Approved by Anvisa’s Board of Directors, the Public Consultations of the New Regulatory Framework for the Evaluation of Good Practices in the Manufacturing and Registration of Active Pharmaceutical Ingredients

Both themes are being worked on concurrently to make possible the major change in this regulatory framework proposed by Anvisa and which is in line with the actions of international regulatory convergence.

Good Manufacturing Practice Certification for API´s

It was unanimously approved last August 6th, by the rapporteur Director Fernando Mendes, the Public Consultation on the proposal of a new Resolution (named RDC by ANVISA) that establishes the criteria for certification of Good Manufacturing Practices (cGMP) for international API manufacturers establishments and a Normative Instruction (named IN by ANVISA) for the supplier qualification of API manufactures related to Good Practices in Distribution and Fractionation of Active Substances.

Considering the lack of application for requirements for registration of manipulated Medicines, and also the need for further study for this sector, it will not be necessary to submit API dossiers (DIFAs) to actors other than the Pharmaceutical Industry (E.g.: Importers, Fractionators, Distributors and Compounding Pharmacies.

The IN proposal will make the process of selection, qualification, approval and maintenance of suppliers of raw materials become more robust, traceable and efficient, reflecting directly on the quality of manufactured medicines.

Regarding Good Manufacturing Practices (GMP) for APIs, the subject is currently regulated by RDC 39/2013, which brings administrative procedures for Certification of Good Practices of Active Pharmaceutical Ingredients, and by RDC 69/2014, which provides requirements for GMP.

Given the health importance of controlling compliance with Good Practices regarding Active Ingredients, the revision of these standards started with the collaboration of the representative entities of the API and Pharmaceutical Industries and the regulated sector.

The focus of this public consultation, is to accept the standardized Inspection reports of the Regulatory Authorities members of Pharmaceutical Inspection Co-operation Scheme (PIC/s) with Anvisa´s risk assessment, without the need for an on-site re-inspection  by ANVISA. It also proposes compulsory cGMP for all API manufacturers, regardless of their presence in the prior listing of ANVISA, IN 15/2009 and IN 03/2013 (list of 30 prior API´s and their salts and hydrates to be registered at ANVISA).

Thus, the Public Consultation brings the following possibilities for granting and renewing certification by ANVISA:

1 – Upon Inspection Report evaluation, since it was inspected by a regulatory member present of PIC/s for the API cGMP.

2 – Through document evaluation and conducting risk analysis that underlies the grant of cGMP.

3 – By conducting on-site inspection, that can be motivated by risk analysis and the absence of a report. The certification, if granted, will be valid for 2 years.

It is important to mention that the certification based on items 1 and 2 does not exempt the company from receiving an inspection from ANVISA,, anytime, even with valid certification.

In the oral manifestation of the class associations, ANVISA was congratulated for the discussion process between the technical group formed, and that even long awaited by the national API Industry sector, this change in Regulation will allow an equality between national and international API manufacturers.

It was also reinforced that the National API Industry is at the same level as International and is prepared for this new phase.

The proposed public consultation should be published shortly on ANVISA’s website http://portal.anvisa.gov.br/consultas-publicas#/ and will have 60 days for public participation.

Active Pharmaceutical Ingredient Register

The Public Consultation for the revision of the Regulatory Framework for the registration of APIs was also unanimously approved at the same meeting, It was proposed the revision of RDC 57/2009 (actual regulation for API´s registration) and a proposal for an amending of RDC 73/2016 and RDC 200/2017 in the points that regards to the topic.

The main motivation of this revision is a centralized analysis of the API documentation by API Registration Department  (COIFA), favouring greater efficiency and standardization of analyses resulting in greater control of health risk in this class. Today, when an API is not in the priority list, the documentation is evaluated by the department responsible for the drug product analyses.

In December 2016, a Technical Working Group was set up with representatives from General Management of Medicines and Biological Products (GGMED) and Inspection General Management (GGFIS) and also from the regulated sector with representatives from API Industry , drug product manufacturers and importers.

The productive sector representatives in the Working Group were redefined in December 2018, which resulted in the base text of the proposed Public Consultation Draft and was attended by the following entities: Abrifar, Abifina, Abiquif, Alanac, Farmabrasil, Interfarma, Progenéricos, Sindifargo and Sindusfarma.

In addition to this systematic discussion with the regulated sector, the issue was also discussed with ANVISA´s directors involved, as well as their advisors.

