Brazilian Health Regulatory Agency – ANVISA

API Registration Department – COIFA

Summary of changes

Current version: 6 (01/05/2019)

Tab Change Description & Justification
Version 5 (04/06/2018) → Version 6 (01/05/2019)
Introduction FAQ and Summary of Changes. A brief description of the tabs FAQ and Summary of Changes was included. These tabs were included in version 6.
Assessment Policy CTD 3.2.S.1.1 - Link DCB The link was changed to the general website for the Brazilian Non-Proprietary Name (DCB) to prevent outdated lists from being consulted. brazilian non-proprietary name brazilian non proprietary name inn
Assessment Policy CTD 3.2.S.1.1 - DCB & INN The expression "in its absence" was deleted, so as to prevent the need for custom documentation.

Previous text:
Brazilian Non-Proprietary Name (DCB) or, in its absence, International Non-Proprietary Name (INN);

Current text:
Brazilian Non-Proprietary Name (DCB) or International Non-Proprietary Name (INN);
Assessment Policy CTD 3.2.S.1.1 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.1.2 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.1.3 - Aqueous pH solubility profile A statement was included to waive the aqueous pH solubility profile in the following circumstances:
  1. The DMF (full or open part) is submitted along with the drug product dossier and the information is available (e.g., dissolution method development report, BCS based biowaiver report);
  2. The API is not used in solid oral dosage forms or oral suspensions;
  3. The API is knowingly not highly soluble, in which case a statement to this effect is sufficient;
  4. The DMF contains a thorough discussion about the solid phase properties of the API, including characterization and stability of the crystalline form.
BCS SCB sistema de classificação biofarmacêutica
Assessment Policy CTD 3.2.S.1.3 - Permeability A statement was included to emphasize that BCS permeability data need not be included in the DMF. BCS SCB sistema de classificação biofarmacêutica
Assessment Policy CTD 3.2.S.1.3 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.2.1 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.2.2 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.2.3 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.2.4 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.2.5 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.2.6 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.3.1 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.3.1 - Particle size distribution (PSD) Some adjustments were made regarding other quality attributes of the API that can be influenced by PSD:
  1. Content uniformity;
  2. Processability;
  3. Stability;
  4. Appearance.
3.2.S.3.1 3.2.S.4.1 psd particle size distribution
Assessment Policy CTD 3.2.S.3.2 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.3.2 - ICH Q3C(R7) The ICH Q3C(R7) link was updated (correction of the PDE for ethyleneglycol).
Assessment Policy CTD 3.2.S.3.2 - ICH Q3D(R1) The ICH Q3D(R1) link was updated (revision of the PDE for cadmium).
Assessment Policy CTD 3.2.S.3.2 - ICH M7(R1) The ICH M7(R1) link was updated (adoption of the addendum).
Assessment Policy CTD 3.2.S.3.2 - Qualification of impurities The following statement was included, considering to document to be published by GESEF:

Qualification studies for impurities or alternative approaches to the justification of limits should be submitted according to GESEF (Department of Safety and Efficacy) guidelines/instructions.
Assessment Policy CTD 3.2.S.3.2 - ICH Q3D(R1) Links to the EDQM and WHO Prequalification guidelines regarding the implementation if ICH Q3D by API manufacturers were included:

