1 Copenhagen, Denmark 24 – 27 September 2018
Implementation of the CTD format for the
vaccine prequalification
Dr Alain Fauconnier, Scientist, Vaccines Assessment
New format of Vaccine Prequalification dossier
• Until recently, the format of the dossier to be submitted for
vaccine prequalification was PSF, as specified in TRS 978,
Annex 6
• The PSF format requirements (effective from 2012) had
only changed marginally from the previous process
revision (2005) but did allow for the PSF to be
supplemented by cross referenced CTD dossier
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PSF…
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• Common Technical Document
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… versus CTD
4
• ICH
• The global use of CTD format has increased significantly since the last
revision of the vaccine prequalification procedure
• Most manufacturers have a prepared dossier in CTD format that they
have used to register the product in one or more countries
• Reduces manufacturers’ regulatory burden for maintaining and
updating dossiers in multiple formats
• Many countries that import prequalified products require submission of
a CTD format dossier for registration
• Easier exchange of regulatory information between Regulatory
Authorities
• A common format is paving the way to electronic submissions
• CTD dossier format was already used for WHO prequalification
submissions for pharmaceuticals
The reasons to change
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Designed to be a ‘living’ document
As a consequence, modular format (granularity)
Granularity is the extent to which a system is broken
down into small parts, either the system itself or its
description or observation. It is the extent to which a
larger entity is subdivided. (Wikipedia)
CTD
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• The electronic Common Technical Document (eCTD) is
an interface for the pharmaceutical industry to agency
transfer of regulatory information
• Internationally agreed (ICH) standard for structured
electronic submissions
• The eCTD is a particular type of electronic submission
• Important distinction: eSubmission or non- eCTD
electronic submission (NeeS) ≠ eCTD
eCTD (electronic CTD)
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• eCTD is much more than a simple electronic information
transfer tool
• It is structured as a tree of folders following the CTD
format and including essentially pdf documents
• It includes an index (xml backbone) which constitutes the
table of content (TOC) of the eCTD folder, allowing
navigation within the folder
• It requires dedicated softwares (specialized eCTD
viewers)
eCTD (electronic CTD)
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m3-2-p-5-3-validation-of-analytical-procedures
Validation of Analytical Procedures [new]
Method Validation Summary Report - Aluminum Assay [new]
Method Validation Summary Report - Antigenicity Assay [new]
Method Qualification Summary Report – Appearance [new]
Method Validation Summary Report - Identity [new]
Method Validation Summary Report - Polysorbate 80 [new]
Method Validation Summary Report - Protein [new]
m3-2-p-5-4-batch-analyses
Batch Analyses [new]
m3-2-p-5-5-characterisation-of-impurities
Charaterization of Impurities [new]
m3-2-p-5-6-justification-of-specifications
Justification of Specifications [new] m3-2-p-6-reference-standards-or-materials
Reference Standards or Materials [new] m3-2-p-7-container-closure-system
Container Closure System [new]
Drw-DMC119: Syringe Barrel Customer Product Drawings [new]
Drw-CDP9108: Stopper Customer Product Drawings [new]
eCTD
• Electronic applications are expected for vaccine PQ
• Under NeeS (and not eCTD) format
• Avoiding extreme granularity
Electronic submission
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• Modules 2-5 of CTD format include information on quality/safety/efficacy
• They are (supposed to be) common wherever the dossier is submitted
Content – Modules 2-5
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• Comparison of ASEAN, India, Jordan, PAHO and Thailand
versus ICH (FDA)
• The degree of difference for Modules 2–5 of CTDs is more
than 75% different in contents and above 79% different in
sections’ numbering
• This is higher than the degree of difference for Module 1
(38% different in content and 70% different in numbering)
• Modules 2-5 of vaccine PQ applications should follow the
standard ICH-CTD format, as described in ICH guidelines
Content – Modules 2-5
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• Module 1 of CTD format is used for specific information
depending on the agency to which the dossier is
submitted
• WHO website indicates proposed content of Module 1 for
WHO PQ submission
• Comment on the content was invited from interested
parties before finalisation
Content – Module 1
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1.1. Table of content
1.2. Correspondence
1.3. Site Master File
1.4. Compliance information
1.5. Vaccine composition, presentation and scheduling information
1.6. Supplemental pre-clinical and clinical Information (Pre & post marketing)
1.7. Regulatory actions
1.8. Distribution information
Content – Module 1
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• December 2017: PQT/VXA decided to adopt a CTD based format for
the Vaccine Prequalification dossier
• Ongoing transitional period: PQT/VXA continues to accept dossiers in
the PSF format
• May – June 2018: survey addressing the state of readiness of the
manufactures/applicants in the implementation of the new format
• Received comments are currently under review
Timeframe
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• Objective : intended to identify the manufactures/ applicants
◦ that are ready to submit immediately using the CTD format
◦ who need a grace period to transition into the new format
• Survey sent to 46 manufacturers, DCVMN, IFPMA
• 25 responses were collected
Feedback on the survey
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• Out of 25 responses
Feedback on the survey
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Yes No Not
responded
Use the CTD format? 21 84% 4 16% 0 0%
Ready to switch? 17 68% 2 8% 6 24%
Need support ? 2 8% 15 60% 8 32%
• Seeming favourable situation needs to considered with
cautious
• Half of the manufacturers did not answer
• 24% did not answer to question ‘ready to switch’
• 32% did not answer the question ‘need support’
Feedback on the survey
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• Worst case interpretation: only 14 (out of 50), i.e. 28%,
use CTD, are ready to switch and do not need support
• What is the CTD format actually used?
◦ 1 respondent mentioned aCTD
◦ What about the others?
Feedback on the survey
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• There are sound reasons for switching from PSF to CTD
format
• ‘Standard’ ICH-CTD format is to be used for PQ
• Electronic submission under NeeS (not eCTD)
• In the end, switching will be favourable for all parties
• One cannot exclude that a number of manufacturers are
not ready to make the leap yet
• The transitional period should not be abruptly interrupted
To conclude
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• Current WHO Prequalification procedure
http://www.who.int/entity/immunization_standards/vaccine_quality/TRS_978_61
st_report_Annex_6_PQ_vaccine_procedure.pdf?ua=1
• Web notification of proposed change to CTD dossier format
http://www.who.int/entity/immunization_standards/vaccine_quality/TRS_978_61
st_report_Annex_6_PQ_vaccine_procedure.pdf?ua=1
• Adoption of CTD format for vaccine PQ dossier, including content of Module 1
http://www.who.int/immunization_standards/vaccine_quality/vaccine_PQ_dossi
er_122017/en/
• ICH guidelines for Modules 2,3,4 and 5 http://www.ich.org/products/ctd.html
• Dellepiane et al - Differences in CTD dossier requirements
https://www.sciencedirect.com/science/article/pii/S0264410X18304055
References
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Thank you