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Resolution - RDC nº 133 of 29 May 2003(*)
Republished in the D.O.U of 09/19/2003
RE nº 896, dated
05/29/03 has the GUIDE FOR RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE
TESTS
Regulates
the registration of Similar Drugs and other provisions
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, that establishes
the sanitary surveillance that drug products, pharmaceutical inputs
and correlates, cosmetics, sanitizing products and others are
subject to;
Whereas Law nº 9.787, dated 10 February 1999, that alters
Law nº 6.360, dated 23 September 1976, that disposes on sanitary
surveillance, establishes the definition of Generic Drug, Regulates
the use of generic names in pharmaceutical products and gives
other provisions;
Whereas ANVISA has as its institutional mission within the pharmaceutical
market to ensure that drug products present guarantee of safety,
efficacy and quality;
Whereas Decree nº 3.961, dated 10 October 2001, that alters
Decree nº 79.094, dated 5 January 1977 that updates the definition
of Similar Drug, Reference Drug or Generic Drug;
Whereas the guidelines of the National Medicine Policy instituted
by Presidential Decree/MS nº 3916/98, regarding sanitary
regulation, the promotion of production within the framework of
pharmaco-economics, as well as the rational promotion of drug
products,
Adopts the following resolution and I, the Chairman, determine
its publication:
Article 1 Approve the attached Technical Regulation for the registration
of Similar Drugs.
Article 2 Determine that companies interested in registering a
drug product as Similar Drug shall comply with the dispositions
of this Regulation.
Article 3 Determine that only those centers licensed by ANVISA
can undertake the tests that prove pharmaceutical equivalence
(REBLAS) and the Relative Bioavailability trials demanded by this
Regulation.
Article 4 This resolution enters into force on the date of its
publication, revoking Presidential Decree nº 19 dated 16
February 1996 and resolution - RDC nº 157 dated 31 May 2002.
CLAUDIO
MAIEROVITCH PESSANHA HENRIQUES
ANNEX
TECHNICAL REGULATION FOR SIMILAR MEDICINES
SCOPE
This regulation establishes the criteria for the registration
of Similar Drugs.
COMPOSITION
This regulation is divided in three parts: the pre-registration
measures, the legal and technical demands for registration and
the post-registration measures.
The technical details for compliance with the legal demands for
registration and the alterations and inclusions of registrations
are listed in theme-specific official guides.
For the definitions of the technical terms of this regulation
already defined in legislation, see the GLOSSARY OF LEGAL DEFINITIONS.
The other definitions are as follows:
DEFINITIONS
RELATIVE BIOAVAILABILITY – Rate and extent of absorption
of an active ingredient that reaches systemic circulation as a
result of the extravascular administration of a preparation compared
to those of a reference product that contains the same active
ingredient.
PHARMACEUTICAL FORM – Final presentation of an
active pharmaceutical ingredient having the characteristics a
certain administration route after it has undergone one or more
pharmaceutical operations, with or without the addition of excipients,
in order to facilitate its use and obtain the desired therapeutic
effect.
FORMULA – Quantitative relation of the pharmacochemicals
that compose a drug product.
REBLAS – Common denomination of the licensed laboratories
that integrate the Brazilian Network of Health-Related Analytic
Laboratories.
I – PRE-REGISTRATION MEASURES FOR SIMILAR MEDICINES
Before submitting the registration petition of a product as Similar
Drug, the applicant shall formally:
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
similar. 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. In a maximum period of 60 days,
ANVISA will either deliberate favorably, indicate another drug
product to be used as Reference, or suggest that the company apply
for a New Drug registration.
2. Notify the production of pilot batches in compliance with the
GUIDE FOR THE NOTIFICATION OF PILOT BATCHES OF MEDICINES, with
the exception of imported products.
