#1Drugs Registration in Brazil Ananda Ferreira GLOBAL REGULATORY PARTNERS#2Table of Content Definitions ▪ Different Steps of Drugs Registration in Brazil Step 1: Preparation and Submission of Registration Dossier to Anvisa Structure of Registration Dossier ☐ Content of Registration Dossier Step 2: ANVISA GMP Inspection of Manufacturing Sites Step 3: Local testing ANVISA Review Timelines References#3Definitions DRUG CATEGORY New Drugs Branded Generics Non-Branded Generics (Similar Drugs) DEFINITIONS Innovative products for which safety, efficacy and quality have been proven via multiple non-clinical and clinical studies before registration with Anvisa. Products that contain the same active ingredient(s), has the same concentration, dosage form, administration route, dosage administration and therapeutic recommendation, as the reference drug registered with Anvisa. It may differ only in the product's size and form, expiration date, packaging, labelling, excipients, and it must always be identified by trade name or brand name. Products that contain the same active ingredient, formulation, pharmaceutical form, mode of administration, dosage and indication than the reference drug that drugs already registered with Anvisa. They are intended to be interchangeable with the reference product.#4Different Steps of Drugs Registration in Brazil Step 1 • Preparation and submission of registration dossier to Anvisa • Anvisa GMP inspection of manufacturing sites Step 2 • Local testing in Brazil Step 3#5Structure of Registration Dossier In Brazil the registration dossier is structured in eCTD format and it has two main parts: Part 1- Administrative Part: It corresponds to Module 1 and includes compilation of all administrative data and local information Quality T Overall Summary 1 Regional Admin Information Module 1 Nonclinical Overview Nonclinical Summary I Clinical Overview Clinical Summary Part 2 - Technical Part: It corresponds to Module 2, Module 3, Module 4 and Module 5 that include summaries od pre-clinical studies; CMC information; nonclinical data and reports; and clinical information and reports. Module 2 Quality Nonclinical Study Reports Clinical Study Reports Module 3 Module 4 Module 5#6Content of Registration Dossier Dossier Content Branded Generic New Drug Similar Drug Drug Module 1 Sanitary license of local representative V V V Local representative operating authorization V V V Registration of local Pharmacist at professional counsil V V V Petition form V V V Justification for product registration V V V Labeling of different presentations V V V Previous Communications with ANVISA V V V#7Content of Registration Dossier Module 1 Dossier Content Branded Generic New Drug Similar Drug Drug CPP issued from the HA in country of origin V V V GMP certificates issued from the HA in country of ป V V origin GMP certificates granted by Anvisa V V V Registration status worldwide V V V Pharmacovigilance data Product labeling in portuguese TSE information V V V V V V V V V#8Content of Registration Dossier Dossier Content Module 2 2.1 Table of contents of Module 2 2.2 Introduction 2.3 Quality Overall Summary 2.4 Non-clinical Overview 2.5 Clinical Overview 2.6 Non-clinical 2.7 Clinical Summary New Drug Branded Generic Drug Similar Drug V V V V#9Content of Registration Dossier Module 3 Dossier Content 3.1 Table of contents of Module 3 3.2 Body of data 3.2.1 Drug Substance 3.2.2 Drug Product Branded Generic New Drug Similar Drug Drug V V V V V V ป ป V V V V V 3.3 Literature references used in Module 3#10Content of Registration Dossier Module 4 Branded Generic Dossier Content New Drug Similar Drug Drug 4.1 Table of contents of Module 4 4.2 Study reports 4.2.1 Pharmacology 4.2.2 Pharmacokinetics 4.2.3 Toxicology 4.3 Literature references used in Module 4 V V V V V V#11Content of Registration Dossier Module 5 Dossier Content Branded Generic New Drug Similar Drug Drug 5.1 Table of contents of Module 5 5.2 Tabular listing of all clinical studies 5.3 Clinical