Legislation
Resolution

Resolution - RE nº 476, of March 19, 2002
(Official Journal of 20/03/2002)

The Director of the Collegiate Board of Directors of the National Sanitary Surveillance Agency, in the use of the attributions vested in him under Administrative Rule 724, issued by the Director-Chairman, on October 10, 2000,

WHEREAS

paragraph 3 of article 111, of the Bylaws approved by Administrative Rule 593, of August 25, 2000, re-published in the Official Journal of the Union of December 22, 2000;
that the matter was submitted to the examination of the Collegiate Board of Directors, which approved the matter in a meeting held on March 13, 2002, decides:

Article 1 - To determine the publication of the "Guide for the Undertaking of Study and Preparation of Report of Pharmaceutical Equivalence", attached.

Article 2 - This Resolution enters into force on the date of its publication.

GONZALO VECINA NETO

GUIDE FOR UNDERTAKING OF THE STUDY AND REPORT PREPARATION OF PHARMACEUTICAL EQUIVALENCE - 1/2002

1. CRITERIA FOR PHARMACEUTICAL EQUIVALENCE STUDIES FOR DRUG PRODUCT EXEMPT FROM THE BIOEQUIVALENCE STUDY

The studies must be undertaken in test and reference drug products, preferably manufactured for up to six months. The reference drug product must comply with all pharmacopeial requirements.

1.1. To be registered as generic, the drug product must:

a) Fully comply with the pharmacopoeial requirements of the individual monograph, registered in the Brazilian Pharmacopoeia. In case another code authorized by the legislation in force is used, the requirements from the pharmacopoeia of the monograph must be completed with assays described in the general methods of the Brazilian Pharmacopoeia in force, for the dosage form being studied. In the absence of an official pharmacopoeial monograph, the study must be undertaken using the method supplied by the requesting company, validated by the laboratory undertaking the study, being completed with assays described in general methods of the Brazilian Pharmacopoeia in force.

b) The study must be undertaken using chemical substances of reference and/or official biological standards from the Brazilian Pharmacopoeia or from other codes authorized by the legislation in force. The assays proving pharmaceutical equivalence must be undertaken, simultaneously, in the test and the reference drug products;

c) for creams, salves, ointments, gel and paste, it must be verified whether the size of the particles contained in the test and the reference drug products are compatible.

1.2. Submit Technical Report of Pharmaceutical Equivalence, including:

1.2.1. Certificate(s) of Pharmaceutical Equivalence analysis of test and reference drug product(s), considering the following items:

1.2.1.1. on the certificates heading:

a) brand name of the reference drug product;
b) generic name according to CBD and INN;
c) name of the manufacturer;
d) dosage form;
e) batch number;
f) date of manufacture;
g) expiry date;
h) number and date of certificate issuance;

1.2.1.2. on the certificates contents:
a) drug product characteristics;
b) tests undertaken (chemical-physics, chemicals, biological etc);
c) specifications of each assay mentioning researched sources;
d) results found;

1.2.1.3. on certificates foot-note:
a) date and signature of analyst(s) and professional expert(s) in charge;
b) relevant observations;

1.2.2. Conclusive report about the Pharmaceutical Equivalence of the studied drug product

1.3. Individual records of analyses undertaken, containing the data used for the assessment of each assay, including statistical data, charts with results, copy of chromatograms and spectra of the test and the reference drug products, will be available to the applicant and to ANVISA.

2. CRITERIA FOR PHARMACEUTICAL EQUIVALENCE STUDIES WHEN THE PHARMACEUTICAL EQUIVALENCE IS ACCEPTED AS A BIOEQUIVALENCE INDICATOR

When pharmaceutical equivalence is accepted as a bioequivalence indicator, to obtain a generic drug registration, the drug must comply with the requirements mentioned on item 1. A comparative study of the dissolution profile in relation to the reference drug product must also be carried out according to the GUIDE FOR DISSOLUTION TESTING OF ORAL SOLID IMMEDIATE RELEASE DOSAGE FORMS

3. CRITERIA OF PHARMACEUTICAL EQUIVALENCE STUDIES FOR DRUG PRODUCTS TO BE SUBMITTED TO THE BIOEQUIVALENCE STUDY

The studies must be undertaken in test and reference drug products preferably up until six months of being manufactured. The reference drug product must comply with all requirements from the pharmacopoeia.

3.1. To obtain the registration as a generic, the drug product must:

3.1.1. fully comply with the requirements from the pharmacopoeia of the individual monograph, registered at the Brazilian Pharmacopoeia. In the case of using any other code authorized by the legislation in force, the requirements from the pharmacopoeia of the monograph must be completed with assays described in general methods in the Brazilian Pharmacopoeia in force, for the dosage form being studied. In the absence of the official monograph from the pharmacopoeia, the study must be undertaken using a method given by the requesting company, validated by the laboratory executing the study, being completed by assays described in general methods of the Brazilian Pharmacopoeia in force. The study must be undertaken using chemical substances of reference and/or biological standards officially recognized by the Brazilian Pharmacopoeia or by other codes authorized by the legislation in force. The assays for the pharmaceutical equivalence verification must be undertaken simultaneously for the test and the reference drug products;

3.1.2. the difference in the drug proportions between the test and the reference drug product must not be greater than 5%, but it must not, however, exceed the pharmacopoeial limits.

3.2. Submit the results of the comparative study of the dissolution profile, according to the GUIDE FOR DISSOLUTION TESTING OF SOLID ORAL IMMEDIATE RELEASE DOSAGE FORMS

3.3. Submit the Technical Report of pharmaceutical Equivalence, including:

3.3.1. analysis certificate(s) of test and reference drug products, observing the following items:

3.3.1.1. on the certificates heading:
a) brand name of the reference drug product;
b) generic name according to CBD and INN;
c) name of the manufacturer;
d) dosage form;
e) batch number;
f) date of manufacture;
g) expiry date;
h) number and date of certificate issuance;

3.3.1.2. on the certificates contents:
a) drug product characteristics;
b) tests undertaken (chemical-physical, chemical, biological, etc);
c) specifications of each test mentioning researched sources;
d) results found;

3.3.1.3. on certificates foot-note:
a) date and signature of analyst(s) and professional expert(s) in charge;
b) relevant observations;

3.3.2. Conclusive report about the pharmaceutical equivalence of the studied drug product.

3.4. Individual records of analyses containing the data used for the assessment of each assay, including statistical data, charts with results, copy of chromatograms and spectra of the test and the reference drug products will be available to the applicant and to ANVISA.

3.5 Drug products presented as coated tablets whose reference drug is presented as simple tablets, or vice-versa, will be accepted as generic, provided the coating does not have gastro-protective function. Furthermore, the results obtained in the dissolution profile comparative study carried out according to the GUIDE FOR DISSOLUTION TESTING OF ORAL SOLID IMMEDIATE RELEASE DOSAGE FORMS MUST BE PRESENTED, as well as technical report on relative bioequivalence and/or bioavailability study.