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How to prepare an application
for revision of a CEP
P.Poukens-Renwart, PhD
Certification of Substances Division
EDQM
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Summary
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Validity of a CEP
Revision background
Types of revisions and examples
How to prepare the application for revision
When are CEPs revised and what to do when
a revision is approved
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Validity of CEP
Once your CEP has been granted it must be
maintained throughout its lifetime!
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Basic principles for maintaining a CEP
• Any change (administrative or technical) must be
reported to EDQM for approval
• Original CEP: valid 5 years.
• Holder needs to apply for renewal in time (6 months
before expiry)
• After renewal, CEP valid for an unlimited period,
provided the dossier is kept up-to-date
• In all cases, holder to inform customers of the change
• Revised CEP to be sent to customers
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Revisions of CEPs: Background
• Based on EU Regulations on Variations to
Marketing Applications
• Specific guidelines for revisions of CEPs:
– Guideline on requirements on revision / renewal of CEPs
(PA/PH/CEP (04) 2 4R)
– New procedures for management of revision / renewal of
CEPs (PA/PH/Exp. CEP/T (04) 18 2R)
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Types of changes
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Notifications
Minor changes
Major changes
Renewal (after 5 years)
Update following revision of the
monograph or regulatory change
NB: Possibility to group variations
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Notification: Do and Tell principle
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Immediate notifications (IN)
•
Annual Notifications (AN)
or
(to be submitted within 12 months after implementation)
Timescale
: 1 month
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Workflow for Notification
• No Acknowledgement of Receipt
• Letter sent to advise that either the notification has
been accepted as valid or has been rejected.
No request for additional information
• Revised CEP only issued when the information on
the CEP is changed (i.e.name and address)
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Minor Change
• Minor change is “by default” => No conditions
• Some typical minor changes listed in the guideline:
Timescales :
• Single
• Multiple or grouped
30 days
60 days
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Workflow for minor changes
• Acknowledgement of Receipt sent within 5 days
• One request for additional information sent if
necessary
• Holder has 30 days to respond to this request
• EDQM has 30 days to evaluate the response
• EDQM feed-back:
• Notice of approval or revised CEP issued
• request for revision rejected
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Major Changes
• Timescale
60 days
• Workflow:
• Acknowledgement of Receipt sent within 5 day
• One request for additional information sent if
necessary
• Holder has 30 days to answer this request
• EDQM has 30 days to evaluate the response
• EDQM feed-back:
o Revised CEP issued
o Request for revision rejected
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Update after Monograph
Revision
• Initiated by EDQM: when a revised monograph is
published, EDQM sends request for data (either
demonstration of compliance or suitability of the
monograph)
• Holder asked to supply the requested information
within 3 months (it is mandatory to answer)
• Response assessed within 3 months
• EDQM feed-back:
o Approval
o Revised CEP issued (if the information on the CEP changes)
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Renewal
• Holder to apply about 6 months before expiry
• The following documentation should be provided:
– Declaration that no change has occurred since
the last revision OR
– In case of changes included in the request (no
major changes):
• updated dossier (CTD)
• comprehensive list of changes
• supportive data
• Timescale 3 months
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Workflow for Renewal
• Acknowledgement of Receipt sent within 5 days
• If request for additional information sent
- Holder has 30 days to respond to this demand
- EDQM has 30 days to evaluate the response
• If holder applied in time and evaluation on-going at
expiry date: the CEP will be temporarily renewed
unless there is an unresolved issue with the dossier
• EDQM feed-back:
– Renewed CEP issued (if assessment finalised before expiry)
– Revised CEP issued (if conclusion of assessment invalids
temporarily renewed CEP).
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Assessment of Renewal
dossiers
– Compliance with General Monograph 2034
“Substances for Pharmaceutical Use”
– Compliance with recent European quality
guidelines: e.g. impurities, residual solvents,
residual catalysts
– Any declared changes
Not an administrative job!
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Submission of a notification /
revision
• Each submission should be composed of the
following modules
– Module 1:
• Cover letter describing the request
• Application form
• Supporting documentation
– Module 3: All updated section of the dossier
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Module 1: application form :
– Give appropriate administrative information
– Select type of revision in the classification table (notification
or major revision) or detail the specific minor revision
– Select the corresponding revision(s) on the invoicing sheet
– Sign the commitment to inform your customers in case of
CEP revision, CEP suspension, withdrawal or negative
outcome of an EDQM inspection
– Sign the commitment that you are informed and you accept that
assessment reports may be shared with competent authorities
NB: The signature of these commitments is part of the criteria for
validating the applications at receipt.
