1. Revisions of Certificates of Suitability (CEP) to the Monographs of the European Pharmacopoeia
Dr Pascale POUKENS-RENWART
Scientific Officer
Certification of Substances Division
EDQM
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2. Validity of CEP
Once your CEP has been granted it must be maintained throughout its lifetime!
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

3. 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
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4. How EDQM handles variations ?
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

5. 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 3R)*
New procedures for management of revision / renewal of CEPs (PA/PH/Exp. CEP/T (04) 18 1R)*
*available on EDQM website
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

6. Revisions of CEPs: Background
Review and changes implemented on July 2008
-> Previously, CEP was revised after each request for revision (even if content was not affected)
-> Now : for minor revisions except change of specification of the final substance, the CEP is NOT revised anymore but a notification of approval is sent instead.
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

7. Types of changes Notifications Minor changes Major changes
Renewal (after 5 years)
Update following revision of the monograph / regulatory change
Fee and deadlines available on EDQM website
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

8. Application for a revision
Application form (specific for revisions/available on
website)
Technical data (as detailed in Guideline on requirements on revision / renewal of CEPs (PA/PH/CEP (04) 2)) :
Justification of change
Assurance that the conditions are fulfilled
Updated pages of the dossier
Specific supporting documents
COMPARATIVE DATA - Full batch results
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

9. Notification Simple 2 weeks/500 euros
Timescales and Fees
Simple 2 weeks/500 euros
Multiple (max. 3) 30 days/1000 euros
Workflow:
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. and address)
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

10. Typical notifications
Change in holder, manufacturer references: holder name, address (no move),...
Deletion of information from CEP: manufacturing site, retest period, country of origin for TSE,..
Change in batch size by < x 10
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

11. Typical notifications
Minor changes to test procedures (no changes in performances - few cases in practice)
Tightening limits (methods not affected)
Post-stability commitment data.
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

12. Minor Change Single 30 days/1000 euros
Timescales and Fees
Single 30 days/1000 euros
Multiple (max. 3) 60 days/1500 euros
Workflow:
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
Notice of approval, revised CEP issued or request for revision rejected
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

13. Typical minor changes Minor change in manufacture Upscaling > x10
Change in specification of the final substance (new or replaced test parameter)
Change in specification of raw materials
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

14. Typical minor changes Change/Addition of manufacturing site
(! Route of synthesis should be identical
Change of supplier of starting material
(! Route of synthesis should be identical)
Change from a TSE risk to a non-TSE risk material
Change/Addition of retest period on CEP
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

15. Major Change 90 days/1500 euros
Timescales and Fees
90 days/1500 euros
Possibility to include several changes (1major, up to 3 in total)
Workflow:
Acknowledgement of Receipt sent within 5 days
One request for additional information sent if necessary
Holder has 30 days to answer this request
EDQM has 30 days to evaluate the response
Revised CEP issued or request for revision rejected
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

16. Typical major changes
Any changes not included in the guideline (or where conditions not fulfilled)
Examples (chemical):
Introduction of new reagents, solvents
Alternative process (-> Specification of the final substance should remain identical, otherwise NEW certificate)
Process replaced
Change of supplier of starting material with a different route of synthesis
Examples (TSE):
Addition of new source countries or suppliers of materials
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

17. Consolidated Revision
Timescales and Fees:
Multiple revisions (> 3) days/2500 euros
- can include major changes
Workflow:
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
Approval, revised CEP issued or request for revision rejected
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

18. Monograph Revision Workflow:
Job 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
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19. Monograph Revision (cont)
Workflow (cont):
Response assessed within 3 months
Approval or revised CEP issued (if the information on the CEP changes)
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20. Renewal  Renewed CEP issued prior to expiry date
Holder to apply about 6 months before expiry
Possibility to include changes in the request (no major changes): an updated dossier (CTD) with a comprehensive list of changes and supportive data must be submitted
If declaration that no change has occurred since the last revision : dossier is assessed with priority
 Renewed CEP issued prior to expiry date
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21. Renewal (cont) Timescales and Fees Workflow: 4 months/1500 euros
Acknowledgement of Receipt sent within 5 days
4 months to evaluate the request
Revised CEP issued, request for additional information sent
If Demand 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: the CEP will be temporarily renewed at expiry unless there is an unresolved issue with the dossier
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

22. Renewal (cont)
Assessment of the dossier covers:
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!
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23. Some clarifications Change in the analytical method: N7 or R3
Replacement of a solvent: Major
Change of strain in fermentation process: Major
Alternative process: if the specifications are changed :
New application to be submitted
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24. Some clarifications (cont)
New supplier of starting material/intermediate with a declaration that the route of synthesis of the concerned materials is exactly the same as that already approved:
Minor
!Any invalid declaration, will be rejected at any time
New supplier of starting material /intermediate when route of synthesis is not identical: Major
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25. Some clarifications (cont)
Any change not listed in the descriptions for notifications or minor change is generally considered a major change.
Possibility to contact EDQM for clarification (via Helpdesk)
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

26. Some clarifications (cont)
Replacement of acetonitrile in the route of synthesis / analytical methods due to global shortage :
Such changes will require the submission of variation applications together with appropriate supporting data.
Any resulting revision will be assessed as a fast-track procedure (within 1 month of receipt), provided no other changes are included in the request for revision.
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

27. What to do after approval of a request for revision ? Quid for MAA ?
What to do with a revised CEP ? RX-CEP Rev YY
Provide a copy to customers
Update of relevant Marketing Applications
Type IA variation in most cases (cf. European
regulation Variation)
 Mandatory
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

28. After approval
What to do when change is approved but CEP not revised?:
Inform customers to allow them to check potential
impact on the finished medicinal product
 Mandatory
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

29. When are CEPs revised ?
After minor revisions related to change of specification of the final substance (since July 2008), even if the content remains unchanged.
After any major revisions
After any notification/minor revisions impacting the content of CEP
When conclusion of assessment of renewal invalids the temporarily renewed CEP at expiry
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

30. Coming soon…
Revised Regulation on Variations to marketing applications adopted, implementation on 01/01/2010
Related guidelines on operations and classification under public consultation, adoption foreseen before end 2009
Impact on management of revisions of CEPs
 EDQM guidelines will also be revised accordingly
Some changes in the classification
Some operational changes as well
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

31. Support to applicants Before preparing a request for revision
Check EDQM website for:
Published Guidelines & Notes (pages “Revisions & Renewals)
FAQs
contact EDQM for clarification (Helpdesk)
Read How to prepare a good revision/renewal dossier (PA/PH/Exp. CEP/T (07) 49)
Use Technical advice in case of doubt / complex schemes / specific questions:
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

32.  Thank you !
P. Poukens Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved