ii workshop on medicines regulation in the caribbean region barbados, september 8 th and 9 th, 2009...

II Workshop on Medicines Regulation in the Caribbean Region

Barbados, September 8th and 9th , 2009 Se 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/[email protected]/[email protected]



Content of the PresentationContent of the Presentation

1. Drug registration as a regulatory function2. What does drug registration is?3. Regulatory requirements for drug

registration4. Ways to implement registration5. Steps of the registration process6. Drug registration requirements according to

the Pan American Network for Drug Regulation Harmonization (PANDRH)



An approach of Regulatory Functions of Medicines An approach of Regulatory Functions of Medicines National Regulatory Authorities National Regulatory Authorities (1)(1)

Inspection of manufacturers

& distributors

Product assessment

& registration Monitoring quality of

drugs

Control of drug

promotion & advertising

Standards Specifications Guidelines Procedures

Technical elements

Regulatory Functions

Administrative Elements

Licensing of premises,

practices & persons

Central State/province District Community

Policy, legislation, regulations Human resources Finance Infrastructure

Adverse drug reaction

monitoring

Regulation level

(1) Ratanawijitrasin S. & Wondemagegnehu E. Effective drug regulation. A multicountry study. WHO, 2002



Another approach of Regulatory Functions of Another approach of Regulatory Functions of Medicines National Regulatory Authorities Medicines National Regulatory Authorities (2)(2)

1 Regulatory System

2 Licenses: For medicines -vaccines- (Registration)

Licenses: For Companies (manufacturing, importing, exporting, distributing)

3 Post-marketing surveillance

4 Lot Release

5 Access to Laboratory (for quality controls)

6 Regulatory Inspections: GMP and distribution channels

7 Regulatory 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



Drug RegistrationDrug 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.



Drug RegistrationDrug 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.



Drug Registration ResultsDrug 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



ManufacturerManufacturer

Pharmaceutical ProductPharmaceutical Product

Drug Registration Drug Registration

GMP GMP RequirementsRequirements

QualityQualitySafetySafetyEfficacyEfficacyInformationInformation

Inspections and Establishment Licenses

Rational Use/Promotion and Advertising

Laboratory

Post Marketing Controls and Surveillance

•Registration

•Variations

•Renewals



Drug Registration Requirements in Drug Registration Requirements in Terms of Regulation for a NRA Terms of Regulation for a NRA

• Legal BasesLegal Bases

• GuidelinesGuidelines

• Assessment proceduresAssessment procedures

• Human resources and othersHuman resources and others

• Records Records

• Availability of the informationAvailability of the information

(5) WHO DATA COLLECTION TOOL (To be used jointly with the Guidance for the (5) WHO DATA COLLECTION TOOL (To be used jointly with the Guidance for the assessment of Drug Regulatory Systems). WHO, 2009assessment of Drug Regulatory Systems). WHO, 2009



BASIS OF REGISTRATIONBASIS OF REGISTRATION

Drug Registration Assessment and Drug Registration Assessment and Requirement CharacteristicsRequirement Characteristics

OWN OWN ASSESSMENTASSESSMENT

RELY ON EXPORTING RELY ON EXPORTING COUNTRY´S NRACOUNTRY´S NRA

RELY ONRELY ON REPORTS OF REPORTS OF ASSESSMENT FRON ASSESSMENT FRON

ANOTHER NRAANOTHER NRA



REGISTRATION. REGISTRATION. RELY ON EXPORTING CONTRY´S NRARELY ON EXPORTING CONTRY´S NRA

Does Product have Registry in Exporting Country?Does Product have Registry in Exporting Country?

YesYes No

Is the Product the same as Is the Product the same as in exporting country?in exporting country?

YesYes No

Are differences acceptable?Are differences acceptable?

