Biomedical Engineering Reference
In-Depth Information
radiation effects. Freeze-drying PAT devices that have been developed with these
considerations in mind include a cold plasma ionization device based on inductively
coupled plasma-optical emission spectroscopy (ICP-OES) [53] and a tunable diode laser
absorption spectroscopy (TDLAS) device [54]. The cold plasma ionization device is
connected to the freeze-dryer chamber through a sampling port, and contact points at the
internal parts of the freeze-dryer are able to withstand sterilization. The plasma sensor
measures the ratio of water vapor to nitrogen under vacuum conditions, tracks the
primary drying process, and indicates the end of primary drying. This device was
reported to provide operationally equivalent measurements in tracking primary drying in
four different freeze-dryers, two at pilot scale, one at intermediate scale, and a full-scale
industrial freeze-dryer. The TDLAS device is installed between the freeze-drying
chamber and the condenser and conducts velocity and mass flow measurements of the
water vapor exiting the chamber. These concentration measurements can be used to
determine the primary and secondary drying end points. Measurement of sublimation
rate is useful for scaling-up drying cycles. As the TDLASmeasurements are independent
of the freeze-drying equipment size and capacity, shelf configurations and operational
requirements, it appears very scalable and usable for both pilot-scale equipment and
large-scale industrial equipment. The application of the TDLAS device in determining
design space for a freeze-drying process has also been suggested [55]. Measurements of
shelf temperature, product temperature, and sublimation rate would serve to define the
boundaries for design space of freeze-drying processes with chamber pressure being the
additional factor.
13.6 CONCLUSIONS
Pharmaceutical manufacturers and regulators are moving gradually but steadily toward
QdB and PAT approaches. There is a common goal to achieve a state where we have an
integrated development and quality system approach that enables reliable, flexible, and
cost-effective manufacture of high-quality drug substances without extensive regulatory
oversight. Although manufacturers may be most intrigued by what is meant by “without
extensive regulatory oversight,” it should not be forgotten that the primary goal is to
ensure the general public of safe, efficacious, and cost-effective therapies supported by a
blossoming pipeline.
Regulators have formed task forces and working groups and are collaborating with
the industry to train investigators and reviewers and to develop new approaches to
submissions. In contrast manufacturers remain apprehensive about adopting new
approaches and technologies and sharing information [56]. Currently QbD and PAT
concepts are mainly limited to one or two production steps, rather than whole processes,
or are used in development to gather information to eliminate a step or variable [57].
There is a general agreement of the benefits of the combination of PAT and QbD
approaches, but most applications are likely to be implemented in the mid- to long-term,
rather than short-term.
QbD and PAT can be viewed as independent but closely linked approaches.
Independently, they may at first seem to be contrasts—QbD strives for “right first
