The EMA has released a revision to the Guideline on stability testing for applications for variations to a marketing authorisation (EMA/CHMP/QWP/441071/2011-Rev.3), coming into effect on 15 January 2026.
This is a critical update for anyone managing post-approval changes for chemical or herbal medicinal products.
Key Focus and Scope
Goal: To outline the stability data that needs to be generated when applying for variations.
Applicable To: Chemical active substances and related finished products, herbal substances, herbal preparations, and related herbal medicinal products.
Not Applicable To: Radiopharmaceuticals, biologicals/immunologicals, and products derived from biotechnology.
Guidance Type: It offers general guidance for Type IA and Type IB variations and specifies data requirements for common TypeII variations.
General Requirements
Duration of Studies:
Stability studies for variations must continue up to the approved shelf-life/retest period.
Monitoring:
Authorities must be informed immediately if any stability problems appear during storage.
Design Basis:
The scope and design of stability studies are based on the knowledge and experience acquired of the active substances and finished products.
Comparison:
Stability results of the varied product (using long-term and accelerated testing) should be compared to the unchanged product to ensure the change does not negatively impact the stability profile.
"Stable Active Substance" Definition (Annex I):
An active substance is considered stable if it remains within initial specifications when stored at:
- 25C/60% RH or 30C/65% RH (2 years)
- 40C/75% RH (6 months)
Specific Type II Variation Requirements (General Example)
The guideline specifies data for common Type II variations (Section 6), generally recommending:
- For Conventional Dosage Forms (Active Substance Stable):
- 6 months of comparative stability data (long term and accelerated testing) on at least two batches of at least pilot scale.
- For Critical Dosage Forms (Active Substance Unstable):
- 6 months of comparative stability data (on at least three primary batches).
Commitment Batches
Type IA and IB Variations:
Adequate follow-up studies on commitment batches are necessary.
Type II Variations:
At least the first production-scale batch manufactured after the variation must be placed on the long-term stability testing protocol and studies must continue to cover the entire shelf life.
Make sure your change control procedures and documentation are updated to reflect the new requirements, especially for Type II submissions.
Review the definition of a "stable active substance" in Annex I to correctly classify the required batch sizes.
