Pharma IT Insights
The Changing Landscape: What the New CTD Guideline Means for IMPDs/INDs
By Torben Elhauge
September 10, 2026
Pharma IT Insights
Changes and Additions in the New Eudralex vol. 4, Chapter 4: Documentation
By Torben Elhauge
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This content is published by Pharma IT.
“What’s new in the ICH M4Q(R2) guideline?” and “How will this affect our IMPD/IND preparation?” These are the questions my team is hearing more and more as the updated Common Technical Document (CTD) framework moves closer to adoption¹.
Since alignment across regulatory submissions is key, especially for biotech and pharma operating internationally, changes in the CTD often ripple into how we plan, structure, and justify our IMPD/IND content for clinical trials. Let’s look at what’s changing and why it matters.
Understanding the M4Q(R2) Update
The updated ICH M4Q(R2) guideline sets out a more granular, digitally friendly structure for Quality information in registration applications. While the original M4Q(R1) from 2002 gave the basic sectional format, M4Q(R2) reflects two decades of lessons learned, technological advances, and harmonization needs. To support this a new IT system, eCTD v4.0, will be implemented as well. In Japan eCTD v4.0 is already mandatory while EU and USA wait until implementation of the M4Q(R2) guide², though the two regions are not equally “waiting”. The US has required eCTD for commercial INDs since 2018 and has accepted new applications in eCTD v4.0 since September 2024, while the EU’s own eCTD v4.0 roll-out remains phased³.
For IMPDs, which follow the EMA IMPD guidance, and INDs, which follow the US FDA’s requirements for the chemical and pharmaceutical quality data, the richer structure in M4Q(R2) provides clearer placement for emerging manufacturing and control technologies, think platform processes, advanced analytics, AI/Machine Learning based control strategies, and structured data submissions.
Key Differences Impacting IMPDs and INDs
Expanded “Overall Development and Control Strategy” Section
- Old (M4Q(R1)): The Quality Overall Summary had brief development and manufacturing descriptions.
- New (M4Q(R2)): Introduces Quality Target Product Profile (QTPP) and Critical Quality Attributes (CQAs) explicitly, plus a consolidated Overall Control Strategy (OCS).
- IMPD/IND relevance: Sponsors can now justify early phase process design with a lifecycle view, even in Phase I/II. This supports EMA’s focus on risk-based assessment and aligns with ICH Q8/Q11 principles, improving how early manufacturing decisions are documented.
Granularity in Core Quality Information
- Old: Module 3 sections grouped broader categories; IMPDs tended to have brief summaries in early phases.
- New: Breaks content down for drug substance, intermediates, raw materials, devices, packaged products, analytical procedures, facilities, even if optional for IMPDs.
- IMPD/IND relevance: Makes it easier for trial sponsors to present only applicable sections while still aligning with final MAA structure. Early adoption means smoother transition from IMPD to eventual marketing submission.
Development Summary and Justification
- Old: Limited to Pharmaceutical Development narrative.
- New: Includes Integrated Development and Justifications, cross-referencing CQAs, design space, prior knowledge, and platform technologies.
- IMPD/IND relevance: Especially useful for comparator products, biosimilars, or modified manufacturing, encourages IMPD applicants to justify process changes or comparator sourcing with scientific rationale early on.
Product Lifecycle Management (PLCM)
- Old: No dedicated lifecycle section.
- New: Adds Change Summary, PLCM Document, and Post Approval Change Management Protocols.
- IMPD/IND relevance: While PLCM isn’t typical in IMPDs, integrating change rationales during development supports future variations and helps in cases like midtrial manufacturing shifts (changing a filter supplier as one example).
Digitalisation & Emerging Technologies
- Old: Paper driven, broad headings.
- New: Designed for structured data capture, analysis, and knowledge management, accommodating AI, bioinformatics, advanced manufacturing.
- IMPD/IND relevance: Early-phase dossiers can now place advanced controls and analytics in recognized sections, supporting regulatory confidence.
Challenges with Applying the Revised Framework to IMPDs and INDs
While the update is exciting, early-phase IMPD compilers will face:
- Deciding applicability: Many M4Q(R2) subsections aren’t mandatory for an IMPD; careful selection is required to avoid overloading early submissions.
- Aligning terminology: EMA IMPD guidance uses its own headings; mapping to M4Q(R2) structure will require cross-reference tables.
