Observations on the Changing Shape of the Ice Mass and the Determination of the Sublimation End Point in Freeze-Drying: An Application for Through-Vial Impedance Spectroscopy (TVIS).

Bhaskar Pandya,Geoff Smith,Evgeny Polygalov,Irina Ermolina

doi:10.3390/pharmaceutics13111835

Bhaskar Pandya, Geoff Smith + Show 2 more

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https://doi.org/10.3390/pharmaceutics13111835

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Journal: Pharmaceutics	Publication Date: Nov 2, 2021
Citations: 2	License type: CC BY 4.0

Affiliation: De Montfort University

Abstract

Models for ice sublimation from a freeze-drying vial rely on the assumption of a planar ice interface up to ~25% loss of ice mass (which is difficult to qualify) whereas single-vial determinations of the sublimation endpoint (by temperature sensors) are based on the point when the observed temperature reaches a plateau, which cannot differentiate between sublimation and desorption-drying. In this work, the real part capacitance of TVIS vial(s) containing frozen water (during sublimation drying) was measured at 100 kHz. This parameter was shown to be highly sensitive to the shape and volume of the ice mass and is therefore a useful parameter for monitoring ice sublimation. By placing a digital camera in front of an isolated TVIS vial containing ice, it was possible to relate the changes in the shape of the ice mass with the changes in the trajectory of the time profile of and determine the point of deviation from a planar ice interface and ultimately determine the point when the last vestiges of ice disappear. Thereafter, the same characteristics of the time-profile were identified for those TVIS vials located out of sight of the camera in a separate full-shelf lyo study, thereby obviating the need for photographic examination.

Highlights

Freeze drying or lyophilization is a multi-stage down-stream processing method for preserving unstable liquid drug formulations [1]
We considered a single through-vial impedance spectroscopy (TVIS) vial to demonstrate the features of the high frequency capacitance timeline from the beginning of primary drying to the visual endpoint of this individual vial
The first feature is the linear region in the trajectory of the C 0 (100 kHz) time profile that results from a constant rate of reduction in the height of the ice cylinder, without any change in the shape of the sublimation interface

Summary

Introduction

Freeze drying or lyophilization is a multi-stage down-stream processing method for preserving unstable liquid drug formulations (e.g., biopharmaceutical drug products such as monoclonal antibodies) [1]. The formulated drug solution is contained in glass containers (e.g., vials) which are placed on temperature controlled stainless steel shelves in a hexagonal array within a stainless-steel frame that prevents the edge rows of vials from falling off the edge of the shelf. Analytical Technology (PAT) initiative in 2003 [3] there has been much interest in the development of in-line measurement techniques for freeze-drying process development. Comprehensive reviews of batch and single vial technologies have been provided by Fissore et al [4] and Nail et al [5] A mathematical model [6] based on the classical heat and mass balance equation has been developed to assist in freeze-drying process understanding and scale-up (Equation (1)).

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