Applications and benefits of PAT

1
Applications and benefits of PAT

• Steve Hammond
• Global Manufacturing Services
• Process Analytical Support Group
• Sandwich, UK

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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

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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
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Focused Beam Reflectance Measurement
Probe inserted into crystalliser Circulating
light beam bounces of particles suspended in
solvent Measures crystal diameter
Lasentec
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Crystal size change during formation
0-50 microns
O-10 microns
Seed point
50-100 microns
gt 100 microns
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Endoscope picture inside crystalliser
Benefit - Control of fines or agglomerates in
API Reduced need to mill Control of particle
size
7
Pan Dryer
Outlet
Online
NIR
Sample Point
Drain Point
NIR Outside Dryer Room
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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
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Glatt Multi-Cell Fluid Bed Dryer
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On-Line analysis of blending

• Driven by safety issues with new potent APIs
• Uses battery power and radio communication
• Small fast diode array instrument
• Mounted on the moving blender
• Controlled outside of containment area

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On- line NIR bin blender
Battery RF Module
Fibre optic
NIR Instrument
Reading Head
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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
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Saccharin Specific Absorption
Avicel
Lactose
Saccharin increasing absorbance with blending
Saccharin
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Magnesium Stearate Specific Absorption
Avicel
Mag Stearate decreasing absorbance with blending
Lactose
Saccharin
Mag Stearate
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Absorbance of Blend Components (Step 1)
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Saccharin Uniformity (Step 1)
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Magnesium Stearate Uniformity (Step 2)
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NIR Instrument in production plant
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Blender Filling
Drug Substance
Excipients
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Online Monitoring of Aromatic Absorption
Profile at this point
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Online Monitoring of Aromatic Absorption
Profile plot
Phase 2
Phase 1
Phase 3
Phase Change
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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

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NIR Tablet Transmission Device
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Tablet core potency - blend segregation in the
bin
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Automated tablet analysis
Weight Thickness Hardness Dr S Pharmatron
NIR Identity Potency Uniformity Bruker
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Bruker NIR Transmission Head
Open architecture for process analysis
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Absorbance of active tablets Vs placebos
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NIR transmission Vs conc in tablets 0.1 - 2.0
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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
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The Future..

• Take Off Crude bulk NIR measurement.
• Use more sophisticated NIR method and actually
  image the blend in the blender!

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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