How to prepare a CTD/eCTD compliant with the ICH M Guidelines: operational guide

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Introduction

Preparing a CTD/eCTD dossier according to the ICH M Guidelines requires method, structure and meticulous attention to detail.
Even seemingly minor mistakes (naming conventions, metadata, incomplete specifications, insufficient stability data) can lead to Refuse-to-File decisions, FDA/EMA questions or critical delays in approval timelines.

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Step 1: Setting up MODULE 1

• prepare a clear and concise cover letter
• complete the eAF (EU) or FDA Form 356h
• include SmPC, PIL, labeling (QRD or PI compliant)
• upload GMP certificates, RMP, expert statements
• verify that the structure follows the exact regional requirements

Watch out:
Module 1 is often a reason for refusal when mandatory documents are missing (fees, certificates, correctly completed eAF).

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Step 2: Module 2 – Technical Summaries

• write the QOS in parallel with Module 3
• prepare clinical and nonclinical overviews with interpretation of the data
• ensure numerical consistency with Modules 3–5
• include summaries of BE data and stability data

Common errors:

• copy/paste from main modules → causes inconsistencies
• overviews that are too descriptive and not analytical enough

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Step 3: Module 3 – Quality (CMC)

Operational activities:

• prepare S and P sections in compliance with M4Q
• include processes, validations, specifications, impurities, packaging
• present stability according to ICH Q1A/Q1E
• use clear tables for methods, results and impurity profiles
• ensure alignment with DMF/CEP where applicable

GMP Best Practices:

• CQA and CPP clearly identified
• every specification limit justified
• stability presented with trend analysis and scientifically justified shelf-life

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Step 4: Module 4 – Nonclinical Studies

• attach GLP reports with QA statement
• organise studies according to M4S
• use node extension (EMA) when necessary
• ensure consistency with overviews 2.4/2.6

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Step 5: Module 5 – Clinical Studies

• follow M4E(R2) and ICH E3
• include pivotal CSRs, ADME, Phase I and BE studies
• attach synopsis, appendices, datasets
• verify data consistency with Module 2.7

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Step 6: Conversion to eCTD

• clear naming convention
• descriptive leaf titles
• use node extensions where useful (EMA)
• apply STF for FDA
• hyperlinks must be internal only
• verify envelope metadata

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Handling non-conformities

If issues arise:

• update leaves using the “replace” operation
• document deviations in the RFI package
• coordinate with QA regarding change-control impact
• prepare clear scientific justifications

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Concise operational checklist

• QOS consistent with Module 3
• complete BE studies with 90% CI
• ≥12 months real-time stability
• process description with CPP/CQA
• QRD/PI-compliant labeling
• complete ICH E3 CSRs
• validated XML backbone

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Case study

A company submits a generic with only 6 months of stability data.
EMA grants only 12 months of shelf-life instead of the requested 24 and requires additional post-approval data — a classic example of incomplete documentation.

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Conclusion

For flawless dossiers and faster approvals. Explore the full guide on GuideGxP.com.