Legislation
Resolution

Resolution - RDC nº 84, of March 2, 2002
(Official Journal of 20/03/2002)

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 Regulation of ANVISA approved by Decree 3.029, of April 16, 1999, in a meeting held on March 13, 2002,

WHEREAS

that Law 9.787, of February 10, 1999, established the legal basis for the institution of generic drugs in the Country;

that the same Law, in its Article 2, determines that its regulation is to be given by the Federal Agency responsible for the sanitary surveillance;

that the implantation of generic drugs in the Country is a priority of the drug products policy of the Ministry of Health;

the need to assure the quality, safety and effectiveness of generic drugs, as well as to guarantee its interchangeability  with respective products of reference,

adopted the following Resolution and I, the Chairman, determine its publication:

Article 1 - Approve the attached Technical Regulations for Generic Drugs.

Article 2 - Determine that, for the registration of generic drugs, interested companies must comply with all provisions of this regulation.

Only paragraph - Under the  provisions set forth in this Resolution, companies must comply with the technical procedures described in the Form related to the respective themes, approved by the Collegiate Board of Directors and published in the Official Journal of the Union.

Article 3 - Determine that only the specialized establishments duly authorized by ANVISA may carry out the necessary tests for the proofs of pharmaceutical Equivalence, Bioavailability and Bioequivalence stated in this Regulation.

Only paragraph - Companies interested in carrying out those tests must arrange their registration with ANVISA and comply with legal requirements pertaining to their activity.

Article 4 - The Resolution RDC 10, of January 2, 2001 is hereby revoked.

Article 5 - This Resolution enters into force on the date of its publication.

GONZALO VECINA NETO

ANNEX

TECHNICAL REGULATION FOR GENERIC DRUGS

-          SCOPE

This regulation shall consist of:

I-           Definitions used for registration of generic drugs;

II-         Measures taken prior to registration;

III-        Legal and technical aspects of registration;

IV-      Post-registration measures;

V-        Criterion for prescription and dispensation of generic drugs;

VI-      Requirements for new bioequivalence studies;

VII-     Description of drugs that shall not be accepted as generic;

Annex I - Cover page of the process of registration and post-registration of generic drugs;

Annex II - Form for requesting post-registration alteration/inclusion.

The technical procedures for executing and fulfilling the legal requirements pertaining to registration or registration alterations/inclusions and registration renewal shall be presented in specific guidelines according to themes, published in the Official Journal. 

I-      DEFINITIONS

1.       Common Brazilian Denomination (CBD): denomination of the drug or pharmacologically active principle approved by the Federal Agency responsible for the sanitary surveillance.

2.       International Nonproprietary Names (INN): denomination of the drug or pharmacologically active principle recommended by the World Health Organization.

3.       Bioavailability: indicates the speed and the extension of absorption of one active principle in a dosage form, from its concentration/time curve in the systemic circulation or from its excretion in the urine.

4.       Pharmaceutical Equivalents: are drug products containing the same drug , that is, the same salt or ester of the same active therapeutic molecule, in the same quantity and dosage form, either or not containing identical excipients. They must comply with the same updated specifications of Brazilian Pharmacopoeia and, in the absence of these, with the specifications of other authorized codes by the legislation in force or, furthermore, with other applicable quality standards, related to identity, dosage, purity, strength, content uniformity, disintegration time and dissolution speed, whenever necessary.

5.       Bioequivalent Drug products: are pharmaceutical equivalents that, when given in a same molar portion, under the same experimental conditions, do not present statistically significant differences in relation to the bioavailability.

6.       Therapeutic Equivalence - two drug products are considered therapeutic equivalents if they are pharmaceutically equivalent and, after the administration of the same molar portion, its effects in relation to the efficacy and safety are essentially the same, what is appraised by means of appropriate bioequivalence studies, pharmacodynamic trials, clinical trials or studies in vitro.

7.       Drug product: pharmaceutical product, technically obtained or elaborated, with a prophylactic, curative, palliative aim or for diagnosis purpose. It's a finished dosage form containing the drug, generally in association with pharmaceutical adjuvants.

