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1 SARI 2014 Pharmaceutical Science, Medicine Registration and Control “A scientific approach” Estelle Taute, MCC eCTD and CTD update
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SARI 2014
Pharmaceutical Science, Medicine Registration and Control
“A scientific approach”
Estelle Taute, MCC
eCTD and CTD update
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Overview
Specifications, Guidelines Guidance and Technical requirements
How to find documents in CTD and eCTD
Requirement vs actual CTD
Technical validation failure
Business validation failure
Evaluation phase
Do’s and don’ts
Guidelines & Specifications
Everything required for paper CTDs PLUS
eCTD specific documents
CTD e.g.:
– ZA CTD
– Module 1.2.1
– 2.01 General Information
– 2.05 Stability
– 2.06 Biostudies
– 2.07 Dissolution
– …..
– 2.24 Guidance General Module 1
– 2.25 P&A CTD
– 6.15 Screening template for new
applications for registration
Plus
– 2.21 South African Specification for
eCTD Regional & Module 1
– 2.22 South African eCTD Validation
Criteria
– 2.23 Guidance for the Submission of
Regulatory Information in eCTD
format
– 2.27 eCTD Checksums
– 2.28 Q&A Implementation of eCTD in
South Africa
– Electronic Common Technical
Document Specification V3.2.2
(http://estri.ich.org/eCTD/)
1.3 Technical requirements
The specification is designed to support high-level functional
requirement such as
• Copying and pasting
• Viewing and printing of documents
• Annotation of documentation
• Facilitating the exporting of information to databases
• Searching within and across applications
• Navigating throughout the eCTD and its subsequent
amendments/variations
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eCTD requirements
2.21 Specification
2.23 Guidance
3 Structure and content
e.g. eCTD identifier, envelope, folders, Module 3.2.R, letter of
application
4.1 Submission media
• Hard media e.g. CD / DVD - no laptops or other hardware
• Large application – single DVD rather than multiple CDs
• Individual modules not split over multiple CDs
• Adequately packed and labelled
4.3 PDF files
• Version 1.4, 1.5, 1.6 or 1.7
• Maximum individual acceptable file size is approximately 100 MB.
File size should ensure clarity, speed of download and ease of
review.
4.5 Hyperlinks
4.7 Additional files in Word format
Appendix 2: List of documents in paper format
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eCTD requirements cont.
2.21 Specification
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eCTD requirements cont.
2.23 Guidance
3.5 Letter of Application – folder 1.0 of Module 1
Accompany all submissions - in both paper and portable
document format (PDF). The PDF should be a scan of the
originally signed document and must be searchable
(OCR scanned).
State the context of the submission, e.g. the submission type
and the application or registration number.
The paper and PDF letters must have the same content.
Document operation attribute should always be “new”.
The printout of the checksum file (index-md5.txt) should be
attached as an annex to the letter (paper version). The annex
must be dated and signed.
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eCTD requirements cont.
• The following statement must be included:
- “We confirm that the CD/DVD-burning session is closed
and the submission is checked with an up-to-date and
state-of-the art virus checker: [name of the antivirus
software and version of the virus checker]”
• Tabular format of tracking (history) of the submitted
sequences (or in annex)
• The letter (paper version) must be signed
• Include / annex eCTD ”Reviewer’s Guide” or similar
document for reviewers if there are specificities
concerning the eCTD submission, e.g.
Hyperlink appearance and strategy
Bookmarks
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Letter of application cont.
3.2.R structure
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3.2.R Granularity
3.2.R 3.2.R.1 3.2.R.1.1 Overview
3.2.R.1.2 Reference product (identification/docs)
3.2.R.1.3 Certificates of Analysis
3.2.R.1.4 3.2.R.1.4.1 Dissolution
3.2.R.1.4.2 Exemptions and Other
3.2.R.2 3.2.R.2.1 API parent manufacturer and sites
3.2.R.2.2 CoAs
3.2.R.3 CEPs
3.2.R.4 3.2.R.4.1 Comparison of API synthesis routes
3.2.R.4.2 Tabulated comp results >1 API manufacturers
3.2.R.4.3 Confirmation of compliance with guidelines
3.2.R.4.4 Certificates of Analysis each batch in 3.2.R.4.2
3.2.R.4 Declaration - similarity of FPP process
3.2.R.5 Medical device
3.2.R.6 Materials of animal / human origin
3.2.R.7 Batch records of sample confirm availability
3.2.R.8 Other
Documents rolled up to this level are not considered appropriate
One document may be submitted at this level
How do we find documents?
CTD
2.24 Guidance – General
Module 1.1 Comprehensive table of contents
Module 1 should include a comprehensive table of contents for the entire
application. The comprehensive table of contents should include a
complete list of all documents provided in the application by module.
In the table of contents, the location of each document should be identified
by referring to the volume numbers that contain the relevant documents and
any tab identifiers. In general, the name for the tab identifier should be the
name of the document (section heading according to the CTD format e.g.
