Hotsite - Genéricos - Legislação - Resolução - RDC nº 10, de 2 de janeiro de 2001

Legislação
Resolução

Resolution - RDC nº 10, of January 2, 2001 (*)
(*) Republished, due to error in the original, in the OJU nr 6-E, of 9/1/2001, Section 1, page 18.
(Of. El. nº 18/2001)

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 December 28, 2000,

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 interchangeableness with respective products of reference,
adopted the following Resolution and I, the Chairman, determine its publication:

Article 1 - Approve the 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 - In case ANVISA has not yet made any official communication about any reference drug product, companies interested in the registration of its corresponding generic drug must inquire about it by writing to ANVISA, which will provide the requested indication.

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

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

Article 4 - The Resolution 391, of August 9, 1999, published in the Official Journal of the Union (OJU) on November 19, 1999, 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

1. SCOPE

The bioequivalence tests, the therapeutical andpharmaceutical equivalence measurements, the registration, the interchangeableness and the dispensation of generic drugs are governed by this regulation.

2. DEFINITIONS

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

2.2 International Nonproprietary Names (INN) - denomintation of the drug or pharmacologically active principle recommended by the World Health Organization.

2.3 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.

2.4 Pharmaceuticalal Equivalents - are drug products containing the same drug , that is, the same salt or ester of the same active therapeutical 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.

2.5 Bioequivalent Drug products - arepharmaceutical 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.

2.6 Therapeutical Equivalence - two drug products are considered therapeutical equivalents if they are phamaceutically equivalents 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 assays, clinical assays or studies in vitro.

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

2.7.1. Generic Drug - drug product similar to a product of reference or innovator, which intends to be interchangeable with it, generally produced after the expiration or rejection of the patent protection or of any other rights of exclusiveness, verified its effectiveness, safety and quality, and designated by the CDB or, in its absence, by the INN.

2.7.2. Innovator Drug Product - drug product presenting in its composition at least one active drug that has been under patent, even 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 innovator drug product is considered drug product of reference, however, in the absence of the same, ANVISA will indicate the reference drug product.

2.7.3. Reference Drug Product - innovator drug product registered at the Federal Agency responsible for the sanitary surveillance and commercialized in the Country, with effectiveness, safety and quality, scientifically verified by the qualified Federal Agency, at registration time.

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

3. CRITERIA AND CONDITIONS FOR THE REGISTRATION AND QUALITY CONTROL OF GENERIC DRUGS

The registration process of generic drugs will include three (03) steps: first step: pre-submission; second step: submission; third step: post-registration. Information about the necessary documents are found in the articles of the respective steps. All documents for the registration of generic drugs sent to ANVISA must be accompanied by a " Cover Page " (ANNEX X), duly completed.

Obs.: The Step 1 Pre-Submission is optional. In case the applicant prefers, it is possible to start the process at Step 2 Submission, provided that the requirements described in item 3.1 are fulfilled and observed in this step.

3.1 Step 1 - Pre-submission (phase of preparation for the drug product registration)

3.1.1. National Drug product

3.1.1.1. Drug product WITHOUT registration in ANVISA

3.1.1.1.1. Authorization request for the manufacture of pilot batches

The request must contain the following information:

a) standard formula, process and equipments used for the manufacture of the drug product;

b) detailed protocol, with study of stability, according to GUIDE FOR THE UNDERTAKING OF THE STUDIES OF STABILITY (ANNEX I, of this regulation);

c) Analytical methods employed;

d) Protocol of the pharmaceutical equivalence study, indicating the reference drug product, with the description of assays to be carried out, according to the GUIDE FOR THE UNDERTAKING OF THE STUDY AND REPORT PREPARATION OF PHARMACEUTICAL EQUIVALENCE (ANNEX II, of this regulation);

e) Bioequivalence study protocol, in two copies, presented in accordance with the GUIDE FOR PROTOCOL AND TECHNICAL REPORT OF THE BIOAVAILABILITY AND BIOEQUIVALENCE STUDY (ANNEX III, of this regulation). In case these studies are not necessary, as indicated in the GUIDE FOR EXEMPTION AND SUBSTITUTION OF BIOEQUIVALENCE STUDY (ANNEX IV of this regulation), submit technical justification supporting such waiver.

3.1.1.1.2. Authorization for the manufacture of pilot batches

Once fulfilled the requirements in item 3.1.1.1.1., the company will be authorized to manufacture three batches of drug products containing, at least, 100.000pharmaceutical units for the solid dosage forms of oral use. For the other dosage forms, batches of at least 10% of the industrial batch will be required. For drug products with high aggregated value, a manufacture of at least 30.000pharmaceutical units or a technical justification for a smaller size production will be required.

3.1.1.2. Drug product WITH registration in ANVISA

In the case of a drug product already registered in the Ministry of Health, for the purpose of registration and commercialization as a generic drug, requirements of item 3.1.1.1. may be observed retrospectively, provided that the analytical method(s) of validation is verified, according to the GUIDE FOR VALIDATION OF ANALYTICAL METHODS (ANNEX V of this regulation), as well as the validation of the manufacture process, or chronogram of its execution, and the standard operational procedure of cleanliness of equipment. In these cases, the company must submit:

a) copies of complete files of production and quality control, related to three batches manufactured in the last three years;

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

c) Stability data of three batches, within the established validity period;

d) Study protocol of pharmaceutical equivalence (ANNEX II of this regulation);

e) Study protocol of bioequivalence (ANNEX III of this regulation), in two copies. In the cases that the undertaking of those studies is not applicable, submit a technical justification supporting such exemption;

Obs.: in the impossibility of complying with requirements specified in the previous items, the company must follow procedure regarding to the respective requirement(s) of item 3.1.1.1.

