Continuous Education by Perfect Pharmaceutical Consultants Pvt.

Ltd, Pune, India

Perfect Pharmaceutical Consultants Pvt. Limited, 2013, Feb 2013
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TOP 100 TIPS ON FILING eCTD

By Rajkumar Gupta, Managing Director Perfect Pharmaceutical Consultant
Pvt. Ltd

Mr. R.M. Gupta (M. Pharm.), is a free lance consultant for US DMF, COS, ANDA,
ACTD, CTD, eCTD and other regulatory submissions. guptarmg1952@gmail.com
He is an expert editor for CTD, ANDA, eCTD, CEP, DMF and other regulatory
submissions. Till now he has authored hundreds of regulatory documents
He is associated with Perfect Pharmaceutical Consultants Pvt. Limited
(http://sites.google.com/site/ppcdmf) and Global Institute of Regulatory affairs
(Pune, India). He is dedicated solely to regulatory profession.
He is well recognized expert for eCTD and eNDA. Recently he was selected as
honored speaker on eCTD at International Regulatory Conference organized at
Shanghai (United Business media and Nextgen China)
This article is solely written to guide, educate and train regulatory community at
large.
This article is based self experience of the author
He invites you to join his personal linked group GLOBAL INSTITUE OF
REGULATORY AFFAIRS www.linkedin.com/groups?gid=4777398

INTRODUCTION

eCTD is a new way of authorizing and publishing technical documents required for
marketing authorizations. The backbone of eCTD presentation is XML (Extensible
Markup Language) which is both human and machine readable. It contains a bunch of
small 300- 400 documents planted on XmL backbone However
NEES differs from ECTD with respect to XML component.


ADVANTAGES OF eCTD

eCTD has potential advantages as per below:

1. Ease in handling, transporting and archiving of submissions
2. Ease in maintaining Life Cycle of the regulatory compliance
3. Ease in locating, copying, printing and highlighting the documents
4. Ease in navigating through the submission (via bookmarks/hyperlinks)
5. Ease in filing amendment/variations
6. Ease in restructuring the presentation for different markets.
7. Ease in maintaining data integrity through Meta data and MD5 Checksum
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1.0 ELEMENTS OF eCTD

1.1 TABLE OF CONTENTS

1 Ensure that all the modules have sufficiently detailed (TOC). As a thumb rule TOC
shall be more than few pages.
2 Ensure that Module I of eCTD is adequately modified to suit different market
places.
3 Ensure that TOC is hyper linked to specific leaf files, tables and figures
4 Ensure that the xml backbone is used to define the overall structure of the TOC.
5 Ensure that TOC holds separate main folders and sub folders for different strengths
of the same product.

1.2 LEAF FILES
1 Ensure that all leaf files are standalone and represent table of contents. One
document =one file .
Ensure that documents are not cumulated in a single file
2 Ensure that final Leaf Files are prepared from corresponding MS Word files using
PDF format and are searchable
3 Ensure that technical information in leaf files is appropriate to their heading
4 Ensure that there are no blank files in the eCTD structure.
5 Ensure that each leaf file contains appropriate information in text/tabular/image or
in structured form
6 Ensure that leaf titles are concise
7 Ensure that you do not design the leaf files as per your convenience. The same shall
be designed for the convenience of reviewers who is expected to be unfamiliar with
your product and information.
8 Ensure that leaf files are stuffed with too much data. The contents shall be just
enough to match the heading.
9 Ensure that leaf files with the note : no relevant content should not be placed in
the eCTD structure:
10 Ensure that Following characters are not used in file names:
blank spaces
/ - forward slash
\ - backslash
: - colon
? - question mark
- quotation marks
<- less than sign
>- greater than sign
| - vertical bar
11 Ensure that Each leaf file holds: Descriptive Title, bookmarks, Page No, Headers
and footers.
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12 Ensure that each leaf file is in eCTD is in PDF format created from corresponding
word file.
13 Ensure that Each leaf file can be easily replaced, amended, deleted and modified as
necessary over the time.
14 Ensure that there are separate xml backbones : for module 1 and for modules 2
to 5 with proper interlinking with each other.

1.3 SCANNED DOCUMENTS

1 Ensure that OCR (Optical character Recognition) system is used to enable the
scanned documents readable. OCR facility is available in the latest version of
Adobe systems
2 Ensure that the scanned documents are kept to minimum as they consume large
space and can not be bookmarked / hyperlinked with source documents. Further,
they can not be searched for specific text using keywords/phrases and can not be
extracted for inclusion in investigators report.


