CTD/eCTD Dossier: Practical Step-by-Step Guide to Registration

The Registration Dossier as a Finished Product

For a Regulatory Affairs professional, the finished product of their work is not the pill, but the registration dossier. Before international harmonization, submitting a drug to different countries meant preparing completely different dossiers, with specific formats and requirements for each country. A logistical nightmare and a huge waste of time.

Everything changed with the introduction of the ICH M4 guideline, which standardized the format of the Common Technical Document (CTD) . Today, the CTD (and its electronic version, the eCTD) is the universal format accepted by the EMA, FDA, Japanese PMDA, and many other authorities. Mastering its structure and management (the lifecycle ) is the fundamental operational skill of every RA.

This practical guide takes a step-by-step look at how to build, submit, and maintain a CTD/eCTD dossier.

Phase 1: Choosing the Strategy (The Authorization Procedure)

Even before writing Module 1, the most important decision is how to submit the application. In Europe, the RA must define the strategy:

1. Centralized Procedure (CP): A single application is submitted to the EMA. If approved, the MA is valid throughout the EU. It is mandatory for innovative medicines (biotech, advanced therapies, orphan drugs).
2. Decentralised Procedure (DCP): The application is submitted simultaneously to multiple EU countries, choosing a Reference Member State (RMS) that leads the evaluation.
3. Mutual Recognition Procedure (MRP): It is used if you already have an AIC in one EU state (RMS) and you want to extend it to other countries (Involved Member States - CMS).
4. National Procedure (NP): Rarely used for new products, it is limited to drugs intended for the national market only.

The choice depends on the nature of the product, the commercial strategy and the desired timing.

Phase 2: Building the Dossier (The 5 CTD Modules)

The core of the RA work is assembling the thousands of pages of scientific data into the rigid structure of the CTD. Here's what each module contains:

Module 1: Administrative and Regional Information

This is the only non-harmonized form. It contains information specific to the region in which it is submitted:

• Application Form (e.g. the eAF in Europe).
• Information about the applicant and production sites (GMP certificates, licenses).
• The labelling proposal: Summary of Product Characteristics (SmPC), Package Leaflet (PL or PIL) and labels.
• Declarations (e.g. Pediatric compliance, Orphan Drug, etc.).

Module 2: Summaries (Overview and Summary)

This is the most strategic form, it's the one that evaluators read first to get an idea of the drug.

• 2.3 Quality Overall Summary (QOS): The summary of all quality data (CMC) from Module 3.
• 2.4 Non-clinical Overview: Critical appraisal of toxicology and pharmacology studies.
• 2.5 Clinical Overview: The most important summary, which presents the critical analysis of the benefit/risk balance based on clinical data.
• 2.6/2.7 Non-clinical/Clinical Summaries: More detailed tabular summaries of studies.

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

This is the technical-pharmaceutical module. It describes how the drug is manufactured and controlled.

• 3.2.S (Substance): Active Ingredient (API) data: production, specifications, impurities, stability.
• 3.2.P (Product): Finished Product Data: pharmaceutical development, formulation, manufacturing process, finished product controls, stability studies (according to ICH Q1).

Module 4: Non-Clinical Studies (Safety)

Contains all complete reports of pre-clinical studies (GLP).

• Pharmacology (primary and secondary).
• Pharmacokinetics (ADME).
• Toxicology (single dose, repeated dose, genotoxicity, carcinogenicity, reproductive toxicity).

Module 5: Clinical Studies (Efficacy)

Contains complete Clinical Study Reports (CSRs) of all human studies (GCP), in line with ICH E3.

• Clinical Pharmacology Studies (Phase I).
• Efficacy and Safety Studies (Phase II and III, the pivotal studies ).
• Any post-marketing studies, if relevant.

Beware of... Inconsistency Between Modules A fatal error, which leads to inevitable List of Questions , is inconsistency. If the dosage mentioned in Module 1 (SmPC) does not match that tested in Module 5 (Clinical Studies), or if the specifications in Module 2.3 (QOS) do not match those in Module 3 (Quality), the entire dossier loses credibility. The RA must perform a meticulous cross-check .

Phase 3: Submission and Review Management

Once the dossier is assembled (today almost exclusively in eCTD format), it is sent to the authorities via dedicated portals (e.g. CESP in Europe).

From here begins the evaluation phase, a close dialogue with the authorities:

1. Validation: The authority checks that the dossier is technically complete.
2. Evaluation Phase (Clock-stop): The evaluators analyze the dossier and prepare an initial list of questions (List of Questions - LoQ, or Deficiency Letters).
3. Response to LoQs: The evaluation clock stops. The company, coordinated by the RA, has a set period of time (e.g., 3-6 months) to respond to the questions, providing additional data or justifications.
4. Final Evaluation: If the answers are satisfactory, the application proceeds to approval. Otherwise, there may be a second round of questions (List of Outstanding Issues - LoOI) or, in the worst case, a negative opinion.

Phase 4: Managing the "Lifecycle" (Variations and Renewals)

Approval isn't the end, it's the beginning. A drug lives and changes: a manufacturing site changes, an analytical method is updated, an indication or safety warning is added. Every change must be reported and approved.

This is lifecycle management , managed through Regulatory Changes (in EU, Reg. 1234/2008):

• Type IA/IAIN (Minor): Minor changes with minimal impact (e.g., fixing a typo). Often, these are simply reported.
• Type IB (Minor): Changes that require notification and "silent consent" approval (e.g. minor change in a manufacturing process).
• Type II (Major): Changes with significant impact (e.g., addition of an indication, change of specifications). Requires formal evaluation.
• Line Extensions: Changes so large (e.g., new pharmaceutical form) that they almost require a new dossier.

Operational Checklist (Summary) for Submission

Before pressing "send" on an eCTD, the RA must verify [based on Sec. 14.1]:

• [ ] Consistency: Are the data (name, dosage, sites) identical in Modules 1, 2, and 3?
• [ ] Completeness: Are all clinical and non-clinical study reports cited in the summaries (Module 2) present in Modules 4 and 5?
• [ ] Labelling: Are the RCP and PL compliant with official templates (e.g. QRD in EU) and efficacy/safety data?
• [ ] Signatures: Are all declarations (e.g. clinical/non-clinical expert, GMP) present and signed?
• [ ] eCTD Validation: Does the electronic dossier pass the technical validation (e.g. EURS validator) without "high" errors?

Conclusion: The CTD as an Act of Precision

Managing the CTD/eCTD dossier is an exercise in scientific precision, project management, and regulatory strategy. Each form must be flawless and consistent, as it forms the legal and scientific basis for drug approval.

To master the structure of each individual module, manage LoQ responses and optimize the change lifecycle, the " Complete Guide to Regulatory Affairs " by GuideGxP.com provides detailed checklists and operational diagrams.