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Application form : how to fill it?
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Specify the type of application by ticking ONE box:
If Notif + minor => « minor »
If Notif + major => « major »
If Notif and/or minor + renewal => « renewal »
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Application form: Names and addresses
• Give appropriate administrative information
=> reported on the CEP
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Application form: specific information
• Tick the type of
notifications (INx, ANx)
and specify implementation
date for Annual notification
• Tick the type of major
change
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Application form: specific information
• When applying for minor change(s) please select or give
details related to these not listed changes
• ! AN4: minor change to the manufacturing process …
should not be reported in this box
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Application form: invoicing details
• Item selected should be in line with selection
under 1.2 type of application.
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Module 1: Supporting documentation
• A complete list of the changes + brief summary
• For notifications : confirmation that all conditions
of EDQM guideline are fulfilled
• For minor or major revisions : justification of the
classification + supportive data (comparative tables,
declarations, discussion on impurity carry-over,
batch data...) and/or reference to the relevant parts
of the dossier where information is to be found.
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Module 3: Updated sections of the dossier
• Sections impacted by the changes
• Sections should be complete and in line with the
original granularity of the dossier
• Annexes should be avoided (info should be
included in Module 1 and also in the relevant
sections
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Some examples
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Changes related to the manufacturing process
• A synthetic route is characterized by the starting materials,
intermediates and process steps, and also by the reagents,
the solvents and any catalysts used for the synthesis.
• A declaration stating that the synthetic route remains
unchanged implies that all these elements remain the same.
• Declarations that the route is “essentially” the same are not
acceptable :any difference between the approved and
proposed synthetic routes has to be detailed and discussed.
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Changes related to the manufacturing process
• = Notification when all conditions listed in the guideline are
fulfilled (covers mainly minor changes to quantities of materials or
operating conditions)
• = Major revision if there is any substantial change to the
synthetic route which may impact the qualitative and quantitative
impurity profile of the final substance (e.g. any new solvent
independently of its class, reagents, catalysts introduced or
changed in the synthesis).
• = Minor revision (by default), if the request is neither a
notification nor a major revision
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Change to a manufacturer / manufacturing
site for an intermediate or final substance:
• = Notification when the synthetic route, QC procedures and
specs of the intermediate and final substance remain the
same as those already approved and when the new
manufacturer is of the same group as the approved
manufacturer
• = Major revision when there is a change to the synthetic
route, to the quality control procedures or to the
specifications for the proposed manufacturer (or site) of an
intermediate or for the proposed manufacturing site of the final
substance
• = Minor revision (by default), if the request is not a major
revision nor a notification
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Change to a manufacturer of starting
material:
• = Notification when the synthetic route, QC procedures and
the specs of the SM remain the same as those already
approved and when the new manufacturer is of the same
group as the approved manufacturer.
• = Major revision when there is a change to the synthetic
route, to QC procedures or to specs for the proposed
manufacturer (common situation)
• = Minor revision (by default), if the request is not a major
revision nor a notification
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Changes to an analytical procedure:
• = Notification provided that the method remains essentially the
same. NB: changes should be within the ranges allowed by
the Ph. Eur general chapter 2.2.46-Chromatographic
separation techniques.
• ! Any notification related to a test method appended to a CEP
=> revision of CEP.
• = Minor revision (by default), if the conditions for a notification
are not met (Cross validation data required)
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
When are CEPs revised ?
• After any notification/minor revisions impacting the
content of CEP
• After any major revisions
• After renewal
• When conclusion of assessment of renewal invalids
the temporarily renewed CEP at expiry
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
What to do after approval of a
request for revision ?
• What to do with a revised CEP ?
– Provide a copy to customers
– Update of relevant Marketing Authorisation
Applications
→ Mandatory
• What to do when a change is approved but CEP is
not revised ?
– Inform customers
→ Mandatory
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Support to applicants
Before preparing a request for revision
• Check EDQM website for:
– Published Guidelines & Notes (pages “Revisions &
Renewals) – New guideline available on how to
submit a request
– FAQs
– Contact EDQM for clarification (Helpdesk)
• Use Technical advice in case of doubt / complex
schemes / specific questions
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
Acknowledgements
My special thanks to
• Hélène Bruguera
(Head of Certification Division at the EDQM)
• All my colleagues from the Certification Revision
Team
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved
☺ QUESTIONS ?
P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved