1 THE EURASIAN ECONOMIC COMMISSION THE BOARD DECISION September 22, 2015 No. 119 Moscow On the Concept of the harmonization of the Pharmacopoeia of the Eurasian Economic Union Member States According to Article 5 of the Agreement on Single Principles and Rules of Circulation of Medicines in the Eurasian Economic Union dated December 23, 2014, para. 27 of Annex 2 to the Regulation of the EEC approved by Decision of the Supreme Eurasian Economic Council No. 98 dated December 23, 2014, and Decision of the Supreme Eurasian Economic Council No. 108 dated December 23, 2014 "On implementation of the Agreement on Single Principles and Rules of Circulation of Medicines in the Eurasian Economic Union", the EEC Board decided: 1. To approve the enclosed Concept of the harmonization of the Pharmacopoeia of the Eurasian Economic Union Member States. 2. This Decision comes into force from the date of entry into force of the Agreement on Common Principles and Rules of Circulation of Medicines within the Eurasian Economic Union dated December 23, 2014. Chairman of the Board of the Eurasian Economic Commission Stamp: THE EURASIAN ECONOMIC COMMISSION FOR DOCUMENTS V. Khristenko
2 APPROVED by Decision No. 119 of the Board of the Eurasian Economic Commission dated September 22, 2015 CONCEPT of the harmonization of the Pharmacopoeia of the Eurasian Economic Union Member States I. Introduction Harmonization of requirements to medicines is a necessary process in the conditions of operation of the common market of medicines within the Eurasian Economic Union (hereinafter - the Union). At the present stage of the regulation of the common market, harmonization is one of the ways to develop pharmacopoeial standards in the Union Member States (hereinafter - the Member States). This Concept was developed in accordance with Article 30 of the Treaty on the Eurasian Economic Union dated May 29, 2014, Article 5 of the Agreement on Common Principles and Rules of Circulation of Medicines within the Eurasian Economic Union dated December 23, 2014, and Decision No. 108 of the Supreme Eurasian Economic Council dated December 23, 2014 "On implementation of the Agreement on Common Principles and Rules of Circulation of Medicines within the Eurasian Economic Union". This Concept defines the model and principles for development of the Pharmacopoeia of the Eurasian Economic Union (hereinafter - the
3 Pharmacopoeia of the Union) based on the Pharmacopeia of the Member States and basic pharmacopeias, approval by the Pharmacopoeial Committee of the Eurasian Economic Union (hereinafter - the Pharmacopoeial Committee of the Union) of harmonized pharmacopoeial monographs of the Pharmacopoeia of the Union that are pharmacopoeial monographs jointly prepared by experts of the Member States and approved in the established procedure by the Pharmacopoeial Committee of the Union, as well as adoption of the Pharmacopoeia of the Union by the EEC Board for the purpose of establishment of transparency of all procedures in this sphere and ensuring continuous process of development of new harmonized pharmacopoeial monographs. The Concept covers harmonization issues of the Pharmacopeia of the Member States regarding both human medicines and veterinary drugs. For the purpose of due development, amending, updating and approval of harmonized pharmacopeial monographs, this Concept defines principles for interaction of the Pharmacopeial Committee of the Union and authorized bodies of the Member States in the sphere of medicines circulation with respect to creation of the common Pharmacopoeia of the Union. This Concept is aimed at implementation of the following tasks: formation of the harmonization model for the Pharmacopeia of the Member States; selection of the main pharmacopeias, which requirements should be considered in harmonization of the pharmacopeia of the Member States, defining their priority; ensuring application of the common process for harmonization of pharmacopeia of the Member States;
4 ensuring uniform principles for the development of pharmacopeial monographs of the Pharmacopoeia of the Union. II. Modern approaches to harmonization of the pharmacopeia of the Member States Harmonization of international pharmacopeias was first started in 1948 when the Secretariat of the World Health Organization (WHO) received the corresponding mandate. The first volume of the first edition of the International Pharmacopeia was published in 1951 for the purpose of harmonization of requirements for the quality of pharmaceutical substances in the whole world. Starting from 2012, for the purpose of global harmonization under the auspices of the WHO Expert Committee on medicines specifications, the WHO standard "Good pharmacopeial practices" (GPhP) has been actively developing. The main objectives of the WHO standard "Good pharmacopeial practices" (GPhP) include: ensuring global quality of medicines through adoption of pharmacopeial standards; assistance in recognition of global pharmacopeial activity; increasing trust of regulatory bodies to the pharmacopeial quality standards for medicines globally; deepening cooperation between all stakeholders (national and regional pharmacopeial committees and other organizations, regulatory bodies, representatives of the pharmaceutical industry) and reduction of expenses related to the development of the pharmacopeial quality standards for
5 medicines; simplification of the procedure for harmonization and recognition of the pharmacopeial quality standards for medicines globally; assistance to the pharmacopeial committees of the Member States in their work for creation of harmonized pharmacopeial quality standards for medicines. The WHO standard "Good pharmacopeial practices" (GPhP) has to become guidelines for national and regional pharmacopeial committees and other organizations engaged in development, publication and distribution of pharmacopeial requirements. The principles and methods for the development of pharmacopeial monographs described in it apply for: pharmaceutical substances; natural medical raw materials (vegetables, animals); pharmaceuticals; biologicals; ex-temporal medicines; reference samples used for medicines testing. Examples of efficient efforts on harmonization of the pharmacopeias are the Pharmacopeial Discussion Group (PDG), Group on harmonization of the common Southern American market (MERCOSUR), etc. The Pharmacopeial Discussion Group (PDG) is directly engaged in harmonization of requirements of the European Pharmacopeia, the United States Pharmacopoeia, and the Japan Pharmacopeia. Within the Group on harmonization of the common Southern American market (MERCOSUR), harmonization of pharmacopeial standards of such Latin American countries as Argentina, Brazil, Paraguay, and Uruguay is performed.
