ISPE Annual Meeting 29 October 1 November 2017 San Diego, CA

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1 Ministry of Industry and Trade/ Department of pharmaceutical and medical industry development Moscow September 22, 2017 MEDICINES CIRCULATION SYSTEM IN THE RUSSIAN FEDERATION Ministry of Healthcare Medicines registration Monitoring of clinical trials Quality expertise of medicines Issuing marketing authorizations for medicines Maintenance of medicines register Ministry of Industry and Trade Licensing of medicines manufacturing and maintenance of licenses register License control GMP Inspecting of Russian medicines manufacturers GMP Inspecting of foreign medicines manufacturers Federal Service for Surveillance in Healthcare (Roszdravnadzor) Federal state surveillance in the field of drugs for medical use circulation State control for medical devices circulation State control of quality and safety of medical activity GDP Inspecting Pharmacovigilance Federal Service for Veterinary and Phytosanitary Surveillance (Rosselkhoznadzor) Registration of medicinal products for veterinary use State surveillance in the sphere of medicines circulation with regard to medicines for veterinary use Licensing of manufacturing of medicines for veterinary use and maintenance of the license register License control GMP Inspecting of Russian manufacturers of medicines for veterinary use GMP Inspecting of foreign manufacturers of medicines for veterinary use 2 1

2 ORGANIZATIONAL STRUCTURE Ministry of Industry and Trade of the Russian Federation Department of pharmaceutical and medical industry development* Department Director - А. Alekhin Department Deputy Director E. Denisova FSI «State Institute of Drugs and Good Practices»** (Director - V. Shestakov) Other Departments of Minpromtorg of Russia Department of Licensing the production of medicines Head M. Sottaeva (12 employees) OTHER DEPARTMENT UNITS Administration of pharmaceutical producers inspection Head Т. Nikolko (58 employees) Other units of FSI «SID & GP» * According to the order of the Minpromtorg of Russia of June 7, 2013 No. 877, the structural subdivision of the Ministry responsible for licensing and inspecting manufacturing of medicines is the Department of the Pharmaceutical and Medical Industry Development ** According to the order of the Minpromtorg of Russia No of December 21, 2015, FSI «SID & GP» is authorized to inspect manufacturers of drugs for medical use that are produced outside the Russian Federation to meet the requirements of the rules of Good Manufacturing Practice in order to issue compliance certificates of medicines manufacturer to the requirements of the rules of Good Manufacturing Practice. 3 Significant dates and events History of Ministry of Industry and Trade of the Russian Federation 14 June 1946: Ministry of Medical industry of USSR was based on plants of chemical-pharmaceutical, medical-instrumental and prosthetic industries of the Ministry of Healthcare of USSR and Ministries of Social Support of the Union Republics. 12 May 2008: Ministry of Industry and Trade was established with the subsequent transfer to him: functions (in part of industry) of the disbanded Ministry of Industry and Energy of the Russian Federation; trade regulation functions of the Economic Development and Trade Ministry; functions of subordinated Federal Agency of Technical Regulation and Metrology (Rosstandart). 4 2

3 Significant dates and events GMP history in Russia 1991 : Approved directive document Good manufacturing and quality control of drugs practice 1998 : Approved industry-specific standard Industry standard. Good manufacturing and quality control of drugs practice 2004 : Resolution of Gosstandart of Russia of 10 March 2004 N160-st on approval of State Standard R «Good manufacturing and quality control of drugs practice» 2009 : Approved State Standard R Good manufacturing and quality control of drugs practice by the Order of Federal Agency of Technical Regulation and Standardization of 20 May 2009 N159-st 5 Significant dates and events 2010: Federal law of 12 April FZ On Circulation of Medicines 2011: Federal law of 4 May FZ «On Licensing of certain types of activities» 2012: Government Decree of 6 July «Concerning approval of Statement for the Licensing of medicines manufacturing» 2013 : Order of the Ministry of Industry and Trade of the Russian Federation of 07 June "On approval of the Administrative Regulations of the Ministry of Industry and Trade of the Russian Federation for the provision of a state service for licensing the production of medicinal products for medical use" 6 3