8.       Generic Drug: drug product similar to a reference or innovative product, which intends to be interchangeable with it, generally produced after the expiration or waiver of the patent protection or of any other rights of exclusiveness, upon verification of its effectiveness, safety and quality, and designated by the CDB or, in its absence, by the INN.

9.       Innovative Drug Product: drug product presenting in its composition at least one active drug that has been under patent, even if already extinguished, by the company responsible for its development and introduction in the market of the country of origin, and available in the national market. Generally, the innovative drug product is considered reference drug product, however, in the absence of the same, ANVISA will indicate the reference drug product.

10.   Reference Drug Product: innovative drug product registered at the Federal Agency responsible for the sanitary surveillance and commercialized in the Country, whose effectiveness, safety and quality, have been scientifically proven by the qualified Federal Agency, upon registration.

11.   Similar Drug Product: drug product containing the same or more active principles, presenting the same concentration, pharmaceutical form, means of administration, recommended dosage therapeutic indication, and that is equivalent to the registered drug product at the Federal Agency responsible for sanitary surveillance. It may only differ in characteristics related to the size and shape of the product, validity period, packaging, labeling, excipients and vehicles, always identifiable by the trade name or trade mark.

II - MEASURES PRIOR TO REGISTRATION OF GENERIC DRUGS

The objective of this stage is to:

1. authorize companies to manufacture pilot batches in accordance with the GUIDE FOR PRODUCTION OF PILOT BATCHES ;

2. verify their capacity to manufacture the generic drug;

3. authorize companies to import samples for undertaking of in vitro and in vivo trials, in the case of imported products;

4. request the indication of the reference drug in case it is not included in the official list divulged by ANVISA;

5. evaluate, in the case of products to be submitted to in vivo test, the pharmaceutical equivalence study protocol, indicating the reference drug, with the description of the trials to be undertaken, in accordance with the GUIDE FOR THE UNDERTAKING OF THE STUDY AND PREPARATION OF PHARMACEUTICAL EQUIVALENCE REPORT ;

6. evaluate, in the case of products to be submitted to in vivo test, the bioequivalence study protocol, presented in accordance with the GUIDE FOR PROTOCOL AND TECHNICAL REPORT OF THE BIOAVAILABILITY AND BIOEQUIVALENCE. In case these studies are not necessary, as indicated in the GUIDE FOR EXEMPTION AND SUBSTITUTION OF BIOEQUIVALENCE STUDY , submit technical justification supporting such waiver.

Importing companies and those that already hold registration of drug product at ANVISA and wish to register and commercialize it as generic are exempt from requesting authorization for manufacturing pilot batches.

In the case of an imported drug product or a drug product that is already registered at the Ministry of Health, for the purpose of registration and commercialization as a generic drug, requirements pertaining to the production of pilot batches may be complied with retrospectively, provided that the validation of the analytical method(s) is verified, according to the GUIDE FOR VALIDATION OF ANALYTICAL METHODS, as well as the validation of the manufacturing process, the validation of equipment cleaning and the stability study that prove the validity of the drug product, on the packaging in which it is commercialized.

The assessments proposed in items  5 and  6 of this stage are optional for the companies, which must present the results of the trials related to the said assessments sin the registration stage of the product.

II-     REGISTRATION

For this stage, there is a single procedure for requesting registration of both national or imported generic drugs.

1. legal aspects

a) proof of payment of generic drug registration fee;

b) copy of the Operation License of the company and/or up-to-date Sanitary Permit;

c) copy of the Operation Authorization of the company, published in the Official Journal of the Union;

d) certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug product, to be registered, will be manufactured;

Obs: for imported drug products, it is necessary to present the registration certificate of the drug product, stating the manufacture site, which must be the same as the drug to be registered in Brazil.

2. Technical aspects

2.1. Petition forms PF1 and PF2

2.2. General data that must be contained in the instructions for use and the packaging, in compliance with legislation in force; information contained in the instructions for use of generic drug products must not be inferior to that contained in the instructions for use of the reference drug, at the discretion of ANVISA, the right being reserved to this agency to request the complementation of any data, whenever it is deemed necessary for the clarification of the users of the drug product.

