1. Welcome to: eCTD Hands-on Workshop
Creating your first eCTD Submission
(Session 2) 1

2. Agenda (Session 2) Steps involved in creating an eCTD Submission
Create Submission Map
Create Submission Documents
Compile the Documents in eCTD format
Publish the eCTD Assembly 2

3. Create Submission Map Overview Sample Submission Map Template
Submission Metadata
Document to Module Mapping 3

4. Submission Map
A successful submission begins with creating a roadmap for the entire submission 4

5. Submission Metadata(1)
EU-Envelope
Country
EMEA
Application Number cp
Applicant
Take Pharma
Agency Name
European Medicines Agency
ATC
L01DB03
Submission Type
Initial Marketing Authorisation
Procedure Type
Centralised Procedure
Invented Name
Medicinal Product
INN
Active Ingredients
Sequence
OOOO
Related Sequence NA
Submission Description
This is a MAA for Drug product for belgium under national procedure 5

6. Submission Metadata (2)
Application Number (EU)
Application number is Alpha Numeric
EU/1/00/150/001
Application number is key – ties all submissions together as an application 6

7. Submission Metadata (3)
Sequence Number (EU)
Sequence number values must be four digits -
No alpha characters
No “-”, “,” or other punctuation
No spaces
Sequence number is key and relates all submission components together
Sequence numbers need not be received/submitted in sequence 7

8. Submission Metadata (4)
Procedure Type
Centralised procedure
National procedure
Mutual recognition procedure
Decentralised procedure 8

9. Submission Metadata (5)
Application Types (EU)
New Active Substance (Same as NDA)
Abridged Applications ( Same as ANDA)
Biological and Biotechnological Products (Same as BLA)
Active Substance Master File (ASMF) 9

10. Submission Metadata (6)
Submission Types (EU)
Initial marketing authorisation application
Supplemental information after questions
Follow-up measure
Specific obligation
Variation type 1a
Variation type 1b
Variation type 2 10

11. Submission Metadata (7)
Submission Types (EU)
Periodic Safety Update Report
Renewal
Drug master file
Arbitration under article 29, 30 or 31
Specific obligation following conditional approval
Safety restriction 11

12. Submission Map Template12

13. Create Submission Documents
Overview
Image-Based Docs
Document Scanning
Page Numbering
Navigation Aids 13

14. Submission Docs (1) Avoid Image based docs
Agency strongly urges sponsors to provide text-based documents rather than scanned image-based documents because:
Occupies more storage space
Electronically unsearchable
Longer time to print them
Can be difficult to read 14

15. Submission Docs (2) Image-based docs
Scanned image-based documents can be considered in the following situations:
Hand-written and signed documents
Documents generated outside the company
Documents that are available only in paper 15

16. Submission Docs (3)
Scanned documents at a resolution of 300 dpi balances
Legibility (computer screen/printouts) and the file size
Use of Gray Scale and Color
Increases the file size
Should be used only to improve the reviewability of the material
Post Scanning
Avoid re-sampling to lower resolution (sizing) 16

17. Submission Docs (4) Scanning Resolution Document Types Resolution 1
Handwritten Notes
300 dpi (black ink) 2
Plotter output graphics
300 dpi 3
Photographs – Black & White
600 dpi (8-bit gray scale) 4
Photographs – Color
600 dpi (24-bit RGB) 5
Gels and Karyotypes
600 dpi (8-bit grayscale depth) 6
High pressure liquid chromatography 17

18. Submission Docs (5) Page Numbering
Across documents paging is not required
Easy navigation
If page numbers of the document and PDF numbering are in synch
Page numbers are Arabic numerals, numbered consecutively, starting with page 1 including appendices and attachments
Avoid Roman numerals (e.g. Title page, TOC)
Avoid unnumbered pages (e.g. Title page) 18

19. Navigation Aids – Bookmarks
Submission Docs (6)
Navigation Aids – Bookmarks
Provide Bookmarks with intuitive names 19

20. Submission Docs (7)
Bookmarks arranged hierarchically enhance reviewability 20

21. Submission Docs (8) When to provide hyperlinks?
Anytime the text refers to a reference (table, figure, etc.) that is not on the same page
Validate all hyperlinks and bookmarks
Broken hyperlinks and bookmarks diminish reviewer confidence in the submission
Include TOCs in almost all PDF documents 21

22. Submission Docs (9) Documents should conform to eCTD granularity
Avoid combining documents at higher parent leaf level
Tempting – small initial savings in combining
Large cost in lifecycle complexity 22

23. Compile in eCTD Format Overview eCTD Triangle
Leaf Title & Leaf Operations
Lifecycle Management
Files, Folder naming conventions
Assembling M1-M5
Study Tagging File
Document Re-Use 23

24. Nonclinical Study Reports Clinical Study Reports
eCTD Triangle
Module 1
Regional Admin
Module 2
Summaries
Japanese
Language
2.3.R
ISS/ISE
3.2.R
Node
Extensions
Case Report
Forms
Module 3
Quality
Module 4
Nonclinical Study Reports
Module 5
Clinical Study Reports
Tab List
Trial Subj
STF
Dataset
Folders 24

25. Leaf Metadata Leaf Title Leaf Operation
Should be informative and succinct
Should not include the eCTD numbering
Should immediately reveal to the reviewer what’s inside
Leaf Operation 25

26. Leaf Title Example
Note: Reviewers would not be able to view the entire title if it is too long 26

27. Leaf Operation Attribute
It is a key to managing each individual file in a submission
Applicant uses this attribute to inform the reviewer how he intends the files in the submission to be used
It describes the relation between files in subsequent submissions during the lifecycle of a medicinal product 27

28. Accepted Leaf Operations
New: The file has no relationship with files submitted previously.
Append: There is an existing file with which this file should be associated (e.g., providing missing or new information to that file). Append should not be used to associate two files in the same submission (e.g., splitting a file due to size restrictions). 28

29. Accepted Leaf Operations
Replace: This means there is an existing file that this file replaces.
Delete: This operation identifies the file in a previous submission that is to be considered no longer relevant to the review. There is no file submitted in this case. 29

30. Accepted leaf Operations
In the very first submission all the files will have operation “New”
In subsequent submissions for an application, files can have different values depending on their relation with previous submitted files 30

31. Document (leaf) Lifecycle
App#
0000
Sequence
0001
Net View
index.xml
index.xml
M2.2
M2.2
M2.3.P
Introduction.pdf
Introduction.pdf
Desc_comp-
prod.pdf
M2.3.P
M3.2.P.1
Desc_comp-
prod.pdf
M3.2.P.1
Desc_comp-
prod.pdf X
Delete operation
Folders
Files
XML
Legend 31

32. Lifecycle Sample 32

33. Lifecycle Sample 33

34. File Names Rules File Extensions Naming Conventions
Only one file extension
File extensions indicate the format of the file
Naming Conventions
Lowercase
No spaces
Alphanumeric, hyphen and minus are allowed
Maximum characters allowed is 64, including the extension
File name and extension are separated by a period 34

35. Folder & Path Names Rules Folder names cannot exceed 64 characters
Path cannot exceed 230 characters including the file name and extension
Folder and file names need to be abbreviated in situations exceeding 230 characters 35

36. Files, Folders & File Path
File names, folders and file paths are not displayed explicitly to reviewers
A good eCTD builder tool would check for all the file, folder and file path validations and intuitively enable the user to conform 36

37. Application / Submission Identity
Assembling Module 1
Application / Submission Identity
Module 1 is the only place where application administrative/identification information is provided in “machine readable” form
Include Module 1 in all your eCTD Submissions
Forms and cover letters should be considered “new” documents submitted to an application 37

38. Assembling Module 1 What if there’s no available heading?
Special programs
Accelerated approval
Priority Review Cover
Subpart E
General Investigational Plan (outside of an annual Report
Make Use of the Cover Letter 38

39. Assembling Module 1 39

40. Assembling Module 2 40

41. Assembling Module 2 Things to Do Summarize Modules 3, 4 & 5
Make your points in sum and refer to (don’t repeat) details in other sections
Use leaf titles for differentiation of documents at the same level
Ensure your Module 2 meets the definition of a summary 41

42. Assembling Module 2 Things Not to Do
Don’t include 10,000 pages of detailed patient profiles and other data
Patient Data  Module 5
ISS and ISE  Module 5
Don’t use Node extensions
Don’t combine documents together at too high a granularity level 42

43. Assembling Module 3 Multiple drug substances (e.g. Augmentin)
<m3-2-s-drug-substance substance=“amoxicillin”
manufacturer =“ABC, Inc; Ringaskiddy, IE; CFN ”>
Substance 2
<m3-2-s-drug-substance substance=“clavulanic acid”
manufacturer =“XYZ, Inc; Mumbai, IN; CFN ”> 43

44. Assembling Module 3 One drug substance Two Manufacturers Case 1 Case 2
<m3-2-s-drug-substance substance=“amoxicillin”
manufacturer =“ABC, Inc; Ringaskiddy, IE; CFN ”>
manufacturer =“XYZ, Inc; Mumbai, IN; CFN ”>
Case 2
manufacturer =“ABC, Inc; Ringaskiddy, IE; CFN and
XYZ, Inc; Mumbai, IN; CFN ”> 44

45. Assembling Modules 4 & 5 Modules 4 & 5 are very similar
Both contain study results, data and related information
Module 4 – Pre-clinical (Safety)
Module 5 – Clinical (Efficacy)
Approach for building M4 and M5 is very similar 45

46. Similarities and Differences
Assembling Modules 4 & 5
Similarities and Differences 46

47. Study Example 47

48. Document Re-Use
A document can be associated with more than one heading.
However, the actual electronic file would only be provided once.
The eCTD specifications provide details on how to refer to an electronic file. 48

49. eCTD Specifications
EU Module 1 Specification
ICH Modules 2 to 5 Specification 49

50. Publishing in eCTD format
Overview
Publishing in eCTD format
Published Package
Testing the Published Package 50

51. Publishing in eCTD format
Follow your internal SOP before publishing the dossier in eCTD format
Validate the XML backbone against the schema
Preview and Review the pre-published package
Get the concerned Approvals and record the Publishing act through an electronic signature or system audit trails 51

52. Published Package (1) 52

53. Published Package (2)
Published package must contain the following standard components
Util folder
3 standard DTDs
3 standard style sheets in util folder
Custom components create issues in Agency’s environment
Checksum file
One or more Module folders
Avoid GIFs, custom CSS, custom DTDs, custom elements with standard DTDs 53

54. Test the Published package
Test the Published package before you submit
Open the eCTD XML backbone in a browser
Validate all the file references from the XML backbone
Check for the Util folder and the checksum files
Write the Package to a CD/DVD and send it to the Agency 54

55. Session 2 Review…
How many repeatable sections (such as drug substance) are there in Module 3?
If a document has to be reused in two different sections within a single submission, is it necessary to send two copies of the document with the submission? 55

56. Questions
END OF SESSION 2
Any Questions? 56