1. HELM AG Module 3 Christa Clasen Ankara, 6./7. April 2006

2. Christa Clasen Ankara, 6./7. April 2006 Module 3 3.1 Table of Content 3.2 Body of Data 3.2.S Drug Substance 3.2.P Drug Product 3.2.A Appendices 3.2.R Regional Information 3.3 Literature References

3. Christa Clasen Ankara, 6./7. April 2006 3.2.S Drug Substance 3.2.S.1General Information 3.2.S.2Manufacture 3.2.S.3Characterisation 3.2.S.4Control of drug substance 3.2.S.5Reference Standards or Materials 3.2.S.6Container Closure System 3.2.S.7Stability

4. Christa Clasen Ankara, 6./7. April 2006 3.2.S.1.1 Nomenclature INN, Compendial name, chemical name, other name, laboratory codes, CAS – number 3.2.S.1.2 Structure Physical form, structural formula (incl. stereochemistry) 3.2.S.1.3 General Properties Physico-chemical characterisation (solubility, physical characteristics, polymorphism, other) 3.2.S.1 General Information

5. Christa Clasen Ankara, 6./7. April 2006 3.2.S.2Manufacture 3.2.S.2.1 Manufacturer 3.2.S.2.2 Description of Manufacturing Process and Process Controls 3.2.S.2.3 Controls of Materials 3.2.S.2.4Control of Critical Steps and Intermediates 3.2.S.2.5 Process Validation and/or Evaluation 3.2.S.2.6Manufacturing Process Development

6. Christa Clasen Ankara, 6./7. April 2006 3.2.S.2Manufacture 3.2.S.2.1Manufacturer Address office Address plant Company profile is not obligatory If starting materials/ or used intermediates already contains a key-structure of the final drug substance, information of those manufacturer(s) are required

7. Christa Clasen Ankara, 6./7. April 2006 3.2.S.2Manufacture 3.2.S.2.2Description of Manufacturing Process and Process Controls Applicant‘s Part: Synthetic route: overview Flow chart Brief narrative description of the process

8. Christa Clasen Ankara, 6./7. April 2006 3.2.S.2Manufacture 3.2.S.2.2Description of Manufacturing Process and Process Controls Restricted Part: Synthetic route: Overview Flow chart including molecular formula, weights, yields, chemical structures of starting materials, intermediates, reagents and drug substance reflecting stereochemistry, operating conditions and used solvents Narrative description of the process covering in more detail the information given in the flow- chart

9. Christa Clasen Ankara, 6./7. April 2006 3.2.S.2Manufacture 3.2.S.2.3Control of Materials List of used raw materials identifying where each material is used in the process. Control of starting materials (Specifications, Description of Test methods) Control of solvents and other reagents (Specifications, Description of Test methods) If starting materials already contains the key- structure of the final API, a synthesis-outline (including solvents, reagents, catalysts, potential Impurities) for these starting materials are required

10. Christa Clasen Ankara, 6./7. April 2006 3.2.S.2.Manufacture 3.2.S.2.4Control of Critical Steps and Intermediates Control of Intermediates (Specifications, Description of test methods) Tests and acceptance criteria (with justification including experimental data) performed at critical steps identified in 3.2.S.2.2

11. Christa Clasen Ankara, 6./7. April 2006 3.2.S.2Manufacture 3.2.S.2.5Process Validation and/or Evaluation Process Validation studies should be included (only for aseptic processes or sterilisation) In any case: Validation studies have to be perfomed and needs to be available at request

12. Christa Clasen Ankara, 6./7. April 2006 3.2.S.2Manufacture 3.2.S.2.6Manufacturing Process Development A description and discussion about the significant changes/improvements to the manufacturing process and/or manufacturing site of the drug substance is awaited

13. Christa Clasen Ankara, 6./7. April 2006 3.2.S.3Characterisation 3.2.S.3.1.Eludication of Structure and other Characteristics Evidence of the chemical structure (elemental analysis, mass spectrum, 1 H-NMR, 13 C-NMR, IR, UV, other) Potential isomerism Stereochemistry Polymorphism

14. Christa Clasen Ankara, 6./7. April 2006 3.2.S.3Characterisation 3.2.S.3.2.Impurities List of potential impurities originating from the route of synthesis List of potential impurities arising during the production and purification List of actual existing impurities (synthesis by- products, degradation products) List of potential residual solvents List of actual residual solvents in API Evidence of the chemical structure (elemental analysis, mass spectrum, 1 H-NMR, 13 C-NMR, IR, UV, other) for each Impurity

15. Christa Clasen Ankara, 6./7. April 2006 3.2.S.4Control of Drug Substance 3.2.S.4.1 Specification According to which pharmacopoeia, in-house Characteristics Identification tests Purity tests (including limits for known, total, unidentified single and unidentified total) Other tests Assay

16. Christa Clasen Ankara, 6./7. April 2006 3.2.S.4Control of Drug Substance 3.2.S.4.2 Analytical Procedures Reference to pharmacopoeia, or detailed description of all tests 3.2.S.4.3 Validation of Analytical Procedures Validation of all used methods according to ICH Guidelines Q2A and Q2B (if they are not pharmacopoeial)

17. Christa Clasen Ankara, 6./7. April 2006 3.2.S.4Control of Drug Substance 3.2.S.4.4Batch analysis Batches tested (date of manufacture, place of manufacture, batch size) Results of tests (3 - 5 consecutive certificates of analysis) 3.2.S.4.5 Justification of the drug substance specification Comments on the Choice of Routine Tests Justification of Specification Limits

18. Christa Clasen Ankara, 6./7. April 2006 3.2.S.5. Reference Standards or Materials List of used Reference Standards or Materials Preparation of Reference Standards, if appropriate Elucidation of Structure for synthesized Materials Specification for Reference materials Description of Test Methods Validation of Analytical Methods if not covered by 3.2.S.4.3

19. Christa Clasen Ankara, 6./7. April 2006 3.2.S.6 Container Closure System Description of Container Closure System including Identity of Materials and their specification Discussion of suitability of Packaging material

20. Christa Clasen Ankara, 6./7. April 2006 3.2.S.7 Stability 3.2.S.7.1.Stability Summaries and Conclusions Program of stability studies (including forced degradation studies if appropriate, e.g. testing parameters, packaging material, storage conditions, batch number, manufacturing date, batch size Conclusion

21. Christa Clasen Ankara, 6./7. April 2006 3.2.S.7 Stability 3.2.S.7.2Post-approval Stability Protocol and Stability Commitment Program of stability study including testing parameters, packaging material, storage conditions, batch number, manufacturing date, batch size, which will be performed post-approval

22. Christa Clasen Ankara, 6./7. April 2006 3.2.S.7 Stability 3.2.S.7.3 Stability data Results of: Long-term study (initial, 3, 6, 9, 12, 18, 24, 36 months) for at least 3 batches Accelerated study (initial, 1, 2, 3, 6 months) for the same batches as long-term study Intermediate study (initial, 3, 6, 9, 12, 18, 24, 36 months) for at least 3 batches, if appropriate Forced degradation study (alkaline conditions, acidic conditions, higher temperature, oxidative condition, light )

23. Christa Clasen Ankara, 6./7. April 2006 3.2.P Drug Product 3.2.P.1 Description and Compostion of the Drug Product 3.2.P.2 Pharmaceutical Development 3.2.P.3 Manufacture 3.2.P.4 Control of Excipients 3.2.P.5 Control of Drug Product 3.2.P.6 Reference Standards or Materials 3.2.P.7 Container Closure System 3.2.P.8 Stability

24. Christa Clasen Ankara, 6./7. April 2006 3.2.P.1 Description and Composition of the Drug Product Description of dosage form List of components and their amount Function of components Reconstitution diluent(s)

25. Christa Clasen Ankara, 6./7. April 2006 3.2.P.2 Pharmaceutical Development 3.2.P.2.1 Components of Drug Product 3.2.P.2.2 Drug Product 3.2.P.2.3 Manufacturing Process Development 3.2.P.2.4 Container Closure System 3.2.P.2.5 Microbiological Attributes 3.2.P.2.6 Compatibility

26. Christa Clasen Ankara, 6./7. April 2006 3.2.P.2Pharmaceutical Development 3.2.P.2.1Components of the Drug Product 3.2.P.2.1.1 Drug Substance -Compatibility with Excipients -Key physicochemical Characteristics 3.2.P.2.1.2 Excipients -Justification of Choice

27. Christa Clasen Ankara, 6./7. April 2006 3.2.P.2 Pharmaceutical Development 3.2.P.2.2 Drug Product 3.2.P.2.2.1 Formulation Development Brief summary, which is describing the development 3.2.P.2.2.2 Overages Justification of Overages 3.2.P.2.2.3 Physicochemical and Biological Properties

28. Christa Clasen Ankara, 6./7. April 2006 3.2.P.2Pharmaceutical Development 3.2.P.2.3 Manufacturing Process Development Selection and optimisation of the manufacturing process with its particular critical steps 3.2.P.2.4 Container Closure System Suitability of the Container Closure System used for storage, transportation and drug product

29. Christa Clasen Ankara, 6./7. April 2006 3.2.P.2Pharmaceutical Development 3.2.P.2.5 Microbiological Attributes Microbiological Attributes should be discussed 3.2.P.2.6 Compatibility Compatibility of with reconstitution diluent(s)

30. Christa Clasen Ankara, 6./7. April 2006 3.2.P.3 Manufacture 3.2.P.3.1 Manufacturer(s) 3.2.P.3.2 Batch Formula 3.2.P.3.3 Description of Manufacturing Process and Process Controls 3.2.P.3.4 Controls of Critical Steps 3.2.P.3.5 Process Validation and/or Evaluation

