The document discusses risk-based pharmaceutical development using quality by design principles. It outlines how a science and risk-based regulatory approach incorporating integrated quality systems can help ensure strong public health protection. It provides examples of applying emerging technologies like sensors, modeling, and multivariate analysis across the drug development process from raw materials characterization to formulation, processing, coating, and testing to better understand variability and design quality in. Taking an integrated approach linking these principles and techniques can help lower development risk and ensure product quality.

1. Risk-Based Development for Quality by Design Ken Morris Purdue University Department of Industrial and Physical Pharmacy FDA SAB Manufacturing Sub-Committee September, 17 th , 2003

4. The Issue: API, Formulation, and Process Variables and Dosage Form Performance Ajaz Hussain, Arden House 2003 Low Solubility - High Permeability - Acidic compound in SIF

8. Form Screening, Selection, and Control Hilden et.al., Crystal Growth and Design, 2003, in press

9. Cefotaxim Sodium Moisture Uptake - Ulrich Griesser, Univ. of Innsbruck, Simultaneous Multi-sample instrument Ulrich Griesser, PHANTA 9/03

10. Single Crystal Structure +PXRD Pattern experimental PXRD Pattern simulated BFDH Morphology Comb. Simple Forms Morphology +Index Major Faces SPO/DIFRAC Model Average Shape

11. Summary of Estimated Average Shapes and Areas 110 = 64% 001 = 31% -201 = 5% 110 = 43% 011 = 29 % 200 = 15% 001 = 7% -201 = 6% 002 = 60% 102 = 33% 100 = 4%

13. Powder Flow Avalanche testing TSI Inc. Powder Rheology Freeman Tech. Shear Cell Virendra M. Puri, Penn State

14. Development of the Heckel Equation P A

15. Shape and Flow PROCESS 1 PROCESS 2

16. TREND BETWEEN MASS FLOW AND SHAPE

18. Particle Size Reduction Models Rittinger’s law: The work required in crushing is proportional to the new surface created. Where: P =power required, dm/dt=feed rate to crusher, D sb = ave diameter before crushing, D SQ =ave after crushing, K r =Rittinger’s coef. Kick’s law : the work required for crushing a given mass of material is constant for the same reduction ratio, that is the ratio of the initial particle size to the finial particle size K k = Kick’s coef.

19. Powder Charging: Qualitative Trends in a Faraday Pail-Blender System David Engers, unpublished data Purdue

20. Modeling Blending : Cascade Region For fine grains, the boundary between the characteristic region and the remaining powder bed is parabolic in shape The powder bed below the boundary rotates with the mixer as a solid body. Characteristic region Blender head space

21. Blending Scaled “Down” 180kg Run 16kg Run

24. Monitoring and Modeling of Fluid Bed Granulation Paul Findlay, Ph.D dissertation, Purdue Univ, 2003

25. At the capillary stage, the water may interact with the surface in such a way as to change the two prominent NIR bands (1450 and 1940 nm) differently. Modeling Wet Granulation Pendular Funicular Capillary Droplet Drying Over Wetting

26. NIR during granulation–wet massing and Particle size Unpublished CAMP data, Dr. Jukka Rantanen – X2=255 rpm X1=110 g (=X3) NIR Treated Response

27. DRYING : NIR -Exit Temp vs. Time for APAP Granulation Drying Time (min) MM55 Reading Temperature (°C) T MM55 0 30 25 20 15 10 5 K.R. Morris, S.L. Nail, G.E. Peck, S.R. Byrn, U.J. Griesser, J.G. Stowell, S.-J. Hwang, K. Park Pharm Sci Tech Today 1 6 235–245 (1998). Evaporative Diffusive Critical moisture Temperature Moisture Content 40 60 80 100 120 140 160 180 45 47 49 51 53 55 57 59 61 63 65

28. Full Scale Fast Drying Trials of an Ibuprofen Granulation Morris et.al., Drug Dev. Ind. Pharm., 26 (9) :985-988 (2000)

29. Drying Excursions and Dissolution CAMP unpublished data

30. Tablet CU : Testing a Model T. Li, et. al., in press Pharm. Res. BioMed Anal. CU for constant size portions of tablets must be larger than for the whole, so in spec using real time monitoring of “part” of the tablets means in spec for the whole tablet

31. COATING HPMC, Sulfanilamide and, Moisture Real-Time Measurements Unpublished CAMP data, P. Findlay,In prep for JPS