During method validation, the FDA expects forced degradation studies to be conducted to assess the stability-indicating capability of the analytical method. These studies involve subjecting the drug substance or product to various stress conditions (e.g., heat, light (Day and UV light), acid/base hydrolysis, oxidation) to induce degradation.
By monitoring changes under these conditions, the method’s ability to separate, detect, and quantify the drug and its degradation products should be demonstrated.
This ensures that the analytical method is suitable for accurately determining the drug’s stability over time and provides valuable information for formulation and storage recommendations during product manufacturing and its life cycle storage.
Here are key steps to ensure a successful study:
Clearly define the study objectives, such as assessing method specificity, identifying degradation products, knowing degradation pathways, evaluating the stability-indicating capability of the method, etc.
Select Stress Conditions:
Choose stress conditions relevant to the drug substance or product, including factors like temperature, humidity, light, pH (acidic and alkaline), and oxidation to mimic product stability and storage.
Generally, FDA expects 10% to 30% degradation from the Forced Degradation Study. Hence, control of environmental and chemical conditions is very important.
Prepare samples for each stress condition using a representative drug substance or product. Follow appropriate dilution or extraction methods to ensure the detection of low levels of degradation products.
Select final samples that represent the drug substance or product in its final state (final process or formula) for FD study. Analyze unexposed samples for comparison purposes.
Use suitable analytical techniques (e.g., HPLC, GC, Spectroscopy) to monitor degradation (mostly HPLC with PDA detector and some time Mass detector are used).
Evaluate the data to identify and characterize degradation products. Determine the extent of degradation and the conditions under which it occurs. Report the mass balance.
Validate the analytical method using the data obtained from forced degradation studies.
Adhere to relevant regulatory guidelines (e.g., ICH Q1A) and document how the study aligns with these guidelines. This is essential for regulatory submissions.
From forced degradation study, draw the following conclusion with scientific justification:
a. Stability-indicating characteristics of the proposed method,
b. % Degradation achieved,
c. Degradation pathway,
d. Active compound sensitivity to any environmental or chemical condition.