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Resolution - RDC nº 136 of 29 May 2003
D.O.U 06/02/2003
Regulates
the registration of New Drugs
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”,
§ 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,
Adopted the following resolution and I, the Chairman, determine
its publication:
Article 1 – Approve the attached Technical Regulation for
New Drugs with Synthetic or Semi-Synthetic Active Ingredients
Article 2 – This resolution enters into force on the date
of its publication.
CLAUDIO
MAIEROVITCH PESSANHA HENRIQUES
ANNEX
TECHNICAL REGULATION FOR NEW OR REFERENCE DRUGS WITH SYNTHETIC
OR SEMI-SYNTHETIC ACTIVE INGREDIENTS
SCOPE
This regulation applies to all new or Reference Drugs with the
exception of those subject to specific legislation, and establishes
the criteria and documentation necessary for:
The registration of New Drugs with synthetic or semi-synthetic
ingredients, associated or not;
The registration of pharmaceutical forms, concentrations, routes
of administration and indications of drug products with active
synthetic or semi-synthetic ingredients that are new in the country
by companies that do not have the initial registration for that/those
active ingredient(s);
The registration of a product resulting from:
a) an alteration in pharmacokinetic properties;
b) the withdrawal of an active ingredient of an already registered
product;
c) new salts or isomers, even when the corresponding molecular
entity has already been authorized.
COMPOSITION
This regulation is made of three parts: pre-registration measures,
registration and post-registration measures. The technical details
to comply with the legal demands for registration or for any alterations
made in a registration will be dealt with in specific guides by
subject. The definitions of the technical terms of this Regulation
can be found in the GLOSSARY OF LEGAL DEFINITIONS;
I – PRE-REGISTRATION MEASURES FOR NEW DRUGS
1. In case of a new national drug product, submit the protocols
of the clinical studies and the results or current status of the
studies in compliance with the legislation in force.
2. In case of a new imported drug product that will undergo phase
III clinical studies in Brazil, submit the study protocol and
the results or current status of the studies in compliance with
the legislation in force.
3. Whenever phase III will take place with a new product manufactured
in the country, submit pre-notification for the production of
pilot batch according to the GUIDE FOR THE NOTIFICATION OF PILOT
BATCHES OF MEDICINES.
II - REGISTRATION
1. Upon applying for the registration of a product as a New Drug,
the company shall protocol a single application with separate
reports for each pharmaceutical form 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;
f) Good Manufacturing and Control Practices certificate (GMP)
emitted by ANVISA for the production line in which the product
classified as New Drug will be manufactured, or copy of the inspection
petition protocol for the emission of GMP certificate. This protocol
will be valid provided the intended production line was considered
satisfactory in the last inspection for compliance with GMP.
2. In the act of protocol of a petition to register a product
as a New 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. 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 ongoing long-duration stability
tests and studies in compliance with the GUIDE FOR UNDERTAKING
STABILITY STUDIES;
c) Report of pre-clinical trials: acute, sub-acute and chronic
toxicity, reproductive toxicity, mutagenic toxicity and oncogenic
potential in compliance with specific legislation;
d) Report of clinical trials to prove therapeutic efficacy in
compliance with specific legislation. Data shall be accompanied
by bibliographic references whenever available. Information shall
be submitted in the following order: phase I, II and II clinical
studies. ANVISA may review the data of phase III clinical studies
to check whether the difference found in the results of the groups
that received different interventions was sufficient to warrant
statistical and clinical-epidemiological significance.
e) In case of drug associations or of two or more presentations
in one same packaging for concomitant or sequential use, besides
the other items the applicant shall submit the results of the
following studies:
- relative
bioavailability studies among the associated active ingredients
and of each active ingredient in isolation ensuring that the absorption
and distribution of the associated active ingredients is not affected;
- controlled
clinical studies for each therapeutic indication proving that
associations with the same doses have an additive or synergic
effect without resulting in increased risks when compared to the
use of each active ingredient in isolation, or that the association
with a lower dose of at least one of the active ingredients will
provide the same benefit with equal or less risks when compared
to an association with known doses. A maximum of 3 active ingredients
in the same formula will be accepted per oral or injected presentation.
In these cases, only oral formulas with a maximum of 3 active
ingredients in the same formula or 4, if one of them is caffeine,
will be accepted.
- regarding antibiotics: studies that show that an association
will prevent the advent of microbial.
f) In case of pharmaceutical forms, concentrations, routes of
administration or indications for use that are new in the country
for synthetic or semi-synthetic active ingredients by companies
that do not possess the initial registration of that/those active
ingredient(s), the applicant shall submit the documents listed
in item 1, and item 2 except for c and d. However, in the circumstances
detailed below, they shall submit the following trials:
1. The results of the Phase III studies for companies that discover
a new therapeutic indication in the country for an active ingredient
registered by another company, in the same concentration and pharmaceutical
form.
2. The results of the Phase II and III studies for companies that
discover a new concentration and/or pharmaceutical form, and/or
administration route in the country for the same therapeutic indication
for a pharmaceutical ingredient registered by another company.
