Resolution - RDC nº 135 of 29 May 2003
Republished in the D.O.U of 08/12/2003

The Collegiate Board of Directors of the National Sanitary Surveillance Agency, in the use of the attributions vested in it under Article 11, item IV of the ANVISA Regulation approved by Decree Nº 3.029 dated 16 April 1999, c/c Article 111, item I, letter “b”, Paragraph 1 of the Internal Regulation approved by Presidential Decree nº 593 dated 25 August 2000, republished on 22 December 2000 in meeting held on 6 March 2003,
Whereas Law nº 6.360, dated 23 September 1976 and its Regulation approved by Decree nº 79.094 dated 5 January 1977 that establishes the legal base for the concession of drug product registrations;

Whereas the same Law in its article 2 determines its regulation by the federal organization responsible for sanitary surveillance;

Whereas Generic Drugs are a priority of the Brazilian Ministry of Health’s drug policy;
Whereas the need to ensure the quality, safety and efficacy of Generic Drugs as well as to ensure their interchangeability with their respective reference products;

Adopts the following resolution and I, the Chairman, determine its publication:

Article 1 Approve the attached Technical Regulation for Generic Drugs.

Article 2 Determine that companies interested in the registration of Generic Drugs shall fully comply with the dispositions of this Regulation.
Sole Paragraph. In order to comply with this Regulation the companies shall use the technical procedures described in specific guides approved by the Collegiate Directorate and published in the DOU.

Article 3 Determine that only those centers authorized by ANVISA may undertake pharmaceutical equivalence and relative bioavailability/bioequivalence tests.
Sole Paragraph. Companies interested in undertaking tests shall provide their accreditation at ANVISA and comply with the legal requisites pertaining to their activity.

Article 4 resolution RDC nº 84, dated 19 March 2002 is hereby revoked.

Article 5 This resolution enters into force in the date of its publication.

CLAUDIO MAIEROVITCH PESSANHA HENRIQUES

ANNEX

TECHNICAL REGULATION FOR GENERIC DRUGS
Scope

This regulation serves to establish the technical precepts and procedures for the registration of Generic Drugs in Brazil, as follows:
I. Definitions used for the registration of Generic Drugs.
II. Pre-registration measures.
III. Documentation for registration.
IV. Drug products that will not be accepted as Generic.
V. Post-registration measures.
VI. Criteria for the prescription and dispensation of Generic Drugs.

This regulation encloses annex I, entitled "Title page of the registration and post-registration process of Generic Drugs”.
The definition of the technical procedures for compliance with the technical requisites of registration and post-registration can be found in specific guides published in the DOU.
I – Definitions used for the registration of Generic Drugs

1. Bioavailability: "indicates the rate and the extension of absorption of a drug product in a dosage form, based upon its concentration/time curve in the systemic circulation or its excretion in urine ". (Law nº 9.787, dated 02/10/99)

2. Common Brazilian Denomination (DCB): "name of the pharmaceutical substance or pharmacologically active ingredient approved by the federal agency in charge of sanitary surveillance.” (Law nº 9.787, dated 02/10/99)

3. International Nonproprietary Name (INN): “name of the pharmaceutical substance or pharmacologically active ingredient recommended by the World Health Organization.” (Law nº 9.787, dated 02/10/99)

4. Therapeutic equivalence: two drug products are considered therapeutically equivalent if they are pharmaceutically equivalent and, after administration of the same molar dose, their effects concerning efficacy and safety are essentially the same. This is evaluated by appropriate bioequivalence studies, pharmacodynamic assays, clinical trials or in vitro studies.

5. Pharmaceutical equivalents: drug products containing the same active ingredient, that is, the same salt or isomer of the same therapeutically active molecule, in the same amount and therapeutic form, being or not identical excipients. They shall comply with the same updated specifications of the Brazilian Pharmacopoeia or in lack of these with those of other codes authorized by the legislation in force or with other fitting quality standards related to identity, dosage, purity, potency, uniformity of content, disintegration time and dissolution rate, when fitting.

