1. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW 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

2. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach A science and risk-based approach to product quality regulation incorporating an integrated quality systems approach 1.Risk-based orientation 2.Science-based policies and standards 3.Integrated quality systems orientation 4.International cooperation 5.Strong Public Health Protection

3. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach What’s New? Good science isn’t new, we all do it now Some technologies, techniques, and models are Computers Sensors Chemometrics Phenomenological and Fundemental Models The mutual FDA-Industry-Academic recognition of the technical “way forward “ in application of the state of the science

4. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW The Issue: API, Formulation, and Process Variables and Dosage Form Performance Ajaz Hussain, Arden House 2003 Low Solubility - High Permeability - Acidic compound in SIF

5. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW

6. Initial Drug Substance Characterization Property 1. Purity 2. Solubility/dissolution 3. Partitioning 4. Stability 5. Solid state form/shape 6. Hygroscopicity Theory-method 1. Chemistry - HPLC 2. Thermodynamics, Kinetics - traditional and automated measurement 3. Thermo - various 4. Chemistry and HPLC - SS methods 5. Crystallography SS physics - screening, prediction control 6. BET - Automated systems

7. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Pharmaceutical Technology Europe, 17, June 1994 “Formulations and processes are only as robust as their ability to accommodate changes in the raw materials” KRM

8. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Form Screening, Selection, and Control Hilden et.al., Crystal Growth and Design, 2003, in press

9. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Ulrich Griesser, PHANTA 9/03 Cefotaxim Sodium Moisture Uptake - Ulrich Griesser, Univ. of Innsbruck, Simultaneous Multi-sample instrument

10. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Single Crystal Structure +PXRD Pattern experimental PXRD Pattern simulated BFDH Morphology Comb. Simple Forms Morphology +Index Major Faces SPO/DIFRAC Model Average Shape

11. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW 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%

12. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Formulation Design and API Process Development Formulation element 1. Dosage form selection 2. Excipient selection 3. Stability to processing 4. Mechanical properties 1. Flow 2. Compaction 5. Initial processing Theory-method 1. Medical processability 2. Excipient properties – interaction studies, phsico-chemical properties 3. PIT – 4. ME/MSE – 1. flow correlations, 2. heckel analysis 5. Process models – prototypes and PAT

13. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Avalanche testing TSI Inc. Powder Rheology Freeman Tech. Shear Cell Virendra M. Puri, Penn State Powder Flow

14. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW From Heckel, Trans. AIME, 221: 1961.14 Development of the Heckel Equation P A

15. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW PROCESS 1PROCESS 2 Shape and Flow

16. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW TREND BETWEEN MASS FLOW AND SHAPE

17. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Processing/PAT Operation 1. Particle size reduction 2. Charging 3. Blending 4. Dry granulation (RC) 5. Wet granulation Fluid bed High shear 6. Drying 7. Segregation 8. CU 9. Hardness 10. Coating Modeling 1. Surface energy-size laws 2. Triboelectric series model 3. Cascade Model, DEM 4. Density-Strength 5. Various Size-Moisture-Attrition Water Environ Model 6. Heat/Mass transfer/FAST 7. Sinusoidal Variation 8. Partial volume analysis 9. Density response 10. Geometric Growth Compensation

18. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW 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. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Powder Charging: Qualitative Trends in a Faraday Pail- Blender System David Engers, unpublished data Purdue

20. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW 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. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW 180kg Run 16kg Run Blending Scaled “Down”

22. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Dry Granulation by Roller Compaction Unpublished CAMP data – A.Gupta  The strength is a linear function of the density which is monitored by NIR  Semi Empirically F=(S NIR -0.17)/0.37

23. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW  The particle sizes of the milled material is also manifest in the slope of the NIR signal (as predicted) Dry Granulation by Roller Compaction Unpublished CAMP data – A.Gupta

24. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Monitoring and Modeling of Fluid Bed Granulation Paul Findlay, Ph.D dissertation, Purdue Univ, 2003

25. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Modeling Wet Granulation 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. Pendular Funicular Capillary Droplet Drying Over Wetting

26. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW 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. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Critical moisture Temperature Moisture Content 40 60 80 100 120 140 160 180 Drying Time (min) MM55 Reading 45 47 49 51 53 55 57 59 61 63 65 Temperature (°C) T MM55 030252015105 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). DRYING : NIR -Exit Temp vs. Time for APAP Granulation Evaporative Diffusive

28. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Full Scale Fast Drying Trials of an Ibuprofen Granulation Morris et.al., Drug Dev. Ind. Pharm., 26 (9):985-988 (2000)

29. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Drying Excursions and Dissolution CAMP unpublished data

30. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW 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. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW COATING HPMC, Sulfanilamide and, Moisture Real- Time Measurements Unpublished CAMP data, P. Findlay,In prep for JPS

32. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW Where do we stand?  Taken individually these theories and techniques look independent  Together, however, they show a concerted effort to describe contributions to the overall process of drug development.  These principles and techniques are applicable to batch and continuous processing and may be linked by multi-variate (chemometric) methods after univariate conformation.  Ultimately this give us the ability to understand how development variables interact to influence the final product and to design in the quality.

33. · Industrial & Physical Pharmacy · CAMP - NSF CPPR - PMW The Business Case  Using existing scientific principles, monitoring and modeling capabilities one will understand more about processes and be able to detect variations quickly The earlier you start collecting information the more you’ll know the more comfortable everyone will be  Given this level of knowledge and communication with FDA, you will be at the lowest risk (as proposed) possible for your product/process  If your studies show up variability, the sooner you know the better. There is no such thing as what you don’t know won’t hurt you in science based development.  The companies have many of the tools to lower their risk levels RIGHT NOW This will only improve with more research.