The Submission Dossier

The submission dossier is the packet of documents that are to be submitted to a health authority for registration of a product, or for other life-cycle maintenance activities, such as renewal of registration or CMC variations.

The requirements vary very widely from country to country, but in general a dossier contains administrative documents, (such as forms) legal documents, (contracts, authorizations, letters of representation, intelectual property documents, etc) technical CMC -Chemistry, Manufacturing and Control- documents, (quality specifications and testing standarts, list of ingredients, manufacturing description, validations, etc) clinical and/or preclinical documents, (clinical protocols, clinical trial results, patient informed consent documents, etc) labeling documents. (patient information leaflet, packaging artwork and labeling, physician’s information)

Some countries request the dossier to be structured with a specific format and layout, such as CTD or ASEAN dossier, whereas some other countries only request a list of documents without any specification on presentation. Some countries require or prefer electronic submission.

CTD: Common Technical Document

The CTD is a set of specifications for submission dossier for the registration of medicines.  and designed to be used across Europe, Japan and the United States. It is an internationally agreed format developed by the European Medicines Agency, the Food and Drug Administration (U.S.) and the Ministry of Health, Labour and Welfare (Japan). It is maintained by the ICH. After the United States, the EU and Japan, the CTD has been adopted by several other countries including Canada, Switzerland, Australia, New Zealand, India, and China.

The agreement to assemble all the Quality, Safety and Efficacy information in a common format has revolutionised the regulatory review processes, led to harmonised electronic submission that, in turn, enabled implementation of good review practices. For industries, it has eliminated the need to reformat the information for submission to the different ICH regulatory authorities. (from ICH website)

This figure below is a schematic representation of the structure of the CTD.

The eCTD is the electronic version of this dossier format.

CTD Format: module numbering and section heading.

1 Administrative and Product Information
Module 1 is not harmonized, its content will depend on the country or region in which the product is intended to be registered. It includes local forms and more administrative and legal documents and information.

2 Common Technical Document Summaries
2.1 Common Technical Document Table of Contents (Modules 2-5)
2.2 Introduction
2.3 Quality Overall Summary
2.4 Nonclinical Overview
2.5 Clinical Overview
2.6 Nonclinical Summary and Tabulated Summaries
2.7 Clinical Summary

3 Quality
3.1 Table of Contents of Module 3
3.2 Body of Data
3.2.S Drug Substance
3.2.S.1 General Information
3.2.S.1.1 Nomenclature
3.2.S.1.2 Structure
3.2.S.1.3 General Properties
3.2.S.2 Manufacture
3.2.S.2.1 Manufacturer(s)
3.2.S.2.2 Description of Manufacturing Process and Process Controls
3.2.S.2.3 Control of Materials
3.2.S.2.4 Controls of Critical Steps and Intermediates
3.2.S.2.5 Process Validation and/or Evaluation
3.2.S.2.6 Manufacturing Process Development
3.2.S.3 Characterisation
3.2.S.3.1 Elucidation of Structure and other Characteristics
3.2.S.3.2 Impurities
3.2.S.4 Control of Drug Substance
3.2.S.4.1 Specification
3.2.S.4.2 Analytical Procedures
3.2.S.4.3 Validation of Analytical Procedures
3.2.S.4.4 Batch Analyses
3.2.S.4.5 Justification of Specification
3.2.S.5 Reference Standards or Materials
3.2.S.6 Container Closure System
3.2.S.7 Stability
3.2.S.7.1 Stability Summary and Conclusions
3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment
3.2.S.7.3 Stability Data
3.2.P Drug Product
3.2.P.1 Description and Composition of the Drug Product
3.2.P.2 Pharmaceutical Development
3.2.P.3 Manufacture
3.2.P.3.1 Manufacturer(s)
3.2.P.3.2 Batch Formula
3.2.P.3.3 Description of Manufacturing Process and Process Controls
3.2.P.3.4 Controls of Critical Steps and Intermediates
3.2.P.3.5 Process Validation and/or Evaluation
3.2.P.4 Control of Excipients
3.2.P.4.1 Specifications
3.2.P.4.2 Analytical Procedures
3.2.P.4.3 Validation of Analytical Procedures
3.2.P.4.4 Justification of Specifications
3.2.P.4.5 Excipients of Human or Animal Origin
3.2.P.4.6 Novel Excipients
3.2.P.5 Control of Drug Product
3.2.P.5.1 Specification(s)
3.2.P.5.2 Analytical Procedures
3.2.P.5.3 Validation of Analytical Procedures
3.2.P.5.4 Batch Analyses (For BGTD): Batch Analyses (For TPD):
3.2.P.5.5 Characterisation of Impurities
3.2.P.5.6 Justification of Specification(s)
3.2.P.6 Reference Standards or Materials
3.2.P.7 Container Closure System
3.2.P.8 Stability
3.2.P.8.1 Stability Summary and Conclusions
3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment
3.2.P.8.3 Stability Data
3.2.A Appendices
3.2A.1 Facilities and Equipment
3.2.A.2 Adventitious Agents Safety Evaluation
3.2.A.3 Excipients
3.2.R Regional Information
3.2.R.1 Production Documentation
3.2.R.2 Medical Devices
3.2.R.3 Lot Release Documentation (for BGTD)
3.2.R.4 Yearly Biologic Product Reports (BGTD only)
3.3 Literature References

