1. Study Medication  Time schedule  Résumé Development of an improved tablet formulation  Long term stability  Reasonable production conditions  Focus on packaging material G&H Meeting Sep 29 - Oct 2, 2003 Munich, Germany WP 7 Pharmaceutics (Lichtwer Pharma)  Objectives…

2. Time schedule Time schedule  7 th -8 th WeekProduction Verum & Placebo 7 th -8 th Week  7 th -8 th WeekWriting & Authorisation production protocol 9 th -10 th Week  9 th -10 th WeekWriting Randomisation Plan 12 th Week  9 th -10 th WeekQuality Control Verum & Placebo 13 th Week  10 th -11 th WeekWriting & Authorisation(!) packaging/labelling 12 th Week  12 th WeekPackaging & Labelling 16 th Week  14 th WeekFinal Release & Delivery 22 th Week Final Release & Delivery (first part) 33 th Week Final Release & Delivery (second part)

3.  Tabletting: Difficulties with the flowability and compressibility of the EU garlic powder  Coating: Everything went fine…  Sugar Coating: Everything went fine…  Release: Full compliance with specifications!  GCP: Minor deviations  Résumé …

4. Details on Stability Studies Organic film based  Full compliance to ICH-guidelines  Up to seven different packaging materials  Two different dosage forms Aqueous film based  Reformulation of tablet core  Formulation of coating  Establishing aqueous coating procedure

5. Stability of Commercial Products (Dragees)

6. Commercial Products (Dragees)

7. Organic Film Tablets (100 mg)

10. Organic Film Tablets (300 mg)

16.  It is possible to prolong shelf life up to 4 times when… 1.the residual humidity of the tablets is limited to 3,5 – 4 % 2.a strictly humidity controlled coating procedure is applied 3.a packaging material providing a 100% humidity barrier is used  It is possible to produce the improved tablets in an economic way (e.g. no freeze drying necessary!)  Concerning the high demands on the water barrier there is no sufficient polymer blister material available  Conclusion Organic Coated Film Tablet I

17.  Further optimisation is possible to solve… … the poor disintegration time of the 300 mg tablets from up to 45 min to < 30 min … poor robustness of the formulation concerning high speed tabletting … residual organic solvent problem (film coating)  Conclusion Organic Coated Film Tablet II

18.  Transforming  Transforming… an organic film coated tablet into… an aqueous film coated tablet!  Why? a)More flexible production process b)No organic solvents necessary c)Adaptable at Lichtwer’s Facilities

19.  Three production scale batches according ICH-Guidelines have been manufactured successfully in Aug 2003  The residual water content of the tablets are 2.6 to 2.8% (limit: 3.5%)  The batches have been packed in PE bottles and COC300 Blister (Alu/Alu blister coming up next)  The batches are stored under 25°C/60%, 30°C/65%, and 40°C/75% conditions  Overview Status Aqueous Coated Tablets

20. Production Scheme Production Scheme 1.Weighing and Mixing 2.Tabletting 3.Coating suspension 4.Coating 5.In-Process Controls 6.Packaging

21. Weighting/Mixing

22. Tabletting

23. Coating Suspension

24. Coating

25. In-Process Control

26. Packaging (Blister)

27. The Team you can trust… The Team you can trust… Wolfgang Lüdeke José Galan-Sousa Silvia Striegl Anke Wermann & Anja Müller Anke Wermann & Anja Müller

28. The Team you can trust… part II The Team you can trust… part II Bianca Beutke Stability Coordination Bianca Beutke Stability Coordination You can‘t get enough stability!

29. Thank you very much for… !!! !!!