3.1.2. Imported drug product

3.1.2.1. With bioequivalence test to be carried out IN the Country

The procedures are:

a) import samples for this purpose, follow the legislation in force for obtaining the import license of samples for experiments in vitro and in vivo;

In the case of imported drug products, destined to registration and commercialization as a generic drug, the requirements of item 3.1.1.1. can be observed retrospectively, once the validation of analytical method (s) is verified, according to the GUIDE FOR THE VALIDATION OF ANALYTICAL METHODS (ANNEX V of this regulation), as well as the validation of the manufacture process, or the chronogram of its execution, and the standard operational procedure of cleanliness of the equipment. In these cases the company must submit:

b) copies of complete files of production and quality control, related to three batches manufactured in the last three years;

c) validation of analytical methods employed. In the case of the pharmacopoeic methodology, it is necessary to present data of precision, accuracy and linearity;

d) Stability data of the three batches, within the established validity period;

e) Study protocol of pharmaceutical equivalence (ANNEX II of this regulation);

f) Study protocol of bioequivalence (ANNEX III of this regulation), in two copies. In case the undertaking of these studies is not applicable, submit a technical justification supporting such exemption;

Obs.: 1 in the impossibility of observance of any of the previous items, the company must comply with the respective requirement(s) of item 3.1.1.1.

3.1.2.2. With bioequivalence test carried out ABROAD

For drug products manufactured abroad, which the bioequivalence studies have already been carried out as per directives of this Resolution, it is needed:

a) import samples for this purpose, observing the legislation in force for obtaining the import license of samples for tests in vitro;

In the case of imported drug products, destined to registration and commercialization as a generic drug, the requirements of item 3.1.1.1. can be observed retrospectively, provided that the validation of analytical method (s) is verified according to the GUIDE FOR THE VALIDATION OF ANALYTICAL METHODS (ANNEX V of this regulation), as well as the validation of the manufacture process, or the chronogram of its execution, and the standard operational procedure of cleanliness of the equipment. In these cases, the company must submit:

b) file copies of comparative assays of dissolution among the three drug products: test, international reference employed for the study of bioequivalence and national reference, in accordance with the directives of the GUIDE FOR DISSOLUTION TESTING OF ORAL SOLID IMMEDIATE RELEASE DOSAGE FORMS (ANNEX VIII of this regulation);

c) technical report of the studies of in vitro/in vivo correlation (ANNEX IX of this regulation), or technical justification that it was not undertaken;

d) copy of documents proving the origin of the drug product of reference used in the bioequivalence study (international reference), by means of the manufacturer information (same company, licensing, etc);

e) complete file copies of production and quality control related to three batches manufactured in the last three years;

f) validation of analytical methods employed. In the case of the pharmacopoeic methodology, it is necessary to present data of precision, accuracy and linearity;

g) stability data of three batches, showing the established validity period;

h) study protocol of pharmaceutical equivalence (ANNEX II of this regulation);

i) technical report of bioequivalence study (ANNEX III of this regulation), in two copies. In the cases that the undertaking of these studies is not applicable, submit a technical justification supporting such exemption;

Obs: 1 in the impossibility of observance of any of the previous items, the company must comply with the respective requirement (s) of item 3.1.1.1.

Obs: 2 at ANVISA discretion, after the publication of the registration, a new bioequivalence study may be requested taking as reference the drug product indicated by the Agency, to be undertaken, preferably, in Brazil.

Obs: 3 for drug products manufactured outside of the country, that do not conform with item 3.1.2.2., all requirements described in item 3.1.1.1. must be observed, without the obligation to present the manufacturing authorization described in item 3.1.1.1.2.

3.2. Step 2 Submission (Registration Request of Generic Drug)

For this step, the procedure for the registration request of generic drugs is unique, that is, it is the same for national and for imported drug products.

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

d) certificate of Technical Responsibility, issued by the Pharmaceutical Regional Council;

e) certificate of Good Practices of Manufacture and Control (GPM) issued by ANVISA for the line of production in which the drug product, to be registered, will be manufactured.

Obs: for imported drug products, the presentation of the registration certificate of generic drug in the country of origin is required.

3.2.2. Technical aspects

3.2.2.1. Petition forms PF1 and PF2

3.2.2.2. Technical report

The technical report must contain:

3.2.2.2.1. General data

a) physical and physicochemical characterization of all components of the formula including melting point, solubility, pKa, impurities, polymorphism, physical form (amorphous/crystalline), solvation (solvate/hydrate/anydrous) and chirality, among others;

b) dosage form;

c) formula indicating the components per dose, and whenever possible, per gramme, milliliter, international standard unit, relation salt/base and excess used;

d) function performed by the substances in the formula;

e) route of administration (for liquid dosage forms describe the dosage meter included in the package, when there is one);

f) directions for use, when that is the case;

g) indications, purpose or appropriate use;

h) contra-indications;

i) side effects and adverse reactions;

j) restrictions and care to be considered;

k) precautions and warnings;

l) medicinal and alimentary interactions;

m) change in the laboratory clinical examinations;

n) overdosage: signs, symptoms and treatment;

o) validity period;

p) storage instructions.

