Section Question Answer
GENERAL QUESTIONS
General questions What is the role of the API Registration Department (COIFA)? The API Registration Department (COIFA) is a unit within the General Office for Medicinal Products (GGMED). Is is primarily responsible for the assessment of API marketing authorisation applications (API MAs), also reffered to as API registration. The procedure currently only applies to a subset of APIs.

The requirements for API MAs are listed on RDC 57/2009.

The APIs that are currently subject to the API MA procedure are listed on IN 15/2009 and IN 3/2013.

More recently, COIFA began to assess DMFs associated with drug product marketing authorisation applications and variations (e.g., addition of new API manufacturer). The procedure is described in OS nº 58/2019 (only available in Portuguese). If a DMF is associated with multiple applications, the DMF holder might be contacted by COIFA, in which case it will be given instructions on how to proceeed.
API MARKETING AUTHORISATION | API REGISTRATION
API MA Which company may apply for an API marketing authorisation (API MA) in Brazil? An API MA must be submitted by an entity legally established in Brazil, meaning it should have a CNPJ (National Registry of Legal Entities). Generally, companies that apply for API MAs are:
  1. API manufacturers established in Brazil;
  2. Trading companies/distributors established in Brazil;
  3. Drug product marketing authorisation holders.
 api marketing authorisation api registration api ma api marketing authorization
API MA When a company has an API MA for a given API, if a different company wishes to import the same API, does it also need to submit an API MA application? Yes, every company that imports the API must have an API MA. However, an API can be acquired from a company that already has an API MA without the need for a new API MA application. api marketing authorisation api registration api ma api marketing authorization
API MA Should the API MA be submitted parallel to the drug product MA or drug product variation (e.g., addition of new API manufacturer)? Not necessarily.

The API MA can be submitted prior or parallel to the drug product MA or drug product variation (e.g., addition of new API manufacturer). However, the drug produt MA will only be granted (or the variation approved) if/when the API MA is granted. 		api marketing authorisation api registration api ma api marketing authorization
API MA If the drug product MA is cancelled/withdrawn, what happens to the API MA? There are no automatic repercussions to the API MA, as the API MA is not dependent on that of the drug product. api marketing authorisation api registration api ma api marketing authorization
API MA If the API MA is cancelled/withdrawn, what happens to the drug product MA? If an API is listed on IN 15/2009 or IN 3/2013, the API used in the formulation of the drug product must have an API MA. Therefore, if the API MA is cancelled/withdrawn, the drug product MA holder should use an alternative source of the API, for which an API MA is currently valid or submit a new API MA for an alternative source. api marketing authorisation api registration api ma api marketing authorization
API MA Does the API MA procedure only apply to APIs used in the formulation of drug products manufactured in Brazil? No.

If an API is listed on IN 15/2009 or IN 3/2013, the API used in the formulation of the drug product must have an API MA, regardless of where the drug product is manufactured. The difference is the submission code (10414 instead of 10308) and the stability requirements, depending on where the API and drug product are manufactured.		 api marketing authorisation api registration api ma api marketing authorization
API MA When a company imports the API and has an API MA, should other companies within the same pharmaceutical group also submit an API MA for the same API? No, unless these companies also import the API directly. This also applies to companies that are not part of the same pharmaceutical group. api marketing authorisation api registration api ma api marketing authorization
API MA Can the API MA applicant submit a CEP (Certificate of Suitability) instead of the documentation required by RDC 57/2009? No.

ANVISA has signed a Memorandum of Understanding with EDQM, which enables the sharing of information and documents. COIFA has requested assessment reports from EDQM in specific situations, as a means to facilitate the assessment of API MAs and as a confidence building exercise. 		api marketing authorisation api registration api ma api marketing authorization
SUBMISSION PROCEDURE
Submission procedure What is the submission code for API MAs?
    The submission codes are the following:
  • 10308, if the drug product is manufactured in Brazil.
  • 10414, if the drug product is imported to Brazil.
 submission code
Submission procedure What is the submission codes for supplementary documents? It depends on the type of submission with which the supplementary documents are associated.

For API MAs, supplementary documents should be submitted with the code 10322 (unless the information pertains to the restricted part; see question below).

Supplementary documents associated with GMP certification applications should be submitted with the code 7401. 		closed part
Submission procedure What are the submission codes for the restricted part of the DMF?
    It depends on the type of submission with which the restricted part is associated:
  • 10731, for API MAs;
  • 10903, for generic drug product MA applications;
  • 10909, for "similar" drug product MA applications;
  • 10905, for new drug product MA applications.
Submission procedure How should the restricted part associated with an API MA be submitted? The documents should be personally delivered at GEDOC (at ANVISA HQ) or sent by mail to the following address:

ANVISA
A/C COIFA/GGMED/SUMED
Setor de Indústria e Abastecimento (SIA)
Trecho 5, Área Especial 57
Brasília-DF - CEP 71205-050
Brazil

A cover page/application form should be included (template available on NT 01/2015).

It is preferable for DMFs to be submitted in digital media, as indexed and searchable pdf files.
Submission procedure Can the DMF be submitted in English? Yes.

ANVISA accepts DMFs in Portuguese, English and Spanish.
Submission procedure Can the restricted part be evaluated during the GMP inspection instead of being submitted along with the API MA application? No, and its absence can lead to the rejection of an API MA application. DMF
Submission procedure Can the API MA application be submitted with the GMP certification application number (instead of the GMP certificate)? Yes. However, the API MA will only be approved once the GMP certificate is granted.
Submission procedure Should the GMP certificate application(s) cover all manufacturing sites (from the starting material to the API)? Yes.
Submission procedure Does ANVISA accept DMFs in CTD format? Yes. ANVISA encourages applicants and API manufacturers to submit DMFs in CTD format. ich m4 common technical document
3.2.S.1.1 - NOMENCLATURE
3.2.S.1.2 - STRUCTURE
3.2.S.1.3 - GENERAL PROPERTIES
3.2.S.2.1 - MANUFACTURER(S)
3.2.S.2.1 If a manufacturing site is responsible for a single step of the manufacturing process (e.g. micronization), can the API MA application cover only this single step? No.

The API MA and GMP certificate applications should cover all manufacturing sites, from the starting material to the final API, regardless of how many manufacturing sites are involved.
3.2.S.2.2 - DESCRIPTION OF MANUFACTURING PROCESS AND PROCESS CONTROLS
3.2.S.2.3 - CONTROL OF MATERIALS
3.2.S.2.4 - CONTROL OF CRITICAL STEPS AND INTERMEDIATES
3.2.S.2.5 - PROCESS VALIDATION AND/OR EVALUATION
3.2.S.2.6 - MANUFACTURING PROCESS DEVELOPMENT
3.2.S.3.1 - ELUCIDATION OF STRUCTURE AND OTHER CHARACTERISTICS
3.2.S.3.2 - IMPURITIES
3.2.S.4.1 - SPECIFICATION
3.2.S.4.1 Is a test for particle size distribution (PSD) for the API mandatory?

Should PSD be controlled by the API manufacturer? 		There should be a test for particle size distribution when it is critical to:
  1. Dissolution, solubility, or bioavailability;
  2. Drug product content uniformity;
  3. Drug product processability;
  4. Drug product stability;
  5. Drug product appearance.

ICH Q6A decision tree #3 can be used as reference.

PSD should be controlled by the API manufacturer if the manufacturing step (e.g., milling, micronization) is carried out under its responsibility. 		3.2.S.3.1 3.2.S.4.1 psd particle size distribution
3.2.S.4.1 If conducted, should the test for PSD be declared in the DMF specification (i.e., Section 3.2.S.4.1)? It is recommended for the test to be listed in the DMF specification (3.2.S.4.1).

