What Is eCTD? The Complete Guide to Electronic Common Technical Document

What is eCTD? The Electronic Common Technical Document (eCTD) is the internationally standardized digital format for submitting drug and biologic applications to regulatory agencies. Developed by the International Council for Harmonisation (ICH), eCTD replaced paper submissions and is now mandatory for FDA, EMA, and over 60 regulatory authorities worldwide.

If you're preparing a regulatory submission in 2026, understanding eCTD isn't optional-it's essential. A single formatting error in your eCTD submission can trigger rejection at the gateway, delaying your drug approval timeline by weeks or months.

In this guide, you'll learn:

• The complete definition and history of the eCTD format
• All 5 eCTD modules and their specific contents
• Regional eCTD submission requirements for FDA, EMA, and other agencies
• How eCTD validation works and common errors to avoid
• Step-by-step guidance for preparing compliant eCTD submissions

What Is eCTD? Understanding the Electronic Common Technical Document

What is eCTD in regulatory terms? The Electronic Common Technical Document (eCTD) is a standardized file format and folder structure for organizing and submitting pharmaceutical regulatory dossiers electronically. The eCTD format uses XML backbone files to create a navigable, hyperlinked structure that regulatory reviewers can efficiently access and search.

The eCTD was developed to solve a critical problem: before electronic submissions, pharmaceutical companies shipped truckloads of paper documents to regulatory agencies. A single New Drug Application (NDA) could contain 100,000+ pages of clinical data, manufacturing specifications, and safety information.

Key characteristics of eCTD:

• XML-based backbone providing navigation and metadata
• Standardized 5-module structure accepted globally
• PDF documents organized in predefined folder hierarchies
• Hyperlinked cross-references between related documents
• Lifecycle management for amendments and supplements

The term "Common Technical Document" reflects the harmonized structure agreed upon by the three ICH founding regulatory authorities: the U.S. FDA, the European Medicines Agency (EMA), and Japan's Pharmaceuticals and Medical Devices Agency (PMDA). The "e" prefix signifies the electronic implementation of this standard.

History of the Electronic Common Technical Document

Understanding where eCTD came from helps explain why it's structured the way it is. The journey from paper to electronic submissions spans over two decades of international regulatory cooperation.

Timeline of eCTD Development

Why eCTD Replaced Paper Submissions

Paper submissions created enormous inefficiencies:

For regulators:

• Physical storage of millions of pages
• Manual searching through documents
• No ability to hyperlink between sections
• Difficulty coordinating multi-reviewer assessments

For sponsors:

• Printing costs exceeding $100,000 per major submission
• Shipping logistics and customs delays
• Version control nightmares
• Inability to update documents efficiently

The eCTD format addressed all these challenges by creating a structured, searchable, and updateable digital format. A complete NDA that once required shipping pallets now transmits electronically in hours.

The 5 eCTD Modules Explained

The eCTD structure consists of five modules that organize all regulatory submission content. Understanding these eCTD modules is fundamental to preparing compliant submissions.

eCTD Module Structure Overview

The first module is region-specific (different for FDA, EMA, Health Canada, etc.), while Modules 2-5 are harmonized across all ICH regions. This harmonization allows sponsors to prepare core dossier sections once and use them for multiple regulatory submissions worldwide.

Module 1: Administrative Information and Prescribing Information

Module 1 contains all region-specific administrative documents, regulatory forms, and product labeling. This is the only module that differs between regulatory agencies.

FDA Module 1 Contents:

• FDA Forms (1571, 356h, 3674)
• Cover letters
• US Prescribing Information (USPI)
• Patient labeling (Medication Guide, Instructions for Use)
• Promotional materials (if required)
• Environmental assessments
• Pediatric assessments
• Risk Evaluation and Mitigation Strategy (REMS)

EMA Module 1 Contents:

• Cover letters and application forms
• Summary of Product Characteristics (SmPC)
• Product Information (labeling)
• Package leaflet
• Mock-ups and specimens
• Expert statements
• Environmental risk assessment
• Orphan drug documentation

Module 2: Common Technical Document Summaries

Module 2 provides high-level summaries and overviews of the detailed data contained in Modules 3, 4, and 5. Regulatory reviewers often start their assessment here.

