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Mandating CADIFA for drug registration in Brazil

Navigating through API requirements to successfully register a drug product can be challenging, especially when these requirements are embedded in drug product regulations. This was indeed the case for Brazil where rules and regulations for APIs were very much available but were unclear as they formed a part of the drug product regulations rather than as separate regulations. Hence, it was the pharmaceutical company dealing with ANVISA regarding the API rather than the API supplier themselves. However, now a centralized procedure for submitting API DMFs in Brazil exists as a result of ANVISA’s dedicated regulations that solely focus on APIs.

One of these requirements is CADIFA, which is a letter of suitability that confirms the compliance of DIFA per Resolution RDC 359/2020. This requirement came into effect in August 2020, however, has been made mandatory from August 2023. All drug companies (domestic and international) that wish to register their drug products in Brazil must obtain a CADIFA from ANVISA. Only the DMF holder can request a CADIFA. 

Confirming API quality

CADIFA confirms that the API quality is suitably controlled; though manufacturers must ensure that the API is in accordance with GMP requirements, CADIFA application assessment does not verify GMP compliance, which is why CADIFA and GMP certificate are required for approval. It also is important to note that a CADIFA DOES NOT replace a Certificate of Analysis.  The DIFA reference number must be mentioned in the ANVISA GMP certificate application form; hence the order of submission suggested by ANVISA is as follows:

  1. CADIFA application with DIFA reference number
  2. ANVISA API GMP certificate application with ANVISA API GMP certificate application number
  3. Marketing Authorization/post approval variation application

CADIFA Application Assessment Timelines

Associated CADIFA applications shall be assessed based on the marketing authorization/post-approval change application deadlines and counted form the date of submission of marketing authorization/post approval change application that can be extended for up to 1/3rd of the original term:

  1. Ordinary category: 365 days for marketing authorization application + 180 days for post-approval variation application
  2. Priority category: 120 for marketing authorization application + 60 days for post-approval variation application

New drugs that have been classified for treating rare diseases must meet the following timelines for CADIFA assessment:

  1. 60 days for first manifestation, and
  2. If required, 45 days for analysis of deficiency letter response

This is always counted from the marketing authorization/post-approval change submission date.

Communicating via Solicita system

Solicita is ANVISA’s web-based system that facilitates the exchange of regulatory information between the agency and the DIFA holder. DIFA holders must register on the Solicita system, choose their application type, and organize documentation accordingly. Initial CADIFA application can be submitted as:

  1. Associated CADIFA Application (with a marketing authorization or post approval change application for a drug product);
  2. Expression of Interest (where a DIFA holder intends to have a CADIFA via a stand-alone procedure)
  3. Standalone CADIFA Application (when demanded by ANVISA after the approval of Expression of Interest or public invitation by ANVISA’s DICOL/board of directors)

Get in touch with our regulatory consulting team to know more about CADIFA to ensure successful drug registration in Brazil.

References and Further Reading