The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) has released the draft version of the M4Q(R2) guideline for public consultation.Â
This landmark update significantly overhauls the Common Technical Document (CTD) Module 2 (Quality Overall Summary) and Module 3 (Quality) to better align with current scientific advancements, regulatory expectations, and global lifecycle management strategies.
What’s New in M4Q(R2)?
The Expert Working Group (EWG) behind M4Q(R2) has outlined several key updates:
Expanded Scope
M4Q(R2) extends and refines the previous M4Q(R1) to apply not only to chemical drug substances and products but also to biologicals and complex multiconstituent products, including those containing medical devices and advanced therapy medicinal products (ATMPs).
The revised guideline is structured for flexibility and scalability, enabling support for:
- Initial marketing authorization applications
- Variations and lifecycle submissions
- Master files and platform-based products
- Digitalization and AI/ML-driven assessments
Importantly, M4Q(R2) is positioned as the central source for organizing quality data, replacing fragmented regional practices and supporting a globally harmonized dossier format.
Central Role in CTD Quality Structure
M4Q(R2) will now serve as the primary framework for organizing regulatory quality data across the CTD. It harmonizes the location, structure, and level of detail expected in both initial marketing authorization and post-approval submissions.Â
This revision enables greater consistency across global regulatory regions, ensuring that agencies and applicants operate from a common structural foundation, reducing redundancy and misalignment.
Integration with ICH Q-Series Guidelines
The revised guideline integrates concepts from ICH Q8 through Q14, reinforcing the use of:
- Quality by Design (QbD)
- Risk-based approaches
- Design space
- Established Conditions (ECs)
- Analytical Procedure Lifecycle (Q14)
This alignment encourages science-driven submissions that articulate development rationale, risk control strategies, and lifecycle expectations more transparently and consistently.
Improved Data Accessibility and Knowledge Management
To support digital transformation, M4Q(R2) introduces structured granularity across modules that enhances:
- Digital submissions
- AI/ML compatibility
- Structured data extraction
- Knowledge management systems
This approach enhances data traceability, comparison, and lifecycle management, particularly in jurisdictions that adopt eCTD 4.0 and advanced dossier review tools.
Focus on Control Strategy and Development Rationale
A key feature of M4Q(R2) is the enhanced focus on control strategy design and the rationale behind product development. Applicants must now clearly describe the:
- Quality Target Product Profile (QTPP)
- Critical Quality Attributes (CQAs)
- Overall Control Strategy (OCS)
These elements are consolidated in Module 2.3, providing a high-level narrative that supports regulatory assessment, especially in submissions that utilize platform technologies or prior knowledge.
Enhanced Module 2.3 Summary
The Quality Overview (Module 2.3) has been significantly restructured to support regulatory evaluation and lifecycle submissions. New elements include:
- Integrated justifications (e.g., extractables/leachables, adventitious agents)
- Development summaries and rationale
- Structured cross-links to Module 3
- Product Lifecycle Management (PLCM) documentation
These changes aim to streamline the review process and ensure transparency across manufacturing, control, and post-approval considerations.
Post-Approval Change Management
M4Q(R2) incorporates tools better to manage post-approval changes through alignment with ICH Q12. Applicants are encouraged to:
- Define Established Conditions (ECs)
- Use Post-Approval Change Management Protocols (PACMPs)
- Maintain a Product Lifecycle Management Document (PLCM)
These features enable more predictable and flexible regulatory pathways for post-marketing variations, supporting continuous improvement and innovation throughout the product lifecycle.
Implications for Industry
Pharmaceutical companies preparing marketing authorization dossiers will need to revise their document structures and adopt the risk- and science-based thinking emphasized in M4Q(R2).Â
The new guideline is especially relevant for firms developing biosimilars, combination products, and those using advanced manufacturing platforms or continuous processing.
For those involved in regulatory writing, QA, CMC development, or dossier preparation, early alignment with M4Q(R2) principles will be crucial in ensuring future-proof submissions.
Next Steps and Timeline
The M4Q(R2) draft guideline is at Step 2 of the ICH process and is now open for regional and public consultation. Finalization and adoption of Step 4 are expected following stakeholder feedback.
ICH encourages industry stakeholders, regulatory agencies, and scientific experts to review the draft and submit comments during the consultation phase.
