Drug Product Registration in Brazil

The National Sanitary Surveillance Agency (ANVISA), established on January 26, 1999 (Law No. 9,782/99), is responsible for protecting public health by regulating the production and marketing of pharmaceuticals, food, sanitizers, cosmetics, medical devices, smoking products, and more.

Drug Product Registration Categories

ANVISA classifies drugs into the following categories for registration in Brazil:

1. Medicinal Products: Medicines for human use, consisting of active ingredients and other substances.
2. Pharmaceutical Raw Materials: Substances or raw materials used in medicines, such as excipients.
3. Health Products and Medical Devices: Equipment and devices used in hospitals, including those in medical, dental, or hemotherapy centers, as well as those for laboratory and imaging diagnosis.

Registration Application

New Medicine Product/Innovator Drug: 

These are branded medicines with patent protection, scientifically proven efficacy, safety, and quality, and can be identified by their brand.

Generic Product (Branded Generics):

Medicines that are similar to a reference product or originator drug with which it is intended to be exchangeable, generic products can only be produced after the expiry or refusal of patent protection and other exclusivities, with its efficacy, safety and quality having been scientifically proven, and named in accordance with the Common Brazilian Name Listing (DCB) or the Common International Name Listing (DCI).

Similar Product (Non-Branded Generics): 

A product containing the same active principle or principles in a similar concentration with the same pharmaceutical form, means of administration, dosage, and therapeutic or diagnostic indication as the reference medicine registered with the Regulatory Agency.

Clone Product:

A clone application can be submitted when a similar product or generic product has already been approved, or when an innovator drug applicant seeks approval for a generic or similar product.

Required Documents for Submission

In Brazil registration dossier is made up of Legal documents, Quality documents, Degradation profile and identification & qualification of degradation products, finished product stability studies, Dissolution method development report, Bioequivalence study & Bio waiver study. Required data for each application may differ, depending on submission type such as a new medicine, similar/generic product or clone product. However, all the required data is more or less similar to the CTD structure.

Dossier requirements to be submitted from a local agent of a foreign company include a Technical Report on the product, informing the components of the formula, instructions, directions, cautions, etc.

Label samples, brochures, and pertinent information about the products, all translated into Portuguese; If a medical equipment, all documents showing product safety, country of origin, detailed schematic diagram or technical drawing of the equipment's inner parts and user manual, have to be presented for registration.

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Administrative Document Requirements

For Legal documents an applicant must submit the Application form issued by the Brazilian Ministry of Health, together with a comprehensive table of contents and information regarding the medicine to be registered, eg, Name and Composition of the drug; dispensing requirements; proposed shelf life. Besides this, there are several legal documents which need to be attached. 

These include:

1. Proof of registration fee payment: Original copy of the machine stamped bank slip
2. Manufacturing site certificate of API supplier and manufacturer issued by ANVISA
3. Documents issued by the certification authority stating the technical responsibility of the distributor/manufacturer
4. Copy of the notification protocol of pilot batch production
5. Business license ("Alvará de Funcionamento") issued by the State authority to the manufacturer's distributor.
6. Operating Permit ("Autorização de Funcionamento"), issued by the Federal authority to the manufacturer's distributor.
7. In case of products not clearly mentioned in the Brazilian law, it is mandatory to demonstrate their efficacy and safety.
8. Copy of the legal Distributor Agreement document, by which the manufacturer authorizes its distributor to trade and distribute the products.
9. Information on the regulatory status of medicine in other countries (Imported products) with respective registration dates
10. Original legalized Certificate of a Pharmaceutical Product (CPP) from the Brazil embassy in WHO Format
11. Free sale certificate, Good Manufacturing Practice (GMP) certificate.
12. Documentary evidence of the medicine’s registration and marketing in the country of origin (where the manufacturer is located) with its respective registration numbers and dates (Product should be registered in domestic market licensed by state FDA from the same site). 
13. Two samples of the finished product in its original container. For Combination – A maximum of 3 is allowed for oral or injectable preparations. Four combinations are allowed only if the fourth ingredient is caffeine.