6. Drug product: "pharmaceutical product technically obtained or elaborated for the diagnosis, cure, mitigation, treatment or prevention of disease”. (Law nº 5.991, dated 12/17/73). It is a finished pharmaceutical form that contains an active ingredient, generally, but not necessarily, in association with other active or inactive pharmacotechnical ingredients.

7. Bioequivalent drug products: pharmaceutical equivalents that, upon administration of the same molar dose in the same experimental conditions do not present significant statistical differences concerning bioavailability.

8. Reference Drug – “innovator product registered at the federal agency in charge of sanitary surveillance and marketed in the country, for which effectiveness, safety and quality have been scientifically proven to the competent federal agency, upon its registration ". (Law nº 9.787, dated 02/10/99)

9. Generic Drug- “drug product similar to a reference or innovator product, expected to be interchangeable with the latter, usually produced after the expiration or waiver of patent protection or of other exclusiveness rights, its effectiveness, safety and quality being proven, and designated by DCB or, in its absence, by INN". (Law nº 9.787, dated 02/10/99)

10. Reference Drug: drug product commercialized in the Brazilian market made of at least one active ingredient that has been the object of a patent (even if no longer valid) on behalf of the company in charge of its development and introduction in the market of the country of origin. An Reference Drug is generally considered a Reference Drug, however, in its absence ANVISA will indicate the Reference Drug.

11. Similar Drug – “that which contains the same drug product(s), submits the same concentration, dosage form, route of administration, strength and therapeutic indication, preventive or diagnostic, of the Reference Drug registered at the federal agency in charge of sanitary surveillance, being allowed to differ only in characteristics related to size and form of the product, expiration date, packaging, labeling, excipients and vehicles, always being identified by its trade mark”. (Draft by MP 2.190-34, dated 23 August 2001)" (Law nº 9.787, dated 02/10/99)

II – Pre-registration measures
Before applying for the registration of a Generic Drug, the company shall:

1. Consult the list of Reference Drugs available at the ANVISA website to check whether this indication, concentration and pharmaceutical form already exists for the product it intends to register as generic. In its absence, protocol a petition for the indication of a Reference Drug at ANVISA, submitting the following data both for the drug product and for the appointed Reference Drug: company, product, active ingredient, pharmaceutical form, concentration and proof of commercialization/distribution in Brazil of the drug product appointed as reference.

2. Request a drug product import license (IL) to ANVISA to undertake in vitro and in vivo studies.

3. Notify the production of pilot batches in compliance with the GUIDE FOR THE NOTIFICATION OF PILOT BATCHES OF MEDICINES, excepting imported products.
The company will have the choice of submitting the bioequivalence study protocol.
III – Registration

a) The process to request the registration of national and imported drug products shall consist of the documentation below. Applications with incomplete documentation will not be analyzed.

b) A maximum of three manufacturers shall be accepted per active ingredient.
1. Proof of payment of Sanitary Surveillance Inspection Fee or proof of exemption (original);

2. Up-to-date copy of the company’s Operation License (Sanitary Permit);

3. Copy of the company’s Functioning Permit or of the Special Functioning Permit when fitting, published in the DOU.

4. Copy of the Good Manufacturing and Control Practices certificate (GMP) emitted by ANVISA for the production line in which the drug product will be manufactured.

5. For imported drug products:
5.1. Submit the Medicine Registration Certificate including the manufacturing site that shall be the same manufacturing site of the drug product being object of registration in Brazil.
5.2. Specify the stage of the imported drug product as raw material, in bulk or finished product;
5.3. Copy of the Good Manufacturing and Control Practices certificate (GMP) emitted by ANVISA for the production line in which the drug product object of registration will be manufactured.
5.4. Copy of the Good Manufacturing Certificate emitted by ANVISA for the packaging line facilities of the company requesting registration when dealing with raw materials or in bulk products;
5.5. Copy of the Good Manufacturing and Control Practices certificate (GMP) of at least one production line emitted by ANVISA for the facilities of the company requesting registration in cases of imported raw materials or in bulk products in which the registration petitioner has a permit to manufacture drug products or needs to outsource its distribution, storage and/or packaging.
5.6. Submit the quality control specifications and methodology used by the importer. These shall be the same ones submitted for the approval of the registration.

