How to prepare an application for revision of a CEP

Transcription

1 How to prepare an application for revision of a CEP P.Poukens-Renwart, PhD Certification of Substances Division EDQM

2 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

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

4 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

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 4R) New procedures for management of revision / renewal of CEPs (PA/PH/Exp. CEP/T (04) 18 2R)

6 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 variations

7 Notification: Do and Tell principle Immediate notifications (IN) or Annual Notifications (AN) (to be submitted within 12 months after implementation) Timescale : 1 month

8 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)

9 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

10 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

11 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

12 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)

13 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

14 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).

15 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!

16 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

17 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.

18 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»

19 Application form: Names and addresses Give appropriate administrative information => reported on the CEP

20 Application form: specific information Tick the type of notifications (INx, ANx) and specify implementation date for Annual notification Tick the type of major change

21 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

22 Application form: invoicing details Item selected should be in line with selection under 1.2 type of application.

23 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.

24 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

25 Some examples

26 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.

27 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

28 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

29 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

30 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 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)

31 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

32 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

33 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

34 Acknowledgements My special thanks to Hélène Bruguera (Head of Certification Division at the EDQM) All my colleagues from the Certification Revision Team

35 QUESTIONS?