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Stochastic shelf-scale modeling framework for the freezing stage in freeze-drying processes.

Leif-Thore Deck1, David R Ochsenbein2, Marco Mazzotti1

  • 1Institute of Energy and Process Engineering, ETH Zurich, Sonneggstrasse 3, 8092 Zurich, Switzerland.

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|November 12, 2021
PubMed
Summary

This study introduces a novel modeling framework to understand batch heterogeneity in pharmaceutical freezing processes. Simulations reveal how ice nucleation and vial interactions cause variations, offering pathways for process optimization.

Keywords:
Freeze-DryingFreezingLyophilizationModelingMonte CarloNucleationStochastic Processes

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Area of Science:

  • Pharmaceutical Sciences
  • Chemical Engineering
  • Computational Modeling

Background:

  • Pharmaceutical formulations rely on freezing and freeze-drying for stability and shelf-life extension.
  • Batch heterogeneity in frozen products, stemming from stochastic ice nucleation and variable heat transfer, poses a significant risk to process integrity and product quality.

Purpose of the Study:

  • To develop and present a first-principles-based modeling framework for large-scale vial freezing processes.
  • To investigate the mechanisms driving batch heterogeneity in pharmaceutical freezing.
  • To evaluate the impact of different cooling protocols on nucleation and solidification.

Main Methods:

  • Developed a modeling framework coupling heat transfer with ice nucleation kinetics for vial freezing on a shelf.
  • Implemented an open-source Python package for large-scale freezing process simulation.
  • Utilized Monte Carlo simulations for an inhomogeneous Poisson process model of ice nucleation.
  • Analyzed thermal interactions among vials and their effect on heterogeneity.

Main Results:

  • Identified a novel mechanism where ice nucleation, influenced by thermal interactions between vials, leads to batch heterogeneity.
  • Simulations demonstrated the impact of cooling protocols (shelf-ramped cooling, holding steps, controlled nucleation) on freezing behavior.
  • Holding schemes were found to achieve solidification times comparable to controlled nucleation under general conditions.

Conclusions:

  • The developed modeling framework provides a tool to study and understand batch heterogeneity in pharmaceutical freezing.
  • Thermal interactions between vials play a crucial role in the observed heterogeneity.
  • Holding schemes offer a promising strategy for optimizing pharmaceutical freezing processes and mitigating batch variability.