Technical Document Requirements

Quality documents vastly include Active Pharmaceutical Ingredient information, Formulation development details, Quality control of raw material, finished product manufacturing and quality control, Degradation profile, Packaging material description, and Finished product stability studies. In the case of drug registration in Brazil, several documents besides general technical documents are required.

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Specific registration documentation and required tests to be performed are as follows:

1. DCB (Common Brazilian Denomination) number has to be mentioned for each ingredient used in the formulation.
2. Brazil comes under climatic zone IVb, stability studies to be conducted as 30°C ± 2°C & 75 ±5% RH for long-term study and for accelerated stability study 40°C ± 2°C & 75% ±5% RH for 12 and 6 months, respectively, in case if stability batch fails here, study can be done for 30°C ±2°C & 65% ±5% RH.
3. As per ANVISA guidelines method validation should be performed by three-time independent sampling at manufacturing sites and results to be attached in a triplicate manner for both API and finished product. Following to this in the Batch analysis part Identification test must be performed for each container of raw materials of all batches including API and excipients. Three copies of Certificate of Analysis for drug substance from supplier and product manufacturer and finished product Certificate of Analysis signed by authority with name and date in block letters.
4. The final yield of any finished product batch must not be less than 90%.
5. In AMV, a reference standard has to be used, and if not available then a working standard with its characterization is required. Linearity has to be performed in triplicate for each level in Analytical Method Validation.
6. For a drug product stability study of the finished product for each strength in the primary pack for three batches is required as per ICH climatic Zone IVb for Accelerated and Long-term stability study. Release and shelf life specifications for at least three stability batches should be tested for the polymorphic form to confirm that there is no change in the polymorphic form stated by ANVISA. 

• While submitting a Pharmaceutical development report, a dissolution development report will need to be attached as per ANVISA guidelines. Incompatibility part control strategy and Product Lifecycle Management and continuous improvement are added. As per RDC 31/2010 of Pharmaceutical equivalence studies by ANVISA Comparative Dissolution Profile has to be performed. A photostability study for the API and finished product also performed for at least three batches.

Clinical Study Reports

Clinical study reports are submitted in Module 5, and must be conducted at ANVISA-certified centers, using a Brazilian reference drug. Bioequivalence studies are also mandatory.

Registration Time and Fees

Drug approval timelines in Brazil are generally longer than in other Latin American countries. The process takes 12-14 months for new medicines/originator drugs, 6-8 months for generic drugs, and 8-12 months for similar products. Fees vary depending on the product and manufacturer size, ranging from USD 2,700 to USD 27,000 for originator drugs and around USD 7,000 for similar products.

Drug Labeling

In Brazil, similar requirements apply to prescription drug and OTC formulations. During the registration process, drug labels for registering drugs should be submitted and preclearance is required as part of the procedure. The product label should not contain any designs, figures, geographical names, symbols or other indications that may mislead indicated on the label or in advertisements. Additionally, any modification on the medicine label after registration is actionable and leads to the cancellation of the registration.

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The details that should be printed on the package label include the Name of formulation (Generic/ Trademark), Pharmaceutical form, Number of units packed, Active Ingredients, Quantitative composition formula of product, Details of manufacturer, Responsible pharmacist, Date of issue, and product license number, Manufacturing and expiry date, Batch number, in case of prescription medicine “Prescription only” indications, Storage, Side effects and Precautions (if applicable).

It is not compulsory to include Pack inserts for all the products, but in case company wants to include a package insert, it should have approved well in advance. Pack inserts/Leaflets are generally physician-oriented. After approval changes in inserts must be submitted for assessment along with its technical justification for the suggested change.

The language used in product's final packing (on blister & carton) must be Portuguese with Braille embossing.

