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Publication of the new API regulatory framework: what is essential to know?

Updated: Feb 24

After a long period of discussion with the regulated sector, the regulatory framework for Active Pharmaceutical Inputs (API) was published, which instituted the Active Pharmaceutical Input Dossier (APID) and the Adequacy Letter of Active Pharmaceutical Input Dossier (ALAPID), and it inserts the need for the Good Manufacturing Practices certificate, so that the API is regularized for use in medicines.

The API regularization logic has been completely changed, leaving a model where the API was evaluated together with the drug registration dossier (with the exception of the assets included in RDC 57/2009) to a model where the APIs will be fully evaluated independent, and the approval of the drug registration will be linked to the issuance of the Adequacy Letter of Active Pharmaceutical Dossier (ALADIP) and the approval of the certificate of good manufacturing practices of the asset manufacturer.

3 API standards have been published:

1. RDC 359/2020: which institutes the Active Pharmaceutical Input Dossier (APID) and the Adequacy Letter of Active Pharmaceutical Input Dossier (ALADIP), sets out the technical requirements for obtaining the ALADIP and post-registration of API, as well as the transition rules.

2. RDC 361/2020: Amends RDC 200/2017 (Registration of Synthetic Medicines) and RDC 73/2016 (post-registration of synthetic medicines) to provide for the submission of APID.

3. RDC 362/2020: Provides for the criteria for certification of Good Manufacturing Practices and institutes the inspection program for international establishments that manufacture active pharmaceutical ingredients.

ANVISA changed RDC 200/2017 and RDC 73/2016, which deal with the registration and post-registration of synthetic medicines respectively, in order to incorporate and harmonize the new system with the previous legislation in terms of requirements, and make it clear what must be presented at the APID and in the registration and post-registration of medicines. In addition, it created a new system for post-registration of the API, which is now made in the APID and later incorporated into the drug registration.

Technical requirements for obtaining the APID:

In terms of technical requirements, there was no major change, since ANVISA had already been requesting the items contained in CP 682/2029 long before the official publication of this regulatory framework and companies have already learned to deal with them. The documents to demonstrate the quality in the Active Pharmaceutical Input Dossier are described in Chapter IV of RDC 350/2020 and are basically the same information requested in module 3.2.S of the CTD format plus Annex I, which requests the implementation of the ICH Guide Q3D for elemental impurities.

API technical requirements for drug registration:

The information that is now required about the API in the drug registration is relative to its responsibility, such as compatibility of the API with excipients, quality control, and changes that it makes after receiving the API as micronization or sterilization. It should be noted that ANVISA makes it clear that the applicant for the registration of the medication is responsible for the quality of the API used in the manufacture of the medication.

Good Manufacturing Practices (GMP) for international API manufacturers:

Another major impact change was that RDC 362/2020 imposed the need for certification in Good Manufacturing Practices for international API manufacturers, and determined in Article 3 the documents necessary to obtain the GMP certificate. ANVISA provided for 3 procedures to obtain certification:

I - evaluation of the documents required for companies inspected by the health authority of a country recognized by Anvisa as equivalent in relation to the controls for the proof of GMP of API;

II - evaluation of documents and conducting risk analysis that justifies the issuance of the CBPF;

III - evaluation of the inspection report issued by Anvisa as a result of conducting an on-site inspection.

Entry into force and transition rules:

RDC 359 will only come into force in August / 2020 and the current rules will only be revoked as of March 1, 2021 (RDC 57/2009, IN 15/2009, IN 3/2013 and NT 01/2016). In addition, there will be a transition period of 3 years according to the transience rule validated with COAPI and disclosed by Sindusfarma described below:

1 - API of RDC 57/09: product on the market, already registered with API and regularized medication. It must maintain the renewal of API registration until the revocation of RDC 57/09 (03/01/2021). The post-registration provided for in the API registration and the drug must be carried out until the revocation of RDC 57/09.

2- API of RDC 57/09: product is still under development and the drug registration will be filed between August 2020 and March 2021. The company can choose to request the API registration and the drug registration, or request ALADIP and registration of the drug (ie, it already fits the new rule).

3 - API that does not belong to RDC 57/09, optional for ALADIP within three years, starting in August 2020. As long as the rule of batch production for registration purposes is met within 18 months.

4 - API that is not RDC 57/09, current rules up to 3 years from August 2020.

5- As of August 2023, new rules for all projects.


There has been a profound change in the system of regularization of API in Brazil and there is a justified fear of increasing the time to complete the analysis of a drug, mainly because two new steps have been created and, as the Serra Law did not provide for a GMP certification period for API and no analysis for APID, the registration queue can simply migrate.

We have to remain calm and wait for ANVISA's clarification cycle and see how this new dynamic will work in practice, especially since we will have an adaptation period. As the article is very extensive, in the coming weeks we will publish articles detailing the most relevant points.

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