6. Copy of the Pilot Batch Production Notification with the ANVISA protocol number, if existent.

7. Up-to-date copy of the Technical Responsibility Certificate emitted by the Regional Pharmacy Council of the federated unit in which the pharmacist acts professionally.

8. Compliance with the conditions established in the legislation in force for the control of Transmissible Spongiform Encephalopathy (TSE).

9. FP1 and FP2 petition forms.

10. Model of the package insert, label and cartridge. The information in the package insert can be no less than that contained in the package insert of the Reference Drug. ANVISA may request complementary data whenever there are technical recommendations to do so. The copy of the Reference Drug’s package insert shall be included in the documentation.

11. Production report
11.1. Standard formula; production process; equipment used in the drug product’s manufacture with details of the maximum individual capacity and definition of the size of the industrial batch;
11.2. Complete description of the master formula with designation of the components, respecting the denominations of the DCB, INN or the name listed in the Chemical Abstract Substance (CAS), in this order of priority;
11.3. Description of the amount of each substance expressed in the metric system or Standard unit, with indication of its function in the formula and the respective quality specification reference described in the Brazilian Pharmacopoeia or, in its absence, in another official code authorized by the legislation in force;
11.4. Copy of the complete production and quality control reports including the order of production, detailed production process and ongoing controls referring to three manufactured pilot batches or to three industrial batches produced in the last three years. In case of drug products with three or more different concentrations and proportional formulas, submit the reports of the smallest and highest concentration.
11.5. Additional documentation whenever there is more than one manufacturer of the active ingredient:
a) This documentation refers to the drug product batches that were not submitted to pharmaceutical equivalence and bioequivalence tests, in case of more than one manufacturer of the active ingredient(s):
b) This documentation does not include the three batches whose production and quality control reports were used in the pharmaceutical equivalence and bioequivalence tests and in the stability study.
11.5.1. Production and quality control report of a batch of the drug product produced with the active ingredient that corresponds to each manufacturer presented;
11.5.2. Results and evaluation of the accelerated stability study of a batch of the drug product produced with the active ingredient that corresponds to each manufacturer presented, in compliance with the criteria contained in the GUIDE FOR UNDERTAKING OF STABILITY STUDIES;
11.5.3. Comparative dissolution profile with the drug product submitted to bioequivalence and pharmaceutical equivalence studies for solid pharmaceutical forms;
11.5.4. In case of suspension, test results verifying the size of the particles between one batch of the drug product submitted to bioequivalence and pharmaceutical equivalence studies and one batch of the drug product produced with active ingredient that corresponds to each manufacturer presented, for the smallest and greatest concentration of the product, when fitting.

12. Quality control report of the raw materials
12.1. Excipients
12.1.1. List the bibliographic reference (official compendium) of all the excipients used in the formula of the drug product. In case of excipient not described in the official compendia, submit the specifications and the analysis methods used.
12.2. Active Ingredient(s)
a) The company requesting registration shall submit copy of the original documentation listed below of the manufacturing company or companies of the active ingredient(s). The indication of a maximum of three manufacturing companies will be accepted.
b) The documentation of the active ingredient shall be submitted in sealed stationary of the manufacturing company.
12.2.1. General data of the manufacturing company including complete address of the manufacturing site of the active ingredient;
12.2.2. Synthesis route including description of the intermediary molecules and their chemical names;
12.2.3. Description of the specifications of the manufacturer;
12.2.4. Identification of the analytic methods used by the manufacturer;
12.2.5. Quantification and limits of the main contaminants according to the synthesis route of the active ingredient;
12.2.6. List of the solvents used in the process according to the synthesis route of the active ingredient;
12.2.7. Data on the stereoisomer content, in case of active ingredients that present quirality, whose proportion of stereoisomers may compromise the efficacy and safety of the drug product;
12.2.8. Information and determination of the probable polymorphs and the analytical methodology for active ingredients that present polymorphism;
12.2.9. Validation of the analytical method in case of active ingredients not described in official compendia.
12.2.10. Specify the manufacturer(s) of the active ingredient(s) used in the production of the drug product submitted to the pharmaceutical equivalence and bioequivalence studies, when fitting;
12.2.11. The manufacturer(s) of the active ingredient(s) have the option of sending directly to ANVISA the documentation specified in this item duly identified with the number of the application to which it is related.

