ICH releases overhauled stability guideline for consultation

The International Council for Harmonisation (ICH) on 17 April issued its long-awaited update of its Q1 guideline on stability testing of drug substances and drug products. The new guideline consolidates the existing five stability guidelines into one and addresses new topics such as stability considerations for advanced therapies, bracketing and matrixing, stability modeling, and stability considerations for reference materials and novel excipients.

This document has been signed off as a Step 2 document and has now been issued to regulators to be released for public consultation. The guideline “should be considered in its entirety for a comprehensive approach to stability studies,” according to a Step 2 informational presentation released with the guideline.

The draft completely rewrites the previous Q1A(R2) guidance issued in August 2003. Due to the consolidation of guidances and the inclusion of new information, it is five times longer than the original.

In 2023, a pharmaceutical official from Amgen presaged the changes at DIA Europe, saying that stakeholders should to expect “substantial” revisions of the ICH Q1A-Q1E suite of guidelines on stability testing as well as the Q6A and Q6B guidelines on setting specifications; these revisions were prompted by members of the ICH Quality Discussion Group (QDG), which identified stability and specification topics as the “highest priorities” for a majority of their members in November 2020 (RELATED: Pharma official: Expect “substantial” revision of ICH stability and specification guidelines, Regulatory Focus, 27 March 2023).

According to a concept paper, the current versions of ICH Q1A through E and ICH Q5 C on stability testing of biological products “do not align with the format of more recently developed ICH guidelines that embrace a harmonised core document approach supported by topic-specific annexes/appendices.”

This format also “leads to interpretation of the guidelines on an individual basis, with uncertainty around how they should work together. ICH Q5C, for example, is specific to stability of biotechnological/biological products and it is often unclear which chapters of the ICH Q1 series apply to biologics as well.”

The original Q1A guideline was first adopted in 1993 and was one of the first guidelines to be finalized at ICH. In the early 2000s, the guideline was revised, and supplementary guidelines covering additional areas such as Q1B, Q1C, Q1D, Q1E, and Q1F were developed.

The guidelines span 108 pages and are divided into 18 sections and three annexes.

Section 1 serves as an introduction, outlining the purpose of the guideline and explaining how its structure differs from existing stability guidelines.

Section 2 focuses on the development of stability studies conducted under stressed and forced conditions. It aims to consolidate the content related to stressed stability and forced degradation that is currently found in ICH Q1A and ICH Q5C.

Sections 3-7 focus on the protocol design for formal stability studies, selecting batches, the container closure system, testing frequency, and storage conditions. “These sections combine, align, clarify, and modernise content from ICH Q1A and ICH Q5C for primary stability studies,” according to the ICH presentation.

Sections 8-11 discuss stability studies that complement the primary stability study, including photostability testing, processing and holding conditions for intermediates, short-term storage conditions, and in-use stability studies.

Section 12 is a new addition that addresses stability considerations for reference materials, novel excipients, and adjuvants. The guidance highlights that “novel excipients and adjuvants are discussed due to their significant potential impact on the quality of the drug product.”

Section 13 covers the evaluation of data and introduces a new section on statistical evaluations. Section 14 pertains to labeling and storage statements resulting from stability studies, while Section 15 discusses stability lifecycle management.

Annex 1 addresses bracketing and matrixing currently captured in ICH Q1D.

Annex 2 provides guidance on stability modelling. This section includes guidance currently provided in ICH Q1E.

Annex 3 provides stability guidance on ATMPs, which are new to ICH. This annex is not meant to be a “stand-alone guideline for ATMPs,” according to the presentation.

Guideline; Step 2 Presentation

ICH releases overhauled stability guideline for consultation

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