David Rudd PhD Process Technology GlaxoSmithKline Research and Development, UK

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

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

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

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

5. 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

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

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

8. 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

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

10. 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)

11. 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

12. 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)

13. Powder blend imaging using spectroscopy

14. Powder blend dynamics

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

16. Power consumption curve during granulation

17. 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

18. Acoustic monitoring of high shear granulation process

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

20. Actual versus predicted Mass Median particle size

21. Actual versus predicted Flowability Index

22. Actual versus predicted maximum crushing strength

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

24. 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

25. 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?

26. 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

27. 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

28. 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)

29. 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

30. 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