4 Nonclinical Study Reports
4.1 Table of Contents of Module 4
4.2 Study Reports
4.2.1 Pharmacology
4.2.1.1 Primary Pharmacodynamics
4.2.1.2 Secondary Pharmacodynamics
4.2.1.3 Safety Pharmacology
4.2.1.4 Pharmacodynamic Drug Interactions
4.2.2 Pharmacokinetics
4.2.2.1 Analytical Methods and Validation Reports (if separate reports are available)
4.2.2.2 Absorption
4.2.2.3 Distribution
4.2.2.4 Metabolism
4.2.2.5 Excretion
4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical)
4.2.2.7 Other Pharmacokinetic Studies
4.2.3 Toxicology
4.2.3.1 Single-Dose Toxicity (in order by species, by route)
4.2.3.2 Repeat-Dose Toxicity
4.2.3.3 Genotoxicity
4.2.3.3.1 In vitro
4.2.3.3.2 In vivo (supportive toxicokinetics evaluations)
4.2.3.4 Carcinogenicity (including toxicokinetics)
4.2.3.4.1 Long-term studies (not included in repeat-dose toxicity or pharmacokinetics)
4.2.3.4.2 Short- or medium-term studies (not included under repeat-dose toxicity or pharmacokinetics
4.2.3.4.3 Other studies
4.2.3.5 Reproductive and Developmental Toxicity
4.2.3.5.1 Fertility and early embryonic development
4.2.3.5.2 Embryo-fetal development
4.2.3.5.3 Prenatal and postnatal development, including maternal function
4.2.3.5.4 Studies in which the offspring (juvenile animals) are dosed and/or further evaluated
4.2.3.6 Local Tolerance
4.2.3.7 Other Toxicity Studies (if available)
4.2.3.7.1 Antigenicity
4.2.3.7.2 Immunotoxicity
4.2.3.7.3 Mechanistic studies (if not included elsewhere)
4.2.3.7.4 Dependence
4.2.3.7.5 Metabolites
4.2.3.7.6 Impurities
4.2.3.7.7 Other
4.3 Literature References

5 Clinical Study Reports
5.1 Table of Contents of Module 5
5.2 Tabular Listing of Clinical Studies
5.3 Clinical Study Reports
5.3.1 Reports of Biopharmaceutic Studies
5.3.1.1 Bioavailability (BA) Study Reports
5.3.1.2 Comparative Bioavailability (BA) and Bioequivalence (BE) Study Reports
5.3.1.3 In vitro-In vivo Correlation Study Reports
5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies
5.3.2 Reports of Studies Pertinent to Pharmacokinetics using Human Biomaterials
5.3.2.1 Plasma Protein Binding Study Reports
5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies
5.3.2.3 Reports of Studies Using Other Human Biomaterials
5.3.3 Reports of Human Pharmacokinetic (PK) Studies
5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports
5.3.3.2 Patient PK and Initial Tolerability Study Reports
5.3.3.3 Intrinsic Factor PK Study Reports
5.3.3.4 Extrinsic Factor PK Study Reports
5.3.3.5 Population PK Study Reports
5.3.4 Reports of Human Pharmacodynamic Studies
5.3.4.1 Healthy Subject PD and PK/PD Study Reports
5.3.4.2 Patient PD and PK/PD Study Reports
5.3.5 Reports of Efficacy and Safety Studies
5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication
5.3.5.2 Study Reports of Uncontrolled Clinical Studies References
5.3.5.3 Reports of Analyses of Data from more than one study, including any formal integrated analyses, meta-analyses, and bridging analyses
5.3.5.4 Other Clinical Study Reports
5.3.6 Reports of Postmarketing Experience
5.3.7 Case Report Forms and Individual Patient Listings (when submitted)
5.4 Literature References