Information on the Certification Procedure Dr P. Poukens-Renwart Certification of Substances Division, EDQM P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council.

Summary Some deficiencies How to read and use a CEP? Finding information on the procedure Key figures Recent developments Benefits of the procedure P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Deficiencies Observed during the validation process of the application Observed during assessment process of the application and other then those listed in top 10. P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

A complete application requires: Application form (for new application) Single copy of the dossier in English preferably (or French) under CTD format; Quality Overall Summary: use the EDQM template and submit electronic version as Word file Samples: ! new policy: commitment to provide samples upon request from EDQM Electronic submission welcome:NEES (instructions on EDQM website) Send the package to EDQM. Fee to be paid after receipt and invoicing P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Validation at receipt applications are blocked when: 1.Administrative information is not complete 2.Technical information is not sufficient P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Administrative validation at receipt Dossier is blocked when: Dossier not in CTD format QOS is missing or not signed Information from application form is missing: –Names and addresses of the parties involved –Agreement letters Representative 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 Manufacturer, and holder if different –Use of animal (TSE risk or other origin) / human material P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Validation at receipt (cont) Summarise the commercial history - make clear if, and in what product THIS source of API is on the EUROPEAN market. 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 impurities P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Validation at receipt (cont) Retest period –Is an Option –Specify the proposed retest period: Justified by stability data Studies according to ICH conditions –Recommended storage conditions –Specify the packaging material P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Technical validation at receipt Applications are blocked when: Reference is made to an old version of the Ph. Eur monograph Description of route of synthesis and/or impurity profile of the starting material is missing Use of Class I solvents without justification and control Unsuitable information on impurities, solvents,… Absence of validation data Quantitative method to replace a non-specific TLC test of the monograph Sterile substances: validation of the sterilisation P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Validation at receipt 23% blocked at this step in June 2009 (up to 38% in 2007 = not suitable to start the evaluation) Application blocked --> the clock does not start until suitable information is given. ! An incomplete application delays the CEP  Read PA/PH/Exp CEP/T (08) 37 Note for applicants: « Procedure for validation of new applications » P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

After evaluation (the clock has started) Most applications require one or several requests for additional information (3% only of applications accepted at the time of first evaluation) Evaluation of additional information takes 4 months ! A deficient application delays the CEP P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Deficiencies: How to avoid them ? Read : PA/PH/ CEP (04) 1 4R issued, February 2007, entitled “Content of the dossier for chemical purity and microbiological quality” It is FREE, It is available on our website and is the Revision of Annex I, Resolution AP-CSP (93) 5 as amended. It describes what we expect to see in the dossier. P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Deficiencies: How to avoid them ? Keep in mind –The scheme is Certification of suitability to the monographs of the EUROPEAN Pharmacopoeia. –References, terminology, etc. should be to the Ph. Eur or at least traceable to it –There is a requirement to show that the monograph is suitable to control the actual quality of your substance. P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Deficiencies: How to avoid them ? Presentation on top ten deficiencies 2008 (9th September 2009) Read summary of the main deficiencies found in the dossiers for Certificates: PA/PH/CEP (08) 11 P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Other deficiencies observed Manufacturing Process Control of Materials Control of Critical steps and Intermediates Stability P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

3.2.S.2.2 Manufacturing Process and Process controls You should provide: Brief outline and flow chart for your process Detailed process description : –typical/maximum batch size –narrative description of the synthesis (incl temperatures, quantities, times etc.) –structure of isolated intermediates P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

3.2.S.2.2 Manufacturing Process and Process Controls Different sites, different manufacturing methods (including alternatives) and reprocessing can be included in one dossier if: the impurity profile of final substance is the SAME -> detailed information to be provided re-working is not allowed (->introduction of new solvents) -> normally this results in a change in the impurity profile P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

3.2.S.2.2 Manufacturing Process and Process Controls For semi-synthetic products:  Fermentation steps involved in synthesis of starting material, must address: Characterisation of fermented starting material, incl. detailed impurity profile, compliance with the GM 1468 Carry-over of fermentation impurities, proteins, DNA,… Use of TSE risk substances in manufacture? P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

3.2.S.2.3 Control of Materials If material of animal origin is used: If a TSE risk substance is involved: CEP will not be granted for a chemical until the TSE risk has been assessed  “Double” CEP The use of animal or human origin material will be mentioned on the CEP and the viral safety risk has to be assessed for the relevant marketing application. P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

3.2.S.2.4 Control of Critical steps and Intermediates Provide sufficient information on the intermediate control and the in-process controls. Especially important if you use this control to avoid a control later in the process!! P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

3.2.S.7 Stability CPMP guideline “Stability testing of existing active substances” (CPMP/QWP/ 122/02 Rev. 1) A retest period is optional (does not block the granting of the CEP) ICH conditions, incl. accelerated conditions Study description - relevant parameters Detailed results Validation of in-house methods (stability indicating) + cross validation with Ph.Eur method Majority of monograph methods are stability indicating but some older methods may need to be supplemented by (validated!) in-house methods P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Conclusions: how to avoid deficiencies? Data given in the dossier should be: –Clear –Concise –Readable –Obtained from recent analysis Use CTD format –Address the requirements of « Content of the Dossier » –Address the deficiencies detailed in this presentation –Implement recent developments if appropriate Provide complete administrative information Visit our website (news and general information) P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

