Implementation of the CTD format for the vaccine prequalification · • The electronic Common...

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

Copenhagen, Denmark 24 – 27 September 2018 2

PSF…


• Common Technical Document

Copenhagen, Denmark 24 – 27 September 2018

… 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


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


• 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)


• 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)



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


• 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


• 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


• 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


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


• 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


• 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


• Out of 25 responses



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’



• 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?



• 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


• 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


http://www.who.int/entity/immunization_standards/vaccine_quality/TRS_978_61st_report_Annex_6_PQ_vaccine_procedure.pdf?ua=1
















http://www.who.int/immunization_standards/vaccine_quality/vaccine_PQ_dossier_122017/en/





http://www.ich.org/products/ctd.html








Thank you

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