Background
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has revised its pivotal quality guideline M4Q with the intention of establishing a globally harmonised framework for organising and presenting quality data for the registration of human medicinal products, which would ideally enable a single dossier to be maintained across countries or regions.
ICH M4Q(R2) ‘Guideline on the Common Technical Document for the registration of pharmaceuticals for human use: Quality’ is currently under public consultation following ICH member endorsement on 14 May 2025. It will be a major revision of the ICH M4Q(R1) guideline, which was originally published in 2002 and defined the structure for the Quality section of the Common Technical Document (CTD) for pharmaceutical registration, as Module 2.3 (Quality Overall Summary – QOS) and Module 3.2 (Body of Data).
The guidance looks to modernise and improve registration and life-cycle management efficiency, and will be applicable to both biological and chemical entities with the overall aim of accelerating patient access to medicines. This revised guideline reorganises Module 2.3 and 3.2 to a suitable format that is compatible with eCTD 4.0 for easy access, analysis, and knowledge management, which will minimise duplication, facilitate digital review, and support provisions for emerging and complex products. In addition, the revisions will align with the quality guidelines ICH Q8 to Q14.
Structure of Dossier
Under the reorganisation, Module 2.3 will serve as the basis for a science and risk-based regulatory assessment by providing a comprehensive overview of the product and core quality information, an understanding and justification of the product and manufacturing process and the post approval life-cycle management tools.
In contrast, Module 3.2 will become supportive and serve as a repository for detailed descriptions of analytical methods, analysis data, and other relevant quality information. Data in Module 3.2 will be linked directly to the high-level summaries in Module 2.3.
M4Q(R2) will introduce specific subsections to the dossier to align with ISO IDMP (Identification of Medicinal Products) standards; separating the product into the role of each component such as Drug Substance (DS), Raw Material (RM), Starting Material (SM), Excipient (EX), Drug Product (DP) etc. The information across each subsection will then be further organised using the standardised DMCS (Description, Manufacture, Control, Storage) model to streamline the information management and retrieval process:
- Description: Material identification and key characteristics
- Manufacture: Manufacturing process and process controls
- Control: Specifications, analytical procedures, validation
- Storage: Container closure system, stability, shelf-life and storage condition
An example of the relationships between Module 2.3 and Module 3.2 under the DMCS Model is presented below*:
| 2.3.3 Core Quality Information | 2.3.4 Development Summary and Justification | 3.2 Body of Data | |
| Information related to what the material is and its key characteristics, which is considered necessary to enable marketing authorization and facilitate lifecycle management. | Scientific and risk-based development summary and justifications related to what the material is and its key characteristics. | Supportive information including reports and data related to what the material is and its key characteristics. | |
| Description | Nomenclature, structure, composition, key characteristics | Characterization summary, formulation development and justification | Characterization data, formulation development and justification data |
| Manufacture | Manufacturing process description, IPCs, critical process parameters | Process development and validation/evaluation summary | Process development and validation/evaluation data |
| Control | Specifications | Overview of batch analysis, justification of specifications | Batch analysis and justification data |
| Storage | Container closure system description, storage conditions, and retest period/shelf life | Overview of stability studies, justification of proposed container closure system | Container closure selection and stability data |
Impact of Guideline
The current timelines indicate that the guideline will be adopted in June 2027, however, the plans beyond this are still to be established.
The implementation of the guideline is expected to have significant impact on both regulators and industry with regards to finance and resource and there is uncertainty within industry about how the transition will be applied.
Comments on the guideline received in Europe indicate that industry is concerned by both the lack of clarity regarding the timeline for transition to the new format, and whether the guideline will apply in full to established products. In addition, the comments received indicate that industry believes that the administrative cost and burden of updating a dossier to ICH M4Q will offer little benefit to the quality of established products but could have a significant impact on supply and availability of a medicine if the benefit-cost balance is affected.
Industry groups are therefore recommending that adequate time for transition of up to 5 years should be put in place to allow for systems and processes to be adapted, and that the full transition of the guideline to established products is not mandated meaning a full update of the dossier to ICH M4Q (R2) for such products would not be required.
The next steps on how to proceed with implementation of this guideline are, therefore, eagerly awaited.
How can S-cubed help you?
Although the implementation plans for ICH M4Q (R2) are still not defined, S-cubed can provide regulatory support for Module 3 dossier content, including gap analysis and authoring modules from source data. We would be pleased to discuss and advise on the impact of the new M4Q(R2) structure on your products, in preparation for the eventual adoption of this guideline.
Any Questions?
If you have any questions on this topic, please don’t hesitate to ask. You can contact us here, via email (info@s-cubed.co.uk), and telephone (S-cubed Ltd: +44 1235 77 22 60).
* from slides presented by Ivica Malnar at the Certified For Success Conference 23-24 September 2025, Budapest, Hungary