In Brazil, the National Health Surveillance Agency (ANVISA) is the regulatory body responsible for registering medicines throughout the national territory. According to Law nº 5.991/1973, medicine is defined as any pharmaceutical product, technically obtained, or elaborated, with prophylactic, curative, palliative, or diagnostic purposes. Therefore, any product that makes therapeutic claims, regardless of its nature (plant-based, animal-based, mineral or synthetic), must be considered a medicine and requires ANVISA´s registration to be manufactured and marketed.
The requirement for drug registration is stipulated in Law No. 6,360 of 1976. This law also establishes deadlines for ANVISA to issue a final decision on the registration process, considering the technical complexity and the clinical, economic, and social benefits of medication usage.
As of March 2017, when the Law No. 13,411 of 2016, came into effect, the deadlines for making decisions on registration processes started to be divided based on the classification of the medicine. They were categorized into two evaluations types: priority and regular (non-priority).
The regulatory categories for drug registration are:
New;
Innovative;
Phytotherapy;
Generic;
Similar;
Radiopharmaceutical;
New biological;
Biosimilar;
Advanced therapy;
Homeopathic;
Specific;
Notified;
Clone.
For a drug to be registered with ANVISA, the Agency must evaluate the administrative and technical-scientific documentation related to the quality, safety, and efficacy of the drug. There is a specific technical regulation for each category. For example, RDC 753/2022 regulates synthetic drugs and RDC 55/2010 regulates biological drugs.
Step by step for the registration of medicines in Brazil
Before reaching the stage of registration and approval for use by ANVISA, the company needs to develop the medicine. This process is divided into the following steps:
Non-clinical phase: Cells and animals assays assist in investigating the action and safety of the molecule in the laboratory (applies only to new and innovative drugs);
Drug development: This step includes selecting the manufacturer of the active pharmaceutical ingredient, formula development, manufacturing process, analytical methods, packaging, and stability studies. Analyzes are conducted to assess product quality, pharmaceutical form, and the most convenient formulation for patients. Furthermore, criteria are defined to ensure that the product is consistently marketed with the required level of quality;
Clinical phase: Studies conducted in human, with a reminder that bioequivalence and relative bioavailability studies are also considered clinical studies.
In addition to demonstrating the technique and providing evidence of safety and efficacy, for a drug to be registered in Brazil, the company requesting for registration must have an Operating Authorization issued by ANVISA and other documents that prove the company's regularity, such as an Operating License and a Certificate of Technical Responsibility.
One of the most important documents at this stage, and worth mentioning is that the Manufacturing Plant needs to be certified in Good Manufacturing Practices - Boas Práticas de Fabricação - (GMPs) by ANVISA. This certification applies to both the drug manufacturer and the Active Pharmaceutical Ingredient (IFA) manufacturer.
It is not uncommon for the Agency to request adjustments even in Facilities certified by other leading international agencies, as it conducts a more comprehensive look than other international regulatory agencies.
“The Food and Drug Administration (FDA), for example, tends to focus its attention on specific technical documentation related to the product, while ANVISA also observes the entire quality system that involves the manufacturing process, quality control, material receipt, the treatment of non-conformities, among other specifications", emphasized Claudia Cilento, Partner-Director at the consulting firm Inovatie Health Services. She is the responsible for the Regulatory Affairs area and serves as a professor in postgraduate courses on Sanitary Regulatory Law and Regulatory Affairs for Medicines and Cosmetics at Faculdade Oswaldo Cruz.
Another noteworthy point is that starting from August 1, 2023, obtaining the Letter of Adequacy of Active Pharmaceutical Inputs (CADIFA) has become a mandatory requirement for the registration of synthetic drugs. The CADIFA must be requested by the API manufacturer.
After gathering data on quality, safety, and efficacy, the drug registration application with ANVISA is initiated. The interested company is required to submit a registration request that includes:
Administrative documentation;
Quality proof documentation;
Documentation proving the safety and efficacy of the drug.
After compiling all of this information, the registration will be submitted to ANVISA, where the drug will undergo a careful analysis to assess its quality, efficacy, and safety determining whether it can be approved for use.
Main points that must be observed in the registration submission:
Claudia explains that, for each stage of the registration process, there are issues that must be observed carefully for the registration of a medication to be accepted. Therefore, the following points stand out:
Submission of documentation, demonstrating the company´s compliance with GMPs. If the product is imported, it is important to present its registration in the country of origin, package leaflet, and a detailed pharmacovigilance plan.
Chemistry, Manufacturing and Controls (CMC) requirements encompass all stages of drug development and ensure quality and consistency during the manufacture of the pharmaceutical product. According to Claudia, ANVISA is particularly careful in evaluating the requirements related to the technical part of the dossier.
Proof of safety and efficacy: The design of the study is essential and must be adequate to the type of product and indication. If a company intends to conduct a clinical study to support the registration, it must pay attention to obtaining authorization for the study by ANVISA through the submission and approval of the Clinical Development Dossier (DDCM) and the Clinical Development Dossier of Product Advanced Therapy (DDCTA). Without this authorization, it is not possible to use the search results to obtain the record. Regarding the clinical study, it must be specific, measurable, with appropriate endpoints and address all regulatory questions.
ANVISA’s response time
Under the standard regulatory process, ANVISA has a maximum of one year to analyze the product, with the possibility of extending this period by up to one-third. However, currently, the average time to obtain the registration can extend to up to two years.
When the process is prioritized, such as for the launch of the first generic, medication for diseases without existing treatment or those with pediatric indications, the response must be provide within 180 days. In the case of drug registration for rare diseases, this deadline is reduced to 120 days. In all cases, these deadlines may be extended by up to one third.
If ANVISA requests clarifications or corrections from the company requesting the registration, the deadline is paused until the requested requirements are satisfactorily addressed.
How to prevent a registration from being denied or having pending issues
“Performing a good gap analysis is indispensable. This involves a detailed evaluation of the registration dossier to ensure compliance with applicable regulatory and technical requirements, the preparation of technical justifications, and preparation of an action plan to mitigate weaknesses. According to Claudia, this proactive approach prevents approval delays.
This action can be conducted either by an internal team within the company or by an external consultancy, which will be responsible for reviewing each item in the dossier.
Claudia emphasizes the importance of the company having a clear understanding of the weaknesses in its dossier and proactively addressing them before submission. For items that may not attend ANVISA's requirements, it is recommended that a prior action plan be created, as the Agency sets a deadline of 120 days for a requirement to be fulfilling. After that period, the process may be rejected.
The drug registration process must adhere to multiple standards, technical guidelines, and legal deadlines. Therefore, it is very decisive for the company to have the guidance of experienced professionals accompanying the entire process.