CTD and eCTD Submission

CTD and eCTD Submission• CTD (Common Technical Document):- is a

harmonized format for submission of detailed information on medicines to regulatory authorities and agencies for the purposes of obtaining approval to market a product.

• eCTD (Electronic Common Technical Document): is the electronic version of CTD.

• An eCTD is simply a standard electronic format for sending data from the applicant to the regulatory authority.

History of CTD• The Concept of CTD was introduced by ICH in

the year of 2000 for the public consultation.• Before 2000 there was no uniformity to submit

dossier in regulatory authority. This creates many hassles for applicant as well as auditors to submit and reviewing the dossier information in an organized manner. Hence concept of CTD was come for harmonization in dossier submission.

• It is important to note that on July 1, 2003 use of the CTD format will become mandatory across all three regions like EU, FDA and Japan.

Impact of CTD

• The ICH CTD represents one of the most ambitious and successful international harmonization activities undertaken for medicines product of human use.

• It will significantly reduce time and resources needed by industry to compile applications for global registration.

• Applies to all NDAs, ANDAs, BLAs and INDs application.

Benefits of CTD

• Easy “Reviewable” applications.• Complete, well-organized submission.• More predictable format.• More consistent reviews.• Easier analysis across application.• Easier Exchange of information.• Facilitates electronic submission.

CTD Triangle

CTD Dossier

The CTD is organized into FIVE modules:1.0 Module 1:- Regional Administrative Information2.0Module 2:- Introduction, Quality Overall

Summary, Nonclinical Overview, Clinical Overview, Nonclinical Written and Tabulated summaries, Clinical Summary

3.0 Module 3:- Quality4.0 Module 4:- Nonclinical Study Reports5.0 Module 5:- Clinical Study Reports

Numbering System: Module 2Module 2

2.1 OVERALL CTD TABLE OF CONTENTS OF MODULES 2, 3, 4, AND 5 2.2 INTRODUCTION 2.3 QUALITY OVERALL SUMMARY 2.3.S DRUG SUBSTANCE 2.3.S.1 General Information 2.3.S.2 Manufacture 2.3.S.3 Characterization 2.3.S.4 Control of Drug Substance 2.3.S.5 Reference Standards or Materials 2.3.S.6 Container Closure System 2.3.S.7 Stability 2.3.P DRUG PRODUCT 2.3.P.1 Description and Composition of the Drug Product 2.3.P.2 Pharmaceutical Development 2.3.P.3 Manufacture 2.3.P.4 Control of Excipients 2.3.P.5 Control of Drug Product 2.3.P.6 Reference Standards or Materials 2.3.P.7 Container Closure System 2.3.P.8 Stability

Numbering System: Module 2Module 2 (Cont.)

2.3.A APPENDICES 2.3.A.1 Facilities and Equipment 2.3.A.2 Adventitious Agents Safety Evaluation 2.3.A.3 Novel Excipients 2.3.R REGIONAL INFORMATION 2.4 NONCLINICAL OVERVIEW 2.4.1 Overview of the Nonclinical Testing Strategy 2.4.2 Pharmacology 2.4.3 Pharmacokinetics 2.4.4 Toxicology 2.4.5 Integrated Overview and Conclusions 2.4.6 List of Literature Citations 2.5 CLINICAL OVERVIEW 2.5.1 Product Development Rationale 2.5.2 Overview of Biopharmaceutics 2.5.3 Overview of Clinical Pharmacology 2.5.4 Overview of Efficacy 2.5.5 Overview of Safety 2.5.6 Benefits and Risks Conclusions 2.5.7 References

Module 2 (Cont.) 2.6 CONTENT OF NONCLINICAL WRITTEN AND

TABULATED SUMMARIES 2.6.1 Introduction 2.6.2 Pharmacology Written Summary 2.6.3 Pharmacology Tabulated Summary

(Appendix B) 2.6.4 Pharmacokinetics Written Summary 2.6.5 Pharmacokinetics Tabulated Summary

(Appendix B) 2.6.6 Toxicology Written Summary 2.6.7 Toxicology Tabulated Summary (Appendix B) 2.7 CLINICAL SUMMARY 2.7.1 Summary of Biopharmaceutics and

Associated Analytical Methods 2.7.2 Summary of Clinical Pharmacology Studies 2.7.3 Summary of Clinical Efficacy 2.7.4 Summary of Clinical Safety 2.7.5 References 2.7.6 Synopses of Individual Studies

Numbering System: Module 3Module 3

3.1 MODULE 3 TABLE OF CONTENTS 3.2 BODY OF DATA 3.2.S DRUG SUBSTANCE 3.2.S.1 General Information 3.2.S.2 Manufacture 3.2.S.3 Characterisation 3.2.S.4 Control of Drug Substance 3.2.S.5 Reference Standards or Materials 3.2.S.6 Container Closure System 3.2.S.7 Stability 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.4 Control of Excipients 3.2.P.5 Control of Drug Product 3.2.P.6 Reference Standards or Materials 3.2.P.7 Container Closure System 3.2.P.8 Stability

Module 3 (Cont.) 3.2.A APPENDICES 3.2.A.1 Facilities and Equipment 3.2.A.2 Adventitious Agents Safety Evaluation 3.2.A.3 Novel Excipients 3.2.R REGIONAL INFORMATION 3.3 LITERATURE REFERENCES

Numbering System: Module 4

Module 4 4.1 MODULE 4 TABLE OF CONTENTS 4.2 STUDY REPORTS 4.2.1 Pharmacology 4.2.2 Pharmacokinetics 4.2.3 Toxicology 4.3 LITERATURE REFERENCES

Module 5: Clinical Study Reports

• 5.1- Table of Content• 5.2- Tabular Listing of All Clinical Studies

Like Type of Study, Study Identifier, Location of Study Reports, Objective of the Study, Number of Subjects, Study design, Test Product; Dosage Regimen; Route of administration, Healthy Subjects, Duration of Treatment, Study Status, Type of Report.

. 5.3 Clinical Study Reports

. 5.4 Literature References

Module 5.3 Clinical Study ReportICH E3

• 1-3-15, Study report• 2-Study Synopsis• 16.0 Appendices• 16.1.1 Protocol and its amendment• 16.1.2 Sample Copy of CRF• 16.1.3 List of IEC, their CVs and Informed Consent

Form• 16.1.4 List of Investigator and their CVs• 16.1.5 Compliance Statement• 16.1.6 Listing of Subject Receiving Test and Reference

Product From Specific batches

Module 5.3 Clinical Study ReportICH E3

• 16.1.7 Randomization scheme and codes• 16.1.8 Audit Cert.• 16.1.9 Documentation of statistical Method• 16.1.10 QA Statement• 16.1.11 Publication based on the study• 16.1.12 Important reference used in the Study• 16.2 Subject Data Listing• 16.2.1 DS Subject• 16.2.2 Protocol deviation

Module 5.3 Clinical Study ReportICH E3

• 16.2.3 Subject excluded from efficacy Analysis• 16.2.4 Demographic Details• 16.2.5 Drug Concentration data• 16.2.6 Individual Efficacy Data• 16.2.7 AE Table• 16.2.8 Individual Abnormal Lab Parameter• 16.3 Case Report Form• 16.3.1 CRF of withdrawn subject due to AE or death or

other serious AE• 16.3.2 Other CRFs• 16.4 Individual Subject Data Listings

eCTD• The electronic Common Technical Document

(eCTD) is the electronic equivalent of the Common technical document, which is standard format for submissions to the authorities and agencies responsible for regulation of pharmaceutical of products in US, Europe and Japan.

• Why Electronic?- Improve the submission and review process.- Increase accuracy of the Submission.- Decrease total costs.

How are eCTD built?

• An eCTD can be built manually or automatically, using integrated document management and publishing software. Such Solutions are available commercially from numerous vendors.

• Example of eCTD Software:-1.0 ROSETTA Regulatory Software2.0 Pharmaready eCTD Product which is fully

validated, international regulatory Compliant software that is 21 CFR Part 11 compliant.

Benefit of eCTD

• Improve handling and archiving of submission.• Support Life cycle Management.• Immediate access to complete and Up to date

information.• Search functionally for assessors and increased

tracking ability.• Reduced Workload.• Better communication with industry.

Benefits of eCTD

Requirement of eCTD

• PDF Version should be 5.0 or higher• Optimize pdf files for fast web view.• The Print area for pages should fit on a sheet

of A4 and letter (8.5” X 11”) paper.• A sufficient margin (at least 2.5 cm) on the left

side of each page should be provided to avoid obscuring information.

• Header and footer information can appear within these margins.

Requirement of eCTD• Fonts and Font Size Times New Roman, Arial, Courier and Fonts supported in

the Acrobat set itself. 12- point font. Use of Color fonts Black font color is recommended. Blue color can be used

for hypertext link.. Page Orientation

Page Should be properly oriented so that all portrait pages are presented in portrait and all landscape pages are presented in landscape.

. Headers and FootersUnique header or footer that identifies its subject matter.

Requirement of eCTD• Source of Electronic Document

Scanning should be avoided where possible.Document Should be generated from electronic source documents and not from scanned material, except where access to the source electronic file is unavailable or where a signature is called for.All scanned documents should be OCR. (Optical Character Recognition).

. Methods for creating PDF documents and ImagesIt is recommended that scanning be undertaken at a resolution of 300 dpi (dots per inch) to balance legibility and file size.

Requirement of eCTD• Hypertext Linking and Bookmarks1.0 Improve navigation through PDF documents.2.0 Use- to support annotations, related sections,

references, appendices, tables or figures that are located on the same page are helpful and improve navigation efficiency.

3.0 Hyperlink- Designated by rectangles using thin lines or by blue.txt as appropriate.

4.0 Bookmark- Hierarchical level. No more that 4 levels in hierarchy is recommended.

5.0 The magnification setting Inherit Zoom should be used.

Requirement of eCTD• Page Numbering:- The first page of the document

should be numbered 1, and all subsequent pages should be numbered consequentially with Arabic numbers.

• Open Dialog Box:- The initial view of the PDF files should be set as

Bookmarks and Page. If there are no bookmarks, the initial view as page

only should be set.The Magnification and Page layout should be set

as default.

Requirement of eCTD• Folder and file Naming Conventions The maximum length of the name of a single folder or file is

64 character including file extension. Only lower case letters should be used in all file and

directory names. The maximum length of a path is 230 characters, including

file name, and extension. Name is a taken composed of the following characters.1.0 Letters “a” to “z”2.0 Digits “0” to “9”3.0 hyphens “-”> Security:- No security settings or password protection for

PDF files should be included.

Other files that has been Submitted to Regulatory

1.0 xpt files:- For USFDA

2.0 INF and DAT files:- For CANADA (TPD and HPFB)

3.0 EXCEL of drug Concentration and Pharmacokinetic parameter of each Subject:- For ANVISA

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