1-Dr. Pascal Poukens, Renwart- 27-9 How to …

1 How to prepare a new CEP applicationTop ten deficiencies during assessment of CEP , PhDEuropean Directorate for the Quality of Medicines & HealthCare (EDQM) Hyderabad, 27 September , 27-09-12 2012 EDQM, Council of Europe, All rights reservedSummary How to apply for a new CEP How to avoid deficiencies? Some , 27-09-12 2012 EDQM, Council of Europe, All rights reservedReminder of the Scope of the CEP procedure Substances described in monographs in the Ph. Eur. (Active substances, excipients, herbal drugs / herbal preparations) if you apply for a Chemical or Herbal CEP.

2 Products with risk of TSE(SM, intermediates, reagents,..) if you apply for a TSE , 27-09-12 2012 EDQM, Council of Europe, All rights reservedOut of Scope of the CEP procedure Substances not included in Ph. Eur Human tissues derivatives, blood derivatives, vaccines Finished products Products extracted from animal tissues (still acceptable for TSE risk): Ex. heparins, aprotinin,.. , 27-09-12 2012 EDQM, Council of Europe, All rights reservedRequirements for a complete application: Application form (for new application) available from (updated version to be used from 01 September 2012 Contains tables to be filled in, statements and declarations to be signed Quality Overall Summary using the template available on the EDQM website , 27-09-12 2012 EDQM, Council of Europe, All rights reservedRequirements for a complete application: Dossier in English preferably (or French); single copy.)

3 Content in compliance with:- Content of the Dossier for Chemical CEP : comparable to ASMF or of CTD- For TSE risk CEP: requirements from Ph Eur general text, (=EU nfg)- Content of the dossier for herbal drugs/herbal drug , 27-09-12 2012 EDQM, Council of Europe, All rights reservedRequirements for a complete application: Fee: 3000 Euros - to be paid after receipt and invoicing Electronic submissions encouraged (eCTD, NeeS, pdf). Guidance available on our website PA/PH/CEP (09) 108, 1R( ) , 27-09-12 2012 EDQM, Council of Europe, All rights reservedElectronic submission requirements: Content of submission:Module 1containing : application form (including declarations) cover letter Expert (information about expert, CV etc.)

4 Other supporting information ( Toxicological report, signed copy of referenced CEP etc.)Module 2 containing Quality Overall Summary, in pdf format using template available from the EDQM , 27-09-12 2012 EDQM, Council of Europe, All rights reservedElectronic submission requirements:Module 3 containing: Dossier containing technical documentation in CTD : eCTD draft guidance document from EMA Practical guidelines on the use of the eCTD format for ASMFs for Active Substance Master File Holders and Marketing Authorisation Holders may be used as a basis and this may be found at.

5 Is not encouraged to submit Applicant s and Restricted parts but it can be accommodated. , 27-09-12 2012 EDQM, Council of Europe, All rights reservedElectronic submission requirements: Choice of formats: PDF NeeS eCTD (only for chemical CEP applications not for TSE applications) , 27-09-12 2012 EDQM, Council of Europe, All rights reservedElectronic submission requirements: PDF: The documents in module 1 should typically be submitted as individual pdf files within the module structure. The eQos should be submitted in module 2 as a single pdf The technical dossier should be submitted in module 3 as a single pdf structured and bookmarked according to CTD , 27-09-12 2012 EDQM, Council of Europe, All rights reservedElectronic submission requirements: NeeS:The guidance documents for a NeeS submission are available at the following internet locations: The NeeS structure and specification should be in accordance with the following guidance: The validation criteria for NeeS may be found at.

6 The CTD file/directory structure shall be implemented with the addition of a Table of Content(s) as , 27-09-12 2012 EDQM, Council of Europe, All rights reservedElectronic submission requirements: eCTD: Submission of an eCTD is recommended for chemical submissions. The eCTD structure should be in accordance with the current ICH M2 EWG eCTD specification which can be found at: - ICH eCTD specification: - EU M1 eCTD specification: The eCTD CEP dossier remains, from a technical perspective, a stand alone dossier and is distinct from any marketing authorisation eCTD dossier and , 27-09-12 2012 EDQM, Council of Europe, All rights reservedCEP Process , 27-09-12 2012 EDQM, Council of Europe, All rights reservedAdministrative validation at receipt * Dossier not in CTD format* QOS is missing or not signed* Dossier is not written in official language* Electronic submission not in accordance with the , 27-09-12 2012 EDQM, Council of Europe.

7 All rights reservedAdministrative validation at receipt Dossier is also blocked when: Information from application form is missing: Names and addresses of the parties involved Agreement letters oRepresentative agent or when holder manufacturer Declaration of Manufacture according to the dossier and GMP (ICH Q7/EU GMP if sterile) Declaration of Willingness to be inspected oManufacturer, and holder if different Use of animal (TSE risk or other origin) / human material Holder s , 27-09-12 2012 EDQM, Council of Europe, All rights reservedTechnical validation at reception Summarise the commercial history - make clear if, and in what product THIS source of API is on the EUROPEAN market.

8 Information on ASMF submitted for the same substance Give as much information as possible (companies, products names, countries, registration dates, marketing dates). --> Impact on Qualification (limits) of , 27-09-12 2012 EDQM, Council of Europe, All rights reservedTechnical validation at reception (cont) Clarify whether a retest period is requested (recommended) and if yes, specify the proposed retest period: Justified by stability data based on ICH conditions studies Recommended storage conditions Specify the packaging material (primary & secondary packaging will be mentioned on the CEP) , 27-09-12 2012 EDQM, Council of Europe, All rights reservedTechnical validation at reception (cont) Applications are blocked when: Reference is made to an old version of the Ph.

9 Eur monograph Description of route of synthesis and/or impurity profile of thestarting material is missing Use of Class I solvents without justification and control Unsuitable information on impurities, solvents,.. Absence of validation data for analytical methods Absence of quantitative method to replace a non-specific TLC test of the monograph Sterile substances: absence of validation data on the , 27-09-12 2012 EDQM, Council of Europe, All rights reservedTechnical validation at reception (cont) Application blocked (20% in 2011) information not suitable to start the evaluation process the clock does not start until suitable information is givenAn incomplete application delays the CEP!

10 !! Read PA/PH/Exp CEP/T (08) 37 Note for applicants: Procedure for validation of new applications , 27-09-12 2012 EDQM, Council of Europe, All rights reservedEvaluation 1 After validation is satisfactorily completed, the dossier After validation is satisfactorily completed, the dossier is then evaluated is then evaluated EDQM has 5 months to complete EDQM has 5 months to complete the evaluation and inform the applicant of the the evaluation and inform the applicant of the Currently the deadlines are being the deadlines are being respected.