Determination of End Point of Primary Drying in Freeze-Drying Process Control

Abstract

Abstract. Freeze-drying is a relatively expensive process requiring long processing time, and hence one of the key objectives during freeze-drying process development is to minimize the primary drying time, which is the longest of the three steps in freeze-drying. However, increasing the shelf temperature into secondary drying before all of the ice is removed from the product will likely cause collapse or eutectic melt. Thus, from product quality as well as process economics standpoint, it is very critical to detect the end of primary drying. Experiments were conducted with 5% mannitol and 5% sucrose as model systems. The apparent end point of primary drying was determined by comparative pressure measurement (i.e., Pirani vs. MKS Baratron), dew point, Lyotrack (gas plasma spectroscopy), water concentration from tunable diode laser absorption spectroscopy, condenser pressure, pressure rise test (manometric temperature measurement or variations of this method), and product thermocouples. Vials were pulled out from the drying chamber using a sample thief during late primary and early secondary drying to determine percent residual moisture either gravimetrically or by Karl Fischer, and the cake structure was determined visually for melt-back, collapse, and retention of cake structure at the apparent end point of primary drying (i.e., onset, midpoint, and offset). By far, the Pirani is the best choice of the methods tested for evaluation of the end point of primary drying. Also, it is a batch technique, which is cheap, steam sterilizable, and easy to install without requiring any modification to the existing dryer.

Design of the Lyophilization Process of a Doxorubicin Formulation Based on Thermal Properties

“…The determination of glass transition temperature helps to set freezing temperature of the product, collapse temperature for formulation determines the operational parameters during sublimation and the proper product characterization facilitates the ex ecution of a safe and efficient process [14,15] . A variety of analytical techniques were available to estimate the heat and mass transfer rates in the drying chamber and condenser to achieve such characterization [16,17] . These techniques include gravimetric measurements, product temperature sensors and heat transducers, manometric temperature measurements, tuneable diode laser absorption spectroscopy, visual monitoring of the ice interface, differential scanning calorimetry (DSC), differential thermal analysis (DTA) and electrical impedance (EI), and freeze drying microscopy (FDM).…”

Lyophilization of Biologics: An FDA Perspective

“…However, these methods are invasive and are not applicable at the commercial scale due to sterility issues. PAT tools that allow for noninvasive control of the freezing step include a scalable method, called ContrLyo™ Technology, which works by rapidly pressurizing and depressurizing the chamber using an inert gas such as argon to uniformly trigger the onset of ice nucleation during freezing [27,32]. This causes the product in the chamber to nucleate simultaneously at a lower degree of supercooling (Fig.…”

Emerging Freeze-Drying Process Development and Scale-up Issues

“…If thermocouples are used to determine the end point of primary drying they might indicate that primary drying is done in the local region around the sensor, but there could still be regions of ice in the (17). In such cases, it is particularly important to have a technique that would monitor the entire batch based on gas composition in the drying chamber, such as Pirani vs. Capacitance Manometer differential pressure or dew point (18). In general, aluminum trays, because of their relatively higher thermal conductivity, are preferred over stainless steel trays.…”