On November 7, 2019, ANVISA published the Resolution RDC 318/2019, which defines the criteria for conducting stability studies of medicinal products and active pharmaceutical ingredients (APIs), except for biologicals, for the evaluation of results, and for the preparation of protocols and stability reports.

The stability studies of medicinal products and APIs to be marketed in Brazil should be performed whenever specific normative acts providing for registration or post-registration changes require them, and also in accordance with the parameters defined by the Resolution.

The defined parameters aim at a harmonization with the international ones, defined by the International Council for Harmonization (ICH). Thus, it is expected that the development of projects for medicines imported to Brazil will be facilitated.

Resolution RE 1/2005, Resolution RDC 45/2012, item 5.6.3 of RDC 8/2001, Normative Instruction 4/2007, and Service Guidelines (SG) 2/2013 and 1/2012 are revoked.

Check out the most important points of the new resolution:

Climatic conditions and packaging

Climatic conditions are maintained as zone IV b. Zone II conditions may be accepted for products intended for hospital use.

Studies should be performed on packaging intended for commercialization, including secondary packaging.

New concepts in Brazil

The Resolution defines the acceptance of reduced studies (by bracketing or matrixing), which should be evaluated with the same criteria as those used for a complete model study.

Follow-up Studies

Follow-up stability studies should be performed, and also be in accordance with good manufacturing practices regulations. Reports should be made available whenever requested by the health authority.

Follow-up stability studies should be performed according to the protocol approved in the registration or in the last post-registration change.

Bulk Products

Products imported and stored as bulk must have additional studies to ensure the maintenance of product quality until packaging.

Raw Data

For any study performed by the company, raw data must be archived and made available to the Authority upon request.

Presentation of studies

For regularization of APIs and registration of medicinal products containing APIs not yet registered in the country, the studies to be submitted should include at least 12 months of ongoing long-term studies results, accompanied by the full report of the completed accelerated study.

For APIs post-regularization petitions, medicinal products registration petitions containing APIs already registered in the country, and medicinal products post-registration applications, the studies to be submitted should include at least 6 months of ongoing long-term study results, as well as the full report of the completed accelerated study.

The presentation of a stability protocol is acceptable only if defined in the medicinal products post-registration regulation.

Marketing Authorization Holder (MAH) Responsibilities

In addition to presenting the documentation in ANVISA submissions, the company must keep on file, the protocols, reports and raw data for presenting to the health authority upon request.

If results are out of specification in already submitted studies, the MAH should investigate them. If the investigation is conclusive for an out-of-specification result, or if the investigation result is inconclusive, the MAH should notify ANVISA.

Special cases

Justification for exemption from compliance with requirements set out in RDC 318/2019 will be accepted provided that they are well founded.

The following may be justified as defined in the RDC:

• The permeability or impermeability of the packages, also depending on the form of the API or medicinal product.

• APIs and medicinal products which require storage conditions other than those defined in the Resolution will be evaluated on a case-by-case basis, provided that shelf life and feasible conditions are ensured.

Specific Studies

In each case, additional studies to long-term and accelerated ones should be performed:

• Post-reconstitution and / or dilution, to determine shelf life of medicinal products in use.

• In-use stability studies, for medicinal products packaged in multi-dose packages.

• Forced degradation studies for APIs and medicinal products (Note: this Resolution does not revoke RDC 53/2015, which mandates about forced degradation).

• Photostability studies for APIs and medicinal products.

Protocol and reports

The minimum information required for the preparation of protocol and stability report of APIs and medicinal products is defined, such as necessary tests and schedules and schedule and methods of sampling, batch selection and testing, among others.

Provisional shelf life

The provisional shelf life is determined from the long-term study time in progress, adding a maximum of 12 months to the last time point presented, provided that the accelerated study is completed, considering historical data and statistical analysis of the data.

Transience period

For medicinal products subject to simplified notification procedure, stability studies carried out in accordance with the previously in force regulation will be accepted under the following conditions:

• Studies completed prior to the publication of RDC 318/2019 and notification made within 6 months of its publication, that is, the maximum date for notification is May 6th, 2020.

• Study started before the date in which the RDC 318/2019 is in force, and notification made within 24 months from the beginning of the stability study, that is, in the worst case the maximum date for notification is November 6th, 2021.

• For medicinal products notified prior to the publication of RDC 318/2019, stability studies carried out in accordance with the previously in force regulation will be accepted provided that they are completed within 36 months of their publication, that is, in the worst case, completed by November 6th, 2022.

For medicinal products registration and post-registration submissions and API regularization or change procedures, stability studies conducted in accordance with the previously in force regulation will be accepted under the following conditions:

• For studies finalized prior to the publication of RDC 318/2019 and submissions filed within 6 months of its publication, that is, the maximum submission date is May 6th, 2020.

• For medicinal products post-registration changes or API post-regularization changes, with study initiated prior to publication of RDC 318/2019 and submission filed within 6 months after expiration date of the oldest study batch, considering the shelf life approved before the change.

• For medicinal product registration and API regularization, study started before the resolution and submission filed no more than 24 months from the beginning of the stability study, that is, worst case date for submission is November 6th, 2021.

A Document containing non-binding guidelines for conducting the studies has also been published. Follow the next publications with Vita.

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