14/15 April 2021
Which stability data must be submitted in the context of an application for variations regarding marketing authorisations in the EU? A new EMA Guideline entitled "Guideline on stability testing for applications for variations to a marketing authorisation" (EMA/CHMP/CVMP/QWP/441071/2011-Rev.2) provides information about the topic. This Guideline was published on 9 April 2014 on the EMA's News page with the hint "adopted" and will become applicable as of July 2014. It replaces the current "Guideline on stability testing for applications for variations to a marketing authorisation" from 2005 and is meant as extension of the "Guideline on stability testing of existing active substances and related finished products" (CPMP/QWP/122/02, rev 1 corr).
The new Guideline contains detailed variations scenarios for Type II variations and the stability data to be respectively submitted. For Type I variations, the text refers to the provisions laid down in the "Guidelines on the details of the various categories of variations..." which sufficiently specify the requirements with regard to stability studies. For certain and rather frequent Type II Variations facts, no precise indications had existed - neither in the "Various Categories" Guideline nor in the Guideline "Stability testing of existing active substances and related finished products"; that's why the new document represents a significant supplement to both regulations named above.
The following Type II variations are described:
In most of the scenarios named, the following stability data must be submitted: long term and accelerated conditions of 6 months; at least two batches of the finished product should be of at least pilot scale. Three pilot batches are partly necessary - i.e. for active substances known to be unstable.
The Annex I of the Guideline concretely defines the term "stability": An active substance is considered as stable if it is within the initial specifications when stored at 25°C/ 60 % RH or 30°C/65% RH, respectively, (2 years) and 40°C/75 % RH (6 months).
Annex II sets the rules to the postponement of the expiry date of the medicinal product and the extension of the retest period of the active substance in those cases where favourable real time data are available. Extrapolation will be acceptable and the shelf life of the medicinal product / the retest period of the active substance may be extended beyond the end of real time studies - however not more than 12 months.
The Guideline applies to chemical active substances and related finished products as well as APIs, preparations and herbal medicinal products. Radiopharmaceuticals, biologicals/immunologicals and products derived from biotechnology are not included in the scope of this document.