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API, BPF and drug dossier - How to align the processes to ensure success in registration?




As part of the series on the API regulatory framework, I will address the issue of obtaining the Good Manufacturing Practice (GMP) certificate and the API in the drug registration dossier.


As described in the first article on the API regulatory framework, a GMP certification will become mandatory for all international API manufacturers and ANVISA provides 3 procedures for obtaining 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 proving GMP of API;


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


III - evaluation of the realization report issued by ANVISA as a result of the realization on site.


It is noteworthy that for procedure I to be possible, the declaration report of the international health authority must cover the API object of the certification request because, if it does not include it, an analysis will follow through the risk analysis mechanism II.


In procedure II, ANVISA will carry out risk analysis considering the result of the evaluation of the documents that instruct the certification process taking into account the complexity of the manufacturing unit, the technologies involved and the intrinsic risk of the inputs.


Even if not requested by ANVISA, a tip to provide an extra subsidy and pass security in ANVISA's decision-making process through risk analysis, is to send the audit report to the manufacturer of the pharmaceutical ingredient provided for in art. 181 of RDC 301/2019, carried out by the applicant for the registration of the medication or by a company acting on its behalf.


The idea here is that companies reflect what other documents can provide security in the granting of the GMP by ANVISA and send it as an attachment so that it increases the chance of approval without having to go to procedure III; to carry out the on-site inspection; that will only happen when the first two are eliminated.


It is important to note that, even if the manufacturer of the API is already certified, Anvisa can perform a routine health inspection or investigation of a complaint or possible irregularity at any time. For this reason, the mechanisms for supervising suppliers based on the risk matrix provided for in RDC 301/2019 must always be updated in order to avoid surprises.


It is also important to evaluate RDC 361/2020 in depth, it alters RDC 200/2017, including news such as the granting of the drug registration only after obtaining the CADAPI and the GMP certification from the active manufacturer, as well as the inclusion new technical requirements for the registration of synthetic and semi-synthetic drugs.


Although ANVISA has already made it clear that it will no longer be necessary to forward the information related to the process of obtaining the API in the drug registration dossier by simply sending the ALAPID., the obligation to send the documents related to the API under the responsibility of the manufacturer is maintained of the medication and those related to the impact of the API on the medication, such as: description of the physical steps (micronization, grinding, sifting, lyophilization), when not carried out under the responsibility of the holder of the APID.


For sterile API, description and validation of the API sterilization process, when not carried out under the responsibility of the APID holder information on the compatibility of the API with the excipients, the main physicochemical characteristics of the API that may influence the performance of the finished product; adequacy of the API specification to the maximum daily dose, route of administration and pharmaceutical form of the drug object of registration justification in case of excess of actives.


specifications, analytical methods and analytical report for the active pharmaceutical ingredient, accompanied by a bibliographic reference, performed by the manufacturer of the medication.


An interesting point where the articulation between API, GMP, and registration standards is clear is the request for a declaration signed by the technical responsible, attesting that the manufacturing of the API is conducted in accordance with good manufacturing practices based on audit of good practices, and conducted under the terms of the Collegiate Board Resolution - RDC 301/2019.


This reinforces the message of the new regulatory framework where the registrant is responsible for the quality of the API used in the manufacture of the drug, that all areas of the pharmaceutical industry are connected and must work together to obtain the registration!


Questions on the topic? Forward to our e-mail contato@inovatie.net.br




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