However, if the acceptance criterion is client-specific (not a standard grade), the API manufacturer can state that the test is conducted, but that its acceptance criterion is client-specific.		 3.2.S.3.1 3.2.S.4.1 psd particle size distribution
3.2.S.4.1 Is microbiological testing mandatory for release and stability specifications of the API? A risk assessment should be conducted to determine whether the API is capable of supporting microbial growth and, if so, the release or stability specifications should contain the tests.

ICH Q6A decision tree #6 can be used as reference.. 		specification microbial test microbial testing microbiological test
3.2.S.4.2 - ANALYTICAL PROCEDURES
3.2.S.4.3 - VALIDATION OF ANALYTICAL PROCEDURES
3.2.S.4.3 Considering art. 10 of RDC 45/2012, must the assay method used in API stability studies be stability indicating? No.

The interpretation of art. 10 of RDC 45/2015 is that the collection of analytical methods should be stability indicating, not necessarily each method individually, Therefore, for instance, if a monograph contains a titration method for assay, it can be used in the API stability study, provided that its lack of specificity is compensated by that of a stability indicating method (ex. related substance by HPLC). 		método de teor por titulometria método de teor titulométrico método de teor indicativo de estabilidade
3.2.S.4.4 - BATCH ANALYSES
3.2.S.4.5 - JUSTIFICATION OF SPECIFICATION
3.2.S.5 - REFERENCE STANDARDS OR MATERIALS
3.2.S.6 - CONTAINER CLOSURE SYSTEM
3.2.S.7.1 - STABILITY SUMMARY AND CONCLUSIONS
3.2.S.7.1 What should be the test frequency of follow-up stability studies? According to art. 34 da RDC 45/2012, follow-up stability studies should be conducted with at least one batch per year, except when no batch is manufactured.

The recommended test frequency is each 12 months and, additionally, the final time point. For example, if an API has a retest period of 42 months, the following time points should be tested: 0, 12, 24, 36 and 42 months.
3.2.S.7.1 If a drug product is manufactured in Europe and imported to Brazil, should the long term API stability study be conducted at 30ºC/75%RH (Zone IVb)? The condition for the stability study of the API should be the most critical among the stability zones of the countries in which the API is manufactured/stored prior to the manufacture of the drug product.

    For example:
  1. Drug product manufactured in Brazil (regardless of where the API is manufactured) → API stability study: 30ºC/75%RH;
  2. API manufactured in Europe + drug product manufactured in Europe and imported to Brazil → API stability study: 25ºC/60%RH or stricter;
  3. API manufactured in China + drug product manufactured in Europe and imported to Brazil → API stability study: 30ºC/65%RH or stricter;
  4. API manufactured in India + drug product manufactured in Europe and imported to Brazil → API stability study: 30ºC/70%RH or stricter.
Stability conditions for WHO Member States by Region.

These concepts do no apply if the storage condition of the API is 2/8ºC or -25ºC/-15ºC.
3.2.S.7.1 Can stability studies be outsourced to a third party? Yes. However, all of the requirements of RDC 45/2012 apply, including follow-up stability studies.
3.2.S.7.1 Should stability studies for the micronized grade of the API be provided? Yes, due to the significant increase in surface area, which may have an impact on stability.

When the acceptance criterion for PSD is client-specific, it is not necessary to provide a stability study for each range of acceptance criteria. Instead, the API manufacturer should consider a worst case approach, generally meaning the smallest PSD (highest surface area). 		3.2.S.3.1 3.2.S.4.1 psd particle size distribution
3.2.S.7.2 - POST-APPROVAL STABILITY PROTOCOL AND STABILITY COMMITMENT
3.2.S.7.3 - STABILITY DATA
VARIATIONS/POST-APPROVAL CHANGES
GENERAL
IN DEVELOPMENT XXX XXX

RDC 359/2020

**In development**