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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
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-1
Red – Step (starting material, 1) at 930 cm-1
Green – Step (product, 2) at 1308 cm-1
Mid-IR to Monitor and Control Reactions
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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 formationMeasurement of Gabapentin Recrystallisation Using FBRM
0
200
400
600
800
1000
1200
1:16:00 1:20:48 1:25:36 1:30:24 1:35:12
Reaction Time (hrs)
Part
icle
Co
un
t sec
-1
#/sec, No Wt 0 10 #/sec, No Wt 10 50 #/sec, No Wt 50 100 #/sec, No Wt 100 1000
0-50 microns
O-10 microns
50-100 microns
> 100 microns
Seed point
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Endoscope picture inside crystalliser
Benefit -
Control of fines or agglomerates in API
Reduced need to mill
Control of particle size
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Pan Dryer
Sample Point
Outlet
NIR Outside Dryer Room
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.
Online NIR
Drain Point
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Drying API in a vacuum dryer
Absorption of dry cake
Empty dryer
Wet CakeChargedinto 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
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NIR on a fluid bed dryer - granule drying
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Glatt Multi-Cell Fluid Bed Dryer
40 80 120 160 200
-2.0
-1.8
-1.6
-1.4
-1.2
sec
Sep.21.2000/11:51:25AMSECT: RUN5D2.DAT / 1409.2nm [10E-4]
R5D2DP.DAT Pfizer Ltd. / Aspect Plus V1.52
Filter cleaning
Wet
Dry
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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
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On- line NIR bin blender
Reading Head
NIR Instrument
Battery RF Module
Fibre optic
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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
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Saccharin Specific Absorption
Saccharin
Avicel
Lactose
Saccharin increasing absorbance with blending
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Magnesium Stearate Specific Absorption
Saccharin
Mag Stearate
Avicel
Lactose Mag Stearatedecreasing absorbance with blending
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Absorbance of Blend Components (Step 1)
-12
-10
-8
-6
-4
-2
0
2
4
0 6 12 18 24 30 36 42 48 54 60
Sample Points (~12 seconds each)
Ab
so
rba
nc
e
Saccharin 1630nm Lactose 1450nm Avicel 1425nm
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Saccharin Uniformity (Step 1)
0
0.1
0.2
0.3
0.4
0.5
0.6
0 6 12 18 24 30 36 42 48 54 60
Sample Point (~12 seconds each)
8 P
oin
t V
ari
an
ce
Saccharin (Step1)
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Magnesium Stearate Uniformity (Step 2)
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
0.45
0 6 12 18 24 30 36 42 48 54 60
Sample Point (~12 seconds each)
8 P
oin
t V
ari
an
ce
Mag Stearate 1390nm
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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 1
Phase 2
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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Fibre Optic Probe
InGaAs (Indium Gallium Arsenide) Detector
Fibre Bundle
Removable Probe Tip
Tablet Holder
Tablet
Light Path
NIR Tablet Transmission Device
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Tablet core potency - blend segregation in the bin
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Automated tablet analysis
NIRIdentityPotencyUniformityBruker
Weight ThicknessHardnessDr S Pharmatron
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Bruker NIR Transmission Head
Open architecture for process analysis
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Absorbance of active tablets Vs placebos
1.261.281.301.321.341.361.38
-0.5
0.0
0.5
1.0
1.5
2.0
Ab
sorb
an
ce U
nits
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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
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Microscopic View of Dosage Form
Blend Tablet
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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!
Imaging Optics??
Reading Head
NIR Instrument
Battery RF Module
Fibre optic
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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