These studies shall be considered unnecessary and substituted
by relative bioavailability tests whenever they fall within the
already approved therapeutic range;
g) Report containing the up-to-date retail price of the drug product
in countries where it is already on the market, together with
their respective information source. In case of a new product
that has not yet been marketed in another country, the retail
price proposal shall be attached. Lack of this document will not
hinder submission, but will hinder final approval.
h) Technical information on the active ingredient(s) as follows,
when fitting:
h01) structural formula;
h02) molecular formula;
h03) molecular weight;
h04) complete synonyms and references;
h05) physical form of the salt;
h06) fusion point;
h07) solubility;
h08) specific optical rotation;
h09) organoleptic properties (color, smell, texture ...);
h10) possible isomers (structural, geometric, optical ...);
h11) polymorphism, discriminating the characteristics of the used
polymorph and of others related to the active ingredient;
h12) describe the salt/base proportion and any excesses used;
h13) molecular infrared structure;
h14) other analyses necessary for the correct identification and
quantification of the molecule(s) submitted by the manufacturer
or as determined by ANVISA.
i) Synthesis route of the active ingredient
01) description of the synthesis of the active ingredient, specifying
the structure and name of the known intermediary products, stages
of production and/or extraction of the active ingredient by means
of a diagram
i02) stability studies of the active ingredient
i03) list of solvents used;
i04) list of residual solvents and respective concentrations;
j) Pharmacodynamics:
j1) Action mechanism;
j2) Dosage (maximum and minimum doses), for adult, pediatric and
geriatric use, liver and kidney insufficiency and any others that
are found pertinent, resulting from studies that justify the indicated
doses and therapeutic index;
k) Pharmacokinetics of each active ingredient in the formula:
k1) pKa;
k2) biologic half-life;
k3) distribution volume;
j4) Absorption;
k5) Distribution,
k6) Biotransformation;
k7) Elimination;
l) Submit additional information in compliance with the legislation
in force on the control of Transmissible Spongiform Encephalopathy,
when fitting.
m) Production report:
m01) Complete formula: detailed description of the complete formula
naming components according to the Brazilian Common Denomination
(DCB), International Nonproprietary Nomenclature (INN) and denomination
described in the Chemical Abstracts Service (CAS), respecting
this order of priority;
m02) description of the amount of each substance expressed in
the decimal metric system or standard unit;
m03) indicate its function in the formula;
m04) indicate the respective reference for quality specification
described in the Brazilian Pharmacopoeia or, in its absence, in
other official codes authorized by the legislation in force;
m05) minimum and maximum size of the industrial batch to be produced;
m06) description of all the production stages including the equipment
used;
m07) methodology of ongoing controls;
m08) criteria adopted to identify the production batch;
n) Quality control of all the raw materials used:
n01) detailed description of the specifications of the analysis
parameters;
n02) analytic methods used to identify and quantify the formula’s
components and its main contaminants. The reference values of
each parameter shall be mentioned in official compendia recognized
by ANVISA in compliance with the legislation in force, with accompanying
bibliographic references. In case they are not official compendia
recognized by ANVISA, submit specifications in which the analytic
methods are duly validated for the active ingredient(s), indicating
their bibliographic or developmental source. In the last case,
a translation shall be included whenever the language is neither
English nor Spanish;
n03) Whenever a dropper is used, submit routine analytic tests
accompanied by methodology and specification;
o) Quality control of finished product:
o1) detailed description of the analytic methods;
o2) specifications accompanied by bibliographic references;
o3) graphic of dissolution profile, when fitting.
p) Specifications of the raw materials used.
3. Besides the dispositions listed above, manufacturers and their
representatives who wish to import New Drugs shall:
a) Specify the stage of the drug product to be imported - primary
packaging, in bulk or finished product;
b) Submit an authorization of the manufacturing company of the
drug product for the registration, commercial representation and
use of the brand in Brazil, when fitting.
c) Up-to-date copy of the GMP emitted by ANVISA for each production
line of the manufacturing company;
c.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.
c.2. ANVISA may, in compliance with specific legislation, inspect
the manufacturing company in the country or block of origin.
d) Submit a registration receipt emitted by the sanitary authority
of a country that hosts the company and the respective package
insert text. Lack of this document will not hinder submission,
but will hinder final approval.
e) Submit the physicochemical, chemical, microbiological and biological
quality control methodology 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.
f) For pharmaceutical products imported in bulk, Certificate of
Good Manufacturing Practices emitted by ANVISA for the packaging
line used in the country.
g) For imported pharmaceutical products - primary packaging, in
bulk or finished product - 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.
h) 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.
I) Any materials that make up the product’s dossier such
as production and quality control reports, information contained
in the label, 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.
4. 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.
5. 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.
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.
2. ANVISA may undertake a control analysis of commercialized batches
in official laboratories in order to monitor the quality and conformity
of the drug with the drug registered. Whenever necessary, ANVISA
may request that the companies train their technicians in order
to enable them to undertake this monitoring.
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 registration 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 the 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.
h) Data concerning phase IV studies, if they exist.
i) Pharmacovigillance data in compliance with the PSUR/ICH model.
This data can be requested by ANVISA before the revalidation period.
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