1. Process Analytical Technologies Subcommittee Product and Process Development: An Industry Perspective David Rudd PhD Process Technology GlaxoSmithKline Research and Development, UK

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

3. 3 Manufacturing process Process feed Process output Store or hold Current manufacturing philosophy

4. 4 Manufacturing process Process control Process feed Process output Closed loop control (process parameters only) Store or hold Temperature Time Pressure etc. Current control philosophy

5. 5 Manufacturing process Policing function Off-line (lab-based) review of product quality parameters Process control Process feed Process output Closed loop control (process parameters only) Store or hold Temperature Time Pressure etc. Current control philosophy

6. 6 Guaranteed product quality Avoidance of delay Optimal utilization of resource Minimization or elimination of waste Movement towards continuous processing Business case for improvement

7. 7 Optimized process Scaleable process Ease of technology transfer Well-characterized (well-understood) process Reliable and robust process Product and process development objectives

8. 8 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 R&D responsibilities - in conjunction with Manufacturing

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

10. 10 Homogeneity of powder blend (on-line NIR, at-line HPLC or UV-visible and/or imaging techniques) Homogeneity of powder blend (on-line NIR, at-line HPLC or UV-visible and/or imaging techniques) Moisture content (on- line near infra-red and/or ERH probes) Moisture content (on- line near infra-red and/or ERH probes) Blending

11. 11 Concentration of analyte versus time Near infra-red monitoring of powder blend process

12. 12 Replication of spectra (moving block of 12 samples) Near infra-red monitoring of powder blend process

13. 13 Powder blend imaging using spectroscopy

14. 14 Powder blend dynamics

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

16. 16 Power consumption curve during granulation

17. 17 2 5 8 11 258 Karl Fischer value (%w/w) NIR predicted 0 200 400 600 800 0200400600800 Particle size (sieve analysis) in microns NIR predicted Near infra-red monitoring of granulation process

18. Acoustic monitoring of high shear granulation process

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

20. 20 Actual versus predicted Mass Median particle size

21. 21 Actual versus predicted Flowability Index

22. 22 Actual versus predicted maximum crushing strength

23. 23 Effect of scale on acoustic signature of a granulation process

24. 24 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 ‘signature’

25. 25 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? Process specification

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

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

28. 28 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 and new research areas

29. 29 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 Implications during product and process development

30. 30 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 Final thoughts