ANVISANational Health Surveillance Agency

PREPARED BY;ANKIT GOTECHA13MPH101SEM 1 (M-PHARM)PHARMACEUTICAL TECHNOLOGYAND BIOPHARMACEUTICS

GUIDED BY;Dr. TEJAL MEHTAPHARMACEUTICS

Introduction• ANVISA is regulatory body of BRAZIL. Brazil is biggest

country of South America. Some of the small countries nearby Brazil are following the rules according to ANVISA.

• ANVISA means “Agencia Nacional de Vigilancia Sanitaria”. This abbreviation is in Portuguese language. In English, it means “National Health Surveillance Agency” or sometimes it is written as “Brazilian Health Surveillance Agency”.

• ANVISA is established on 26th January, 1999. Thus it does not have long historical backgrounds.

• To get information about ANVISA, one has to open the website www.anvisa.gov.br. The website will open in Portuguese language first.

BACKGROUND

• The National Health Surveillance Agency was established in 1999 by president Fernando Henrique Cardoso. Linked to the Ministry of Health, the agency coordinates:– The National Sanitary Surveillance System– The National Program of Blood and Blood Products– The National Program of Prevention and Control of

Hospital Infections

• Anvisa's Mission– "To protect and promote health, ensuring the hygiene

and safety of products and services and taking part in developing access to it."

• Values– Transparency– Knowledge (as a springboard for action)– Cooperation

• Vision– To be an agent for transformation of the decentralized

sanitary surveillance system, within a network, holding a distinct position, legitimized by the population, as regulator and promotor of social well-being.

• ANVISA is responsible for– monitoring drug prices – prices of medical devices– control and inspection of smoking products– technical support in granting of patents by the National

Institute of Industrial Property.– protection of the health of the population by exercising

sanitary control over production– marketing of products and services subject to sanitary

surveillance, controlling ports, airports and borders – linked to the Brazilian Ministry of Foreign Affairs and foreign

institutions over matters concerning international aspects of sanitary surveillance.

ANVISA is a part of NSSS

• National System of Sanitary Surveillance (NSSS) is an organization of Brazil whose responsibility is – To keep a watch over certain professional activities– To put a stop to charlatanism– To inspect ships, cemeteries and places where food was on sale

to the public.

• The federal, state and municipal units of this sanitary surveillance are: – National Agency for Sanitary Surveillance (ANVISA)– The National Council of State Health Secretaries (CONASS)– The National Council of Municipal Health Secretaries

(CONASEMS)– The State, Federal District and Municipal Sanitary Surveillance

Centers (VISAS)– The Central Public Health Laboratories (LACENS)– The National Institute for Quality Control in Health (INCQS)– The Oswaldo Cruz Foundation (FIOCRUZ)– The State, District and Municipal Health Councils

HIGHLIGHTS OF ANVISA

National System of Sanitary Surveillance

• In this section, you will find the addresses (in portuguese) of the federal, state and municipal units of sanitary surveillance that make up the National System of Sanitary Surveillance.

Generic Drugs

• FAQs section• Industry – – In this section, industry professionals can obtain

information about Brazil's Generic Drugs Policy. – If your company wishes to apply for registration of a

generic drug, whose reference drug has not yet been informed by ANVISA, please make a formal request to the Office of Generic Drugs.

– Pharmaceutical equivalence and bioequivalence tests needed for registering generic drugs can only be carried out by reference centers duly authorized by ANVISA.

• Legislation – Rules and documents related to regulation and registration of drugs in Brazil. Various Guidelines different categories are given.

Medicine Bioavailability Bioequivalence Centers

• Application Forms for BA/BE centers• Certification for Medicine Bioavailability/Bioequivalence Centers• Renewal of Certification for Medicine BA/BE centers• Centers for carrying out BA/BE shall observe the rules and

technical regulations in force. • BA/BE Good Practices Manual is given in two volumes

Travelers Information

• This section is covered under a specific part of ANVISA related to Airport and Border regulation. Any new visitor of Brazil has to take Vaccine against YELLOW FEVER at least 10 days before his arrival to Brazil. And on arrival he has to show “International Certificate of Vaccination (ICV)”.

• If he had taken Vaccine against yellow fever, before 10 years, then he has to take it again a booster dose.

• Anvisa's Public Health Care Centers and Vaccination Rooms (in Portuguese) are ready to provide the vaccine and to issue the International Certificate of Vaccination (ICV), which is yellow.

• Every person vaccinated in one of the Sanitary Units of the Unified Health System (SUS) receives the National Certificate of Vaccination, which is white and accepted in the whole country.

• If, after that, you need the ICV, you should go to a Public Health Care Center or to a Vaccination Room of ANVISA to copy the National Certificate data to the International one.