3.2.2.2.2. Pharmacodynamic data

a) action mechanism;

b) strenght (maximum and minimum doses);

c) justification of indicated doses;

d) therapeutical range, when that is the case.

3.2.2.2.2. Pharmacokinetic data

a) absorption;

b) distribution;

c) biotransformation;

d) excretion;

3.2.2.3. Production and quality control report

3.2.2.3.1. Production

Submit report showing:

a) a complete description of the master formula designating the components as per a CBD, INN or a denomintation described in the Chemical Abstract Substance (CAS), following this order of priority;

b) 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;

c) the validation of analytical methods employed;

d) the validation of the productive process, or chronogram of its execution, and the standard operational procedure of cleanliness of the equipments;

Obs: the reproductibility 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 and other manuals recognized by the legislation in force. Otherwise, the methods and specifications proposed in the drug product registration file can be used, undertaking, whenever appropriate, the in vitro/in vivo correlation study taking in account the drug characteristics of solubility and permeability (ANNEX IX of this regulation).

3.2.2.3.2. Quality control

3.2.2.3.2.1. Raw material

3.2.2.3.2.1.1. Excipients

Quote bibliographic reference.

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

3.2.2.3.2.1.2. Drug s

For drug products described in official manuals, submit:

a) the manufacture companies 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;

f) for the drug s 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;

g) for the drug s presenting polymorphism: information about probable polymorphs and whenever possible, the analytical methodology for its determination.

Obs: 1 in case the drug is not described in official manuals submit, in addition, the analytical method duly validated.

Obs. 2 the maximum indication of three manufacturer 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.

3.2.2.3.2.2. Drug product

3.2.2.3.2.2.1. specifications and analytical methods (send, in addition, copy in disk in MS-Word)

For the drug products belonging to the pharmacopoeia, describe the specifications and analytical methods used, highlighting, whenever the case, the in vitro assay (s) that assure (s) a reproductibility of the bioavailability batch per batch, provided the in vitro-in vivo correlation is verified, whenever the case (ANNEX IX of this regulation); the quality specifications must take in consideration relevant aspects of its effectiveness and safety.

Obs: for the drug products not belonging to the pharmacopoeia, submit, in addition, a validation of the analytical method used.

3.2.2.3.2.2.2.pharmaceutical equivalence

In all cases, the company must prove thepharmaceutical 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 as perpharmaceutical equivalence report model (ANNEX II of this regulation).

3.2.2.3.2.2.3. Stability

a) submit the results and assessments of the accelerated stability study of the three batches produced. The drug products classified in items 3.1.1.2. and 3.1.2, of the pre-submission step, must show stability data, observing the established validity period;

Obs: in the case of recently registered drug products which the stability test at long term has not been concluded, exceptionally, at ANVISA discretion, the accelerate test may be accepted.

b) generic drugs imported in great quantities must present the results and the assessment of the stability test in the final arrangement for commercialization;

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

3.2.2.3.2.3. Packing material and packaging Describe the specifications and analytical methods used.

3.2.2.4. Biopharmaceutical tests report

Submit technical report containing the results and the assessment of the bioequivalence study as per ANNEX III 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, provided that the stability of such batch was verified. The technical report must be sent in two copies.

3.2.2.5. Sayings of the secondary and primary packagings and of the printed instructions for the use of drug product

The sayings of the secondary and primary packagings and of the printed instructions for the use of drug product must be equivalent to the ones of the drug product of reference, being in accordance with the legislation in force. Send copy in disk MS-Word and two printed copies.

3.3. Step 3: post-registration

3.3.1. Information the company must send after the publication of the registration

a) indicate the distribution of the first manufactured batches (at least 3) to ANVISA that, 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 of the approved protocol;

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

d) report of adverse reactions and therapeutic inefficacy occurrence;

3.3.2. changes that need previous approval in order to be implemented by the manufacturer

a) replacement of the drug manufacturer;

b) alterations of the drug synthesis path;

c) alterations in the formula and/or packing material and packaging;

d) change of manufacture place, production area and used equipment;

e) increase and decrease of the batch size;

f) alterations in the process of production.

The company must submit the Petition Forms (PF1 and PF2) accompanied by the documentation required in item 3.2.1, including the technical report related to aspects inherent to alteration proposals.

3.3.3 Information about the alimentary effects on the absorption and request of a new bioequivalence study

Bioequivalence studies that estimate the alimentary effect on the drug s absorption may be required during the post-registration phase. Other situations where new bioequivalence studies may be required are described in the ANNEX VI of this regulation.

4. BIOAVAILABILITY PROOFS OF DRUGS IN GENERAL

The bioavailability proofs must be presented in accordance with the ANNEX III of this regulation.