4 Significant dates and events 2013: Order of the Ministry of Industry and Trade of the Russian Federation of 14 June «On approval of Good Manufacturing Practice Rules» 2013: Order of the Ministry of Industry and Trade of the Russian Federation of 4 October «On approval of the Administrative Regulation for execution by the Ministry of Industry and Trade of the Russian Federation of a state service for licensing control of the production of medicinal products for medical use» 2013: Order of the Ministry of Industry and Trade of the Russian Federation of 12 December «On approval of recommendations for production and quality control of medicines» 2015: Government Decree of 3 December «On determination of drugs for medical use manufacturers compliance with the requirements of the rules of Good Manufacturing Practice» 7 Laws and regulations for medicines production in the Russian Federation Federal law of 12 April FZ «On Circulation of Medicines» Federal law of 4 May FZ «On Licensing of certain types of activities» Federal law of 26 December FZ «On protection of rights of legal entities and individual entrepreneurs upon implementation of state control (supervision) and municipal control» Government Decree of 5 June «On the Ministry of Industry and Trade of the Russian Federation» 2012: Government Decree of 6 July «Concerning approval of Statement for the Licensing of medicines manufacturing» Government Decree of 3 December «On determination of drugs for medical use manufacturers compliance with the requirements of the rules of Good Manufacturing Practice» 8 4

5 Laws and regulations for medicines production in the Russian Federation Order of the Ministry of Industry and Trade of 7 June "On approval of the Administrative Regulations of the Ministry of Industry and Trade of the Russian Federation for the provision of a state service for licensing the production of medicinal products for medical use" Order of the Ministry of Industry and Trade of the Russian Federation of 14 June «On approval of Good Manufacturing Practice Rules» Order of the Ministry of Industry and Trade of 4 October «On approval of the Administrative Regulation for execution by the Ministry of Industry and Trade of the Russian Federation of a state service for licensing control of the production of medicinal products for medical use» 9 Laws and regulations for medicines production in the Russian Federation Order of the Ministry of Industry and Trade of the Russian Federation of 12 December «On approval of recommendations for production and quality control of medicines» Order of the Ministry of Industry and Trade of the Russian Federation of 4 February "On approval of the application form for issuing the compliance certificate of manufacturer (foreign manufacturer) of drugs for medical use with GMP Rules requirements; the form of GMP inspection report upon the results of inspection of drugs for medical use manufacturer on compliance with GMP Rules requirements and the form of GMP compliance certificate of the manufacturer (foreign manufacturer) of drugs for medical use compliance with GMP Rules requirements» Order of the Ministry of Industry and Trade of the Russian Federation of 17 December «On approval of the Procedure for maintaining the State register of GMP compliance certificates of the manufacturers of drugs for medical use with GMP Rules requirements» 10 5

6 Rights and authorities of the Ministry of Industry and Trade of the Russian Federation Department of Pharmaceutical and Medical Industry Development of the Ministry of Industry and Trade of the Russian Federation Department of medicines manufacturing licensing and inspection licensing the production of drugs for medical use and maintenance of the issued licenses register; license control; organization and (or) conduction of GMP Inspecting of manufacturers of drugs for medical use on compliance with GMP Rules requirements; issuing of certificates on compliance of the manufacturers of drugs for medical use with GMP Rules requirements; maintenance of State register of certificates on compliance of the manufacturers of drugs for medical use with GMP Rules requirements; issuance of a document confirming that production of a drug for medical use is carried out in accordance with the requirements of Good Manufacturing Practice rules, and is required to be submitted at the request of the authorized body of the country into which the medicinal product is imported (hereinafter referred to as the SRR document); issuance of a document containing data on technological process stages of drugs for medical use production, carried out on the territory of the Eurasian Economic Union (hereinafter SP document); 11 Structure of the regulatory framework of the Russian Federation Structure of the regulatory framework of the Russian Federation Constitution of the Russian Federation Level 1 Federal laws Level 2 Decrees of the Government of the Russian Federation Level 3 Departmental orders, including administrative orders, regulations (registered by the Ministry of Justice of the Russian Federation) Level 4 Internal orders and instructions on activities organization of the Ministry of Industry and Trade of the Russian Federation and FSI «SID & GP» Level 5 Internal documentation of the Department of pharmaceutical and medical industry development and FSI «SID & GP» (regulations, orders, instructions, etc.) 12 6