13. Quality control report of the drug product
13.1. Specifications and analytical methods;
13.2. Submit validation of the analytical methods used, in compliance with the GUIDE FOR THE VALIDATION OF ANALYTICAL AND BIOANALYTICAL METHODS;
13.3. Submit diskette with the specifications and analytical methods in MS-Word format. The diskette shall be labeled with the following data: name of the company, name of the drug product; concentration(s); pharmaceutical form; type of method used (pharmacopoeia or company’s internal method).

14. Stability studies
a) Medicines containing three or more different concentrations and proportional formulas shall submit only the results and evaluation of the stability study of the smallest and greatest concentrations.
14.1. Submit the results and evaluation of the accelerated stability study of three pilot batches and timeframe of the long duration stability studies including expected expiration date, in compliance with the GUIDE FOR UNDERTAKING STABILITY STUDIES;
14.2. In case of Generic Drugs imported in bulk, submit the results and evaluation of the accelerated stability study in its final trade packaging, in compliance with the GUIDE FOR UNDERTAKING STABILITY STUDIES;
14.3. Submit results and evaluation of the long duration stability studies, including the expiration date established for national drug products already registered in the country as well as imported ones;
14.4. In case of drug products with an expiration date greater than 24 months, submit the finished long duration stability study. In case of stability studies undertaken in a manner that does not comply with the GUIDE FOR UNDERTAKING STABILITY STUDIES, through justification, the maximum expiration date granted will be of 24 months;
STABILITY STUDIES, through justification, the maximum expiration date granted will be of 24 months;
14.5. In case of drug products with three or more different concentrations and proportional formulations, submit the results and evaluation of the stability study of the smallest and greatest concentration.

15. Data concerning the primary packaging
15.1. describe the specifications and analytical methods used in the quality control of the primary packaging

16. Pharmaceutical equivalence report
a) Any drug product that comes in the shape of a coated tablet whose Reference Drug is a simple tablet or vice versa may be registered as a Generic Drug provided that the coating does not present a gastro-protective function.
16.1. Submit a technical report containing the results and evaluation of the pharmaceutical equivalence study of the Reference Drug marketed in the country in compliance with the GUIDE FOR THE UNDERTAKING OF THE STUDY AND PREPARATION OF THE PHARMACEUTICAL EQUIVALENCE REPORT;

17. Report of the biological, pharmacological and technical tests
a) Medicines exempt of bioequivalence study and those cases in which this study may be substituted by pharmaceutical equivalence test are defined in the GUIDE FOR THE EXEMPTION AND SUBSTITUTION OF BIOEQUIVALENCE STUDIES

b) In cases in which the exemption is based on the comparison of the dissolution profiles, this shall be undertaken in laboratories duly authorized by ANVISA using the same analytical methodology used in the pharmaceutical equivalence. In case of non-pharmacopoeic method, the comparative dissolution profile shall be established by using the test and Reference Drugs in various conditions. These shall include at least three different dissolution means in compliance with the GUIDE FOR DISSOLUTION ASSAYS OF IMMEDIATE RELEASE SOLID PHARMACEUTICAL FORMS.
c) Immediate release oral formulations with active ingredient(s) of high solubility, high intestinal permeability and broad therapeutic range will be exempt of the bioequivalence studies provided they have already been exempted of the relative bioavailability test by the regulatory organizations of the United States (FDA) and Europe (EMEA), and submit documentation to prove this exemption.
d) The bioequivalence study shall be undertaken on the same batch used in the pharmaceutical equivalence study.
e) Bioequivalence studies that fail to use an adequate design for statistical treatment shall not be accepted, even if the acceptance criteria comply with those dictated.
17.1. Submit a technical report with the results and evaluation of the report of the bioequivalence study, undertaken with the Reference Drug marketed in the country, in compliance with the GUIDE FOR RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE TESTS OF MEDICINES. ANVISA may request complementary studies when fitting.
17.1.1. The company shall attach the following to the report:
17.1.1.1. copy of FP1 and FP2;
17.1.1.2. copy of the title page (model in Annex I of this Regulation);
17.1.1.3. pharmaceutical equivalence report of the products used in the bioequivalence study;
17.1.1.4. report of the comparative study of the dissolution profiles, between dosages, accompanied by table containing the individual values of all the determinations for cases of bioequivalence exemption petitions;
17.1.1.5. copy of the Good Bioavailability and Bioequivalence Practices Certificate of Medicines or publication in the DOU, or in its absence, copy of the certification petition protocol.
IV – Medicines not accepted as generic
The following products shall not be admitted for registration as Generic Drug:
1. drug products exempt of registration, in compliance with Article 23 of Law 6.360, dated 9/23/75;
2. small volume parenteral solutions and unitary high volume parenteral solutions that do not contain active ingredients, such as water for injection, glucose solutions, sodium chloride, other electrolytic compounds or sugars;
3. biological products, immunotherapeutic drug products, plasma derivates and human blood;
4. products obtained through biotechnology, excepting antibiotics, fungicides and others determined by ANVISA;
5. herbal drug products;
6. drug products containing vitamins and/or mineral salts;
7. antiseptics for hospital use;
8. oral contraceptives and endogenous hormones of oral use;
9. products with diagnostic purposes and radiological contrasts;