4.1. Stages of the bioavailability study

4.1.1. Clinical stage

a) the drug products to be subjected to the study of bioavailability must, at first, be analyzed according to its monograph registered in the Brazilian Pharmacopoeia and, for lack of it, in other codes authorized by the legislation in force;

b) the bioavailability study is generally undertaken by means of the drug quantification or the active metabolite in the circulation (frequently in plasma or serum), or through its quantification in the urine, whenever justified;

c) the bioavailability study is of the open, random, crossed type. The volunteers receive the test and the reference drug products (the drug product is given intravenously when a drug oral solution is not indicated) in separate occasions (periods), following a scheme of simple or multiple dose. The interval between the periods must be of, at least, seven half-lives of the drug elimination, or the metabolite elimination, whenever the same is active;

d) the chronogram of samples collection must observe a length of time equal or greater to 3-5 times the half-life of the elimination of the drug , or the metabolite, whenever the same is active;

e) the minimum number of healthy volunteers must be of 12, male (excepting for the cases where the drug product is indicated only to women), aged between 18 and 50 years old and capable to express their free and informed consent. ANVISA may require a greater number of volunteers for drug s presenting a great variability;

f) the weight of volunteers must be within a limit of ± 15% of the weight considered normal, considering the height and physical structure;

g) smokers and subjects with a history of alcohol and drug abuse must be avoided. In case smokers are included, these subjects must be identified;

h) cytotoxic drug products must be tested in volunteer patients, carrying the pathology for which the drug product is indicated, with their free and informed consent or that of their legal representative, in case of incapability of the patient;

i) the researcher must fill out a registration form of adverse events and list the adopted procedures for the control or treatment of the same;

j) the research project, the experimental protocol and the free and informed consent term must be submitted to a Committee of Ethics in Research (CEP) accredited by the National Committee of Ethics in Research (CONEP) of the National Council of Health/Ministry of Health (CNS/MS);

k) the volunteers taking part of clinical studies, and in the need of housing, must stay in appropriate place attending the Good Clinic Practices (GCP), under the responsibility of a doctor.
4.1.2. Analytical stage

a) all stages of the study must be achieved in compliance with international norms of Good Laboratory Practices (GLP);

b) analytical methods must be validated as per ANNEX V of this regulation;

c) stability studies of the drug in biological liquids must be achieved in compliance with item 3 of the ANNEX V of this regulation;

d) the analytical protocol must contain directives for the re-analysis of the samples. Not more that 20% of the samples can be re-analysed;

e) the lost of samples during any one of the analytical process stages must be justified;

f) the analysis of the samples may be done in the following conditions: without reply, in duplicate or triplicate. For the analysis of samples in duplicate, the mean value must be used, and in triplicate, the mean of the two nearest values;

4.1.3. Statistical stage

4.1.3.1. the pharmacokinetics parameters are obtained from the blood concentration curves of the drug versus time, statistically analysed for the determination of the bioavailability;

4.1.3.2. the following pharmacokinetics parameters must be determined:

4.1.3.2.1. area under the blood concentration time curve, calculated using the method of the trapezoids, from time zero to time t (ASC0-t), where t is the time related to the last concentration determined through experimentation;

4.1.3.2.2. area under the blood concentration time curve, calculated from time zero to time infinite (ASC0-inf), where ASC0-inf = ASC0-t + Ct/lz, where Ct is the last concentration of the drug determined through experimentation and lz is the elimination constant of the terminal stage. The ASC0-t must be equal or greater than 80% of the ASC0-inf;

4.1.3.2.3. the peak of maximum concentration (Cmax) of the drug and/or metabolite and the timing to reach this peak (Tmax) must be directly obtained without interpolation of figures;

4.1.3.2.4. the depuration (D), the apparent volume of distribution (Vd) and the half-life of elimination (t1/2)b of the drug and/or the metabolite must also be determined, although there is no need of statistical treatment;

4.1.3.2.5. in the studies employing multiple doses the following parameters must be determined:

a) ASC0-t calculated in the interval of the dose (t) in steady state;

b) Cmax e Tmax, obtained without interpolation of figures;

c) Minimum concentration of the drug (Cmin), determined at the end of each dose interval in steady state;

d) Mean concentration of the drug in steadystate (C* = ASC0-t /t);

e) Fluctuation rate in steady state [GF = (Cmax - Cmin)/C* x 100];

4.1.3.2.6. in the case of studies with multiple doses it has to be proved that the steady state has been reached after the administration of the test and the reference drug product;

4.1.3.2.7. the absolute bioavailability (F) of the drug product must be determined and corresponds to the fraction of the dose administered of the drug effectively absorbed. It is calculated through the relation between the area under the curve (ASC0-inf) obtained after the extravascular administration of the test product (Te) and the ASC0-inf obtained after the intravenously administration of the reference product (R). In case the intravenous administration is not possible, a solution containing the drug can be orally administered. The calculation of F is obtained through the formula:

ASC0-inf (Te) x Dose (R)

F(%) = -------------------------------- x 100

ASC0-inf (R ) x Dose (Te)

4.1.3.2.8. inform software programs used for the statistical analysis of the figures.

5. CRITERIA FOR PROOFS OF BIOEQUIVALENCE OF GENERIC DRUGS

The bioequivalence proofs of generic drugs must observe three stages: clinical, analytical and statistical, and must be presented in accordance with the ANNEX III of this regulation.

5.1. Clinical stage

a) the test and the reference drug products to be subjected to the study of bioequivalence must, at first, be analyzed according to its monograph registered in the Brazilian Pharmacopoeia and, for lack of it, in other codes authorized by the legislation in force, following the pharmaceutical equivalence protocol (ANNEX II of this regulation). The difference in the drug proportions between the test and the reference drug products must not be greater than 5% (five per cent);

b) the bioequivalence study is generally undertaken through the quantification of the drug or the active metabolite in the circulation (frequently in plasma or serum), or through its quantification in the urine, whenever justified. Alternatively, the study may be undertaken through the comparison of pharmacodynamic measures.

c) the bioequivalence study is of the open, random, crossed type. The volunteers receive the test and the reference drug products in separate occasions (periods), under a scheme of single or multiple doses. The drug products must be administrated with a standard (usually 200mL) liquid (generally water) volume.

d) The number of periods and the study sequences will be determined by the number of drug products analyzed, in order to assure the statistical validity. The interval between the periods must be, at least, of seven half-lives of the drug or the metabolite elimination, whenever it is active;

e) In general, the quantification of the drug in samples of blood, plasma or serum are employed. The chronogram of samples collection must observe a length of time equal or greater than 3-5 times the half-life of the elimination of the drug , or the metabolite, whenever it is active;

f) The number of healthy volunteers must always assure sufficient statistical power in order to guarantee the trustability of the results of the bioequivalence study. The minimum number of volunteers is, generally, equal to 24subjects, aged between 18 and 50 years old and capable to express their free and informed consent.

g) Depending on the drug product, volunteers taking part in the studies may be male, female or both, noting that in this last case, the number of men and women must be the same.

h) the weight of volunteers must be within a limit of ± 15% of the weight considered normal to men and women, considering the height and physical structure;

i) smokers and subjects with a history of alcohol and drug abuse must be avoided. In case smokers are included, these subjects must be identified;

j) cytotoxic drug products must be tested in volunteer patients, carrying the pathology for which the drug product is indicated, with their free and informed consent or that of their legal representative, in case of incapability of the patient;

k) the researcher must fill out a registration form of adverse events and list the adopted procedures for the control or treatment of the same;

l) the research project, the experimental protocol and the free and informed consent term must be submitted to a Committee of Ethics in Research accredited by the National Committee of Ethics in Research (CONEP) of the National Council of Health/Ministry of Health (CNS/MS).

In the title of the project must be included the drug name, the dosage, the dosage form and name of the manufacturers of the test and the reference drug products. This title must also be included in the experimental report, in the free and informed consent term, as well as in the report prepared by the Committee of Ethics in Research.

m) the volunteers taking part of clinical studies, and in the need of confinement, must stay in appropriate place attending the Good Clinic Practices (GCP), under the responsibility of a doctor.

5.2. Analytical stage

a) all stages of the study must be achieved in compliance with international norms of Good Laboratory Practices (GLP);

b) analytical methods must be validated as per ANNEX V of this regulation;

c) stability studies of the drug in biological liquids must be achieved in compliance with item 3 of the ANNEX V of this regulation; d) the analytical protocol must contain criteria for the samples re-analysis. Not more that 20% of the samples can be re-analyzed;

e) any lost of samples must be justified;

f) the analysis of the samples may be effectuated in the following conditions: without reply, in duplicate or triplicate. For the analysis of samples in duplicate, the mean value must be considered, and for triplicate, the mean of the nearest two values;

g) all determinations with values lower than the Quantification Limit (QL), must be considered equal to zero for the statistical calculations.

5.3. Statistical Stage

5.3.1. General Methodology

5.3.1.1. the pharmacokinetics parameters are obtained from the blood concentration curves of the drug versus time, statistically analyzed for the determination of the bioequivalence;

5.3.1.2. the following pharmacokinetics parameters must be determined:

5.3.1.2.1. the area under the blood concentration time curve, calculated using the method of the trapezoids, from time zero to time t (ASC0-t), where t is the time related to the last concentration determined through experimentation;

5.3.1.2.2. the area under the blood concentration time curve, calculated from time zero to time infinite (ASC0-inf), where ASC0-inf = ASC0-t + Ct/lz, where Ct is the last concentration of the drug determined through experimentation and lz is the elimination constant of the terminal stage. The ASC0-t must be equal or greater than 80% of the ASC0-inf;

5.3.1.2.3. the peak of maximum concentration (Cmax) of the drug and/or metabolite and the timing to reach this peak (Tmax) must be directly obtained without interpolation of figures;

5.3.1.2.4. the depuration (D), the apparent volume of distribution (Vd) and the half-life of elimination (t1/2) of the drug and/or the metabolite must also be determined, although there is no need of statistical treatment;

5.3.1.2.5. for studies employing multiple doses the following parameters must be determined:

a) ASC0-t calculated in the interval of the dose (t) in steady state;

b) Cmax e Tmax, obtained without interpolation of figures;

c) Minimum concentration of the drug (Cmin), determined at the end of each interval of the dose in steady state;

d) Mean concentration of the drug in steady state (C* = ASC0-t /t);

e) Fluctuation rate in steady state [GF = (Cmax - Cmin)/C* x 100];

5.3.1.2.6. for the bioequivalence assessment the parameters ASC0-t, Cmax and Tmax must be employed;

5.3.1.2.7. in the case of studies with multiple doses it must be proved that the steady state was obtained after the administration of the test and the reference drug products.

