ectd

1. Global Perspective and Overview
of eCTD
Department of Pharmaceutics

2. 2
G L O S S A R Y
 CTD – Common Technical Document
 ICH - International Conference on Harmonisation
 eCTD – Electronic Common Technical Document
 NeES – Non-eCTD Electronic Submission
 RIMS – Regulatory Information Management System
 EMA - European Medicines Agency
 NCA - National Competent Authorities
 FDA - Food and Drug Administration
 CDER - Center for Drug Evaluation and Research
 CBER - Center for Biologics Evaluation and Research
 SPL - Structured Product Labeling
 XML – eXtensible Markup Language
 XSL – eXtensible Stylesheet Language
 DTD – Document Type Definition

3. 3
Overview of Regulatory
Submissions & Their Structure

4. 4
Regulatory Submissions
 Why? Need to gain approval from Regulatory agencies to market
pharmaceutical drug products in their respective countries
 When? Innovator discovers a new molecule, Formulator knows of a
patent expiration, API Manufacturer markets Drug Substance, Annual
Reports, Amendments, etc.
 What? Administrative, prescription, manufacturing, CMC, quality, non-
clinical and clinical study information
 How? Paper, Non-eCTD Electronic Submission (NeES), electronic
Common Technical Document (eCTD)
 Whom? ICH Countries (US, EU, JP, CA) and Emerging Markets (TGA,
MCC, Africa, South East Asia, Latin America, etc.)

5. Regulatory Submissions – contd.
Phases

6. 6
Regulatory Submissions – contd.
 Partial list of Regions and Countries for Regulatory Submissions
 GCC (Saudi Arabia, Oman, UAE, etc.)
 LEVANT (Turkey, Israel, Jordan, Lebanon, Palestine, Northern Cyprus, Syria)
 ASEAN (Malaysia, Singapore, Thailand)
 APAC (Australia, Brunei, Cambodia, etc.)
 EU (England, Austria, Belgium, etc.)
 CEE (Albania, Slovakia, Croatia, etc.)
 Some important MoH Websites:
 http://www.aseansec.org http://mccza.com/
 http://www.sfda.gov.sa http://www.fda.gov
 http://www.jfda.jo http://www.ema.europa.eu/ema/
 http://www.hc-sc.gc.ca https://www.swissmedic.ch/

7. 7
History
 Fast forward to early 2000, the International Conference on
Harmonization (ICH) has prepared a guideline on the
organization of a common technical document for
registration of pharmaceuticals for human use or a CTD.
 Move forward to 2004, the ICH has issued another guideline
on the specifications and requirements for submission of a
marketing application in electronic form or the eCTD, which
has a designation of ICH M2.
 In the year 2008, on January1 the FDA indicated that all
marketing application submissions were to be submitted
electronically in eCTD format.

8. 8
APPLICABILITY
 Required in EU, Japan, and Canada for marketing
applications.
 “Highly recommended” by FDA for NDA, BLA.
 Required by CDER for eCTD submissions.
 Required in EU (IMPD) and Canada for investigational
applications.
 Accepted by FDA for IND.

9. 9
CTD Structure
 CTD stands for Common Technical Document
 It is a logical ordering and organization of information
 It is a way of managing information at the document level
1. Came into effect in 2000
2. Adopted by ICH
(International Conference
on Harmonization)
 3. Organization of the data
into modules and nodes

10. 10
A comparison between Paper, NeES and eCTD formats

11. 11
Paper, NeES, eCTD
Paper NeES eCTD
Contains one or more volumes
with continuous table of contents
Contains folders with module and
global table of contents
Contains folders with XML based table
of contents
Printed documents are organized
using slip sheets, page separators
and cover letters
Published PDF documents are
organized into folders under
different modules and nodes
Same as NeES with separate provision
for accommodating Study Tagging
Files (STFs)
Up to 5 copies have to be
couriered to the agency
The entire application is to be
sent to the agency via the Drop
Box or on CD/DVD
Single sequence can be sent to FDA
via CD/DVD or Gateway (ESG).
No need to create bookmarks,
hyperlinks. Just a ToC will do
Need to strictly adhere to the
agency specified document
publishing guidelines
Same as NeES. Need to also create
cross-document and cross-application
hyperlinks for easy navigation
Agency can only validate the
contents of the dossier and not
the structure
Agencies have extensive
Validation criteria to accept
NeES.
Same as NeES. Also checks
checksums, file attribute, life cycle
operations, etc.
No tools are required to create a
paper submission
Sophisticated tools are required
to create and manage NeES
submissions
Same as NeES. In addition, the tool
must be 21 CFR Part 11 compliant
Has become the exception Still accepted by some NCAs Is the most preferred format

