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

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

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

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”

Calibration comparison

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Reference (%, w/w)

Pre

dict

ion

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w/w

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API

MCC

HPCStarch

data5

API MCC HPC StarchRMSEC (%) = 1.40 0.95 1.08 0.70RMSECnom (%) = 1.66 1.09 1.25 0.75

API MCC HPC StarchRMSEC (%) = 1.56 0.81 0.98 0.41RMSECnom (%) = 1.93 1.58 1.38 0.50

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Predicted (%, w/w)

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eren

ce (%

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API

MCC

HPC

Starch

Laboratory scale Scale-up

Blend end point

• At laboratory scale1. Both instruments gave similar outputs

2. RMSNV under error of validation

• At scale up1. 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