5.3.2 Statistical Analysis

a) analysis of variance (ANOVA) of the pharmacokinetics parameters ASC0-t and Cmax must be achieved in order to evaluate the effects of sequence (group), of volunteers, of period and of treatment;

b) for a study employing only one dose of the test and the reference drug products, the ANOVA is generally undertaken with the data of ASC0-t and Cmax transformed in logarithm. The distribution of the transformed data is closer to a normal distribution in relation to the data not transformed;

c) for the anlysis of ASC0-t e Cmax, two test t unicaudal must be employed, with a level of significance of a= 0,05, building a 90 % confidence interval (CI) for the ratio between the means of the values obtained with the test and the reference drug products, for each of these parameters, using ln-transformed data. Tmax is analyzed as the individual difference: test(-)reference, building a 90% CI, using nonparametric test;

d) two drug products are considered bioequivalents when the 90% CI for the ratio between the means of ASC0-t and of Cmax is included between 80 and 125%. Other limits of the 90% CI can be accepted through scientific justifications. When clinically relevant, Tmax is also to be considered;

e) for drugs presenting low therapeutical range, such as carmazepine, valproic acid, clindamycin, and others, a 95% CI must be adopted;

f) validated statistical programs must be used;

g) whenever necessary, appropriate statistical models, depending on the kind of bioequivalence study (for exemple, of multiple doses), must be employed;

h) in cases of vounteers presenting different behaviour on the absorption parameters, in relation to the remaining volunteers, their exclusion from the study must be justified. The results of the study must be presented with and without the inclusion of their data;

i) inform software programs used for the statistical analysis of the data.

6. PRESCTRIPTION AND DISPENSATION OF GENERIC DRUGS

The requirements described in this chapter will only be effective with the existence of the generic drug(s), in accordance with Law 9787/99, registered under ANVISA and available to consumption.

6.1 Prescription

a) in the scope of the System Unique of Health (SUH), 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 health private 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 to the interchangeability;

c) in the case that the professional prescriber decides for a 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, labelling, sealing or other automatic forms allowed.

6.2 Dispensation

a) it is allowed for the pharmacist to do a substitution of the prescribed drug product, exclusively, for the corresponding generic drug, unless expressed restritions by the professional prescriber;

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

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 to the patient or user the dispensation made in detail, 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 approval generic drugs by the National Agency of Sanitary Surveillance and which registration have been published in the Official Journal of the Union;

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

ANNEX I

GUIDE FOR THE UNDERTAKING OF THE STABILITY STUDIES

1. TYPES OF STUDY

1.1. Accelerated stability studies studies destined to raise the chemical degradation speed and physical modification of one substance and/or characteristic alterations of the dosage form, using forced storage conditions, with the purpose of monitoring the degradation reactions and foresee a validity period in normal storage conditions;

1.2. Long term stability studies are experiment validations in relation to physical, chemical, biological characteristics of the medicament, during and after the expected validity period.

2. PROCEDURE

2.1. Sampling

2.1.1. for authorization purposes: three batches

2.1.1.1. the sampling batches must contain, a minimum of 100.000 pharmaceutical units for solid dosage forms of oral use.

2.1.1.2. for drug products with high aggregated value, the sampling batches must contain a minimum of 30.000 pharmaceutical units. Batches of smaller size must be technically justified;

2.1.1.3. for the remaining dosage forms batches of, at least, ten percent of the industrial batch will be required;

2.1.1.4. the batches must be manufactured with different batches of the drug ;

2.1.2. The study must contain all details about the batch

a) batch number;

b) batch size;

c) storage conditions;

d) assay results;

e) date of manufacture;

f) type of packing material;

g) number of samples tested per batch;

h) number of samples analyzed per period;

2.1.3. The study must be undertaken with the drug product in its original packing for commercialization.

2.1. Assay conditions

2.2.1. the accelerated stability study must be undertaken at 40 ± 2 °C / 75 ± 5% of relative humidity (RH), during six months, with analysis in 0, 30, 60, 90, and 180 days, or at 50 ± 2ºC / 9± 5% of RH during three months, with analysis in 0, 30, 60 and 90 days;

2.2.2. the stability study of long duration must be undertaken at 30 ± 2 °C / 70 ± 5% of RH, during the period in which the product stability is intended to be proved. In this case, in the first year, the samples must be analysed at 0, 3, 6, 9 and 12 months, and once a year after this period;

2.2.3. for drug products of drug sensitive to the heat and that require storage in alternating conditions of lower temperature, the studies of accelerated stability must be undertaken, at a minimum of 15 ºC above the recommended temperature for storage. This study must be undertaken for six months, in conditions of appropriate relative humidity. Other conditions may be accepted under justification;

2.2.4. special considerations may be necessary for drug products that can suffer physical and/or chemical alterations due to low temperatures; for example, suspensions or emulsions that can cause sedimentation, creams, oils or half-solid preparations that can present alterations of the viscosity; and, liquid preparations that can produce precipitation problems, for instance, concentrated solutions;

2.2.5. when drug products are packed in containers which represent an obstacle for the water vapor (ampoule, ampoule bottle, full syringes), there is no need for a storage in conditions of high relative humidity. Low relative humidity may affect in a contrary way the liquid drug products packing in packages semipermeable (solutions in plastic bags, nasal drops in plastic bottles, and similars). In these cases the accelerated stability study must also be undertaken in the same conditions;

2.2.6. the study protocol must consider physical, chemical, chemical physics and biological assessments, whenever necessary. The qualitative or quantitative presence or building up of sub-products and/or degradation products, must also be appraised using the appropriate methodology.

3. GENERAL DISPOSITIONS

3.1. The assays of accelerated stability allow to establish a temporary period of useful life. These assays must be completed with long term studies undertaken in appropriate storage conditions for the drug product. It is part of a stability program.