Severe Acute Respiratory Syndrome

• In Brazil, there may be probability of getting Severe Acute Respiratory Syndrome (SARS) disease, similar to yellow fever. Thus, ANVISA had provided information on website for it. They had provided WHO website link for direct information.

OFFICES OF ANVISA

• Advisory Council • Office of Ombudsman

ADVISORY COUNCIL

• It monitors and follows up the development of activities carried out by ANVISA. Council comprise of Representatives from…– Public Administration Institutions– Organized Civil Society – Scientific Community • The main function of advisory council is to provide information

upon request by any citizen, patient, industrialist or health professional on any topics. Unlike other well known regulatory bodies, ANVISA does not have specific offices for each topic to provide specific information only. It has a general functioning common Advisory council.

OFFICE OF OMBUDSMAN

• It is an independent body for direct communication of Citizens or Institutes to attend the Complaints.

• It is characterized by impartiality and transparency. • It has no direct or indirect linking with ANVISA. It is regulated

directly under the Brazilian ministry of health.• It Start action against complaints within 2 days, if appropriate.

Regulations by ANVISA• Blood and blood products• Cosmetics• Drugs• Generic Drugs• Food • Health services• International Affairs• Market regulations• Medical devices• Pharmacovigilance• Ports, airports and borders• REBLAS – Brazilian network of Analytical Laboratory• Sanitizing Products • Tobacco• Toxicology

ANVISA - GUIDELINES

REGISTRATION OF NEW DRUG

• Registration procedure of new drug is divided in mainly 3 parts as follows…

1. Pre-registration measures• Protocol for Clinical study 2 Registration• Documents to be submitted• Protocol for the new drug• Protocol for import of new drug 3 Post-registration• Alteration in Registration, Renewal of Registration Thus, these three parts can be considered similar to IND, NDA and

Supplementary NDA as per US FDA.

I. Pre-registration measures

• In case of a new national drug product, the protocols of the clinical studies and the results or current status of the studies in compliance with the legislation in force has to be submitted.

• In case of a new imported drug product that will undergo phase III clinical studies in Brazil, the study protocol and the results or current status of the studies in compliance with the legislation in force has to be submitted.

• Whenever phase III will take place with a new product manufactured in the country, pre-notification for the production of pilot batch according to the GUIDE FOR THE NOTIFICATION OF PILOT BATCHES OF MEDICINES has to be submitted.

II. Registration

1. Documents to be submitted

• Registration petition forms• Proof of payment of Sanitary Surveillance Inspection• copy of the company’s Operation License• Technical Responsibility Certificate by the Regional

Pharmacy Council• Copy of the notification protocol of pilot batch production• Good Manufacturing Practices certificate (GMP) emitted

by ANVISA

2. Protocol for the new drug• General data: package insert text, label etc…• Expiry date by Stability studies• All Toxicity study reports• Clinical trial data with statistical treatments• For Combination – Maximum 3 is allowed for oral or

injectable preparations. Four combinations are allowed only if the fourth ingredient is caffeine.

• Retail Price: if the product is available in other market then applicator has to submit retail price of product to consumer. If product is not available anywhere, and first time registered in Brazil, then has to submit the Proposed retail cost of new drug product.

• Physico-Chemical parameters of drug• Synthesis route (all reagent, solvent, condition)• Pharmacodynamic parameters• Pharmacokinetic parameters• Production Report(Batch size ,methods and equipments used)• Q.C. of raw material and finished products

3. Protocol for the import of new drug GMP of importing country or Inspection by ANVISA. Documentation is allowed in Portuguese, English or Spanish

language. Label, Package Insert must be in Portuguese (Brazilian)

language Official Documents like certificates given by importing

country, if it is in foreign language that must be translated with Legal translator only.

In some cases, applicator wants to import Bulk drug from foreign and then Pack the product in Brazil. In such cases, Expiry Date must be counted from Manufacturing date in foreign, and not the packaging date in Brazil

Additionally all document should be submitted in CD

III. Post-registration measures• Any registration changes shall follow the procedures specified

in the GUIDE FOR MAKING POST-REGISTRATION ALTERATIONS AND INCLUSIONS IN MEDICINES.

• ANVISA may undertake a control analysis of commercialized batches in official laboratories in order to monitor the quality and conformity of the drug with the drug registered. Whenever necessary, ANVISA may request that the companies train their technicians in order to enable them to undertake this monitoring.

TECHNICAL REGULATION OF GENERIC DRUGS

Definition: • Generic drug product is similar to a reference or innovator

product, expected to be interchangeable with latter, usually produce after expiration or waiver of patent protection or of other exclusive rights, and its effectiveness, safety and quality had been already proven.

