Biomedical Engineering Reference
In-Depth Information
over this time is measured. These measurements are converted by the use of a series of
equations to provide data for product temperature at the sublimation interface [46], a
key measure of the completion of primary drying, to determine dry product resistance
to vapor flow [47], which impacts the primary drying time, and to determine heat mass
transfer [48], which is equivalent to the heat transfer from the shelf and other sources in
the freeze-drying chamber and is used to estimate the shelf temperature required to
maintain the target product temperature. Combining all of the different data obtained by
the MTM method through an expert software system has led to the development of the
“Smart Freeze Dryer,” which can be used to optimize the freeze-drying process in a
single run [49]. Optimization of chamber pressure, target product temperature, and
primary and secondary drying time can be determined by the algorithm of the expert
system.
13.5.10 In-Line or Online Spectroscopic PAT Tools
Both near infrared (NIR) and Raman have been explored as real-time PAT tools for
freeze-drying due to their noninvasive capabilities. Both techniques provide product
quality information reflecting both physical and chemical properties of the solid drug
product. Raman spectroscopy has been used in a noninvasive manner with the probe
placed in the freeze-dryer but outside the product vials to collect a variety of data during
the freeze-drying process [50]. Data processing using principal component analysis
determined underlying factors contributing spectral variation and hence provided clear
trends in the data [51]. The data provided information on the solid state of the drug
product, the end points of primary and secondary drying, and physical changes occurring
in the drug product during the process. The solid-state information included crystalliza-
tion states and polymorph states of excipients and the crystallization of ice and the onset
of sublimation. NIR has been developed for use as an in-line noninvasive tool for
end-product moisture level testing of freeze-dried product in a continuous manner in a
production line. The NIR spectra are recorded through the bottom of the vials in the
diffuse reflection mode, with 5 scans per vial at a continuous moving rate of up to 300
vials per minute [52].
13.5.11 Scaling-Up PAT Technologies
One aspect of PAT tools, which is of some concern, is the scalability of the sensors and the
measurements while going from laboratory-scale to pilot-scale and to full-scale com-
mercial manufacturing equipment. In addition to the size difference while going from
laboratory-scale to the full-scale commercial equipment, consideration has to be
given to commercial manufacturing operations, which automates as many parts of the
process as possible including loading of the freeze-dryer, stopper placement, and
cleaning of the chamber by CIP methods another limit is the temperature ramp rates
that is limited in large scale units. In addition, aseptic handling, leakage controls, and
product integrity may not be compromised by the use of sensors and analyzers during
full-commercial GMP production. Note that the geometry of the shelf and its loading
density have an impact on the lyo speed which is a function of adjacent vials due to
