ANVISA updates requirements for forced degradation studies and impurity parameters in synthetic and semi-synthetic medicines

On February 24, 2025, the Brazilian Health Regulatory Agency (ANVISA) published Collegiate Board Resolution (RDC) No. 964/25, which establishes the general requirements for conducting forced degradation studies (stress testing) in medicines containing synthetic and semi-synthetic active pharmaceutical ingredients (APIs).

In its sole exhibit, the resolution defines the limits for notifying, identifying, and qualifying impurities in these medicines, which apply to:

• Marketing authorization applications, regularization, inclusion of new concentration or new pharmaceutical form of these medicines.
• Changes in the composition of these medicines, such as including new excipients or significantly changing API and excipient proportions.
• Changes that impact the impurity profile, if they generate a new impurity that must be monitored.

The resolution does not apply to isolated APIs, isolated excipients, medicines used in clinical study development, or medicines containing exclusively biological/biotechnological APIs, peptides, oligonucleotides, opotherapeutic fermentation products, vitamins, minerals, amino acids, proteins and inorganic compounds, semi-synthetic APIs derived from fermentation products, radiopharmaceuticals, plant APIs, dynamized APIs, and other atypical APIs.

The resolution, which was the object of a Regulatory Impact Analysis (RIA) published in July 2023, seeks to:

• Improve the wording and technical content of the norm;
• Update concepts and definitions;
• Reduce the number of studies required for impurity qualification; and
• Align the criteria for conducting forced degradation studies with the international guidelines on the subject, such as the guidelines of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

Additionally, ANVISA will update the technical manual with more instructions on practical aspects of conducting studies, requirements on the analysis method, interpretation of results, among others.

What is forced degradation in medicines?

Forced degradation is a test that subjects medicines to stress conditions to identify potential impurities resulting from chemical alterations of the API that may arise during the manufacturing and/or storage of the medicine.

Furthermore, the forced degradation study aims to assist in validating the stability-indicating power of the analytical procedure used by exposing the API or finished product to stress conditions (e.g., light, heat, or humidity, among others).

Forced degradation study criteria

Among other provisions, the new RDC waives the requirement for placebo studies and for conducting liquid-phase tests for solid-phase medicines.

The forced degradation study must address the following experimental conditions for APIs and the finished product:

• Liquid phase: In this phase, the API or finished product is solubilized or dispersed in a liquid medium before exposure to a degrading agent and/or degradation condition. The degrading agents in this phase include acid; base, oxidant, auto-oxidation, peroxidation, and oxidation catalyzed by transition metals.
• Original phase: In this phase, the API or finished product is directly exposed to the degrading agent and/or degradation condition, without prior solubilization or dispersion. The degrading agents in this phase include heating, humidity, ultraviolet and visible light, according to the light source requirements in the ICH Q1B guide.

The company must provide a technical rationale if any of the listed conditions cannot be employed due to inherent sample characteristics, physicochemical properties, results of previous studies, or other scientific considerations.

For medicines in solid form, liquid phase studies of the finished product may be waived, provided that the studies conducted are adequate to demonstrate the stability-indicating power of the method with:

• APIs in liquid and original phases; and
• The medicine in the original phase.

The RDC came into effect on February 24, 2025, and repealed:

• RDC No. 53/15, which provides for the parameters for notifying, identifying and qualifying degradation products in medicines with synthetic and semi-synthetic active substances, classified as new, generic, and similar, among other provisions.
• RDC No. 171/17, which reviews the applicability of RDC No. 53/15 to post-approval changes and the deadlines of this resolution for authorized products.

Until February 24, 2027, companies may submit studies that comply with RDC No. 53/15, which will be accepted by ANVISA.