1. Birgit Schmauser | April 2008 1 |1 | Pharmaceutical Development with Focus on Paediatric formulations WHO/FIP Training Workshop Hyatt Regency Hotel Sahar Airport Road Andheri East, Mumbai, India 28 April 2008 – 2 May 2008

2. Birgit Schmauser | April 2008 2 |2 | Dossier maintenance including Variations Presented by: Birgit Schmauser, PhD Federal Institute for Drugs and Medical Devices (BfArM) b.schmauser@bfarm.de

3. Birgit Schmauser | April 2008 3 |3 | Dossier maintenance including Variations In this presentation: Changes to a dossier after prequalification Changes to a dossier after prequalification Classification of Changes Classification of Changes Dossier requirements according to Guidelines Dossier requirements according to Guidelines Examples Examples Conclusion Conclusion

4. Birgit Schmauser | April 2008 4 |4 | Dossier maintenance including Variations Changes made to a dossier after prequalification are variations to the prequalified dossier Changes made to a dossier after prequalification are variations to the prequalified dossier Variations are subject to approval because they may impact the pharmaceutical quality Variations are subject to approval because they may impact the pharmaceutical quality Implementation of a system to regulate variations was deemed necessary for the prequalification project Implementation of a system to regulate variations was deemed necessary for the prequalification project

5. Birgit Schmauser | April 2008 5 |5 | Dossier maintenance including Variations Variations to a melody Mozart, Sonata, KV 331, I Variations to a melody Mozart, Sonata, KV 331, I....“What are more striking than the differences, however, are the similarities. So similar, indeed, are the above variations to the original theme that they give the impression of being ornamentations not just of the theme itself but of an even simpler melodic outline, of which Mozart´s original theme is perhaps itself an ornamentation”........“What are more striking than the differences, however, are the similarities. So similar, indeed, are the above variations to the original theme that they give the impression of being ornamentations not just of the theme itself but of an even simpler melodic outline, of which Mozart´s original theme is perhaps itself an ornamentation”.... From: Piston, DeVoto, HARMONY, 4th edition, W. W. Norton and Company From: Piston, DeVoto, HARMONY, 4th edition, W. W. Norton and Company

6. Birgit Schmauser | April 2008 6 |6 | Dossier maintenance including Variations Various systems to handle variations exist in the ICH- region Various systems to handle variations exist in the ICH- region –Decision for PQ-project EU-system seemed most suitable: EU-system seemed most suitable: Build up knowledge & experience initially Give assistance by a corresponding guideline adapted for PQ purposes Open for future modifications by outcome of assessments and experience

7. Birgit Schmauser | April 2008 7 |7 | Dossier maintenance including Variations Guide on Variations to a prequalified product dossier (http://mednet3.who.int/prequal/info_general/documents/TRS943/TRS943.pdf#page=121) Guide on Variations to a prequalified product dossier (http://mednet3.who.int/prequal/info_general/documents/TRS943/TRS943.pdf#page=121) –Gives assistance in how to adequately document variations It is in the interest of all to handle variations in a time-saving and efficient manner It is in the interest of all to handle variations in a time-saving and efficient manner This presentation is intended to assist in clarifying potential problems and/or misunderstanding around variations

8. Birgit Schmauser | April 2008 8 |8 | Dossier maintenance including Variations Guide on Variations to a prequalified product dossier (Variation Guide) Three categories of variations according to their potential impact on pharmaceutical quality Three categories of variations according to their potential impact on pharmaceutical quality –Notification (mainly administrative, some potential impact on quality) –Minor change (potential minor impact on quality) –Major change (potential major impact on quality) Certain variations are considered „so major“ that a new application (line extension) is necessary Certain variations are considered „so major“ that a new application (line extension) is necessary