3.2. The results of the long term stability studies are employed for:

a) establish a useful life period of the drug product;

b) confirm the projected period of useful life;

c) recommend storage conditions;

3.3. the accelerated stability studies for the determination of the useful life period and storage conditions, may be temporarily accepted for a period of 6 months, or three months, in drastic situations, as a requirement for a drug product registration;

3.4. Once the period defined as temporary is expired, the useful life period must be confirmed through the presentation of a long term stability study;

3.5. The useful life period is always determined according to storage conditions;

3.6. If the batches of determined drug product present different stability profiles, the useful life period proposed must be the one based in the less stable batch;

3.7. A tentative useful life period of 24 months may be established when:

a) the active principle is considered stable;

b) the studies undertaken according to the protocol are positives;

c) there are data indicating that similar formulations have a useful life period of 24 months or more;

d) there is a continuity of the long term studies until the useful life period is reached.

3.8. after the assessment of the stability, the following storage conditions must appear on the secondary and primary packaging of the drug product:

a) keep at local temperature (15ºC - 30ºC);

b) keep between 2ºC e 8ºC, under refrigeration;

c) keep below 8ºC, under refrigeration;

d) keep frozen (-5ºC - -20ºC);

e) keep below 18ºC;

3.9. Additional information such as: keep out of sun light and keep in dry place must be included provided that they do not conceal stability problems;

3.10. In the case of the products that require reconstitution or dilution, the period during which the product maintain its stability after the reconstitution, in determined storage conditions, must be reported;

3.11. the studies must be conducted using the specific diluent for the drug product reconstitution or, if more than one, using the one through which the less stable reconstituted drug product is to be obtained, in the most disadvantageous temperature conditions.

ANNEX II

GUIDE FOR THE UNDERTAKING OF THE STUDY AND REPORT PREPARATION OF PHAMACEUTICAL EQUIVALENCE

1. CRITERIA FOR PHARMACEUTICAL EQUIVALENCE STUDIES FOR DRUG PRODUCTS EXEMPTED OF THE BIOEQUIVALENCE STUDY, ACCORDING TO ANNEX IV OF THIS REGULATION

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

1.1. To be registered as generic, the drug product must: Fully comply with the pharmacopoeic 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 pharmacopoeic 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. 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 phamaceutical equivalence must be undertaken, simultaneously, in the test and the reference drug products;

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) validity period;

h) number and date of issue of the certificate;

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 with quotes of the 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 historical of analysis 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, ACCORDING TO ITEM 2 OF ANNEX IV OF THIS REGULATION

In the cases that the pharmaceutical equivalence is accepted as a bioequivalence indicator, to obtain a generic drug registration, the drug has to comply with the requirements mentioned on item 1, in addition to the undertaking of a comparative study of the dissolution profile in relation to the reference drug product according to the GUIDE FOR DISSOLUTION TESTING OF ORAL SOLID IMMEDIATE RELEASE DOSAGE FORMS (ANNEX VIII of this regulation).

3. CRITERIA OF PHARMACEUTICAL EQUIVALENCE STUDIES FOR DRUG PRODUCTS TO BE SUBJECTED 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 pharmacopoeic limits.

3.2. Submit the results of the comparative study of the dissolution profile, according to the ANNEX VIII of this regulation.

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) validity period;

h) number and issue date of the certificate;

3.3.1.2. on the certificates contents:

a) drug product characteristics;

b) tests undertaken (chemical-physics, chemicals, biologicals, etc);

c) specifications of each test with quotes of 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 historical of analysis 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.

ANNEX III

GUIDE FOR PROTOCOL AND TECHNICAL REPORT OF THE BIOAVAILABILITY AND BIOEQUIVALENCE STUDY

1. title of the project (must contain the name of the pharmaceutical substance, strenght, dosage form and manufacturer's name of the test and the reference drug products);

2. main researcher (researcher in charge);

3. clinical researcher (must necessarily be a doctor);

4. protocol number and date;

5. study objective;

6. study design:

6.1. type;

6.2. test and reference drug products (description, batch number, date of manufacture, expiry date, etc);

6.3. dosage (dose and liquid volume for administration);

6.4. housing of volunteers;

6.5. fasting and feeding time table;

6.6. sampling schedule;

6.7. samples manipulation procedures;

6.8. analytical methods;

7. population of the study:

7.1. detailed description (sex, age, weight, height);

7.2. subject selection:

7.2.1. clinical assessment (medical history and physical exam);

7.2.2. clinical laboratory exams: electrocardiogram, hematological and biochemical exams (including proofs of hepatical and renal function), serological exams (Hepatitis B, Hepatitis C, HIV), beta HCG (for women) and urine type I.

7.3. inclusion criteria;

7.4. exclusion criteria;

7.5. restrictions and prohibitions: before, during and after study;

7.6. criteria for subjects discontinuation or withdraw from the study;

8. adverse reactions and emergency procedures;

9. ethical considerations:

9.1. basic principles - must follow the resolutions in force of the National Health Council-Ministry of Health (CNS/MS), that regulate the research norms on human beings;

9.2. report from the Committee of Ethics in Research accredited by the National Committee of Ethics in Research (CONEP) of the National Health Council-Ministry of Health (CNS/MS);

10. data analysis:

10.1. validation of the analytical methods;

10.2. statistical treatment;

11. appendices;

11.1 retention samples (it must be informed the number of units of the test and the reference drug products that must be kept, which should be enough to repeat the test. These samples must be stored in proper conditions to preserve the original characteristics of the products up to their expiry date);

