New EMA Guideline on Stability Testing for Applications for Variations

Recommendation

20/21 February 2024
Munich, Germany

GMP meets Regulatory Affairs
Applying for and maintaining marketing authorisations: What you need to know from a GMP perspective

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:

• Change in the manufacturer of a starting material / reagent / intermediate used in the manufacturing process of the API or change in the manufacturer of the active substance
• Changes in the manufacturing process of the API; other geographical source of the herbal active substance
• Changes in immediate packaging of the active substance
• Changes in the composition of the excipients in the finished product
• Changes in coating weight of oral dosage forms or change in weight of capsule shells
• Change in concentration of a single-dose, total use parenteral product, where the amount of the active substance per unit dose remains the same
• Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product
• Change in the manufacturing process of the finished product (..) that may have a significant impact on the quality, safety and efficacy of the medicinal product
• Introduction of a non-standard terminal sterilisation method in the manufacturing process of the finished product
• Introduction or increase in the overage that is used for the active substance
• Change in the batch size of the finished product
• Change in immediate packaging of the finished product
• Change in shape or dimensions of the container or closure (immediate packaging) of the finished product
• Change in pack size of the finished product

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.