6 Thus, it makes sense to use global and regional experience in harmonization of pharmacopeia for the process of harmonization of the pharmacopeia of the Member States. III. Pharmacopeias of the Member States In the Russian Empire, and then in the USSR, the state quality control of medicines was carried out according to standards and provisions of the State Russian Pharmacopeia (6 editions), and after 1925 it was carried out according to standards and provisions of the State Pharmacopeia of the USSR. The latest editions of the State Pharmacopeia of the USSR, namely editions 10 (1969) and 11 (the first edition in 1987, and the second edition in 1990) retained their regulative character until now, though to a limited extent. For the purpose of gaining experience in the development of pharmacopeial standards, the authorized bodies of the Member States on medicines circulation became official observers of the European Pharmacopeial Commission of the Council of Europe. Pharmacopeial Committees have been established and are functioning in the Republic of Belarus, the Republic of Kazakhstan, and the Russian Federation. The Pharmacopeias of the Republic of Belarus and the Republic of Kazakhstan are almost completely harmonized with the European Pharmacopeia. The structure of the majority of their pharmacopeial monographs has a general part based on requirements of the European Pharmacopeia and a national part based on requirements of the State Pharmacopeia of the USSR and the legislation of the Republic of Belarus and the Republic of Kazakhstan, respectively.
7 The general part of the pharmacopeial monographs of the Member States contains requirements for the quality of medicines produced under the Rules of Good Manufacturing Practices. The national part of the pharmacopeial monographs of the Member States' pharmacopeia reflects individual approaches for the quality of medicines in the Member States. It covers alternative methods and additional information materials. The requirements of the national part of the pharmacopeial monographs are often stricter than the requirements of the European pharmacopeial monographs. 1. The Republic of Belarus Norms concerning the State Pharmacopeia of the Republic of Belarus are established in Law of the Republic of Belarus No. 161-3 "On medicines" dated July 20, 2006. The First edition of the State Pharmacopeia of the Republic of Belarus in 3 volumes was published and effected in 2007 - 2009. The national pharmacopeia monographs include requirements for test methods, quality of medicines and pharmaceutical substances, reagents, containers, preparation and quality control of ex-temporal medicines, study of bioavailability and bioequivalence of reproduced medicines, statistical analysis of the results of chemical experiments, validation of test methods, as well as general requirements for dosage forms, etc. Since January 1, 2013, the first volume of the second edition of the State Pharmacopeia of the Republic of Belarus was effected, which included general pharmacopeial monographs on analysis methods, containers, reagents, ex-temporal medicines, single-unit dosage forms, homeopathic
8 medicines, etc. Pharmacopeial monographs of the national status and amendments to the pharmacopeial monographs have been substantially updated. The first volume of the second edition of the State pharmacopeia of the Republic of Belarus is based on requirements of the 7th edition of the European Pharmacopeia. The official permission for harmonization of the State Pharmacopeia of the Republic of Belarus with the requirements of the European Pharmacopeia was granted by the European Directorate for the Quality of Medicines and Health Care of the Council of Europe (EDQM). The second volume of the second edition of the State Pharmacopeia of the Republic of Belarus will combine pharmacopeial monographs from the second and third volumes of the first edition of the State Pharmacopeia of the Republic of Belarus (463 pharmacopeial monographs for pharmaceutical substances, 136 pharmacopeial monographs for natural medical raw materials, including pharmacopeial monographs of national status). The second volume of the second edition of the State Pharmacopeia of the Republic of Belarus based on the requirements of the European Pharmacopeia (EP 8.0 - 8.4) is expected to be published and effected in 2015. Tests envisaged during development of pharmacopeial monographs shall be carried out in laboratories certified for compliance with STB ISO/IEC 17025-2007 "General requirements for competence of test and calibration laboratories", laboratories complying with international standard ISO/IEC 17025 and being a member of the General European Official Medicines Control Laboratories Network (GEON), as well as laboratories pre-qualified by the WHO and recognized as complying with the WHO
