ICH M4Q(R2): What the New CTD Quality Structure Means for the Pharmaceutical Industry
The proposed revision of ICH M4Q(R2) represents one of the most significant changes to the Common Technical Document (CTD) Quality Module since its introduction in 2002. While the CTD has provided the global standard for pharmaceutical submissions for over two decades, advances in pharmaceutical science, lifecycle management and quality risk management have highlighted the need for a more modern approach.
The revised guideline aims to improve the consistency and efficiency of dossier preparation and regulatory assessment while aligning the CTD with current ICH Quality guidelines, including ICH Q8–Q13.
For pharmaceutical companies, the changes will have implications not only for future marketing authorisation applications but also for lifecycle management strategies, dossier maintenance and regulatory operations.
Objectives of ICH M4Q(R2)
The revised guideline has four primary objectives:
- Improve the efficiency and consistency of dossier preparation and regulatory review
- Support a lifecycle approach to pharmaceutical quality rather than a one-time submission
- Provide a harmonised structure covering both chemical and biological drug substances and drug products within a single guideline
- Align the CTD Quality Modules with modern pharmaceutical development principles outlined in ICH Q8–Q13
To achieve these objectives, ICH has proposed a substantial restructuring of Modules 2 and 3 of the CTD, together with revised documentation requirements.
Current Timeline
The public consultation phase has now concluded. The ICH Expert Working Group (EWG) is expected to complete its review and resolution of comments by November 2026, with Step 4 adoption of the final guideline currently anticipated in June 2027.
Implementation is currently expected to begin in 2028. However, many practical aspects of implementation – including how legacy dossiers (current MA’s) will transition to the new structure – remain unclear.
Companies with products currently in development should begin assessing the potential impact now, particularly where submissions are planned from 2028 onwards.
What is Changing?
The most significant change is the complete restructuring of CTD Modules 2.3 (Quality Overall Summary) and Module 3 (Quality).
Module 2 shall become the assessment-focused document
Under the revised structure, Module 2.3 is intended to become the primary document supporting regulatory assessment. Greater emphasis will be placed on summarising the pharmaceutical development strategy, demonstrating product knowledge and outlining the principles of quality risk management.
Module 3 shall become the central data repository
Rather than containing narrative summaries, Module 3 will function primarily as the repository for supporting data, reports, protocols, specifications and detailed technical information.
This clearer distinction between assessment summaries and supporting evidence is intended to improve both dossier preparation and regulatory review.
A New Organisational Structure
The traditional separation between Drug Substance and Drug Product will be replaced by a more flexible product lifecycle structure.
New categories include:
Each section will follow a consistent framework covering:
This standardised approach is intended to make dossiers easier to navigate while improving consistency across product types.
Why This Matters
Although the revised structure should ultimately simplify global submissions, implementation will represent a significant change for Regulatory Affairs, CMC, Pharmaceutical Development and Quality functions.
Companies will need to review not only how dossiers are assembled, but also how technical information is generated, maintained and updated throughout the product lifecycle.
Training, internal procedures and document management processes will all require review and revision.
Key Questions Facing Industry
One of the biggest uncertainties is how our national competent authorities (NCA) will implement the revised guideline alongside existing registrations.
Legacy Products
Many companies, including generic pharmaceutical manufacturers maintain large global portfolios of approved products prepared using the current CTD structure. Questions that remain unanswered include:
- Will companies need to maintain both current and revised CTD structures during the transition period?
- Will baseline submissions or dossier conversions be required?
- Will regulators provide mapping tools to support migration to the new structure?
- How should companies manage lifecycle changes where information expected under M4Q(R2) was never included in legacy dossiers?
These issues will be particularly important for companies with extensive post-approval maintenance activities.
Products Currently in Development
Companies with submissions planned from 2028 onwards should begin evaluating whether their development programmes align with modern ICH quality principles, including:
- Quality Target Product Profile (QTPP)
- Critical Quality Attributes (CQAs)
- Quality Risk Management
- Control Strategy Development
- Pharmaceutical Development in accordance with ICH Q8
- Pharmaceutical Quality Systems in accordance with ICH Q10
- Product Lifecycle Management and Established Conditions under ICH Q12
Early planning may help minimise future rework as implementation requirements become clearer.
Global Implementation Considerations
Another important consideration is global regulatory alignment.
Implementation of ICH M4Q(R2) is expected to coincide with wider adoption of eCTD version 4.0 for new MAA globally. Whether regulatory authorities will implement both changes simultaneously – and whether implementation timelines will remain harmonised across ICH regions – remains uncertain.
Global companies should therefore monitor regional announcements carefully and consider the potential operational impact on regulatory publishing, submission planning and lifecycle management.
Looking Ahead
The ICH Expert Working Group’s review of consultation comments, expected in November 2026, will be an important milestone. The publication of the final guideline in 2027 should provide greater clarity on implementation expectations, transition arrangements and regulatory timelines.
Although many practical questions remain, organisations should not wait until formal implementation begins. Assessing current processes, identifying potential gaps and planning for change now will place companies in a stronger position when the revised guideline comes into effect.
How Acorn Regulatory Can Help
At Acorn Regulatory, we continuously monitor developments across the global regulatory landscape to ensure our clients remain informed and prepared for upcoming changes.
Whether you are assessing the impact of ICH M4Q(R2) on products in development, planning your lifecycle management strategy, or preparing your organisation for implementation, our experienced Regulatory Consultants can help you develop a practical, risk-based approach tailored to your business.
To discuss how these changes may affect your organisation, contact us at enquiries@acornregulatory.com.
