When FDA first 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 put into motion 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 the introduction of new technologies that would enhance
process understanding and assist in identifying and controlling critical points in a process (2). These technologies include:
appropriate measurements 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 (3).
Illustration by Dan Ward
So how far has the industry come in advancing PAT and where may future innovation lie? Pharmaceutical Technology conducted an industry roundtable to gain perspective on advances in analytical instrumentation and methods development. Participating
are: Tim Freeman, managing director of Freeman Technology and past chair of the Process Analytical Technology Focus Group
of the American Association of Pharmaceutical Scientists; Kevin Aumiller, TOC product manager at GE Analytical Instruments;
Andy Salamon, senior staff scientist and customer advocate at PerkinElmer; Chris Heil, product specialist, Antaris NIR analyzers
at Thermo Fisher Scientific; and Scott Samojla, senior director of PATROL process systems at Waters.
Advances in PAT
What would you identify as the most significant advances in PAT used in the pharmaceutical industry during the past five
Freeman (Freeman Technology):
Before focusing on specific technologies, I'd like to highlight what I believe is an important shift in the perception of
PAT over the last five years. Initially introduced by the regulators in 2004 to support efficiency in development, manufacturing,
and quality assurance, PAT has, in the intervening years, progressively proven its potential value. Collective and individual
experience has led to a widespread appreciation of the integral role that PAT will play in achieving new levels of manufacturing
efficiency and product quality, and as a result, the uptake of PAT is now increasing significantly, most notably for the information-gathering
needed to support the development of more efficient processes.
Industry roundtable participants, from left to right: Tim Freeman, managing director of Freeman Technology and past chair
of the AAPS Process Analytical Technology Focus Group; Kevin Aumiller, TOC product manager, GE Analytical Instruments; Andy
Salamon, senior staff scientist and customer advocate at PerkinElmer; Scott Samojla, senior director of PATROL process systems,
Waters; and Chris Heil (not pictured), product specialist, Antaris NIR analyzers, Thermo Fisher Scientific
This focus on information-gathering and process monitoring is reflected in the technologies that have advanced most during
the past five years. The use of on- or in-line systems with a proven track record has increased considerably but so too has
the application of at-line methods that provide unique information and insight.
In- and on-line systems deliver value by enabling the real-time tracking of process behavior and the changing properties of
in-process materials. Today, the pharmaceutical industry is making greater use of some traditional on-line techniques, such
as pH measurement, and also newer real-time technologies, such as particle sizing, and, of course the spectroscopic methods
such as NIR. In the at-line arena, I'd recognize particle-imaging and bulk powder characterization systems, as examples of
technology that are really advancing understanding. By providing the information needed to rationalize particle and powder
behavior, these technologies support the attainment of better powder processing performance, which is vital for greater manufacturing
Heil (Thermo Fisher Scientific):
NIR spectroscopy has matured into a common technique for PAT analysis across the whole pharmaceutical manufacturing life cycle
from raw material identification to granulation and drying to blending and tablet production. The advent of fit-for-purpose
and total solution NIR analyzers has unlocked the full potential of NIR spectroscopy as a process analytical technology for
monitoring and controlling pharmaceutical production processes. We have witnessed the development of dedicated PAT NIR analyzers
during the past five years, which offer total process analysis solutions. The evolution in design was witnessed not only in
the NIR analyzers but also in the software, accessories, and probes required for a total analysis solution. Software integration
and process communication also are key aspects of a total analyzer package.
Experience has shown that the most challenging and often most important facet to a successful process analysis is representative
sampling. The interface of the analyzer to the sampling point is critical since this is where the NIR spectrometer interrogates
the sample for analysis. A perfect example is the challenge in getting a representative sample on a probe installed in a fluid-bed
dryer when the product is being fluidized and the moisture level dictates whether the product will coat or foul the probe
window. Advances in fiber-optic probe design have led to self-cleaning probes with purge air or retraction mechanisms to prevent
probe fouling. In addition, probes that use side-view windows, angled tips, and curved, cupped design have been developed
to ensure that representative samples are in contact with the probe window. These advances in NIR analyzers, software, and
accessories have furthered the application of PAT for production process optimization, reduction in production costs, and
improved product quality through timely measurements of critical quality attributes.
: The need for an improved scientifically based understanding of the manufacturing process has been and will continue to be
key to future success in the pharmaceutical industry. The advent of ultra-performance liquid chromatography provided the
power to not only meet these needs within the laboratory, but enables on-line chromatographic use for process monitoring and
control. The benefits of this approach reduce process variability and risk while adding automation and information not previously
Aumiller (GE Analytical Instruments):
A prime example of PAT advancement has been associated with equipment cleaning and release. Clean-in-place (CIP) systems,
which have historically been used in the biopharmaceutical space, have gained traction within traditional pharmaceutical facilities
and contract manufacturing organizations. This has been promoted by the unprecedented merger and acquisition activity seen
in the past three to five years. With an industry focus on increasing plant capacity and reducing overall operating costs,
facilities are taking on more products, which in turn, spawns the need for rapid equipment changeover. The implementation
of CIP to replace manual cleaning has provided significant opportunities for efficiency in this area.
Offering the benefits of automated, predictable, and repeatable cleaning cycles, CIP systems satisfy the main objectives of
PAT by building quality into the process and providing real-time assurance of quality. The critical quality and performance
attributes associated with cleaning can be monitored and controlled continuously. For example, the temperature and concentration
of cleaning solutions can be monitored with in-line conductivity probes and temperature sensors. The agitation of the vessels
can be actively controlled with flow meters and pressure transducers. With the use of process logic control (PLC) systems,
sequences can be timed to provide consistent exposure to the cleaning agents and rinse water.
Once cleaning is complete, indirect sampling of final rinse water can be performed in near real-time with at-line total organic
carbon (TOC) analyzers and in-line conductivity sensors. Direct swab samples can also be analyzed with at-line TOC instrumentation.
TOC instruments provide detection of residual product and other non-ionic species present in the process. The conductivity
sensors can detect the presence of ionic contaminants, such as cleaning agents in the rinse water. The combination of test
methods provides expedient feedback to release the equipment for use.