In April 2020, ANVISA, the Health Regulatory Agency of Brazil, published new landmark regulations referring to active pharmaceutical ingredients (APIs).
The new set of rules consisted of three separate guidelines regarding APIs in Brazil, known as RDCs. These are RDC 359/2020, RDC 361/2020 and RDC 362/2020, and they represent a complete overhaul of the API regulatory landscape in Brazil.
The goal of these new regulations is to create one, clear, distinct regulatory process in Brazil, as well as to align with international practices. The hope is that everyone will benefit from this new way of working — from ANVISA, to marketing authorization holders (MAH) and API manufacturers.
In August 2020, the new regulations came into effect in Brazil. There is currently a three year grace period where companies can either follow these new regulations, or stick with the previous way of working. In August 2023, the new regulations will be enforced, and any company wanting to register its drug products in Brazil will have to first obtain a CADIFA.
Over the last few years, ANVISA has been moving towards regulatory convergence. In 2016, it became a member of the International Council for Harmonization, and also signed a memorandum of understanding with the European Directorate for the Quality of Medicines in 2017.
The paradigm shift embedded in the landmark new regulatory framework will bring about a much-anticipated direct interaction between ANVISA and the drug master file (DMF) holder or API supplier.
Prior to these changes, there were rules for APIs but they weren’t necessarily so clear and were always embedded in the regulations of the drug product. This meant that it was the pharmaceutical company who dealt with ANIVSA regarding the active ingredient, and not the API supplier themselves.
Now, for the first time, ANVISA has designated a set of regulations solely focused on APIs, which affect all APIs shipped to, or manufactured in, Brazil. There is now a centralized procedure for submitting API drug master files (DMFs), which will also streamline the process for subsequent petitions using any given prior-reviewed DMFs.
What is a CADIFA?
From August 2023, any domestic or foreign company wanting to register its drug products in Brazil will have to first receive a CADIFA.
A CADIFA is a letter from ANVISA showing that a DIFA, which is a certain DMF together with other administrative documents, was evaluated by them and considered suitable to be part of the composition of any drug product in the market. (DIFA is an acronym in the local language for Active Pharmaceutical Ingredient Dossier.) The drug product application should then receive marketing authorization.
This letter contains basic information about the API, such as the CADIFA number, API name, name and address of the DMF holder, name and addresses of the manufacturing sites where API and intermediates are produced, API specification, storage conditions, packaging description, retest or expiry date, and declaration of access.
A CADIFA serves a similar purpose to a CEP in Europe, with the flexibility of not being tied to a specific monograph, i.e. ANVISA allows for the application of any of their recognized Pharmacopoeias (RDC 511/2021) or even in-house specifications.
Who can apply for a CADIFA?
A CADIFA can only be requested by the DMF holder. This is the company that possesses the knowledge about the entire manufacturing process of the API and is responsible for this process, all the way from the introduction of the starting material. The DMF holder is ideally the manufacturer of the final API.
Do I need a CADIFA?
The simple answer is yes, from August 2023, a CADIFA will have to be obtained by any company wanting to register its drug products in Brazil.
In addition, since February 1, 2022, more and more APIs have become part of the CADIFA framework. If your regulatory pilot batch was manufactured after this date, a CADIFA application is obligatory.
A CADIFA can be requested in the following 3 situations:
- For a new submission or a post-approval variation for a drug product associated with an MAH.
- When a DMF holder expresses interest to have one, with no link to a MAH dossier.
- Through invitation by DICOL, which is when ANVISA’s board of directors invites DIFA holders of a specific API to apply for one.
There is no cost for obtaining a CADIFA and it will not need to be renewed, though it must be kept up-to-date by the DMF holder, should any changes occur. It is unlikely that the DMF/DIFA part of a CADIFA with a valid status would need to be re-assessed at a later date for a new submission. So it is safe to say that once it is approved, any subsequent submission that relies on the API covered by the CADIFA is also covered. Any variation procedure is dealt firsthand by the CADIFA holder together with ANVISA, which means the process should be more seamless than it was before.
The Teva api advantage for a pharma company
If you’re a pharmaceutical company still not sure on how to navigate this new CADIFA framework, don’t worry. You’re in reliable hands with Teva api.
And here’s why:
- We’ve built a dedicated ‘CADIFA team’ made up of regulations experts and scientific support experts, to fully support customers with their submission. Our team are on the ground in Brazil and have knowledge of all the nuances needed to obtain a CADIFA.
- Teva api’s global presence means we have extensive knowledge of similar centralized processes for DMF review, specifically in Europe. So we know what we’re doing and we have the right connections to make the process smooth and easy for you.
The Teva api CADIFA digital tool
Try out our new digital tool that simplifies the CADIFA variations for you! You’ll know exactly what needs to be done for a post-approval variation. The tool is intuitive, easy to navigate and will help you on your day-to-day assessment of changes that may be needed during the lifecycle of the API in your product.