EDQM - Implementation of ICH Q3D in the Certification Procedure

WHO - Use of ICH Q3D Guideline in the Assessment of Active Pharmaceutial Ingredients Master Files (APIMFs)
Assessment Policy CTD 3.2.S.4.1 - Particle size distribution Questions regarding the following topics were included:
  1. Need for PSD test;
  2. Control of PSD by the API manufacturer;
  3. Test for PSD in the API specification;
The questions were also included in the tab FAQ.
3.2.S.3.1 3.2.S.4.1 psd particle size distribution
Assessment Policy CTD 3.2.S.4.1 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.4.1 - Elemental impurities The term "elemental impurities" was included (color code: red).
Assessment Policy CTD 3.2.S.4.1 - ICH Q3C(R7) The ICH Q3C(R7) link was updated (correction of the PDE for ethyleneglycol).
Assessment Policy CTD 3.2.S.4.1 - ICH Q3D(R1) The ICH Q3D(R1) link was updated (revision of the PDE for cadmium).
Assessment Policy CTD 3.2.S.4.1 - ICH M7(R1) The ICH M7(R1) link was updated (adoption of the addendum).
Assessment Policy CTD 3.2.S.4.1 - Specification The requirement "Dated and signed copy of the specification" was changed to "Specification, containing version and date.".
Assessment Policy CTD 3.2.S.4.1 - Microbial limits A question related to the current policy regarding microbial limits for APIs was included. The question was also included in the tab FAQ.
Assessment Policy CTD 3.2.S.4.2 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.4.3 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.4.3 - Partial validation The term "verification" was changed to "partial validation", which is the terminology used in RDC nº 166/2017.
Assessment Policy CTD 3.2.S.4.3 - Partial validation The color code of the topic regarding partial validation was changed from green to black, considering RDC nº 166/2017.
Assessment Policy CTD 3.2.S.4.3 - Stability indicating method for assay A question regarding the current policy on the use of titration methods for assay in API stability studies was included. The question was also included in the tab FAQ.
Assessment Policy CTD 3.2.S.4.4 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.4.4 - Batch analyses The word "all" was deleted (i.e, for new chemical entities, the applicant is expected to provide data from the batches that support the dossier, not necessarily all pre-clinical, clinical, pilot, stability, commercial batches, etc.).
Assessment Policy CTD 3.2.S.4.5 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.4.5 - ICH Q3C(R7) The ICH Q3C(R7) link was updated (correction of the PDE for ethyleneglycol).
Assessment Policy CTD 3.2.S.4.5 - ICH Q3D(R1) The ICH Q3D(R1) link was updated (revision of the PDE for cadmium).
Assessment Policy CTD 3.2.S.4.5 - ICH M7(R1) The ICH M7(R1) link was updated (adoption of the addendum).
Assessment Policy CTD 3.2.S.5 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.6 - References The links to EDQM and Health Canada guidelines were updated.
Assessment Policy CTD 3.2.S.7.1 - Micronized API A question regarding the need for stability studies of the micronized grade of an API was included.

The question was also included in the tab FAQ.
Limits Compound-specific acceptable intakes Impurities with compound-specific acceptable intakes were included in the spreadsheet (Appendix 3 of ICH M7(R1)).
  • Acrylonitrile
  • Benzyl chloride
  • Bis(chloromethyl)ether
  • 1-Chloro-4-nitrobenzene
  • p-Cresidine
  • Dimethylcarbamoyl chloride
  • Ethyl chloride
  • Glycidol
  • Hydrazine
  • Methyl chloride
  • Aniline or aniline HCl
  • Hydrogen peroxide
  • p-Chloroaniline or p-chloroaniline HCl
  • Dimethyl sulfate
mutagênicas mutagenicidade genotóxicas genotoxicidade
Limits Provisional limits for N-nitrosamines Provisional limits set by the FDA for N-nitrosamines (NDMA, NDEA and NMBA) were included in the spreadsheet.
Limits PDE for ethyleneglycol The PDE for ethyleneglycol (class 2 solvent) was changed from 6.2 mg/day to 3.1 mg/day, in line with ICH Q3C(R7).
Limits PDE for cadmium (inhalation) The PDE for cadmium (class 1 elemental impurity) by inhalation was changed from 2 µg/day para 3 µg/day, in line with ICH Q3D(R1).
ANVISA Guidelines Link updates
    The following updates were made:
  • The column "Laws and Decrees" was included;
  • The link to the revised ANVISA statute (RDC nº 255/2018) was updated;
  • A link to RDC 283/2019 (Nitrosamines - Portuguese) was included;
  • The link to OS 58/2019 was included. This document addresses the assessment of DMFs by COIFA, including the simplified procedure, which applies when there are multiple applications associated with a DMF;
  • The column "Guidance documents and FAQs" was included.
mutagênicas mutagenicidade genotóxicas genotoxicidade
Other Guidelines Link updates The following updates were made:
FAQ Tab "FAQ" A tab with frequently asked questions (FAQ) was included.
Summary of Changes Tab "Summary of Changes" A tab with a Summary of Changes was included as a means to provide transparency and traceability to the changes of the website. The Summary of Changes will be available from version 5 (04/06/2018).
Pharmacopoeias Link updates
Other References Link updates The following links were included: