When FDA announced in 2002 a new initiative, Pharmaceutical Current Good Manufacturing Practices (CGMPs) for the 21st Century, and later issued its report, Pharmaceutical CGMPs for the 21st Century—A Risk-Based Approach, in 2004, it began an effort to enhance product quality and modernize pharmaceutical manufacturing through a science- and
risk-based approach under quality-by-design (QbD) principles (1). That effort was further encouraged by the issuance of guidance
on process analytical technology (PAT) in 2004 to facilitate new technologies that would enhance process understanding and
assist in identifying and controlling critical points in a process (2). These technologies include: appropriate measurement
devices, which can be placed at-, in-, or on-line; statistical and information technology tools; and a scientific-systems
approach for data analysis to control processes to ensure production of in-process materials and final products of desired
quality (1–4). Lyophilization is one specific application of QbD and PAT in parenteral drug manufacturing, and a review of
recent literature shows several developments in this field.
JurgaR/Getty Images; Dan Ward
Evaluating the technology
In applying QbD to the lyophilization process, the first task is to define the parameters that have the potential to affect
process performance and product-quality attributes (5). Key points include the freeze-drying process operating parameters,
formulation parameters, equipment, and component preparation and devices (5). PAT may be applied through sensors at various
stages in freeze-drying, which may include using temperature sensors, pressure-rise analysis, manometric temperature measurements,
calorimetry, microscopy, and spectroscopic techniques, such as near-infrared (NIR), Raman, and infrared spectroscopy (6).
Assessing the tools
An established approach for PAT in lyophilization is offered by SP Scientific's SMART freeze-dryer technology, which is used
to optimize the freeze-drying cycle. The SMART technology was developed by the University of Connecticut and Purdue University
through the Center for Pharmaceutical Processing Research and licensed to SP Scientific. The technology relies on the use
of manometric temperature measurement, which calculates the product temperature at the sublimation interface without having
to place thermocouples or other temperature sensors in product vials (7). The SMART freeze-dryer technology is used on SP
Scientific's Lyostar 3 development freezer. The SMART technology uses information, such as the number of vials, fill volume,
fill weight, freeze-dryer chamber volume, and critical formulation temperature to optimize a cycle (8). It contributes to
several key points in lyophilization: selects an optimum freezing cycle based on whether the formulation is crystalline or
amorphous; selects the optimum chamber pressure; determines the target temperature of the product; and adjusts the shelf drying
during primary drying to keep the product at a predetermined target temperature (8).
SP Scientific has partnered with the industrial-gas company Praxair for another PAT-based tool for lyophilization, Praxair's
ControLyo Nucleation on Demand Technology, used to control the nucleation of the product solution in the freeze dryer. The
companies first partnered in 2010, which gave SP the exclusive, global rights to commercialize the technology on development
lyophilzers. In 2012, the companies expanded their collaboration to allow SP Scientific to equip its clinical, pilot, and
production dryers with theControLyo Technology and to transfer the technology to allow SP to retrofit existing pilot and production
IQ Mobil Solutions, based in Holzkirchen, Germany, offers wireless and battery-free temperature sensors (Temperature Remote
Interrogation System, TEMPRIS) as a PAT tool for lyophilization. In a recent study, the TEMPRIS system was assessed for measurement
accuracy, capability of accurate endpoint detection, and effect of positioning by using product runs with sucrose, mannitol
and trehalose (9). Data were compared to measurements with 36-gauge thermocouples and to noninvasive temperature measurement
from manometric temperature measurements. The results showed that the TEMPRIS temperature profiles agreed with thermocouple
data when sensors were placed center bottom in a vial. In addition, TEMPRIS sensors revealed reliable temperature profiles
and endpoint indications relative to thermocouple data when vials in the edge position were monitored (9).
Researchers at Ghent University in Belgium used Raman and NIR spectroscopy as PAT tools in a freeze-drying process (10). For
the study, Raman and NIR probes were built in the freeze-dryer chamber to allow simultaneous process monitoring of a 5% (w/v)
mannitol solution. Raman and NIR spectra were continuously collected during freeze-drying and analyzed using principal component
analysis and multivariate curve resolution (10). Raman spectroscopy provided data about the mannitol solid state, the endpoint
of freezing, and several physical and chemical conditions (e.g., onset of ice nucleation and onset of mannitol crystallisation).
NIR spectroscopy monitored key points in drying, the endpoint of ice sublimation, and the release of hydrate water during
storage (10). A later study further examined the use of in-line spectroscopic process analyzers (Raman, NIR, and plasma emission
Another recent study examined the use of tunable diode laser absorption spectroscopy (TDLAS) for monitoring secondary drying
in laboratory-scale freeze-drying with the purpose of targeting intermediate moisture contents in the product (12). An earlier
study examined TDLAS to determine the average product temperature in primary drying (13).