The API importance and impact in the quality of the final medicinal product was reinforced, and this fact was already foreseen by Law nº 6360/76, which determined the need for an authorisation by the competent health authority to perform activities involving APIs.

However, it was only with the publication of RDC 57/2009 that specific criteria were established by the Agency, prioritizing through narrow lists, IN 15/2009 and IN 3/2013, narrow therapeutic index drugs (NTI), antibiotics and essential drug substances necessary for the manufacture of medicines from the Brazilian Public Health System.

Based on the experience of the current API Registry evaluation model, the technical area identified some difficulties in the analysis flow, such as:

– Possibility of rework with the analyses of the same documentation submitted by different manufacturers of the drug product, reviewed several times;

-Possibility of divergence between technical evaluations, leading to the possibility of antagonistic decisions and a lack of equality in the process;

-Possibility of different levels of documentation detail of the same API and synthetic route, given the possibility of different negotiations between the drug product manufacturers submissions, who usually only have access to the open part of the DMF.

The priority APIs registration scenario started by ANVISA was aimed to gradually update the number of assets to be compatible with ANVISA’s service capacity in the areas responsible for evaluating the API Registration (COIFA/GGMED) and the area responsible for cGMP, General Management of Inspection and Health Inspection (GGFIS), in addition to predictability for the Pharmaceutical Industry suitability to new requirements. However, data from COIFA demonstrate the registration of only 60 different molecules (including ether esters and hydrates), derived from the 30 listed drug substances, which represents less than 3% of available molecules or 5% of all drug molecules.

It was reinforced by Director Alessandra Soares that, even if only these API´s are compulsorily registered so far, all medicinal products already approved by ANVISA had the API’s quality evaluated in the registration and post-registration processes of the final dosage product, being a mandatory documentation throughout the regulatory evolution of the agency.

The health model used in the draft proposal was that of the European Medicines Agency – EMA, which relies on the API’s assessment conducted by the European Directorate for the Quality of Medicine (EDQM), which is also responsible for the European Pharmacopoeia.

In this model, the responsible for submitting the API documentation is its manufacturer, which after EDMQ’s full evaluation of the restricted part receives the certificate of suitability called CEP.

This centralization allows of analysis of greater detail of documentation by a single department, avoiding the discussion of issues related to the API manufacturer’s industrial secrets with the drug product manufacturer.

The proposal brings the issuance of the API Letter of Approval– named CADIFA by ANVISA – that will be similar to CEP, which allows the construction of a consistent database and the simplification of the submission process through direct dialogue with the API manufacturer, dispensing the intermediation of Pharmaceutical Industry or Importers

CADIFA would be presented in the drug product registration / post-registration documentation just like the process in the European Agencies.

As for the adequacy time, the draft proposes the immediate suitability for the APIs that were already in the registration regime (belonging to the INs 15/2009 and 3/2013) when submitting new drug product registration containing the API or when requesting variations after the registration. This includes the presentation of documentation in CTD format that is already commonly used in the submissions, even if not compulsory, as well as the other documentation presented on the draft.

For the other APIs, it is proposed a period of up to 3 years to accomplish the new standard. The Director Alessandra reinforced that the definition of this adequacy period was based on the average development period of a drug product.

Optional compliance with the new legislation is proposed during this period with the contemplation of batches of medicines produced within 18 months from the publication of the new RDC, allowing an additional 18 months to completion of the product development and submit documentation for CADIFA issuance by the agency.

During the proposed adjustment period, the current legislation will be still valid, thus allowing a moderate and gradual transition of the area responsible for the evaluation, which will have its demand substantially increased from 300 (current number of API Registrations) to 1800 CADIFAS.

The attorney general’s office was consulted on the draft text, providing support for the following impact topics of the proposal:

· There is legal support for ANVISA’s direct communication with API manufacturers, with will require a system that allows the direct access of foreign legal entities.

· Possibility of appeal by the API manufacturer, in case of non-granting of CADIFA, therefore, the API Manufacturer should have a legal representative in Brazil, in accordance with current legislation.

Following the presentation of the proposal by the rapporteur, Director Alessandra, oral support was granted to the class associations representing the API and Pharmaceutical sectors, who congratulated the agency on the transparency in the discussion process with the Working Group, giving both impacted sectors the opportunity to manifest their opinion and give their contribution.

Director Renato Porto was the draftsman drawn to follow-up on the next steps of this new API Registration regulatory framework .

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