How to prepare an application for revision of a · PDF fileHow to prepare an application for revision of a CEP P.Poukens-Renwart, 27-09-12 ©2012 EDQM, ... Any notification related

How to prepare an application for revision of a CEP

How to prepare an application for revision of a CEP

P.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved

P.Poukens-Renwart, PhDCertification of Substances Division

EDQM

Summary

• 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


Validity of CEP

Once your CEP has been granted it must be maintained throughout its lifetime!


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


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)


Types of changes• Notifications• Minor changes• Major changes• Renewal (after 5 years)• Update following revision of the

monograph or regulatory change

NB: Possibility to group variationsP.Poukens-Renwart, 27-09-12 ©2012 EDQM, Council of Europe, All rights reserved

Notification: Do and Tell principle

• Immediate notifications (IN) or

• Annual Notifications (AN)(to be submitted within 12 months after implementation)

Timescale : 1 month


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)


Minor Change• Minor change is “by default” => No conditions• Some typical minor changes listed in the guideline:

Timescales :

• Single 30 days• Multiple or grouped 60 days


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


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


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)


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).


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!


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


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 authoritiesNB: The signature of these commitments is part of the criteria for validating the applications at receipt.


Application form : how to fill it?

• Specify the type of application by ticking ONE box:• If Notif + minor => « minor »• If Notif + major => « major »• If Notif and/or minor + renewal => « renewal »


Application form: Names and addresses

• Give appropriate administrative information=> reported on the CEP


Application form: specific information

• Tick the type of notifications (INx, ANx) and specify implementation date for Annual notification

• Tick the type of major change


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


Application form: invoicing details

• Item selected should be in line with selection under 1.2 type of application.


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.


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


Some examples


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.


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


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 finalsubstance

• = Minor revision (by default), if the request is not a major revision nor a notification


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


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)


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


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


Support to applicantsBefore 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


Acknowledgements

My special thanks to

• Hélène Bruguera (Head of Certification Division at the EDQM)

• All my colleagues from the Certification Revision Team


☺ QUESTIONS ?


Documents

How to prepare an application for revision of a · PDF fileHow to prepare an application for revision of a CEP P.Poukens-Renwart, 27-09-12 ©2012 EDQM, ... Any notification related