Registration of APIs in Brazil - Q&As

In March 2023, the ECA offered the Live Online Training "How to register APIs in Brazil". During the Q&A sessions, many interesting questions were posed to the speakers' team.

With regard to Brazil's Registration procedures for APIs, a set of the most important questions raised during the training and the respective answers provided by the speakers Ms Marieke van Dalen, Global Regulatory Specialist, Aspen, The Netherlands, and Ms Susan Swiggers, Customer & Regulatory Support Officer, Aspen, The Netherlands, are listed in the following. All answers reflect the opinion of the speakers based on her experiences. 

Question 1: Is the CEP accepted in Brazil?

Answer:
The CEP as such is not accepted in Brazil as a registration tool, although ANVISA is looking at that for the future (will probably still take some years).
However, when the API manufacturer has a CEP available for a specific API, it is possible to apply for the optimized analysis procedure as an amendment to a submitted CADIFA application. When ANVISA approves the use of the optimized analysis procedure, the contents of the CEP dossier and EDQM assessment report will be used (partly) for a short-track review of the CADIFA application. The optimized analysis procedure is described in the temporary RDC 750/2022 and RDC 781/2023. The latter extends the validity of RDC 750/2022 up to 31 March 2024. In the meantime, ANVISA is working on a definite reliance procedure for assessments of CADIFA applications (public consultation No. 1.108).

Question 2: Is there any deadline to switch from DIFA to CADIFA for existing API registrations or are both systems foreseen to exist in parallel?

Answer:
The system will probably run in parallel for quite some time. At present, there is no such deadline. However, if a new customer wants to use your API as of August 2023, it is no longer possible for a new drug product submission to link to an already approved DIFA. Until August 2023, it is still possible to submit via this 'old' process but only when the drug product validation batches are manufactured before February 2022.

For existing drug product registrations, only in case of major changes the switch to CADIFA is mandatory. Furthermore, there is a voluntary change (immediate implementation) available for drug product manufacturers to link an existing registration to a CADIFA without any further changes. This is described in RDC 361/2020: Annex I, change 1l.

Question 3: Are regulatory agents mandatory for the registration?

Answer:
For a CADIFA application a regulatory agent in Brazil is not required. This process can be done by the international API manufacturer itself.
However, when the international API manufacturer intends to apply for its own GMP certification in Brazil, a Brazilian agent (with a Brazilian CNPJ number; Brazilian tax-ID) is required to apply for the GMP certificates. All communication with ANVISA will be done with the Brazilian agent (or Brazilian affiliate of your company when available). ANVISA GMP certification can also be done via the drug product manufacturer. In that case the drug product manufacturer may need a Brazilian agent or affiliate to apply for the GMP certification.

Question 4: Once CADIFA has been issued, should it be renewed after certain time? Should an annual report be submitted?

Answer:
There is no renewal needed for CADIFAs. You are of course expected to file any change with ANVISA for them to assess whether the CADIFA needs to be revised or not. An annual notification only needs to be submitted in case of specific changes classified as 'annual notification' in RDC 359.

Question 5: Does ANVISA accept GMP certificates issued by an authority within the ICH region?

Answer:
No, ANVISA only accepts GMP certificates issued by themselves. Having a GMP certificate issued by another authority is helpful. Currently ANVISA is working on an optimized assessment of the GMP certification where ANVISA uses different levels of acceptance of GMP inspection reports/GMP certificates of Equivalent Foreign Regulatory Authorities (Public consultation No. 1,135). The Equivalent Foreign Regulatory Authorities should always be members of PIC/s and ICH. This procedure is not yet issued.

Question 6: How likely it is to receive an on-site inspection by ANVISA?

Answer:
This is always difficult to predict. Like many other authorities ANVISA uses a risk-based approach to determine where their inspectors should go based on the complexity of the manufacturing unit, technologies involved and the intrinsic risk of the APIs. There are many EU companies that received ANVISA inspection in the past year, usually companies that request certificates for a site producing more than one API.