Amendments To The Cabinet Of Ministers On 31 October 2000 By Regulation No 381 "rules Of Registration Of Medicinal Products"

Original Language Title: Grozījumi Ministru kabineta 2000.gada 31.oktobra noteikumos Nr.381 "Zāļu reģistrēšanas noteikumi"

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Read the untranslated law here: https://www.vestnesis.lv/ta/id/87998

Clarifies 03.06.2004., Journal No. 89 (3037) Cabinet of Ministers Regulations No. 418 in 2004 (April 22. No 24, 55), amendments to the Cabinet of 31 October 2000 of Regulation No 381 "rules of registration of medicinal products" Issued in accordance with article 5 of the law of Pharmacy (3) to make a Cabinet of 31 October 2000 of Regulation No 381 "rules of registration of medicinal products" (Latvian journal, 2000, 2003,/393.nr.; 391.116. no) the following amendments: 1. To make paragraph 1 by the following: "1. the provisions laid down in the industrially produced medicinal product (with the exception of veterinary medicinal products and veterinārfarmaceitisko products) registration procedures."
2. To supplement the provisions under point 1.1 as follows: "1.1 the provisions do not apply to: 1.1 1. any medicinal product which is prepared in accordance with the recipe (any medicinal prescription issued by a professional person qualified to do so permits) to a particular patient (the magistral formula);
1.1 2. any medicinal product which is prepared in the pharmacy, meets Pharmacopoeial monograph and intended for distribution to patients served by the pharmacy in question (the officinal formula);
1.1 3. medicinal products intended for research, as well as to the study of the product development process;
4. intermediate products by 1.1 licensed manufacturer of medicinal products intended for further processing;
1.1 5. radionuclides (radioactive isotopes) in the form of sealed sources.
1.1 6. blood, human blood plasma and blood cells. "
3. Add to paragraph 2 to 2.3 and 2.4. subparagraph by the following: "2.3. including this provision referred to in paragraph 18.16. generators and 22.8. referred to radiopharmaceutical products, radiopharmaceutical kits (kits) and other radionuclides;
2.4. including mineral waters, if they meet the definition of a medicinal product and the national medicines agency accepted by them. "
4. Replace the words "in paragraph 3.1., oral (through the mouth)" with the word "oral".
5. Make paragraph 8 by the following: "8. the national medicines agency medicine registration procedure completed 210 days, taking into account the provisions of paragraph 136. If the registration request is that the medications are recorded in the mutual recognition procedure and medicines registration request for the same medicinal product appearance by another Member State of the European Union or European Free Trade Association (EFTA), which is a signatory to the agreement on the European economic area, the competent authority (hereinafter referred to as Member States), and the applicant for registration (the applicant for holding of the registration certificate) shall inform the State Agency of medicines of the reference Member State (in the registration of medicinal products, mutual recognition procedure means the Member State which medications are recorded initially), the State Agency of medicines shall decide on the registration request the suspension of the proceedings until the day of the receipt of the reference Member State (which has declared the registration applicant) approved pharmaceutical analytical, farmakotoksikoloģisk and clinical outcome evaluation report (evaluation report), and of the decision taken shall inform the reference Member State and the applicant. "
6. To supplement the provisions under point 8.1 as follows: "Where courtroom public 8.1 medicines agency is in the process of registration and the applicant for registration of the reference Member State has specified Latvia, but the national medicines agency has received information from other Member States that it has decided to suspend the registration of the medicinal product concerned the details of the request, to wait for the national medicines agency approved the assessment report, the national medicines agency submitted for registration after verification of the particulars and documents and a decision on registration has been sent a copy of the assessment report to the Member State concerned."
7. Make paragraph 9 by the following: "9. Where, in accordance with the provisions of this paragraph 18.11. The National Medicines Agency informed that the medicinal product which is the subject of the registration application, is registered in the Member States, and request that the request is for mutual recognition of registration procedures, national medicines agency: 9.1 of the processing of the application for registration be suspended and sent to the reference Member State to send its request approved assessment report;
9.2. within 90 days after the receipt of the assessment report of the reference Member State shall acknowledge the registration and the summary of product characteristics that it has approved and registered with the medicine or, if it considers that the registration of the medicinal product concerned (allow) the risks to public health, these rules shall apply the procedures referred to in section I1. "
8. To supplement the provisions of this chapter with the I1: ' I1. Mutual recognition of registration of medicinal products 12.1 registration certificate (marketing authorisation) owner (hereinafter referred to as the owner of a registration): 12.1 1. before submitting a request to the Member State concerned shall inform the competent authority of the reference Member State (Latvia, national medicines agency) that the request to submit for registration to another Member State for recognition and notify any additions in the registration dossier;
12.1 2. asked by the reference Member State, the competent institution to prepare or, if necessary, restore the assessment report on the medicinal product, which is intended to launch a mutual recognition procedure of registration;
3. According to this provision the 12.1 point 15 requirements submitted to the competent institution of the Member State of registration of the request for mutual recognition, adding these provisions in certain data and documentation, and certify that: 12.1 3.1 registration documentation is identical to the reference Member State shall submit to the competent institution information, or indicate any amendments made in it;
12.1 3.2. in accordance with the provisions of paragraph 36 of the requirements set out in the summary of product characteristics is identical to the reference Member State the approved summary of product characteristics;
12.1 3.3. all documentation that is submitted to the Member States as part of the procedure is identical;
12.1 4. notify to the European Agency for the evaluation of medicinal products set up by Council of 22 July 1993, Regulation (EEC) No 2309/93 laying down the procedure for the European Community, to confirm and monitor the medications that are intended for use in humans and in veterinary medicine, and establishing a European Agency for the evaluation of medicinal products (hereinafter referred to as the Council Regulation No 2309/93) (hereinafter referred to as the European Agency for the evaluation of medicinal products), for the Member States concerned and of the dates of submission of the and send it to the other Member States a copy of the certificate of registration and indicate whether the request is currently being examined by another Member State;
12.1 5. is entitled to submit the matter for consideration by the European Agency for the evaluation of medicinal products medicinal products (English: the Committee for Proprietary Medicinal products) (hereinafter medicinal products), to start the registration procedure for the examination of the question: where is 5.1 12.1 submitted in several Member States and the Member States have adopted divergent decisions concerning the registration of the medicinal product, the suspension of the registration (the registration of the medicinal product certificate suspension) or cancellation of the registration. Medicine shall submit to the Committee all the relevant questions of the information available and the subject is clearly identified. Registration, the owner has the right to respond in writing or orally;
12.1 if you have affected 5.2. European Community's interests before the Member State has taken a decision on the registration or registration suspension, or cancellation of the registration, or other changes to the terms of the registration certificate (changes in the registration dossier), particularly in the light of information obtained by monitoring pharmacovigilance side effects (adverse reactions). Medicine shall submit to the Committee all the relevant questions of the information available and the subject is clearly identified;
6. following these rules 12.1, 12.3 2. referred to information submitted to the Committee for medicinal products for data, documents and information that has been submitted to the Member State in accordance with this rule 12.1.3.
12.1 7. is entitled to 15 days of the European Agency for the evaluation of medicinal products for an opinion in writing to the European Agency for the evaluation of medicinal products of their intention to challenge the European Agency for the evaluation of medicinal products (the appeal) and 60 days from the date of receipt of the opinion of the European Medicines Evaluation Agency detailed justification of the appeal;
12.1 8. a request for a change in the certificate of registration (the registration dossier) shall submit to the Member States concerned in which the medicinal product is authorised, and appearance changes according to the European Commission of 3 June 2003, Regulation (EC) no 1084/2003 concerning the examination of variations, the competent authorities of the Member State of the issuing of a marketing authorisation for medicinal products for human use and veterinary medicinal products conditions (hereinafter referred to as Commission Regulation (EC) no 1084/2003).
12.2 If the reference Member State Latvia, national medicines agency: 12.2 1. is entitled to request the owner of the registration after this rule 12.1 1. receiving referred to submit data and documents to verify whether the registration dossier is identical to the national medicines agency information submitted;

12.2 2. preparing evaluation reports or renew within 90 days of this rule 12.1 2. referred to in the request and shall forward the assessment report to the Member State concerned after a request has been submitted, as well as cooperate with the Member States concerned to reach agreement on the requests submitted.
12.3 the national medicines agency: 12.3 1. acknowledges the reference medicinal product issued by a Member State of a certificate of registration within 90 days of the request and the assessment report, if there is no reason to believe that the registration of the medicinal product concerned may present a risk to public health. The decision taken shall inform the reference Member State, the Member States concerned, a European Agency for the evaluation of medicinal products and the owner of the registration (the applicant);
12.3 2. where there is reason to believe that the registration of the medicinal product concerned may present a risk to public health, shall inform the reference Member State, the Member States concerned, a European Agency for the evaluation of medicinal products and the owner (applicant), detailing the reasons for the decision and identify remedial actions required. The State Agency of medicines shall cooperate with the Member States concerned to reach agreement on the action, and enables the applicant to comment in writing or orally;
12.3 3. is entitled to submit a matter to the Committee for medicinal products so as to initiate the examination procedure questions: 12.3 3.1. If not agreed that rule 12.3 1. the time limit referred to in subparagraph 2 of this provision contained in subparagraph 12.3. question. Pharmaceutical Committee and the applicant shall provide a detailed description of the matters on which agreement has been reached, and indicate the reasons for the disagreement;
12.3. If the request is submitted to 3.2 in several Member States and they have adopted divergent decisions on the registration, registration suspension and cancellation of the registration. Use the submit a question clearly define and inform the owner of the registration. Medicine shall submit to the Committee all the relevant questions of the information available;
12.3 3.3. If the European Community is affected interests before the Member State has taken a decision on the registration or registration suspension, or cancellation of the registration, or other changes to the terms of the registration certificate (changes in the registration dossier), particularly in the light of information obtained by monitoring pharmacovigilance side effects (adverse reactions). Medicine shall submit to the Committee all the relevant questions of the information available and the subject is clearly identified;
12.3 4.28 days after the receipt of the draft decision prepared by the European Commission on the registration request in connection with the European Agency for the evaluation of medicinal products, may submit in writing the Standing Committee (in English: the Standing Committee) observations on the draft decision and request its discussion in the Standing Committee with a detailed statement of reasons;
12.3 5. within 30 days after a final European Commission decision pursuant to decision medicine registered or a registration is cancelled, or make changes in the conditions of certificate of registration (the registration dossier) and shall inform the European Commission and the European Agency for the evaluation of medicinal products;
12.3 6. submit the matter to the European Agency for the evaluation of medicinal products, if it finds that the registration certificate changes (changes in the registration dossier) or suspension of registration or cancellation of the registration is necessary for the protection of public health;
12.3 7. exceptionally, in the case where the protection of public health is essential for urgent action, without prejudice to the provisions of subparagraph 12.3 3.3 conditions may take a decision on the suspension of the registration certificate within its territory (to prevent the distribution and use of medicinal products) before a final decision is taken. The decision taken by the Member States shall inform the European Commission and the other Member States no later than the next working day after the decision.
12.4 the requirements laid down in this chapter do not apply to homeopathic medicinal products which are subject to special rules for the toxicological and pharmacological tests and clinical research in accordance with the principles and characteristics of homeopathy according this rule 29.1.. "
9. Express 13, 14 and 15 of the following paragraph: "registration and re-registration 13 the applicant: 13.1 provides registration and renewal information and necessary for the preparation and submission of data in accordance with the requirements laid down in these provisions;
13.2. The State shall draw up and submit to the medicines agency the registration and/or renewal of the request, and then add the data, documents and information drawn up in accordance with the pharmaceutical law referred to in article 28.1, the European Commission's recommendation on documentation and requirements for the quality of medicines, safety and efficiency, the European Commission published the European Community pharmaceutical legislative framework volumes;
13.3. ensure that this rule 11.6., 12.8 and 19.2. referred to in documents and data before submission to the national medicines agency prepares and signs the experts according to their qualifications and responsibilities in accordance with the provisions of paragraph 14. Expertise shall be borne by the applicant for registration.
14. The experts according to their qualifications has the following responsibilities: 14.1. in accomplishing tasks that are part of it represented in relevant sectors (analytical chemistry, Pharmacology and similar experimental sciences, clinical trials) and to describe objectively the (qualitative and quantitative) the results obtained;
14.2. to describe their observations in accordance with the provisions of annex 2 of "analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products ' requirements, in particular: 14.2.1. analytical chemistry specialists — product compliance with the specified yield, providing also a justification the manufacturer's control methods used;
14.2.2. the pharmacologist or the specialist with similar experience — on the toxicity of the medicinal product and the pharmacological properties observed;
14.2.3. clinical research professionals (doctors), of the results of clinical trials of medicinal products (medicinal products for humans, corresponding to the registration data provided by the applicant in accordance with these rules 18, 19 and 21, including the doctor's recommended dose of tolerance), as well as of any contra-indications and blakusprādīb;
14.3. If necessary, assess the scientific literature use this rule 19.2. in the case referred to in subparagraph.
15. the registration owner (the person who is responsible for the distribution of medicinal products) has the following responsibilities: to provide medicines established 15.1. compliance with the conditions of the certificate of registration (registration);
15.2. to submit to the competent institutions of the Member States where the medicinal product is authorised (Latvia, national medicines agency), information and data on changes in the registration dossier (including the expansion of the registration certificate), as well as to carry out urgent safety restrictions (to make temporary changes to the summary of product characteristics, therapeutic indication, in drug contraindications, warnings, and the withdrawal period) and provide for procedures, in accordance with: 15.2.1 Commission Regulation (EC) no 1084/2003 medicinal products registered in accordance with the national registration procedure and the registration of which is subject to the reciprocal recognition of the registration procedure (also apply medicinal products which are authorised by the Committee for medicinal products for 1995 to 1 January);
15.2.2. the requirements laid down in these rules for medicinal products that have been registered in accordance with the national procedure of registration (not subject to mutual recognition of registration of medicinal products);
15.2.3. 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 humans and in veterinary medicine, and establishing a European Agency for the evaluation of medicinal products (hereinafter referred to as Commission Regulation No 1085/2003) products that have been registered in accordance with Council Regulation No 2309/93;
15.3. to draw up and submit to the national medicines agency for approval the changes (including the expansion of the registration certificate). Request to add the data, documents and information that have been drawn up in accordance with this rule 13.2. referred to the recommendations of the European Commission;

15.4. these rules and in 18.7 18.4 information on production and control methods to prepare according to technical and scientific progress and make any changes necessary to the products have been manufactured and tested with the accepted scientific techniques, as well as to ensure that these changes are approved by the competent authority of the Member State concerned. If you need to submit receipts for medicines and/or their ingredients (substances) and at an intermediate state control the production process in accordance with the rules laid down in paragraph 11.6 methods. To ensure that manufacturers of immunological preparations by the national medicines agency at the request of the State Agency of medicines of the series release certificate (control message) copies, signed by the qualified person;
21.4. re-evaluate according to national registration of medicinal products registered in the benefit/risk ratio, after receipt of the registration certificate shall submit to the national medicines agency the latest information not included in the original registration request, and the information on the monitoring of adverse reactions of the medicinal product in accordance with the laws and regulations for pharmacovigilance. Follow the pharmaceutical Act referred to in article 28.1, the European Commission's recommendations (guidelines), which is published by the European Commission European Community pharmaceutical legislative framework, included in volume 9;
15.6. to inform the Member States in which the medicinal products concerned distributes (Latvia, national medicines agency): 15.6.1. any prohibition of medicines, as well as the use of the limit accepted by the competent authorities of the Member State concerned;
15.6.2. any action to remove the grass from the market and halt the distribution of medicinal products and the reasons;
15.6.3. about possible changes to the registration data and/or documents;
15.7. to sign a contract with a drug company that guarantees that the manufacturing operation to comply with the laws and regulations on the production and control of medicinal products, to the requirements and the documentation of registration specified in the conditions of production, if the owner of the registration certificate is not the manufacturer of the medicinal product;
15.8. to ensure the scientific validity of the services of the service in respect of the medicinal product concerned the drawing up of scientific information, as well as its restoration;
15.9. to maintain documentation and data for the medicinal product concerned and put archive storage in accordance with the laws and regulations on document storage requirements. "
10. Make the following introductory paragraph 18: "18. To register the medication (except this rule 22 of the cases referred to in paragraph), the applicant for the registration of medicinal products in the national agency. The request includes the data and documents, and in accordance with the requirements of this regulation specifies the following information: "11." delete the words "in paragraph 18.4 short".
12. the supplement to the second paragraph 11.7. sentence the following wording: "labelling and package leaflets comply with pharmaceutical law referred to in article 28.1, the European Commission's recommendations (guidelines) for documentation and requirements on quality, safety and efficiency, the European Commission has published a European Community regulatory framework for medicinal products included on the volume label and instructions for use for legibility requirements, and it contains the excipient according to the recommendations."
13. Express 19.2. subparagraph by the following: "19.2. constituents of the medicinal product (s) in use in medicine is large (generally good either), with recognized efficacy and an acceptable level of security, giving references to scientific literature;".
14. Replace paragraph 19.3 and 19.4. the words "paragraph 20 of these regulations in such products obtained by using advanced methods of technology" with the words "high-technology medicinal products, the Committee for medicinal products for 1995 1 January is authorised by the Member States".
15. Express 24.3. subparagraph by the following: "15.1. clinical expert reports and other statements and certificates, if any, is required;".
16. To supplement the provisions of this paragraph 24.5: "15.2. the Member State concerned shall issue a certification of compliance with good manufacturing practice (not older than three years)."
17. To supplement the rules by 26.1 points in the following wording: "26.1 data and documents that are added to the request for registration (registration), the State Agency of medicines shall be submitted in accordance with the provisions of annex 2, and taking into account the pharmaceutical law referred to in article 28.1, the European Commission's recommendations (guidelines) for the documentation published by the European Commission European Community pharmaceutical legislative framework volume 2, part B. Registration applicants in the preparation of the registration documentation (Assembly) (including the renewal and change of the medicinal product registration documentation) take into account the scientific guidelines relating to the quality of medicinal products for human use, safety and effectiveness, as adopted by the Committee for medicinal products and published by the European Agency for the evaluation of medicinal products, as well as take into account the other European Community pharmaceutical guidelines which the European Commission has published a European Community regulatory framework for medicinal products volumes. "
18. To supplement the rules with 27.1 points by the following: "registration of 27.1 data and documents shall be submitted in five modules (common technical document, hereinafter KTD) in accordance with the provisions of annex 2 to the requirements and follows the form, content and the numbering system set out in this rule referred to in paragraph 2.26.11. volume part B. KTD design applies to all registration requests. Registration dossier quality part (chemical, pharmaceutical and biological documentation), the European Pharmacopoeia Monographs including General monographs and General chapters. Registration dossier in the production process comply with the laws and regulations on the production and control of medicinal products and the pharmaceutical law for medicinal products referred to in article 51.1 the principles and guidelines of good manufacturing practice, which European Commission European Community pharmaceutical legislative framework 4. volume. "
19. Put 29 the following: "29. Registration (the registration dossier) shall contain all the information relevant to the evaluation of medicinal products, regardless of whether it is positive or negative, with particular emphasis on the information about the incomplete and/or end of farmakotoksikoloģisk and/or clinical tests or studies, as well as showing the completed clinical trials on therapeutic indications not covered by the registration request. Homeopathic medicinal products: 29.1. which does not apply to the provisions in paragraph 4, that medicinal product, the toxicology and pharmacological tests and clinical trial requirements implemented, taking into account Latvia practiced homeopathy principles and features;
29.2. which have been registered by 1993 31 December, whether or not by that date, the product is re-registered in accordance with the legislation of the Member State concerned, the national medicines agency said registration, renewal or change approval shall take into account the registration previously granted by another Member State. The State Agency of medicines has the right not to apply the requirements of proof of therapeutic effect. "
20. Add to paragraph 30 with the third and fourth sentence as follows: "clinical trials of medicinal products meet regulations for clinical trials of the medicinal product, including, if the clinical trial took place in third countries (countries that are not Member States of the European Union or the European Free Trade Association countries (EFTA) countries signatory to the agreement on the European economic area). Non-clinical (farmakotoksikoloģisko) studies are conducted in accordance with good laboratory practice. "
21. Amend paragraph 32.
22. Chapter IX be expressed as follows: "IX. Changes in registration dossier, which shall submit an additional certificate of registration of the application for extension 111. In accordance with the national procedure established for registration of medicinal products, which shall not be subject to mutual recognition of registration, changes in the registration dossier, which shall submit an additional application, of the registration certificate are set out in annex 3 of these rules. The name of the medicinal product for the expansion of the registration certificate in the application is the same as that of the registration certificate.
112. the State Agency of medicines shall evaluate the request and submitted data and accompanying documents, and shall take a decision on the approval of a change to the certificate of registration of the medicinal product or the approval of a change to the extension in accordance with the provisions of chapter XI or X, or adopt a decision to refuse approval of the change. "
23. Chapter X be expressed as follows: "X. Minor changes in the registration dossier 113. According to the national registration of the registered medicines, which are not subject to mutual recognition of registration, type IA and type IB registration documentation is defined in annex 4 of these rules.
114. the registration shall be submitted by the owner of the national medicines agency request for confirmation of the change. The request shall be accompanied by: 114.1. amended data, documents and other information;

114.2. the document certifying the payment of the assessment in accordance with the provisions of paragraph 6.
115. the request only one type I changes. If more than one type I do changes on every submitted request. Each request contains a reference to the other requests, if any.
116. If one of the variations of type IA, emerges several type IA, for each of the resultant changes the owner of the registration shall submit a separate request. If one of the variations of type IB follows type IA or type IB, for each of the resulting change in the registration holder shall submit a separate request for type IB variation. The request indicates the relation between all the consequential type I variations.
117. where type I variations, the summary of product characteristics and/or markings and/or the manual is immutable, it is regarded as part of the change.
118. If a request for the approval of changes to comply with this provision 114., 115, 116, 117 and 118. the conditions laid down in point, national medicines agency 14 working days from the date of receipt of the request recognizes that the request is valid, and shall inform the holder of the registration certificate. The State Agency of medicines shall examine the request and: on request and 118.1. added data, documents and other information assessment decide on small type IA approval or not approval and shall notify the holder of the registration;
118.2. upon request and if the data, documents or other information in the evaluation of the national drug agency considers the request for minor variations of type IB, it is not acceptable within 30 days after receipt of a valid application is received, giving reasons for your opinion, inform the owner of the registration, which has submitted the request. within 30 days after the national medicines agency receiving the opinion of the owner of the registration shall have the right to amend the request, subject to the opinion of the national medicines agency in that basis. If the owner of the registration request, the request is deemed to have been rejected, and the national medicines agency decision on approval of the change, notify the owner of the registration. If the national medicines agency has not sent the holder of the registration decision on approval of the change, believes that the National Green changes have been approved by the Agency.
119. If the changes are related to the name of the owner of the registration and/or change of address and the owner is not the same person, the registration holder shall submit to the national medicines agency request. The request shall be accompanied by the following documents and specify the following information: 119.1. the document certifying the change of owner;
119.2. name of the medicinal product, the registration certificate number and date of registration of the medicinal product;
current registration holder 119.3. name and address, as well as the name and address of the person that is expected to pass the registration certificate;
119.4. a document showing a complete and updated at the time of the transfer the registration dossier or its availability and transfer of the copy to the person transferring the registration certificate;
119.5. date when the person that is expected to pass a certificate of registration will be able to take over from the previous owner of the registration of all the registration holder's duties;
119.6. a document showing that the person to whom the certificate of registration of the transfer, the ability to ensure the registration of owner's obligations according to the requirements of laws and regulations on the production and control of medicinal products, medicinal products, import, export and distribution, advertising of medicines, side effects and drug clinical trials. Document: 119.6.1. the 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;
119.6.2. the service that is responsible for the promotion and distribution of medicines, as well as the business address, phone and fax numbers;
119.7. Summary of product characteristics, labelling and package leaflet;
119.8. document confirming the payment for the evaluation in accordance with the provisions of paragraph 6.
120. the national medicines agency according to the rules referred to in paragraph 119 of the conditions change as the appearance of type IA. The date when the certificate of registration will be transferred to the new owner of the registration certificate, the national medicines agency, and it is recorded in the contract between the owner of the existing registration and the new registration. The period of validity of the certificate of registration shall not change. "
24. Make the following chapter XI: "XI. Significant changes in the registration dossier 121. Significant changes to the type II changes that do not meet these rules referred to in annex 3 changes or changes that define the content of the registration certificate of the extension in accordance with the provisions of annex 4.
122. the registration shall be submitted by the owner of the national medicines agency request significant changes of the type II for approval. The request shall be accompanied by: 122.1. these rules 13, 14 and 15 and referred to in chapter III data and supporting documents, expert reports, reviews and finding attachments that are updated according to changes in the registration dossier, and data to support the change, for which the request;
122.2. document confirming the payment for the evaluation in accordance with the provisions of paragraph 6.
123. the request shall only concern one type II variation. If one of the registered products must complete a number of type II variations for each type II changes submitted a separate request. Each such request is in reference to the other requests. If one of the variations of type II follows other changes, for any such modifications can make one request, and it indicates a relationship between all resulting changes. If the changes resulting from that description and/or markings, and/or the manual is immutable, it is regarded as part of the change.
124. If the application complies with this provision in paragraph 122 and 123, the State Agency of medicines shall notify the owner of the registration, when the processing of the application will be launched. 60 days from the initiation of the proceedings at the request of the State Agency of medicines shall prepare an assessment report and a draft decision. This period may be reduced to take account of the urgency of the matter, especially in relation to security issues.
125. If the changes associated with therapeutic indications or in a new indication of the replenishment, this period may be extended to 90 days.
126. the State Agency of medicines has the right to ask the owner of the registration for additional information. In that case, the procedure shall be suspended until such time as the owner of the registration shall submit to the national medicines agency, in addition to the information requested. The State Agency of medicines shall take a decision on the approval or non approval of changes to the laws and established, and notify the owner of the registration.
127. According to changes in the influenza vaccine for human use, the conditions of the certificate of registration (registration), the following procedures shall apply: 127.1. national medicines agency within 30 days after the initiation of the procedure, based on the quality of the supporting documents referred to in annex 2 to these regulations 3. module, prepare an assessment report and a draft decision and sends to the owner of the registration;
127.2. the registration owner 12 days submit to the State Agency of medicines in the clinical data and, if necessary, the stability of the medicinal product;
127.3. national medicines agency within seven days from the receipt of the data evaluated the data and prepare the final draft decision.
128. 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 Community, the State Agency of medicines has the right exceptionally to declare changes in influenza vaccines for human use of the certificate of registration (registration) in the period from the receipt of the request to the provision in paragraph 127 of the procedure, if the owner of the registration shall submit complete data about clinical safety and effectiveness.
129. the urgent safety restrictions: 129.1. implementing the registration owner, if there is a risk to public health. The owner of the registration in the same day shall inform the State Agency of medicines. If the national medicines agency within 24 hours after receipt of the information referred to is not voiced objections, the urgent safety restrictions shall be deemed accepted;
129.2. National Medicines Agency. Registration the holder of national medicines agency request for change approval, taking into account the national medicines agency limits.
130.129. These provisions in the case referred to in paragraph urgent safety restrictions on the holder of the registration exercise period to be agreed with the State Agency of medicines. Request for change of registration dossiers according to the urgent safety restrictions shall be submitted by the owner of the registration of the national medicines agency not later than 15 days after the urgent safety restriction. "
25. To supplement the provisions of this subparagraph with 135.4.:

"it is right to 135.4. exceptional circumstances (after consultation with the applicant for registration) to issue registration certificates to their specific duties, including the continuation of the study after the receipt of the certificate of registration, and information on adverse reactions to medicinal products. Those decisions have the power to take an objective and verifiable reasons and must be based on one of those provisions of annex 2, paragraph 52 causes. "
26. Express and 137.136. paragraph by the following: "136. For the consideration of the registration request, the national medicines agency, if required, shall be entitled to ask the applicant for registration to submit additional data according to these rules 18, 19 and 21 of the said requirements. In this case, the rules set out in point 8 a time limit shall be suspended until the requested additional information. Time limit also suspended for the time allowed for oral or written explanations.
137. the national medicines agency when issuing a certificate of registration shall inform the owner of the registration of the medicinal product for the summary of the product characteristics as approved by it and provide a summary of the relevance of the information provided in the registration dossier. If the product is registered in the registration of the medicinal product in the mutual recognition procedure, the State Agency of medicines shall forward to the European Agency for the evaluation of medicinal products medicinal products a copy of the registration certificate and summary of product. "
27. Delete paragraph 138, the words "and comments".
28. Add to 140.2. subparagraph after the word "prescribed" by the words "if it is found that the medicine can not get the therapeutic results".
29. To supplement the provisions under section 140.7. the following wording: "140.7. the product is included in the European list of the medicinal products which are prohibited in the community."
30. To complement the 141.2. subparagraph after the word "point" with the words "if it is found that the medicine can not get the therapeutic results".
31. To supplement the provisions of the following paragraph 141.1: "the national medicines agency 141.1 has the right to decide on an urgent suspension of the registration of the medicinal product in accordance with the monitoring of the adverse results of the evaluation of the data, if it shall inform the European Agency for the evaluation of medicinal products, the European Commission and the other Member States no later than the following working day."
32.143 points to express the following: "143. National Medicines Agency on the basis of registration of medicinal products, the recommendations of the Commission shall take a decision on the registration of the medicinal product: 143.1. or refusal of registration;
registration or reregistration of 143.2. refusal;
143.3. registration cancellation, if the circumstances which were the basis for the making of the decision;
143.4. suspension of registration or, if the circumstances which were the basis for the decision, the lifting of the suspension of registration;
143.5. cancellation of the registration or, if the circumstances which were the basis for the decision, the annulment of the cancellation of the registration;
143.6. registration dossier change approval or refusal to approve the change. "
33. To supplement the provisions and paragraph 143.1 143.2 as follows: "If 143.1 shall decide on the registration (Reregistration), they assign a registration (re-registration) number, which you specify in the registration certificate.
drug registration process in 143.2 or after the adoption of the decision on registration, determine their affiliation to the prescription or non-prescription medicines in accordance with Cabinet of Ministers regulations on the classification of medicinal products prescription and non-prescription medicinal products, as well as taking into account the pharmaceutical law referred to in article 28.1, the European Commission's recommendations (guidelines) for the documentation, which is published by the European Commission European Community pharmaceutical legislative framework volume 2 the classification of the medicinal product, included in the guidelines. "
34.144 and 145 express the point as follows: "144. Decision on the refusal of the registration or refusal of registration of the revocation, suspension or lifting of the suspension, withdrawal or cancellation of the registration of the cancellation of the national medicines agency not later than 10 days after the decision is issued (sent by registered post) to the person to which the decision applies.
145. the decision on the registration of the medicinal product concerned or the renewal of the national medicines agency shall notify the person to whom the decision relates, and shall issue a certificate of registration which certifies registration or re-registration, no later than 30 days after the adoption of the decision. National medicines agency draws up a certificate of registration pursuant to the provisions laid down in annex 5 to the form. Registration certificate is valid if there is a decision on the cancellation of the registration or the registration suspension. "
35. To supplement the provisions under paragraph 148.3.1 as follows: "148.3.1 national medicines agency after the registration, the Commission shall notify the meeting of medicine price to the Agency of the decision taken, to the price of the medicinal product, the Agency could assess operational information on medicinal products that are included in or eligible for inclusion in the list of medicinal products;".
36. Supplement with 148.5, and section 148.6 148.7. by the following: "148.5. ensure that the European Agency for the evaluation of medicinal products are immediately informed of decisions relating to the registration of the medicinal product in accordance with the mutual-recognition procedure or the refusal, cancellation or withdrawal, as well as provide grounds. National Medicines Agency provides adequate information on the actions taken that may affect public health protection in third countries, and shall send it to the World Health Organization and the European Agency for the evaluation of medicinal products;
148.6. shall communicate to the other Member States the information necessary for the European Community manufactured and distributed in the homeopathic drug quality and safety, in particular the provision in question referred to 148.5.;
148.7. published national language registration, re-registration and change approval request forms, which the European Commission has published a European Community regulatory framework for medicinal products volumes, and shall advise the owner of the registration certificate and applicants of the design documentation requirements established by the relevant Latvian and European Community law, as well as the European Commission working groups addressed the issues. "
37.5, 16, 20, 28, 139, 156, 160 and 163. and chapter XII.
38. To replace the words "paragraph 166 to special cabinet from the date of entry into force of the provisions" with the figures and the words "until 30 April 2004".
39. Replace 165. and in paragraph 167, the words "specific provisions" of the Cabinet, with numbers and words, "may 1, 2004".
40. To supplement the rules by 168.169.170, and point as follows: "168. State Agency of medicines has the right to refuse registration and renewal by May 1, 2004, if the applicant for registration is not established in the European Community.
169. The provisions specified in annex 5 of the marketing authorisations does not concern the design registration certificates issued to the date of entry into force of the provisions.
170. the national medicines agency under the European Commission recommendations (guidelines) for the documentation, which is published by the European Commission European Community regulatory framework for medicinal products volumes, take note that the Member States new registration requests the registration documentation of standardized format went into effect in December 31, 2003. More detailed information on the format of the registration dossier specific recommendations of the European Commission (guidelines) for the documentation, which is published by the European Commission European Community pharmaceutical legislative framework in which specific volume 2. incidents in which allowed the previous registration of the design documentation (according to this provision, 26, 27, 33, 34, 35, 37, 38, 39, 40, 41, 42 and 43, and V, VI, VII, VIII, chapter). "
41. To replace the 49.4.3.,.,., 135.2 55.1.5 65.2 in and 150.151.167 points, and the word "Annex" (fold) with a number and the words "annex 1" (fold).
42. Make an informative reference to European Union directives as follows: "Informative reference to European Union directives, the regulations include provisions resulting from: 1) 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;
2) Commission in 2003 25 July Directive 2003/63/EC of 25 June 2003, amending European Parliament and Council Directive 2001/83/EC on the Community code relating to medicinal products for human use. "
43. Supplement with 2, 3, 4 and 5 of the annex by the following: "2. the annex to Cabinet of 31 October 2000 of Regulation No 381 analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products A standardised registration section in the documentation requirements module 1, chapter I. 1. Administrative information Provided in the registration application submitted documentation 1., 2., 3., 4. and 5. module table of contents.
2. the request form:

(1) the medicinal product which is the subject of the request, identified by name and active substance (s) name, as well as pharmaceutical form, route of administration, the strength and the final presentation (including packaging).
(2) indicate the applicant's name and address, the name and address of the manufacturer, as well as sites involved in the different stages of production, also the manufacturer of the finished product and the active substance (s) producer (s), if applicable, name and address of the importer.
(3) the applicant indicates the type of request, as well as the samples submitted, if any.
(4) the administrative data included in the annex of manufacturing authorization (license) and a list of countries that have granted that authorization, the Member States approved copies of the summary of product characteristics in accordance with this provision, 36, and a list of countries in which the registration request.
(5) the applicant, inter alia, provide detailed information about the medicinal products which are subject to registration, the legal basis of the request, the expected registration holder (hereinafter referred to as the owner of the registration) and the manufacturer (s), as well as information on the status of the medicinal product as an orphan, scientific advice and paediatric development program.
3. The summary of product characteristics, labelling and package leaflet: (1) the applicant for registration provides a summary of product in accordance with the provisions of paragraph 36.
(2) the applicant for the registration of a label's text to the primary and secondary packaging, as well as usage instructions. Labelling shall comply with the following requirements: 1) the information on the label and package leaflet of the medicinal product, as well as the used symbols or pictograms complies with the requirements of the legislation on the labelling of medicinal products and medicinal products, instructions for use. The information is in the official language or languages of the Member State where the product is distributed;
2) instructions are written to the user it should be clear and understandable;
3) label and in the instructions for use of the pharmaceutical law are complied with, referred to in article 28.1, the European Commission's recommendations (guidelines) for the documentation published by the European Commission European Community pharmaceutical legislative framework 2. volume requirements, labelling and instructions for use readability;
4) allowed the label to specify the data and print the instruction manual in several languages if all languages provides the same data and information.
(3) the applicant for the registration of the medicinal product concerned provides primary and secondary packaging, labelling (label) and manual samples or models.
(4) the request form in the annex to administrative data, if necessary, provide Member States approved copies of the summary of product characteristics in accordance with this provision, 137 and 138 36 and a list of countries in which the registration request.
4. information on experts: (1) in accordance with the provisions of paragraphs 13 and 14 experts submit detailed observation reports on the documents and data that make up the registration dossiers, in particular on the 3., 4. and 5. module (chemical, pharmaceutical and biological documentation, non-clinical documentation and clinical documentation). Experts draw attention to the critical points related to the quality of the product, and the studies carried out in animals and people, as well as all important data for evaluation.
(2) that the requirement of providing a general overview of the quality, non-clinical study report (data from studies carried out in animals) and the report of the clinical trial, which shall be annexed to the registration documentation for module 2. A declaration signed by experts along with brief information on their education, training and professional experience provides the module 1. Experts in the require suitable technical or professional qualifications. Experts and should reflect the registration applicant's professional relationship.
5. the specific requirements of different registration requests are provided in chapter II.
6. Environmental risk assessment: (1) if necessary, the registration requests include a risk assessment overview evaluating possible drug use, as well as the destruction of the risk to the environment, and make proposals for appropriate labelling provisions. To pay attention to the environmental risk associated with product release into the environment of genetically modified organisms under the law on the deliberate release into the environment of genetically modified organisms.
(2) information concerning the environmental risk, add module in Appendix 1.
(3) the information is provided in accordance with the said rules, taking account of guidelines published by the European Commission on their implementation.
(4) Information includes: 1) introduction;
2) written consent (or a copy of the consent) on the deliberate release into the environment of genetically modified organisms for research and development purposes in accordance with the regulations;
3) information on the genetically modified organism detection and identification methods and code, as well as environmental risk assessment for important additional information about genetically modified organisms as or in products, in accordance with laws;
4) environmental risk assessment, drawn up on the basis of the information specified in the regulations;
5) in the light of the above information and environmental risk assessment, opinion, suggesting that an appropriate risk management strategy and plan included the sales of genetically modified organisms and products to post market surveillance, and special data, which must be included in the summary of product characteristics, labelling and package leaflet;
6) relevant public information activities.
(5) require the author's signature and the date, as well as information about the author's education, training and professional experience and a statement of the author's relationship with the applicant.
2. Chapter II module. 7. Summary This module aims to collect chemical, pharmaceutical and biological data, the non-clinical research data and clinical trial data provided in the registration dossier, 3., 4. and 5. module, as well as to provide these rules 13 and 14 referred to reports and accounts.
8. Focus on the critical points and analyzes them. Provides a summary of the facts (in the table). 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) in the main documentation. Information contained in module 2 shall provide, subject to the form, content and numbering system of the specified volume 2 of the notice of registration of the applicant. The report and the summary conform to the following basic principles and essential requirements.
9. the overall table of contents for module 2 include 2., 3., 4. and 5. scientific documentation submitted in module table of contents.
10. Enter information on the pharmacological class, mode of operation and the intended clinical use, which requires registration.
11. General summary provides an overview of the quality for the chemical, pharmaceutical and biological data. Highlights the key critical parameters and quality issues, as well as the reasons for non-compliance with the relevant guidelines. 3. This document, complied with the module provided detailed data and presentation.
12. an overview of clinical trials: (1) required an integrated and critical assessment of paediatric clinical trials with animals (in vitro). Outline and justify the testing strategy and deviations from the relevant guidelines.
(2) the report shall include a clinical trial of impurities and degradation products, and their potential pharmacological and toxicological assessment (except for biological medicinal products). Hilaritāt the appearance, chemical form and impurity differences between clinical trials connection used and izplatāmaj products on the market.
(3) evaluate medicinal products not of biological origin in clinical research and the clinical research of the material used and the comparability of medicinal products marketed.
(4) the new adjuvants are particularly valued in terms of security.
(5) determine the characteristics of the product are not clinical studies, as well as the findings about the safety of the medicinal product intended for clinical use in humans.
13. the review of clinical trials: (1) clinical study report is intended to provide a clinical summary and module 5 clinical data included critical analysis. Provides pharmaceutical clinical development method, including critical research, and research-related decisions and research.
(2) clinical trial report provides a brief overview of clinical data obtained, including the relevant restrictions, as well as the benefits and risk assessment, on the basis of clinical research findings. Need clarification on how data on the efficiency and safety of the proposed dose of basic and mērķindikācij, as well as an assessment of how the summary of product characteristics and other techniques will optimise the benefits and manage the risks.
(3) explain the effectiveness and safety issues that have arisen during the development of the medicinal product, as well as unresolved issues.

