In-Line Monitoring of the Freeze-Drying Process by Means of Heat Flux Sensors

Abstract

The final qualities of a pharmaceutical product can be adversely affected by a suboptimized freeze-drying process. Multiple variables and operating conditions come into play, thus making the overall process difficult to control. In this study, we show how heat flux sensors can guide the in-line monitoring of freezing and primary drying of placebo formulations, leading to significant insights that contribute to our understanding of the phenomena involved. It was found that heat flux sensors can be used as a practical and robust tool to monitor a lyophilization cycle by defining the processing time and investigating different process scenarios. Concerning the freezing step, the heat flux sensors proved to be an effective way to detect both nucleation and end of crystal growth. Additionally, the sensors' signal highlighted the end of cooling and freezing steps and thus helped to eliminate uncertainty about the time required to reach thermal equilibrium across the batch. An ultimate potential of the devices was addressed to build the design space for freezing and primary drying, laying the foundations for new research on this topic.

Understanding Heat Transfer During the Secondary Drying Stage of Freeze Drying: Current Practice and Knowledge Gaps

“…The idea of using heat flux sensors to track energy flow during freeze drying is a relatively new technology in the pharmaceutical space − an excellent discussion of this technology is in . 36,41 Lastly, to ensure homogeneity in heating all the vials in the chamber, we control the temperature of the outer aluminum blocks that make direct contact with the outer vials (T sim , see Fig. 1).…”

“…, where A tot is the area of the sensor, A v is the area occupied by the bottom of a single vial, N v is the number of vials on the heat flux sensor based on hexagonal packing, 41 and K air is the heat transfer coefficient to the air which was determined by a separate measurement without the vials in place. Further details of this process are found in the supporting information (Figs.…”

Surface Treatment of Glass Vials for Lyophilization: Implications for Vacuum-Induced Surface Freezing

“…This is extremely useful for automatizing the controlled-freezing protocol, as the presence of an operator is not required if the values of P n and t n are already known. Moreover, this is a necessary requirement for a whole batch, where most of the vials are not in-sight of the operator, and the only way to properly select the nucleation pressure and time is by means of prior knowledge (as in this work), or alternatively, through the use of a suitable monitoring device (for instance, heat flux sensors [41] or infrared thermography [42] that were recently applied to the VISF protocol).…”

Combining Mathematical Modeling and Thermal Infrared Data in the Freezing of Pharmaceutical Liquid Formulations

“…Additionally, the acquired data must be extrapolated to the neighboring vials, assuming similarities in the conditions, which do not always correspond to reality. To overcome this problem, it is possible to use different technologies . Freezing was experimentally studied using simple image analysis to obtain the freezing progression in a solution. , In recent years, many papers have been produced to validate and study the application of infrared (IR) imaging as a noninvasive method to obtain in-line temperature measurements during freeze-drying. − This technology is up-and-coming not only because it does not interfere with the process itself but also because it can provide temperature distributions among vials both in the freezing and in the drying stages.…”

“…To overcome this problem, it is possible to use different technologies. 12 Freezing was experimentally studied using simple image analysis to obtain the freezing progression in a solution. 13,14 In recent years, many papers have been produced to validate and study the application of infrared (IR) imaging as a noninvasive method to obtain inline temperature measurements during freeze-drying.…”