1. DEVELOPMENT OF QUALITY BY DESIGN (QBD) GUIDANCE ELEMENTS ON DESIGN SPACE SPECIFICATIONS ACROSS SCALES WITH STABILITY CONSIDERATIONS Scale up consideration – NIR calibration Benoit Igne, Sameer Talwar, Brian Zacour, Carl Anderson, James Drennen Duquesne University Center for Pharmaceutical Technology

2. Blend Scale up issues Volume of powder sampled decreased Differences in fill volume Blending dynamics changed Blender shape changed Different NIR sensors –ThermoFisher Spectral Probe to ExpoTech ePAT 601 Blend monitor

3. Efficient calibration approach Used limited number of levels –0%, 100%, nominal, granule Classical least squares based method –Regression vector is based on the pure components Consequently, the differences in regression vector from scale to scale, from NIR sensor to NIR sensor was mainly a function of the instrument differences

4. Efficient calibration approach No unique samples No degradation of sample No transfer set / standardization method Reduced time and effort for calibration model development: “calibration in hours”

5. Calibration comparison API MCC HPC Starch RMSEC (%) = 1.40 0.95 1.08 0.70 RMSECnom (%) = 1.66 1.09 1.25 0.75 API MCC HPC Starch RMSEC (%) = 1.56 0.81 0.98 0.41 RMSECnom (%) = 1.93 1.58 1.38 0.50 Laboratory scaleScale-up

6. Blend end point At laboratory scale 1.Both instruments gave similar outputs 2.RMSNV under error of validation At scale up 1.RMSNV under error of validation Blend was stopped in a similar manner, based on similar criteria –Similar definition of homogeneity –Differences in scales of scrutiny