9 recommendations. For the purpose of relevance of the State Pharmacopeia of the Republic of Belarus, and also possible inclusion of new pharmacopeial monographs lacking in the European Pharmacopeia, an agreement with the United States Pharmacopeial Convention (USP) was signed in November, 2013, allowing copying of texts of the United States Pharmacopoeia for their inclusion in pharmacopeial monographs of the State Pharmacopeia of the Republic of Belarus. 2. The Republic of Kazakhstan The need for creation of the State Pharmacopeia of the Republic of Kazakhstan was established by Order of the President of the Republic of Kazakhstan No. 2655 "On medicines" dated November 23, 1995, which has been effected as the law. Further development of the topic was defined by the Law of the Republic of Kazakhstan No. 522-P "On medicines" dated January 13, 2004. The lack of national pharmacopeia requirements made it necessary to recognize the world’s leading pharmacopeia (the European pharmacopeia, the Pharmacopoeia of the USA, the British pharmacopeia, and the German homeopathic pharmacopeia) as an important step to develop the state quality control of medicines in the Republic of Kazakhstan. This was effected by the order of the Committee of pharmacy of the Ministry of Health of the Republic of Kazakhstan No. 21 dated February 11, 2004. The State Pharmacopeia of the Republic of Kazakhstan was created thanks to the state support in 2005 - 2008, approved and effected in 2008. The provisions establishing the status of the State Pharmacopeia of the Republic of Kazakhstan are given in the Code of the Republic of Kazakhstan
10 No. 193-IV "On health of people and health care" dated September 18, 2009. Application of the pharmacopeial standards existing in the Republic of Kazakhstan is ensured according to the agreed priority level. The first priority level is the State Pharmacopeia of the Republic of Kazakhstan. The European Pharmacopeia (the second priority) is applied in case of missing first-priority pharmacopeial monographs in it. The United States Pharmacopeia and the British Pharmacopeia have the third priority level. The first edition of the State Pharmacopeia of the Republic of Kazakhstan was published in 2008 - 2009 in 2 volumes in Kazakh and Russian languages. The first volume contains general pharmacopeial monographs, the second volume contains 300 pharmacopeial monographs for pharmaceutical substances, 26 pharmacopeial monographs for natural medical raw materials, 77 pharmacopeial monographs for medicines, 15 pharmacopeial monographs for human vaccines and human antibodies. Besides harmonized texts, the State Pharmacopeia of the Republic of Kazakhstan includes 100 national pharmacopeial monographs for natural medical raw materials and medicines. The official permission for copying texts of the European Pharmacopeia was granted by its patent holder - the European Directorate for the Quality of Medicines and HealthCare (EDQM). For the purpose of harmonization of the State Pharmacopeia of the Republic of Kazakhstan with the requirements of the United States Pharmacopoeia the Republic of Kazakhstan became the official observer in July, 2009, and in November, 2010 - a voting member of the United States Pharmacopeial Convention (USP). In October, 2010, an agreement on harmonization of the State Pharmacopeia of the Republic of Kazakhstan with
11 the standards of the United States Pharmacopoeia was signed, which allowed copying its texts and their further inclusion in national pharmacopeial monographs in full and/or partly. For the same purpose, an agreement with the British Medicines and Healthcare products Regulatory Agency (MHRA) was signed in April 2014, which envisaged a ability of harmonization of the State Pharmacopeia of the Republic of Kazakhstan with the standards of the British Pharmacopeia. Further development of the State Pharmacopeia of the Republic of Kazakhstan is provided for by the State Program of Health Care Development of the Republic of Kazakhstan "Salamatty Kazakhstan" for 2011 - 2015 approved by Order of the President of the Republic of Kazakhstan No. 1113 dated November 29, 2010. The third volume of the State Pharmacopeia of the Republic of Kazakhstan harmonized with the requirements of the European Pharmacopeia (EP 8.0 - 8.2), the United States Pharmacopoeia (USP 37), and the British Pharmacopeia (BP 2014) has already been published. The edition contains 304 new general and individual pharmacopeial monographs for pharmaceutical substances, natural medical raw materials, medicines, radio-pharmaceutical medications and raw materials for radio-pharmaceutical medications, homeopathic medicines, and medical products. Tests envisaged during development of pharmacopeial monographs shall be carried out in laboratories accredited for compliance with ST RK ISO/IEC 17025-2007 "General requirements for competences of test and calibration laboratories". At the moment, works are ongoing on the entry of these laboratories in the General European Official Medicines Control