2.3. Technical report

The technical report must include: production report, quality control report, stability, packing and packaging material, pharmaceutical equivalence report, biopharmaceutical tests report.

2.3.1. Production report

a) standard formula, production process and equipment used in the manufacturing of the drug product, with information about maximum individual capacity and definition of the size of the industrial batch;

b) complete description of the master formula designating the components according to the CBD, INN or the denomination described in the Chemical Abstract Substance (CAS), observing the order of priority;

c) description of the quantity of each substance, expressed in the decimal metric system or standard unit, indicating its function in the formula and respective reference of quality specification described in the Brazilian Pharmacopoeia or, for lack of it, in other official codes authorized by the legislation in force;

d) validation of the manufacturing process of the drug product, including the validation of the cleaning procedures of the equipment. For proof, the company must present the validation protocol and  conclusive report;

e) copy of complete dossier on production and quality control referring to the three pilot batches manufactured. For drug products already registered and/or imported, the dossier must refer to the last three years of manufacturing. 

Obs: The reproducibility of results between the batch used in the bioequivalence study and other batches produced subsequently must be verified employing methods described in the Brazilian Pharmacopoeia or other code recognized by the legislation in force. Otherwise, the methods and specifications proposed in the drug product registration dossier can be used, undertaking, whenever appropriate, the in vitro/in vivo correlation study according to the GUIDE FOR IN VITRO-IN VIVO CORRELATION STUDIES .

2.3.2. Quality control report

2.3.2.1. Raw material

2.3.2.1.1. Excipients

Quote bibliographic reference.

Obs: in the case of drug products not described in official codes, present specifications and methods of analysis adopted.

2.3.2.1.2. Drugs

Regarding drug products, the following information must be included:

a) the manufacturing company(ies) and the synthesis path;

b) specification descriptions;

c) analytical methods used and the identification;

d) quantification and limits of their main contaminators, according to the synthesis path of the drug;

e) list of solvent agents used in the process;

Obs. 1: For the drugs presenting chirality, and whose proportion of stereoisomers may compromise the effectiveness and safety of the drug product: data about the proportion of stereoisomers, whenever the analytical methodology is available.

Obs. 2: For the drugs presenting polymorphism: information about probable polymorphs and whenever possible, the analytical methodology for its determination.

Obs. 3: In case the drug is not described in official codes submit, in addition, the analytical method duly validated.

Obs. 4: Indication of a maximum of three manufacturing companies of the drug will be accepted, provided that all parameters previously mentioned are informed in the registration process. The drug proceeding from any one of the manufacturers mentioned must comply entirely with the specifications adopted in the development and testing of the drug product.

2.3.2.2. Drug product

a) specifications and analytical methods (send, in addition, copy in disk in MS-Word);

For the drug products included in the pharmacopoeia, describe the specifications and analytical methods used, highlighting, whenever the case, the in vitro trial(s) that ensure(s)  reproducibility of the bioavailability batch per batch, provided the in vitro-in vivo correlation is verified, whenever the GUIDE FOR IN VITRO-IN VIVO CORRELATION STUDY is applicable.

The quality specifications must take in consideration relevant aspects of its effectiveness and safety.

b) validation of the analytical methods employed. In the case of pharmacopoeic methodology, present precision, accuracy and linearity data.

2.3.3. stability

a) submit the results and assessments of the accelerated stability study of the three batches produced. The national drug products already registered in the country, as well as the imported ones, must present stability data, observing the established validity period;

b) generic drugs imported in great quantities must present the results and the assessment of the stability test in the final packing for commercialization, in accordance with the GUIDE FOR THE UNDERTAKING STABILITY STUDIES;

c) the assessment of the stability study results must emphasize the projection of the validity period and recommended storage and distribution conditions.

2.3.4. packing material and packaging

Describe the specifications and analytical methods used.

2.3.5. pharmaceutical equivalence report

In all cases, the company must prove the pharmaceutical equivalence in relation to the drug product of reference, using, whenever the case, up-to-date monograph of the Brazilian Pharmacopoeia or, for lack of it, of other codes authorized by the legislation in force. The results must be displayed in accordance with the GUIDE FOR THE UNDERTAKING OF THE STUDY AND PREPARATION OF PHARMACEUTICAL EQUIVALENCE REPORT ;

In the case of presentation in drops (oral, nasal and ophthalmic solutions and suspensions) the number of drops corresponding to 1ml must be determined, indicating the concentration of the drug per ml. The certificate  of pharmaceutical equivalence must contain the interchangeability in drops/mg between the test drug and the reference drug.

2.3.6. biopharmaceutical tests report

Submit technical report containing the results and the assessment of the bioequivalence study, in accordance with the GUIDE FOR BIOEQUIVALENCE OF GENERIC DRUGS of this regulation. The bioequivalence study must be undertaken using the same batch employed for the pharmaceutical equivalence study. In the case of new generic drugs (production of three batches), one of the batches must be used to carry out bioequivalence and pharmaceutical equivalence tests. The technical report must be sent in two copies.

IV- POST-REGISTRATION MEASURES

1. information the company must send after the publication of the registration

After publication of the registration, the company must present to ANVISA:

a) indication of the distribution of the first manufactured batches (at least 3) to ANVISA, which, at its discretion, will apprehend for control analysis;

b) results and final assessment of the long term stability study of the three batches produced in accordance with the approved protocol. In the case of registered drug whose stability does not comply with the Guide for undertaking stability study, a new study must be presented.

c) declaration of the validity period and definite storage and distribution conditions;

d) report of adverse reactions and therapeutic inefficacy occurrence;

e) information about the effects of feeding on absorption.

Obs.: Bioequivalence studies that estimate the alimentary effect on the drugs absorption may be required during the post-registration phase.

2. Post-registration Alterations and Inclusions

The process of registration of alteration and/or inclusion of generic drug will be composed of two stages, as described below:

a) Stage 1: Authorization request for the manufacture of pilot batches

For carrying out changes and/or inclusions in drugs products already registered, the company must previously forward a request to GGMEG ANVISA, according to  (ANNEX II).

b) Stage 2: Approval of Alteration and/or Inclusion

The company must forward to ANVISA all the trials undertaken in the pilot batches and other documents, according to the GUIDE FOR MAKING POST-REGISTRATION ALTERATIONS AND INCLUSIONS OF DRUG PRODUCTS . The company is only allowed to commercialize the product with the proposed alteration and/or inclusion after publication, in the Official Journal of the Union, of the approval of the petition.

In case an inclusion or alteration is found in the product that has not been previously communicated to ANVISA and approved by it, the company shall be penalized with the cancellation of the drug registration.

3. Alterations and inclusions that need prior approval for their implementation by the manufacturer

a) label alterations;

b) alterations in the text of the indication for use;

c) alterations of validity period;

d) alterations of restrictions for use;

e) alterations in preservation conditions;

f) alterations of the drug synthesis path;

g) alteration of the manufacture site/manufacturer;

h) alterations of registration due to changes of excipients;

i) alteration in the manufacturing process of the drug product;

j) alteration of the batch size;

l) changes of equipment used;

m) substitution and inclusion of manufacturer of the drug;

n) registration of New Commercial Presentation;

o) registration of New Packing;

p) registration of New Concentration.

q) form for requesting post-registration alteration/inclusion.

4. Criteria and conditions for registration renewal

The revalidation/renewal of the registration of any drug product is subject to the assessment of ANVISA, which, in addition to observing compliance with the rules set forth in this regulation, shall make use of local or international surveillance data, inspection data and market monitoring data to accept or reject the said revalidation/renewal. 

For revalidation/renewal of generic drug registration, the company must present documentation referring to legal and technical aspects, as follows.