3.2.P.4.2). If the full name of the document is too long for the tab identifiers,
an alternative name that adequately identifies the document should be
substituted. Page numbers should not be used in the table of contents to
refer to documents, rather, tab identifiers as described above should be
used.
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CTD cont.
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2.01 General Information 4.3 The application for registration of a dossier should have clearly labelled tabs to
indicate each PART and sub-PART or appendices/documents/reports of the dossier.
Responses to recommendations should comply with the format and requirements of the
Amendments guideline. Each part / section of the response should be indicated by
clearly labelled tabs.
2.24 Guidance – General
3 Organising documents
Documents can be combined in volumes as long as they are separated by appropriately
named tab identifiers.
5 Pagination
A document is a set of pages, numbered sequentially and divided from other documents
by a tab.
Page numbering should be at the document level and not at the volume or module level.
(The entire submission should never be numbered consecutively by page.)
In general, all documents should have page numbers. Since the page numbering is at the
document level, there should only be one set of page numbers for each document.
Cross-referencing to documents should be made by referring to the CTD module, volume,
tab identifier, and page number (for example: “see Module 3, Vol. 6, P.4.3 Method
validation, p 23”).
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How to find documents in eCTD
Hypertext linking and Bookmarks
ICH eCTD Specification v3.2.2
Appendix 3 General Considerations for the CTD
Modules (page 3-1)
Appendix 7 Specification for Submission Formats
(page 7-3 to 7-4)
http://theectdsummit.com/eCTD/bookmarks-and-hyperlinks/
2.23 Submission in eCTD format
4.5 Hyperlinks
References in documents (e.g. tables, figures, images, sections,
inter-document links)
ToCs hyperlinked to the corresponding sections in the document
3.5 Letter of Application
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Bookmarks
Provide bookmarks for documents
exceeding 5 pages that contain multiple
headings/sections, tables, figures
Provide enough bookmarks for easy
navigation in the document
Use meaningful names
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Leaf titles
Each document in the eCTD has both a file
name and a leaf title.
File name is the actual name of the file – the
evaluator doesn’t see this
e.g. application-letter-10mg.pdf and label-10mg.pdf
are the file names
Leaf title is displayed when the evaluator views
the submission
Leaf titles cont.
Requirement vs Actual
What have we have found to date
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Presentation
CTD
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ToC not comprehensive – refers to main modules only
Tabs are not included
Tabs are not sequential
documents in incorrect sequence
Tabs do not reflect section number
Tabs fall off during handling
Tabs are illegible – handwritten or names too long
Coloured pages included as dividers but no tabs
Module numbered instead of at document level
3.2.R not completed e.g. for NCEs
Post-screening sets in sequence of MRF1 and not CTD
Amendment schedule not used correctly – reply to Committee
recommendations and post-reg amendments
Hybrid submissions (only allowed for post-reg amendments)
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Examples of what reviewer sees
Submission Explorer Document Explorer
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What does reviewer see
EURS is Yours colour code identifies changes by the applicant
Modifications to
former submission
Modifications in documents
eCTD pilot Validation & other errors
Only 2 submissions passed technical & business validation upon first
submission
4 submissions failed technical validation
12 submissions passed technical but failed business validation
Up to 4 sequences before complying
New sequence 0000 instead of 0003 to minimise confusion in first review
Because of invalid sequence 0000, non-compliance in business validation
only detected in sequence 0001
Errors corrected in 0001 only to find new errors, e.g.
• letter OCR scanned in 0000 but not in 0001
• Application forms of different strengths identified in 0000 but not in
0001 (leaf titles)
• PIL no longer hyperlinked
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Technical Validation Failure cont.
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Technical Validation Failure
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All showed own validation = valid
Validation carried out on the submission e.g. on
desktop and not on medium submitted
Files in Module 3 found to be missing
Export path too long
Checksum not valid
PDF protected by security settings or a
password (rule no. 18)
File or folder name contains invalid characters
Unable to make ISO copy
DVD-RW or CD-RW used
Multisession DVD suggesting that it may not have
been properly closed
Zipped file submitted
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Technical Validation Failure cont.
Unreferenced files
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Technical Validation Failure cont.
The thumbs.db files resulting in the error can be
prevented.
Link to the Microsoft webpage in this regard:
http://social.technet.microsoft.com/Forums/wind
ows/en-US/fbc49141-96b3-4350-870a-
5b74dcf59c20/how-to-disable-thumbsdb-files-
generation-on-network-folders
Won’t see thumbs.db files unless you’ve
checked “Show Hidden Files and Folders” in the
Folder Option panel and are using the icon
mode in Explorer
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Technical Validation Failure cont.
To disable thumbs.db for Windows XP
Open My Computer
Click on Tools
Click Folder Options
Click the View tab
Put a check in the box next to “Do not cache thumbnails”
Click OK
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Technical Validation Failure cont.