12 Laboratories Network (GEON). 3. The Russian Federation There is a succession chain between the State Pharmacopeia of the Russian Federation and the State Pharmacopeia of the USSR which, in turn, was a result of further development of the State Russian Pharmacopeia. The history of these pharmacopeias publications began more than 200 years ago. Provisions on the State Pharmacopeia of the Russian Federation defining its official status are established in the Federal law No. 61-FZ "On medicines circulation" dated April 12, 2010. Today, the twelfth edition of the State Pharmacopeia of the Russian Federation (Part 1) 2007 is in force in the territory of the Russian Federation. However, given that general pharmacopeial monographs from the State Pharmacopeia of the USSR of the eleventh edition (1986, 1989) and partly the tenth edition (1968) were not included in it, all the three specified editions are in use in the Russian Federation. During the period between the issue of the eleventh edition of the State Pharmacopeia of the USSR and the twelfth edition of the State Pharmacopeia of the Russian Federation, some general pharmacopeial monographs and those pharmacopeial articles, changes and amendments thereto were brought in force with the legal force equal to the legal force of the State Pharmacopeia of the Russian Federation. The Russian system of standardization of medicines is based on the following fundamental elements: general pharmacopeial monographs; pharmacopeial monographs; pharmacopeial reference samples.
13 229 general pharmacopeial monographs for analysis methods, general methods, dosage forms, immunobiological drugs, natural medical raw materials, and their analysis methods will be included in the thirteenth edition of the State Pharmacopeia of the Russian Federation, which is planned for publishing in the nearest future. Requirements of almost all the new general pharmacopeial monographs are aligned with the requirements of similar pharmacopeial standards of leading foreign pharmacopeias as much as possible (European, British, Japan Pharmacopeia, and the United States Pharmacopoeia). After these general pharmacopeial monographs (except for several obsolete general pharmacopeial monographs) are effected, general pharmacopeial monographs from the tenth and eleventh editions of the State Pharmacopeia of the USSR, as well as the twelfth Pharmacopeia of the Russian Federation will be cancelled. Moreover, the thirteenth edition of the State Pharmacopeia of the Russian Federation will include more than 179 pharmacopeial monographs for medicines of synthetic, natural and biological origin. The thirteenth edition of the State Pharmacopeia of the Russian Federation will include all main pharmacopeial monographs, including pharmacopeial standards for a number of immunobiological drugs and their analysis methods. Today, the Federal State Budgetary Institution "Scientific Center for Testing Human Medical Products" of the Ministry of Health of the Russian Federation represented by the Center of Pharmacopeia and International Cooperation actively cooperates with the leading foreign pharmacopeias (European, British, Japan Pharmacopeias, and the United States
14 Pharmacopoeia) and the pharmacopeias of the Member States. Representatives of the Russian Federation are members of the WHO Working Group that is working on the development of Good Pharmacopeial Practices (GPhP) standard established at the initiative of the WHO for perspective harmonization of pharmacopeial standards. Tests envisaged during the development of pharmacopeial monographs shall be carried out in the Test Center of the Quality of Medicines of the Federal State Budgetary Institution "Scientific Center for Testing Human Medical Products" of the Ministry of Health of the Russian Federation, 4 laboratories of which are certified for compliance with international standard ISO/IEC 17025 and are associated members of the General European Official Medicines Control Laboratories Network (GEON), and 2 its laboratories have been pre-qualified by the WHO and recognized as conforming to the WHO standard "Good Laboratory Practices for quality control of pharmaceutical products". 4. Baseline analysis for harmonisation of the Pharmacopoeias of the Member States and development of the Pharmacopoeia of the Union Analysis of the status and prospects of developing the pharmacopoeial standards of the Member States gives the possibility to define their following strong points: experience of harmonisation - in most cases, the pharmacopoeias of the Member States are harmonised with the requirements of the European Pharmacopoeia; understanding of the role and operating mechanism of the Pharmacopoeias of the Member States, the necessity for continuous
15 development and updating of the pharmacopoeial standards of the Member States; understanding of the necessity for further harmonisation of the pharmacopoeial standards of the Member States with the requirements of the leading world pharmacopoeias (European, British, Japan Pharmacopoeias and the United States Pharmacopoeia) and with each other; experience (knowledge, methodologies, etc.) related to the development and implementation of the pharmacopoeial standards, acquired through regular participation in sessions of the European Pharmacopoeial Commission of the Council of Europe and in the course of creating the Pharmacopoeias of the Member States; experience of international cooperation, participation in the global pharmacopoeial activities, development and discussion of the WHO standard "Good Pharmacopoeial Practices" (GPhP), creation of the Global Pharmacopoeial Index with the support of the United States Pharmacopoeial Convention and the Chinese Pharmacopoeial Commission and other international projects. Weaknesses of the pharmacopoeial standards of the Member States are as follows: differences in the requirements of the pharmacopoeial monographs of the Pharmacopoeias of the Member States; insufficient coverage of medicines, in particular, pharmaceuticals, by the pharmacopoeial monographs of the Pharmacopoeias of the Member States; lack of experience in multilateral harmonisation at the regional level of the pharmacopoeial requirements of the Member States as equal participants;