4.1. Legal Aspects

a) original proof of bank deposit and legalized copy;

b) copy of the Operation License of the company and/or up-to-date Sanitary Permit;

c) certificate of Technical Responsibility, issued by the Pharmacy Regional Council;

d) certificate of Good Manufacturing and Control Practices issued by ANVISA for the line of production in which the drug product, to be registered, will be manufactured;

e) proof of commercialization of the product (for example, copy of the tax bill).

4.2 Technical Aspects

4.2.1. petition forms (FP1 and FP2);

4.2.2. present models of secondary and primary packaging and instructions for use;

4.2.3. registration background

The company must present the complete background of the registration, including:

a) all the alterations made to the product during the period preceding the revalidation, together with the copy of the Official Journal of the Union that proves the approval of such alterations;

b) proof of presentation of report of adverse reactions and therapeutic inefficacy occurrence;

c) information of the effects of feeding on absorption.

Obs.: The methodologies used by the company for analysis of the raw material and the finished product must comply with the new editions of the official codes.

V - PRESCRIPTION AND DISPENSATION OF GENERIC DRUGS

1. Prescription

a) within the Unified Health System (UHS), the prescriptions given by the professional expert in charge must necessarily adopt the Common Brazilian Denomination - CBD, or, in its absence, the International Nonproprietary Names (INN);

b) in the private health services, the prescription is left to the discretion of the professional expert in charge and may be made using the generic or the trade name, emphasizing, whenever necessary, the restrictions regarding interchangeability;

c) in the case that the professional prescriber decides for non-interchangeability of his prescription, this decision must be taken for each item prescribed, in a clear, legible and unmistakable way, in handwriting, with no printing, labeling, sealing or other automatic forms allowed.

2. Dispensation

a) the professional pharmacist is allowed to substitute the prescribed drug product, exclusively, for the corresponding generic drug, unless the professional prescriber expressly restricts the substitution;

b) in these cases, the pharmacist must indicate the substitution made in the prescription, affix his seal where his or her name and inscription number of the Pharmacy Regional Council must be stated, date and sign the prescription;

c) in the case of prescriptions using a generic name, only the dispensation of a reference drug product or of a corresponding generic will be permitted;

d) it is the obligation of the pharmacist to explain in detail the dispensation to the patient or user, as well as to give all necessary instructions for the rational consumption of the generic drug;

e) the generic substitution must be based on the list of approved generic drugs by the National Sanitary Surveillance Agency and whose registrations have been published in the Official Journal of the Union;

f) the list of generic drugs must be made public by ANVISA through the media.

VI- SITUATIONS IN WHICH A NEW STUDY FOR PROOF OF BIOEQUIVALENCE MAY BE REQUIRED

The National Sanitary Surveillance Agency may request new studies for proof of bioequivalence of a product already registered as generic in the following situations:

a) clinical evidence that a product does not present therapeutic equivalence in relation to the reference drug;

b) documented evidence that a product is not bioequivalent in relation to the reference drug.

VII - DRUGS THAT WILL NOT BE ACCEPTED TO BE REGISTERED AS GENERIC DRUGS

1. Drugs exempt of registration according to Art. 23 of Law 6360 of 23/09/75;

2. Unitary small volume parentheral solutions and large volume parentheral solutions, exempt of drugs, such as, water for injection, glucose solutions, sodium chloride, other electrolytic compounds or sugars;

3. Immune-therapeutic biological products derived from the plasma and human blood;

4. Products obtained through biotechnology, with exception of the antibiotics, fungicides and others, according to ANVISA;

5. Botanical drug products;

6. Drug products containing vitamins and/or mineral salts;

7. Antiseptics for hospital use;

8. Non-synthetic oral contraceptives and hormones;

9. Products used in diagnosis and radiological contrasts;

10. Drugs exempt from medical prescription, except:

10.1. simple antacids, antacids with antiphysetics or carminatives, simple antiphysetics and carminatives;

10.2. non-narcotic analgesics;

10.3. balsamics and mucolitics;

10.4. topical non steroid anti-inflammatories;

All the stages included in this regulation must be preceded by the cover sheet according to ANNEX  I.

ANNEX I

Cover page of the process of registration and post-registration of generic drugs