Module 2 Sections:

• 2.1 Table of Contents (entire eCTD)
• 2.2 Introduction
• 2.3 Quality Overall Summary (QOS)
• 2.4 Nonclinical Overview
• 2.5 Clinical Overview
• 2.6 Nonclinical Written and Tabulated Summaries
• 2.7 Clinical Summary

The Quality Overall Summary in section 2.3 is particularly critical-it must accurately summarize all Module 3 content. Inconsistencies between Module 2.3 and Module 3 are a common cause of FDA information requests.

Module 3: Quality (Chemistry, Manufacturing, and Controls)

Module 3 contains all Chemistry, Manufacturing, and Controls (CMC) information for both the drug substance (active ingredient) and drug product (final dosage form).

Module 3 Structure:

Module 3 is often the largest section of an eCTD submission, particularly for complex biologics or products with multiple manufacturing sites.

Module 4: Nonclinical Study Reports

Module 4 contains all nonclinical (animal and in vitro) study reports supporting the safety of the drug.

Module 4 Structure:

• 4.2.1 Pharmacology (primary, secondary, safety)
• 4.2.2 Pharmacokinetics (ADME studies)
• 4.2.3 Toxicology (single-dose, repeat-dose, genotoxicity, carcinogenicity, reproductive toxicity)

Each study report follows the ICH M4S format, providing standardized presentation of nonclinical data across regions.

Module 5: Clinical Study Reports

Module 5 contains all clinical study reports and related data. For NDAs and BLAs, this module often contains thousands of pages documenting every clinical trial.

Module 5 Structure:

• 5.2 Tabular Listing of All Clinical Studies
• 5.3.1 Reports of Biopharmaceutic Studies
• 5.3.2 Reports of Studies Pertinent to Pharmacokinetics
• 5.3.3 Reports of Human Pharmacodynamic Studies
• 5.3.4 Reports of Efficacy and Safety Studies
• 5.3.5 Reports of Post-Marketing Experience
• 5.3.6 Case Report Forms and Individual Patient Data
• 5.4 Literature References

Clinical study reports in Module 5 must follow ICH E3 formatting guidelines, ensuring consistent presentation of clinical data for regulatory review.

eCTD Format Technical Requirements

The eCTD format has specific technical requirements that must be met for successful submission. Understanding these requirements prevents gateway rejections and validation failures.

XML Backbone Structure

The eCTD uses XML (Extensible Markup Language) files to create the navigable structure that links all PDF documents together. The XML backbone provides:

• Index file (index.xml): Master navigation file
• Regional XML: Region-specific metadata
• MD5 checksums: File integrity verification
• DTD/Schema: Structure validation rules

Each PDF document in the eCTD is referenced in the XML backbone with metadata including:

• Document title
• File location
• Operation (new, replace, append, delete)
• Leaf ID (unique identifier)
• MD5 checksum

PDF Document Requirements

Folder Naming Conventions

The eCTD specifies exact folder naming conventions that must be followed:

Sequence numbers (0000, 0001, etc.) track submission lifecycle-initial submission, amendments, supplements, and annual reports.

Regional eCTD Submission Requirements

While the core eCTD structure is harmonized, each regulatory region has specific requirements for submission format and gateway specifications.

FDA eCTD Requirements

The FDA's Electronic Submissions Gateway (ESG) accepts eCTD submissions for:

• Investigational New Drug Applications (INDs)
• New Drug Applications (NDAs)
• Biologics License Applications (BLAs)
• Abbreviated New Drug Applications (ANDAs)
• Master Files (DMFs, VMFs)

FDA-Specific Requirements:

EMA eCTD Requirements

The EMA accepts eCTD submissions through the Common European Submission Portal (CESP) or eAF (electronic Application Form) portal.

EMA-Specific Requirements:

Regional Comparison Table

eCTD vs CTD: Understanding the Difference

A common question is: what is the difference between CTD and eCTD? While the terms are related, they represent different submission formats.

