1. Applications and benefits of PAT Steve Hammond Global Manufacturing Services Process Analytical Support Group Sandwich, UK

2. Agenda l API Manufacture u Reaction monitoring u Crystallisation u Drying l Drug product manufacture u Granule dying - fluid bed dryers u Blending u Compression - PQRI recommendations l Benefits u Control, knowledge, quality and costs

3. No sampling No operator exposure Accurate end point Control of impurities The profile was generated using peak heights referenced to a 2-point baseline, producing the following curves.  Blue - Step (starting material, 1 ) at 2239 cm  Red – Step (starting material,1) at 930 cm  Green – Step (product,2) at 1308 cm Mid-IR to Monitor and Control Reactions

4. Focused Beam Reflectance Measurement Probe inserted into crystalliser Circulating light beam bounces of particles suspended in solvent Measures crystal diameter Lasentec

5. Crystal size change during formation 0-50 microns O-10 microns 50-100 microns > 100 microns Seed point

6. Endoscope picture inside crystalliser Benefit - Control of fines or agglomerates in API Reduced need to mill Control of particle size

7. Pan Dryer Sample Point Outlet NIR Outside Dryer Room Maximum Capacity 300litres. Typicalbatchsizeforunit100Kg withaminimumof50Kganda maximum of 200Kg. Thevacuumappliedistypically 1mbar at the end of drying. Theprobeisfittedinthe1-inch drainnozzleatthebaseofthe vessel. Online NIR Drain Point

8. Drying API in a vacuum dryer Absorption of dry cake Empty dryer Wet Cake Charged into dryer Absorption of wet cake 15:64 Volatile 0.46% at 19:18 Volatile 0.51% at 20:18 Volatile 0.27% at 21:18 Disappearance of acetonitrile clearly evident. Control of dryer residence time Benefits- quality and cost

9. NIR on a fluid bed dryer - granule drying

10. Glatt Multi-Cell Fluid Bed Dryer

11. On-Line analysis of blending l Driven by safety issues with new potent API’s l Uses battery power and radio communication l Small fast diode array instrument l Mounted on the moving blender l Controlled outside of containment area

12. On- line NIR bin blender Reading Head NIR Instrument Battery RF Module Fibre optic

13. Corona Sensor Head Light Lid of blender & window Focal Point just inside bin 30mm Fibre Optic Collector Fibre Optic to Detector Contributing sample weight is ~300mg

14. Saccharin Specific Absorption Saccharin Avicel Lactose Saccharin increasing absorbance with blending

15. Magnesium Stearate Specific Absorption Saccharin Mag Stearate Avicel Lactose Mag Stearate decreasing absorbance with blending

16. Absorbance of Blend Components (Step 1)

17. Saccharin Uniformity (Step 1)

18. Magnesium Stearate Uniformity (Step 2)

19. NIR Instrument in production plant

20. Blender Filling Drug Substance Excipients

21. Online Monitoring of Aromatic Absorption Profile at this point

22. Online Monitoring of Aromatic Absorption Profile plot Phase 1 Phase 2 Phase 3 Phase Change

23. On-line blending - benefits l No operator contact - safety l No sampling errors - no thief l Real-time information l Multi-ingredient uniformity l Process understanding l Process finger- printing for scale up l Right first time l Fast release of the blend - reduced cycle times

24. NIR Tablet Transmission Device

25. Tablet core potency - blend segregation in the bin

26. Automated tablet analysis NIR Identity Potency Uniformity Bruker Weight Thickness Hardness Dr S Pharmatron

27. Bruker NIR Transmission Head Open architecture for process analysis

28. Absorbance of active tablets Vs placebos

29. NIR transmission Vs conc in tablets 0.1% - 2.0%

30. On-line tablet cores - benefits l No operator contact - safety l Sampling - comply with PQRI l Real-time information l Multi-ingredient uniformity l Process understanding l Process finger- printing for scale up l Right first time l Immediate release - reduced cycle times

31. Microscopic View of Dosage Form

32. The Future….. l Take Off ‘Crude’ bulk NIR measurement. l Use more sophisticated NIR method and actually image the blend in the blender! Imaging Optics?? Reading Head NIR Instrument Battery RF Module Fibre optic

33. Benefits of Improved Control l Conventional methods give product which is fit for intended use, but… l Advanced control gives u better batch to batch consistency u better quality (less impurities) u fewer reworks/rejects u improved process understanding u faster response times u better productivity u lower cost