16 significant difference of the level of development and export orientation of the pharmaceutical industry of the Member States, which can influence the stringency of the pharmacopoeial requirements of the Member States and hinder the process of their harmonisation; significant difference in the degree of harmonisation of the pharmacopoeial requirements of the Member States with the leading world pharmacopoeias (European, British, Japan Pharmacopoeias and the United States Pharmacopoeia). Within the framework of the present Concept, it is envisaged that the action programme of the Member States and (or) authorised authorities of the Member States shall include: support of the authorised authorities of the Member States in circulation of medicines to ensure the harmonisation of the Pharmacopoeias of the Member States; training of highly qualified personnel in the field of medicine and pharmacy, as well as ensuring their participation in the development of national and harmonised regional pharmacopoeial requirements; promoting the establishment of test laboratories equipped with the modern analytical equipment and possessing trained personnel for carrying out experimental works on the preparation of the pharmacopoeial monographs (their verification, validation, etc.); involvement in the provision of advisory and methodological assistance of international organisations, regulatory and pharmacopoeial authorities of other states on the development and harmonisation of the requirements of the pharmacopoeial monographs.
17 IV. Stages and terms of implementation of the Concept Given the fact that the development of general and individual pharmacopoeial monographs is a continuous process not limited in time, implementation of this Concept is ongoing. There are 2 stages of implementation of this Concept. The first stage envisages the development of harmonised general pharmacopoeial monographs of the Pharmacopoeia of the Union establishing requirements for the following aspects: quality control methods for medicines and equipment required for conducting quality testing of medicines; packaging materials; reagents; dosage forms; pharmaceutical substances; reference samples; excipients used in the production of medicines intended for circulation within the Union. Development and, starting from 2016, introduction of the harmonised general pharmacopoeial monographs of the Pharmacopoeia of the Union shall be provided by the authorised bodies of the Member States for circulation of medicines. The second stage envisages the development of harmonised specific pharmacopoeial monographs for pharmaceutical substances (including substances for veterinary pharmaceuticals), natural medical raw materials(plant, animal), pharmaceuticals and other medicines by the authorised bodies of the Member States in circulation of medicines on the
18 basis of the Pharmacopoeial Committee of the Union. V. Approaches to the harmonisation of the Pharmacopoeia of the Member States and its contents Approaches to the harmonisation of the Pharmacopoeia of the Member States include: introduction and application of the WHO standard "Good Pharmacopoeial Practices" (GPhP) at all levels of development, preparation and assessment of regulatory documentation on quality control of medicines; gradual transition from using the Pharmacopoeia of the Member States to using the Pharmacopoeia of the Union; creation of a single expert body - the Pharmacopoeial Committee of the Union and its centralized dissemination of the harmonised pharmacopoeial monographs and guidelines on the quality of medicines. In accordance with this Concept, the following will be harmonised in the Member States: conceptual framework and the used systems of measurement units; pharmacopoeial requirements for the equipment used in the quality control of medicines; pharmacopoeial requirements for physical, physical & chemical, chemical, biological and other methods of analysis; pharmacopoeial requirements for identification (authentication) of pharmaceutical substances; pharmacopoeial requirements for impurities testing; pharmacopoeial requirements for methods of quantification; biological test methods and pharmacopoeial requirements for
