necessary to incorporate protective devices and introduce processing protocols that ensure both safe operation and prevent product
cross-contamination [36].
The primary scale-up factors in freeze-drying may be defined
as:
1. Equipment specification and performance limitations (e.g.,
refrigeration capacity, condenser trapping rate, use of different
pressure gauges, chamber size, control system differences).
2. Upstream processing factors (e.g., scale of compounding and
filling, use of sterile filtration).
3. Differences in personnel in R&D laboratories/pilot plants/
sterile GMP facilities.
Many of the potential effects of the above differences at various
scales can be assessed in-process using process analytical technologies (PAT) that are available for integration into freeze-dryers or as
standalone devices that can give real-time feedback. Product temperature is conventionally monitored using a suitable temperaturemeasuring device such as a wired thermocouple (usually Type T) or
resistance thermometer (almost invariably a Pt100); however, more
recently, wireless probes have become more widely used
[37]. Another method of measuring the sublimation interface temperature is by the use of the noninvasive Manometric Temperature
Measurement (MTM): this is a batch method which is central to
various software-based cycle development systems that calculate the
“average” sublimation interface temperature of all the samples
within the product chamber based on different algorithms that
take into account the size and heat transfer characteristics of the
container, number of samples, and the physicochemical characteristics of the formulation itself [38]. Other methods of monitoring
the progress of the lyophilization process by examining “whole
batch” parameters (as opposed to individual samples) include Tunable Diode Laser Absorption Spectroscopy, or TDLAS, which provides real-time data on the instantaneous mass flux, arguably a more
scalable parameter than many others [39], while some methods can
be applied to specific samples, such as the use of NIR [40]. A recent
comprehensive review of PAT methods in lyophilization is given by
Fissore et al. [41].
5 Factors Affecting Freeze-Dried Products
Freeze-dried products should be formulated to minimize storage
decay and should ideally be able to tolerate storage at ambient
temperatures for distribution purposes. However, it is imprudent
to assume that a freeze-dried product remains immune to damage
during storage simply due to the relative lack of residual water;
Principles of Freeze-Drying
123
cross-contamination [36].
The primary scale-up factors in freeze-drying may be defined
as:
1. Equipment specification and performance limitations (e.g.,
refrigeration capacity, condenser trapping rate, use of different
pressure gauges, chamber size, control system differences).
2. Upstream processing factors (e.g., scale of compounding and
filling, use of sterile filtration).
3. Differences in personnel in R&D laboratories/pilot plants/
sterile GMP facilities.
Many of the potential effects of the above differences at various
scales can be assessed in-process using process analytical technologies (PAT) that are available for integration into freeze-dryers or as
standalone devices that can give real-time feedback. Product temperature is conventionally monitored using a suitable temperaturemeasuring device such as a wired thermocouple (usually Type T) or
resistance thermometer (almost invariably a Pt100); however, more
recently, wireless probes have become more widely used
[37]. Another method of measuring the sublimation interface temperature is by the use of the noninvasive Manometric Temperature
Measurement (MTM): this is a batch method which is central to
various software-based cycle development systems that calculate the
“average” sublimation interface temperature of all the samples
within the product chamber based on different algorithms that
take into account the size and heat transfer characteristics of the
container, number of samples, and the physicochemical characteristics of the formulation itself [38]. Other methods of monitoring
the progress of the lyophilization process by examining “whole
batch” parameters (as opposed to individual samples) include Tunable Diode Laser Absorption Spectroscopy, or TDLAS, which provides real-time data on the instantaneous mass flux, arguably a more
scalable parameter than many others [39], while some methods can
be applied to specific samples, such as the use of NIR [40]. A recent
comprehensive review of PAT methods in lyophilization is given by
Fissore et al. [41].
5 Factors Affecting Freeze-Dried Products
Freeze-dried products should be formulated to minimize storage
decay and should ideally be able to tolerate storage at ambient
temperatures for distribution purposes. However, it is imprudent
to assume that a freeze-dried product remains immune to damage
during storage simply due to the relative lack of residual water;
Principles of Freeze-Drying
123