11.2. inventory of the drug products used in the study (the units number of test and reference drug products used in the study, as well as any occurring loss, must be informed);

11.3. model of informed consent form;

11.4. adverse events charts;

11.5. random list

12. the documents to be submitted to ANVISA, together with the technical report of the bioequivalence study, are:

12.1. validation study figures;

12.2. calibration curves and respective equations;

12.3. analytical runs validation;

12.4. complete series of the chromatograms of 20% of the volunteers, with calibration curves and quality controls;

12.5. all the standard operational procedures (SOP) of the analytical part, original data, concentration calculation and samples re-analysis;

12.6. biological samples transport procedures, when necessary;

12.7. clinical procedures- SOP of the clinical part: instructions to the volunteer, samples identification, blood collection procedure, drug products administration procedure;

12.8. protocol deviations report

Obs: 1 All the documentation submitted, concerning the clinical and analytical phases, must be signed by the respective people in charge.

Obs: 2 The technical report about the bioavailability and the bioequivalence study must be returned in two printed copies and one copy in diskette with a spreadsheet in MS-Excel with the results of the pharmacokinetics parameters calculated separately (ASC0-t, Cmax e Tmax), and the individual values of the plasmatic drug concentrations, for all the phases of the study.

Obs: 3 The study protocol, in two copies, must be handed in together with the technical report.

ANNEX IV

GUIDE FOR THE BIOEQUIVALENCE EXEMPTION AND SUBSTITUTION STUDY

1. THE FOLLOWING TYPE OF DRUG PRODUCTS ARE EXEMPT OF THE BIOEQUIVALENCE STUDIES

1.1. drug products administered via parenteral route (intravenous, intramuscular, subcutaneous or intratecal), like the aqueous solutions containing the same drug , at the same concentration of the reference drug product and components of same function, with compatible concentration levels;

1.2. oral use solutions that contain the same drug , at the same of concentration of the reference drug product and that does not contain components that could affect the gastrointestinal motility or the drug absorption;

1.3. powders for the reconstitution that would result in a solution which fulfills all the requirements (1.1) e (1.2);

1.4. gases;

1.5. otological and ophthalmic aqueous solutions containing the same drug , at the same concentration of the reference drug products and components of same function, with compatible concentration levels;

1.6. for topical use drug products, not meant for systemic effect, containing the same drug , at the same concentration of the reference drug product and components of the same function, with compatible concentration levels, meant for the otological and ophthalmic use, presented in a suspension form, the pharmacodynamics studies results that support the therapeutic equivalence must be presented, but the pharmacodynamic study model must first be approved by ANVISA;

1.7. inhalant drug products and nasal sprays assimilated with or without a device, presented in an aqueous solution and containing the same drug , at the same concentration of the reference drug product and components of same function, with compatible concentration levels;

1.8. oral used drug products of which drugs are not absorbed in the gastrointestinal treatment.

2. CASES IN WHICH THE BIOEQUIVALENCE MAY BE SUBSTITUTED BY THE PHARMACEUTICAL EQUIVALENCE

2.1. in the case of generic drugs of immediate release, with several dosages, same pharmaceutical characteristics and equivalent formulations, manufactured by the same manufacturer, in the same place of production, the bioequivalence study must be undertaken with the largest dosage exempting of this study those with lower dosage, if the drug dissolution profiles, among all dosages, are comparable (according to the GUIDE FOR DISSOLUTION TESTING OF ORAL SOLID IMMEDIATE RELEASE DOSAGE FORMS (ANNEX VIII of this regulation). The non-possibility to use the larger dosage in the bioequivalence study must be technically justified. This rule is applied to the drug s that present a linear pharmacodynamics in the therapeutic zone;

2.2. for drug products exempt of medical prescription, containing the phamaco substance acetylsalicylic acid, paracetamol, dipyrone ou ibuprophen, in the solid dosage form, they will be exempt of bioequivalence study if the dissolution profile is comparable to the reference drug products, using the comparison criteria described in the ANNEX VIII of this regulation.

2.3. topical use drug products, with the exception of those foreseen in item 1.6, at the same level of concentration in respect of the reference drug product and components of same function, with compatible concentrations levels.

ANNEX V

GUIDE FOR THE VALIDATION OF ANALYTICAL METHODS

1. GENERAL CONSIDERATIONS

a) The validation must guarantee, through experimental studies, that the method meets the requirements of the analytical applications, ensuring the reliability of the results. For this, it must show precision, accuracy, linearity, sensibility and specification, suitable for the analysis. Thus, it is important to point out that all equipment and materials must be properly calibrated and the researchers must be qualified and properly trained;

b) reference chemical substances and/or biological standards made official by the Brazilian Pharmacopoeia or by any other code authorized by the current legislation must be used. Studies using secondary standards will be admitted provided its certification is proved, in the absence of reference chemical substances and/or biological pharmacological standards;

c) for the bioavailability and bioequivalence studies the internal standard must be used whenever the chromatographics methods are used. The impossibility of its use must be justified;

d) the information enclosed in this guide are more indicated for the chromatographics methods used for the drug s determination and their metabolites in biological matrixes, like blood, serum, plasma or urine. It also must be employed for other analytical techniques, like microbiological and immunological methods, or for other biological matrixes, although in these cases, a high degree of variability can be observed.

1.1. Precision

1.1.1. The method repetitiveness is verified