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 Compression - PQRI recommendations

Benefits Control, knowledge, quality and costs

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

Focused Beam Reflectance Measurement

Probe inserted into crystalliser

Circulating light beam bounces of particles suspended in solvent

Measures crystal diameter

Lasentec

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

Endoscope picture inside crystalliser

Benefit -

Control of fines or agglomerates in API

Reduced need to mill

Control of particle size

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

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

NIR on a fluid bed dryer - granule drying

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

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

On- line NIR bin blender

Reading Head

NIR Instrument

Battery RF Module

Fibre optic

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

Saccharin Specific Absorption

Saccharin

Avicel

Lactose

Saccharin increasing absorbance with blending

Magnesium Stearate Specific Absorption

Saccharin

Mag Stearate

Avicel

Lactose Mag Stearatedecreasing absorbance with blending

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

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)

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

NIR Instrument in production plant

Blender Filling

Drug Substance

Excipients

Online Monitoring of Aromatic Absorption

Profile at this point

Online Monitoring of Aromatic Absorption

Profile plot

Phase 1

Phase 2

Phase 3

Phase Change

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

Fibre Optic Probe

InGaAs (Indium Gallium Arsenide) Detector

Fibre Bundle

Removable Probe Tip

Tablet Holder

Tablet

Light Path

NIR Tablet Transmission Device

Tablet core potency - blend segregation in the bin

Automated tablet analysis

NIRIdentityPotencyUniformityBruker

Weight ThicknessHardnessDr S Pharmatron

Bruker NIR Transmission Head

Open architecture for process analysis

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

NIR transmission Vs conc in tablets 0.1% - 2.0%

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

Microscopic View of Dosage Form

Blend Tablet

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

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