Population Balance Model Validation and Predictionof CQAs for Continuous Milling Processes: toward QbDin Pharmaceutical Drug Product Manufacturing

Abstract

Continuous tablet manufacturing has been investigated for its potential advantages (e.g., cost, efficiency, and controllability) over more conventional batch processes. One avenue for tablet manufacturing involves roller compaction followed by milling to form compactible granules. A better understanding of these powder processes is needed to implement Quality by Design in pharmaceutical manufacturing. In this study, ribbons of microcrystalline cellulose were produced by roller compaction and milled in a conical screen mill. A full factorial experiment was performed to evaluate the effects of ribbon density, screen size, and impeller speed on the product size distribution and steady-state mass holdup of the mill. A population balance model was developed to simulate the milling process, and a parameter estimation technique was used to calibrate the model with a subset of experimental data. The calibrated model was then simulated at other processing conditions and compared with additional unused experimental data. Statistical analyses of the results showed good agreement, demonstrating the model’s predictive capability in quantifying milled product critical quality attributes within the experimental design space. This approach can be used to optimize the design space of the process, enabling Quality by Design.

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Acknowledgments

This work is supported by the National Science Foundation Engineering Research Center on Structured Organic Particulate Systems Grant NSF-ECC 0540855. The authors would also like to thank their industrial mentors: Nishanth Gopinathan and Brian Anderson (Abbott); Mehdrad Langroudi and Jean Hacherl (Merck); Dan Blackwood (Pfizer); Joe Zhou, John Chlapik, and Patrick Putman (Lilly); Dongmei Quiang (Boehringer Ingelheim); Vishwas Nesarikar and Xiaodong Chen (Bristol-Myers Squibb); Mike Brandley (GlaxoSmithKline); Kevin Bittorf and Marco Verwijs (Vertex); and Pieter Schmal (Process Systems Enterprise).

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Correspondence to Rohit Ramachandran.

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Barrasso, D., Oka, S., Muliadi, A. et al. Population Balance Model Validation and Predictionof CQAs for Continuous Milling Processes: toward QbDin Pharmaceutical Drug Product Manufacturing. J Pharm Innov 8, 147–162 (2013). https://doi.org/10.1007/s12247-013-9155-0

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Keywords

  • Conical screen mill
  • Population balance modeling
  • Parameter estimation
  • Continuous milling
  • Quality by Design