7 Quality Management System (QMS, system of internal documentation) Internal documentation of the Department of pharmaceutical and medical industry development and FSI «SID & GP» (regulations, orders, instructions, etc.) that are distributed on 5 Levels Level 1 Quality Policy Goals in Quality External documents Level 2 Quality Manual Level 3 Standards, Provisions, Job descriptions Level 4 SOPs, Programs, Plans, Schedules Level 5 Reports, logs, records, fill-in forms 13 Quality Management System (QMS, system of internal documentation) Level 1 - Quality policy that gives the overall intentions and direction of the organization related to quality, formally expressed by top management. Quality policy defines specific and measurable goals in the areas of quality that had to be brought to the notice of all the staff. Level 2 - Quality Manual RK-FI-01/MPT the document which is describing the quality system of the organization in whole, the sequence and interaction of all processes included into the quality system; references to the documented procedures. Level 3 - Fundamental documentation which describe individual processes and activities necessary for the quality system functioning, which requires detailed descriptions of actions within a process. These include the organization standards, the provisions according to the functional and organizational issues, provisions on departments, job descriptions. Level 4 - Documents containing the detailed description of individual actions within the processes of the quality system and necessary to ensure the effective implementation of processes and control of them. These include standard procedures, programs of specific activities, plans of the main activity, schedules. Level 5 - Registered data (records) required by standards and procedures and accompanying the implementation of specific actions. These include forms of blanks, logs, reports, which are filled in during or immediately after the implementation of actions within the processes of the quality system. 14 7

8 The Quality Management System (QMS, system of internal documentation) Codex of Inspector Quality Policy 15 The Quality Management System (QMS, list of approved documentation) Level Document code Document name Level 1 Quality Policy Level 1 Codex of Inspector Level 1 Regulations of Inspectorate Level 2 RK-FI-01/MPT Quality Manual Level 3 STO-FI-VА-04/MPT Conducting of Self audits Level 3 STO-FI-ОП-05/MPT Training of Personnel Level 3 STO-FI-UD-01/MPT Records Administration Level 3 STO-FI-ОI-02/MPT Organization of medicines manufacturers inspecting Level 3 STO-FI-IP-03/MPT Inspecting of medicines manufacturers 16 8

9 The Quality Management System (QMS, list of approved documentation) Level Document code Document name Level 4 SP-FI-IP-06/MPT Risk Management while Inspecting of Medicines manufacturing Level 4 SP-FI-IP-08/MPT Selection of samples (examples) during inspecting of medicines manufacturers with the purpose of quality control Level 4 SP-FI-IP-09/MPT Procedure of collaboration with involved experts Level 4 SP-FI-IP-02/MPT Procedure for dealing with complaints from the Applicant Level 4 SP-FI-UD-03/MPT Procedure for the Order of documents registration of Quality System Level 4 SP-FI-UD-04/MPT Procedure for Records control Level 4 SP-FI-SK-05/MPT Terms, Definitions and Abbreviations Level 4 SP-FI-ОP-11/MPT Evaluation of candidates for the inspections positions Level 4 SP-FI-RK-01/MPT Estimation of Efficiency and Effectiveness of Quality System Level 4 SP-FI-RK-10/MPT Oder of assurance of joint inspections conducting 17 The Quality Management System (QMS, list of approved documentation) Level Document code Document name Level 5 ОL-FI-01/MPT Pharmaceutical Quality System Level 5 ОL-FI-02/MPT Warehouse Level 5 ОL-FI-04/MPT Specific Guidance for APIs Manufactured by Cell Culture/Fermentation (18) in Part II (B) Level 5 ОL-FI-05/MPT Pharmaceutical substances for clinical trials (Part II.19) Level 5 ОL-FI-07/MPT Manufacture of Biological (including immunobiological) active substances and Medicines (Annex II) Level 5 ОL-FI-08/MPT Manufacture of Radiopharmaceuticals (Annex 3) Level 5 ОL-FI-10/MPT Manufacture of Herbal Medicinal Products (Annex 7) Level 5 ОL-FI-11/MPT Manufacture of Liquids, Creams and Ointments (Annex 9) 18 9

10 The Quality Management System (QMS, list of approved documentation) Level Document code Document name Level 5 ОL-FI-13/MPT Manufacture of Medicines Derived from Human Blood or Plasma (Annex 14) Level 5 ОL-FI-14/MPT Computerized Systems (Annex 11) Level 5 ОL-FI-15/MPT Applying of Ionizing Radiation in the Medicines Manufacturing (Annex 12) Level 5 ОL-FI-16/MPT Medicines for clinical trials (Annex 13) Level 5 ОL-FI-17/MPT Qualification and validation (Annex 15) Level 5 ОL-FI-17/1/MPT Water treatment systems. Qualification and validation Level 5 ОL-FI-17/2/MPT Qualification and validation of equipment for Solid Dosage forms manufacturing Level 5 ОL-FI-18/MPT Solid Dosage forms manufacturing Level 5 ОL-FI-20/MPT Inspecting of laboratories of medicines manufacturers quality control 19 The Quality Management System (QMS, system of personnel training) Special requirements to the inspectors were developed: University degree in one of the following specializations or one of the following programs: biology, biotechnology, veterinary, clinical medical science, radiation, chemical and biological protection, pharmacy, basic medical science, chemical technology, chemistry. Work experience in the area of production and (or) quality control of medicines at least five years. Specially developed program «Rules of organization of production and quality control of medicines theory and practice of GMP inspection/audit» for training of inspectors was organized and conducted for professional retraining of specialists

