Revisions of Certificates of Suitability CEP to the

Revisions of Certificates of Suitability (CEP) to the Monographs of the European Pharmacopoeia Dr Pascale POUKENS-RENWART Scientific Officer Certification of Substances Division EDQM P. Poukens Renwart, 05/09/09 © 2009 EDQM, Council of Europe, All rights reserved

Validity of CEP Once your CEP has been granted it must be maintained throughout

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, 05/09/09 © 2009 EDQM, Council of Europe, All rights reserved

How EDQM handles variations ? P. Poukens Renwart, 05/09/09 © 2009 EDQM, Council of

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

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

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

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

Notification 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

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

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

Minor Change 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

Typical minor changes • Minor change in manufacture • Upscaling > x 10 • 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

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

Major Change Timescales and Fees • 90 days/1500 euros • Possibility to include several changes (1 major, 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

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

Consolidated Revision Timescales and Fees: • Multiple revisions (> 3) 120 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

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 P. Poukens Renwart, 05/09/09 © 2009 EDQM, Council of Europe, All rights reserved

Monograph Revision (cont) Workflow (cont): • Response assessed within 3 months • Approval or revised CEP issued (if the information on the CEP changes) P. Poukens Renwart, 05/09/09 © 2009 EDQM, Council of Europe, All rights reserved

Renewal • 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 P. Poukens Renwart, 05/09/09 © 2009 EDQM, Council of Europe, All rights reserved

Renewal (cont) Timescales and Fees • 4 months/1500 euros Workflow: • • 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

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 ð Not an administrative job! P. Poukens Renwart, 05/09/09 © 2009 EDQM, Council of Europe, All rights reserved

Some clarifications • Change in the analytical method: N 7 or R 3 • Replacement of a solvent: Major • Change of strain in fermentation process: Major • Alternative process: if the specifications are changed : New application to be submitted P. Poukens Renwart, 05/09/09 © 2009 EDQM, Council of Europe, All rights reserved

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 P. Poukens Renwart, 05/09/09 © 2009 EDQM, Council of Europe, All rights reserved

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

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

What to do after approval of a request for revision ? Quid for MAA ? • What to do with a revised CEP ? RX-CEP 2009 -001 -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

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

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

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

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