Making the move to RTRT
Now that RTRT has moved from a concept to a realistic option for drug products, says Senior Director of Global Manufacturing
Services at Pfizer Global Manufacturing Holly Bonsignore, there are many benefits for industry to take advantage of. For example,
RTRT can "improve process control by generating more data while the manufacturing process is taking place, as opposed to traditional
release testing conducted on small samples after batch manufacture is complete." The availability of RTRT data at the time
of batch manufacture can also improve operational efficiency and inventory control by eliminating the time and resources needed
to test batches in a laboratory post-manufacture.
There are a few downsides to the approach as well. Because RTRT is not yet globally accepted by regulatory agencies, explains
Bonsignore, manufacturers are caught somewhat in the middle of a paradigm manufacturing shift. Some companies need to continue
to use traditional batch-release testing for certain markets even if other markets have approved the approach and even if
the company is ready to move full speed ahead with RTRT.
Bonsignore's colleague, Steve Hammond, a director and team leader in Pfizer Global Manufacturing's analytical sciences group,
notes a more technical limitation with RTRT: testing for impurities and stability. "PAT technology is being developed that
may be capable of that category of 'stability indicating' analysis, but at this time, there is a gap," he explains. "The approach
at Pfizer is to propose RTRT for products for which we have a history of stability (e.g., active pharmaceutical ingredients
that do not degrade due to the manufacturing process)."
Adds Terry Redman, product manager for particle-system characterization at Mettler-Toledo AutoChem, "It is not always feasible
or cost-effective to implement direct measurement of all critical process parameters (CPPs) and critical quality attributes
(CQAs) with RTRT. In many cases, gaps in measurement technology must be filled with inferred measurements that must be proven
statistically reliable," he says. However, that may change in the coming years. New measurement technologies are on the horizon
that will improve industry's ability to monitor process control and provide analytical measurements for quality control.
The key, according to many industry experts, is going to be increased product and process knowledge—a fundamental concept
of quality by design (QbD) and the harmonized ICH quality guidelines. As Tim Freeman, director of operations at Freeman Technology,
points out, "Although RTRT is the future for efficient, safe and competitive pharmaceutical manufacturing, it relies on capturing
more information about the materials being processed and the equipment and configuration employed during manufacturing."
FDA's Moore offers a specific example. "By understanding your process and controlling its associated risks through a PAT system,
you can monitor and control the process at the most important points," she says. "Some critical quality attributes, such as
dissolution, cannot be measured directly by a specific probe. Instead, to utilize a RTRT approach, you need to understand
the relation between the desired product attribute and relevant material attributes and process parameters and then monitor
and control them accordingly."
Selecting appropriate unit operations
In terms of gaining knowledge before applying RTRT to a manufacturing process, pharmaceutical firms may need to determine
which operations, from blending and compaction to tablet coating, are conducive to its use. The good news, according to Pfizer's
Hammond, is that PAT applications are now well developed for most all unit operations. "For most products, nearinfrared (NIR)
can handle a high proportion of unit operations, and the emergence of light-induced fluorescence instruments with an order
of magnitude greater sensitivity than NIR has taken PAT into low-dose products," he says. In addition, he notes that technologies
such as terahertz spectroscopy are emerging for coating monitoring and control, but says that further development is required
in this application area.
In terms of tableting and powder processing, Freeman says he has come across several advances in measurement technologies
that are driving material and process understanding toward an RTRT approach. "There are now GMP suites for continuous manufacturing
of tablets that rely heavily on PAT and that function with real-time, closed-loop feedback on parameters such as size, moisture
content and blend uniformity," he says. "For this reason, RTRT has become much more of a reality in the last couple of years.
However, there are many material properties that are still not measured routinely at-line or on-line, even though they will
influence final product quality."
According to FDA's Moore, "Many of the sensors used for in-process measurements of pharmaceutical technologies have been well
established in other similar industries, such as the chemical or food processing industry. Undoubtedly, there is a sensor
available that could be used at every unit operation of tablet or other dosage form manufacturing. Monitoring every step does
not necessarily add value though." She adds, "The challenge is to perform the right measurement, at the right time, and at
the right location. Furthermore, you want the right control systems in place to make appropriate and timely adjustments to
the process based on the information collected."