• Registration procedure for Generic drug is similar to new drug registration. – Pre registration measures– Registration– Post registration

Additional Requirements in registration includes… • Pharmaceutical Equivalence : Generic and Reference• If anyone of Generic or Reference is Coated tablet, prove that

coating does not present Gastro-protection• Bioequivalence study in Laboratories duly authorized by

ANVISA• Exemption of Bioequivalence study– Based on comparison of dissolution profile– For BCS Class I product – High solubility & permeability

Medicines NOT accepted as GENERIC• Parenteral that don’t contain API like WFI, glucose solution,

NaCl solution, electrolytes solution etc.• Biological products: Blood, Plasma products• Products obtained through Biotech except antibiotics• Herbal drug products• Vitamins &/or Mineral salts• Antiseptics for Hospital use• Endogenous Hormones of oral use• Products with Diagnostic purpose and Radiological contrasts• Some of OTC products

Similar Drugs• Similar drugs are similar to Reference Drug product. It has

Same Concentration, Dosage Form, Route of Administration, Strength ,Therapeutic action, but it only Differs in Size, Form of product, Packaging, Labeling, Expiry date, Excipients, Vehicles, and it is mainly identified by Trade Mark / Brand Name.

• The advantage of similar drug is that it can be Dispense in place of Reference drug, unless denied by Doctor in written prescription.

How to identify the types of drugs in the Brazilian market: generic and branded?

• Generic drug package / box contain phrase“ Generic Drug Law 9.787/99 “

• Generic will be identified in blue large letter “ G “ printed over a yellow emblem located in the lower part of the package which carry the product.

Harmonisation of already registered drugs

• ANVISA had introduced some modification in Registration procedures and Documents after 1st December 2004.

• Drugs Registered before this date, has to submit information or data or documents related to drug, for harmonization with Newer Registered drug products

Homeopathic drugs• Registration of Homeopathic drugs is valid upto 5 years.• For Injectables Homeopathic medicines, applicator has to

submit Risk/Benefit compared with oral presentation of same product

• Combination of any synthetic/ semi-synthetic/ biological product/ vitamins/ mineral salts/ herbal along with homeopathic is forbidden.

Registration EXEMPTED for…• Simple drug product (Single Ingredient)• Without trademark or brand name• Manufacturing as per Brazilian Homeopathic Pharmacopoeia• Or in official compendia recognized by ANVISA

Registration REQUIRED for… • Simple or Compound (2 or more Ingredient)• With trademark and brand name• whose formulation is composed of substances of verified

therapeutic action described in the homeopathic drug product literature, official compendia, clinical studies or indexed journals and manufacturing procedures are as per Brazilian Homeopathic Pharmacopoeia

GITE :List of specified therapeutic group and indications

• Drugs described in GITE can be sold OTC• Parentrals can not sold OTC (can not sell without Prescription)• Drugs not listed in GITE can not sell without PRESCRIPTION.• Any NEW DRUG, not to be sold under GITE• If New Drug has minimum 5 years experience in USA or

European market (with FDA or EMEA approval), and if it comes under GITE list, applicator may request to classify it as OTC product.

In-vitro Diagnostic productANVISA had classified in vitro diagnostic product into 4 classes as follows…Group A - Materials, devices, accessories & inputs for support of in vitro

diagnostic products. Group B - for diagnosis of non-transmissible diseases. Group C - for diagnosis of infectious-contagious diseases, except those

classified in Group D. Group D - for diagnosis of infectious-contagious diseases, sexually

transmissible diseases or diseases spread by blood and blood products, as well as identification of blood groups, transfusion or preparation of blood products.

Documents required for Registration…• Application form, Fee payment receipt• Copy of License or Permit for Manufacturing.• Label on the package of product, Instruction for Use • Technical Report• If imported, proof of Registration at competent health agency of

importing country

Cosmetics

Four Categories– Hygiene Product - Soap, Shampoo, Tooth paste…– Cosmetic – Lipstick, Beauty Creams, Hair dye, Talc, Eye

cosmetics, Nail cosmetics, Sunscreens, Oils…– Perfume– Children’s Product

Level of Risk Level 1 - Products with minimum risk Level 2 - Products with potential risk• ANVISA is more conscious about cosmetics and thus a

stringent rules and conditions are observed for cosmetics.• ANVISA gives a List of Allowed PRESERVATIVES (56

preservatives) with the following details of preservatives Ref. No. Substance Name Maximum Allowable Concentration Limitations Condition of Use and Warning

• Similar to preservatives, ANVISA also gives List of Allowed SUNSCREEN AGENTS (23) with similar details

• Similarly, List of Allowed COLORING AGENT also given by ANVISA with following information…

Name or Number of Coloring Agent Colour Field of Application : 1 / 2 / 3 / 4 Other Limitation or Requirements• Field of Application is important to write for coloring agent.

Classification is… Permitted for All Cosmetics For All Cosmetics, Except EYE Area In Cosmetic which don’t come in contact with Mucosa In Cosmetic which come in contact with Skin & Hair only Briefly

List of RESTRICTIVE SUBSTANCES is also given by ANVISA. • Restrictive substances can be used with some established

conditions and a specific warning for each individual restrictive substance should be printed on Label as per requirement. For such restrictive substance ANVISA had given following information….

• Ref. No.• Substance Name, Field of application or use• Maximum Allowable Concentration• Limitations and Requirements• Condition of Use and Warning

List of PROHIBITED SUBSTANCE (412) is also given which cannot be used in cosmetic products.

For Registration of Cosmetic, one has to enter the CODES in the application form given in guideline.

• Codes are given for… Cosmetic Product Group i.e. Toothpaste, Beauty cream For Physical form i.e. Cream, Powder, Aerosol, Gel Preservation Care Primary Packaging i.e. Al tube, film, vial, jar External Packaging i.e. plastic bag, cloth bag, case, jar

GMP

• As per the latest updates of “GMP Guide for Pharmaceutical Industry” approved by WHO’s World Health Assembly – WHA.

• For Import of Drug in Brazil from country which is not included in MERCOSUL group requires Inspection of Drug Manufacturing unit by ANVISA.

• MERCOSUL = Mercado Commun del Sul means “South Common Market” includes Argentina, Brazil, Chile, Paraguay & Uruguay (Group of Countries of South America)

• All documents should be submitted in Portuguese language and Certified by the Brazilian Consulate, of the Country, where the Drug for Importation in Brazil is manufactured

• GMP Certificate is Valid upto 1 year only.

BA/BE GuidelnesThree stages of testing• Clinical Stage• Follow clinical studies as per Brazilian Pharmacopoeia• There should be not more than 5% difference in amount of

Test and Reference API• Clinical researcher has to Quantify Unchanged API and

Metabolites both. • Interval before 2nd dose – atleast 7 t1/2 of API• Weight of Volunteer should be +/- 15% of Normal Wt.• If t1/2 > 24 hrs. – Collect sample upto 72 hrs• Modified Release DF – Add Study with FOOD• Protocol approved & licensed by National Committee of Ethics

in Research

Analytical Stage• As per GCP, GLP ; using SOPs• Use Enough Std. for Calibration Curve• Chromatographic Methods are recommended• NMT 20% samples are Re-analyzed.• Loss of Samples shall be Justified• Results below LQL (Lower Quantification Limit) are considered

as ZERO for statistical calculation.

Statistical Stage• Calculate ASC, Cmax, Tmax. (ASC in Portuguese means AUC in

English)• For Multiple doses…– Average Conc. In Steady state– Fluctuation Rate in Steady state• Submit – ANOVA, SSR, DF, F value, p value…• Necessary to build 90% Confidence Interval (CI) • For Low therapeutic Range API – 95% CI• Information about Software Program used.

BA – BE GOOD PRACTICE MANUAL

• Volume I• Module 1. Clinical Step• Module 2. Analytical Step• Module 3. Statistical Step

• Volume II• Module 1. Micropipettes• Module 2. Water for Chemical Analysis• Module 3. Analytical Instrumentations

OTHER FUNCTIONS OF ANVISA:

REBLAS - Brazilian Network of Analytical Laboratories. It is the laboratory network and every analysis and clinical studies must be performing at any one of the REBLAS center approved by ANVISA.

• Along with Drugs and Cosmetics, ANVISA have also regulation on…– Medical devices– Food– Tobacco products– Toxic products– Pharmacovigilance

RECENT TRENDS OF ANVISA:

• Launched the project to prevent the resistance against Anti-biotic drugs

• The site is among the ten best in two categories of the iBest Awards. ANVISA’s site is among the ten finalists in two categories i.e. “Government” and “Health and Well-being”

• Launched the project to prevent the resistance against Anti-biotic drugs.

INDIAN PHARMA IN BRAZILIAN MARKET:

Prominent product exporters:• Zydus Cadila• Torrent Pharmaceuticals• Dr. Reddys Labs• Ranbaxy Pharmaceuticals• Intas Pharmaceuticals• Sun Pharmaceuticals

Major Drugs exported:• Losartan Potassium• Zolpidem tartarate• Alprazolam• Enalapril Maleate• Nortryptiline• Carbamazepine• Clonazepam• Fluconazole• Fluoxetine, etc.

ANVISA approved CROs in Ahmedabad:

• Accutest• BioArc Research Labs• Zydus Research Center (ZRC)• Torrent Research Center (TRC)• Cadila Pharma• Lambda Research Center• Veeda Research Center• Synchron Research Labs

REFERENCE

www.anvisa.gov.br

THANK YOU