As eCTD 4.0 adoption inches forward, a new ICH guideline puts it to the test
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Karl-Heinz Loebel
These steps by the regulators show commitment to the standard after some uncertainty as to whether it was the right approach. Previously, there had been proposals to adopt a more radical approach based on Fast Healthcare Interoperability Resources (FHIR) standard rather than continue with the evolution of the eCTD.3
Ultimately, however, the regulators moved forward with eCTD 4.0. One likely reason for this is the compatibility with the current format, v3.2, and the ability to seamlessly reference back to previously submitted documentation.
eCTD 4.0 offers an even more sophisticated option for document re-use between any applications, as long as a central document and submission repository exists at the receiving agency. This involves tagging each document with the eCTD 4.0 universally unique identifiers (UUID).5 Finally, eCTD 4.0 promises to also allow for faster adjustments of the submission content structure (outline) if the addition of new or differently formatted regulatory information is required as a consequence of e.g. updates of regulatory guidelines.
Will eCTD 4.0 meet its moment with the M4Q update?
Although there is still a way to go with eCTD 4.0 implementation, its potential will soon be tested with the new M4Q (R2) guideline, which “establishes the location and structure of quality information” in Modules 2 and 3 of the CTD.6 The guideline update was published in May 2025 for public consultation, which ended in October 2025. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) will review and discuss the feedback over the next 18 months, and the final guideline is expected in June 2027.
One of the big changes in M4Q is to introduce a more detailed structure to the Module 2 quality summary, with its sections 2.3.1 through to 2.3.6 providing a more holistic narrative view of the product and core quality information.7 This includes:
- 2.3.1 – general information
- 2.3.2 – overall development and control strategy
- 2.3.3 – core quality information
- 2.3.4 – development summary and justification
- 2.3.5 – product lifecycle management
- 2.3.6 – product quality benefit risk
The structure will be further enhanced by introducing new substructures -- Description, Manufacture, Control, Storage (DMCS) -- for 2.3.3, 2.3.4, and for 3.2. With the narrative now in the summary documents in Module 2, Module 3 will be more of a technical data repository, making it compatible with eCTD 4.0 and structured data formats.
These capabilities will allow reviewers to read the Module 2 overview documents and, instead of spending their time searching for detailed documents in Module 3, they can rely on reviewing tools and automation to extract structured technical data from Module 3 and organize the information the way they want to. This should make the assessment more efficient for reviewers, while for industry the updated guideline is expected to support lifecycle management and post-approval changes.
One other crucial difference with the new M4Q guideline is that it represents the first connection between eCTD and IDMP (Identification of Medicinal Products), with the new guideline specifically stating that eCTD should use IDMP terminology for how the pharmaceutical product is described.4
Moving forward with M4Q (R2) with (or without) eCTD 4.0
Questions remain as to how agencies deal with the implementation. For example, if the guidelines are implemented under the old eCTD 3.2 standard, it seems likely that M4Q requirements will be more complicated to implement. Another consideration is that the US FDA has developed a Pharmaceutical Quality/Chemistry, Manufacturing & Controls (PQ/CMC) standard for structured CMC data beyond IDMP, which is currently not considered in M4Q (R2).
Furthermore, the IDMP connection poses some difficulty since the standard has only been implemented by European agencies. As we get closer to the final M4Q (R2) guideline, these and other questions will need to be assessed more thoroughly. Until then, while these questions remain salient, so too does the fact that we finally have a guideline that creates a strong case for eCTD 4.0 adoption.
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Disclaimer:
The information provided in this article does not constitute legal advice. Cencora, Inc., strongly encourages readers to review available information related to the topics discussed and to rely on their own experience and expertise in making decisions related thereto.
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Sources
1. eSubmission, eCTD 4.0, EMA. https://esubmission.ema.europa.eu/eCTD%20NMV/eCTD.html
2. Electronic Common Technical Document (eCTD) v4.0, FDA. https://www.fda.gov/drugs/electronic-regulatory-submission-and-review/electronic-common-technical-document-ectd-v40
3. Opinion: eCTD 4.0 - Just Say No! Matt Neal Linked In article, April 2024. https://www.linkedin.com/pulse/opinion-ectd-40-just-say-matt-neal-6clwc/?trackingId=LpHewj5iQa2uBPc%2BqDjuIg%3D%3D
4. Electronic Common Technical Document (eCTD) v4.0, Technical Conformance Guide. FDA, March 2025. download
5. ICH Electronic Common Technical Document (eCTD) v4.0 Implementation Guide v1.6, May 2024. ICH Official web site : ICH
6. ICH M4Q(R2) Guideline on the Common Technical Document for the registration of pharmaceuticals
for human use: Quality, ICH, June 2025. https://www.ema.europa.eu/en/documents/scientific-guideline/ich-m4qr2-guideline-common-technical-document-registration-pharmaceuticals-human-use-quality-step-2b_en.pdf
7. ICH M4Q (2), ICH presentation, June 2025. Microsoft PowerPoint - M4Q(R2)_Step 2_Slides to Accompany Consultation_2025_0624_SEC.pptx
