate, or reagent used in the manufacturing process of the active substance in the substance of conditions 16.1 not.
(I) 17.
Change: 17.1. active substances within the repeating check conditions: 1, 2, 3 (see below) (I) (B) 17.2. active substances storage rules: 1., 2. I B conditions: 1. Stability studies conducted in accordance with the approved Protocol. Study to prove that certain are still met the relevant specifications.
2. changes have led to unexpected events during production or the reason is stability.
3. the active substance is not a biological substance.
18. replacement of an excipient with a comparable excipient.
I B conditions: 1. the Adjuvant has the same functional characteristics.
2. the dissolution profile of the new product determined by at least two experimental series, is comparable to the previous (no significant differences in comparability, see. "Guidelines for bioavailability and bioequivalence" (annex II); where appropriate, these guidelines on medicinal products for human use, these principles should also be taken into account in respect of veterinary medicinal products). If herbal medicines solubility tests cannot be done, the new product of the decay time is comparable to the previous.
3. the new adjuvants are not used in human or animal material, which must verify the data on viral safety.
4. Does not apply to products containing biological active substance.
5. at least two pilot or industrial series in accordance with the relevant guidelines of the stability studies are initiated, and the applicant has at least three months in the satisfactory stability data, as well as proof that these studies will be completed. The data (including the proposed action) shall immediately be submitted to the competent authorities, if they are approved at the end of the storage period do not or may not meet the specifications.
19. change in specification of Excipients 19.1. tighter restrictions on the specification conditions: 1, 2, 3 (see below) (I) (A): 2., 3. I B a new test parameter 19.2. adding the specification conditions: 2., 4., 5. I B conditions: 1. No changes have occurred, one of the other previous assessments resulting obligations (for example, they do not make the registration procedure or type II variation procedure).
2. changes have led to unexpected events during production.
3. Any changes to comply with the approved limits.
4. New test method does not apply to the new non-standard technique or a standard technique used in a novel way.
5. the change does not concern adjuvant for vaccines or biological excipient.
20. Change in the method of testing the excipients 20.1. minor changes to an approved testing method: 1., 2., 3., 5. (see below) I A 20.2. minor changes to an approved excipient biological testing method: 1., 2., 3. I B 20.3. other changes in the method of testing, including test methods approved the substitution of the new test method: 2., 3., 4., 5. I B conditions: 1. The method of analysis should remain the same (for example , the column length or temperature changes, but not the other column or method). No new impurities are established.
2. In accordance with the relevant guidelines is made in accordance with the (re) validation studies.
3. the results of the validation method to prove that a new inspection method is at least equal to the previous method.
4. New test method does not apply to the new non-standard technique or a standard technique used in a novel way.
5. the substance is not a biological excipient.
21. a new or updated European Pharmacopoeia certificate of compliance submission for adjuvant 21.1. from the currently approved manufacturer conditions: 1, 2, 3 (see below) I A 21.2. from new manufacturer (replacement or the inclusion of new producer) sterile substance 21.2.1. Conditions: 1, 2, 3 (I) (B) other substances 21.2.2. Conditions: 1, 2, 3. (I) the conditions: 1. the quality of the finished product specifications, the finished product release and shelf life specifications have not changed.
2. Unchanged additional specification (in addition to the European Pharmacopoeia) for product specific requirements (e.g. particle size, polymorphic form).
3. Aids in the production process is not used for human or animal material, which must verify the data on viral safety.
22. a new or updated TSE European Pharmacopoeia certificate of conformity for the submission from the currently approved adjuvants 22.1. manufacturer or a new manufacturer (replacement or new involvement) conditions (I) 23.

Changes associated with adjuvant reagent or origin: any product that may pose a risk of TSEs, substitution with vegetable or synthetic material 23.1. adjuvant or reagent used in the production of biologically active substances or complete product that contains biologically active substances: (see below) (B) (I) 23.2. other necessary conditions: (see below) I A condition: AIDS and the quality of the finished product specifications, release of finished products and storage specifications do not change 24.
