Overview of e-CTD and Modules

V 02 Effective date: 20-Sep-2017

Copyright © 2017 Tata Consultancy Services Limited
Objective

• Understand the need for Electronic Submissions to Heath Authorities (HA)

• Understand the different types of eSubmissions
• Differentiate between the eSubmission types
• Understand the various validation requirements for eSubmissions
• Be aware of the process for submitting eSubmissions to HAs

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Overview

• Background
• Electronic Submission formats
– eCTD
– NeeS
• Regional requirements of major Health Authorities
• Submissions Validation requirements in USFDA
• Submissions Validation requirements in EMA
• Submission mode to major HAs
– FDA Electronic Submissions Gateway (ESG)
– EMA eSubmission Gateway
– CESP (Common European Submission Platform)
• References

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Background

Introduction to eRegulatory Affairs

• Due to the emerging global necessity to have lifesaving medicines that cures life threatening
diseases soon in the market, the necessity to have rapid approvals from the Health Authorities
(HAs) has become an hectic task to the entire pharmaceutical industry
• To have the marketing authorisations / regulatory approvals from the HAs quickly, the time spent
on the review process of the regulatory submissions by the HAs needs to be decreased significantly.
• Hence some of the HAs decided to go fully electronic right from submission  review 
communication  approval.
• This paved the way to the concept called "eRegulatory Affairs" that means fully electronic
regulatory activities

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Life before Electronic Submissions…

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Background

• The first HA to go electronic was USFDA

– Since January 1, 2008 the USFDA accepts only electronic submissions to CDER for granting
approval to market a new drug in the US
– Since August 2009 it mandated electronic only submissions for CBER
• EMEA (now EMA) went partially electronic in July 2008 and fully electronic in June 2010
– Some EU member states still require paper
• Since 2010 till date
– MHLW (Japan) (in addition to paper)
– Health Canada
– Swissmedic (only electronic)
– All EU, RSA, Singapore, GCC (Gulf Countries Council), ASEAN countries and some of the African
countries (Nigeria, Uganda etc.,) : Strong Preference to Electronic

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Electronic Submission Formats

Electronic Common Technical Document

(eCTD)
Non-eCTD Electronic Submission

NeeS

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Electronic Common Technical Document

(eCTD)

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Introduction to eCTD

• The electronic Common Technical Document (eCTD) is an interface between the pharmaceutical
industry and the agency for the transfer of regulatory information. The content is based on the
Common Technical Document (CTD) format.
• The CTD was developed by the International Council for Harmonisation (ICH) Multidisciplinary
Group 2 Expert Working Group (ICH M2 EWG).

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The Emergence of eCTD

• Based on the CTD format of ICH

• Contains XML backbone (TOC – index.xml)
• MD5 Checksum file (index-md5.txt) – to ensure the authenticity of the submission
• DTD and XSL files to support the electronic compliance
• M1 is region specific XML backbone
– us-regional; eu-regional; ch-regional; jp-regional
• Life-cycle management of regulatory activity and/or submission documents
– Regulatory Activity
 Original, Amendment, Resubmission, Efficacy Supplement, Annual Report etc.,
– Documents
 New, Replace, Append, Delete
• MUST be processed by a eCTD publishing tool
– eCTDXpress, Liquent Insight Publisher, Lorenz DocuBridge, Extedo eCTD Manager
• Submission documents must be from a validated electronic repository
– Documentum (EDMS), SharePoint
• Validation of the eCTD submission is required post creation of eCTD
– Extedo EURS validator, Lorenz eValidator, Global Summit validator
• eCTD validation criteria differs between HAs

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eCTD Structure

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eCTD Structure

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eCTD Structure

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eCTD Publishing Tool Process

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eCTD Publishing Tool

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eCTD Publishing Tool

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eCTD Submissions Basics

• No need to be an expert in XML

• Should be technically sound
– CTD granularity (M2 to M5), File naming conventions, Interpretation of Validation issues etc.
• M1 should be region specific CTD content
– us-regional.xml for IND/NDA etc.
– eu-regional.xml for MAA, Variations etc.
• The inter-document hyperlinks should meet the specific HA requirements
– CSR Appendix 16.1.5 to the respective signature pages (for EU only)
– CSR Section 14.3.3 Narratives to the respective CRF (for US only)

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eCTD folder Structure

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Non-eCTD Electronic Submission

NeeS

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Non-eCTD Electronic Submissions

• NeeS comply fully with the folder and file organisation as presented in the ICH eCTD Specification
Document (including naming conventions). The only difference is that the two relevant XML files
(the index.xml, regional.xml) and the util folder (dtd and xsl) are not present.
• Navigation through such an electronic submission is based on electronic tables of content,
bookmarks and hypertext links

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Non-eCTD Electronic Submissions

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eCTD vs NeeS
eCTD
Need eCTD software to build the submission
TOC – XML backbone
index.xml (overall) & regional.xml (m1)
Contains metadata, application history and
Lifecycle attributes
Can see what has changed and when
Typically viewed using a reviewer tool
Each sequence is unique
Validation: eCTD validation criteria
NeeS
Can be built with typical desktop software
TOC – Module wise
ctd-toc, m1-toc, m2-toc etc.,
No lifecycle, No metadata
Can be part-built and completed elsewhere (re-used)
More often handled as individual dossiers
Heavily reliant on file/folder structure
Validation: NeeS validation criteria
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Regional requirements of major HAs

• Unique requirements for US FDA

– Signed and executed batch manufacturing records

– Integrated Summary of Safety and Efficacy (ISS and ISE)

– Study Tagging Files (STF) for Module 4 and 5 data

 XML file used to aggregate all components of a study

report (e.g., CSR, CSR amendments, CSR Signatures,
Study CRFs, CRTs etc., all well organised in a folder)

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Regional requirements of major HAs (contd…)

• For FDA (Contd…)

– Datasets for Clinical Study Reports (M5)

– Signed Case Report Forms (CRFs)

 Single PDF file for each CRF

 Should be bookmarked by visit and then by domain

 CRFs also need to be included in the respective STF

 CSR Section 14.3.3 Narratives should have direct hyperlinks to the respective CRFs

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Regional requirements of major HAs (contd…)

• Unique requirements for EMA

– EU Envelope
 Should contain the 'metadata' (descriptive information) of the submission
– Submission Description – Changes to the manufacturing process of the finished product
– Procedure – Centralised
– Submission Type – Variation Type 1B
– Submission Mode – Single
– Sequence Number – 0022
– Related Sequence Number – none
– Submission Tracking number – EMEA/H/C/000171/IB
– Manufacturer name – ABC Company Ltd
– Product Name – Wonder Pill
– INN – Drug Substance
– For 'Labelling' the folder structure should be organised by 'country' folder and then by 'language' folder
 For CP – XXXX\m1\eu\13-pi\131-spclabelpl\emea\en  English
XXXX\m1\eu\13-pi\131-spclabelpl\emea\de  German
XXXX\m1\eu\13-pi\131-spclabelpl\emea\es  Spanish
 For MRP/DCP – XXXX\m1\eu\13-pi\131-spclabelpl\fr\fr  French
XXXX\m1\eu\13-pi\131-spclabelpl\be\be  Belgium
 For National – XXXX\m1\eu\13-pi\131-spclabelpl\common\fr  French

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Submissions Validation in USFDA

• General Information -

• May 5, 2015, FDA published the final “Guidance on Providing Regulatory Submissions in Electronic Format -- Certain Human
Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications.” Submission types NDA, ANDA and
BLA must be submitted in eCTD format beginning May 5, 2017. IND submissions and master files must be submitted in eCTD
format beginning May 5, 2018 .

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Submissions Validation in USFDA

• Validation Errors for eCTD submissions in US FDA

– Three levels of severity
 High: The error is a serious technical error which prevents the processing of the submission and will require
resubmission. The submission is considered not received by FDA.
 Medium: The error may impact the reviewability of the submission but cannot be determined without further
inspection by the review staff. The submission might be considered received by FDA.
 Low: The error is a technical error which may or may not impact the reviewability or the integrity of the submission.
The submission will likely be considered received by FDA.
– High severity examples
 Application number in form does not match application number in regional.xml
 Wrong application form (An NDA with Form 1571 instead of Form 356h)
 Unsupported DTD version and/or Stylesheet
 Invalid index.xml or regional xml file
 eCTD sequence number in XML backbone doesn't match the number in form
 No 'related sequence' for an amendment application
 Proper lifecycle attribute is not used for documents

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Submissions Validation in USFDA (contd…)

• Validation Errors for eCTD submissions in US FDA (Contd…)

– Medium severity examples
 STF is missing for a study report (in M4 and M5)
 PDF security used (password protected)
 Fillable form not used
 Missing application form
 Hyperlinks and/or Bookmarks are not in "Inherit Zoom"
 Broken hyperlinks and/or bookmarks (target file is missing)
 Corrupt hyperlinks and/or bookmarks (target file is present but cannot be opened)
– Low severity examples
 Replace/Append lifecycle attribute is given for Application Form and/or Cover Letter
 Folder contains no files or sub-folders
 STF title and the Document title doesn't match
 Submission date in form doesn't match the date in regional.xml
 Document is placed in wrong location (Application Form under Cover Letter folder)
 PDF version is incorrect (should be between 1.4 and 1.7)
 Document contains excessive hyperlinks
 File size exceeds the specified limit (100mb)

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Submissions Validation in EMA

• Validation Errors for eCTD submissions in EMA

– EMA checks the eCTD submission validation as 'Pass' or 'Fail' or 'Best Practice'
– The electronic submission should 'Pass' all the criteria mentioned as per the “current” guideline in the EMA eSubmission
webpage below
 http://esubmission.ema.europa.eu/ectd/index.html
– Examples of checks that 'Fail' may include the following (not exhaustive)
 Invalid 'eu-regional.xml' file
 Node Extension is missing the title
 Submission Mode is not specified for Variation submissions
 File names (including extensions) exceed the specified limit (64 characters)
 Invalid characters are used in file names / \ " @ # % & * ( ) + | =
 File that is not referenced in the XML backbone is present in the submission
 The recommended file naming conventions are not followed
 PDF with version 1.3 or earlier exists in the submission

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Submissions Validation in EMA (contd…)

• Validation Errors for eCTD submissions in EMA (Contd…)

– Examples of checks that come as 'Best Practice' may include the following (not exhaustive)
 Hyperlinks does not comply ISO 32000-1:2008 (Backslashes present in the folder paths)
– \\0000\m1\eu\responses\emea\emea-responses.pdf (not correct)
– //0000/m1/eu/responses/emea/emea-responses.pdf (correct)
– (Links with backslashes will work only on Windows file system, but, links with forward slashes will work on all operating systems
e.g., SmartPhones, Tablets etc.,)
– The current validation tools have been updated to check this criteria and once detected the tool will give a BP warning.
• Validation Errors for NeeS submissions
– Examples may include but not limited to the following
 'ctd-toc.pdf' is not present in the submission
 'ctd-toc.pdf' file contains links to documents, other than module tocs
 Module tocs (m1-toc, m2-toc etc.,) contains hyperlink to 'ctd-toc.pdf'
 A file exists within the physical folder structure of the submission that is not referenced by any TOC
 A file is referenced in any TOC but is not present in the submission

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Submission Mode to major HAs

• eCTD submissions to US FDA are sent via Electronic Submission Gateway (ESG)
– Digital certificates for each contributor (Webtrader)
– Registration of the company and Webtrader – Send email to esgprep@fda.gov
– Test Account provided initially for sending a Pilot submission
– https://esgtest.fda.gov and https://esg.fda.gov
– Contact esgreg@gnsi.com for any clarifications
– Once test submission is approved, start sending production submissions
• eCTD/NeeS submissions to EMA are sent through various methods
– Through eSubmission Gateway (Only for eCTD submissions)
– Through CESP (Common European Submission Platform) – for submissions in MRP/DCP and National procedures (eCTD
and NeeS)
– Through CD/DVD couriered to EU member states (that don’t accept submissions through ESG or CESP yet – eCTD and
NeeS)
– Through EUDRALINK – General Correspondence, Meeting minutes etc.

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FDA Electronic Submission Gateway

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EMA eSubmission Gateway

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CESP

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Objective - Refresher

 Understand the need for Electronic Submissions to HAs

 Understand the different types of eSubmissions

 Differentiate between the eSubmission types

 Understand the various validation requirements for eSubmissions

 Be aware of the process for submitting eSubmissions to HAs

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Reference

• FDA Electronic Submissions page:

http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064994.htm
• EMA Electronic Submissions page:
http://esubmission.ema.europa.eu/index.htm

• ICH eCTD guidance's page:

http://www.ich.org/products/guidelines/multidisciplinary/article/multidisciplinary-guidelines.html
• ESTRI page:
http://estri.ich.org/eCTD/

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 Thank You

For any feedback/comment/clarification please contact us at PALS@tcs.com

Document Release Notice

• This Overview of e-CTD and Modules, Version 02, is released for use in Tata Consultancy Services (TCS) with effect from 20-Sep-2017
• This Training Material is subject to TCS Document Control Procedure. TCS reserves the right to make additions, modifications or
alterations to the existing content or release a newer version of this document.
• Softcopy of the latest version of the document is available in the https://g01.tcsion.com/LX/home/home_page?c_id=life-science-on-
ion-regulatory-affairs
• Comments suggestions or queries should be addressed to PALS@tcs.com.

Date: 12-June-2017 Date: 12-June-2017

Prepared by Rahul Pawar Reviewed by Anita Bachal

Role Regulatory Affairs SME Role Domain Consultant-Regulatory Affairs

Overview of e-CTD and Modules

Effective Date: 20-Sep-2017 V 02
Change/Revision History

Change type Date Modified

Version No. Revision Description Slide No. Rationale for the Change Modified By
(Add/Modify/Delete) (DD-Mmm-YYYY)
00 Initial Release NA NA NA NA NA
Updated content. Many
Updated with respect to current
01 changes, mostly all All Add, Modify and Delete Venkatesh Rao 23-Jun-2014
regulations and guidelines
slides.
Submission validation in
02 27 For Better understanding Add Rahul Pawar 12-June-2017
US FDA

V 02
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