Registration Procedure

Dossier Evaluation Process

Regulatory Challenges for Drug Registration

Although the submission format follows the Common Technical Document (CTD), ANVISA imposes several complex, country-specific requirements for drug product registration in both the administrative and quality sections. The Certificate of Pharmaceutical Product (CoPP) must be legalized by the Brazilian embassy. Both the API supplier and manufacturer must have their manufacturing sites inspected and certified by ANVISA.

The product being submitted must also be registered in the domestic market from the same site, with a product license from the local FDA. As per ANVISA guidelines, identification tests must be performed by testing raw material samples from each container of both API and excipients. If the API claims a polymorphic form, the stability of the finished product and API must be tested using X-ray powder Diffraction patterns. The release and shelf-life specifications of at least three stability batches should also be tested to confirm no change in the polymorphic form.

ANVISA requires that analytical method validation be conducted only at the manufacturing site for both the API and the finished product. Additionally, the Dissolution Development Report must be included in the product development section, per Brazilian guidelines. For generic drug registration, applicants must send samples to Brazilian authorities for pharmaceutical equivalence testing. A comparative dissolution profile must be conducted using Brazil’s reference drug, following RDC 31/2010 (ANVISA guidelines), and tested at a laboratory in Brazil. Once the tests are passed, the analytical method validation and bioequivalence studies must be performed in ANVISA-certified centers. Furthermore, the price of the generic drug should not exceed 65% of the reference drug's price. ANVISA also recommends conducting a photostability study of both the API and the finished product for all strengths of three batches, per Brazilian regulations.

A stability study of the finished product in the primary packaging for three batches is required under ICH climatic zone IVb conditions, with accelerated and long-term studies. If applicable, a genotoxic impurity study must be performed by the API supplier. Moreover, linearity, accuracy, and photostability data should be provided in triplicate. Three copies of the Certificate of Analysis from both the API supplier and the finished product manufacturer, signed by an authorized person with their name in block letters and the date, must be included. Validation studies for ANVISA must be conducted at the manufacturing site. For assay studies, five points between 80% and 120% must be used, and the study should be performed in triplicate. Degradation products exceeding the identification threshold but below the qualification threshold must be identified, with RDC 58 data (including chemical structure information) provided. Characterization test data for the working standard used must also be included. Pharmaceutical equivalence and comparative dissolution profile studies must be conducted in REBLAS (ANVISA-approved analytical laboratories). The bioequivalence study must be performed in an ANVISA-approved laboratory, following the recommendations in the BE lists, and only after successful PE/CDP study results.

Additionally, the bioequivalence study must use the same batch samples, and if the product is already commercialized, samples must be collected from the Brazilian market. The BE study must be repeated for any site addition or product variation involving a modified drug release profile. Finished product samples required for registration must be sent to Brazil with an import permit. The Certificate of Analysis should be signed by an authorized person, with their name in capital letters and the date.

It is also important to note that the ANVISA website (www.anvisa.gov.br) is primarily in Portuguese and does not always contain the latest laws or summarized guidelines for easy reference. Sometimes, only selected parts of laws are repealed, while others remain in effect. Therefore, applicants must stay updated through the National Official Gazette, where laws, decrees, and resolutions are published, or through private companies that provide regulatory guidance. All prepared dossiers and documents must be translated into Portuguese and physically submitted in Brasilia, the capital of Brazil, adding to the overall complexity of the submission process. Additionally, many ANVISA employees return to their hometowns due to difficulties adapting to a new city, which can significantly delay the drug review process—sometimes taking up to two years—greatly impacting the applicant company's business. Furthermore, ANVISA uses a comparative pricing criterion, ensuring that the price of the drug cannot exceed the lowest price at which it is sold in countries like Australia, Canada, France, Greece, Italy, New Zealand, Portugal, Spain, and the U.S., or the manufacturer's price in the product’s country of origin. Consequently, companies may choose not to commercialize a registered medicine if the assigned price is non-competitive.

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