9. Birgit Schmauser | April 2008 9 |9 | Dossier maintenance including Variations Variation Guide Timelines for the different types of variations Timelines for the different types of variations –Notifications (N) If no objection is received by WHO within 3 months the variation can be considered approved If no objection is received by WHO within 3 months the variation can be considered approved –Minor changes Based on satisfactory documentation of the variation WHO will inform applicants on approval Based on satisfactory documentation of the variation WHO will inform applicants on approval –Major changes Based on evaluation of documentation of the variation WHO will inform applicants on approval Based on evaluation of documentation of the variation WHO will inform applicants on approval

10. Birgit Schmauser | April 2008 10 | Dossier maintenance including Variations Variation Guide FOCUS on minor variations FOCUS on minor variations –Lists types of variations that are subject to notification or approval Appendix 1 Appendix 1 –Gives assistance in identifying the intended change Particular conditions to be fulfilled Particular conditions to be fulfilled –Gives assistance in documentation to be provided Appendix 1 Appendix 1 SCOPE of major changes and line extensions SCOPE of major changes and line extensions –Appendix 2, Appendix 3 GENERAL ASSISTANCE in (additional) stability requirements for all changes (N, minor, major) GENERAL ASSISTANCE in (additional) stability requirements for all changes (N, minor, major) –Appendix 4

11. Birgit Schmauser | April 2008 11 | Dossier maintenance including Variations Prequalification of FPPs Prequalification of FPPs Prequalification of APIMFs (since 2007) Prequalification of APIMFs (since 2007) Variation Guide addresses conditions & documentation requirements in case of a variation to both API and FPP Scenario 1 (Variation Guide) –FPP/API is affected by the variation (without use of APIMF-procedure) Scenario 2 (Variation Guide and Guideline on the APIMF-procedure) –APIMF is affected by the variation 3.4 Changes and updates to the APIMF (mainly administrative)3.4 Changes and updates to the APIMF (mainly administrative)

12. Birgit Schmauser | April 2008 12 | Dossier maintenance including Variations Exception The Variation Guide is not applicable to FPPs that are prequalified based on the assessment of a DRA of the ICH-region and associated countries (Innovator Guideline) Variations on these types of FPPs are approved by the respective DRAs of the ICH region and associated countries and WHO is notified subsequently

13. Birgit Schmauser | April 2008 13 | Dossier maintenance including Variations “Regulatory” clarification A change made to a dossier after it has been prequalified is considered a variation A change made to a dossier after it has been prequalified is considered a variation A change made to a dossier while application for prequalification is still ongoing is considered additional data A change made to a dossier while application for prequalification is still ongoing is considered additional data

14. Birgit Schmauser | April 2008 14 | Dossier maintenance including Variations Variation versus additional data No difference from a technical point of view No difference from a technical point of view –Changes made to a dossier within PQ must be adequately documented and communicated Before prequalification Before prequalification – Evaluation of its impact on quality –Prequalification of the correct/up-to-date characteristics After prequalification After prequalification – Evaluation of its impact on quality –Update of prequalified characteristics

15. Birgit Schmauser | April 2008 15 | Dossier maintenance including Variations Enjoy advantages Enjoy advantages –Grouping of dossiers affected by a variation –Grouping of dossiers affected by a variation A single variation application may be filed if more than one dossier is affected by the same variationA single variation application may be filed if more than one dossier is affected by the same variation –Grouping of variations affecting a dossier –Grouping of variations affecting a dossier Different types of variations affecting the same dossier may be grouped within one variation applicationDifferent types of variations affecting the same dossier may be grouped within one variation application –No fees charged to date –No fees charged to date not enyoyed by applicants within the parent EU-system

16. Birgit Schmauser | April 2008 16 | Dossier maintenance including Variations General considerations for variation applications (I) –Justification/background why changes need to be introduced –Comparison of „present/prequalified“ and „proposed“ state in tabular format (transparency) –“ Replacement of the relevant pages of the dossier according to the structure listed in the PQIF “ Parts of the dossier that are affected by the variation need to be resubmitted according to the structure of the pharmaceutical quality information form (PQIF)

17. Birgit Schmauser | April 2008 17 | Dossier maintenance including Variations Example for „Justification/Background“ –„Replacement of an excipient with a comparable excipient“ In order to avoid incompatibilities of magnesium stearate with ethambutol-HCl we intend to exchange magnesium stearate with stearic acid In order to avoid incompatibilities of magnesium stearate with ethambutol-HCl we intend to exchange magnesium stearate with stearic acid

18. Birgit Schmauser | April 2008 18 | Dossier maintenance including Variations „Justification for using variable „types of equipment“ „Justification for using variable „types of equipment“ We are using different types of umbrellas for protection against light as they have proven to perform „equivalently“ We are using different types of umbrellas for protection against light as they have proven to perform „equivalently“

19. Birgit Schmauser | April 2008 19 | Dossier maintenance including Variations Example for a „Comparative Table“ (replacement of Mg stearate) ProposedPresent - Comparability of the replaced excipient is demonstrated - Comparative dissolution profiles of batches with old and new excipient presented - Justification for not submitting a new bioequivalence study provided - No interference with finished product test method observed - The new composition is presented - CoA of stearic acid attached together with a copy of the monograph and data on TSE-safety - CoAs of three batches are presented - Stability studies with three production scale batches were started 3.2.P.2 Pharmaceutical development as is 3.2.P.3.2 Batch formula as is 3.2.P.4 Control of Excipients as is 3.2.P.5 Control of FPP as is 3.2.P.8 Stability as is

20. Birgit Schmauser | April 2008 20 | Dossier maintenance including Variations General considerations for variation applications (II) Consequentiality Consequentiality –SmPC consequentially needs to be changed, if affected by the change e.g. change in pharmaceutical attributes listed in the SmPC/container label (manufacturing site, container material, excipients etc.)e.g. change in pharmaceutical attributes listed in the SmPC/container label (manufacturing site, container material, excipients etc.) –Additional variation applications to be filed if „effected“ by the original variation application e.g. change in manufacturing site may necessitate adaptation of batch size due to equipment needse.g. change in manufacturing site may necessitate adaptation of batch size due to equipment needs

21. Birgit Schmauser | April 2008 21 | Dossier maintenance including Variations Specific considerations –Conditions frame a particular variation –In case all conditions are met the variation is considered minor –In case one of all conditions is not met the variation is considered major Documentation requirements beyond those of Variation Guide Essential to clarify whether the conditions are met

22. Birgit Schmauser | April 2008 22 | Dossier maintenance including Variations Condition No. 1: –You must proceed at a minimum velocity of 30 miles/hour It is essential to clarify whether the conditions are met

23. Birgit Schmauser | April 2008 23 | Dossier maintenance including Variations Experience with the Variation Guide in PQ Experience with the Variation Guide in PQ –Variations that are “minor in nature” are classified major because they are “not listed as minor” variations –Only few types of variation predominantly occur Potential future perspective Potential future perspective –Complementary parts of the SUPAC-Guidelines may be adopted –Experience with annual reports from requalification –Variations within design space require that FPPs are prequalified based on design space

24. Birgit Schmauser | April 2008 24 | Dossier maintenance including Variations Examples Notifications Notifications

25. Birgit Schmauser | April 2008 25 | Dossier maintenance including Variations Conditions - 1 The manufacturing site remains the same Documentation - 1…, - 2… Documentation to be supplied Conditions to be fulfilled 4Change in the name and/or address of the manufacturer of the finished pharmaceutical product N 1, 2 1

26. Birgit Schmauser | April 2008 26 | Dossier maintenance including Variations Conditions -1 No changes to the manufacturing methods other than those necessitated by scale-up, e.g. use of different sized equipment -2 Test results of at least two batches according to the specifications should be available for the proposed batch size -3 The change does not affect the reproducibility of the process -4 The change should not be the result of unexpected events arising during manufacture or because of stability concerns Documentation (-1…, -2…, -3…, -4…) Documentation to be supplied Conditions to be fulfilled 9 Change in batch size of API or intermediate N 1, 2 1, 2, 3 a)Up to 10-fold increase compared to the prequalified batch size N 1, 2 1, 2, 3, 4 b)Downscaling 1, 3, 4 1, 2, 3 c) More than 10-fold increase compared to the prequalified batch size

27. Birgit Schmauser | April 2008 27 | Dossier maintenance including Variations Examples Minor changes Minor changes

28. Birgit Schmauser | April 2008 28 | Dossier maintenance including Variations Documentation to be supplied Conditions to be fulfilled 26Change in the qualitative and/or quantitative composition of the immediate packaging material 1, 2, 3, 4, 5 1, 2, 3, 4 a)Semisolid and liquid pharmaceutical forms N 1, 4, 5 1, 2, 3, 4 b)All other pharmaceutical forms 1, 2, 3, 4, 5 1, 3, 4 Conditions 1- The product concerned is not a sterile product 1- The product concerned is not a sterile product 2- The packaging type and material remain the same (e.g. a different blister, but same type) 2- The packaging type and material remain the same (e.g. a different blister, but same type) 3- The relevant properties of the proposed packaging material must be at least equivalent to those of the prequalified material 3- The relevant properties of the proposed packaging material must be at least equivalent to those of the prequalified material 4- Relevant stability studies with the relevant guidelines have been started with at least two pilot- scale or production scale batches, and at least three months´ stability data are at the disposal of the applicant. Assurance is given that these studies will be finalised and that the data will be provided immediately to WHO if outside specifications or potentially outside specifications at the end of the prequalified shelf life (with proposed action) 4- Relevant stability studies with the relevant guidelines have been started with at least two pilot- scale or production scale batches, and at least three months´ stability data are at the disposal of the applicant. Assurance is given that these studies will be finalised and that the data will be provided immediately to WHO if outside specifications or potentially outside specifications at the end of the prequalified shelf life (with proposed action) Documentation (-1…, -2…, -3…, -4…, -5…)

29. Birgit Schmauser | April 2008 29 | Dossier maintenance including Variations Documentation to be supplied Conditions to be fulfilled 26Change in the qualitative and/or quantitative composition of the immediate packaging material 1, 2, 3, 4, 5 1, 2, 3, 4 a)Semisolid and liquid pharmaceutical forms N 1, 4, 5 1, 2, 3, 4 b)All other pharmaceutical forms 1, 2, 3, 4, 5 1, 3, 4 All dosage forms All dosage forms –Sterile FPPs are handled as major variations Semisolid and liquid preparations Semisolid and liquid preparations –Change in type/material of packaging material: major variation All other dosage forms All other dosage forms – Change type/material of packaging material: minor variation but extended documentation requirements (1 – 5)

30. Birgit Schmauser | April 2008 30 | Dossier maintenance including Variations Conditions - 1 The specifications (including in-process controls, methods of analysis of all materials), method of preparation (including batch size) and detailed route of synthesis are identical to those already prequalified - 2 Where materials of human or animal origin are used in the process, the manufacturer does not use any new supplier for which assessment is required of viral safety or of compliance with the current “...WHO or EU or ICH Guidelines on TSE...” Documentation (-1…, -2…, -3…, -4…, -5…) - 2 A declaration from the supplier of the prequalified FPP that the route of synthesis, quality control procedures and specifications of the API and key (ultimate) intermediate in the manufacturing process of the API (if applicable) are the same as those already prequalified. Documentation to be supplied Conditions to be fulfilled 12Change in the manufacturer of the API or final (ultimate) key intermediate in the manufacturing process of the API 1, 2, 3, 4, 5 1, 2 a)Change in site of the already prequalified manufacturer (replacement or addition) 1, 2, 3, 4, 5 1, 2 b)New manufacturer (relacement or addition)

31. Birgit Schmauser | April 2008 31 | Dossier maintenance including Variations How to verify that the specifications/method of preparation/detailed route of synthesis are the same as those already prequalified? How to verify that the specifications/method of preparation/detailed route of synthesis are the same as those already prequalified? –Comparison of API-data of prequalified and proposed API-manufacturer by the FPP-manufacturer Available from the API-part of the dossier/OP of APIMFs/DMFsAvailable from the API-part of the dossier/OP of APIMFs/DMFs Tabular presentation of data (documented evidence)Tabular presentation of data (documented evidence) Documentation to be supplied Conditions to be fulfilled 12Change in the manufacturer of the API or final (ultimate) key intermediate in the manufacturing process of the API 1, 2, 3, 4, 5 1, 2 a)Change in site of the already prequalified manufacturer (replacement or addition) 1, 2, 3, 4, 5 1, 2 b)New manufacturer (relacement or addition)

