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]
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Barbados, September 8th and 9th , 2009 Se 2
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)
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Barbados, September 8th and 9th , 2009 Se 3
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
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Barbados, September 8th and 9th , 2009 Se 4
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
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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.
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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.
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Barbados, September 8th and 9th , 2009 Se 7
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
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Barbados, September 8th and 9th , 2009 Se 8
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
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Barbados, September 8th and 9th , 2009 Se 9
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
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Barbados, September 8th and 9th , 2009 Se 10
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
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Barbados, September 8th and 9th , 2009 Se 11
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…..
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Barbados, September 8th and 9th , 2009 Se 12
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.
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Barbados, September 8th and 9th , 2009 Se 13
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.
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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.
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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)
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Barbados, September 8th and 9th , 2009 Se 16
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)
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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)
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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)
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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
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Barbados, September 8th and 9th , 2009 Se 20
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)
PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR QUALITYQUALITY
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Barbados, September 8th and 9th , 2009 Se 21
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,
PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR QUALITYQUALITY
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Barbados, September 8th and 9th , 2009 Se 22
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
PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR QUALITYQUALITY
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Barbados, September 8th and 9th , 2009 Se 23
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
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Barbados, September 8th and 9th , 2009 Se 24
Applicable for New Molecular EntitiesApplicable for New Molecular Entities
• Pharmacodinamics studiesPharmacodinamics studies
• Pharmacokinetics studiesPharmacokinetics studies
PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR
NON CLINICAL STUDIESNON CLINICAL STUDIES
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Barbados, September 8th and 9th , 2009 Se 25
Applicable for New Molecular EntitiesApplicable for New Molecular Entities
• 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
PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR
NON CLINICAL STUDIESNON CLINICAL STUDIES
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Applicable for New Molecular EntitiesApplicable for New Molecular Entities
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
PANDRH REGISTRATION REQUIREMENTSBASIC INFORMATION FOR
CLINICAL STUDIESCLINICAL STUDIES
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THANK YOU VERY MUCH
MUCHAS GRACIAS