14. Summary of clinical trials in animals (in vitro) of the pharmacology, pharmacokinetics and toxicity studies provided in writing as a fact (also in the table) to be submitted in the following order: (1) introduction.
(2) a written summary of Pharmacology.
(3) summary of Pharmacology in a table.
(4) a written summary of the pharmacokinetics.
(5) summary of pharmacokinetics table.
(6) a written summary of toxicology.
(7) summary of toxicology in the table.
15. The clinical trial summary provides a detailed summary of the facts about clinical drug information contained in module 5. Biofarmaceitisk research, include clinical pharmacology research and clinical efficacy and safety studies. You need a separate study synopsis. Aggregate information about clinical trials submitted in the following order: (1) a summary of the biofarmaceitiskaji research and related analytical methods.
(2) Clinical Pharmacology research summary.
(3) summary of clinical efficacy.
(4) a summary of clinical safety.
(5) individual study synopsis.
3. Chapter III of the module. Chemical, pharmaceutical and biological information for medicinal products containing both chemical and biological active substances 16. Form and design. A general outline of module 3 is as follows: 16.1. table of contents;
16.2. data set: 16.2.1. active substance: (1) General information: 1) nomenclature;
2) structure;
3) General characteristics.
(2) production: 1) manufacturer (s);
2) manufacturing process and process control;
3) raw material control;
4) critical points and the intermediate examination;
5) process validation and/or evaluation;
6) improving the production process.
(3) characteristics: 1) the structure and other characteristics explanation;
2) impurities.
(4) the control of the active substance: 1) specification;
2) analytical procedures;
3) analytical procedure validation;
4) series analysis;
5 reasons) specifications.
(5) reference standards or materials.
(6) the sealing system.
(7) stability summary and conclusions: 1) for stability;
2) stability Protocol (after approval) and stability commitment;
3) data on stability;
16.2.2. finished medicinal product: (1) description and composition of the medicinal product.
(2) pharmaceutical development: 1) the constituents of the medicinal product: (a) the active substance);
b) adjuvants;
2): (a) the preparation of medicinal products);
(b) increasing the dose);
c) physico-chemical properties;
d) biological properties;
3 improving the production process);
4) sealing system;
5) microbiological characteristics;
6) compatibility.
(3) production: 1) manufacturer (s);
2) series composition;
3) manufacturing process and process control;
4) critical points and the intermediate examination;
5) process validation and/or evaluation.
(4) control of excipients: 1) specifications;
2) analytical procedures;
3) analytical procedure validation;
4) justification of the specification;
5) of human or animal origin for excipients;
6) new adjuvants.
(5) the control of the finished medicinal product: 1) specification (s);
2) analytical procedures;
3) analytical procedure validation;
4) series analysis;
5) characteristics of impurities;
6) specification (s) grounds.
(6) reference standards or materials.
(7) the sealing system.
(8) stability summary and conclusions: 1) for stability;
2) stability Protocol (after approval) and stability commitment;
3) data on stability;
16.2.3. appendices: (1) equipment and facilities (only for biological medicinal products).
(2) the possible disease agent security assessment.
(3) the excipients;
16.2.4. European Community additional information: (1) pharmaceutical process validation scheme.
(2) a medical device.
(3) conformity certificate (s).
(4) medication, or the production process used for animal and/or human origin (TSE procedure);
16.3. literature references.
17. content has the following basic principles and essential requirements: 17.1. chemical and biological, pharmaceutical data shall include the following information on the active substance (s) (s) and for ready-made products: 17.1.1.;
17.1.2. the production process;
17.1.3. characteristics and properties;
17.1.4. quality control activities and requirements;
17.1.5. stability;
17.1.6. the composition of the finished product and design;
17.2. provide two main information packages on the active substance (s) (s) and of ready-made medicinal products;
17.3. in addition to the module provides detailed information about raw materials and raw materials used for the active substance (s), and on the excipients incorporated into the finished medicinal product;
17.4. 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 could repeat the checks carried out by the competent authority (Latvia, national medicines agency). 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);
17.5. The monographs of the European Pharmacopoeia on the substances, preparations and pharmaceutical forms. In respect of other substances, each Member State may require observance of its own national pharmacopoeia.
(1) If the European Pharmacopoeia or in the pharmacopoeia of a Member State that the material is prepared by a method which can stay impurities not covered in the pharmacopoeia monograph, these impurities must be specified and the maximum quantity and description of appropriate analytical procedure.
(2) If the European Pharmacopoeia or in the pharmacopoeia of a Member State in the specification may not be sufficient to ensure the quality of the substance, the competent authorities (Latvia, national medicines agency) may require the owner of the registration of the appropriate specifications. The competent authorities (in Latvia-national medicines agency) informed of the pharmacopoeia concerned responsible authorities. The registration holder shall provide the authorities of that Pharmacopoeia with the details of the alleged insufficiency and the additional specifications applied.
(3) included in the European Pharmacopoeia, this description of analytical procedures in each relevant section by the appropriate detailed is replaced by reference to the monograph (s) and General Chapter (s) (s);
17.6. where the raw materials and raw materials, active substance (s) or excipient (s) is not described in the European Pharmacopoeia nor in the pharmacopoeia of a Member State, can accept compliance with the monograph of a third country (a country which is not a Member State of the European Union or European Free Trade Association (EFTA), which signed the agreement on the European economic area) pharmacopoeia. In such cases, the registration, the applicant shall submit a copy of the monograph accompanied by the analytical procedures contained in the monograph a monograph and, if necessary, translation;
17.7. If the active substance, the raw material, as well as raw material (s) or excipient (s) include (s) a monograph of the European Pharmacopoeia, the registration, the applicant may request a certificate of compliance, which you specify in the relevant section of this module, if it is granted by the European Directorate for the quality of medicines. Considers that the European Pharmacopoeia Monographs are replaced by a certificate of conformity to the relevant section of this module described data. Producer registration applicant provides written confirmation that the manufacturing process has not changed since the European Directorate for the quality of medicines issued a certificate of compliance;
11.1. the active substance manufacturer or the applicant for registration may agree that information about a specific active substance for a detailed description of the production process, quality control during manufacture and process validation to be submitted by the manufacturer of the active substance in a separate document as the active substance master file directly to the competent authorities (in Latvia-national medicines agency). In this case, the manufacturer shall provide to the applicant for registration details that may be necessary for the latter to take responsibility for the medicinal product concerned. The manufacturer shall confirm in writing to the applicant for registration that he provides a series of consistency and without registration requesting not modify the manufacturing process or specifications. Competent authorities (Latvia, national medicines agency) shall submit the documents and information supporting the request for the registration of the above changes. These documents and particulars shall also submit the registration request to the applicant, the examination of the active substances of the open part of the master;
11.1. specific actions related to the transmission of animal spongiform encephalopathies, the applicant for registration must demonstrate at each stage of the production process of the materials used in compliance with the "guidelines for animal spongiform encephalopathy agent to reduce the risk of dissemination of medicinal products" and their updated versions, 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 in the certificate of conformity to the relevant monograph of the European Pharmacopoeia or to provide scientific data to substantiate this compliance;

17.10. about 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;
17.11. sufficiently detailed description of the manufacturing process of the medicinal product and the tests used special equipment and facilities;
17.12. where relevant, the CE marking is required by European Community legislation on medical devices;
17.13. special focus on the following elements: individual 17.13.1. active substance (s): (1) General information and information about the raw materials and raw materials: 1) provides information on the nomenclature of the active substance, including recommended international non-proprietary name, the European Pharmacopoeia name if necessary, chemical (s) name (s). Structural formula, also indicate the relative and absolute chemistry, the molecular formula and relative molecular mass shall be provided. Biotechnological medicinal products if appropriate schematic amino sequence and relative molecular mass shall be provided. Provides a list of the active substances and any other properties. Biological medicines indicate biological activity;
the meaning of this annex 2) raw materials, manufactured or extracted from the active substance. For biological medicinal products, starting 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 biotechnology cell structure (cell substrates, which are recombinant or not, including stem cells). A biological medicinal product is a product, in which the active substance is a biological substance. A biological 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) in production or extraction, 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. For biological medicinal products: immunological preparations (a)) (any medicinal product consisting of vaccines, toxins, serums or allergen);
(b)) from human blood and plasma derived medicinal products (public or private industrial companies made products based on blood constituents, including such drugs as human albumin, clotting factors and immunoglobulin);
c) drugs which may not be placed on the market of the European Community, the European Community has granted a marketing authorisation in accordance with the Council of 22 June 1993, the Regulation (EEC) No 2309/03, laying down the procedures for the European Community, the approval and supervision of medicinal products for human and veterinary use and establishing a European Agency for the evaluation of medicinal products;
(d) of this annex defined) advanced therapy medicinal products.
3) vaccines, toxins and serums shall relate in particular to: (a)) agents used to produce active immunity (such as cholera vaccine, Used in tuberculosis Kalmet-vaccine bcg, polio vaccines, smallpox vaccine);
b) agents used to diagnose the State of immunity, including tuberculin and tuberculin PPD, toxins for the Schick and Dick tests, brucellin;
c) agents used to produce passive immunity (such as diphtheria antitoxin, anti-smallpox globulin, antilymphocytic globulin);
4) allergens are drugs designed for the specific change for or in response to the triggering of allergies immunological agents.
(2) the active substance (s) production process: 1) it describes registration determines the applicant's commitment for the manufacture of the active substance. To adequately describe the manufacturing process and process control, appropriate information is to be provided, in particular the European Agency for the evaluation of medicinal products published guidelines;
2) lists 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 production and testing the facility name, address, and responsibility;
3) for biological medicinal products, subject to the following additional requirements: a) described and documented the origin and history of starting materials;
(b)) as to the particular measures of animal spongiform encephalopathies prevention registration applicant must demonstrate that the active substance complies with the "guidelines for agents of animal spongiform encephalopathies proliferation risk reduction with drugs" and their updated versions, published by the European Commission in the official journal of the European Union;
c) when cell banks are used, indicating that the cell characteristics remain unchanged before and after the passage level used for the production;
(d)), check that the 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;
e) if potentially pathogenic potential presence of adventitious agents is inevitable, the corresponding material shall be used only when further processing ensures their elimination and inactivation, and that requires validation;
f) 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;
g) for medicinal products derived from human blood or plasma, in accordance with chapter IV of this Annex provisions describe and document the origin of the raw materials, criteria and collection, transport and storage procedures;
(h)) describes the production facilities and equipment;
4) if necessary, provides 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;
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 that requires validation section on viral safety evaluation;
6) describes and explains the major changes in the development of the active substance during the production process and production site.
(3) the active substance (s) characteristics: 1) provides data on the active substance (s) of the structure and other characteristics;
2) provide proof of active substance (s) based on any structure or imūnķīmiskaj, or biological methods, as well as information on impurities.
(4) the active substance (s) control: 1) provides detailed information on the specifications used for the active substance (s) regular control, giving the choice of these specifications, as well as information on methods of analysis and their validation;
2) reflect the separate development during a series of tests produced results.
(5) determine the detailed description and reference preparations and standards of reference. If necessary, use the European Pharmacopoeia chemical and biological reference materials.
(6) Provide active substances in packing and sealing system (s) and their specifications.
(7) the active substance (s) stability: 1) summarizes studies undertaken, the protocols used, and the results of the study;
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;
3) submitted to the stability Protocol (after approval) and stability commitment;
17.13.2. finished medicinal product: (1) a description of the finished product and composition: 1) shall provide a description of the finished product and indicates their composition. The information includes the pharmaceutical form and a description of the composition, showing the components of the finished product, the unit and the function of these components: a) the active substance (s) (s);
b) components of the excipients, whatever their nature or the quantity used (such as pigments, preservatives, adjuvants, stabilizers, thickeners, emulsifiers, flavouring and aromatic substances);
(c) the outer covering of the medicinal products) components, intended to be ingested or otherwise administered to the patient use (for example, hard capsules, soft capsules, rectal, coated tablets, tablets film packaging). 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;
18.3. these rules 2) laid drug qualitative and quantitative composition of simple terminology, to describe the components of medicinal products are:

(a)) the main title of the monograph in question, with reference to the pharmacopoeia concerned, in respect of substances which appear in the European Pharmacopoeia or, failing this, in the national pharmacopoeia of one of the Member States;
b) recommended by the World Health Organization, the international non-proprietary name, or, if not, the scientific name for other substances. Substances not having an international non-proprietary name or the scientific name, description, outlining how and from what they were prepared, supplemented, where appropriate, by any other relevant details;
(c) with the code E) designation, conferred by the provisions specified in annex 1, as well as the regulations governing food coloring — allowed for colours;
3) to specify 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);
4) active substances designated quantitatively in the form of compounds or derivatives shall, when indicating the total mass, and if necessary, — molecular units of mass;
5) for medicinal products containing an active substance which is subject to first registration in any Member State, quantitative assessment of the active substance, which is a salt or hydrate shall be systematically expressed in terms of the molecules of the active unit or unit mass. All subsequently authorised medicinal products in the Member States shall have their quantitative composition in respect of one and the same point of active substances in the same way;
6) units of biological activity shall be used for substances that can not be defined molecularly. If the World Health Organization an international unit of biological activity has been defined by, then use it. The absence of 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, if necessary by using the European Pharmacopoeia units.
(2) pharmaceutical development: 1) this section provides information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, sealing system, microbiological attributes and usage instructions corresponds to the intended use specified in the registration dossier;
2) study described in this section are different from regular control tests conducted according to specifications. Defines and describes the process of the preparation and properties of critical parameters that may affect the reproducibility, medicinal product series performance and the quality of the product. If necessary, additional data, refer to the relevant documentation of the registration module 4 (non clinical study reports) and module 5 (clinical study reports) chapter: (a) the active substances) document compatibility with excipients as well as active substances the main physicochemical parameters that can affect the operation of the finished product or the compatibility of different active substances connections;
(b) the choice of excipients), especially with regard to their respective functions and concentration;
(c)) provides the finished product a description of the development, taking into consideration the proposed route of administration and usage.
(d) increasing the dose);
e) describes and document the parameters relating to the operation of the finished product, as far as any chemical and biological characteristics;
f) indicates the selection and the 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;
g) document the packaging and sealing systems for finished product suitability for storage, transportation and use. If necessary, consider drug and packaging the potential interaction;
(h) the sterile and not sterile) product the dosage the microbiological characteristics correspond to the European Pharmacopoeia, and document them in the European Pharmacopoeia;
(I)) in order to provide useful information on the label of the finished product, document compatibility with the renewal of the solvent (s) or dosage devices.
(3) the manufacturing process of the finished product: 1) indicates the description of the manufacturing method, which according to this provision is added to paragraph 18.4 registration request, be prepared to provide a sufficient overview of the nature of the operations employed. It shall include at least: (a) a reference to the different) production stages, including process management and acceptance criteria to be assessed, or pharmaceutical form used in the production process can cause unwanted changes in components;
(b)) if the production is a continuous, full details concerning precautions taken to ensure the homogeneity of the finished product;
(c) the validation of the manufacturing process) used the results of the pilot studies, where a non-standard method of manufacture is used or where they are critical for the product;
(d)) for sterile medicinal products, details of the sterilization processes, as well as aseptic procedures;
e) detailed information about the composition of the series;
2) indicated for each manufacturer (including contractors) and each proposed production site or production and testing the facility name, address, and responsibility;
3) include data on 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 defined by their methods of manufacture;
4) submitted to validation studies, documentation and critical points in the manufacturing process of fixing results.
(4) control of excipients: 1) lists the excipient (s) the necessary materials for production, identifying where each material is used in the process. Provides information on the quality and control of these materials. Provide information demonstrating that materials meet standards of use envisaged. Colouring matters must satisfy this rule 1. the requirements set out in the annex, as well as the provisions on authorized colouring matters in food. Colours correspond to regulations on the purity criteria applicable to food colours;
2) details each excipient specifications and justify them. Describes and appropriately validated analytical procedures;
3) special focus on the human or animal origin for excipients. 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 "guidelines for animal spongiform encephalopathy agent to reduce the risk of dissemination of medicinal products" and their updated versions, 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 in the certificate of conformity to the relevant monograph of the European Pharmacopoeia or to provide scientific data to substantiate this compliance;
4) new adjuvants: a) according to the active substance used to 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.
(b) document with details) by chemical, pharmaceutical and biological information. This information is presented in the same way as module 3 section of the active substance (s) (s);
c) information about 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, national medicines agency);
(d) the documentation of module 4) provides additional information on toxicity studies with the new excipient;
e) for information on clinical trials provided 5. module.
(5) the control of the finished medicinal product: 1) so you can check 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;
2) unless there is appropriate justification, the active substance content of the finished product the maximum permitted deviation during production does not exceed 5%;
3) provides detailed information on the specifications, (release and shelf life) and justification for their choice of methods of analysis and their validation shall be provided.
(6) a detailed description of the reference and the preparations and reference standards used for testing of the finished medicinal product, if this information is provided in the section on active substance.
(7) the packaging of the finished product and sealing system:

1) provides 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);
2) of a functional secondary packaging material gives only a brief description. For functional secondary packaging materials provide additional information.
(8) stability of the finished medicinal product: 1) summarizes studies undertaken, the protocols used, and the results of the study;
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, provide information about the overall stability of the vaccine;
3) submitted to the stability Protocol (after approval) and stability commitment.
4. Chapter IV module. Reports of clinical trials not 18. Form and design. A general outline of module 4 is the following: 18.1. table of contents;
18.2. reports of studies: (1) Pharmacology: 1) primary pharmaco-Dynamics;
2) secondary pharmaco-Dynamics;
3) safety pharmacology;
4 pharmacodynamic interactions).
(2) the pharmacokinetics: 1) analytical methods and validation reports;
2) absorption;
3);
4) metabolism;
5) discharge from the body;
6) pharmacokinetic interactions (clinical trials);
7) other pharmacokinetic studies.
(3) the Toxicology: 1) single dose toxicity;
2) repeated dose toxicity;
3) genotoxicity: a) in vitro;
(b)) in vivo (including toxicokinetic evaluations);
4): (a) the long-term carcinogenicity) studies;
b) temporarily or medium studies;
(c) other studies);
5) reproductive toxicity and developmental toxicity: a) of fertility and early embryonic development;
b) embryonic (fetal) development;
(c)) and postnatāl prenatal development;
d) study drug intake gives the offspring (juvenile animals) and/or additional assessed;
6) local tolerability.
(4) other toxicity studies: 1) antigenitāt;
2) imūntoksicitāt;
3) mechanism;
4);
5) metabolic products;
6) impurities;
7) other;
18.3. literature references.
19. the basic principles and the essential requirements of the contents. Special focus on individual elements.
(1) the pharmacological and toxicological tests must show: 1) the potential toxicity of the product and in dangerous or undesirable toxic effects that may occur, the people they use under the proposed conditions. It assessed in relation to the pathological condition concerned;
2) pharmacological properties of the medicinal product qualitative and quantitative relationship to the proposed use. The results are reliable and universally applicable. If possible, experimental techniques and the evaluation of results using mathematical and statistical methods. Information on herbal cures and toxicological potential of providing clinical professionals.
(2) the requirements of the module can be adapted to individual 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: 1) plans to test, requiring repeated administration of the product, taking account of the possible induction of antibodies and interference;
2) reproduction, embryo, and fetus and perinatal toxicity, of mutagenic potential and of carcinogenic potential. If a reason is considered other components other than the active substance (s) are incriminated, validation of their removal may replace the study.
(3) study the first Pharmaceutical Excipients used in the toxicology and pharmacokinetics.
(4) If storage possible significant degradation of the medicinal product, the toxicology of degradation products assessed.
(5): 1) Pharmacology Pharmacology study shall follow two distinct lines of approach: (a) study and description), due to the proposed therapeutic use. If possible, use a recognised and validated assays in vivo and in vitro. New experimental techniques described in detail so that they can be used. 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;
(b) the applicant for registration) explores 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, so should be described in detail, so that they could use, and the investigator determines whether they are valid. Exploring the reactions possible changes that might arise, reuse;
2) pharmacological or therapeutic effect assumption indication may be required because of the urgency of the active substance combination for the test drug interactions pharmacodynamic pharmacodynamic study of: (a)) shows the interactions which might make the combination is worth using;
(b) if the combination of scientific justification) looking for therapeutic experimentation, research determines whether the expected combinations of effects can be displayed with animals and what is its significance.
(6) the pharmacokinetics: 1) pharmacokinetics the active substance and its metabolites on the activity of the body and relate to the substance of the absorption, distribution, metabolism (biotransformation) and retention studies;
2) that the different phases of the 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;
3) information on distribution and elimination is required when 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 reagents);
4) can also be performed in vitro studies, in comparison with the animal material using human material (binding of proteins, metabolism, drug interactions);
5) need of pharmacologically active substances in pharmacokinetic studies. 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;
6) pharmacokinetic program intends to be able to compare data on the animals and people and can accordingly extrapolate.
(7) the Toxicology: 1) single dose toxicity: a) single dose toxicity test is a toxic reaction in either qualitative or quantitative research that can lead to medicinal products belonging to the active substance or substances from a single administration of the proportions and the physico-chemical state in which they are actually present in the halls;
(b)) one dose toxicity tests shall be carried out in accordance with relevant European Medicines Evaluation Agency's published guidelines;
2) repeated dose toxicity: a) toxicity test for the physiological and/or anatompatoloģisk for the detection of changes caused by the test of the active substance or combination of active substances, as well as to determine how these changes are related to dosage;
(b)) it is desirable to carry out two tests: a 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 Evaluation Agency's published guidelines;
3) genotoxicity. Mutagenic and clastogenic potential is to discover the intention of the research 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;
4) carcinogenicity. Usually requires tests that reveal carcinogenic effects: a) studies are conducted with all the drugs that the patient clinically to use longer (continuously or repeatedly from time to time);
(b)) study is recommended with drugs, 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;
(c)) with clearly genotoxic compounds do not, because the studies are considered 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;
5) reproductive toxicity and developmental toxicity of: (a)) with the corresponding tests study the potential of male and female reproductive function deterioration as well as harmful effects on progeny;
(b)) these 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;

(c) if the tests do not) take it properly justified;
d) depending on the indicated use of the medicinal product, if the product will be used also for children, may require additional research on children's development;
(e)), as well as the embryos foetal toxicity studies shall normally be conducted on two mammalian species, one of which is not a rodent. At least one species take peri and postnatal research. If you know that a particular species of metabolism is similar to a human, preferably choose this species. It is also desirable to one species would be the same as that used in the repeated dose toxicity studies;
f) the design of the study, taking into account scientific knowledge at the time when the request for registration;
6) local tolerance local tolerance): (a) the objective of the study is to determine 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). Testing strategy shall be such that any mechanical effects, which is the use of the medicinal product, or only the physico-chemical action can be distinguished from toxicological or pharmacodynamic effects;
(b) local tolerance studies) performed 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);
(c) 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;
d) studies in 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;
e) chemical substances placed on the skin (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).
5. Chapter v module. Reports on clinical trials 20. Shape, and design. The general outline of module 5:20.1. clinical study reports table of contents;
20.2. all clinical trials listing table;
20.3. reports of clinical trials: (1) reports on the studies: 1) biofarmaceitisk bioavailability studies;
2) bioavailability and bioequivalence study (comparatively);
3) in vivo-in vitro correlation studies;
4) bioanalīz and methods of analysis.
(2) reports of pharmaco-kinetic studies using human bio-materials: 1) research relating to the binding to plasma proteins;
2) liver metabolism and interaction studies;
3) studies using other human bio-materials.
(3) reports of human pharmacokinetic studies in healthy subjects: 1) pharmacokinetics and initial tolerability;
2) patient and initial tolerability pharmacokinetics;
3) internal factors pharmacokinetics;
4) external factors pharmacokinetics;
5) population pharmacokinetics.
(4) reports of human pharmacodynamic studies: 1) a whole subject pharmacodynamic and pharmacokinetic-pharmacodynamic studies;
2) patients and pharmacokinetic-pharmacodynamic pharmacodynamic studies.
(5) reports of efficacy and safety studies: 1) controlled clinical study on indication subject to registration;
2) controlled clinical trials;
3) more than one study, data analysis, including all formal integrated analyses, meta-analyses and bridging analyses;
4 other studies).
(6) the report on the experience after the commencement of distribution of medicinal products.
20.4. literature references.
21. the basic principles and the essential requirements of the contents. Special emphasis on designated items listed.
22. Clinical particulars to be provided pursuant to this rule, is 12.8. enough to give reasonable and scientifically valid opinion as to whether the medicinal product satisfies the criteria governing the granting of the registration. It is important that clinical trial results to communicate (both medication and adverse adverse).
23. before the clinical pharmacological and toxicological always out animal tests 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.
24. the registration holder shall ensure that the important clinical trial documents (including case report forms) other than subject's medical history, the owners of the data store: 24.1. for at least 15 years after completion or discontinuation of the trial;
24.2. at least two years after the last registration of the award in the European Community, the European Community is no longer under consideration or projected registration request;
24.3. at least two years after the preparation under the official termination of the clinical development.
25. the subject of the history stored in accordance with applicable laws and regulations as long as it allows the medical establishment, including the physician's practice.
26. Documents may also be stored longer, as determined by the law or agreement with the sponsor. Is the responsibility of the sponsor to inform the hospital, institution or practice, if the documents are no longer to be kept.
27. The Sponsor or other owner of the data shall retain all other documentation pertaining to the trial as long as the product is authorised. This documentation includes the Protocol, including the rationale, objectives for research, statistical concepts, methodologies, with conditions under which it is performed and managed, the details of the preparations under study, the reference medicinal product and placebo, standard operating procedures, all written opinions on the Protocol and procedures, the investigator's brochure, case report forms on each trial subject, the final report and the audit certificate (s), if any (s) are. Be retained by the sponsor or subsequent owner, final report five years after the medicinal product is no longer authorised.
28. the owner of the Registration shall take additional measures to achieve the European Community research documentation in accordance with the laws and regulations of clinical trials of medicinal products as well as detailed guidelines.
29. data transfer always documented.
30. All the data and documents shall be made available to, if requested by the appropriate authorities.
31. The particulars of each clinical trial is this enough information to be able to make objective assessment: 31.1. Protocol, which includes a research rationale, objectives and statistical design and methodology, with conditions under which it is performed and managed, and details of the investigational medicinal product;
31.2. audit certificate (s), if any (s);
31.3. the list of researchers that represents each researcher's name, address, position, qualifications, responsibilities and clinical research sites. The researchers collected information on each patient individually, including case report forms on each trial subject;
19.5. the final report shall be signed by the researcher, and if the research is carried out at several locations, all researchers or Coordinator (principal investigator).
32. The above clinical trial data to send to the national medicines agency. By agreement with the State Agency for the registration of medicinal products, the applicant may not submit part of this information, but if the national medicines agency requires, immediately submit a full dossier. 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, reporting on the results of the research, conclusions, express an opinion on the preparations examined the safety and efficacy of all research centres.
33. the clinical observations shall be Summarized for each trial indicating: (1) and Treat the subject number and gender.
(2) select groups of patients being investigated, a breakdown by age and comparative tests.
(3) the number of patients the time excluded from the trials and the reasons for such exclusion.
(4) If a controlled study conducted in accordance with those conditions, indicates whether the control group: 1) not treated;
2) has received a placebo;
3) has received another medicinal product of known effect;
4) are treated differently (not with drugs).
(5) the observed side effects (adverse reactions).
(6) information about the increased risk to patients (such as the elderly, children, women during pregnancy or menstruation) or in patients whose physiological or pathological condition requires special attention.
(7) the efficiency parameters or evaluation criteria and results (expressed with these parameters).

