This is the second part of a three-part story on CMC filing challenges and opportunities in Latin America. Part I provided an overview of the region. Part II focuses specifically on Brazil. Part III will provide more detail regarding Mexico, Argentina, Colombia, and Peru.

Brazil—the largest country in South America with the sixth largest population in the world—has a population with many unmet medical needs. Conversely, drug companies have experienced some difficulty accessing this market due to country-specific requirements that, in the past, have proven challenging to navigate.

Since becoming a member of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) in 2016, however, Brazil’s regulatory agency, ANVISA, has begun moving toward regulatory harmonization with international norms and standards.

At the FDA/Xavier PharmaLink conference held virtually in March 2020, Merck CMC Director and Senior Scientist Tatiana Gaban—who has led Merck’s CMC Latin America team based in Sao Paulo—provided an in-depth look at the changing CMC regulatory landscape in Brazil. Her talk included a more detailed look at what ANVISA’s membership in ICH means for drug companies hoping to get their products into the Brazilian market.

ANVISA was founded in 1999. Gaban characterizes it as “a complex agency in terms of the amount of documentation that is required from a CMC standpoint.” She also noted that ANVISA is highly active in terms of the volume of draft and final regulations it publishes and that it welcomes discussion and input on draft guidance documents.

“ANVISA has a very clear and established procedure to release draft and final regulations,” Gaban explained. “It is clear how companies can contribute, and how the information and suggestions are evaluated by the regulators is visible.”

Specific Product Registration Requirements

Brazil has specific requirements in its new drug submission process for product stability data and analytical method validation, among others (see Figure 1).

Overview of Brazil CMC Regulations

Figure 1 Overview of CMC Requirements in Brazil

Country-Specific Requirements

Stability studies must be conducted for Zone IVB (hot, higher humidity) with six months of accelerated stability and six months long-term stability to request a 24-month shelf life. No extrapolation is allowed, and specific studies are expected for each dosage form.

Also, there are specific requirements in terms of analytical validation. While it is becoming aligned with ICH, there are country-specific requirements as well.

Post-registration guidance is also specific with “a huge amount of data and details required that are not aligned with the CTD,” Gaban said.

For large molecules, there is a requirement to provide shipping qualification. ANVISA’s guideline for transport qualification of biological products explains the requirements for validating temperature-control procedures during shipping.

She also noted that ANVISA is highly active in terms of the volume of draft and final regulations it publishes

Average Approval Times

Average approval times are 15 to 18 months for drug products and 24 months for fixed-dose combinations. Variations take six to 14 months. A conditional approval pathway was established through regulation. “It may be granted if ANVISA does not initiate the review within the timelines established by law, after the submission. As a result, timelines have been improving,” Gaban pointed out.

Other Relevant Information

ANVISA became an ICH member in 2016, which means that its guidance must align with ICH over time. However, ANVISA will keep some country-specific requirements. The agency is evaluating the need to establish a balance between what is required at a local level and what is aligned with ICH. In addition, ANVISA has started the process of becoming a Pharmaceutical Inspection Cooperation Scheme (PIC/S) member. For this, it is currently at “Applicant” status.

The Common Technical Document (CTD) format has not been implemented yet, although the local Module 4 guidance is already in place and the agency has indicated that implementation is coming. There is no projected date.

Local release testing is mandatory for small molecules in Brazil. There are some specific guidelines and pathways established for rare diseases and priority submissions as defined by ANVISA.

ICH Implementation Status

ANVISA, like any agency that is approved for ICH membership, must adopt ICH guidelines in a phased approach, with three levels of adoption (see Figure 2).

ICH Implementation Plan for ANVISA

Figure 2 Guidelines for ICH Implementation in Brazil

To be eligible to join, ANVISA needed to revise its stability guidance in line with ICH Q1. In November 2019, it published new requirements for small molecule stability information to be provided in the dossier. There are some meetings occurring within the agency to discuss topics that are potentially not aligned with the ICH.

ANVISA became an ICH member in 2016, which means that its guidance must align with ICH over time

Regarding the status of CTD modules M2 and M4, ANVISA issued a guidance in August 2019. The adoption of the CTD format by applicants will not be mandatory in the beginning. ANVISA plans frequent dialogue with the industry via meetings and events to ensure effective adherence to the new format.

A mandatory adoption deadline will be defined that considers the needs of the industry; companies will also need to implement this guideline internally and the content needs to be harmonized and coordinated to ensure successful implementation. ANVISA plans to adopt the electronic CTD (eCTD) to ensure maximum benefit to CTD format adherence.

ANVISA is a member of the ICH Management Committee, which is the body that oversees operational aspects of ICH on behalf of all members, including administrative and financial matters and oversight of the Working Groups. ANVISA has issued several “calls for contribution” to ICH guidance and ICH review initiatives. This is an important initiative that allows Brazil-specific concerns to be discussed with ICH. A “Call for contributions” has been issued so far for:

  • ICH M10: Bioanalytical Method Validation
  • ICH Q3D (R1): Elemental Impurities
  • ICH M9: Biopharmaceutics Classification System-based Waivers

Next week, Part III will look at CMC requirements for Mexico, Argentina, Columbia, and Peru.

[RELATED: For information on the FDA Drug Review Process, check out our Checklist for interacting with FDA.]

Checklist: Interacting with FDA During Drug Review Process

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