ICH M4Q(R2): How the CTD Quality Module Is Changing

ICH M4Q(R2) is the first substantial revision of the Quality Module of the Common Technical Document (CTD) in more than twenty years: it changes the format on which the registration dossiers of all human medicinal products are built. The draft, published at Step 2b of the ICH process in mid-2025 and now being finalised after public consultation, deeply redesigns Module 2.3 and Module 3, relocates the information used for regulatory assessment and embeds the concepts that ICH guidelines Q8 through Q14 have introduced over the last two decades. In this guide we look at what actually changes, where the revision stands and how QA and Regulatory Affairs can prepare without waiting until the last minute.

ICH M4Q(R2): why the CTD Quality format changes after twenty years

The M4Q(R1) format was implemented in 2003 and has not been substantially revised since. Meanwhile the ICH framework has changed radically: Q8 introduced Quality by Design and the design space, Q9 quality risk management, Q10 the pharmaceutical quality system, Q12 lifecycle management with established conditions, Q13 continuous manufacturing and Q14 the analytical procedure lifecycle. None of these concepts has a natural home in the current dossier structure.

Two further pressures add to this: increasingly complex product types (biologicals, multi-constituent products, drug-device combinations, ATMPs) and the digitalisation of submissions, which calls for structured, machine-readable data rather than monolithic documents. The declared objective of the revision is therefore threefold: improving registration and lifecycle management efficiency, facilitating digitalisation, and ensuring compatibility with recent ICH guidelines and with new product types and technologies.

Where the revision stands: dates and next steps

For planning purposes it helps to pin down the milestones already known:

• The draft guideline reached Step 2b of the ICH process, with the document dated 14 May 2025.
• EMA published the draft for consultation on 25 June 2025, collecting comments until 24 October 2025.
• In February 2026 EMA published the overview of comments received from European stakeholders.
• Adoption at Step 4 is expected once the comments have been assessed; there is no official date yet, and until adoption and subsequent regional implementation the operational reference remains M4Q(R1).

ICH revisions move in long stages, but those who discover them at Step 4 end up chasing. With The Pragmatic GMP, GuideGxP's free weekly newsletter, you follow the evolution of M4Q(R2) and other regulatory developments with updates already translated into operational actions: subscribe and be ready for the next deadline.

Module 2.3: from summary to home of the assessment

The most radical change concerns the role of Module 2.3. Today the Quality Overall Summary is a recap of what sits in Module 3; under the M4Q(R2) proposal, the information that forms the basis of the regulatory assessment moves into Module 2.3, while Module 3 becomes a repository of supporting technical data. The new Module 2.3 is organised into six sections:

• 2.3.1 General Information – general information on substance and product;
• 2.3.2 Overall Development and Overall Control Strategy – QTPP, critical quality attributes and the overall control strategy;
• 2.3.3 Core Quality Information (CQI) – the heart of the dossier: all information subject to lifecycle management in accordance with regional requirements for post-approval changes;
• 2.3.4 Development Summary and Justification – development summaries and justifications;
• 2.3.5 Product Lifecycle Management – established conditions, PACMPs and lifecycle documentation in line with ICH Q12;
• 2.3.6 Product Quality Benefit Risk – the benefit-risk assessment from a quality perspective.

The key distinction is between the CQI, which explicitly defines the perimeter of the MAH's regulatory commitment, and supportive information (sections 2.3.1, 2.3.2, 2.3.4, 2.3.5, 2.3.6 and Module 3), which may be modified or supplemented in post-marketing submissions. For anyone managing variations, it is a much clearer map of what requires a notification and what does not.

Module 3: a technical repository organised by materials

Module 3 is reorganised too: instead of the classic split into S (substance) and P (product) sections, information is grouped by material categories, each with standard Description, Manufacture, Control and Storage subsections. The categories include drug substance, substance intermediates, raw materials, starting/source materials, excipients, reference standards, impurities, drug product, product intermediates, packaged medicinal product, pharmaceutical product and medical devices in combinations; analytical procedures and manufacturing facilities get dedicated sections.

What it means for QA and Regulatory Affairs

The operational consequences go beyond the regulatory team that assembles the dossier:

• Change management: with established conditions and PLCM an organic part of the dossier, internal change control will have to be explicitly mapped to the ECs, as ICH Q12 already envisages.
• Variation classification: the distinction between CQI and supportive information redraws the line between what requires a variation and what the MAH manages within its own quality system.
• Structured authoring: the granularity of the new format is designed for digital submissions and machine-readable data, consistent with eCTD 4.0 and with initiatives such as EMA's Structured Product Quality Submission: monolithic Word documents are on borrowed time.
• Broad scope: the guideline applies to all human medicinal products requiring a marketing authorisation, including biologicals, complex products, drug-device combinations and ATMPs.
• Expectations unchanged: what changes is where and how the information is presented, not the level of scientific evidence assessors require.

GuideGxP recommendation

There is no need, and no point, in rewriting dossiers today: the draft may still change before Step 4. It is worth using this time for three low-cost, high-return activities instead. First: take a representative dossier and try to classify its content into what would be Core Quality Information and what would be supportive information — the grey areas will surface immediately. Second: check how far your change control is already mapped to established conditions along Q12 lines, because M4Q(R2) will make that link structural. Third: assess the state of your authoring, because the move to structured, reusable content requires tools and habits that cannot be improvised close to the deadline.

If you want to consolidate your regulatory team's methods and processes, our Complete Guide to Regulatory Affairs in the Pharmaceutical Industry covers CTD/eCTD dossiers, variations and interaction with authorities with an operational, audit-ready approach.

Official sources

• EMA – ICH M4Q: The Common Technical Document, Quality (guideline page, Step 2b)
• EMA – ICH M4Q(R2) Guideline, draft Step 2b (PDF)
• ICH – Common Technical Document (CTD), official M4 page