(8) the statistical evaluation of the results, if it is intended to be a research plan, and related variables.
34. the investigator will provide observations on: (1) habituation or addiction signs or difficulty in ceasing the use of the product in patients.
(2) any interactions observed with other medicinal products, which are used at the same time.
(3) the criteria determining exclusion of certain patients from the trials.
(4) the deaths during or subsequent monitoring.
35. data relating to the new combination of medicines, is identical to the data of a new product, and it is based on the safety and efficacy of the combination.
36. If the data are not or are only partially, it explained. If research, obtain unexpected results, carry out and review additional pre-clinical, toxicological and pharmacological studies.
37. 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.
38. Reports of biofarmaceitisk studies: (1) Submit reports on comparative bioavailability studies, reports on bioavailability and bioequivalence study reports, reports on in vitro and in vivo correlation study, as well as bioanalīz and methods of analysis.
(2) the Bioavailability assessed if it is necessary to demonstrate that the provisions referred to in paragraph 19 of the drug bioequivalence.
39. Reports of pharmaco-kinetic studies using human biomaterials: (1) human biomaterials are human proteins, cells, tissues and related materials used in vivo or ex vivo to assess the pharmacokinetic properties of the medicinal product.
(2) the report shall be provided for studies relating to binding with plasma protein on liver metabolism and active substance interaction studies and on research using other human bio-materials.
40. Reports of human pharmaco-kinetic studies: (1) describes the following pharmaco-kinetic characteristics: 1) absorption (rate and extent);
2);
3) metabolism;
4) release.
(2) the description of clinically significant features (including the kinetic data for the dosage), especially for patients at risk, as well as differences between pre-clinical trials used humans and animal species.
(3) in addition to the standard pharmacokinetic studies with many copies of the population pharmacokinetic analysis, based on a rare specimen selection, and clinical research can determine how internal and external factors affect the dose and pharmacokinetics. Reports of pharmaco-kinetic and initial tolerability studies in healthy subjects and patients, reports of pharmaco-kinetic studies to evaluate the internal and external influences, and reports on Population pharmacokinetic studies.
(4) if the medicinal product is intended for use in combination with other medicinal products, particulars shall be given of joint administration tests to show the pharmacological effects of possible change.
(5) the active substance and other medicinal products or substances pharmacokinetic interactions.
41. Reports of human pharmacodynamic studies: (1) displays the pharmacodynamic activities relating to effectiveness, including: 1) the dose-response relationship, as well as its changes;
2) and conditions of use;
3) if possible, the type of action.
(2) the description of pharmacodynamic action not related to efficiency.
(3) in order to justify conclusions regarding any particular potential therapeutic effect, there is not enough evidence to show the effect on humans.
(4) 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.
(5) the active substance and other medicinal products or substances pharmacodynamic interaction.
42. Reports of efficacy and safety studies: (1) reports of controlled clinical trials for indications covered by the registration: 1) clinical trials are usually conducted as controlled clinical trials, 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 approved drug effectiveness that have proven therapeutic value: a) to the extent possible, particularly in trials where the action of the medicinal product cannot be objectively measured, appropriately handled to avoid bias — also used the method of randomisation and blinding;
(b)) protocol is included in the statistical methods used for detailed description, 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, particularly random method. If the research involves many entities may not believe that it can replace the control;
2) data on the safety, having regard to the guidelines published by the Commission, with particular attention to cases in which the dose or change was necessary while using other medications, observed serious adverse events, patient excluded from study or 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.
(2) Submit reports of uncontrolled clinical trial data analysis relating to more than one study and other reports on clinical trials.
43. the reports on the experience after the commencement of distribution of medicinal products. If the product is authorised in third countries, 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.
44. Data registration forms and individual patient listings. Data registration forms and lists of individual patient data in the same order as the clinical study reports, indexed by research. They shall be submitted in accordance with the European Agency for the evaluation of medicinal products published by the relevant guidelines.
(B) a special section in the registration dossiers and specific requirements 45. some products have the characteristics that all this should be adapted accordingly laid down in section A of the annex to the request for the registration dossier requirements. In order to take account of these particular situations, registration applicants comply with the relevant documentation and custom design.
46. This section defines specific requirements for registration (marketing authorization) documentation: (1) medicine widely used medications.
(2) similar in substance.
(3) in special cases, the necessary additional data.
(4) a similar biological medicinal products.
(5) a medicinal product with a constant composition.
(6) the dossier for the request for the registration in exceptional circumstances.
(7) registration requests for mixed.
47. Medicine widely used medicine is medicine that active substance (s) are widely used in medicine (s) pursuant to this provision, and which point 19.2. efficiency is recognized and an acceptable level of security: (1) the applicant shall submit this as described in annex 1, module 2 and 3, but 4 and 5 in the detailed and scientific bibliography indicates non-clinical and clinical indicators.
(2) in order to demonstrate the wide use of the medicine, the following special rules shall apply: 1) factors which have to be taken into account in order to prove the drug component in extensive use in medicine, is the following: a) the length of time that a substance has been used;
(b)) the quantitative aspects of the use of the substance;
c) scientific interest in the use of the substance (reflected in the published scientific literature);
(d)) the coherence of scientific assessments;
2) different substances may be required for different time periods to determine that they are widely used. The time required to determine that the component is widely used in medicine, must be not less than 10 years from the first systematic and documented of that substance as a medicinal product for use in the European Community;

3) registration the applicant submitted documentation related to all safety and effectiveness aspects, and it includes a review of the relevant literature or references to it, taking into account pre-and postmarketing studies and published scientific literature concerning experience in epidemiological studies (especially comparative epidemiological studies). Communicate to all documentation, whether favourable or unfavourable. As regards the rules on the use of wide medicine specifically states that the bibliographic reference to other sources of evidence (such as post market studies, epidemiological studies), not only to the data associated with the tests and research, preparation, may be a valid proof of safety and efficacy if the registration information is adequately explained and justified;
4) particular attention all missing information and give reasons why it can be considered that the degree of efficiency and safety is acceptable, although some studies are lacking.
5) non-clinical and clinical overviews explain the relevance of any data submitted which concern a product different from the product intended for distribution. Assess whether the investigational medicinal products can be considered as similar to the product for which the registration request, although there are differences between them;
6) experience gained after the market other products containing the same components is of particular importance and applicants for registration specifically examine these issues.
48. as regards the essentially similar to the product: (1) registration requests, based on the provisions of section 19.1 (essentially similar to a product), include in this section A of annex 1, 2, and 3. the data described in the module, if the original registration holder has agreed that the registration applicant use cross-references to the original registration holder submit modules 4 and 5.
(2) registration requests, based on this rule 19.4. subparagraph (essentially similar products-generic drugs), included in this section A of annex 1, 2, and 3. the data described in the module, and documents showing the bioavailability and bioequivalence compared to an original medicinal product if the original product is not biological medicinal products (chapter IV).
(3) in respect of those products are not clinical (clinical) research reports (summaries) focusing on the following elements: 1) to the justification, why require a very close resemblance;
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 intended to use the product on the market, and this impurity assessment;
bioequivalence evaluation studies 3) or reasons not to perform studies regarding the guidelines for bioavailability and bioequivalence studies;
4) updated published literature relating to the registration of substances and the specific request. For this purpose, you can annotate articles from professional journals;
5) 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 (clinical) research reports (summaries) and based on the literary publications, as well as additional research;
6) if the applicant for registration of a request relating to a very great similarity, it should provide additional data to show the various active substances permitted salts, esters or derivatives of efficiency and safety of the equivalence of the properties.
49. specific situations where additional data: (1) If 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, as well as demonstrate 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 treated as a new active substance.
(2) where a medicinal product is intended for a different therapeutic use or dosage forms is different, or medicinal products intended for use in other ways and went, or medications are different, provide appropriate toxicological and pharmacological tests, as well as the clinical trial results.
50. Similar biological medicinal products: (1) in respect of products of biological origin that rule 19.4. the conditions of point may not be enough. If the information necessary for the essentially similar products (generic drugs), can prove two biological medicinal products of a similar nature, additional data, in particular toxicological and clinical characteristics.
(2) if the registration of an independent applicant after the end of the period of protection shall submit the registration request in this section of the annex set out in paragraph 17 of biological medicines for which a reference is made to an original medicinal product which has been granted the European Community's registration certificate, do the following: 1) submit information about 1, 2, and 3. the module (pharmaceutical, chemical and biological data) with data on Bioequivalence and bioavailability. Additional data types and volume (toxicological and other non-clinical data, as well as the clinical trial data) shall be determined on a case by case basis in accordance with the relevant guidelines;
2) medicinal products of biological origin due to the diversity of the competent authority (Latvia, national medicines agency) require certain module 4 and 5 for research, taking into consideration each individual medicine special characteristics.
(3) the General principles, taking into account the particular biological characteristics of the medicinal product are specified in the European Medicines Evaluation Agency's published guidelines. If the originally authorised medicinal products has more than one indication, subject to registration, the similarity is justified or, if necessary, demonstrated separately for each indication, subject to registration.
51. The medicinal product with the same composition: (1) the request for registration, based on paragraph 21 of these rules, apply to new medicinal products made of at least two active substances not previously authorised as and halls with a constant composition.
(2) in respect of such registration requests submit a full dossier (1., 2., 3., 4. and 5. module) for medicinal products with a constant composition. If necessary, provide information on the place of production and the possible disease agent security assessments.
52. the documentation registration requests under exceptional circumstances: (1) registration may be granted, subject to the specific commitments, if the applicant for registration under this provision in 135.4 specified requirements may prove unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because: 1) the indications for which the product in question is intended are encountered so rarely that can't wait for registration applicants provide comprehensive evidence;
2) comprehensive information cannot be provided so far accumulated scientific knowledge;
3) collect such information would be contrary to generally accepted principles of medical ethics, registration may be granted subject to certain specific obligations.
(2) in this case, the registration shall be granted, subject to the following conditions: 1) national medicines agency within the time specified by the registration applicant completes a specific research programme, the results of which will be repeated in the benefit and risk assessment;
2) the medicinal product in question may be sold only with a doctor's prescription, in some cases, it can be used only under strict medical supervision, if required, in the hospital. Radiopharmaceutical preparations of monitoring shall be performed by an authorised person;
3) instructions for use and medical information shall draw the attention of the medical practitioner to the fact that for the medicinal product concerned, the available data are not yet enough.
53. Mixed for registration is a registration request documentation if the module 4 and 5 consist of reports of limited non-clinical and clinical trials conducted by the claimant for registration, as well as bibliographic references. All other modules comply with this annex describes the structure. National medicines agency accepts the registration request form, a case-by-case basis.
(C) specific medicinal product section 54. This section is subject to special requirements with respect to certain characteristics of the medicinal product: (1) the products of biological origin (from human blood and plasma-derived drugs and vaccines).
(2) Pharmaceutical products.
(3) for Pharmaceutical precursor (precursor to — all other radionuclide produced for radio-labelling of another substance prior to its use for radioactive labelling).
(4) a homeopathic medicinal products.
(5) herbal medicines.
(6) the orphan medicinal products.