12. 12
Benefits of eCTD
 Financial
 Printing and shipping costs are eliminated
 Application can be submitted in multiple countries with relatively minor changes
 Reduce review times, increase your response times to Agency requests, and
ultimately lead to a faster approval
 Improved Application Review Process
 Most Agency reviewers prefer eCTD vs. paper
 Submissions can be uploaded to the Electronic Submissions Gateway (ESG) and are
available to reviewers within hours
 Thanks to bookmarks and hyperlinks, a reviewer can easily jump to the paper you
just cited, the table you just mentioned, or the validation report you just
referenced
 Reviewers no longer have to search through countless paper volumes to
determine what changes have been made to an application
 Convenience
 Multiple people can access the same documents at the same time – no more
sharing paper volumes or making extra copies
 Agency employees can access the application remotely, allowing reviewers to
continue their review regardless of their location
 Agency can audit the software used to create the eCTD submission during site
inspections

13. 13
MODULE 1

14. 14
Module 2 - CTD Summaries

15. 15
2.3 Quality Overall Summary

16. 16
MODULE 2
Module 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

17. 17
2.4 Nonclinical Overview

18. 18
SEQUENCE FOR THE NONCLINICAL
OVERVIEW

19. 19
Module 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

20. 20
2.5 Nonclinical Written and Tabulated
Summaries

21. 21
2.6 Clinical Overview

22. 22
SEQUENCE FOR THE CLINICAL
OVERVIEW

23. 23
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

24. 24
2.7 Clinical Summary

25. 25
Trends in Global Submission formats

26. 26
Global Submission Formats
 Europe
 Mandatory eCTD format for electronic-only submissions since January 1,
2010 for Centralized Procedure
 Almost all member states/NCAs are ready to accept eCTD only submissions
since January 1, 2010
 Since January 2013 and “Mandatory from March 2014″ all eCTD submissions
must be sent using the dedicated submission channels: eSubmission
Gateway or the related eSubmission Web Client
 USA
 eCTD most preferred format of eSubmission. Mandatory for IND
submissions.
 Paper accepted as an exception and is extremely rare
 Health Canada
 “Co-Submissions” and “Hybrid Submissions” no longer accepted by HC since
January 1, 2010.
 eCTD is the most preferred format of eSubmission

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Global Submission Formats – contd.
 Saudi FDA
 Starting on January 05, 2013, the eCTD will be accepted, which will
become the preferred submission format one year later (starting on
January 04, 2014).
 Finally, starting from January 03, 2015, only eCTD will be accepted.
 GCC Nations
 Started accepting NeES submissions from Q1 of 2014.
 Transition to eCTD expected to happen in 2015.
 Australia (TGA) and South Africa (MCC)
 TGA – Accepting NeES since 2011-12. Started accepting eCTD from
2015.
 MCC - eCTD pilot phase completed in February 2014. Industry asked to
submit in eCTD from June 2014
Golden Rule: Once eCTD, always eCTD

28. 28
Fundamentals of eCTD

29. Fundamentals of eCTD
 eCTD Terminology
 XML Backbone
 Application/Sequence
 Granularity
 Life cycle
 Checksum
 Href path
 Attribute
 LeafID
 Folder
 Util/Stylesheet/DTD
 STF
ectd-root-folder*
m1
0000
rr*
m5
m4
m3
m2
util
dtd
style
* Where “rr” = region
code – eu, us, ca, jp
* Defined by regional
guidance
Sequence folder = 0000,
0001, 0002, 0003….etc.

30. Fundamentals of eCTD – contd.
eCTD Folder View eCTD Browser View

31. 31
Fundamentals of eCTD – contd.
Backbone XML View

32. 32
Quick look into the Market Requirements

33. Electronic Submissions to US
 Application Types – FDA
 IND (Investigational New Drug
Application)
 NDA (New Drug Application)
 ANDA (Abbreviated New Drug
Application)
 DMF (Drug Master File)
 BLA (Biological license
Application)
 FDA recommends sponsors to
submit a pilot submission for
technical evaluation
 Submission Types – FDA
 Original Application
 Amendment
 Re-submission
 Pre-submission
 Annual Report
 Establishment Description
Supplement
 Efficacy Supplement
 Labeling Supplement
 CMC Supplement
 Other

34. Electronic Submissions to US – contd.
 Unique FDA Submission
Requirements:
 Filled out Form 356h (ANDA)
 Annotated Label and Proposed
Labeling Text
 Side by Side comparison of
Labeling Text with RLD (ANDA)
 Signed, Executed Batch Records
 Study Tagging Files (STF)
 Clinical Study Reports (CSR)
 Case Report Form (CRF)
 Section 5.3.7 Case Report Forms
no longer used
 Application number is always 6
digits
 All Drug Listings must be sent via
Electronic Submission Gateway
(ESG)

35. Electronic Submissions to EU
Procedure Types – EU
 Centralised Procedure (CP)
 A marketing authorisation granted under the
centralised procedure means the medicinal
product may be put on the market in all
Member States
 Decentralised Procedure (DCP)
 Use if application will be made to several
member states and product has not received
marketing authorization in any member state
at time of application
 Mutual Recognition Procedure (MRP)
 Use if application will be made to several
member states and product has received
marketing authorization in any member state
at time of application
 National Procedure (NP)
 Single application filed to single nation
under existing national laws
Unique EU Sub Requirements
 Country Specific Envelope(s)
 “Common” directory for files common to
all nations receiving the submission
 File naming as per the pattern [country
code]-[document type code]-[variable
component].[file type extension]
 Tracking Table mandatory for MRP and DCP
Submissions
 Node Extensions allowed, especially in the
case of Module 5
 Product Information has both country and
language designations
 “To be Advised” can be used if procedure
number not provided by the RMS or NCA
 Unique Agency Codes and Names
 Drop Box facility available for submitting
dossiers online

36. Electronic Submissions to EU – contd.
 MRP Directory Structure  CP Directory Structure

37. Electronic Submissions to SFDA and GCC
Procedure Types – GCC
 GCC Procedure (GP)
 A marketing authorization granted under the
GCC procedure means the medicinal product
may be put on the market in all 6 Member
countries
 National Procedure (NP)
 Single application filed to single nation
under existing national laws
 Typical Process Flow at GCC/SFDA
Specification - version 1.2
SFDA eCTD vs GCC NeES
KSA CTD GCC CTD
Module 1:
1.7.3 Titled as “certificate of
Analysis – Drug Substance /
Finished Product”
Module 1:
1.7.3 Titled as “certificate of
Analysis – Drug Substance”
Module 2:
2.5 Titled as “Clinical Overview”
Module 2;
2.6 Titled as “Non-Clinical written
& Tabulated Summaries”
Module 2:
2.5 Titled as “Overview of the
Nonclinical Strategy”.
2.6 Titled as “Non-Clinical written
& Tabulated Summaries:
Pharmacology, Pharmacokinetics,
Toxicology”
Module 3:
3.2.R Regional Information
Module 3:
3.2.R Regional Information
3.2.R.1 Alcohol Content
Declaration
3.2.R.2 Porcine/Pork-Content
origin
3.2.R.3 The Diluents and Coloring
agents in the product formula.

38. Electronic Submissions to HC
Submission Types – HC
Technical Validation is based on 4 levels
 Error
 Warning
 Information
 Ignore
Unique HC Requirements
 “Co-Submission” and “Hybrid
Submission” discontinued
 Pre-assigned application number not
required for pilot submissions
 Application numbers are 6 digits and
are prefixed with “e”
 Simple M1/CA folder structure

39. 39
Exposure to the various Tools and Technologies

40. 40
eCTD – Processes and Technologies
 Processes to be followed:
 Global Strategy to launch drugs in single or multiple markets
 Adherence to Current and Country Specific Guidance
 Creating Checklists for Document Assimilation, Assembly and
Review
 Have good experience in using eCTD Publishing Tools
 Following SoPs for generation of WORD and PDF documents
 Ensuring eCTD submission meets country specific Validation
Criteria
 Maintain Communication with Health Authorities
 Tools and Technologies to be used:
 PDF Publishing and Compliance Tool
 eCTD Publisher and Validator
 eCTD Consolidated (All Sequence) Viewer
 eCTD Import Utility

41. Regulatory Information Management
System (RIMS)
Product Registration
Management
Submission Archive
Agency Correspondence
Q&A Database
Document and
Content
Management
eSubmission Publishing
Submission Planning Tool
Portfolio Management
Master Data
Acceleration is the result of the capabilities working in harmony…
Product Quality Systems
Quality Management System
(QMS)

42. 42
Document Publishing Standards
 All PDF documents must be between version 1.4 and 1.6
 All PDF documents that have more than 5 pages must have bookmarks and a table
of contents that is linked to the respective pages. The bookmarks must generally
match the table of contents
 The ZOOM levels for all the bookmarks and hyperlinks must be set to “Inherit
Zoom” only
 The PDF document must be made searchable, or, should be OCRd if scanned and
saved as PDF file
 The initial view should be set to “Bookmarks Panel and Page” if the PDF document
has bookmarks. Else, should be set to “Page only”
 “Fast Web Access” and “Most Recent View” must always be enabled in all PDF
documents

43. Thank You