19 biological methods of quantification; pharmacopoeial requirements for pharmacognostic methods; pharmacopoeial requirements for pharmaceutical and technological tests; pharmacopoeial requirements for reagents, as well as materials and systems for medicines closure; pharmacopoeial requirements for microbiological indicators; pharmacopoeial requirements for dosage forms and groups of pharmaceuticals; pharmacopoeial requirements for homeopathic pharmaceuticals; pharmacopoeial requirements for pharmaceutical substances, herbal pharmaceuticals. VI. Basic principles and provisions to ensure harmonisation of the Pharmacopoeia of the Member States The basic principles for harmonisation of the Pharmacopoeia of the Member States are as follows: continuity of the harmonisation process; transparency of the harmonisation process; copyright compliance; recognition of the right of the Member States to include harmonised pharmacopoeial monographs of the Pharmacopoeia of the Union in the Pharmacopoeias of the Member States. Harmonisation of the Pharmacopoeia of the Member States is based on the following provisions: accounting of all types and mechanisms of harmonisation of
20 pharmacopoeial standards used in the world practice; experience of the formation of the Pharmacopoeia of the Member States and their differences; accounting of pharmacopoeial requirements defined for the purpose of this Concept as core requirements (European Pharmacopoeia, British Pharmacopoeia, United States Pharmacopoeia), depending on their level of priority; interaction of the Pharmacopoeial Committee of the Union and authorised bodies of the Member States in circulation of medicines, including in the provision of accredited testing laboratories of the Member States for the verification of projects of harmonised pharmacopoeial monographs; participation of representatives of business community, scientific and public organisations, and other independent experts in the process of harmonisation of the Pharmacopoeia of the Member States; development of international cooperation within the framework of the global process of harmonisation of pharmacopoeial requirements. VII. Common approach to harmonisation of the Pharmacopoeia of the Member States 1. Choice of the harmonisation model In international practice, the procedure of harmonisation is carried out using the full (adoption) or selective (adaptation) mechanisms. The complete mechanism involves copying a pharmacopoeial monograph recognised as basic. When implementing the selective mechanism, it is allowed for
21 establishing more stringent or more lenient requirements to the quality of medicines in comparison with the requirements of a baseline pharmacopoeia monograph. There are two types of harmonisation - retrospective and prospective. Retrospective harmonisation is applied to pharmacopoeial monographs included in the pharmacopoeias. Prospective harmonisation affects the methods (techniques) of conducting tests and medicines (excipients), which were not previously covered by pharmacopoeial standardisation. The harmonisation objects shall include general sections and pharmacopoeial monographs, as well as individual pharmacopoeial monographs of the Pharmacopoeia of the Member States. Harmonisation of pharmacopoeial monographs shall cover: pharmaceutical substances; herbal medical raw materials (plants, animals); dosage forms; pharmaceuticals; biologicals; tests (physical, physical & chemical, chemical, biological, pharmaceutical & technological, etc.); methods (techniques) of conducting tests; acceptable norms (acceptance criteria) established for the indicators of the quality of medicines and methods (techniques) of testing. In the European Pharmacopoeia, requirements for pharmaceuticals are regulated not by individual, but by general monographs. In addition to general monographs, unlike the European Pharmacopoeia, other pharmacopoeias (the British Pharmacopoeia and the United States
22 Pharmacopoeia) include individual monographs for pharmaceuticals. This Concept comes from the necessity of regulating the harmonised pharmacopoeial requirements of the Pharmacopoeia of the Union both for pharmaceutical substances and the corresponding pharmaceuticals. Harmonised pharmacopoeial monographs for pharmaceuticals can be optionally harmonised with the British Pharmacopoeia and the United States Pharmacopoeia. The differences in the requirements of major pharmacopoeias define the necessity of establishing the levels of priority of major pharmacopoeias in the harmonisation. The first level of priority provides for the selection of a basic pharmacopoeia. The second level of priority involves the use of another pharmacopoeia in the absence of a relevant pharmacopoeial monograph in the basic pharmacopoeia. In order to develop the models of harmonisation of the Pharmacopoeia of the Member States, it is expedient to distinguish the following cases: harmonisation object is regulated by the basic first level pharmacopoeia; harmonisation object is regulated by the second level pharmacopoeias; harmonisation object is regulated neither by the first level nor the second level pharmacopoeias. In the first two cases, harmonisation can be carried out using both full and selective mechanisms. The selective mechanism involves the partial borrowing of individual pharmacopoeial provisions, or methods (techniques) of conducting tests, or the permissible norms acceptance criteria), etc. In case of modification of the pharmacopoeia methods (techniques) of testing, it is required to conduct their verification and validation in accordance with