How to read a CEP chemical? Certifies that the quality of a given substance can be suitably controlled by the Ph.Eur. monograph - with additional tests if necessary (stated on the CEP). It DOES NOT certify that a batch or batches of the substance complies with the Pharmacopoeia monograph. It IS NOT a GMP certificate P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

How to read a CEP TSE ? Certifies that the substance complies with the EMEA NfG on minimising the TSE risk It DOES NOT certify that the quality of the substance can be suitably controlled by the Ph.Eur. monograph It DOES NOT certify that a batch of the substance complies with the monograph It IS NOT a GMP certificate P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

All CEPs specify: Unique Reference number (e.g. R0-CEP 2000-001-Rev01) Title: clear definition of the substance + grade when requested (eg. micronised, sterile,…) Holder + manufacturing site(s) Monograph(s) concerned Starting validity date Line numbering and annex details if appropriate P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

And as necessary, chemical CEPs: Additional impurities/Solvents/Catalysts –With limits and methods Re-test period –With storage conditions + container Specs (limit + test) for a specific grade Tests of the monograph which can be omitted Use or non-use of materials of animal origin P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

And if for a sterile material: Description of sterilisation method and container/closure Statement that the validation of the sterilisation has been evaluated NB: the information on the sterilisation process and its validation needs to be submitted separately in the marketing authorisation dossier P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

And for a TSE certificate: Country(ies) of origin of animals Animal and nature of tissue(s) used Manufacturing process applied (when relevant, e.g. gelatins) Quality assurance system applied P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Certification pages Certification on-line database Useful links Contacting us P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved Finding information on the Certification Procedure http://www.edqm.eu

Homepage - Finding your way Six main groups to help visitors find information directed at them. They are: EDQM: Latest news & general Information about the EDQM HealthCare: Blood Transfusion & Organ Transplantation activities European Pharmacopoeia: Commission & Work Programme, Reference Standards & Biological Standardisation Programme (BSP). P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Homepage - Finding your way (cont) Certification of Pharmaceutical Substances: Procedure of Certification (CEP) Control of Medicines: OMCL Network, PTS Studies, etc Products & Services: Publications, Reference Standards (Ph. Eur. & WHO ISA) & Certification P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Here is an example of the information provided Our databases are linked, clicking on the monograph number takes you into our Knowledge Database Certification On-Line Database (3)

How to contact us ? For general queries for which the answer is not in the FAQs, you can contact us via the helpdesk. For application specific queries you can contact us via the email address which we include in our communications about your application: cep@edqm.eu P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Certificates of suitability > 3700 applications since procedure launched ~ 2250 valid certificates > 760 substance monographs involved … P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Recent developments 1.Validation of new applications at receipt (= completeness check) Implemented in 2007Implemented in 2007 Both administrative & technical informationBoth administrative & technical information Performed within 8 days of application receiptPerformed within 8 days of application receipt If dossier complete: AR --> evaluation clock startsIf dossier complete: AR --> evaluation clock starts P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Recent developments 2.Closing of sleeping dossiers (dossiers lying dormant for months without reply) Applicants are given 6 months to provide additional information following a deficiency letterApplicants are given 6 months to provide additional information following a deficiency letter If no response : dossier closedIf no response : dossier closed P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Recent developments 3.Streamlined evaluation procedure (From September 2008) 1 deficiency letter only1 deficiency letter only if responses unsuitable  dossier closedif responses unsuitable  dossier closed P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Recent developments 4.Electronic submission (from September 2009): EncouragedEncouraged For all types of submissionsFor all types of submissions e-CTD, or NEES suitably bookmarked e-CTD, or NEES suitably bookmarked Check regularly EDQM website forinstructionsCheck regularly EDQM website forinstructions Paper OR electronic (no longer both)Paper OR electronic (no longer both) P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Recent developments 5.Manufacturing sites mentioned on CEPs When manufacturer of API purchases crude or late intermediate and performs only a final purification or salification, the site(s) of manufacture of the purchased material(s) will be mentioned on the CEP;When manufacturer of API purchases crude or late intermediate and performs only a final purification or salification, the site(s) of manufacture of the purchased material(s) will be mentioned on the CEP; GMP apply to manufacturer(s) of crude or late intermediate;GMP apply to manufacturer(s) of crude or late intermediate; Declarations to be submitted;Declarations to be submitted; Also applicable to post-production operations (micronisation or sterilisation), when these are claimed and approvedAlso applicable to post-production operations (micronisation or sterilisation), when these are claimed and approved P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Certification: benefits Single & harmonised assessment Replaces Active Substance Master File Savings of time and resources Updating of monographs (impurities) Revision of monographs (new or replacement test methods) CEPs are recognised in Europe and abroad P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council of Europe, All rights reserved

Information on the Certification Procedure Dr P. Poukens-Renwart Certification of Substances Division, EDQM P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council.

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Information on the Certification Procedure Dr P. Poukens-Renwart Certification of Substances Division, EDQM P.Poukens-Renwart, 05/09/09 ©2009 EDQM, Council.

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