RAPS Webcast BRAZIL Regulatory Challenges with Drug Submissions By Adriana Serrão Marcela Saad February 10, 2012
Speakers: Adriana Serrão Regulatory Affairs serraoguilherme@uol.com.br & Marcela Saad President & Senior Consultant MarcM Consulting Canada www.marcmconsulting.ca saadma@marcmconsulting.ca
BRAZIL Regulatory Challenges with Drug Submissions
BRAZIL Regulatory Challenges with Drug Submissions ANVISA Structure
BRAZIL Regulatory Challenges with Drug Submissions Regulation Timeline 1976: General Health Law 6360/76 1977: General Health Decree 79094/77 1994: Registration requirements resolution IN 01/94 1995: GMP RDC 16/95 1996: National Health Council Resolution RDC 196/96 – Ethics in CT 1997: Leaflet Ordinance 110/96 1999: ANVISA creation Law 9782/99; Generic Law 9787/99 1999: Generic registration RDC 391/99 2000: Vitamins RDC 4/00; Herb Drug register RDC 17/00; Advertisement RDC 102/00
BRAZIL Regulatory Challenges with Drug Submissions Regulation Timeline 2001: Patent Review Law 10196; Generic Registration RDC 10/01 update; GMP update RDC 134/01 2002: Biologic Registration RDC 80/02; Generic Registration update RDC 84/02 2003: Price Control – CMED Law 10742 2003: Innovative; Specific; Similar; Generic update; Homeopathic Drugs registration RDCs 136/03, 132/03 , 133/03, 135/03, RDC 139/03 2003: Guide for OTC (therapeutic indication) – RDC 138/03 (under review) 2003: Registration update – RDC 134/03 2003: Leaflet update RDC 140/03; Labeling RDC 333/03; Pregnancy Risk RDC 1548/03 2004: Herb Drug registration update RDC 48/03; Clinical Trial RDC 219/03
BRAZIL Regulatory Challenges with Drug Submissions Regulation Timeline 2005: Biologic Drugs registration update – RDC 315/05 2007: Generics RDC 16/07 update; Similar Drug registration update RDC 17/07 2008: Registration Review Linkage IN 06/08 2008: Priority – RDC 28/08 (under review) 2008: Clinical Trial update - RDC 39/08 2008: Patent Review – RDC 45/08 2009: Clinical Trial update – RDC 41/09 2009: Leaflet update – RDC 47/09 2009: Labeling update – RD 71/49 2009: API registration – RDC 57/09
BRAZIL Regulatory Challenges with Drug Submissions Regulation Timeline 2010: GMP update RDC 17/10 2010: Herb Drugs registration update RDC 14/10 2010: API GMP RDC 29/10 2010: Biologic Drug registration update RDC 55 (+ 4 guidelines) 2011: QC Imported Drug update RDC 10/11 2011: Specific Drug registration update RDC 24/11 2011: Bio exemption guideline update RDC 37/11 2011: Biologic Drug variation RDC 49/11 2011: Biologic Drug stability RDC 50/11
BRAZIL Regulatory Challenges with Drug Submissions Applicable Guidelines (in force) RE 482/02: In Vitro-In Vivo Study Correlation RE 894/03: Bioequivalence Protocol and Report RE 898/03: Bioequivalence Study Design and Statistic Detailing RE 899/03: Method Validation (under review) RE 01/05: Stability Study (under review) RE 1170/06: Bioequivalence Study IN 02/09: Pivotal Batch RE 48/09: Variation – implementation after approval (under review) IN 11/09: Variation – automatic implementation after 60 days RE 31/10: Pharmaceutical Equivalence and Dissolution Profile Note: Reference Drugs and Biologic Drugs guidelines being re-written
BRAZIL Regulatory Challenges with Drug Submissions Definitions Reference product: registered and marketed innovative drug with demonstrated quality, safety and efficacy Generic product : similar drug to a reference or innovative drug, interchangeable, usually produced after patent expiration, with demonstrated quality, efficacy and safety, named by its DCB or DCI Similar product : contain same API, strength, dosage form, administration form, posology and indication; equivalent to registered reference drug; may be different only regarding shape and size, shelf life, packaging, labeling, excipients; always named by brand or trade mark
Drug Registration Rationale Pre Registration Post Market Registration RDC 136/03: Innovative Product Registration Clinical Trial requirement RDC 55/10: Biologic Product Registration RDC 16/07: Generic Product Registration Equivalence Test requirement RDC 17/07: Similar Product Registration RDC 24/11: RDC 14/10: RDC 135/03: Specific Drug Herb Drug Homeopathic Registration Registration Drug Registration 11
Registration Flow - Pre Submission 1) Brazilian Reference Drug or CT protocol approval - website list or request to ANVISA – similar/generic only - clinical trial protocol approval – innovative/biologic only 2) Samples and Manufacturing Dossier - pivotal batch or imported samples + technical documents - reference drugs: acquired in Brazil by authorized labs or CROs 3) Testing prior to Registration Submission - equivalence: QC specifications + DP (solids) – similar/generic only - accelerated stability study - long term stability study: zone IV b - bioequivalence study: absorbed drugs – similar/generic only - QC test (waiver for biologic drugs/transportation validation) + R&D - clinical trial results – innovative/biologic only
Stability Study Applicable Regulation: RE 01/05 (Stability Study) – similar to ICH zone IVb In vitro test: specification must be maintained during shelf life under normal • storage conditions. Performed only to test drug and prior to bioequivalence test; Samples under controlled temperature and RH conditions, periodic test: • accelerated: 0, 3, 6 months; • long term: 0, 3, 6, 9, 12, 18, 24 months (+ every 12 months); • post market: every 12 months; • Specification: aspect, assay, related substances, pH (if applicable), dissolution (if • applicable). Other specifications on 0 and end point; 3 batches required for registration: > 10% industrial size; • Performed for higher and lower strength (proportional formulation); • Performed for all primary package materials and all storage conditions; • Protocol and report must be attached to the registration dossier. •
Stability Study Study Temperature/RH Period Analysis period accelerated room temp 40 ± 2°C / 75 ± 5% 6 months 0, 3, 6 months 40 ± 2°C / 25 ± 5%* long term room temp 30 ± 2°C / 75 ± 5% 6 months 0, 3, 6, 9,12, 18, 24 (+ every 12) months 30 ± 2°C / 35 ± 5%* accelerated cold chain 25 ± 2°C / 60 ± 5% 6 months 0, 3, 6 months long term cold chain 5 ± 3°C 6 months 0, 3, 6, 9,12, 18, 24 (+ every 12) months long term freezing - 20 ± 5°C 12 months 0, 3, 6, 9,12, 18, 24 (+ every 12) months Notes : 1) Stability test is allowed at 25°C only for hospital drugs that cannot bear zone IVb conditions + chain validation 2) Impermeable packages such as glass can adopt room humidity * Semi-permeable packages
Registration Flow - Submission 4) Registration dossier assembly: legal, technical, testing 5) Submission to ANVISA: dossier (hard copy and CD) + fee 6) Dossier evaluation by ANVISA: 12 to 24 months (questions) 7) Registration grant: Official Gazette 8) Price Submission: innovative, biologic, generic and similar 9) Price Approval: innovative, biologic and similar only 10) Product Launch 11) Registration variation: if applicable 12) Registration renewal: every 5 years
Registration Flow Innovative/ similar/ submission biologic generic Register Reference Stability Protocol Dossier study election Approval Review registration Pivotal Clinical Trial CQ Test certificate Batch Notification Price Equivalence Register /Biostudy Dossier price approval 16
Registration Dossier for Innovative Drugs Forms, fees and legal documents: site license (QC laboratory + warehouse at least) QP certificate power of attorney third part contracts (pre-approved by ANVISA) GMP certificate issued by ANVISA & origin country HA (legalized) CPP or register evidence issued by origin country HA (legalized) Labeling lay out and leaflet model BSE data DMF: API characteristics and manufacturer information methods, specification, validation, stability synthesis route, intermediary products, contaminants, solvents polymorphic and stereoisomer data, if applicable 17
Registration Dossier for Innovative Drugs Product information Formula, dosage form, strengths, presentations pharmacokinetics: pKa, ½ life, absorption, distribution, biotransformation, clearance indication, use, administration, posology warnings, precautions, contra indications, AE action mechanism, overdose, interactions marketing category & restrictions, batch SOP Technical information R&D report QC methods & specification + reference (API, excipient, product, packaging) CofA API and product (local and imported) stability, shelf life, storage & transport condition manufacturing process, in process control, equipment list, batch size method validation if non-pharmacopoeial 18
Registration Dossier for Innovative Drugs Clinical information: Pre-clinical report: toxicity (acute, sub acute, chronic, reproductive), mutagenesis, oncogenesis Clinical trial report: phase I, II and III Bioavailability report for association PSUR, pharmacovigilance plan Price Report Clinical Trial: approved by ANVISA prior to execution (if in Brazil) Patents: approved by ANVISA prior to INPI Price: approved by CMED prior to launch 19
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