Development of a Single Vial Mass Flow Rate Monitor to Assess Pharmaceutical Freeze Drying Heterogeneity.

Abstract

During pharmaceutical lyophilization processes, inter-vial drying heterogeneity remains a significant obstacle. Due to differences in heat and mass transfer based on vial position within the freeze drier, edge vials freeze differently, are typically warmer and dry faster than center vials. This vial position-dependent heterogeneity within the freeze dryer leads to tradeoffs during process development. During primary drying, process developers must be careful to avoid shelf temperatures that would result in overheating of edge vials causing the product sublimation interface temperature to rise above the critical (collapse) temperature. However, at lower shelf temperatures, center vials require longer to complete primary drying, risking collapse or melt-back due to incomplete drying. Both situations may result in poor product quality affecting drug stability, activity, and reconstitution times. We present a new approach for monitoring vial location-specific water vapor mass flow based on Tunable Diode Laser Absorption Spectroscopy (TDLAS). The single vial monitor enables measurement of the gas flow velocity, water vapor temperature, and gas concentration from the sublimating ice, enabling the calculation of the mass flow rate which can be used in combination with a heat and mass transfer model to determine vial heat transfer coefficients and product resistance to drying. These parameters can in turn be used for robust and rapid process development and control.