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Consulta Publica nº 682/2019 - Dossiê de Insumo Farmacêutico Ativo (DIFA) e da Carta de Adequação de Dossiê de Insumo Farmacêutico Ativo (CADIFA)

 

 

 

Welcome to!

General concepts

ANVISA is in the process of revising the regulation of active pharmaceutical ingredients. The proposal relies on three main concepts:

  1. Centralized assessment;

  2. Adoption of ICH guidelines;

  3. GMP audit conducted by the marketing authorization holder/applicant.

  1. Centralised assessment.

This concept draws from already well-established and successful initiatives, namely the CEP (EDQM) and the Prequalification of APIs (WHO-PQ). The objective is to streamline the regulatory process by establishing a direct line of communication with API manufacturers (both domestic or foreign) and avoiding replication of work. The CADIFA will be ANVISA’s analogue of the CEP or the WHO-CPQ and, once granted, will allow for multiple drug product applications to be submitted without a reassessment of the API.

2. Adoption of all ICH guidelines concerning API quality

As an ICH member, ANVISA intends to harmonize its requirements with those of regulated markets for APIs by formalizing the adoption of the following guidelines.

  • ICH M4Q

  • ICH Q2

  • ICH Q3A

  • ICH Q3C

  • ICH Q3D

  • ICH Q6A

  • ICH Q11

  • ICH M7

3.  GMP audit conducted by the marketing authorisation holder/applicant.

 

This concept is based on the premise that the API is a critical component of the drug product formulation and, therefore, compliance with GMP should be verified by the marketing authorisation holder/applicant through an on-site audit of the API manufacturing site.

*ANVISA is also working on a revised policy for inspections of foreign API manufacturer, which is part of a parallel draft Resolution.

 

Public consultation (CP)

The proposal concerns two Resolutions. The first (CP 682/2019) addresses the Active Pharmaceutical Ingredient Dossier (DIFA) and the Letter of Suitability of the Active Pharmaceutical Ingredient (CADIFA). It is primarily aimed at DIFA holders/API manufacturers. The second (CP 683/2019) Resolution alters two already existing Resolutions: 200/2017 and 73/2016. Its purpose is to adjust the submission procedure for the API documentation by drug product marketing authorisation applicants/holders and institute the GMP audit. On August 14, the public consultation for both Resolutions was published (CP 682/2019 and 683/2019). The period for contributions will be of 60 days starting on August 21. Since the Resolution concerning the DIFA/CADIFA directly and extensively involves foreign manufacturers, its public consultation will also be made available in English through a separate platform during the same period. Questions concerning the public consultation may be sent to api@anvisa.gov.br.

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TITLE I - PRELIMINARY PROVISIONS

Art. 1º The Active Pharmaceutical Ingredient Dossier (DIFA) and the Letter of Suitability of the Active Pharmaceutical Ingredient (CADIFA) are instituted.

Art. 1º - Proposal for amendment, addition or deletion:

Art. 1º - Justify your answer:

CHAPTER I - SCOPE

Art. 2º This Resolution applies to active pharmaceutical ingredients (APIs) used in the manufacture of new, innovator, generic and similar drug products.

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Art. 3º In the context of this Resolution, the following definitions are adopted: 

I - Letter of Suitability of the Active Pharmaceutical Ingredient (CADIFA): administrative instrument that attests the compliance of the API with the requirements of this Resolution.
II - design space: multidimensional combination and interaction of input variables and process parameters that have been demonstrated to provide assurance of quality. 

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Art. 5º After receipt of the DIFA submitted according to art. 4º, ANVISA will provide a reference number to its holder.

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Art. 6º The DIFA should contain a version number and table of contents; the documents that make up the dossier should be organized in the order described in Chapter V (Administrative Documents of the Active Pharmaceutical Ingredient) and Chapter VI (Technical Documents of the Active Pharmaceutical Ingredient) of this Resolution.

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CHAPTER II - LETTER OF SUITABILITY OF THE ACTIVE PHARMACEUTIAL INGREDIENT (CADIFA)

Art. 7º Anvisa will issue a Letter of Suitability of the Active Pharmaceutical Ingredient (CADIFA) to the DIFA holder if the DIFA is approved.

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Art. 8º The following information will be included in the CADIFA:
 
I - Number and issue date of the CADIFA;
 
II - DCB, DCB number and CAS registry number of the API;
 
III - name and address of the DIFA holder;
 
IV - name and address of API manufacturing sites;
 
V - synthetic scheme;
 
VI - assessment history;
 
VII - compendial reference, if applicable;
 
VIII - API specification;
 
IX - description of non-compendial analytical methods;
 
X - maximum daily dose used to justify the specification, if applicable;
 
XI - administration route used to justify the specification, if applicable;
 
XII - container closure system;
 
XIII - API storage conditions;
 
XIV - retest period or shelf-life; and
 
XV - information related to elemental impurities, according to ANNEX I of this Resolution;
 
§ 1º The CADIFA may contain additional information considered as relevant.
 
§ 2º The CADIFA may be used to support a drug product marketing authorization application/variation associated with a dosage form with a different maximum daily dose or route of administration than those stated in the CADIFA, provided that the API specification remains appropriate.

§ 3º When issued under subheading “b” of item II of art. 4º, the name and address of the CADIFA holder will be published in ANVISA’s website.
 

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ANNEX I - Proposal for amendment, addition or deletion:

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