1.4 HYPERLINKS

1 Ensure that the hyperlinks leads to the specific section referenced, not to the first
page of the destination document.
2 Ensure that presentation dont have any links pointed at www. All the links shall
point to the documents available within eCTD
3 Ensure that your eCTD does not contain cross-references to other eCTD
applications
4 Ensure that there are Maximum three levels of bookmarks
5 Ensure that all leaf files, tables, figures, and appendices and documents of more
than 10 pages are bookmarked.
6 Ensure that eCTD contains both internal and external hyperlinks texted in blue
for easy navigation of contents
7 Ensure that a hyperlink is introduced anytime the text refers to a reference (table,
figure, summary which are not on the same page.
8 Ensure that each leaf file in Module 2 (summary) is hyperlinked to the full text in
other modules
9 Ensure that all the bookmarks and hyperlinks are correct and functional.
10 Ensure that there are no invalid / non-functional hyperlinks
11 Ensure that the destination documents corresponding to each hyperlink are
provided appropriately
12 Ensure that invalid links (links that point to a non existing document) are either
regularized or deleted.
13 Ensure that non-relative hyperlinks are corrected properly
14 Ensure that all links are validated by an expert or by using software.
15 Ensure that the position and content of each hyperlink is optimized. This may be
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done manually or using hyperlink viewer software

16 Ensure that all hyperlinks and book marks are validated

2.0 USE OF SOFTWARE FOR DESIGNING

1 Ensure that standard eCTD is softwares (Hyperlink manager, eCTD Manager,
eCTD Viewer, eCTD Validator) for the creation, manipulation, validation,
publishing and viewing of regulatory documentation for electronic submission.

2 Ensure that the software is compatible with various Windows based platforms
It shall ensure quick eCTD publishing and validation
3 It shall not require extra server components
4 It shall permit quick book marking, hyper linking, creating pdf view, splitting and
merging of documents
5 It shall ensure automatic optimization: removal of orphaned files and empty
sections
6 It shall have facility to convert word files into PDF version 1.4,
7 It shall have an easy "Envelope" creation facility
It shall have capability to generate MD5 checksum automatically

3.0 SPECIAL NOTES ON DESIGNING

1 Ensure that footer and headers precisely display name of drug, document title,
protocol and study ID numbers, pagination and date
2 Ensure that folder named ctd-toc.pdf holds the table of contents for the entire
document. It shall contain individual leaf files m1-toc.pdf, m2-toc.pdf, m3-toc.pdf,
m4-toc.pdf and m5-toc.pdf
3 Ensure that No, passwords or encrypting is not permitted anywhere in the
submission.
4 Ensure that a consistent approach in used in designing the eCTD
5 Ensure that extra files outside the eCTD (even if asked to do so) are not presented.
The same will not be visible to the reviewer.
6 Ensure that your submission has all the information required. FDA can not add or
delete any information at request.

7
Ensure that the following errors are avoided:
Illegible documents
No meta-data to indicate type of the file, file size and contents
Inaccurate table of contents
Inoperable hyperlinks/bookmarks
Missing files
Empty files
Empty folders
Insufficient granularity or too much granularity
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8 Ensure that you eCTD looks great .It is Organized and Formatted properly.
A critical comparison of how EU and US submissions differ
9 Ensure that eCTD authors shall have hands on experience on MS Word,
Acrobat PDF, OCR, Xml

10
Ensure that the presentation is uniform and consistent throughout.
Ensure that the navigation of information through bookmarks and, hyperlinks is
highly functional.
11 Ensure that pCTD (the paper copy of eCTD) is always maintained with you
along with eCTD

4.0 eCTD VALIDATION

1 Ensure that the integrity of a each leaf file is maintained during archiving/ copying
using MD5 Checksum (a unique mathematical sum of each byte in a file) The
MD5 is a widely used cryptographic hash function that produces a 128-bit (16-
byte) hash value. It has been utilized in a wide variety of security applications, and
is also commonly used to check data integrity. It is something like a fingerprint of
the file. There is a very small possibility of getting two identical checksums of two
different files.
2 Ensure that your eCTD complies with FDA requirements. You may validate the
same through ESUB@fda.hhs.gov
3 Ensure that Each document contains mandatory meta-data (e.g., title, name, of the
file, sequence, operation attribute, etc.) (Meta-data is data about data which are
contained in an xml file.)
4 Ensure that each submission is validated for the following attributes :
Functionality of hyperlinks, integrity of contents , copy/paste/print functions,
consistency , data size and data pattern , version number
5 Ensure that all versions are qualified by MD5 checksum

5.0 QUALITY CONTROL

1 Ensure that your eCTD can be easily created, reviewed and modified for national,
centralized, decentralized and mutual recognition applications.
2 Ensure that the phrases and sentences used in the text do not cause any confusion to
the reviewers.
3 Ensure that all the bookmarks and hyperlinks are correct and functional
4 Ensure that the Scanned documents are totally avoided or kept to the minimum
5 Ensure that all the information, files and folder included in the submission are
within XmL frame work. There shall not be any extra files The files outside the
eCTD frame work are often ignored by reviewers
6 Ensure that the granularity of paper and electronic submissions should be
equivalent
7 Ensure that your submission is properly formatted to avoid unnecessary queries
from the reviewers/ refusal to file notification
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8 Ensure that properties such as page number, link type, link text, target document,
destination, zoom and alike are properly defined.
9 Ensure that the contents are legible and are easy to read
10 Ensure that Adobe Acrobat shall have a minimum 1.4 version. However. Higher
versions such as 1.7 are preferred.
11 Ensure that The official page size is : 8.5 by 11 inch paper;
12 Ensure that presentation allows Full text searching of the documents ,Quick
updating, accessibility to old documents
13 Ensure that there is Facility to mark the comments as the document is reviewed for
sharing the views from the other reviewers
14 Ensure that the Documents are Easy to Navigate through book marks/hyperlinks
15 Ensure that : Gray scales and colors are avoided
HPLLC Graph : Minimum 300 DPI
Handwritten Notes : 300 DPI
Photographs : 600 DPI
16 Ensure that information in landscape pages is not very closely packed. ECTD
allows wider space in landscape pages to make the information legible.
17 Ensure that pages are oriented in Portrait style. The landscape orientation shall be
chosen only when the data is very broad and can not be displayed legibly
18 Ensure that only Arabic Numbers are used for pagination. Roman numbers are not
allowed.
19 Ensure that No special plugs is required for reviewing eCTD
20 Ensure that your submission includes the actual size label image. The colors used
for text and back ground shall be same as included in actual label. Ensure that
images of product container and carton is included in the submission
21 Ensure that it contains view panes of suitable sizes. The entire layout shall be
visible at one time.

7.0 SUBMISSIONS

7.1 Pre Submission Formalities

1 Ensure that you establish Test account with FDA for Pilot submission / amended
submissions to checks for possible deficiencies.
2 Ensure that you provide following details to FDA while registering for
submission: Contact Person Name, Company Name, Mailing address, Phone No,
email ID, likely date for filing eCTD and type of application e.g. NDA/ANDA
3 Ensure that your application number is six digits and your sequence number is of
four digits and the same is displayed throughout the submission

PN: CTD submission Support team is available at ESUB@fda.hhs.gov



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7.2 Pilot Submissions

1 The Electronic Submission Support Team will process the sample submission to
ensure that it conforms to FDA guidance and specifications as well as ICH
specifications and guidelines. Ensure that you receives Compliance report
2 Ensure that you donor submit your pilot eCTD through gateways which accept
Final submissions and vice versa. There is dedicated gateway for accepting final
eCTD
3 Ensure that you receives CTD number in advance with 60 days validity in
advance online at http://www.fda.gov/cder/ogd/#enumber

7.3 Final Submission

1

Ensure that you should correct all errors identified by the FDA before final
submission.
2 Ensure that pre assigned application number is quoted precisely in the final
submission.
3 Ensure that your first submission is provided with sequence no 0000 . and the
next one 0001 , then 0002 , etc.

7.3.1 Submission through Electronic Gateway on worldwide web

1 Ensure that duly signed and scanned copy of form 356h. is accompanied with
fillable and readable pdf application form (356 h) for eCTD
2 Ensure that specific gateway is used for submission of eCTD for drug products
and biological. Further, ensure that specific sub gateways are used for eCTD,
eNDA and eIND.

7.3.2 Submission through Electronic Media such as CDROM

1 Ensure that when eCTD is presented on CD/DVD, the same is labeled with
following details.
Name of applicant
Name of manufacturer
Type of the submission (i.e. NDA/ANDA/Renewal/
Product name
Date of submission
2 Ensure that when eCTD does not fit on a single CD, DVD may be used in place.

8.0 WARNING

1 Ensure that no information is excluded from the original submission unless it is
supported by variation/line extension.
2 Ensure that the side panel displays all valid book marks and hyperlinks
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9.0 CONCLUSION

ECTD is both simple and hard. It is simple who have both technical and electronic
expertise .It is hard for those who lack either in technical or electronic expertise or in
both.

10.0 REFERENCES

You may visit following WebPages to learn more on eCTD.

http://www.fda.gov/cder/regulatory/ersr/eCTD.htm
http://www.fda.gov/cder/guidance/45390.pdf
http://www.fda.gov/cder/regulatory/ersr/5640CTOC-v1.2.pdf
http://www.fda.gov/cder/ogd/anda_checklist.pdf