II – REGISTRATION
1. During the protocol of a registration petition of a product
as Similar Drug, the company shall protocol a single application
with separate reports for each pharmaceutical form. The company
shall have complied with all the pre-registration demands and
submit the following documentation:
a) Registration
petition forms.
b) Proof of payment of Sanitary Surveillance Inspection Fee or
proof of exemption (original);
c) Up-to-date copy of the company’s Operation License (Sanitary
Permit);
d) Up-to-date Technical Responsibility Certificate emitted by
the Regional Pharmacy Council;
e) Copy of the notification protocol of pilot batch production;
2. In the
act of protocol of a petition to register a product as a Similar
Drug, the applicant shall submit a technical report containing
the following information:
a) General data: package insert text, label and packaging "lay-out"
draft in compliance with legislation in force. Regarding the package
insert of drug products produced in official pharmaceutical laboratories,
these shall comply with specific regulations. In case of presentation
in drops (oral and ophthalmic solutions, oral emulsions and oral,
nasal and ophthalmic suspensions), the number of drops that correspond
to 1ml shall be specified and the concentration of the active
ingredient per ml shall be indicated;
b) Expiration date: submit results of the accelerated stability
study of three pilot batches used in the tests, as well as the
ongoing or finished long duration stability studies in compliance
with the GUIDE FOR UNDERTAKING STABILITY STUDIES; For drug products
with three or more concentrations and proportional formulations,
submit the results of the stability study of the smallest and
greatest concentrations.
c) All drug products shall submit the results of the pharmaceutical
equivalence tests performed by licensed laboratories (REBLAS)
describing the methodology used in compliance with the GUIDE FOR
THE UNDERTAKING OF THE STUDY AND PREPARATION OF THE PHARMACEUTICAL
EQUIVALENCE REPORT.
d) Report
of the relative bioavailability tests performed by an ANVISA-certified
laboratory, for Prescription Drugs and for those not exempt of
this study. Batches with proven stability and that have been produced
with the same equipment that will be used for industrial-scale
production shall be used. The relative bioavailability test shall
comply with the GUIDE FOR DESIGNS OF BIOEQUIVALENCE STUDIES. The
company has the option of submitting the protocol of the relative
bioavailability study. This protocol shall comply with the GUIDE
FOR THE ELABORATION OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE
STUDY PROTOCOL. The results shall be submitted according to the
GUIDE FOR THE ELABORATION OF TECHNICAL REPORT OF RELATIVE BIOAVAILABILITY/BIOEQUIVALENCE
STUDIES. (See RE nº 896,
dated 05/29/03 )
d-1 Medicines that are exempt of this study are included in the
GUIDE FOR THE EXEMPTION AND SUBSTITUTION OF BIOEQUIVALENCE STUDIES.
In case of immediate release oral formulations with active ingredient(s)
of high solubility, high intestinal permeability and broad therapeutic
range that have already been exempted of the relative bioavailability
test by the regulatory organizations of the United States (FDA)
and Europe (EMEA), documentation proving this exemption shall
be included.
d-2 If the
pharmacokinetic parameters (C max., AUC and T max) between the
test drug product and the Reference Drug indicate a need of adjustment,
the product’s formula may be altered until they are compatible.
Companies that choose not to modify the formula shall propose
a posology that ensures safety and efficacy when the pharmacokinetic
curves are below the safety limit and above the therapeutic limit.
In this case the drug product will be the product of a change
in pharmacokinetic properties, will be exempt of the presentation
of clinical study and will not serve as a reference product.
d-3 In case
of a Similar Drug made of drug associations or two or more presentations
in one same packaging for concomitant or sequential use, proof
of the relative bioavailability of each of the formula’s
active ingredients shall be given compared to the Reference Drug.
e) Complete production reports: pharmaceutical form, detailed
description of the complete formula naming components according
to the Brazilian Common Denomination (DCB), International Nonproprietary
Nomenclature (INN) and name described in the Chemical Abstracts
Service (CAS), respecting this order of priority;
; description of the amount of each substance expressed in the
international units system (IS) or standard unit indicating its
function in the formula; minimum and maximum size of the industrial
batch to be produced; description of all the production stages
including the equipment used; copy of complete production and
quality control reports including the order of production, detailed
production process and process control referring to three manufactured
pilot batches (for imported drug products the report shall refer
to three industrial batches produced in the last three years of
production). In case of drug products with three or more different
concentrations and proportional formulations, the reports of the
smallest and largest concentrations shall be submitted. A description
of the identification criteria of the industrial batch shall also
be included.