31. Christa Clasen Ankara, 6./7. April 2006 3.2.P.3Manufacture 3.2.P.3.1 Manufacturer(s) Name, address and responsibility of each manufacturer 3.2.P.3.2 Batch Formula Batch formula incl. all components with amounts and references

32. Christa Clasen Ankara, 6./7. April 2006 3.2.P.3Manufacture 3.2.P.3.3 Description of Manufacturing Process and Process Controls Flow diagram Narrative description of the manufacturing process Process parameters Proposals for justification of reprocessing of materials

33. Christa Clasen Ankara, 6./7. April 2006 3.2.P.3Manufacture 3.2.P.3.4 Controls of Critical Steps and Intermediates Critical Steps: Test and acceptance criteria Intermediates: Information of quality and control 3.2.P.3.5 Process validation and/or evaluation Description, documentation, results of validation and/or evaluation studies

34. Christa Clasen Ankara, 6./7. April 2006 3.2.P.4 Control of Excipients 3.2.P.4.1 Specifications 3.2.P.4.2 Analytical Procedures 3.2.P.4.3 Validation of Analytical Procedures 3.2.P.4.4 Justification of Specification 3.2.P.4.5 Excipients of Human or Animal Origin 3.2.P.4.6 Novel Excipients

35. Christa Clasen Ankara, 6./7. April 2006 3.2.P.4 Control of Excipients 3.2.P.4.1 Specification Specification should be provided 3.2.P.4.2 Analytical Procedure Analytical Procedures should be provided 3.2.P.4.3 Validation of Analytical Procedures Information about Validation

36. Christa Clasen Ankara, 6./7. April 2006 3.2.P.4 Control of Excipients 3.2.P.4.4 Justification of Specification Justification for the proposed specification for the excipients 3.2.P.4.5 Excipients of Human or Animal Origin Information regarding adventitious agens should be provided. 3.2.P.4.6 Novel Excipients For excipients used the first time or by a new route of administration detailed information according to the Drug Substance format should be provided.

37. Christa Clasen Ankara, 6./7. April 2006 3.2.P.5Control of Drug Product 3.2.P.5.1 Specification(s) 3.2.P.5.2 Analytical Procedures 3.2.P.5.3 Validation of Analytical Procedures 3.2.P.5.4 Batch Analysis 3.2.P.5.5 Characterisation of Impurities 3.2.P.5.6 Justification of Specification(s)

38. Christa Clasen Ankara, 6./7. April 2006 3.2.P.5Control of Drug Product 3.2.P.5.1 Specification(s) Specification(s) should be provided 3.2.P.5.2 Analytical Procedures Analytical Procedures should be provided

39. Christa Clasen Ankara, 6./7. April 2006 3.2.P.5Control of Drug Product 3.2.P.5.3 Validation of Analytical Procedures Analytical Validation should be provided 3.2.P.5.4 Batch Analysis Descripition of batches and results of batch analysis should be provided

40. Christa Clasen Ankara, 6./7. April 2006 3.2.P.5Control of Drug Product 3.2.P.5.5 Characterisation of Impurities Characterisation of Impurities  if not provided in 3.2.S.3.2 (Impurities) 3.2.P.5.6 Justification of Specification(s) Justification of proposed specification(s) should be provided

41. Christa Clasen Ankara, 6./7. April 2006 3.2.P.6 Reference Standards or Materials Information about reference standards or materials should be provided  if not provided in 3.2.S.5 „Reference standards or materials“

42. Christa Clasen Ankara, 6./7. April 2006 3.2.P.7 Container Closure System Identity and specification of each primary packaging components Brief description of non-functional secondary packaging component Information about functional secondary packaging component

43. Christa Clasen Ankara, 6./7. April 2006 3.2.P.8 Stability 3.2.P.8.1 Stability Summary and Conclusion 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment 3.2.P.8.3 Stability Data

44. Christa Clasen Ankara, 6./7. April 2006 3.2.P.8 Stability 3.2.P.8.1 Stability Summary and Conclusion The Stability Summary should include: Types of Studies Results of Studies Conclusion with respect to storage conditions and shelf-life

45. Christa Clasen Ankara, 6./7. April 2006 3.2.P.8 Stability 3.2.P.8.2 Post-approval Stability Protocol Post-approval stability protocoll and the stability commitment should be provided 3.2.P.8.3 Stability Data Presentation of the results in an appropriate format Information of analytical procedures incl. validation

46. Christa Clasen Ankara, 6./7. April 2006 3.2.AAppendices 3.2.A.1Facilities and Equipment 3.2.A.2Adventitious Agents Safety Evaluation 3.2.A.3Novel Excipients

47. Christa Clasen Ankara, 6./7. April 2006 3.2.RRegional Information (EU) Process Validation Scheme for Drug Product Medical Devices Certificate(s) of Suitability TSE templates (place in 3.2.A.2)