55. From human blood and plasma derived products. Without taking into account the provisions of module 3 this part of the documentation of the medicinal product "information about raw materials and raw materials ' information about raw materials can be replaced by plasma elementary files that is approved, on the basis of the following principles: (1) for the purposes of this Annex: 1) the plasma master file is from the documentation of the individual registration documentation, which contains detailed information on the characteristics of human plasma as raw material, and as a raw material used in the apakšfrakcij and starpfrakcij of the excipient (s) and the active substance (s) in the production of components and is part of the medicine or the law prescribed medical devices incorporating stable derivates of human blood or human plasma;
2) each human plasma fractionation and the processing center or authority shall draw up and update the plasma master file shall be referred to the whole of the relevant details;
3) the plasma master file shall be the European Agency for the evaluation of medicinal products or the competent authority (Latvia-national medicines agency) shall submit a registration to the applicant or the owner of the registration. If the applicant for registration or the registration holder is the holder of the plasma master file, the plasma master file shall be made available to the applicant for registration or the registration holder to submit to the competent authority (Latvia, national medicines agency). The applicant for registration or the registration owner assumes responsibility for a medicinal product;
4) national medicines agency, which evaluates the registration request, fails to take a decision, to the European Medicines Agency issued certificate;
5) registration request documentation that refers to the component that will benefit from human plasma, always refer to the plasma master file on the plasma used as starting material or raw material.
(2) content. Plasma master file shall include the following information on the plasma used as starting material or raw material: 1) plasma origin: a) information on centres or establishments in which blood and plasma collected, including data on inspection and approval, and epidemiological data on infections transmitted by blood;
(b)) information on centres or establishments in which donors make to the material and the testing of plasma pools, including data on inspection and approval;
c) blood and plasma donor selection, as well as exclusion criteria;
d) used system which ensures that you can track every donor material passed the way from the blood and plasma collection to finished product and vice versa;
2) plasma quality and safety: a) the adequacy of the monographs of the European Pharmacopoeia;
(b)) 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);
c) blood and plasma collection bag used for technical characteristics, including information on anticoagulants solutions;
d) plasma storage and transport conditions;
(e) counting procedures) and/or quarantine period;
f) plasma characteristics of the Fund;
3) used in the system, which is determined from the plasma-derived medicinal product manufacturer, plasma fractionator and 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. In addition, the plasma master file shall contain a list of medicinal products covered by the plasma master file, regardless of whether the medicinal product is authorised or are in the process of registration (also for medicinal products in relation to the implementation of good clinical practice in clinical trials with medicinal products for human use).
(3) assessment and certification: 1) on medicinal products has not yet allowed the applicant for registration to the competent authority (Latvia, national medicines agency) shall provide full documentation, and a separate plasma master file, if it has not been submitted;
2) the plasma master file shall be scientific and technical evaluation of the European Agency for the evaluation of medicinal products. If the assessment is positive, the plasma master file shall be issued a certificate stating that it complies with European Community law, as well as the assessment report. The issued certificate is valid throughout the European Community;
3) the plasma master file shall be updated and certified each year;
4) changes the plasma master file shall be assessed according to the rules of procedure laid down 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 humans and in veterinary medicine, and establishing a European Agency for the evaluation of medicinal products (hereinafter referred to as Commission Regulation No 1085/2003);
5) national medicines agency takes into account the plasma master file of the medicinal product concerned certification, re-certification or variation;
6) if the plasma master file shall be limited to those from blood and plasma derived medicinal products whose registration is only valid in the Republic of Latvia, the plasma master file the scientific and technical evaluation carried out by the national medicines agency.
56. The vaccine. If using a vaccine Antigen master file system for human vaccines, without taking into account the provisions of module 3 shall apply to the following requirements: a vaccine registration documentation, which is not a flu vaccine, included in each vaccine Antigen master file, which is the active ingredient in a vaccine that: (1) the principles: 1) vaccine Antigen master file is a separate vaccine registration dossier which contains all relevant information of biological active substances , pharmaceutical and chemical properties that are the constituents of the medicinal product. In a separate part may cover one or more monovalent as well as combined vaccines presented by one and the same registration, the applicant or the holder of the registration;
2) vaccine may contain one or several distinct vaccine antigens. The vaccine is just as active substance (s) as vaccine Antigen (s);
3) combined vaccine contains at least two distinct vaccine antigens, which protects from one or several infectious diseases;
4) monovalent vaccine contains one vaccine Antigen that is protected from any infectious diseases.
(2) content. Vaccine Antigen master file shall contain the following information from the relevant parts of the module 3 (active substance) on the quality of the data, as defined in section A of this annex. With regard to the active substance: 1) General information, including compliance with the relevant (-aj) the monographs of the European Pharmacopoeia (s);
2) information on the manufacture of the active substance (manufacturing process description, information about the raw materials and raw materials, specific measures on TSEs, possible disease agent security assessments, as well as facilities and equipment);
3) active substances;
4) of the active substance quality control;
5) reference standards and materials;
6) active substances in packaging and sealing system;
7 stability of the active substance).
(3) assessment and certification take note that: 1) about vaccines that contain new vaccine Antigen, applicant for registration to the competent authority (Latvia, national medicines agency) shall provide full documentation of the registration application, 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 not been submitted. The European Agency for the evaluation of medicinal products shall take all of the vaccine Antigen master scientific and technical assessment. If the assessment is positive, for each vaccine Antigen master file shall be issued a certificate stating that it complies with European Community law, as well as the assessment report. The certificate is valid throughout the European Community;
2) these conditions also apply to all vaccines consisting of new vaccine Antigen combinations, regardless of whether one or more vaccine Antigen are already permitted in the European Community part of vaccines;
3) European Agency for the evaluation of medicinal products to evaluate the scientific and technical content changes made to the European Community authorised vaccine Antigen master in accordance with Commission Regulation No 1085/2003 established procedure. If the assessment is positive, the European Agency for the evaluation of medicinal products of a vaccine Antigen master file shall issue a certificate stating that it complies with European Community law. The issued certificate is valid throughout the European Community;
4) where a vaccine Antigen master file limited to vaccines, which registration is not or will not be granted according to a Community procedure, and, without taking into account the "1", "2" and "3" the conditions referred to in paragraph 1, if the authorised vaccine includes vaccine antigens which have not been valued in accordance with the procedures of the European Community, the said vaccine Antigen master file and its subsequent changes, the scientific and technical evaluation carried out by the national medicines agency;
5) national medicines agency having regard to the medicinal product concerned vaccine Antigen master certification, re-certification or variation.

57. the Pharmaceutical product registration requests, based on this provision and 18.16. in point 2.3 above, submit a full dossier in which the following specific information: (1) module 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. Radiopharmaceutical Kit description manufacturing method shall include details of the manufacture of the kit and details of its recommended final processing, in which radiopharmaceutical product. The necessary specifications of the radionuclide, if necessary, a description, in accordance with the European Pharmacopoeia Monographs General monographs, or special. Describe all connections, which are important for the radiolabelling. Also describes the structure of the radio-labelled compound. For a description of the relevant radionuclides in nuclear reaction. Generator for active substances considered as both primary and secondary radionuclides;
2) indicated the nature of the radionuclide, the identity of the isotope, likely impurities, the carrier, the use and the specific effects;
3 inputs include irradiation target) material;
4) provides observations on the chemical, as well as the radiochemical purity and its relationship to biodistribution.
5) describes the radionuclide purity, radiochemical purity and specific activity;
6) for generators, details on the primary and secondary radionuclide tests. In respect of eluates ģerator provides information about the primary radionuclides and other system components of the generator tests;
7) 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;
8) for kits in 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;
9) provides information on radionuclide generators, radionuclide kits and radiolabelled product stability. Document the phials of radiopharmaceutical products packed more dose of stability during use.
(2) module 4. Toxicity is desirable to associate with radiation dose. Diagnosis is a radiopharmaceutical product use effects in therapy it is desirable feature. Radiopharmaceutical in safety and effectiveness focus on requirements for medicinal products and radiation dosimetry aspects. Document the radiation exposure to the organs and tissues. Absorbed radiation dose estimates shall be calculated according to a specified, internationally recognised system according to the particular use.
(3) the module 5. If necessary, provide the clinical trial results that otherwise reasonable clinical overviews.
58. in the case of radio-pharmaceutical precursors for markup, if solely for radio-labelling purposes the main precursors for the purpose is to provide information on potential weak radioactive effects in the markup or in vivo dissociation of the radio-labelled conjugate (i.e., on issues related to the exposure, the patient brings free radionuclide) also provides relevant information on arodapdraudējum, the radiation exposure to hospital staff and to the environment. In that case the following information : (1) module 3 the provisions of this annex, paragraph 57, first paragraph the conditions apply to the registration of radio-pharmaceutical precursors.
(2) 4 module provides results of research 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. In that case the mutagenicity studies with radionuclide is not considered valid. Provides information about the "cold" nuclide chemical toxicity and disposition.
(3) the module 5. Precursor in the clinical trials 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 pharmaceutical precursors if it is not attached to relevant sējmolekul.
59. This section contains special rules for modules 3 and 4 the applied homeopathic medicinal products: (1) 3. provisions relate to the module in accordance with the provisions of paragraph 21 of the documents submitted to the simplified registration of homeopathic medicinal products with a procedure, as well as other documents for registration of homeopathic medicinal products with the following changes: 1) terminology. Registration dossier to the homeopathic stock described in the Latin name match the name used in the European Pharmacopoeia in Latin or, if there is no such, — the official pharmacopoeia. If necessary, provide, in each Member State (s) used in traditional (s) name (s);
2): (a) the control of raw materials) together with the registration request submissions and documents for raw materials (for all materials, including raw materials and intermediates up to the final dilution to be incorporated into the finished medicinal product) supplemented by data on homeopathic feedstock;
(b)) 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 final dilution to be included in a combination of toxic components and if the quality can not be controlled because of the high dilution factor. A full description of the manufacturing process of the medicinal products from raw materials to the final dilution;
(c) if dilution is included), dilution 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 official pharmacopoeia of a Member State,;
3) control tests on the finished product: a) general quality requirements apply to ready-made homeopathic medicinal products. Any exception to the registration request duly justified by the applicant;
b) identifies and determines 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 of the show with the production process of dilution and full validation;
4) stability tests prove stability of the finished medicinal product. Stability of homeopathic raw data is usually attributed to dilutions, as well as on the ground that the mass of them. If the active substance identification or detection is not possible due to the degree of dilution, can be taken into account in the form of the stability of the medicinal product data.
(2) module 4 terms apply to the provision in paragraph 3 that the simplified registration of homeopathic medicinal products with additional specifications. Missing information based (for example, justify why the evidence of the level of safety is acceptable, if not some research).
60. with regard to herbal medicines registration requests provide a full dossier in which the following specific details shall be included: 60.1.3. module conditions, including compliance with the monograph of the European Pharmacopoeia (s) apply to the registration of herbal medicinal products. Take into account the scientific knowledge at the time when the registration request;
60.2. the appearance of specific herbal medicinal products: (1) herbal substances and herbal preparations: 1) under "terms" herbal substances and formulations are equivalent to the terms defined in the European Pharmacopoeia;
2) with respect to the nomenclature of the herbal substance the indication of plant scientific binomial name (genus, species, variety and author), and chemotype (where applicable), the parts of the plants, the definition of the herbal substance, the other names (synonyms mentioned in other pharmacopoeias) and the laboratory code;
3) with respect to the nomenclature of the herbal preparation indicate the binomial scientific name of plant (genus, species, variety and author), and chemotype (where applicable), the parts of the plants, the definition of the herbal preparation, the ratio of the herbal substance to the herbal preparation, the extraction solvent (s), the other names (synonyms mentioned in other pharmacopoeias) and the laboratory code;
4) to document the herbal substance (s) and herbal preparation (s), specify the physical form, a description of the components of a therapeutic effect is unknown, or markers (molecular formula, relative molecular mass, structural formula, including relative and absolute chemistry, the molecular formula and relative molecular mass), as well as other component (s) (s);
5) to document the section on herbal substances, the manufacturer shall provide all suppliers (Contracting), as well as the herbal substances in production, collection and testing facilities or involved in the object name, address, and responsibility;
6) to document the section on the manufacturer of the herbal preparation, provide all the manufacturer (contractor), as well as the production of the herbal preparation and testing of the plant or facility name, address, and responsibility;