23 the accepted pharmacopoeial requirements of the Pharmacopoeia of the Union. The full harmonisation mechanism does not require the development of the harmonised pharmacopoeial monograph. Reference to the relevant pharmacopoeia, which is the source of borrowing, is enough. When using the selective mechanism for each harmonisation object, to which it was applied, it is required to develop the harmonised pharmacopoeia monograph with reference to the source of borrowing. In case the harmonisation object is not regulated either by the first level or the second level pharmacopoeias, it is required to develop the harmonised pharmacopoeial monographs. In this case, the type of harmonisation of pharmacopoeial requirements may be both retrospective and prospective. Retrospective harmonisation is possible if the harmonisation object is described in the Pharmacopoeias of the Member States. In the absence of the relevant pharmacopoeial monograph in the Pharmacopoeias of the Member States, it is required to conduct prospective harmonisation based on the quality specifications of the manufacturers of a particular pharmaceutical (excipient). In accordance with the international norms and principles in circulation of medicines, pharmacopoeial monographs are considered to be harmonised, if the same results are achieved when testing pharmaceuticals (excipientss) using the harmonised methods, and a decision on their acceptance is made. 2. Priority levels of major pharmacopoeias, which requirements will be
24 considered when conducting harmonisation of pharmacopoeial monographs of the Pharmacopoeia of the Member States Within the context of harmonisation of the Pharmacopoeia of the Member States, the following pharmacopoeias shall be recognised as the main pharmacopoeias: European Pharmacopoeia; British Pharmacopoeia; United States Pharmacopoeia. As the base pharmacopoeia (major first level pharmacopoeia), it is advisable to recognise the European Pharmacopoeia due to its complete harmonisation with the Pharmacopoeia of the Republic of Belarus and the Republic of Kazakhstan, as well as due to the use of pharmacopoeial monographs of this Pharmacopoeia in full by the Republic of Armenia. The British Pharmacopoeia and the United States Pharmacopoeia have the status of the second level pharmacopoeias. In this case, with regards to veterinary pharmaceuticals, the British Pharmacopoeia has a priority in the harmonisation of texts. 3. General procedure for harmonisation of the Pharmacopoeia of the Member States The procedure for development and adoption of the harmonised pharmacopoeial monographs shall be conducted in accordance with the procedure for harmonisation of the Pharmacopoeia of the Member States defined by the Pharmacopoeial Committee of the Union. For the purposes of harmonisation of pharmacopoeial monographs, the Agreement on Common Principles and Rules of Circulation of Medicines
25 within the Eurasian Economic Union dated December 23, 2014 provides for the establishment of the Pharmacopoeial Committee of the Union comprising of experts recommended by each of the Member States and the Eurasian Economic Commission. The main tasks and powers of the Pharmacopoeial Committee of the Union are established by the Regulation on the Pharmacopoeial Committee of the Eurasian Economic Union approved by the Eurasian Economic Commission. Selection of the harmonisation procedure is carried out by the Pharmacopoeial Committee of the Union and includes the following steps: submission by one of the authorised bodies of the Member State in circulation of medicines to the Pharmacopoeial Committee of the Union of an application on the necessity to develop a harmonised pharmacopoeial monograph, update or amend a pharmacopoeial monograph with the appropriate justification; consideration by the Pharmacopoeial Committee of the Union of the specified application and making the relevant decision on expediency of developing a pharmacopoeial monograph, updating or amending a pharmacopoeial monograph; determination by the Pharmacopoeial Committee of the Union of the authorised body and (or) organisation of the Member State, which will draft a harmonised pharmacopoeial monograph, update or amend a pharmacopoeial monograph (hereinafter - the "Developer"), in the case of making a decision by the Pharmacopoeial Committee of the Union on expediency of developing a pharmacopoeial monograph, updating or amending a pharmacopoeial monograph; submission by the executive Developer to the Secretariat of the
26 Pharmacopoeial Committee of the Union of the draft harmonised pharmacopoeial monograph, updates or amendments to the pharmacopoeial monograph, an explanatory note with the appropriate justification and other required documents; consideration and discussion by the Pharmacopoeial Committee of the Union of the draft harmonised pharmacopoeial monograph, updates or amendments to the pharmacopoeial monograph, the explanatory note with the appropriate justification and the documents attached thereto, as well as, if required, review and discussion by a specialized expert group at the Pharmacopoeial Committee of Union of such draft, explanatory note with the appropriate justification and the documents attached thereto; verification of the draft harmonised pharmacopoeial monograph at the accredited test laboratories of the Member States (if necessary, especially when conducting prospective harmonisation) appointed by the Pharmacopoeial Committee of the Union for these purposes; revision (if necessary) by the executive Developer of the draft harmonised pharmacopoeial monograph on the basis of recommendations received at the sessions of the specialised expert groups at the Pharmacopoeial Committee of the Union; reconsideration of the draft harmonised pharmacopoeial monograph by the Pharmacopoeial Committee of the Union (if required); making a decision on placing the draft harmonised pharmacopoeial monograph in the specialised press of the Member States and on the official website of the Union in the information and telecommunications network "Internet" for public discussion;