f) Complete report of the quality control of all the raw materials
used in the drug product: submit the specifications and bibliographic
references of the consulted pharmacopoeia recognized by ANVISA,
in compliance with the legislation in force. If these are not
official compendia recognized by ANVISA, submit the specifications,
a detailed description of all the methodologies used in the quality
control with analytic methods that are duly validated for the
active ingredient(s) and for the drug product in accordance with
the GUIDE FOR THE VALIDATION OF ANALYTICAL AND BIOANALYTICAL METHODS,
indicating the bibliographic or developmental source. In this
last case, submit a translation whenever the language is neither
English nor Spanish.
Regarding the active ingredient(s), the petitioner shall inform
what manufacturer produced the batch of the drug product that
is being submitted to pharmaceutical equivalence and relative
bioavailability and submit copy of the original documentation
listed below of the company or companies that manufacture the
active ingredient(s):
f.1 general data of the manufacturing company including complete
address and manufacturing site of the active ingredient;
f.2 copy of the official report of the manufacturer(s) of the
active ingredient(s);
f.3 quantification and limits of the main contaminants;
f.4 whenever there is more than one manufacturer of an active
ingredient, besides the items listed above the following documentation
shall be submitted for any drug product that has not undergone
pharmaceutical equivalence and relative bioavailability studies:
f.4.1 results and evaluation of the accelerated stability study
of a batch of the drug product produced by each manufacturer presented,
according to criteria of the GUIDE FOR UNDERTAKING STABILITY STUDIES;
f.4.2 analytical report of the drug product according to the specifications
and methodology submitted in the registration process of each
manufacturer.
f.4.3 for solid pharmaceutical forms, comparative dissolution
profile between the drug product that was submitted to relative
bioavailability and pharmaceutical equivalence studies with the
drug product produced by each manufacturer;
f.4.4 for suspensions, creams, lotions, ointments, gels and pastes,
submit the test result to establish the size of the particles
of a batch of the drug product submitted to relative bioavailability
and pharmaceutical equivalence studies and a batch of the drug
product produced by each manufacturer, for maximum and minimum
concentrations of the product when fitting, in order to demonstrate
that there was no significant change in the size of the particles
of these batches.
g) Specifications of the material of the primary packaging. In
case there is a dropper, submit routine analytic tests together
with the methodology used;
h) Submit additional information in compliance with the legislation
in force on the control of Transmissible Spongiform Encephalopathy,
when fitting.
3. Good Manufacturing and Control Practices certificate (GMP)
emitted by ANVISA for the production line in which the product
classified as Similar Drug will be manufactured, or copy of the
inspection petition protocol for the emission of GMP certificate.
This protocol will be valid as long as the intended production
line was considered satisfactory in the last inspection for compliance
with GMP.
4. Besides the dispositions listed above, manufacturers and their
representatives who wish to commercialize Similar Drugs produced
abroad and imported in bulk, in their primary packaging or as
a finished product shall submit:
a) Authorization of the manufacturing company for the registration,
commercial representation and use of the brand in Brazil, when
fitting.
b) Up-to-date copy of the GMP emitted by ANVISA for each production
line of the manufacturing company;
b.1 If ANVISA
has not yet inspected the manufacturing company, the receipt of
the ANVISA sanitary inspection petition together with the Certificate
of Good Manufacturing Practices of pharmaceutical products per
production line emitted by the organization in charge of Sanitary
Surveillance of the manufacturing country will be accepted.
b.2 ANVISA
may, in compliance with specific legislation, inspect the manufacturing
company in the country or block of origin.
c) Submit a registration receipt of the drug product emitted by
the sanitary authority of the country of origin. If this is not
possible, submit a receipt of the registration in force emitted
by the sanitary authority of the country where the drug product
is marketed or by the international sanitary authority.
d) Submit the physicochemical, chemical, microbiological and biological
quality control methodology to be used by the importer according
to the pharmaceutical form – primary packaging, in bulk
or finished product. If the method used is not pharmacopoeic,
submit the validation of the analytic methodology.
e) For pharmaceutical products imported in bulk, Certificate of
Good Manufacturing Practices emitted by ANVISA for the packaging
line used in the country.
f) For imported pharmaceutical products – primary packaging,
in bulk or finished products - the results and evaluation of the
stability test in the final commercial packaging shall comply
with the GUIDE FOR UNDERTAKING STABILITY STUDIES. A copy of the
original results of the study shall be submitted. Translation
is optional if the language is English or Spanish. For all other
languages translation is mandatory. If it is necessary to import
samples, an import permit shall be requested from ANVISA.
g) The expiration date of products imported in bulk shall be counted
from the manufacturing date of the product abroad, not from the
date of packaging here in Brazil. The expiration date registered
at ANVISA shall be respected.
h) Any materials that make up the product’s dossier such
as production and quality control reports, information contained
in labels, package insert and packaging shall be in the Portuguese
language, in compliance with the legislation in force. Any official
documents emitted by sanitary authorities in a foreign language
that are used in the registration shall be accompanied by a legal
translation.
5. If a company requests registration in more than one manufacturing
site at the same time, submission of the documentation referring
to each site is mandatory. This possibility will be treated as
an alteration/inclusion of manufacturing site and all the documentation
and tests demanded in the GUIDE FOR MAKING POST-REGISTRATION ALTERATIONS
AND INCLUSIONS IN MEDICINES shall therefore be complied with.
6. Similar Drugs shall adopt a trademark or brand name, excepting
those cases foreseen in specific legislation. By law these products
are not interchangeable. The elaboration of the names shall follow
specific legislation.
7. All documents shall be submitted in a printed copy of which
each paper is initialized and the last paper is signed by the
company’s chief technician. A copy of all technical reports
shall be attached in disk or CD-ROM with files in the file.doc
format or any other accepted by ANVISA.
8. ANVISA may request additional proof of the identity and quality
of the components of a drug product and/or request new tests to
prove the relative bioavailability or pharmaceutical equivalence
at any given moment according to what it judges necessary, if
any facts occur that give reason for complementary evaluations
even after the registration has been granted.
III – POST-REGISTRATION MEASURES
1. Any registration changes shall follow the procedures specified
in the GUIDE FOR MAKING POST-REGISTRATION ALTERATIONS AND INCLUSIONS
IN MEDICINES. Failure to perform relative bioavailability or stability
tests in the circumstances defined in this Guide will result in
the petition being rejected.
2. ANVISA may undertake a control analysis of commercialized batches
in official laboratories in order to monitor the quality of the
drug product and its conformity with the drug product registered.
3. Once the declared validity of the drug product has expired,
the company shall file a report of the final results and evaluation
of the long term stability study of the three batches submitted
upon the application in accordance to the previously submitted
time frame, as well as a declaration containing the definitive
expiration date and conservation care. Non-compliance with this
requisite shall constitute a sanitary infraction.
4. In order to renew their ANVISA registration all companies shall
submit the following documentation during the first semester of
the last year of the five years of validity of the already conceded
registration:
a) Duly
filled-in petition form;
b) Proof of payment of Sanitary Surveillance Inspection Fee or
proof of exemption when fitting;
c) Up-to-date Certificate of Technical Responsibility emitted
by the Regional Pharmacy Council;
d) Submit a document that proves the commercialization of the
product for the period of validity of the registration as well
as the numbers of the invoices and a list of the purchasing establishments
in a maximum of 3 (three) receipts per pharmaceutical form. A
declaration concerning commercial presentations that were not
marketed but whose registration the company is interested in keeping
may be submitted, as long as at least one presentation of that
form has been marketed. 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.
e) The final version of the package insert that accompanies the
product in its commercial packaging.
f) A list that includes 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);
g) 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 of three batches imported in the last three years.
(*) Republished
due to incorrections in the original, published in the DOU nº
104 dated 2 June 2003, section 1, Pg 25.
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