Hotsite - Genéricos - Legislação - Resolution nº 41, of April 28, 2000

Legislation
Resolution

Resolution nº 41, of April 28, 2000

The Collegiate Board of Directors of the National Sanitary Surveillance Agency, in the use of attributions vested to it under article 11 item IV, of the Regulation of the National Sanitary Surveillance Agency - ANVISA, approved by Decree No. 3.029 of April 16, 1999, c/c paragraphs 1 and 2 of article 95 of the internal Regulation approved by Resolution No. 1, of April 26, 1999, in a meeting held on April 26, 2000,

WHEREAS,
Law No. 9787/99 and Resolution ANVS/MS No. 391/99;

WHEREAS
the need to establish minimum criteria for the acceptance of units that carry out trials of pharmaceutical equivalence, bioavailability and bioequivalence in medicines;

WHEREAS
those units are allowed to carry out all the tests need to prove the bioequivalence between medicines, or only some of the stages in an isolated form, outsourcing the other stages;

WHEREAS
the lack of a regulation regarding the theme in question;

WHEREAS
the necessary interfaces with other agencies or entities, especially with CONEP (National Committee of Ethics in Research) and CEP's (Committees of Ethics in Researches).

Adopts the following Resolution of the Collegiate Board of Directors and I, Chairman, determine its publication:

Article 1 - The entities or companies that intend to register vis-à-vis ANVS/MS in order to qualify for carrying out the trials of pharmaceutical equivalence, bioavailability and/or bioequivalence must proceed to the completion of the specific form available on the Internet, at the following electronic address: http://anvs.saude.gov.br, section of the Rede Brasileira de Laboratórios, registration item.

Only paragraph. If the company is not able to register through electronic means it should request the official form at the General Management of Public Health Laboratories, fill it out and send it by registered mail to the following address: SEPN 515 - Bloco B - Ed. Ômega - Gerência Geral de Laboratórios de Saúde Pública - cep: 70.770-502 - Brasília - DF.

Article 2 - After registration, the General Management of Public Health Laboratories, shall schedule technical visit to the unit(s).

Paragraph 1 - For the purposes of the technical visit, the criteria to be observed is described in Annex I and the verification itinerary is adopted according to Annex II, both Annexes attached to this resolution.

Paragraph 2 - The units may be authorized to carry out all the stages, pharmaceutical equivalence, bioavailability and/or bioequivalence, or only part of them.

Paragraph 3 - The outsourcing of the other stage(s) can only be carried out by units that also properly authorized.

Article 3 - The units approved in the technical visit mentioned in the previous article, shall be authorized by ANVS/MS, through General Management of Public Health Laboratories, which shall publish on the Internet, a list specifying the centers and the authorized centers and stages, or possible restrictions.

Article 4 - The companies or entities that obtain authorization for carrying out the trials of pharmaceutical equivalence, bioavailability and/or bioequivalence, must deliver the information requested by ANVS/MS allowing access to all pursuant documentation.

Paragraph 1 - The right of access, is hereby ensured to any unit involved in the stages of the tests of pharmaceutical equivalence, bioavailability and/or bioequivalence, of representatives of ANVS/MS in specific mission, at any moment and without prior communication, for verification, evaluation, inspection, technical auditing or any other form of control.

Paragraph 2 - The companies or authorized units must comply with all the norms and regulations issued by ANVS/MS, under this norm, also committing themselves to participate in programs of quality management determined by ANVS/MS.

Article 5 - Every documentation pursuant to the trials carried out must remain filed and available, for a period of 5 (five) years.

Only paragraph. For the purposes of outsourcing the other stages, both the contracting and the contracted party must keep registrations of the full documentation (all stages) of the tests, including their conclusion.

Article 6 - The companies or entities authorized to carry out the tests of pharmaceutical equivalence, bioavailability and/or bioequivalence must forward a monthly activity report, consolidated twice a year and annually, to the General Management of Public Health Laboratories, which may be forwarded by electronic means or mail.

Paragraph 1 - The monthly reports must describe the contracting companies, the products to be tested, the tests to be carried out and the tests to be outsourced, or that are being carried out by third parties, indicating the parties involved in the outsourcing process.

Paragraph 2 - The twice yearly and annual consolidated reports must also contain information about the degree of idleness or occupation of the activities authorized.

Article 7 - The authorization mentioned in article 4 is for unlimited period of time, and may be altered or canceled at any moment, due to non-compliance with pre-established norms, or of proven failure in the execution of the activities of the companies.

Article 8 - This Resolution of the Collegiate Board of Directors goes into force on the date of its publication.

GONZALO VECINA NETO

ANNEX I
REQUIRED MINIMUM CRITERIA

In addition to the requirements contained in Resolution ANVS/MS 391/99, the criteria set forth in this Annex must be met.
The samples for carrying out the trials, tests and reference medicines, must be of the same lot for the stages of pharmaceutical and clinical equivalence.
The acquisition of the samples of the reference medicines must be made by the center contracted to carry out the trials, its identification being ensured by receipts that discriminate the lot number and other forms of control.
In the case of medicines already registered vis-à-vis ANVS/MS, aimed at registration and trade as generic medicines, the acquisition of the samples of the reference medicines and tests must be made by the center contracted to carry out the studies, its identification being ensured by receipts that discriminate the lot number and other forms of control.
Written operational procedures must exist for all the stages.

