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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). Source: UK Department of Trade and Industry.

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david rudd phd process technology glaxosmithkline research and development uk

Process Analytical Technologies SubcommitteeProduct and Process Development:An Industry Perspective

David Rudd PhD

Process Technology

GlaxoSmithKline Research and Development, UK

uk manufacturing profitability by sector 1995 to 1999
UK manufacturing profitability by sector (1995 to 1999)

Source: UK Department of Trade and Industry

current manufacturing philosophy
Current manufacturing philosophy

Manufacturing process

Process output

Store or hold

Process feed

current control philosophy
Current control philosophy

Process control

Closed loop control (process parameters only)

Manufacturing process

Temperature

Time

Pressure

etc.

Process output

Store or hold

Process feed

current control philosophy5
Current control philosophy

Policing function

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

Process control

Closed loop control (process parameters only)

Manufacturing process

Temperature

Time

Pressure

etc.

Process output

Store or hold

Process feed

business case for improvement
Business case for improvement
  • Guaranteed product quality
  • Avoidance of delay
  • Optimal utilization of resource
  • Minimization or elimination of waste
  • Movement towards continuous processing
product and process development objectives
Product and process development objectives
  • Optimized process
  • Scaleable process
  • Ease of technology transfer
  • Well-characterized (well-understood) process
  • Reliable and robust process
r d responsibilities in conjunction with manufacturing
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
tablet manufacturing process
Tablet manufacturing process
  • Dispensing and sieving
  • Blending
  • Granulation and milling
  • Drying
  • Compression
  • Film coating
blending
Blending
  • Homogeneity of powder blend (on-line NIR, at-lineHPLC or UV-visible and/or imaging techniques)
  • Moisture content (on-line near infra-red and/or ERH probes)
near infra red monitoring of powder blend process

2

% w/w

1

0

0

100

200

300

400

500

600

Time (seconds)

Near infra-red monitoring of powder blend process

Concentration of analyte versus time

near infra red monitoring of powder blend process12

80

60

RSD (n=12) / %

40

20

0

0

100

200

300

400

500

600

Time (seconds)

Near infra-red monitoring of powder blend process

Replication of spectra (moving block of 12 samples)

granulation and milling
Granulation and milling
  • Granulation end-point
  • Flow characteristics, bulk density etc
  • Homegeneity of granule
  • Moisture content
  • Particle size
near infra red monitoring of granulation process

11

8

NIR predicted

5

2

2

5

8

11

800

Karl Fischer value (%w/w)

600

400

NIR predicted

200

0

0

200

400

600

800

Particle size (sieve analysis) in microns

Near infra-red monitoring of granulation process
slide19

Acoustic emission produced during granulation process

Wet massing

Dry mixing

Liquid addition(wet granulation)

Machine off

Machine off

process signature
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 to produce a process ‘signature’ which, in turn, offers a means of ensuring process reproducibility and robustness
  • 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
process specification
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?
future control philosophy
Future control philosophy

Control function

On-line monitoring of critical process parameters

Process control

Closed loop control (process parameters only)

Manufacturing process

Temperature

Time

Pressure

etc.

Process output

Process feed

continuous blending process

Key

Mass flow control

Instrumentation

Material flow

Process control loop

Physical control loop

Excipient B

Active

Excipient A

Control philosophy

PAT (NIR, process imaging etc) monitors composition and blend uniformity

Feedback controls mass flow in or out and modifies blend speed, if necessary

Blend speed

Continuous dry blender

Mass flow

Mass flow

Mass flow

Mass flow

PAT

Continuous blending process

To Granulator

implications and new research areas
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)
implications during product and process development
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 in-process measurements
  • Development of process specification
final thoughts
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