Process analytical technology for monitoring pharmaceuticals freeze-drying – A comprehensive review

ABSTRACT

The goal of this paper is to review the available process analytical technology tools for monitoring the batch freeze-drying process for pharmaceuticals. These systems aim evaluating in-line product temperature, sublimation flow rate, and values of some model parameters in such a way that it can be used for in-line or off-line process optimization. A detailed survey of the systems proposed in the literature is presented, grouping them on the basis of monitored variable, namely, product temperature, heat flux to the product, sublimation flux, and, finally, other variables. The advantages and drawbacks of the techniques are critically assessed, taking into account the possibility of using them not only at lab-scale but also at production scale, beside, obviously, the possibility of getting reliable measurements of the desired variables.

KEYWORDS:

• Freeze-drying
• pressure rise test
• process analytical technology
• product quality
• soft sensor
• thermocouple

Abbreviations::

• BTM: barometric temperature measurement
• DPE: dynamic parameters estimation
• DPR: dynamic pressure rise
• FBG: fiber Bragg grating
• MTM: manometric temperature measurement
• PDT: pressure decrease test
• PRA: pressure rise analysis
• PRT: pressure rise test
• QMS: quadrupole mass spectrometer
• TDLAS: tunable diode laser absorption spectroscopy
• VMS: valveless monitoring system

Acknowledgments

Part of the content of the paper is the synthesis of several years of research activity of the team at Politecnico di Torino and of the cooperation with various Italian and foreign groups. The contribution of the colleagues Alberto Vallan, Sabrina Grassini, and Marco Parvis; and of former Ph.D. students (in chronological order): Salvatore Velardi, Valeria Rasetto, Serena Bosca, and Irene Oddone from Politecnico di Torino, is greatly acknowledged.