Pharmaceutical Equivalence Stage
1) the Pharmaceutical Equivalence stage must be carried out in a laboratory that possesses infrastructure compatible with the trials to be carried out, the registration and consequent authorization, of laboratories belonging the producing industries being admitted.
2) in the stage referred to in the previous item the following demands must be met:
the refrigerators for storing samples must have documented temperature control;
b) all volumetric equipment and materials must be gauged and the referring documentation must be available for consultation.
c) the method for the quantification of the pharmaceutical substances must be properly validated.
d) the results of this stage shall indicate whether other trials for the pharmaceutical substances should be continued or not.
3) all safety criteria regarding the identification and origin of the samples must be followed and the documentation shall be filed for a minimum period of five years.

Clinical stage
1) The Clinical stage can only be initiated after approval of the experimental protocol by the Committee of Ethics in Research (CEP) properly accredited vis-à-vis the National Committee of Ethics in Research (CONEP).
2) Laboratory tests for selection and post-study follow-up of the volunteers must be carried out in institutions that take part in quality programs organized by their respective societies.
3) the facilities for confinement of the volunteers must offer safety in the carrying out of the procedures, treatment of possible inter-occurrences and comfort of the volunteers. The following provisions are recommended:
a) minimum of six beds placed as to ensure privacy and the non exposure of the volunteer to patient or to the risk of contracting diseases;
b) medical supervision throughout the confinement period;
c) existence of infrastructure to meet emergencies resulting from the procedure;

4) the storage of samples must be made in freezers with full time temperature control.
5) the documentation pursuant to this stage (clinical records, confinement records, adverse reaction records, etc.) must properly filed for a period of five years and be available for consultation, in the cases of inspection, auditing or other forms of evaluation and control carried out by the competent inspection agency.
6) Main clinical laboratory tests are:
- Electrocardiogram with twelve derivations;
- Complete blood count;
- Urea;
- Creatinine;
- Alkaline Phosphateses;
- Glycemy;
- Total Bilirrubine;
- Total proteins and albumin;
- Transaminase oxalacetic and piruvic (TGO and TGP);
- Uric Acid;
- Total cholesterol;
- Tryglicerides;
- Type I urine (routine urine);
- Beta HCG (for women);
- Serology for hepatitis B, C and HIV;
For all tests, except for serology for hepatitis B, C and HIV, must also be carried out in the post-study period .

Analytical stage
1) The analytical stage must be carried out in a laboratory that possesses proper infrastructure for manipulating biological samples.
2) In the stage mentioned in the previous item the following requirements must be met:
a) the storage of samples must be made in freezers with full time temperature control
b) the equipment for processing of the samples (centrifuges, pipettes, etc.) must be gauged and their documentation must be available for consultation.
c) the method for the quantification of the pharmaceutical substances must be properly validated.
3) the documentation referring to this stage (chromatograms, gauging curves, etc.) must be properly filed for a period of five years and available for consultation.

Statistical stage
1) the pharmacokinetic analyses and data statistics must be carried out by professionals with experience in the respective areas.
2) if a computer program is used it must be evaluated by the General Management of Public Health Laboratories, which shall decide whether to accept it or not.
3) the statistical analyses must fully met the criteria required by Resolution ANVS/MS 391/99.
ANNEX II
VERIFICATION ITINERARY
VERIFICATION OF CONFORMITY OF THE CENTERS REGISTERED AT ANVS IN THAT AUTHORIZATION FOR CARRYING OUT TRIALS OF PHARMACEUTICAL EQUIVALENCE, BIOAVAILABILITY AND BIOEQUIVALENCE OF MEDICINES
Name of Center:
Address:

I PHARMACEUTICAL EQUIVALENCE STAGE

1. Person in Charge: _______________________________________

2. Installed physical area:
( ) Satisfactory
( ) Non Satisfactory
Comments: __________________________________________
______________________________________________________
______________________________________________________

3. Organization of reagents, solutions and solvents:
( ) Satisfactory
( ) Non Satisfactory
Comments: __________________________________________
______________________________________________________
______________________________________________________

4.Operation Conditions of equipment:
( ) Satisfactory
( ) Non Satisfactory
Comments: __________________________________________
______________________________________________________
______________________________________________________

5. There is an equipment gauging program
( ) For all
( ) Some
( ) None
Comments: __________________________________________
______________________________________________________
______________________________________________________

6. Substances used as standard
( ) Primary
( ) Secondary
( ) Others
Comments: __________________________________________
______________________________________________________
______________________________________________________

7. Documentation
Data bank system for the analytical phase:
( ) Computerized
( ) Manual
( ) None
Comments: __________________________________________
______________________________________________________
______________________________________________________
b) Period for keeping the filed documentation:
Comments: __________________________________________
______________________________________________________
______________________________________________________

II BIOEQUIVALENCE - CLINICAL STAGE
Doctor in Charge:
Medical Regional Committee registration number:

1. Area where clinical study is developed:
( ) Public (University)
( ) Private
( ) Mixed
Address:

3. Number of beds available:

4. Exclusive beds for research?
( ) Yes
( ) No
Comments: __________________________________________
______________________________________________________
______________________________________________________

5. Conditions for the confinement of volunteers:
( ) Satisfactory
( ) Non Satisfactory
Comments: __________________________________________
______________________________________________________
______________________________________________________

6. Conditions for eventual emergencies (INTENSIVE CARE UNIT)
( ) Appropriate
( ) Inadequate
Comments: __________________________________________
______________________________________________________
______________________________________________________

7. Systematic Care of volunteers during the trial:
( ) Appropriate
( ) Inadequate
Comments: __________________________________________
______________________________________________________
______________________________________________________

8.Describe the method used for bringing in volunteers
Comments: __________________________________________
______________________________________________________
______________________________________________________

9. System of registration of volunteers :
( ) Computerized
( ) Manual
( ) Both
( ) Others
Comments: __________________________________________
______________________________________________________
______________________________________________________

10. Registration of Data and Retention of Documents:
( ) Computerized
( ) Manual
( ) None
Comments: __________________________________________
______________________________________________________
______________________________________________________

11. Period for keeping the filed documentation: ___________________
Comments: __________________________________________
______________________________________________________
______________________________________________________

12. Identify the Committee of Ethics in Research accredited by CONEP-CNS to which the trial protocol is submitted:
_____________________________________________________
_____________________________________________________
_____________________________________________________
CEP Coordinator: _______________________________
_____________________________________________________

13 - Are there written procedures for the volunteers?
( ) Yes
( ) No
Comments: ___________________________________________
______________________________________________________
______________________________________________________

14. Packaging Conditions of the biological samples
( ) Good
( ) Regular
( ) Unsatisfactory
(exclusive freezer, freezing control, identification, etc) ________
______________________________________________________
______________________________________________________

15. Data bank System:
( ) Computerized
( ) Manual
( ) None
Comments: __________________________________________
______________________________________________________
______________________________________________________

16. Period for keeping the filed clinical documentation:: _______________

17 - STAFF (NUMBER)
( ) Higher level
( ) Technical level
( ) Administrative

Is there staff training before the beginning of the activities?
Type: ____________________________________________________
_________________________________________________________
Length _____________________________________________
____________________________________________________
Description ____________________________________________
____________________________________________________

19. Clinical analysis laboratory

19.1 Place
( ) University
( ) Private
( ) Both
Address: _____________________________________________
_____________________________________________________
______________________________________________________

19.2 General conditions
( ) Satisfactory
( ) Not Satisfactory
Comments: __________________________________________
______________________________________________________
______________________________________________________

19.3. Analysis system
( ) Automated
( ) Manual
( ) Both
( ) Others
Comments: __________________________________________
______________________________________________________
______________________________________________________

III BIOEQUIVALENCE - ANALYTICAL STAGE

1. Person in Charge : _____________________________________
2. Place
( ) University
( ) Private
( ) Both
Address: ___________________________________________
___________________________________________________

3. General conditions
( ) Satisfactory
( ) Not Satisfactory
Comments: __________________________________________
______________________________________________________
______________________________________________________

4. Organization of reagents, solutions and solvents
( ) Satisfactory
( ) Not Satisfactory
Comments: __________________________________________
______________________________________________________
______________________________________________________

5.Operation Conditions of the equipment
( ) Satisfactory
( ) Not Satisfactory
Comments: __________________________________________
______________________________________________________
______________________________________________________

6. There is a equipment gauging program
( ) For all
( ) Some
( ) None
Comments: __________________________________________
______________________________________________________
______________________________________________________

7. Substances used as standard
( ) Primary
( ) Secondary
( ) Others
Comments: __________________________________________
______________________________________________________
______________________________________________________

8. Documentation
7.1Data bank System of the analytical phase
( ) Computerized
( ) Manual
( ) None
Comments: __________________________________________
______________________________________________________
______________________________________________________

8.2 Period for keeping the filed documentation:
_____________________________________________________
_____________________________________________________

8.3 Are there written procedures for operation of the equipment?
( ) All
( ) Some
( ) None
Comments: __________________________________________
______________________________________________________
______________________________________________________

8.4 Are there written procedures for the general operation?
( ) All
( ) Some
( ) None
Comments: __________________________________________
______________________________________________________
______________________________________________________

IV BIOEQUIVALENCE - STATISTICAL STAGE

Computer program specialized in pharmacocinetics? Which ?
____________________________________________________
____________________________________________________
Computer program specialized in statistics? Which ?
____________________________________________________
____________________________________________________
Professional in charge for statistical tests:
____________________________________________________
____________________________________________________

V BIOEQUIVALENCE -

1 Is there professional specialized in the pharmacocinetic area? What is his/her academic background?
___________________________________________________
___________________________________________________
2. Experience in Bioequivalence studies
___________________________________________________
___________________________________________________

Date:

Evaluating Technicians:
(published in the Official Journal of the Union - D.O.U. on May 03, 2000)