II Workshop on Medicines Regulation in the Caribbean Region

1. II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8th and 9th, 2009 Regulatory Function of DRUG REGISTRATION Celeste Sánchez González, PhD. Adviser. CECMED/Cuba sanchez.celeste@gmail.com/evareg@cecmed.sld.cu

2. Content of the Presentation • Drug registration as a regulatory function • What does drug registration is? • Regulatory requirements for drug registration • Ways to implement registration • Steps of the registration process • Drug registration requirements according to the Pan American Network for Drug Regulation Harmonization (PANDRH)

3. An approach of Regulatory Functions of Medicines National Regulatory Authorities (1) (1) Ratanawijitrasin S. & Wondemagegnehu E. Effective drug regulation. A multicountry study. WHO, 2002

4. Another approach of Regulatory Functions of Medicines National Regulatory Authorities (2) (2) Milstein J. Belgharbi L. Regulatory pathways for vaccines for developing countries. WHO. Bulletin of the World Health Organization, February 2004

5. Drug Registration An important task for a Drug National Regulatory Authority (NRA) is to institute a system which subjects all pharmaceutical products to: • Pre marketing evaluation; • Marketing authorization (registration); • Postmarketing review To ensure that they conform to required standards of quality, safety and efficacy (3) Guiding Principles for small national drug regulatory authorities. Quality Assurance of pharmaceuticals:a compendium of gudelines and related materials, Vol. Geneva, WHO, 1997:18-30.

6. Drug Registration Drug registration a function of regulation and control within NRAs that deals with this objectives interrelated with the other regulatory functions It has been defined as: “a system that subjects all pharmaceutical products (under the scope of the NRA) to pre-marketing evaluation, marketing authorization (registration), and post-marketing review to ensure that they conform to required standards of quality, safety and efficacy established by NRA” (4). (4) How to implement Computer-Assisted Drug Registration. Annex 2. Regulatory Support Series, No. 2. Geneva, WHO/MSH, 1998.

7. Drug Registration Results The outcome of the drug registration process is the issuance or denial of a pharmaceutical product marketing authorization or license (registry) The registry holder is obliges the registry holder to commercialize the product for the therapeutic conditions indicated, with the specifications, pharmaceutical form, presentations, manufacturer, storage conditions,etc. Information for patients, health professionals are also results of this regulatory function

8. Drug Registration • Registration • Variations • Renewals Manufacturer Pharmaceutical Product Quality Safety Efficacy GMP Requirements Information Laboratory Post Marketing Controls and Surveillance Rational Use/Promotion and Advertising Inspections and Establishment Licenses

9. Drug Registration Requirements in Terms of Regulation for a NRA • Legal Bases • Guidelines • Assessment procedures • Human resources and others • Records • Availability of the information (5) WHO DATA COLLECTION TOOL (To be used jointly with the Guidance for the assessment of Drug Regulatory Systems). WHO, 2009

10. Drug Registration Assessment and Requirement Characteristics BASIS OF REGISTRATION OWN ASSESSMENT RELY ON EXPORTING COUNTRY´S NRA RELY ON REPORTS OF ASSESSMENT FRON ANOTHER NRA

11. Does Product have Registry in Exporting Country? REGISTRATION. RELY ON EXPORTING CONTRY´S NRA Yes No Is the Product the same as in exporting country? OWN ASSESSMENT No Yes No Yes Are differences acceptable? • Check whether analytical methods for finished product can be applied at NQC laboratory • Check if stability studies were conducted including the national climatic zone requirements • Review, (adapt if necessary) labelling and product information/ Assess interchangeability, if required (5) WHO. Marketing Authorization. A manual for Drug Regulatory Authorities…..

12. Drug Registration. Phases for the Assessment Reception (Checking the formal validity of the Application) Assessment Quality: (Product design/Manufacturing GMP profile) Product Information: (Labels, Information for patients information for health professionals) Interchangeability/Safety and efficacy Follow-up Post-marketing activities (Update stability data, variations of the product/specifications/manufacturing process, update product information, marketing status, control of promotional activities, pharmacoepidemiological studies, monitor adverse drug reactions) (4) How to implement Computer-Assisted Drug Registration. Regulatory Support Series, No. 2. Geneva, WHO/MSH, 1998:50.

13. Drug Registration Requirements OWN ASSESSMENT. DIFFERENT PARTS OF THE INFORMATION LEGAL AND ADMINISTRATIVE INFORMATION PRODUCT INFORMATION QUALITY INTERCHANGEABILITY SAFETY AND EFFICACY (6) PAHO. PANDRH. Working Group for Drug Registration. Proposal of Harmonized Drug Registration Requirements in the Americas Region. 2009.

14. PANDRH* DRUG REGISTRATION REQUIREMENTSLEGAL AND ADMINISTRATIVE INFORMATION • Trademark • INN (7) or generic name • Concentration or strength • Pharmaceutical form • Technical Director • Country Legal Representative • International License Holder. • Manufacturer of Active Pharmaceutical Ingredient (s) (API): Name, address, telephone, fax, mail • Manufacturer (s) of the Finished Pharmaceutical Product (FPP): Name, address, telephone, fax, mail • Another manufacturers of the FPP: Name, address, telephone, fax, mail of other manufacturers in case they participate in any stage of the FPP. For freeze dried products also should be declared the manufacturer of diluents • Commercial presentation (Primary container) • Route of Administration (7) WHO Guidelines on the Use of International Nonproprietary Names (INNs) for Pharmaceutical Substances, 1997, WHO MD. Available at: http://www.who.int/druginformation/general/innlists-shtml.

15. PANDRH REGISTRATION REQUIREMENTSLEGAL AND ADMINISTRATIVE INFORMATION • Shelf life and storage conditions • Dispensing category • Quali-quantitative formulation per dosage unite and %. • Legal documentation for: Technical Director Representative Certificate of a Pharmaceutical Product (CPP) Certificate of GMP for manufacturers taking part in any step of the FPP (including activities authorized) Trade mark certificate • Information of the product:. Labelling (inner container and secondary package) Insert Information for health professionals • Samples or Mock ups of the final package for marketing (including accessories) • Samples of the finished products • Quality Analysis Certificate (corresponding to the bath of the samples)

16. PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR INNER CONTAINERS • Trademark • INN or generic name • Pharmaceutical form • Concentration or strength • Content/Volume • Number of dosages per vial (for multidose presentations) • Route of Administration • Storage conditions (if container size is big enough) • Warnings • Batch number • Expiry date • Manufacturer • Registration Number(according to the country legislation/container size)

17. PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR SECONDARY PACKAGE Distribution level (according to country legislation) Special signals (according to country legislation) Batch number Expiry date Name and address of the manufacturing of the FPP Name and address of the packer of the FPP (if different) Name of the Technical Responsible (according to country legislation) Registration Number (according to country legislation) Trademark INN or generic name Pharmaceutical form Concentration or strength Content/Volume Number of dosages per vial (for multidose presentations) Composition Declaration of excipients (according to country legislation) Storage conditions Route of Administration Instructions for preparation Instructions for use Warnings (according to the package size)

18. PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR INSERTS Trademark INN or generic name Pharmaceutical form Concentration or strength Content/Volume Number of dosages per vial (for multidose presentations) Composition Declaration of excipients Route of Administration Indications Instructions for use Dosage/ Posology Maximal dosage in 24 hours Precautions Warnings Contraindications Over dosage Use in pregnancy and lactation Shelf life and storage conditions Name and address of the manufacturing of the FPP Name and address of the packer of the FPP (if different)

19. PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR QUALITY Active Pharmaceutical Ingredient (s): Chemical name (WHO/Relevant Pharmacopoeia) Manufacturer (s):(According to country legislation). Note: For fixed drug combinations (FDC), this information applies for each API Characteristics: Complete description (odor, taste, flavor, etc.) Physical Chemical Specifications of API • Analytical Method: Validation of the Analytical method (According to country legislation). • Validity period • For New Molecular Entities: Structural and molecular formula/ Molecular weight/ Synthesis/ Source

20. PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR QUALITY Finished Pharmaceutical Product: • Description and composition: • Full description of the FPP, detailing API (s), preservatives, stabilizers and other excipients and their function, • For freeze dried products should be included description and close-container system for dissolvent. • Pharmaceutical development: Studies for establishing the pharmaceutical form, formulation, manufacturing process and close-container system • Manufacturing of the FPP: Batch formula (List of all components according country legislation) Manufacturing process (Flow with critical steps, in process controls, intermediate products and FPP) • Physical and chemical characteristics for excipients (according country legislation)

21. PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR QUALITY FPP Control • Specifications • Analytical Methods • Validation of analytical methods of the FPP including experimental data • Standards and reference materials information • Description of the close-container system (including specifications of component materials) • Stability studies (according to the country legislation and climatic zones): Protocols and results of stability studies justifying validity period:(According to country legislation including: study protocol, specifications, analytical methods,

22. PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR QUALITY FPP Control description of close-container system, storage conditions (temperature and humidity) results of 3 batches minimal manufactured with 3 different batches of API, conclusions and proposed validity period). For freeze dried products should be demonstrated compatibility between lyophilized and diluents • Program of stability studies post registration: Program or commitment including number of batches to be included annually and analytical tests to be performed. Each NRA will establish mechanisms for checking updating of this information • Validity Period and storage conditions • Description of procedures for assuring cold chain: For products to be refrigerated detailed measures for assuring adequate temperature and humidity trough storage and distribution chain indicating controls

23. PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR INTERCHANGEABILITY Biopharmaceutical Information • In Vitro Equivalence Studies (dissolution profiles/SBC System) • In Vivo Equivalence Studies (Pharmacokinetics studies, Bioequivalence studies; Pharmacodinamic studies, Clinical trials)

24. PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR NON CLINICAL STUDIES Applicable for New Molecular Entities • Pharmacodinamics studies • Pharmacokinetics studies

25. PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR NON CLINICAL STUDIES Applicable for New Molecular Entities • Pharmacodinamic studies • Pharmacokinetics studies • Toxicology studies General Toxicology Special toxicology • New Fixed Dose Combinations: According WHO Technical Report Series Nº 929, Annex 5 • For New excipients, new administration routes and FDCs are necessary appropriate toxicological studies

26. PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR CLINICAL STUDIES Applicable for New Molecular Entities Summary of Clinical Studies • Phase I studies (also apply for new concentration/strengths) • Phase II studies • Phase III studies (also apply for new concentration/strengths, new combinations, new formulations) • Phase IV studies (Pharmacovigilance Plan) • Studies in special populations

27. THANK YOU VERY MUCH MUCHAS GRACIAS