11 The Quality Management System (QMS, system of personnel training) Program consist of 3 blocks: theoretical (18 modules) practical (4 modules) courses of training traineeship taking part in inspection as a trainee (not less than 5 inspections). Theoretical course comprises modules that are included in additional professional programs of pharmaceutical education. Among these modules: State Regulation system of medicines circulation, review of the main provisions of legislative and subordinate regulatory legal acts of the Russian Federation, as well as international experience; GMP requirements; Pharmaceutical development of medicines; Statistic methods applied in pharmaceutical manufacturing. Each stage of inspectors training includes the detailed assessment of the competence of the students in the process of theoretical training, as well as during organization and conducting of training GMP inspections. The program provides not only deep theoretical knowledge in GMP, but also practical training inspection (each group takes part in not less than two whole practical training inspections at Russian pharmaceutical sites) 21 Participating in international or regional regulators networks or expert Committees 23/12/2014 at the Council of the Eurasian Economic Union (EEU) meeting were signed: Agreements on the common principals and rules of medicines circulation Agreements include the creation of the common market of medicines circulation for EEU members (Russian Federation, Republic of Belarus, Republic of Armenia, Republic of Kazakhstan, Republic of Kyrgyzstan) from 01 January

12 Achievements Federal law 61-FZ «On Circulation of Medicines» establishes the requirements for inclusion into the registration dossier composition the compliance certificate for conformity of the medicines manufacturer (including foreign manufacturer) with GMP requirements, issued by the authorized federal executive body (the Ministry of Industry and Trade of the Russian Federation) when registering medicines (regulation entered into force on 1 January 2016) and when changes are made to the registration dossier of a previously registered medicine and when the medicine is re-registered (the norm came into force on January 1, 2017) Rules of Good Manufacturing Practice (GMP) approved (Order of the Minpromtorg of Russia of 14 June ) FSI «State Institute of Drugs and Good Practices» is accredited as an expert organization involved in the licensing control of pharmaceutical manufacturers situated on the territory of the Russian Federation (Order of the Minpromtorg of Russia of 8 April ) Rules for inspection of medicines manufacturers in accordance with the GMP rules approved (Government Decree of the Russian Federation of 3 December ) FSI «State Institute of Drugs and Good Practices» is authorized to perform the inspection of foreign manufacturers of medicines for medical use, manufacturing of which is conducted outside the Russian Federation territory, for compliance with the GMP requirements (Order of Ministry of Industry and Trade of 21 December ) On May 6, 2017, after the ratification by the EAEU member countries of the regulatory framework of medicines circulation in the Union, a package of twenty-six documents prepared by the Commission together with member states, including twenty-one decisions of the EEC Council, four decisions and one recommendation of the EEC Collegium, comes into force. 23 Achievements The conformity of the quality management system of the Ministry of Industry and Trade of the Russian Federation to the requirements of the interstate standard GOST R ISO ; Gradual training of Inspectorate staff is carried out, confirmed by appropriate certificates and diplomas; Since January 2016, the procedure for inspecting of foreign medicines manufacturers on compliance with Good Manufacturing Practices requirements

13 Achievements For the period from 18 December 2015 until September 2017 Applications received by Minpromtorg of Russia Transferred to FSI «SID & GP» Inspections completed Transferred inspection reports to the Ministry Refusals in issuing the compliance certificates Issued the compliance certificates out of them upon the secondary documents submission 14 out of them upon the secondary documents submission 25 Plans for future 1. Improvement of the regulatory and legal acts of the Russian Federation towards harmonization with the regulatory and legal acts of the EAEC and international standards; 2. Obtaining by Russia the status of PIC/S applicant; 3. Establishment of the ISPE branch for the EAEC and CIS countries; 4. Establishment of partnership relations with inspectors from other countries; 5. Cooperation with BRICS countries

14 Priority goals 1. Improvement of the system for state control over the conformity of medicines production; 2. Formation of the branch system of advanced training and retraining of personnel in pharmaceutical production; 3. Increase of safety, efficiency and availability of medicines for the population. 27 Address: , Russian Federation, Moscow, Kitaygorodskiy proezd, 7 Tel: +7 (495) Fax: +7 (495) Web site: minpromtorg.gov.ru 14