10. Over the Counter Drugs, excepting:
10.1. simple antacids, antacids with antiflatulence preparations and carminatives or simple antiflatulence preparations and carminatives;
10.2. non-narcotic analgesics;
10.3. topical use non-steroidal anti-inflammatory drug products;
10.4. expectorants, cough sedatives;
10.5. topical antifungal drug products;
10.6. muscle relaxants;
10.7. oral and topical anti-parasitic drug products;
10.8. anti-histamines;
10.9. anti-spasmodic drug products.
V – Post-registration measures
1. After the publication of the registration, the manufacturing company of the Generic Drug shall submit the following to ANVISA:
1.1. proof of the distribution of the first three batches manufactured so that ANVISA can collect samples for control analysis as it sees fitting;
1.2. results and final evaluation of the long duration stability study of the first three batches produced, in accordance to timeframe approved by ANVISA. Registered drug products whose stability studies do not meet the GUIDE FOR UNDERTAKING STABILITY STUDIES, a new study shall be submitted;
1.3. report on the incidence of adverse reactions and therapeutic inefficacy.
1.4. the company will have a maximum of 180 days from the publication date of the Generic Drug registration in the DOU to prove the beginning of the drug product’s commercialization through the presentation of three invoices to ANVISA. This deadline may be prolonged one time only as determined by ANVISA through the explicit request of the company for no longer than the initial 180 days. Non-compliance will result in cancelled registration.
1.4.1. official laboratories are exempt of submitting invoices, but shall prove the production and distribution of the drug products.
2. Post-registration alterations, inclusions, notifications and cancellations
a) The complete documentation referring to the description of the alterations, inclusions, notifications and withdrawals that the drug product has undergone after registration shall be submitted to ANVISA, in compliance with the GUIDE FOR MAKING POST-REGISTRATION ALTERATIONS, INCLUSION, NOTIFICATIONS AND CANCELLATIONS IN MEDICINES.
b) The company shall only market the product with the proposed alteration and/or inclusion after the publication of the petition approval in the DOU.
c) Various alterations and/or inclusions of a same drug product can be requested, provided that the documentation for each one is submitted.
d) If an alteration and/or inclusion are found in the drug product that has not been previously communicated to ANVISA and approved by it, the company will be penalized with the cancellation of the registration.

3. The following alterations, inclusions, notifications and cancellations require previous approval for their implementation by the manufacturer:
3.1. alteration in labeling;
3.2. alteration in expiration date;
3.3. alteration in conservation care;
3.4. alteration in the synthesis route of the active ingredient;
3.5. alteration in the manufacturer of the active ingredient;
3.6. alteration in the manufacturing site;
3.7. alteration by modification in the excipient;
3.8. alteration in the manufacturing process of the drug product;
3.9. alteration in the size of the batch;
3.10. alteration in the equipment used;
3.11. inclusion of a new commercial presentation;
3.12. inclusion of new packaging;
3.13. inclusion of new concentration already approved in the country;
3.14. inclusion of manufacturer of the active ingredient;
3.15. inclusion of batch size;
3.16. temporary suspension of manufacturing;
3.17. reactivation of the manufacturing of the drug product;
3.18. cancellation of the registration of the presentation of the drug product on demand;
3.19. cancellation of the registration of the drug product on demand.

4. Criteria and conditions for registration renewal
To renew the registration of a Generic Drug the company shall submit the following documentation:

4.1. petition form duly filled in;

4.2. Proof of payment of Sanitary Surveillance Inspection Fee or proof of exemption when fitting;

4.3. Up-to-date Certificate of Technical Responsibility emitted by the Regional Pharmacy Council;

4.4. Copy of the invoices proving the commercialization of the drug product. Submit a declaration concerning commercial presentations that were not marketed but whose registration the company is interested in keeping.

4.5 Whenever a drug product is not produced in the said period, Official Laboratories shall submit a justification for the fact that it was not marketed;

4.6. Copy of the final version of the package insert that accompany the product in its commercial packaging;

4.7. A list of all the post-registration alterations and/or inclusions that took place during the product’s last valid period of registration accompanied by a copy of the D.O.U. or in its absence, a copy of the protocol of the corresponding petition(s);

4.8. for imported drug products:
a) Good Manufacturing and Control Practices certificate (GMP) for the packaging line emitted by ANVISA for the company requiring the registration of an in bulk product or in its primary packaging;
b) Good Manufacturing and Control Practices certificate of at least one production line emitted by ANVISA for the installation of the company requesting registration in cases of products imported in bulk or in their primary packaging in which the petitioner has an authorization to manufacture drug products or need to outsource distribution, storage and/or packaging;
c) For imported products, submit the respective technical reports of physicochemical, chemical, microbiological and biological quality control according to the pharmaceutical form made by the importer in Brazil
4.9. results and evaluation of the long duration stability study;

4.10. bioequivalence study undertaken in the Reference Drug marketed in the country if the registration was granted based on bioequivalence study of international Reference Drug.

5. Situations in which a new study may be requested to prove bioequivalence
a) ANVISA may request a new study to prove a Generic Drug’s bioequivalence in the following situations:
5.1. whenever there is clinical evidence that the Generic Drug does not present therapeutical equivalence to the Reference Drug;
5.2. whenever there is documented evidence that the Generic Drug is not bioequivalent to the Reference Drug;
5.3. whenever there is risk of deteriorating health;
5.4. whenever there are alterations and inclusions in the drug product that justify a new interchangeability proof.
VI – Criteria for the prescription and dispensation of Generic Drugs
1. Prescription
1.1. Within the Unified Health System (SUS), prescriptions shall adopt the Brazilian Common Denomination (DCB) or in its absence, the International Nonproprietary Name (INN).
1.2. In public health services the professional in charge will determine whether to prescribe using the generic name or the brand name of the drug product;
1.3. If the professional prescribing the drug product decides for the non-interchangeability of the drug product, this shall be specified in the prescription in a clear, readable and unequivocal manner in his own handwriting, other forms of printing being forbidden.
2. Dispensing
2.1. The pharmaceutical professional shall be allowed to substitute the Brand Drug by the corresponding Generic Drug unless specifically requested by the prescriber.
2.2. In these cases the pharmaceutical professional shall indicate the substitution of the prescription, add his seal, name and inscription number in the Regional Pharmacy Council, and date and sign the prescription.
2.3. In cases of prescription of Generic Drugs, the dispensing of the reference or corresponding Generic Drug shall be permitted.
2.4. It is the duty of the pharmaceutical professional to explain the prescription in detail to the patient as well as to supply all the guidance necessary for the rational consumption of the Generic Drug.
2.5. The substitution of the Generic Drug shall be based on the list of Generic Drugs registered by ANVISA.
2.6. The list of Generic Drugs shall be made public by ANVISA in the media.

ANNEX I

TITLE SHEET OF THE REGISTRATION AND POST-REGISTRATION OF GENERIC DRUGS