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Best Practice Warnings
File size exceeds 100 MB (rule no. 28)
Best Practice Warnings cont.
Broken bookmarks
Broken hyperlinks
PDF does not open in “Most recent view”
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Incorrect information in envelope
Data in support of efficacy
Biostudy + Other
Clinical + Non-clinical
Related sequence
Information in envelope ≠ 1.2.1 ≠ 1.8
Letter not OCR scanned
Application Form 1.2.1 not OCR scanned
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Business Validation issues
PI / PIL / Labels not hyperlinked
Screening template not hyperlinked for ease of
technical verification by reviewer
Module 2 not hyperlinked to 3 / 4 / 5
CDs not correctly labelled
1.2.1 not signed
Confusion of dates in follow up sequences
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Business Validation cont.
Official document name in footer of 1.2.1 and 1.8 changed
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Business Validation cont.
Business Validation cont.
Application number not included in 1.2.1
3.2.R Regional Information
• Node extensions not used
• Section numbers not included
3.2 Body of Data
• Sections included that are not applicable
oThis affects life cycle management of these sections
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Evaluation phase
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Bookmarks & Hyperlinks
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How should the reviewer find the Annexures?
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Appendices not hyperlinked.
Documents that follow this list of Appendices are not the Appendices numbered,
also not in the same order as the list of Appendices
Bookmarks & Hyperlinks cont.
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Clinical report bookmark leads to a Statement
Bookmarks & Hyperlinks cont.
Other
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Not possible to copy text as documents
are not OCR scanned
Whole module numbered, instead of per
document
Module 3.2.R not completed
As for CTD
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Do’s and Don’ts
Granularity
Planning is important!
How does eCTD structure apply to product and
submission, especially with
Multiple manufacturers – API and/or product
Dosage strengths
Level of granularity
Only entire documents can be replaced in eCTD, not sections or
pages within a document
Initial granularity choices affect future updates and / or
amendments
(Refer to the ICH Granularity Document, Annex to M4: Organisation of the CTD)
Once granularity and structure have been decided, they
generally can’t be changed during the life cycle
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Module 1 – mandatory documents
The following documents are mandatory for
all application types:
Letter of application (1.0)
Application form (1.2.1)
• Also for PI amendments
Screening template (1.8), Section A.3
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Hyperlinks
Important to the evaluation process
Evaluators save time following hyperlinks
instead of searching for a reference (table,
figure, document, etc)
Hyperlinks that are not functioning properly can
erode the evaluator’s confidence in the
submission
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Hyperlinks cont.
Include at least the following hyperlinks:
Cross-references in the package insert (1.3.1.1) to the actual
references
Cross-references in the Patient Information Leaflet (1.3.2) to
the package insert (1.3.1.1)
References in Sections B to D of the Screening template (1.8)
to the documents in the eCTD
Summaries in Module 2 to the relevant documents in Modules
3 to 5
Document Table of Contents (ToC) to the corresponding
section in the document
Check the hyperlinks before submitting:
Are there any broken hyperlinks?
Do all hyperlinks go to correct destinations?
Are all external hyperlinks removed?
(e.g. web links, e-mail links)
Do hyperlinks appear as blue text or blue box links if
blue text isn’t possible?
Are hyperlinks set to Inherit Zoom?
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Hyperlinks cont.
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Bookmarks
Check the bookmarks before submitting
Does the bookmark name indicate the bookmark’s
destination/content?
Is the bookmark too long?
Are bookmarks provided for the ToC items?
Does the bookmark match the description/title showing
on the ToC?
Will someone who is unfamiliar with the application know
what content they’ll see before they click on the
bookmark?
Are bookmarks set to Inherit Zoom?
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Quality control
In eCTD format, QC includes
Check all hyperlinks and bookmarks
Check lifecycle functions (new, append, delete, replace)
Technical validation
Ensure no file names are truncated
Typically occurs when the path exceeds limits
Check leaf titles – short, indicative of document content
Correct validation errors before submission
Ensure media contains the submission and doesn’t have
defects
Ensure submission is virus free
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Electronic is not as patient as paper Paper is forgiving – can slot in extra pages or
replace documents just before submission
eCTD is not forgiving – last minute changes will
lead to checking of hyperlinks, re-validation,
re-export
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Before you submit, ask...
If I was an evaluator, could I…….?
Easily locate the information/document
Easily copy and paste from the document
Easily differentiate between same type documents
displayed in the eCTD
Easily navigate and access references in documents
via bookmarks, links and the Table of Contents
The ultimate goal is to provide an evaluator-
friendly eCTD so that the focus of evaluation is
on content, not format.
Conclusion
Presentation and content issues in CTD
manifest in eCTD
Read the guidelines
Follow the guidelines
Check the submission
Check the submission
Think like an evaluator
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Acknowledgements
Anita Smal – Abex Pharmaceutica, local Extedo
partner
Reviewers
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