- Resource allocation: More granularity means more documentation even if optional, requiring coordination across CMC, clinical supply, and regulatory teams.
Starting early with an IMPD/IND–CTD mapping plan is critical. This ensures that when the product moves from clinical phases to MAA, core quality data is already structured in the new format.
Same Burden, Different Trigger: Why Both IND and IMPD Face a Format Rewrite Before Filing
IMPDs and INDs already follow essentially the same CTD/Module 3 structure, so the content M4Q(R2) will add QTPP, CQA, OCS, finer granularity and hits both equally, and since neither is formally in scope today, that rewrite has to happen before the eventual NDA/BLA or MAA can be filed, delaying submission.¹ ⁴ The backbone trigger differs, though. US INDs already sit inside eCTD but face a hard change to eCTD v4.0, where FDA currently allows only new applications and no forward compatibility.³ EU IMPDs aren’t in eCTD at all but filed via CTIS instead, so that leap comes only at MAA stage, by which point the EU is piloting forward compatibility for v4.0.² Net effect: the transition burden is the same for both routes, just triggered by different mechanisms, a backbone rebuild for IND, a system change for IMPD. To date, neither FDA nor EMA/ICH has said how long this exposure lasts or how it will be bridged. It’s an open gap, not a settled transition period with a known end date.⁴
Turning Compliance into Strategic Advantage
Compliance is step one. The opportunity lies in using M4Q(R2) to build a quality narrative from Day 1:
- Document CQAs and control strategies even for early batches, they can evolve but the foundation is laid
- Showcase control of critical materials and processes to strengthen risk management in line with EMA’s IMPD expectations
- Integrate PLCM thinking into development to preempt and smooth later post approval changes
The shift from M4Q(R1) to M4Q(R2) is more than cosmetics. It embeds lifecycle thinking, modernizes quality structuring, and bridges early and late phase regulatory quality requirements. For IMPD and IND sponsors, it’s an invitation to do better science and smarter documentation.
💡Want to learn more?
If you need to map your IMPD or IND documentation into the M4Q(R2) structure ahead of formal adoption, our experienced regulatory CMC consultants can guide you through a fit for purpose, phase appropriate approach.
References
¹ ICH, M4Q(R2) – The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality, signed off as a Step 2 document on 13 May 2025 and released for public consultation. Step 3 sign-off and Step 4 (final) adoption of the guideline is currently targeted for June 2027, per the ICH M4Q(R2) EWG Work Plan (18 March 2026). Source: database.ich.org.
² A firm EU implementation date has not yet been set, but two official sources give an indication: the HMA/EMA eSubmission Roadmap (Annex 1: Implementation of eCTD v4.0), which points to mandatory use for centrally authorised procedures (CAPs) from around 2026 (to be confirmed) and notes other ICH regions plan mandatory use between 2026 and 2028; and EMA’s electronic submissions update (Dadi, Hamilton & Puusaar), confirming optional eCTD v4.0 use for new CAP marketing authorisation applications went live on 22 December 2025, with a further pilot phase planned in 2026 ahead of eventual mandatory use.
³ On the US side: FDA has required eCTD for commercial IND submissions and Master Files since 5 May 2018 (investigator-sponsored and expanded-access INDs remain excluded), and has accepted new applications in eCTD v4.0 since 16 September 2024, with no mandatory-only date yet set (fda.gov, “Electronic Common Technical Document (eCTD)”). FDA’s own draft M4Q(R2) guidance was open for public comment through 23 March 2026, after which FDA will begin drafting the final guidance (Federal Register, 21 January 2026).
⁴ EMA, Overview of comments received: ICH M4Q(R2) Guideline — Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality, Step 2b (EMA/356466/2025, 13 February 2026). BioPhorum and EFPIA both flagged that clinical-stage submissions (INDs and IMPDs) fall outside the draft guideline’s scope and that no early/mid-stage development guidance is provided; Certara raised the same ambiguity for how QTPP/CQA concepts apply pre-marketing-application. No EMA/ICH response to these comments is recorded in this document.
About the author
Torben Elhauge is Director of CMC in Pharma IT and Experienced pharmaceutical professional with 25+ years in analytical chemistry, API development, and regulatory documentation. Skilled in project management, workshop facilitation, and RFP processes, with extensive work coordinating CRO/CMO collaborations and tech transfers. Combines deep API knowledge with the ability to translate scientific needs into clear requirements and drive successful platform selection and process improvement projects.