32. Birgit Schmauser | April 2008 32 | Dossier maintenance including Variations Examples Major changes Major changes

33. Birgit Schmauser | April 2008 33 | Appendix 2 Major changes Major changes –Exceed the scope of minor changes –Do not yet reach the scope of line extensions Most likely the following cases occur: Most likely the following cases occur: –Change in the manufacturing process of the API –Change in the composition of the FPP –Change to the immediate primary packaging of the FPP Dossier maintenance including Variations

34. Birgit Schmauser | April 2008 34 | Appendix 2 Major changes Major changes –Documentation requirements Replacement of particular sections affected by the changeReplacement of particular sections affected by the change –Generic Guideline Potential implications of the change on the FFPPotential implications of the change on the FFP Dossier maintenance including Variations

35. Birgit Schmauser | April 2008 35 | Appendix 3 Changes that afford a new application / line extension Changes that afford a new application / line extension –Changes to the API Replacement, addition, removal, change of dose Replacement, addition, removal, change of dose –Changes to the pharmaceutical form / dosage form From immediate release to delayed or modified release and vice versa From immediate release to delayed or modified release and vice versa From liquid to powder for reconstitution and vice versa From liquid to powder for reconstitution and vice versa Dossier maintenance including Variations

36. Birgit Schmauser | April 2008 36 | Appendix 4 Stability requirements for changes to prequalified FFPs Stability requirements for changes to prequalified FFPs –Scope and design of stability studies for variations based on knowledge and experience acquired on APIs and FPPs Stability profile, supportive data, data on primary batches Stability profile, supportive data, data on primary batches –Investigations on potential impact of changes on stability of API/FPP are at the responsibility of Applicants –Stability studies required due to changes are to be continued up to the proposed shelf life WHO to be informed on deviations immediately WHO to be informed on deviations immediately Dossier maintenance including Variations

37. Birgit Schmauser | April 2008 37 | Appendix 4 Minor changes Minor changes –Comparison of stability data of the changed product to stability data of unchanged product Evidence of unchanged quality characteristics Evidence of unchanged quality characteristics Major changes Major changes –Stability studies depending on the nature of the change the nature of the change the characteristics of the API/FPP the characteristics of the API/FPP Dossier maintenance including Variations

38. Birgit Schmauser | April 2008 38 | Appendix 4 Major changes Major changes –Changed manufacturing process of API Changed quality characteristics of API? Changed quality characteristics of API? – Changed stability profile of API? Impacted stability profile of FPP? –Changed composition/container of FPP Critical dosage form or unstable API? Critical dosage form or unstable API? –Changed container of FPP Risk of interaction/less protection by packaging? Risk of interaction/less protection by packaging? Dossier maintenance including Variations

39. Birgit Schmauser | April 2008 39 | Dossier maintenance including Variations Summary Variations to a prequalified product dossier need to be approved by WHO because they may impact the quality of the FPP Variations to a prequalified product dossier need to be approved by WHO because they may impact the quality of the FPP Most variations occurring in PQ are reflected in Appendix 1 of the Variation Guide (minor changes) Most variations occurring in PQ are reflected in Appendix 1 of the Variation Guide (minor changes) Major changes afford a more thorough documentation approach and evaluation procedure to ensure unchanged quality characteristics Major changes afford a more thorough documentation approach and evaluation procedure to ensure unchanged quality characteristics The concept of the Variation Guide reflects a risk-based- approach The concept of the Variation Guide reflects a risk-based- approach

40. Birgit Schmauser | April 2008 40 | THANK YOU THANK YOU Dossier maintenance including Variations