Process Analytical Technologies Subcommittee Product and Process Development

Process Analytical Technologies Subcommittee Product and Process Development: An Industry Perspective David Rudd Ph. D Process Technology Glaxo. Smith. Kline Research and Development, UK

UK manufacturing profitability by sector (1995 to 1999) Source: UK Department of Trade and Industry 2

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 Policing function Process control Closed loop control (process parameters only) Off-line (lab-based) review of product quality parameters 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 8

Tablet manufacturing process • Dispensing and sieving • Blending • Granulation and milling • Drying • Compression • Film coating 9

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) 10

Near infra-red monitoring of powder blend process Concentration of analyte versus time % w/w 2 1 0 0 100 200 300 400 500 600 Time (seconds) 11

Near infra-red monitoring of powder blend process RSD (n=12) / % Replication of spectra (moving block of 12 samples) 80 60 40 20 0 0 100 200 300 400 500 600 Time (seconds) 12

Powder blend imaging using spectroscopy 13

Powder blend dynamics 14

Granulation and milling • Granulation end-point • Flow characteristics, bulk • • • density etc Homegeneity of granule Moisture content Particle size 15

Power consumption curve during granulation 16

Near infra-red monitoring of granulation process 8 5 2 2 5 8 Karl Fischer value (%w/w) NIR predicted 11 800 11 600 400 200 0 0 200 400 600 800 Particle size (sieve analysis) in microns 17

Acoustic monitoring of high shear granulation process

Acoustic emission produced during granulation process Wet massing Dry mixing Liquid addition (wet granulation) Machine off

Actual versus predicted Mass Median particle size 20

Actual versus predicted Flowability Index 21

Actual versus predicted maximum crushing strength 22

Effect of scale on acoustic signature of a granulation process 23

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 24

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? 25

Future control philosophy Control function Process control Closed loop control (process parameters only) On-line monitoring of critical process parameters Temperature Time Pressure etc. Process feed Manufacturing process Process output 26

Continuous blending process Excipient A Mass flow To Granulator Excipient B Mass flow Key Active Mass flow Continuous dry blender Mass flow control Instrumentation Material flow Process control loop Physical control loop Blend speed 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 27

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) 28

Implications during product and process development • Development scale = Manufacturing scale? • Establish relationship between traditional end -product quality parameters (release and endof-life specification for finished product) and key process measurements • Demonstrate predictive capability of inprocess measurements • Development of process specification 29

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 30