study reports 5.3.1 Reports of biopharmaceutic studies 5.3.2 Reports of human pharmacokinetic (PK) studies 5.3.3 Reports of human pharmacodynamic (PD) studies 5.3.4 Reports of efficacy and safety studies 5.3.5 Reports of post-marketing experience V V V V V V V V 5.3.6 Case report forms and individual patient listings V 5.4 Literature references used in Modulo 5 V BE Studies V V#12Anvisa Review Process of Registration Dossier Applicant submits registration dossier to ANVISA EXTERNAL CONSULTANT ACTIVITY Advice from external consultants used on ad hoc basis GEPEC reviews the Safety, efficacy and pharmacological data provided in the submission dossier (CMED )Chamber of Drug Market Regulation discusses drug price with applicant CATEME ACTIVITY Technical chamber of medicines provides expert advice ANVISA carry out facility GMP inspection ANVISA approves the drug and grants marketing authorization#13ANVISA GMP Inspection Content of the application for GPM inspection: ☐ Petition form completed, stamped and signed Valid GMP certificate issued by the health authority of the country of origin. Certificates issued in English or Spanish will be accepted without the need of a sworn translation. Plant Master File - AMP or Site Master File - SMF. ☐ Periodical Product Review (RPP) Inspection Report from other health authorities in country of origin if availabale#14ANVISA GMP Inspection Timelines for ANVISA inspection: ANVISA inspection of manufacturing site occurs approximately 6 months after submitting the request for inspection to ANVISA ■ ANVISA issues the Good Manufacturing Practice certificate to company 45 to 60 days after inspection#15Requirements for Local Testing The importer located in Brazil is responsible for performing complete quality control tests of finished products in accordance with the specifications and test methods registered in Brazil with ANVISA. The testing frequency depends on the number of shipments made to Brazil each year: ✓ Importation of > 8 shipments/year of each drug to be tested Importation of ≤ 8 shipments/year of each drug 2 years to be tested samples of 2 batches/ year samples of 2 batches/ every The time required for each local testing depends on the product's specifications that need to be tested.#16Anvisa Review Timelines The timelines for drugs' registration and post-approval changes are here below: PRIORITY REVIEW STANDARD REVIEW Registration Post-approval Changes Registration Post-approval Changes 120 days 60 days 365 days 180 days#17References ☐ ANVISA Website. Drug concepts and definitions. Link: http://portal.anvisa.gov.br/medicamentos/conceitos-e-definicoes ■ ANVISA Website. Petition Affairs - New Drugs. Link: https://www9.anvisa.gov.br/peticionamento/sat/Consultas/ConsultaAssuntoCheckList.asp?pCoAssunto=11306&sArea=Medicamento ■ ANVISA Website. Petition Affairs – Branded Generic Drug. Link: https://www9.anvisa.gov.br/peticionamento/sat/Consultas/ConsultaAssuntoCheckList.asp?pCoAssunto=150&sArea-Medicamento ■ ANVISA Website. Petition Affairs - Non-Branded Generic Drug. Link: ☐ ☐ https://www9.anvisa.gov.br/peticionamento/sat/Consultas/ConsultaAssuntoCheckList.asp?pCoAssunto=155&sArea-Medicamento Union Official Journal. RDC 336/2020. Link: http://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-336-de-30-de-janeiro-de-2020-240823596 Union Official Journal. Law 13.411/2016. Link: http://pesquisa.in.gov.br/imprensa/jsp/visualiza/index.jsp?jornal=1&pagina=4&data=29/12/2016 ■ Union Official Journal. RDC 198/2017. Link: http://www.in.gov.br/web/guest/materia/- /asset_publisher/Kujrw0TZC2Mb/content/id/1432285/do1-2017-12-28-resolucao-rdc-n-198-de-26-de-dezembro-de-2017-1432281 ■ Anvisa Website. RDC 10/2011. Link: http://portal.anvisa.gov.br/documents/10181/3315504/%284%29RDC_10_2011_COMP.pdf/12352a77-c0ea- 4c10-96e0-a551140a4d7b Anvisa Website. RDC 183/2017. Link: http://portal.anvisa.gov.br/documents/10181/3612364/%281%29RDC+n%C2%BA+183+-+2017- +english+version.pdf/dfeca3e7-8c83-43c1-bc41-0fa8ccafa5a7