ICH M4Q(R2): Key Changes to CTD Quality Modules 2.3 and 3
Major changes are planned for the structure of Common Technical Documents (CTD), Quality overall Summaries (Module 2.3) and Quality (Module 3).
The ICH harmonized guideline M4Q(R2) was signed off in May 2025, as a new step in improving the organisation and presentation of quality information. It should be adopted in its final form in June 2027, and come into effect at a later date. It was the object of a public consultation up to the end of October 2025 (24 October in Europe, 26 October in the UK).
In 2002, introduction of the Quality – M4Q(R1) guidelines on the CTD harmonized the format of quality information between different regions, for the registration of pharmaceuticals for human use. This offered great benefits to industry, regulators, patients, and consumers compared to the prior state with multiple regional submission formats.
The aim of the M4Q(R2) update is to align with modern quality guidelines (ICH Q8-Q14), and other ICH guidelines that have been developed or given greater focus since the issuance of ICH M4Q(R1). In particular, The M4Q(R2) guideline aims to provide guidance on the location of information supporting multicomponent and/or complex products, such as antibody-drug conjugates, vaccines, ATMPs/Cell & Gene Therapies & Tissue Engineered Products or combination products that meet the definition of a pharmaceutical or biological product.
The structure of the CTD Mod 2.3 and Mod 3 has therefore been re-organised (Figure 1), to better capture the information on the pharmaceutical development and the proposed overall control strategy and to provide a suitable format for easy access, analysis, and knowledge management. M4Q(R2) establishes Mod 2.3 as the basis for regulatory assessment, presenting the overall development, the overall control strategy, and the justifications. This is supported by the body of data provided in Mod 3.
Figure 1: M4Q(R2) guideline: Mod 2.3 and Mod 3 Structure overview
In the current CTD format according to M4Q(R1), the information is divided into sections presenting information and data first for the drug substance(s), and then the drug product(s). These sections are then divided into subsections relating to the different points of development (manufacture, characterisation, control of materials, reference standards etc).
According to M4Q(R2), this organisation of the information has been reshuffled, with the main sections presenting a more holistic view of the quality aspects and development processes. The sections are further divided in subsections focusing on the drug substance(s), drug product(s), intermediates, starting materials, excipients etc.
A further level of granularity in these subsections aims to create a standardised way of presenting quality information across the whole dossier, to support efficient information management and retrieval. This DMCS model (Description, Manufacture, Control, Storage) is used for both Mod 2.3 and Mod 3 (Table 1).
Table 1: the DMCS model: a standardised approach to structure Mod 2.3 and Mod 3
Therefore, the new Mod 2.3., instead of being populated with the juxtaposition of summaries copied from Mod 3, will now capture the overall regulatory narrative, including relevant manufacturing process information, overall control strategy, and lifecycle management tools. At top level, Mod 2.3 will contain the following sections:
CTD Mod 2.3 | ||
2.3.1 | General Information |
|
2.3.2 | Overall Development and Overall Control Strategy | Overall development strategy should provide a concise overview of the development rationale, highlighting the pivotal decisions made to achieve intended quality.
Overall control strategy should provide a comprehensive presentation of measures taken to ensure overall product quality, rather than being a simple compilation of individual controls without consideration of their significance in assuring quality. |
2.3.3 | Core Quality Information | This section should include all information related to what the material is and it key characteristics, which is considered necessary to enable Marketing Authorisation and facilitate lifecycle management. This section is organized in subsections for drug substances, substance intermediates, starting materials, excipients, reference standards, drug products, product intermediates, analytical procedures… These subsections are further organized following the DMCS model (Figure 2). |
2.3.4 | Development Summary and Justification | This section should describe how the drug substance and product, their components (if applicable), and manufacturing process were developed, including the main choices made throughout the development. Scientific and risk-based justifications should be presented, including discussion of the proposed commercial process and control strategy. The subsections format in section 2.3.4 follows the DMCS model and is aligned with the subsections in section 2.3.3 (Figure 3). |
2.3.5 | Product Lifecycle Management | Should include a change summary and justification for post-approval change submissions |
2.3.6 | Product Quality Benefit Risk (Optional) | This section can be used to support the overall benefit risk assessment. It allows the Sponsor to contextualize quality risks in relation to patient risks, which can be particularly beneficial in situations such as accelerated development pathways |
Figure 2: Example of DMCS model for Section 2.3.3 DP Drug Product
Figure 3: Example of DMCS model for Section 2.3.4 DP Drug Product
Figure 4: Example of DMCS model for Section 3.2.Body of Data
The organisation of Mod 3 has also been redesigned, to serve as a technical repository for detailed descriptions of analytical procedures, data, and other relevant quality information that supports Mod 2.3. The presentation format of Mod 3 is aligned with the format of Mod 2.3, and follows the DMCS model (Figure 4). The clear separation of the supportive content (Mod 3) from the core quality information (Mod 2.3), together with the new flexible modular structure of Mod 3, will help to minimize duplication and to manage information updates during the lifecycle of the product.
In conclusion, the guideline M4Q(R2) represents ICH’s effort to modernize the organisation of the CTD quality sections, in line with the standards established by the International Organisation for Standardisation (ISO) -identification of medicinal products (IDMP). The quality information will now be presented in a modular fashion, into consistent and reusable components better designed to support digitalisation, and compatible with eCTD v4.0. The new content of Mod 2.3 and Mod 3 should establish a clear separation of core information (Mod 2.3) and supportive content (Mod 3), helping to reduce duplication. Therefore, this new format should allow for a more streamlined presentation of all pharmaceutical drug substances and products, both chemical and biological, and facilitate the incorporation of concepts and data aligned with the currently recognised international standards and guidelines.
Next Steps and Expert guidance
We are awaiting further details on the workshops scheduled for 2025/2026, as well as additional guidance on implementing the new structure. Clearer information on the transition period is also essential to support effective planning and ensure regulatory compliance.
At Boyds, we are ready to assist clients in preparing for this significant shift in the structuring of quality data. Our experienced team can carry out a thorough gap analysis of your current data package to identify areas that may require enhancement or alignment with emerging standards.
Contact us today and let Boyds help you successfully navigate these changes with confidence and efficiency.
Celine Courtay-Cahen
Senior Manager, Regulatory Affairs
Meet the author
Dr Céline Courtay-Cahen is a highly knowledgeable regulatory affairs professional with over 10 years’ experience as a Regulatory Consultant, co-ordinating and managing projects on behalf of clients. With a PhD in Pharmacology specialising in cancer genomics. She provides operational support and strategic advice ranging from orphan drug designations to marketing applications, including early development support (PRIME in EU; Fast Track and Breakthrough in the US), clinical trials, and scientific advice. She has particular expertise in advanced therapy medicinal products (ATMPs) and biologics in both the US and Europe, and a special interest in live biotherapeutic products.