27 consideration by the specialised expert group at the Pharmacopoeial Committee of the Union of the comments received following the results of the public discussion (if any) and introduction of the required corrections by the executive Developer; approval of the draft harmonised pharmacopoeial monograph by the specialised expert group at the Pharmacopoeial Committee of Union and its subsequent approval by the Pharmacopoeial Committee of the Union; adoption of the approved harmonised pharmacopoeial monograph following the results of consideration at the session of the Pharmacopoeial Committee of the Union by the Chairman of the Pharmacopoeial Committee of the Union and preparation of the draft decision of the Eurasian Economic Commission on the inclusion of such pharmacopoeial monograph or a group of pharmacopoeial monographs in the Pharmacopoeia of the Union; publication of the volume of the Pharmacopoeia of the Union or an addendum to the volume of the Pharmacopoeia of the Union, including: layout of the texts of the pharmacopoeial monographs of the Pharmacopoeia of the Union; scientific editing of the texts of the pharmacopoeial monographs of the Pharmacopoeia of the Union; proofreading of the texts of the pharmacopoeial monographs of the Pharmacopoeia of the Union; publication of the volume of the Pharmacopoeia of the Union or an addendum to the volume of the Pharmacopoeia of the Union.
28 4. Principles for the development of harmonised pharmacopoeial monographs In order to ensure uniform principles for development of harmonised pharmacopoeial monographs, the Pharmacopoeial Committee of the Union approves the guidelines for development and harmonisation of pharmacopoeial monographs. Guidelines for development and harmonisation of pharmacopoeial monographs are created subject to the provisions of the Technical Guidelines for development of monographs adopted by the European Pharmacopoeial Commission of the Council of Europe, the WHO standard "Good Pharmacopoeial Practices" (GPhP) and the relevant guidelines of the International Council for Harmonisation of Technical Requirements for Registration of Human Pharmaceuticals (ICH). 5. Pharmacopoeia of the Union The first volume of the Pharmacopoeia of the Union includes harmonised general pharmacopoeial monographs establishing requirements for the methods of quality control of medicines and equipment required to conduct quality testing of medicines, package materials, reagents, dosage forms, pharmaceutical substances, reference samples, excipients used in the production of medicines intended for circulation within the Union. Subsequent volumes of the Pharmacopoeia of the Union include harmonised individual pharmacopoeial monographs for pharmaceutical substances (including veterinary pharmaceutical substances), natural medical raw materials (plants, animals), pharmaceuticals and other
29 medicines. Harmonised pharmacopoeial monographs for veterinary pharmaceuticals are included in a separate volume of the Pharmacopoeia of the Union (in case if they differ from the pharmacopoeial monographs for human medicines). Harmonised general and individual pharmacopoeial monographs, which are not included in the regular edition of the Pharmacopoeia of the Union, may be issued in the form of addenda. The Pharmacopoeia of the Union has the first priority level in harmonisation regarding the basic pharmacopoeias, subject to the requirements of which it is harmonised. Requirements of the Pharmacopoeia of the Union shall be complied in circulation of medicines within the Union. To ensure the proper functioning of the common market of medicines within the Union, it is required to update the Pharmacopoeia of the Union not less than once in 5 years. Preparation of the edition of the Pharmacopoeia of the Union and its subsequent regular updates shall be carried out by the Eurasian Economic Commission. 6. Reference samples required for ensuring harmonised pharmacopoeial monographs of the Pharmacopoeia of the Union To ensure harmonised pharmacopoeial monographs of the Pharmacopoeia of the Union, it is required to form a list of reference samples, which maintenance shall be determined by the Pharmacopoeial Committee of the Union. Suitable reference samples of the Pharmacopoeia of the Union, the
30 Pharmacopoeia of the Member States and the major pharmacopoeias can be used as the reference samples. Seal: THE EURASIAN ECONOMIC COMMISSION FOR DOCUMENTS