CTD vs eCTD Comparison

The CTD defined the five-module organizational structure that eCTD inherited. The "e" in eCTD simply indicates the electronic implementation of this structure using XML and PDF technology.

When CTD Is Still Used

Paper CTD format is still accepted in some limited circumstances:

• Certain national submissions in non-ICH countries
• Legacy amendments to pre-eCTD submissions
• Emergency or compassionate use situations (rare)

However, for practical purposes, all modern pharmaceutical submissions to major regulatory agencies require eCTD format.

eCTD Validation: Ensuring Submission Compliance

Before submitting an eCTD to any regulatory gateway, validation is essential. eCTD validation checks the technical compliance of your submission against regional specifications.

What eCTD Validation Checks

Common eCTD Validation Errors

Understanding common validation errors helps you avoid gateway rejections:

1. Invalid XML Structure

• Missing required elements
• Incorrect attribute values
• Schema validation failures

2. PDF Document Issues

• Fonts not embedded
• Missing bookmarks
• Password protection applied
• Oversized files

3. Hyperlink Failures

• Broken internal links
• Invalid cross-references
• Incorrect file paths

4. Naming Violations

• Incorrect folder names
• Invalid characters in file names
• Improper sequence numbering

5. Lifecycle Errors

• Invalid operations (e.g., replacing non-existent documents)
• Incorrect leaf ID references
• Missing lifecycle history

Validation Tools and Approaches

Regulatory agencies provide validation tools and criteria:

• FDA: ESG pre-submission validation
• EMA: EU Validation Criteria (publicly available)
• ICH: eCTD specification documents

However, agency validation tools only catch technical errors. They don't validate:

• Content accuracy
• Cross-module consistency
• Regulatory strategy alignment
• Scientific quality

This is why comprehensive validation-combining technical checks with content review-is critical for submission success.

How to Create an eCTD Submission

Creating a compliant eCTD submission requires specialized software, careful planning, and rigorous validation.

eCTD Publishing Software Options

Most organizations use dedicated eCTD publishing software to create submissions:

eCTD Submission Preparation Steps

1. Plan your submission structure

- Map documents to eCTD modules

- Identify cross-references

- Plan sequence strategy

1. Prepare source documents

- Format PDFs to specifications

- Embed fonts

- Add bookmarks and hyperlinks

- Verify page size and margins

1. Build the eCTD structure

- Create folder hierarchy

- Import documents

- Configure XML metadata

- Set document operations

1. Create cross-references

- Link related documents

- Verify hyperlink targets

- Check Module 2 to Module 3/4/5 references

1. Validate thoroughly

- Run technical validation

- Review validation reports

- Fix all errors and warnings

- Re-validate after fixes

1. Quality review

- Content accuracy check

- Cross-module consistency

- Regulatory strategy alignment

1. Submit to gateway

- Package final submission

- Upload to appropriate gateway

- Monitor for acknowledgment

eCTD Best Practices for Success

Following these best practices significantly increases your submission success rate.

Planning Best Practices

• Start eCTD planning early in the development lifecycle
• Create document templates that meet eCTD PDF requirements
• Establish naming conventions for internal documents
• Map your data to eCTD modules during study design

Document Preparation Best Practices

• Use consistent formatting across all documents
• Embed all fonts before finalizing PDFs
• Create bookmarks that match document sections
• Test hyperlinks before submission

Validation Best Practices

• Validate incrementally as you build the submission
• Don't ignore warnings-they often indicate real issues
• Check cross-module consistency manually
• Use multiple validation tools for comprehensive coverage

Lifecycle Management Best Practices

• Track all document versions carefully
• Use consistent leaf IDs across sequences
• Document your submission history clearly
• Plan amendment strategy before initial submission

Key Takeaways

Next Steps

Understanding eCTD is just the first step-executing a compliant submission requires robust validation and quality processes. Whether you're preparing your first IND submission or managing multiple global NDAs, ensuring every document meets eCTD specifications is critical for regulatory success.

Organizations managing regulatory submissions benefit from automated validation tools that catch errors before gateway rejection. Assyro's AI-powered platform validates eCTD submissions against FDA, EMA, and Health Canada requirements, providing detailed error reports and remediation guidance before submission.

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