II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se1 II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Regulatory Function of DRUG REGISTRATION Celeste Sánchez González, PhD. Adviser. CECMED/Cuba

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se2 Content of the Presentation 1.Drug registration as a regulatory function 2.What does drug registration is? 3.Regulatory requirements for drug registration 4.Ways to implement registration 5.Steps of the registration process 6.Drug registration requirements according to the Pan American Network for Drug Regulation Harmonization (PANDRH)

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se3 An approach of Regulatory Functions of Medicines National Regulatory Authorities (1) (1) Ratanawijitrasin S. & Wondemagegnehu E. Effective drug regulation. A multicountry study. WHO, 2002

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se4 Another approach of Regulatory Functions of Medicines National Regulatory Authorities (2) 1Regulatory System 2Licenses: For medicines -vaccines- (Registration) Licenses: For Companies (manufacturing, importing, exporting, distributing) 3Post-marketing surveillance 4Lot Release 5Access to Laboratory (for quality controls) 6Regulatory Inspections: GMP and distribution channels 7Regulatory overview to clinical trials (2) Milstein J. Belgharbi L. Regulatory pathways for vaccines for developing countries. WHO. Bulletin of the World Health Organization, February 2004

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se5 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.

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se6 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.

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se7 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

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se8 Manufacturer Pharmaceutical Product Drug Registration GMP Requirements QualitySafetyEfficacy Information Inspections and Establishment Licenses Rational Use/Promotion and Advertising Laboratory Post Marketing Controls and Surveillance Registration Variations Renewals

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se9 Drug Registration Requirements in Terms of Regulation for a NRA Legal Bases Legal Bases Guidelines Guidelines Assessment procedures Assessment procedures Human resources and others Human resources and others Records Records Availability of the information 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

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se10 BASIS OF REGISTRATION Drug Registration Assessment and Requirement Characteristics OWN ASSESSMENT RELY ON EXPORTING COUNTRY´S NRA RELY ON EXPORTING COUNTRY´S NRA RELY ON REPORTS OF ASSESSMENT FRON ANOTHER NRA

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se11 REGISTRATION. RELY ON EXPORTING CONTRY´S NRA Does Product have Registry in Exporting Country? Yes No Is the Product the same as in exporting country? YesNo Are differences acceptable? Check whether analytical methods for finished product can be applied at NQC laboratory 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 Check if stability studies were conducted including the national climatic zone requirements Review, (adapt if necessary) labelling and product information/ Assess interchangeability, if required Review, (adapt if necessary) labelling and product information/ Assess interchangeability, if required Yes No OWN ASSESSMENT (5) WHO. Marketing Authorization. A manual for Drug Regulatory Authorities…..

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se12 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) 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.

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se13 OWN ASSESSMENT. DIFFERENT PARTS OF THE INFORMATION Drug Registration Requirements QUALITY PRODUCT INFORMATION INTERCHANGEABILITY SAFETY AND EFFICACY LEGAL AND ADMINISTRATIVE INFORMATION (6) PAHO. PANDRH. Working Group for Drug Registration. Proposal of Harmonized Drug Registration Requirements in the Americas Region

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se14 LEGAL AND ADMINISTRATIVE INFORMATION PANDRH* DRUG REGISTRATION REQUIREMENTS LEGAL AND ADMINISTRATIVE INFORMATION TrademarkTrademark INN (7) or generic nameINN (7) or generic name Concentration or strengthConcentration or strength Pharmaceutical formPharmaceutical form Technical DirectorTechnical Director Country Legal RepresentativeCountry Legal Representative International License Holder.International License Holder. Manufacturer of Active Pharmaceutical Ingredient (s) (API): Name, address, telephone, fax, mailManufacturer of Active Pharmaceutical Ingredient (s) (API): Name, address, telephone, fax, mail Manufacturer (s) of the Finished Pharmaceutical Product (FPP): Name, address, telephone, fax, mailManufacturer (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 diluentsAnother 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)Commercial presentation (Primary container) Route of AdministrationRoute of Administration (7) WHO Guidelines on the Use of International Nonproprietary Names (INNs) for Pharmaceutical Substances, 1997, WHO MD. Available at:

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se15 LEGAL AND ADMINISTRATIVE INFORMATION PANDRH REGISTRATION REQUIREMENTS LEGAL AND ADMINISTRATIVE INFORMATION Shelf life and storage conditionsShelf life and storage conditions Dispensing categoryDispensing 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)

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se16 INNER CONTAINERS PANDRH REGISTRATION REQUIREMENTS BASIC 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 (according to the country legislation/container size) Registration Number (according to the country legislation/container size)

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se17 SECONDARY PACKAGE PANDRH REGISTRATION REQUIREMENTS BASIC INFORMATION FOR SECONDARY PACKAGE 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) 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)

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se18 INSERTS PANDRH REGISTRATION REQUIREMENTS BASIC 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 PrecautionsWarningsContraindications 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)

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se19 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 QUALITY PANDRH REGISTRATION REQUIREMENTS BASIC INFORMATION FOR QUALITY

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se20 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) QUALITY PANDRH REGISTRATION REQUIREMENTS BASIC INFORMATION FOR QUALITY

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se21 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, QUALITY PANDRH REGISTRATION REQUIREMENTS BASIC INFORMATION FOR QUALITY

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se22 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 QUALITY PANDRH REGISTRATION REQUIREMENTS BASIC INFORMATION FOR QUALITY

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se23 Biopharmaceutical Information –In Vitro Equivalence Studies (dissolution profiles/SBC System) –In Vivo Equivalence Studies (Pharmacokinetics studies, Bioequivalence studies; Pharmacodinamic studies, Clinical trials) INTERCHANGEABILITY PANDRH REGISTRATION REQUIREMENTS BASIC INFORMATION FOR INTERCHANGEABILITY

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se24 Applicable for New Molecular Entities Pharmacodinamics studiesPharmacodinamics studies Pharmacokinetics studiesPharmacokinetics studies NON CLINICAL STUDIES PANDRH REGISTRATION REQUIREMENTS BASIC INFORMATION FOR NON CLINICAL STUDIES

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se25 Applicable for New Molecular Entities Pharmacodinamic studiesPharmacodinamic studies Pharmacokinetics studiesPharmacokinetics studies Toxicology studiesToxicology 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 NON CLINICAL STUDIES PANDRH REGISTRATION REQUIREMENTS BASIC INFORMATION FOR NON CLINICAL STUDIES

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se26 Applicable for New Molecular Entities Summary of Clinical Studies Phase I studies (also apply for new concentration/strengths)Phase I studies (also apply for new concentration/strengths) Phase II studiesPhase II studies Phase III studies (also apply for new concentration/strengths, new combinations, new formulations)Phase III studies (also apply for new concentration/strengths, new combinations, new formulations) Phase IV studies (Pharmacovigilance Plan)Phase IV studies (Pharmacovigilance Plan) Studies in special populations CLINICAL STUDIES PANDRH REGISTRATION REQUIREMENTS BASIC INFORMATION FOR CLINICAL STUDIES

II Workshop on Medicines Regulation in the Caribbean Region Barbados, September 8 th and 9 th, 2009 Se27 THANK YOU VERY MUCH MUCHAS GRACIAS