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Applications and benefits of PAT

Applications and benefits of PAT. Steve Hammond Global Manufacturing Services Process Analytical Support Group Sandwich, UK. Agenda. API Manufacture Reaction monitoring Crystallisation Drying Drug product manufacture Granule dying - fluid bed dryers Blending

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Applications and benefits of PAT

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

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

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

  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 Seed point 50-100 microns > 100 microns

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

  7. Maximum Capacity 300litres. Typical batch size for unit 100Kg with a minimum of 50Kg and a maximum of 200Kg. The vacuum applied is typically 1mbar at the end of drying. The probe is fitted in the 1-inch drain nozzle at the base of the vessel. Pan Dryer Outlet Online NIR Sample Point Drain Point NIR Outside Dryer Room

  8. Empty dryer 15:64 Volatile 0.27% at 21:18 Volatile 0.46% at 19:18 Volatile 0.51% at 20:18 Wet Cake Charged into dryer Absorption of dry cake Absorption of wet cake Drying API in a vacuum dryer 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 • Driven by safety issues with new potent API’s • Uses battery power and radio communication • Small fast diode array instrument • Mounted on the moving blender • Controlled outside of containment area

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

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

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

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

  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 2 Phase 1 Phase 3 Phase Change

  23. On-line blending - benefits • No operator contact - safety • No sampling errors - no thief • Real-time information • Multi-ingredient uniformity • Process understanding • Process finger- printing for scale up • Right first time • 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 Weight Thickness Hardness Dr S Pharmatron NIR Identity Potency Uniformity Bruker

  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 • No operator contact - safety • Sampling - comply with PQRI • Real-time information • Multi-ingredient uniformity • Process understanding • Process finger- printing for scale up • Right first time • Immediate release - reduced cycle times

  31. Microscopic View of Dosage Form

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

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

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