• Check whether analytical methods for finished product can be applied at NQC laboratoryCheck 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 requiredReview, (adapt if necessary) labelling and product information/ Assess interchangeability, if required

YesYes

No

OWN ASSESSMENTOWN ASSESSMENT

(5) WHO. Marketing Authorization. A manual for Drug Regulatory Authorities…..(5) WHO. Marketing Authorization. A manual for Drug Regulatory Authorities…..



Drug Registration. Phases for the AssessmentDrug Registration. Phases for the Assessment

ReceptionReception(Checking the formal validity of the Application)(Checking the formal validity of the Application)

AssessmentAssessmentQuality:Quality: (Product design/Manufacturing GMP profile) (Product design/Manufacturing GMP profile)

Product Information:Product Information: (Labels, Information for patients information for (Labels, Information for patients information for health professionals) health professionals)

Interchangeability/Safety and efficacyInterchangeability/Safety and efficacy

Follow-upFollow-upPost-marketing activitiesPost-marketing activities

(Update stability data, variations of the product/specifications/manufacturing (Update stability data, variations of the product/specifications/manufacturing process, update product information, marketing status, control of promotional process, update product information, marketing status, control of promotional activities, pharmacoepidemiological studies, monitor adverse drug reactions)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. (4) How to implement Computer-Assisted Drug Registration. Regulatory Support Series, No. 2. Geneva, WHO/MSH, 1998:50.



OWN ASSESSMENT. DIFFERENT PARTS OF THE INFORMATIONOWN ASSESSMENT. DIFFERENT PARTS OF THE INFORMATION

Drug Registration Requirements Drug Registration Requirements

QUALITYQUALITY

PRODUCT INFORMATIONPRODUCT INFORMATION

INTERCHANGEABILITYINTERCHANGEABILITY

SAFETY AND EFFICACYSAFETY AND EFFICACY

LEGAL AND ADMINISTRATIVE INFORMATIONLEGAL AND ADMINISTRATIVE INFORMATION

(6) PAHO. PANDRH. Working Group for Drug Registration. Proposal of Harmonized Drug (6) PAHO. PANDRH. Working Group for Drug Registration. Proposal of Harmonized Drug Registration Requirements in the Americas Region. 2009.Registration Requirements in the Americas Region. 2009.



PANDRH* DRUG REGISTRATION REQUIREMENTSLEGAL AND ADMINISTRATIVE INFORMATIONLEGAL AND ADMINISTRATIVE INFORMATION

• Trademark Trademark • INN INN (7)(7) or generic name or generic name • Concentration or strength Concentration or strength • Pharmaceutical form Pharmaceutical form • Technical Director Technical Director • Country Legal RepresentativeCountry Legal Representative• International License HolderInternational License Holder. . • Manufacturer of Active Pharmaceutical Ingredient (s) (API): Manufacturer of Active Pharmaceutical Ingredient (s) (API): Name, Name,

address, telephone, fax, mail address, telephone, fax, mail • Manufacturer (s) of the Finished Pharmaceutical Product (FPP): Manufacturer (s) of the Finished Pharmaceutical Product (FPP):

Name, address, telephone, fax, mailName, address, telephone, fax, mail • Another manufacturers of the FPP: Another manufacturers of the FPP: Name, address, telephone, fax, Name, address, telephone, fax,

mail of other manufacturers in case they participate in any stage of the mail of other manufacturers in case they participate in any stage of the FPP. For freeze dried products also should be declared the manufacturer FPP. For freeze dried products also should be declared the manufacturer of diluentsof 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:

http://www.who.int/druginformation/general/innlists-shtml.



PANDRH REGISTRATION REQUIREMENTSLEGAL AND ADMINISTRATIVE INFORMATIONLEGAL 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 DirectorRepresentativeCertificate 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) InsertInformation 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)



PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR INNER INNER

CONTAINERSCONTAINERSTrademark Trademark INN or generic nameINN or generic name Pharmaceutical formPharmaceutical formConcentration or strengthConcentration or strengthContent/Volume Content/Volume Number of dosages per vial Number of dosages per vial (for multidose presentations)(for multidose presentations)

Route of AdministrationRoute of AdministrationStorage conditions Storage conditions (if container size is big enough)(if container size is big enough)WarningsBatch number Expiry dateManufacturerRegistration Number (according to the country legislation/container size)(according to the country legislation/container size)



PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR SECONDARY SECONDARY

PACKAGEPACKAGETrademarkTrademarkINN or generic nameINN or generic name Pharmaceutical form Pharmaceutical form Concentration or strengthConcentration or strengthContent/Volume Content/Volume Number of dosages per vial Number of dosages per vial

(for multidose (for multidose presentations)presentations)

CompositionCompositionDeclaration of excipients Declaration of excipients

(according to country (according to country legislation)legislation)

Storage conditionsStorage conditionsRoute of AdministrationRoute of Administration Instructions for preparationInstructions for preparationInstructions for useInstructions for useWarnings Warnings (according to the (according to the

package size)package size)

Distribution level Distribution level (according (according to country legislation)to country legislation)

Special signals Special signals (according to (according to country legislation)country legislation)

Batch numberBatch numberExpiry dateExpiry dateName and address of the Name and address of the

manufacturing of the FPPmanufacturing of the FPPName and address of the Name and address of the

packer of the FPP packer of the FPP (if (if different)different)

Name of the Technical Name of the Technical Responsible Responsible (according to (according to country legislation)country legislation)

Registration NumberRegistration Number (according to country (according to country legislation)legislation)



PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR INSERTSINSERTS

Trademark Trademark INN or generic nameINN or generic name Pharmaceutical form Pharmaceutical form Concentration or strengthConcentration or strengthContent/Volume Content/Volume Number of dosages per vial Number of dosages per vial

(for multidose (for multidose presentations)presentations)

CompositionCompositionDeclaration of excipientsDeclaration of excipientsRoute of AdministrationRoute of Administration IndicationsIndicationsInstructions for useInstructions for useDosage/ PosologyDosage/ PosologyMaximal dosage in 24 hoursMaximal dosage in 24 hours

PrecautionsPrecautionsWarningsWarningsContraindicationsContraindications Over dosageOver dosageUse in pregnancy and Use in pregnancy and

lactationlactationShelf life and storage Shelf life and storage

conditionsconditionsName and address of the Name and address of the

manufacturing of the FPPmanufacturing of the FPPName and address of the Name and address of the

packer of the FPP packer of the FPP (if (if different)different)



Active Pharmaceutical Ingredient (s):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 APICharacteristics:

Complete description (odor, taste, flavor, etc.)PhysicalChemical

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

PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR QUALITYQUALITY



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)




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,




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




Biopharmaceutical Information

– In Vitro Equivalence Studies (dissolution profiles/SBC System)

– In Vivo Equivalence Studies (Pharmacokinetics studies, Bioequivalence studies; Pharmacodinamic studies, Clinical trials)

PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR

INTERCHANGEABILITY INTERCHANGEABILITY



Applicable for New Molecular EntitiesApplicable for New Molecular Entities

• Pharmacodinamics studiesPharmacodinamics studies

• Pharmacokinetics studiesPharmacokinetics studies


NON CLINICAL STUDIESNON CLINICAL STUDIES




• Pharmacodinamic studiesPharmacodinamic studies • Pharmacokinetics studiesPharmacokinetics studies

• Toxicology studiesToxicology studiesGeneral ToxicologySpecial 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 STUDIESNON CLINICAL STUDIES




Summary of Clinical StudiesSummary 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, Phase III studies (also apply for new concentration/strengths, new combinations, new formulations)new combinations, new formulations)

• Phase IV studies (Pharmacovigilance Plan)Phase IV studies (Pharmacovigilance Plan) • Studies in special populations


CLINICAL STUDIESCLINICAL STUDIES



THANK YOU VERY MUCH

MUCHAS GRACIAS

ii workshop on medicines regulation in the caribbean region barbados, september 8 th and 9 th, 2009...

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