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ANVISA

National Health Surveillance Agency


PREPARED BY; GUIDED BY;
ANKIT GOTECHA Dr. TEJAL MEHTA
13MPH101 PHARMACEUTICS
SEM 1 (M-PHARM)
PHARMACEUTICAL TECHNOLOGY
AND BIOPHARMACEUTICS
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 companys 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 dont 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 product
ANVISA 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
Childrens 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 dont 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 WHOs 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 Guidelnes
Three 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. ANVISAs 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