This is the third 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 focused specifically on Brazil. This part provides more detail regarding Mexico, Argentina, Colombia, and Peru.

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 CMC regulatory challenges Latin America. Below are her analyses of the challenges and opportunities in Mexico, Argentina, Colombia, and Peru.

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

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Mexico

COFEPRIS serves as the Mexican regulatory authority. It was founded in 2001. In terms of CMC requirements, it is a complex agency (Figure 1).

FIGURE 1 | Overview of COFEPRIS
FIGURE 1 | Overview of COFEPRIS

“I would call the level of activity medium, although recently Mexico has released some important regulations,” Gaban commented. “But comparing it to the other agencies, COFEPRIS is not that active in terms of creating new draft or final regulations.”

Activity is measured by the volume of draft and final regulations a health authority promulgates and its frequency of interactions with trade associations and the drug companies it regulates, she explained.

Country-Specific Requirements

Regarding critical or country-specific requirements, there are presubmission meetings that occur in the country with the submission beforehand of an extensive amount of specific data:

  • Supporting data for facility information regarding the company’s supply chain
  • Stability data for all approved supply chains, including bill of materials (BOMs), full analytical raw data such as chromatograms, lab records, analytical results, and calculations for all stability tests; this must include time zero and the final timepoint
  • Certificates of Analysis (CoAs) for all drug substances, drug products, excipients, and packaging materials associated with the stability batches

In addition, there is a specific requirement in Mexico to submit batch genealogy.

Also required are GMP certificates for all sites involved in the supply chain. These must be valid during the whole lifecycle until the last product batch expiration date.

COFEPRIS requires validation reports with “wet signatures”—as opposed to electronic signatures—that include analytical, process, and transport exercises.

Approval time for new products is between 12 and 18 months. For approval of variations, it takes between 12 and 24 months.

Gaban also commented on some changes that have taken place in COFEPRIS since the election of Andrés Manuel López Obrador as President in late 2018.

 “There was a change in the government in Mexico and some of the procedures there, such as the presubmission meetings, are not happening as they did in the past,” Gaban explained. “At our company, we are struggling to get this meeting with COFEPRIS. We will have to see how this goes because the presubmission meetings are mandatory by their regulations and those meetings are not happening.”

Argentina

In Argentina, the regulatory agency is ANMAT, founded in 1992. The regulatory complexity and regulatory activity are considered medium (Figure 2).

FIGURE 2 | Overview of ANMAT
FIGURE 2 | Overview of ANMAT

Country-Specific Requirements

Some critical country-specific requirements here include the need for equivalence and bioequivalence studies for products that contain active pharmaceutical ingredients (APIs) considered as a significant health risk. ANMAT also requests raw data for stability studies.

Regulatory approval times are 12 to 18 months for small molecules and 24 months for vaccines and biologicals. Variations take six to 12 months for small molecules and six to 18 months for vaccines and biologicals.

ANMAT became an ICH observer member in 2019. It is a PIC/S member, “but is reluctant to accept inspection reports from other recognized agencies,” Gaban commented.

The regulation around post-approval changes for biologicals and vaccines using the EMA guidance as a basis is still under discussion, with “no significative progress” since 2018.

A new regulation published in 2019 covers authorization of commercialization to start the distribution and commercialization for biologic and vaccine products. A procedure was also published last year on how to request a waiver of bioequivalence demonstration.

 Finally, local QC testing is required for the commercialization of new drugs.

Colombia

Columbia’s regulatory agency is INVIMA, founded in 1994. In terms of complexity and regulatory agency activity, it can be characterized as medium (Figure 3).

FIGURE 3 | Overview of INVIMA
FIGURE 3 | Overview of INVIMA

Country-Specific Requirements

Analytical compendial method information is required in the Common Technical Document (CTD) format.

“If you do not include a description of the compendial information there, you must provide a copy of the pharmacopeia,” the Merck director explained. “This brings complexity because you cannot just reference the pharmacopeia. This is especially difficult for vaccines and biological products.”

Average approval timelines for new products is two-and-a-half years or one-and-a-half years with onsite CMC review for small molecules, “but this was before the release of a new guidance that says new applications can be reviewed in parallel,” Gaban pointed out. In the past, INVIMA had a process in which the company would initially file the clinical data. Then after the clearance, and review, and approval of the clinical data, the other parts of the dossier could be filed.

“At the end of last year, the regulation was changed such that a company now can file the whole thing together,” Gaban said. “As a result, hopefully, the approval timelines will improve for Colombia.”

INVIMA does accept ICH-based approaches as an ICH observer.

Also, there is movement for generating a more regulated environment with regulation improvements.

Peru

In Peru the health authority is DIGEMID, founded in 1990. It is a high complexity agency in the terms of the documentation required for product approval. DIGEMID has numerous country-specific requirements, also some specific forms that must be used when filing a dossier. In terms of generating new draft or final regulations, DIGEMID is not highly active (Figure 4).

FIGURE 4 | Overview of DIGEMID
FIGURE 4 | Overview of DIGEMID

Country-Specific Requirements

There is a lot of information that is required that must be provided and signed off on by the drug product manufacturing site. There are also additional declarations for complementing legal documents for the local trade name, solvent quantity, and primary and secondary packaging sites. DIGEMID has a “High Surveillance Country Declaration” for cases where the company uses in-house specs instead of compendial monographs.

Approval times are 12 to 18 months for new products and six to eight months for variations.

New regulations for small molecules have been released for new product registrations. Once the new products are approved by a high surveillance country such as the United States or the European Union, reduced requirements could be acceptable. It is not a formal reliance pathway, but there are some paths to decrease the timeline and to guide the regulatory approval there.

For biologicals and vaccines, full modules 2.3 and 3 are required according to ICH M4Q. For small molecules, only a few CTD sections are acceptable as is—they need to be put into specific formats.

“DIGEMID does not accept commitments,” Gaban explained. “It will issue only one official deficiency letter with a 30-day deadline, which is not extendable. If the response is not accepted by the health authority, the submission is denied.”

[Editor’s Note: Don’t forget to read Parts I and II of this series on CMC requirements in Latin American countries.]

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

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