7) for plant production process and process control description provides information to adequately describe the plant production and plant collection, including a medicinal plant geographical origin and cultivation, harvesting, drying and storage conditions;
8) in the case of the herbal preparation of manufacturing process and process controls description provides information that properly describes the production of the herbal preparation process (including processing, solvent and reagents, purification stages and standardisation of descriptions);
9) regarding the improvement of the 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 (used in the bibliographic data) with the herbal substance (s) and herbal preparation (s) as active substance (s) include the herbal medicinal product applied for registration;
10) relating to the substances of plant origin and other characteristics of the structure elucidation, if necessary, information on the botanical, macroscopic, microscopic, fitoķīmisk and the characteristics of the biological activity;
11) for herbal preparations and other characteristics of the structure of explanation, if needed, provide information on the physico-chemical characteristics of the fitoķīmisk and and biological activity;
12) where relevant, the herbal substance (s) and herbal preparation (s) specifications;
13) if necessary, indicate the herbal substance (s) and herbal preparation (s), analytical procedures;
14) regarding the validation of analytical procedure provides information on analytical validation, including the herbal substance (s) and herbal preparation (s) used in analytical testing procedures, experimental data;
15) for a series of analysis provides the herbal substance (s) and herbal preparation (s) series and the series analysis results (also for Pharmacopoeial substances);
16) where relevant, the herbal substance (s) and herbal preparation (s) specification;
17) where relevant, information on the herbal substance (s) and herbal preparation (s) used in the test reference standards or materials;
18) If a herbal substance or the herbal preparation is included in the monograph, the registration, the applicant may request the European Directorate for the quality of medicines issued the certificate of compliance.
(2) in relation to the development of the pharmaceutical form provides a synoptic overview of the development of herbal medicinal products, taking into consideration the proposed route of administration and usage. If necessary, compare the product composition fitoķīmisk (used in the bibliographic data) with herbal medicines, applied for registration.
61. Orphan Medicinal products: (1) orphan medicinal products of the European Parliament and of the Council of 16 December 1999, Regulation (EC) No 141/2000 conditions of orphan drugs for the treatment of this annex, paragraph 53 of the General rules. The registration applicant non-clinical and clinical summaries the reasons why Basic is not possible to provide full information, and the basis on orphan medicinal products for the benefit-risk balance.
(2) If the applicant for registration shall not be taken into account in this provision and paragraph 19.2. this annex 48 provisions in accordance with article 10 of the law of Pharmacy 7 terms in medicinal products supplied by running a bona fide order (order is not promoted), and manufactured under authorized healthcare professional specifications and are intended for use in certain patients, taking his direct personal responsibility, the systematic and documented use of the concerned substance can refer to the use of these substances.
(D) section of the advanced therapy medicinal product 62. requirements under this section to advanced therapy medicinal products: (1) gene (human and xenogeneic) medicinal therapy: 1) gene therapy medicinal product diversity;
2) special requirements for module 3.
(2) somatic cell (human and xenogeneic) medicinal therapy.
(3) specific requirements for gene therapy and cell therapy (human and xenogeneic) medicinal product in the context of module 4 and 5:1) module 4;
2. Module 5: a)) Pharmacology and efficacy studies with people;
(b)).
(4) the special requirements of ksenotransplantācij medicine.
63. Advanced therapy medicinal products produced by a production process which 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. This medicinal product registration documentation design meets the requirements of section A of the annex. Example 1., 2., 3., 4. and 5. module. In the case of genetically modified organisms deliberate release into the environment focus on genetically modified organisms to the recipient and also the persistence of genetically modified organisms, as well as modifications to the replication, it is spreading into the environment. Information about the environmental risk is reflected in the annex to module 1.
64. Gene therapy medicinal products (human and xenogeneic) within the meaning of this title is the product obtained 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, as well as its expression in vivo. Gene transfer is an expression system contained within the transfer system, known as vector, which may or may not be the origin of the virus. The vector can also be a human or animal cell.
65. Gene therapy medicinal products are: (1) medicinal products based on allogeneic or xenogeneic cells. Vector before its transfer into the host is ready and is stored. The cells were obtained in advance and can be processed as a cell bank (bank collection or the bank created from stem cells) with reduced viability. The cell, which genetically modified with the vector, is the active ingredient. To obtain the finished product can perform additional steps. In essence, such a medicinal product is intended for use in certain patients.
(2) medicines that use autologous human cells. The active substance is ready vector set before its transfer into the autologous cells are stored. To get the finished product, you can perform additional actions. These drugs are made from a specific patient for cells. 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 injection to the patient shall be considered as one intervention.
(3) the use of the vector with the Ready inserted (prophylactic, diagnostic or therapeutic) genetic material. The active substance is ready for the vector. To get the finished product, you can perform additional actions. This type of medicinal product is intended for use on multiple patients. Genetic transfer may be prepared directly by injecting the vector for the recipient.
66. specific requirements regarding module 3 gene therapy medicinal products: (1) gene therapy medicinal products are: 1) the naked nukleīnskāb;
2) complex nukleīnskāb or vectors that are not viral vectors;
3) viral vectors;
4) genetically modified cells.
(2) in respect of other medicinal products distinguish between three main production factors: 1 — materials) 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);
2) active substance: recombinant vector, virus, the naked or complex plasmids, virus producing cells, in vitro genetically modified cells;
3) finished medicinal product: active ingredient in the final immediate container for medical use. Depending on the gene therapy drug types, usage and conditions may require treatment of the patient's cells ex vivo (see the second paragraph of article 65).
(3) a special focus on the following issues: 1) provides information about gene therapy medicinal products, the relevant indicators, including the expression of the target cell population. Provides information about the encoded gene sequence, structure, characteristics and verification, including its integrity and stability. In addition to the therapeutic gene, the gene was also complete the order, and the basic design of the vector adjuster Assembly;
2) provides information on the characteristics of the vector used in gene transfer and admission. Include its physico-chemical, biological and immunological characteristics. For medicinal products that utilise gene transfer micro-organisms (such as bacteria or viruses (biological gene transfer)), provides data on the pathogenesis of the parental strain and on its tropism for specific tissues and cell types, as well as the interaction of cell cycle dependence. For medicinal products that gene transfer does not use biological means, indicates some component and a combination of physico-chemical properties;
3) cell bank or establishment of the seed lot series principles and characteristics necessary to apply gene therapy medicinal products;

4) in the cells of recombinant vector source. Document the human characteristics (such as age, sex, microbiological and viral results, exclusion criteria and country of origin). About animal cells provide detailed information on the following: (a) determination of animal origin);
(b) animal husbandry and care);
c) transgenic animals (methods of creation, characterisation of transgenic cells, nature of the inserted gene);
d) measures origin (donor) of animal infection prevention and supervision;
e) for testing for infectious agents;
(f));
g) raw materials and raw material control;
5) document the cell collection methods description, location, type of tissue, processing, transportation, storage and traceability as well as during the picking process checks;
6) viral safety assessment, as well as product traceability from the donor to the finished medicinal product is essential part of the documentation to be submitted (for example, turn off the virus unable to replicate in the presence of the virus unable to replicate vector banks).
67. a somatic cell therapy medicinal products (human and xenogeneic) is an 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 (e.g., complex matrix of mikrokapsul, bio-degradable or not). Specific requirements for cell therapy medicinal products regarding module 3:67.1. a somatic cell therapy medicinal products are the following: (1) cells manipulated to qualitatively or quantitatively transformed their immunological, metabolic or other functional properties.
(2) the cells sorted, selected and manipulated later in the production process to obtain the finished medicinal product.
(3) the 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.
(4) autologous cell derivatives that specific culture conditions gets in vitro.
(5) the cells that have been genetically modified or otherwise manipulated by subject to allow previously unexpressed homologous or non-homologous functional properties.
67.2. the whole manufacturing process from the collection of the cells (autologous situation) up to the re-injection to the patient shall be considered as one intervention;
67.3. other medicinal products lays down the following three elements of the manufacturing process: (1) materials: materials from which the active substance is manufactured (organs, tissues, body fluids or cells).
(2) the active substance: the cells, which manipulated the cell lizāt, cell culture and growing cells to be used in conjunction with inert matrixes or other medical devices.
(3) the finished medicinal product: active substance in its final immediate container for use in medicine: 1) General information on the active substance (s) (s). Cell therapy medicinal products the active substance consists of cells which after overworking in vitro show a prophylactic, diagnostic or therapeutic properties that are different from the original physiological or biological one. This section describes the types of cells and culture. Documented in tissues, organs or biological fluids, as obtained from the cell, as well as donor material, allogeneic or autologous xenogeneic characteristics and geographical origin. Detailed description of cell collection, sampling and storage prior further processing. Regarding the cells essentially paying particular attention to the first stages of the process, including donor selection. Specifies the type of the manipulation, the use of active substances in the cell physiological function;
2) information on the active substance (s) raw materials (human and animal somatic cells (xenogeneic)).
68. The annex referred to in paragraph 67 of the human somatic cell therapy medicinal products from a limited number of viable cells (cell Foundation), produced 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. In this chapter, the active substance is a human cell culture Fund, but the finished product is a human cell culture Fund, intended use the medicine. Fully documented and all stages of the production process, as well as viral safety aspects: (1) human origin organs, tissues, body fluids and cells. Document the source of human characteristics, such as age, sex, microbiological status, exclusion criteria and country of origin. Documented sampling site description, type, operating process, funds, transportation, storage and traceability as well as sample checks of the selected.
(2) cell banking system. The relevant requirements described in this annex, apply to the cell bank system and quality control. It can apply to essentially or xenogeneic cells.
(3) auxiliary materials or medical devices. Provides information on all the raw materials (such as cytokine, growth factors, feeds) or of possible ancillary products and medical devices (e.g., cell sorting devices, bio-compatible polymers, matrix, fibres, beads and their biological compatibility, functionality, as well as the risk of infectious agents).
69. The annex referred to in paragraph 67 of the animal somatic cells (xenogeneic) provides the following detailed information: (1) determination of animal origin.
(2) livestock production and care.
(3) the genetically modified animals (methods of creation, characterisation of transgenic cells, inserted, or removed the gene characteristics).
(4) the measures, as well as originating in the donor animal infection prevention and supervision.
(5) testing for infectious agents including vertically transmitted micro-organisms (also the endogenous retrovīrus).
(6) the equipment.
(7) the cell banking system.
(8) the raw materials and raw material control.
70. For this rule 68. medicinal products referred to in paragraph 1, provide the following information: (1) the active substance (s) and finished product manufacturing process. Document the various stages of the manufacturing process (for example, organ (tissue) dissociation, the cell population, in vitro cell culture, cell transformation by physico-chemical agents or gene transfer).
(2) the active substance (s) in the description provides information about the identity of the population of cells (the cells of origin, banding cytogenetics, morphological associated analysis), purity (adventitious microbial agents and cellular contaminants), potency (defined biological activity) and compliance (karyology and tumorigenicity tests) intended use in medicine.
(3) the finished product pharmaceutical development. 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.
(4) traceability. Provide a detailed scheme that ensures product traceability from the donor to the finished medicinal product.
71. specific requirements for gene therapy and cell therapy (human and xenogeneic) medicinal product in the context of: 71.1. module 4: (1) it is known that the 4th module 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, barriers and different imunoloģis plejotropisk response.
(2) the themes underlying the clinical development, and not criteria used in relation to the species concerned and for the selection of the model describes the module 2.
(3) may establish or develop new research models in animals to drug trials in vivo on the action 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.
71.2. Module 5:

(1) advanced therapy medicinal effectiveness proves as defined in module 5. Some medicines and some therapeutic indications may not be possible to make a conventional clinical trials. Deviations from the guidelines in force based module 2. The clinical development of medicines have some special features as active substances is complex and labile properties. Require additional considerations for 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). Registration request indicates 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. 5. Registration module include the 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: 1) Pharmacology and efficacy studies with people: a) for studies of Pharmacology with people provides information on the expected mode of action and effectiveness, in accordance with the intended purpose of the performance based , biosadalījum, adequate dose, schedule, and methods of use or uses, any desired efficacy trials;
b) pharmacokinetics studies may not be relevant to some of the advanced therapy medicinal product, where studies with healthy volunteers not possible and define the dose and kinetics in clinical studies is difficult. Researching the spread of products and activities in vivo, including cell proliferation and activity of long as well as gene, the preparation and the desired gene expression. Carried out and, where necessary, draw up the appropriate tests to trace cell preparation or cell in the human body gets the desired gene, as well as to monitor or transfected cells used;
c) advanced therapy medicinal product efficacy and safety evaluation of therapeutic procedures include the description and assessment of the overall special uses (for example, transfekcij of cells ex vivo, in vitro manipulation or intervention techniques), as well as the related mode checks (including immunosuppressive, antiviral, cytotoxic treatment);
d) procedure tested in clinical research and describes the summary of product characteristics;
2) security: (a) the appearance of security) issues related to the immune response to drugs or to express the proteins the immune rejection, immunosuppression and the mechanism of breakdown of imūnizolācij;
(b) enhanced gene) some 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/or infectious agents. Observe whether the patient may develop infections, as well as pathological sequelae during, as well as the post phase. If necessary, this surveillance extended to people who have contact with the patient, as well as to health care workers;
c) If you use certain somatic cell therapy medicinal products and certain gene transfer medicinal products cannot be fully excluded substances transmissible possible risk, but with module 3 the measures described can mitigate the risks;
(d)) in the production process measures supplemented by testing methods, quality control processes and appropriate monitoring methods, which describe module; 5.
e) enhanced certain 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;
f) where appropriate, the registration request deals and draws attention to the continued monitoring of aspects of the late complications development;
g) where appropriate, the registration, the applicant submitted a detailed risk management plan to include the laboratories of clinical and patient data, potential epidemiological data and, where relevant, the data from the donor and recipient tissue sample archives. Such a system is needed to ensure the traceability of the medicinal product and quick responses to a suspicious adverse events.
72. Special requirements of ksenotransplantācij (ksenotransplantācij is a 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) and their raw materials. Provides detailed information on the following issues: 1) determination of animal origin;
2) livestock production and care;
3) genetically modified animals (methods of creation, characterisation of transgenic cells, inserted, or removed the gene characteristics);
4 origin of the donor) measures for the prevention and monitoring of the infection;
5) testing for infectious agents;
6) equipment;
7) raw materials and raw material control;
8. "traceability") 3. the Cabinet of Ministers on 31 October 2000 by Regulation No 381 of the registration certificate shall contain the extension of the registration documentation changes for which the application for registration shall be submitted by the owner of the content of the registration certificate, are the following: 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) where the efficacy, as well as the 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, as well as the safety characteristics are not significantly different;
1.3. biological or biotechnological product of substance by substance, which is 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) where the efficacy, as well as the safety characteristics are not significantly different;
1.4. a new ligand or coupling mechanism for a radiopharmaceutical preparation;
1.5. changes to the extraction solvent or herbal medicine plant for where the efficacy, as well as the 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 the speed grade);
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). "
 
 








 









Prime Minister i. Emsis Health Minister r. Muciņš