Change in synthesis or non-Pharmacopoeial excipients recovery (when described in the dossier) I B conditions: 1. the specifications are not adversely affected, there is no impurities or change in qualitative or quantitative in physical and chemical properties.
2. Aids is a biological substance.
25. changes to be made to comply with European Pharmacopoeia or national pharmacopoeia of a Member State to 25.1. changes to previously not included in the European Pharmacopoeia specifications of the substance (s) to be made in order to comply with European Pharmacopoeia or national pharmacopoeia of a Member State for the active substance 25.1.1. Conditions: 1, 2 (see below) (B) (I) 25.1.2. adjuvant conditions: 1, 2 (I) (B) 25.2. changes to be made to comply with European Pharmacopoeia or national pharmacopoeia of a Member State to the relevant updated monograph 25.2.1. Conditions for the active substance : 1., 2. I A 25.2.2. adjuvant conditions: 1, 2 (A) (I) the conditions: 1. the changes made only to comply with the pharmacopoeia.
2. Unchanged specifications (additional to the pharmacopoeia) for product specific properties (such as particle size, polymorphic form).
26. changes to primary packaging of finished product specifications more stringent specifications 26.1. restrictions on the conditions: 1, 2, 3 (see below) (I) (A): (I) (B) 2., 3.26.2. adding a new parameter to the test conditions: 2., 4. I B conditions: 1. No changes have occurred, what other resulting from previous assessments to review specification of obligations-restrictions (for example, they do not make the registration procedure or type II variation procedure).
2. changes have led to unexpected events during production.
3. Any changes to comply with the approved limits.
4. Any new test method does not apply to the new non-standard technique or a standard technique used in a novel way.
27. changes, related to the finished product on the primary container inspection method 27.1. minor changes to the approved method of testing conditions: 1, 2, 3 (see below) I A 27.2. other changes in the method of testing, including the test methods, the introduction of replacement or new conditions: 2, 3, 4 (I) (B) the conditions: 1. The method of analysis should remain the same (for example, the column length or temperature, but not a different type of column or method).
2. In accordance with the relevant guidelines made in accordance with the (re) validation studies.
3. Method validation results must demonstrate that the test method is at least equal to the previous method.
4. Any new test method does not apply to new non-standard technique or a standard technique used in a novel way.
28. changes associated with any of the (primary) packaging material not part of the face of the finished products (such as removable cover, color, colour code rings on ampoules, change of needle shield (different plastic used)).
(I) condition: the changes do not affect the packaging material of the core components that affect the delivery of the finished product, use, safety or stability of the 29.
Changes associated with high-quality primary packaging and/or quantitative composition 29.1. soft (slurry) and liquid dosage forms conditions: 1, 2, 3, 4 (see below) (B) (I) 29.2. all other dosage forms conditions: 1., 2., 3., 4. (I) the conditions: 1., 3., 4. I B conditions: 1. The product concerned is not biological or sterile product.
2. The changes apply only to the same type of packaging and materials (for example, strips of tablets (blister) replaced pills Tablet).
3. Proposed packaging material properties must be at least equivalent to the approved material.
4. at least two pilot or industrial series in accordance with the relevant guidelines have been started in the stability studies, and the applicant has at least three months stability data are acquired. It is confirmed that these studies will be completed and the data (including the proposed action) immediately submitted to competent authorities, if they are approved at the end of the storage period do not or may not meet the specifications.
30. the changes associated with the packaging component or device supplier (replace, a new supplier involvement or exclusion) (if mentioned in the documentation), except for metered dose inhaler spacer dose 30.1. the deletion of the condition of the supplier: 1. (see below) I A 30.2. supplier's replacement or new supplier involvement: 1., 2., 3., 4. I B conditions: 1. The packaging component or device is not removed.
2. packaging component or device qualitative and quantitative composition is not changed.
3. Specifications and test method of quality at least equivalent.
4. Sterilization method and conditions do not change (if applicable).
31. changes in the tests carried out in the course of manufacture, or limits applied during manufacture 31.1. tighter restrictions on production conditions: 1, 2, 3 (see below) I A 31.2. new tests and limits the inclusion of conditions: 2, 3 (I) (B): (I) (B) 2, 4. Conditions: 1. No changes have occurred, one of the other previous assessments resulting obligations (for example, they do not make the registration procedure or type II variation procedure).
2. changes have led to unexpected events during production or the reason is stability.
3. Any changes to comply with the approved limits.
4. new test methods do not apply to the new non-standard technique or a standard technique used in a novel way.
32. The finished product serial changes of volume 32.1. increase of up to 10 times in comparison with the original series volume confirmed by giving the registration conditions: 1., 2., 3., 4., 5. (see below) I (A)

32.2. the reduction of up to 10 times: 1., 2., 3., 4., 5., 6. I A 32.3. other cases: 1., 2., 3., 4., 5., 6., 7. I B conditions: 1. The changes do not affect repeatability of the product and/or uniformity.
2. The changes apply only to forms of medicinal products with a quick disposal of the active substance for oral use and non-sterile liquid forms.
3. production methods, as well as in-process inspections are only required because of changes in the volume of the series (for example, different size equipment).
4. There is a validation schema or validation of the manufacture been satisfactory under the existing protocol for at least three series that in accordance with the relevant guidelines meet the new proposed series.
5. Does not apply to products containing biological active substance.
6. changes have led to unexpected events during production or the reason is stability.
7. At least one experimental or industrial series in accordance with the relevant guidelines of the stability studies are initiated, and the applicant has at least three months stability data are acquired. It is confirmed that these studies will be completed and the data (including the proposed action) immediately submitted to competent authorities, if they are approved at the end of the storage period do not or may not meet the specifications.
33. Small changes in the production of the finished product (I) (B): 1. overall production principles do not change.
2. the new process produces identical product and quality, both in terms of efficiency and safety.
3. Medicinal products do not contain biologically active substances.
4. If the changes associated with sterilization process, they relate only to a standard Pharmacopoeial cycle.
5. At least one experimental or industrial series in accordance with the relevant guidelines have accordingly initiated a study of stability, and the applicant has at least three months stability data are acquired. It is confirmed that these studies will be completed and the data (including the proposed action) immediately submitted to competent authorities, if they are approved at the end of the storage period do not or may not meet the specifications.
34. changes in the system or the flavouring colouring system, currently used in the finished product 34.1. one or more components in the reduction or cancellation of the colouring system Conditions 34.1.1.: 1., 2., 3., 4., 7 (see below) (I) (A). the system of flavouring 34.1.2 conditions: 1., 2., 3., 4., 7 (I) 21.3. for one or more of the components increases, add or replace a 34.2.1. colouring system conditions: 1., 2., 3., 4. , 5., 6., 7.
34.2.2. flavouring system I B conditions: 1., 2., 3., 4., 5., 6., 7. I B conditions: 1. No change in pharmaceutical form functional characteristics (such as disintegration time, dissolution profile).
2. all the small composition adjustment made to maintain the total weight should be made by an excipient which currently make up most of the composition of the finished product.
3. The finished product specification has only updated for the look, smell, taste, and the case-to the exclusion of the identification test or inclusion.

4. at least two pilot or industrial series in accordance with the relevant guidelines of the stability studies are initiated (long-term and accelerated), and the applicant has at least three months in the satisfactory stability data, as well as proof that these studies will be completed. Data (with proposed action) shall immediately be submitted to the competent authorities, if they are approved at the end of the storage period do not or may not meet the specifications. In addition, where appropriate, be carried out testing of fotostabilitāt.
5. All new components must comply with the provisions of annex 1 of the "colours, which are allowed to add products".
6. new components do not contain human or animal material, which must verify the data on the safety or compliance with the virus instructions about how to reduce the risk of carry agents of animal spongiform encephalopathies with medicinal products for human or veterinary medicinal products (the last version).
35. Tablet or capsule shell weight of shell weight change of 21.8. pharmaceutical form with a quick disposal of the active substance for oral use: 1, 3, 4 (see below) I A 21.9. gut soluble, modified or prolonged operating pharmaceutical form: 1., 2., 3., 4. I B conditions: 1. the dissolution profile of the new product determined at least two experimental series, is comparable to the previous. If herbal medicines solubility tests cannot be done, the new product of the decay time is comparable to the previous.
2. the coat is not a mechanism of action, the deciding factor.
3. The finished product specification has only renewed for weight and size.
4. at least two pilot or industrial series in accordance with the relevant guidelines of the stability studies are initiated, and the applicant has at least three months in the satisfactory stability data, as well as proof that these studies will be completed. The data (including the proposed action) shall immediately be submitted to the competent authorities, if they are approved at the end of the storage period do not or may not meet the specifications.
36. the closure of the packaging or shape or size changes 36.1. pharmaceutical form sterile and biological medicinal products conditions: 1, 2, 3 (see below) (I) (B) 36.2. other forms of medicinal conditions: 1, 2, 3. (I) the conditions: 1. the quality of the packaging or quantitative composition is not changed.
2. the change does not affect the basic components of the packaging material, which affects the delivery of the finished product, use, safety or stability.
3. If the changes are related to gas volume or surface area and volume, at least two (for biological medicinal products – three) or industrial experimental series in accordance with the relevant guidelines of the stability studies have been launched, and the applicant has at least three months (for biological medicinal products – six months) in the data on stability. It is confirmed that these studies will be completed and the data (with proposed action) immediately submitted to competent authorities, if they are approved at the end of the storage period do not or may not meet the specifications.
37. the changes in the finished product specifications more stringent specifications in 37.1. restrictions

Conditions: 1, 2, 3 (see below).
(I) the conditions: 2, 3 (I) (B) 37.2. a new inspection methods add parameter conditions: 2., 4., 5. I B conditions: 1. No changes have occurred, one of the other previous assessments to review specification of obligations resulting restrictions (for example, they do not make the registration procedure or type II variation procedure).
2. changes have led to unexpected events during production.
3. Any changes to comply with the approved limits.
4. Any new test method does not apply to new non-standard technique or a standard technique used in a novel way.
5. Test method does not apply to biological active substance or biological excipient in medicinal products.
38. the changes associated with the finished product testing method 38.1. minor changes to the approved test method: 1., 2., 3., 4., 5. (see below) I A 38.2. minor changes to an approved biological active substance or biological excipient verification method: 1., 2., 3., 4. (I) (B) 38.3. other changes in the method of testing, including the test methods, or the introduction of new replacement conditions: 2., 3., 4., 5., the conditions I B : 1. The method of analysis should remain the same (for example, the column length or temperature, but not a different column or method).
2. In accordance with the relevant guidelines is made in accordance with the (re) validation studies.
3. the results of the validation method to prove that the new test procedure is at least equivalent to the previous method.
4. Any new test method does not apply to new non-standard technique or a standard technique used in a novel way.
5. Test method does not apply to biological active substance or biological excipient in medicinal products.
39. changes associated with dents, terrain or other markings or such changes (except Division line) on tablets or banners on capsules, including for product marking dyes or adding (I) the replacement of the conditions: 1. the quality of the finished product specifications, the finished product release and shelf life specifications have not been changed (except for appearance).
2. All new colouring matters must comply with the relevant laws and regulations.
40. the changes associated with the tablets, capsules, rectal or pesārij, do not change the qualitative and quantitative composition and total mass of 24.9. gut soluble, modified or prolonged operating pharmaceutical form and multiple tablets conditions: 1, 2 (see below).
(I) (B) 40.2. all other pills, capsules, rectal and pesārij conditions: 1, 2 (A) (I) the conditions: 1. the dissolution profile of the modified product is comparable to the previous. If herbal medicines solubility tests cannot be done, the new product of the decay time is comparable to the previous.
2. specifications for the quality of medicines, the finished product release and shelf life specifications have not been changed (except for dimensions).
41. packaging the finished product size changes 25.5. changes associated with the number of units (e.g. tablets, ampoules) per package 41.1.1. changes associated with approved packing size: 1, 2 (see below) I A 41.1.2. changes associated with non-approved packaging size conditions: 1, 2 (B) (I). daudzdev of parenteral not 41.2 product filling weight and volume changes of conditions: 1, 2 (I) (B) the conditions for the : 1. the new pack size should meet the drug dosage and duration of treatment approved summary of product characteristics.
2. Primary packaging material remains the same.
42. changes: 42.1. the finished product storage time 42.1.1. packaged for sale conditions: 1, 2, 3 (see below) (I) (B) after the first opening 42.1.2. Conditions: 1., 2. I B 42.1.3. after dilution or reconstitution conditions: 1, 2 (I) (B) 42.2. the finished product or the diluted/dissolved product storage conditions conditions: 1., 2., 4. I B conditions: 1. Stability studies conducted in accordance with the approved Protocol. Study to prove that certain are still met the relevant specifications.
2. changes have led to unexpected events during production or the reason is stability.
3. Storage period shall not exceed five years.
4. the product is not a biological medicinal product.
43. The measuring device or administration device that is not directly an integral part, add, replace, or off (except for metered dose inhaler spacer dose) 43.1. medicinal products for human use 43.1.1. Add or replace conditions: 1, 2 (see below) I A 43.1.2. exclusion condition: 3. I B conditions: 1. the proposed measuring device must accurately measured the required dose of the product concerned in accordance with the approved dosage of the medicinal product, and the results of such studies should be available.
2. The new device is compatible with the medicinal product.
3. Medications can still take precise measurements.
The notes.
1. Conditions for specific changes in order to meet A type I or type IB procedure specified for each subcategory and listed after each change.
2. For all other changes must be submitted to the approval of the change of any consequential or parallel changes which may be associated with the changes, for which the request for approval of the change, stating clearly the relation between these changes.
3. As regards communications with the European Pharmacopoeia, a certificate of conformity and, if the changes apply to the documentation submitted, the certificate of these changes required documents should be presented to the European Directorate for the quality of medicines (EDQM). If, after the assessment certificate is processed, to restore all of the relevant certificate of registration (the registration dossier). In many cases this can be done by giving the type IA variations.
4. biological medicinal product is a product, in which the active substance is a biological substance. Organic substances produced by or extracted from a biological source, and its description and quality must take physical, chemical and biological tests, as well as to control the production process. For biological medicinal products consider immunological preparations and from human blood and plasma derived products.

5. changes in the protein-component production process stage due to implementation of biotechnology can be done in accordance with the type I variation 15 or 20. This particular change does not affect other changes listed in this annex, which can be applied to the specific case. This does not apply to biotechnological process for the introduction of a proteinaceous component protein drug consisting of centralized registration of subjects with respect to medicinal products covered by the European Commission of 3 June 2003, Regulation (EC) No 1085/2003 concerning the examination of variations of a marketing authorisation for medicinal products for human use and veterinary medicinal products covered by the conditions of the regulation laying down a Community procedure for how to confirm and monitor the medications that are intended for use in human and veterinary medicine and establishing a European Medicines Agency.
6. the State Agency of medicines need not be notified of the updated European Pharmacopoeia or in the pharmacopoeia of a Member State, if compliance with the updated monograph is implemented within six months after publication of an authorised medicinal product and documentation is a reference to the current version.
7. In this annex, the test procedure the same meaning as analytical procedure and restrictions means the same thing as acceptance criteria.
Health Minister-Minister of culture h. demakova