Product and Process Development--An Industry Perspective

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					Process Analytical Technologies Subcommittee Product and Process Development: An Industry Perspective

David Rudd PhD Process Technology GlaxoSmithKline Research and Development, UK

UK manufacturing profitability by sector (1995 to 1999)
300 250 200 150 100 50 0

ot or

Source: UK Department of Trade and Industry
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ev er ag TV es an d ra di o P la st ic s To ba cc o Fo od st uf fs

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A

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Current manufacturing philosophy

Process feed

Manufacturing process

Process output

Store or hold

3

Current control philosophy
Process control

Closed loop control (process parameters only)
Temperature Time Pressure etc.

Process feed

Manufacturing process

Process output

Store or hold

4

Current control philosophy
Process control

Policing function
Off-line (lab-based) review of product quality parameters

Closed loop control (process parameters only)
Temperature Time Pressure etc.

Process feed

Manufacturing process

Process output

Store or hold

5

Business case for improvement

• Guaranteed product quality • Avoidance of delay • Optimal utilization of resource • Minimization or elimination of waste • Movement towards continuous processing

6

Product and process development objectives

• Optimized process • Scaleable process • Ease of technology transfer • Well-characterized (well-understood) process • Reliable and robust process

7

R&D responsibilities - in conjunction with Manufacturing

• Provision of manufacturing and monitoring
equipment and technical expertise

• Development of process understanding • Identification of critical process parameters • Implementation of critical process controls • Decision-making basis for process feedback
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Tablet manufacturing process

• Dispensing and sieving • Blending • Granulation and milling • Drying • Compression • Film coating

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Blending

• Homogeneity of
powder blend (on-line NIR, at-line HPLC or UV-visible and/or imaging techniques)

• Moisture content (online near infra-red and/or ERH probes)

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Near infra-red monitoring of powder blend process

Concentration of analyte versus time
2

% w/w

1

0
0 100 200 300 400 500 600

Time (seconds)

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Near infra-red monitoring of powder blend process

Replication of spectra (moving block of 12 samples) RSD (n=12) / %
80 60
40 20 0

0

100

200

300

400

500

600

Time (seconds)

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Powder blend imaging using spectroscopy
250

200

150

100

50

0

50

100

150

20 00 15 00 60 0

15 00

50 0

10 00 40 0 10 00

30 0 50 0 50 0 20 0

10 0 50 0 10 00 15 00 20 00 50 0 10 00 15 00 20 00 50 0 10 00 15 00 20 00

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Powder blend dynamics

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Granulation and milling

• Granulation end-point • Flow characteristics, bulk • • •
density etc Homegeneity of granule Moisture content Particle size

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Power consumption curve during granulation
60 3 2 % FLC 1 4

0 Tim e

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Near infra-red monitoring of granulation process
11 NIR predicted 8 5 2
2 5 8 NIR predicted 800 11 600 400

Karl Fischer value (%w/w)

200
0 0 200 400 600 800

Particle size (sieve analysis) in microns

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Acoustic monitoring of high shear granulation process

Acoustic emission produced during granulation process

Wet massing Dry mixing

Liquid addition (wet granulation)

Machine off

Machine off

Actual versus predicted Mass Median particle size
1600.00 1400.00 1200.00
Predicted

1000.00 800.00 600.00 400.00 200.00 0.00 0.00

200.00

400.00

600.00

800.00 1000.00 1200.00 1400.00 1600.00 Actual

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Actual versus predicted Flowability Index

35.00 30.00

Predicted

25.00 20.00 15.00 10.00 10.00

15.00

20.00 Actual

25.00

30.00

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Actual versus predicted maximum crushing strength
11.00 10.50 10.00
Predicted

9.50 9.00 8.50 8.00 7.50 7.50

8.00

8.50

9.00 Actual

9.50

10.00

10.50

11.00

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Effect of scale on acoustic signature of a granulation process

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Process ‘signature’

• Stages of the product manufacturing process can
be characterized and then described based on the use of a variety of diverse measurement techniques

• This multi-dimensional profile can then be used • The process ‘signature’ may also be viewed as
an end-point to work towards during scale-up or after equipment changes or site changes, for example

to produce a process ‘signature’ which, in turn, offers a means of ensuring process reproducibility and robustness

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Process specification

• Perhaps the concept of the process ‘signature’
equates to the establishment of a process specification - that is, a series of requirements which need to be met if the process is to be considered ‘under control’?

• Just as parametric release implies the removal
of critical end-product testing, perhaps the natural corollary is to transfer the critical specification from the product to the process?

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Future control philosophy
Process control

Control function
On-line monitoring of critical process parameters

Closed loop control (process parameters only)
Temperature Time Pressure etc.

Process feed

Manufacturing process

Process output

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Continuous blending process
Excipient A

Excipient B

Active

Mass flow

Mass flow

Mass flow

Key Mass flow control Instrumentation Material flow Process control loop Physical control loop
Blend speed

Control philosophy

Mass flow

Continuous dry blender

PAT

PAT (NIR, process imaging etc) monitors composition and blend uniformity
Feedback controls mass flow in or out and modifies blend speed, if necessary

To Granulator

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Implications and new research areas

• Development of novel analytical monitoring
techniques (or novel applications of existing techniques) appropriate for the type of measurements required

• Emphasis on indicators of ‘change’ rather
than necessarily quantitative measurement

• New data processing methods required (data
reduction and/or combinations of data from diverse sources)

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Implications during product and process development

• Development scale = Manufacturing scale? • Establish relationship between traditional
end-product quality parameters (release and end-of-life specification for finished product) and key process measurements

• Demonstrate predictive capability of inprocess measurements

• Development of process specification
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Final thoughts

• Process Analytical Technology (PAT) is seen as a
means of improving existing manufacturing process monitoring and control strategies

• The most significant advantages are to be gained by
moving towards true process understanding (gained during process development) which, in turn, offers the opportunity of ‘Quality by Design’ manufacturing methods and parametric release concepts

• PAT is vital if the pharmaceutical manufacturing
industry is ever to embrace continuous processing

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