1. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 1 Content of the application for a CEP Hélène BRUGUERA Deputy Head Certification of Substances Division Hélène BRUGUERA Deputy Head Certification of Substances Division

2. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 2 Process to obtain a CEP: outlined in Resolution AP-CSP(07) 1 “Content of the dossier”: –Chemical purity (revised May 2007) –TSE risk See docs on web site www.edqm.eu Process to obtain a CEP: outlined in Resolution AP-CSP(07) 1 “Content of the dossier”: –Chemical purity (revised May 2007) –TSE risk See docs on web site www.edqm.eu Send an application to EDQM

3. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 3 How long does it take? Timeframes: –Applicant notified by EDQM on the assessment conclusion Within 5 months of receipt of new dossier Within 4 months of receipt of additional information –Responses expected within 6 months for original demand within 3 month for any subsequent demand –Responses assessed within 4 months Timeframes: –Applicant notified by EDQM on the assessment conclusion Within 5 months of receipt of new dossier Within 4 months of receipt of additional information –Responses expected within 6 months for original demand within 3 month for any subsequent demand –Responses assessed within 4 months

4. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 4 The situation Mean time to obtain a CEP (chemical): 20 months 3% of CEPs obtained after 1st evaluation 70% of CEPs: 2-3 rounds Mean time to obtain a CEP (chemical): 20 months 3% of CEPs obtained after 1st evaluation 70% of CEPs: 2-3 rounds

5. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 5 How can I speed up the granting of my CEP for chemical purity ? Send a complete application Submit a good technical documentation Prepare a good QOS Hints Send a complete application Submit a good technical documentation Prepare a good QOS Hints

6. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 6 Send a complete application Application form (for new application) www.edqm.eu Dossier in English preferably (or French); 1 copy; Quality Overall Summary (electronic+paper) Samples of 1 or 2 commercial batches Application form (for new application) www.edqm.eu Dossier in English preferably (or French); 1 copy; Quality Overall Summary (electronic+paper) Samples of 1 or 2 commercial batches

7. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 7 At receipt Validation of application: check of completeness If application receivable: dossier nr allocated + clock start New applications blocked if deficient: –Missing pieces (form, declarations, dossier,…) –Technical reasons: Refer to the current Ph. Eur monograph Description of route of synthesis and/or impurity profile of the starting material Use of Class I solvents without proper justification and control Validation of application: check of completeness If application receivable: dossier nr allocated + clock start New applications blocked if deficient: –Missing pieces (form, declarations, dossier,…) –Technical reasons: Refer to the current Ph. Eur monograph Description of route of synthesis and/or impurity profile of the starting material Use of Class I solvents without proper justification and control

8. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 8 Technical reasons (cont) –Suitable information on impurities, solvents,… –Presence of validation data –Quantitative method to replace a non-specific TLC test of the monograph –Sterile substances: validation of the sterilisation If application not receivable: dossier nr allocated but clock does not start. The company has 6 months to submit info + clock start 30% of new applications blocked in 2007 (most of them unblocked) Technical reasons (cont) –Suitable information on impurities, solvents,… –Presence of validation data –Quantitative method to replace a non-specific TLC test of the monograph –Sterile substances: validation of the sterilisation If application not receivable: dossier nr allocated but clock does not start. The company has 6 months to submit info + clock start 30% of new applications blocked in 2007 (most of them unblocked)

9. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 9 How can I speed up the granting of a CEP for chemical purity ? Send a complete application Submit a good technical documentation Prepare a good QOS Hints Send a complete application Submit a good technical documentation Prepare a good QOS Hints

10. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 10 Administrative info (applic. form) Name and addresses of the parties involved (all sites) Declarations ( GMP, Willingness to be inspected, Use of animal (TSE risk or other origin) / human material) History of the substance (give details) Retest period requested ? Name and addresses of the parties involved (all sites) Declarations ( GMP, Willingness to be inspected, Use of animal (TSE risk or other origin) / human material) History of the substance (give details) Retest period requested ?

11. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 11 Technical documentation PA/PH/CEP (04) 1: Content of dossier for chemical purity 3.2.S of CTD –General information –Route of synthesis –Impurities, solvents, catalysts –Control of the substance (specification and methods) –Analytical validation-suitability of the monograph –(Stability is optional) PA/PH/CEP (04) 1: Content of dossier for chemical purity 3.2.S of CTD –General information –Route of synthesis –Impurities, solvents, catalysts –Control of the substance (specification and methods) –Analytical validation-suitability of the monograph –(Stability is optional)

12. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 12 3.2.S.2.2 Manufacturing Process Flow chart Detailed description of the process, including quantities Maximum/typical batch size and yields Describe any reprocessing/recovery of materials Flow chart Detailed description of the process, including quantities Maximum/typical batch size and yields Describe any reprocessing/recovery of materials

13. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 13 Semi-synthetic products:  Fermentation steps involved in synthesis of starting material –Characterisation of fermented starting material, incl. detailed impurity profile, compliance with the general monograph 1468 –Carry-over of fermentation impurities –Use TSE risk substances in manufacture? Different sites, different manufacturing methods or alternatives, reprocessing, in one dossier: –impurity profile of final substance unchanged –detailed information Semi-synthetic products:  Fermentation steps involved in synthesis of starting material –Characterisation of fermented starting material, incl. detailed impurity profile, compliance with the general monograph 1468 –Carry-over of fermentation impurities –Use TSE risk substances in manufacture? Different sites, different manufacturing methods or alternatives, reprocessing, in one dossier: –impurity profile of final substance unchanged –detailed information

14. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 14 3.2.S.2.3 Control of Materials Starting materials:TOP 2 deficiency in 2007 –Propose and justify which substance(s) is the starting material(s) e.g. incorporated as a significant structural fragment into the structure of the final substance. Is the substance purchased or manufactured in-house ? –Short steps synthesis: description of its route of synthesis, and detailed impurity profile (related substances, reagents, solvents, catalysts) –Suitable specifications - limits for impurities, solvents,… –Description of carry-over of its impurities to the final substance –Where more than one supplier is used batch results for the final substance manufactured from the different suppliers Starting materials:TOP 2 deficiency in 2007 –Propose and justify which substance(s) is the starting material(s) e.g. incorporated as a significant structural fragment into the structure of the final substance. Is the substance purchased or manufactured in-house ? –Short steps synthesis: description of its route of synthesis, and detailed impurity profile (related substances, reagents, solvents, catalysts) –Suitable specifications - limits for impurities, solvents,… –Description of carry-over of its impurities to the final substance –Where more than one supplier is used batch results for the final substance manufactured from the different suppliers

15. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 15 3.2.S.2.3 Control of Materials Describe specifications for all reagents, solvents used –Purity tests for solvents (e.g benzene in toluene, acetone, ethanol) –Specifications for pure and recovered solvents –Quality of water Include specification of recovered materials if any Describe specifications for all reagents, solvents used –Purity tests for solvents (e.g benzene in toluene, acetone, ethanol) –Specifications for pure and recovered solvents –Quality of water Include specification of recovered materials if any

16. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 16 3.2.S.3.2 Impurities Need to address: Organic impurities Inorganic impurities (catalysts,…) Residual solvents Genotoxic impurities Need to address: Organic impurities Inorganic impurities (catalysts,…) Residual solvents Genotoxic impurities

17. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 17 3.2.S.3.2 Organic impurities Discussion on impurities should cover: –Potential impurities, origin, correspondence with transparency list of the monograph and individual impurity results –Use of monograph nomenclature or correlation with monograph nomenclature required –Which impurities are actually present? Levels found in production batches (actual data needed) - chromatograms Discussion on impurities should cover: –Potential impurities, origin, correspondence with transparency list of the monograph and individual impurity results –Use of monograph nomenclature or correlation with monograph nomenclature required –Which impurities are actually present? Levels found in production batches (actual data needed) - chromatograms

18. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 18 Organic impurities (cont) Need to address: Suitability of the method(s) of the monograph for the detection of all impurities present in the material If the monograph is not suitable then need to supplement it with an additional (validated!) method Set appropriate limits Need to address: Suitability of the method(s) of the monograph for the detection of all impurities present in the material If the monograph is not suitable then need to supplement it with an additional (validated!) method Set appropriate limits

19. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 19 3.2.S.3.2 Residual solvents  ICH guideline Q3C  CPMP Concept paper (2003) Data for ALL solvents used during synthesis (incl. 1st steps) Batch results + typical chromatograms Solvents likely to be present/used in the last steps justified limits (ICH or lower) validated test methods mentioned on CEP (+ method appended)  ICH guideline Q3C  CPMP Concept paper (2003) Data for ALL solvents used during synthesis (incl. 1st steps) Batch results + typical chromatograms Solvents likely to be present/used in the last steps justified limits (ICH or lower) validated test methods mentioned on CEP (+ method appended)

20. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 20 3.2.S.3.2 Other impurities Demonstrate the absence of particular reagents in the final substance or set a limit Demonstrate absence of residues of catalysts or set a limit –EMEA draft guideline on catalysts (CPMP/SWP/4446/00) Demonstrate the absence of particular reagents in the final substance or set a limit Demonstrate absence of residues of catalysts or set a limit –EMEA draft guideline on catalysts (CPMP/SWP/4446/00)

21. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 21 3.2.S.3.2 Genotoxic impurities TOP 1 Question in 2007 Cf NfG CPMP/SWP/5199/02 since 01/2007 Applicable to: substances not yet marketed in Europe new routes of synthesis Specific discussion with regard to genotoxic impurities: Look for potential genotoxicity (structural alerts) Consult literature and databases TOP 1 Question in 2007 Cf NfG CPMP/SWP/5199/02 since 01/2007 Applicable to: substances not yet marketed in Europe new routes of synthesis Specific discussion with regard to genotoxic impurities: Look for potential genotoxicity (structural alerts) Consult literature and databases

22. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 22 GTI (cont) Principles: –Data available on maximal exposure –TTC approach (1.5  g/day) –Tox tests (AMES) Analytical (sensitive) methods to show residual levels Demonstrate absence (<30% of max exposure or TTC) or justify a limit The use of the substance may be taken into consideration ==> « Questions and Answers » to be published on EMEA website Principles: –Data available on maximal exposure –TTC approach (1.5  g/day) –Tox tests (AMES) Analytical (sensitive) methods to show residual levels Demonstrate absence (<30% of max exposure or TTC) or justify a limit The use of the substance may be taken into consideration ==> « Questions and Answers » to be published on EMEA website

23. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 23 3.2.S.4 Control of Drug Substance Refer to the right monograph and its tests Include additional/alternative tests if necessary Use quantitative method for related substances Appropriate limits for impurities, solvents,…in accordance with the process and relevant guidelines - General monograph 2034 Adequate methods description -> format to be appended to the CEP Refer to the right monograph and its tests Include additional/alternative tests if necessary Use quantitative method for related substances Appropriate limits for impurities, solvents,…in accordance with the process and relevant guidelines - General monograph 2034 Adequate methods description -> format to be appended to the CEP

24. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 24 3.2.S.4 Control of Drug Substance For monographs which still include a non-specific & non-quantitative TLC method: suitably validated QUANTITATIVE method for related substances & suitable limits for impurities to be proposed in the application For monographs which still include a non-specific & non-quantitative TLC method: suitably validated QUANTITATIVE method for related substances & suitable limits for impurities to be proposed in the application

25. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 25 3.2.S.4 How to set limits for related substances Impurities of the monograph: limits of the monograph “Other detectable impurities” of the monograph are known substances detected by the method but NOT normally present above the identification threshold from general monograph (2034). Additional impurities (any impurity not on the transparency list) : apply the general monograph (2034) -Individual limits for specified impurities -Individual limits for identified non-qualified impurities -Limit for unspecified impurities Impurities of the monograph: limits of the monograph “Other detectable impurities” of the monograph are known substances detected by the method but NOT normally present above the identification threshold from general monograph (2034). Additional impurities (any impurity not on the transparency list) : apply the general monograph (2034) -Individual limits for specified impurities -Individual limits for identified non-qualified impurities -Limit for unspecified impurities

26. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 26 Limits for related substances For products out of the scope of the general monograph 2034 (antibiotics, peptides,…): –Characterise the impurity profile –Apply the principles of the general monograph (limits for specified, unspecified, total impurities) –Propose justified limits (not necessarily ICH Q3A)  on the CEP For products out of the scope of the general monograph 2034 (antibiotics, peptides,…): –Characterise the impurity profile –Apply the principles of the general monograph (limits for specified, unspecified, total impurities) –Propose justified limits (not necessarily ICH Q3A)  on the CEP

27. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 27 Qualification of Additional Impurities Qualification by use –History of the product: –Consistency with manufacturing capability –Shown to be present in other products already approved in Europe Qualification by toxicological data Or limited to qualification/identification threshold Qualification of Additional Impurities Qualification by use –History of the product: –Consistency with manufacturing capability –Shown to be present in other products already approved in Europe Qualification by toxicological data Or limited to qualification/identification threshold

28. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 28 3.2.S.4.3 Method validation All in-house methods should be validated (incl. non- routine methods)  ICH Q2B for methodology  Typical chromatograms Cross-validation against Ph. Eur methods:  comparative results obtained from the same samples All in-house methods should be validated (incl. non- routine methods)  ICH Q2B for methodology  Typical chromatograms Cross-validation against Ph. Eur methods:  comparative results obtained from the same samples

29. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 29 3.2.S.4.4 Batch data –Should be in line with specification –Details on batches tested (batch nr, size, dates of manufacture, analysis) –Numerical figures (“complies” not appropriate) –Should be in line with specification –Details on batches tested (batch nr, size, dates of manufacture, analysis) –Numerical figures (“complies” not appropriate)

30. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 30 3.2.S.5 Reference Standards or materials Use the Ph. Eur. standards (EPCRS) or provide traceability to these standards and certificates for the in-house standards used 3.2.S.6 Container closure system Provide a description of the commercial packaging Provide specification for all materials used Reference compliance with appropriate guidelines (i.e. EMEA CHMP Plastic Primary Packaging Materials (CPMP/QWP/4359/03)) Provide a description of the commercial packaging Provide specification for all materials used Reference compliance with appropriate guidelines (i.e. EMEA CHMP Plastic Primary Packaging Materials (CPMP/QWP/4359/03))

31. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 31 3.2.S.7 Stability Option !  EMEA guideline “Stability testing of existing active substances”  EMEA guideline on “Declaration of storage conditions for medicinal products” ICH conditions incl accelerated Study description - relevant parameters Detailed results Validation of in-house methods (stability indicating) Option !  EMEA guideline “Stability testing of existing active substances”  EMEA guideline on “Declaration of storage conditions for medicinal products” ICH conditions incl accelerated Study description - relevant parameters Detailed results Validation of in-house methods (stability indicating)

32. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 32 Proposed retest period and storage conditions: –In accordance with stability results (real time + accelerated) –Extrapolation possible (according to ICH) Proposed retest period and storage conditions: –In accordance with stability results (real time + accelerated) –Extrapolation possible (according to ICH) 3.2.S.7 Stability

33. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 33 How can I speed up the granting of a CEP for chemical purity ? Send a complete application Submit a good technical documentation Prepare a good QOS Hints Send a complete application Submit a good technical documentation Prepare a good QOS Hints

34. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 34 The QOS QOS = Quality Overall Summary Summary of the application highlighting the key points+suitability of the monograph The expert can be anyone having sufficient knowledge/experience in the topic, i.e. from the applicant’s company CV of the expert to be appended QOS = Quality Overall Summary Summary of the application highlighting the key points+suitability of the monograph The expert can be anyone having sufficient knowledge/experience in the topic, i.e. from the applicant’s company CV of the expert to be appended

35. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 35 The QOS (cont) Use template of QOS available on EDQM website –Helps to prepare the QOS –Helps for the assessment report Submit electronic QOS (Word) to EDQM in addition to paper copy Use template of QOS available on EDQM website –Helps to prepare the QOS –Helps for the assessment report Submit electronic QOS (Word) to EDQM in addition to paper copy

36. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 36 How can I speed up the granting of a CEP for chemical purity ? Send a complete application Submit a good technical documentation Prepare a good QOS Hints Send a complete application Submit a good technical documentation Prepare a good QOS Hints

37. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 37 Hints The dossier should be Clear, Concise, Readable, Obtained from recent data The e-QOS should be in line with the dossier Follow recommendations described in “Content of the dossier” + “TOP TEN deficiencies” Technical Advice procedure, workshops,… Submit electronic files The dossier should be Clear, Concise, Readable, Obtained from recent data The e-QOS should be in line with the dossier Follow recommendations described in “Content of the dossier” + “TOP TEN deficiencies” Technical Advice procedure, workshops,… Submit electronic files

38. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 38 Electronic submissions Electronic dossier (new appl., revisions, add info): pdf files welcome –e-QOS obtained from EDQM template (Word) –Paper copies still required if > 10 pages –Dropbox to exchange files –EDQM sends requests for info by e-mail Electronic dossier (new appl., revisions, add info): pdf files welcome –e-QOS obtained from EDQM template (Word) –Paper copies still required if > 10 pages –Dropbox to exchange files –EDQM sends requests for info by e-mail

39. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 39 Additional information Submit in time and in 2 parts: –Questions/Anwers document addressing all deficiencies. To be submitted electronically + paper copies –Updated sections of the dossier as annexes (electronic + paper) Submit in time and in 2 parts: –Questions/Anwers document addressing all deficiencies. To be submitted electronically + paper copies –Updated sections of the dossier as annexes (electronic + paper)

40. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 40 And also… Timetables noted on the letter of acknowledgement of receipt No AR for additional info, but treated in time Do not contact EDQM before the expected dates No possibility of « special fast track » Timetables noted on the letter of acknowledgement of receipt No AR for additional info, but treated in time Do not contact EDQM before the expected dates No possibility of « special fast track »

41. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 41

42. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 42 You have got the CEP, it is not finished…. The CEP has to be maintained through the Revision system

43. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 43 Revisions/Renewals of CEPs Hélène BRUGUERA Deputy Head Certification of Substances Division Hélène BRUGUERA Deputy Head Certification of Substances Division

44. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 44 Basic principles for maintaining a CEP Any change (administrative or technical) to be reported to EDQM for approval  Revised CEP granted Holder to inform customers and/or authorities with revised CEP Original CEP: valid 5 years. Need to apply for renewal in time. After renewal, CEP valid for an unlimited period, provided the dossier is kept up-to-date Any change (administrative or technical) to be reported to EDQM for approval  Revised CEP granted Holder to inform customers and/or authorities with revised CEP Original CEP: valid 5 years. Need to apply for renewal in time. After renewal, CEP valid for an unlimited period, provided the dossier is kept up-to-date

45. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 45 Revisions of CEPs: Background Based on EU Regulations on Variations to Marketing Applications Guideline on requirements on revision / renewal of CEPs (PA/PH/CEP (04) 2) New procedures for management of revision / renewal of CEPs (PA/PH/Exp. CEP/T (04) 18) Available on EDQM website Based on EU Regulations on Variations to Marketing Applications Guideline on requirements on revision / renewal of CEPs (PA/PH/CEP (04) 2) New procedures for management of revision / renewal of CEPs (PA/PH/Exp. CEP/T (04) 18) Available on EDQM website

46. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 46 Guideline on Requirements: documentation Application form (specific for revisions) Technical data: –Justification of change –Assurance that the conditions are fulfilled –Updated pages of the dossier –Specific supporting documents –COMPARATIVE DATA - Full batch results Application form (specific for revisions) Technical data: –Justification of change –Assurance that the conditions are fulfilled –Updated pages of the dossier –Specific supporting documents –COMPARATIVE DATA - Full batch results

47. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 47 Types of changes Notifications Minor changes Major changes Renewal Update following revision of the monograph / regulatory change Notifications Minor changes Major changes Renewal Update following revision of the monograph / regulatory change

48. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 48 Notifications Change in holder, manufacturer references: holder name, address (no move),... Change in batch size by ≤ x 10 Minor changes to test procedures (no changes in performances - few cases in practice) Tightening limits (methods not affected) Post-stability commitment data Deletion of information from CEP: manuf. site, retest period, country of origin for TSE Change in holder, manufacturer references: holder name, address (no move),... Change in batch size by ≤ x 10 Minor changes to test procedures (no changes in performances - few cases in practice) Tightening limits (methods not affected) Post-stability commitment data Deletion of information from CEP: manuf. site, retest period, country of origin for TSE

49. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 49 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 notifications has been accepted as valid or has been rejected - No demand for additional information sent Revised CEP only issued when the information on the CEP is changed (i.e. and address) 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 notifications has been accepted as valid or has been rejected - No demand for additional information sent Revised CEP only issued when the information on the CEP is changed (i.e. and address)

50. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 50 Typical minor changes Minor change in manufacture Up scaling > x10 Change in specification (new or replaced test parameter) Change/Addition of manufacturing site Change from a TSE risk to a non-TSE risk material Change/Addition of retest period on CEP Minor change in manufacture Up scaling > x10 Change in specification (new or replaced test parameter) Change/Addition of manufacturing site Change from a TSE risk to a non-TSE risk material Change/Addition of retest period on CEP

51. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 51 Minor Change Timescales and Fees Single 1 month /1000 euros Multiple (max. 3)2 months /1500 euros Workflow: Acknowledgement of Receipt sent within 5 days One demand for additional information sent if neccessary Holder has 30 days to respond to this demand EDQM has 30 days to evaluate the response Revised CEP issued or demand for revision rejected Timescales and Fees Single 1 month /1000 euros Multiple (max. 3)2 months /1500 euros Workflow: Acknowledgement of Receipt sent within 5 days One demand for additional information sent if neccessary Holder has 30 days to respond to this demand EDQM has 30 days to evaluate the response Revised CEP issued or demand for revision rejected

52. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 52 Major changes Any changes not included in the guideline (or conditions not fulfilled) Examples (chemical): –Introduction of new reagents, solvents –Alternative process (  Spec of the final substance identical, otherwise new certificate) –Process replaced Examples (TSE): –Addition of new source countries or suppliers of materials Any changes not included in the guideline (or conditions not fulfilled) Examples (chemical): –Introduction of new reagents, solvents –Alternative process (  Spec of the final substance identical, otherwise new certificate) –Process replaced Examples (TSE): –Addition of new source countries or suppliers of materials

53. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 53 Major Change Timescales and Fees Single 3 months /1500 euros Multiple (max. 3, 1 major) 3 months /1500 euros Workflow: Acknowledgement of Receipt sent within 5 days One demand for additional information sent if necessary Holder has 30 days to respond to this demand DCEP has 30 days to evaluate the response Revised CEP issued or demand for revision rejected Timescales and Fees Single 3 months /1500 euros Multiple (max. 3, 1 major) 3 months /1500 euros Workflow: Acknowledgement of Receipt sent within 5 days One demand for additional information sent if necessary Holder has 30 days to respond to this demand DCEP has 30 days to evaluate the response Revised CEP issued or demand for revision rejected

54. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 54 Consolidated Revision Timescales and Fees Multiple revisions (> 3)4 months/2500 euros Workflow: Acknowledgement of Receipt sent within 5 days One demand for additional information sent if necessary Holder has 30 days to respond to this demand DCEP has 30 days to evaluate the response Revised CEP issued or demand for revision rejected Timescales and Fees Multiple revisions (> 3)4 months/2500 euros Workflow: Acknowledgement of Receipt sent within 5 days One demand for additional information sent if necessary Holder has 30 days to respond to this demand DCEP has 30 days to evaluate the response Revised CEP issued or demand for revision rejected

55. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 55 Monograph revision Revised monographs published 3 times a year EDQM gives instructions to the holders: –Compliance with the monograph –Suitability of the monograph Timescales and Fees 90 days/No fee Revised CEP issued if necessary after approval Revised monographs published 3 times a year EDQM gives instructions to the holders: –Compliance with the monograph –Suitability of the monograph Timescales and Fees 90 days/No fee Revised CEP issued if necessary after approval

56. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 56 Renewal Holder shall apply about 6 months prior to expiry date Declaration that no change occurred or Updated dossier (CTD) with comprehensive list of changes –General Monograph “Substances for Pharmaceutical Use” –Recent European quality guidelines: eg impurities, residual solvents, residual catalysts  Not an administrative job! Holder shall apply about 6 months prior to expiry date Declaration that no change occurred or Updated dossier (CTD) with comprehensive list of changes –General Monograph “Substances for Pharmaceutical Use” –Recent European quality guidelines: eg impurities, residual solvents, residual catalysts  Not an administrative job!

57. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 57 Renewal Timescales and Fees 4 months /1500 euros Workflow: Acknowledgement of Receipt sent within 5 days 120 days to evaluate the request Revised CEP issued, demand for additional information sent or demand for revision rejected If Demand for additional information sent Holder has 30 days to respond to this demand EDQM has 30 days (90 for TSE) to evaluate the response Timescales and Fees 4 months /1500 euros Workflow: Acknowledgement of Receipt sent within 5 days 120 days to evaluate the request Revised CEP issued, demand for additional information sent or demand for revision rejected If Demand for additional information sent Holder has 30 days to respond to this demand EDQM has 30 days (90 for TSE) to evaluate the response

58. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 58 Common deficiencies Change in the analytical method: N7/R3 Replacement of a solvent: Major Change of strain in fermentation process: Major New supplier of starting material when route of synthesis is not identical: Major Alternative process: if the specs are changed : New application Change in the analytical method: N7/R3 Replacement of a solvent: Major Change of strain in fermentation process: Major New supplier of starting material when route of synthesis is not identical: Major Alternative process: if the specs are changed : New application

59. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 59 What to do with a revised CEP CEP ref number incremented –RX-CEP 2007-001-Rev YY Provide a copy to customers Update of relevant Marketing Applications  Type IA variation in most cases (cf. European regulations) CEP ref number incremented –RX-CEP 2007-001-Rev YY Provide a copy to customers Update of relevant Marketing Applications  Type IA variation in most cases (cf. European regulations)

60. IPA-EDQM Mumbai 11/2007 ©2007 EDQM, Council of Europe 60 Thank you !