Process analytical technology (PAT) is a well-publicized initiative championed by the US Food and Drug Administration to promote
innovation in pharmaceutical processing (1). A pharmaceutical manufacturer following PAT guidelines will be able to understand
areas where process variability may occur and respond instantaneously to account for that variability. This responsiveness
results in higher product quality and reduced cost due to lost batches. In addition to the ultimate goal of better process
understanding, FDA's guidance for industry, A Framework for Innovative Pharmaceutical Development, Manufacturing and Quality Assurance, enumerates the potential benefits from gains in quality, safety and efficiency, including (1):
- Reducing production cycle time by using on-, in- or at-line measurement and controls
- Preventing rejects, scrap, and reprocessing
- Real-time release
- Increasing automation to improve operator safety and reduce human errors
- Improving energy and material use and increasing capacity
- Facilitating continuous processing to improve efficiency and manage variability (1–3).
Despite these advantages, processing using PAT in the pharmaceutical industry has lagged behind other industries such as the
semiconductor-manufacturing or food-processing industries. PAT initiatives in the biopharmaceutical industry have been even
slower (4).
Many aspects are involved in a successful PAT process. Cultural acceptance within the corporate structure ultimately drives
the success, but having confidence in the instruments and hardware can also drive acceptance. The key physical components
of a PAT-compliant process are the analytical probes and instruments used to monitor and control the process. A variety of
instruments are available to the pharmaceutical industry, including simple temperature and pH probes, oxygen and total organic
carbon probes. More complex on-line high-performance liquid chromatographs (HPLC) and mass spectrometers are available as
well, but one of the most commonly relied upon and robust techniques is near infrared (NIR) spectroscopy. NIR systems are
of primary importance in PAT-compliant processes because they do not destroy the sample during analysis. In addition, NIR
systems can be placed at, in, or on-line, and achieve results automatically and in real time.
NIR as part of PAT
Unlike mid-infrared spectroscopy, the material under NIR analysis usually does not need to be diluted or manipulated robotically
or by a laboratory technician to achieve results. The technique allows direct sampling of many materials, enabling probes
to be placed directly in the process stream. The NIR light is of the same type used in the telecommunications industry. It
is easily shunted from the probe to the instrument over long distances using commercially available fiber-optic cables. In
addition, Fourier transform (FT) instruments provide precise and reproducible results—normally in just a few seconds. Best
results are achieved using NIR systems that have been originally designed for process streams. These systems communicate easily
and directly with process-control systems.
NIR spectroscopy relies on the interaction of light to analyze a variety of raw materials, mixtures, intermediates, and finished
products. Specific photons of light with frequencies between 12,000 and 4000 cm-1 can be absorbed by different chemical bonds, which set up characteristic vibrations within the molecules. Light that is
not absorbed by the bonds is collected and displayed as a spectrum. The inherent complexity of mixtures and the unavoidable
interactions between vibrating molecules can make interpreting NIR spectra very difficult. The advent of chemometrics and
powerful computing algorithms, however, has greatly simplified interpretation.
NIR analysis usually requires training the system to recognize concentrations of analytes or the identity of materials. A
series of standards of known composition are characterized with a primary method and scanned with the NIR system. The key
to a robust NIR analysis is to have adequate and appropriate standards for this training, as well as accurate primary data
on the composition of the material. The spectroscopic and composition data are deconstructed through chemometric software,
which can correlate even subtle spectroscopic variation with the material composition, and this method can then be used to
determine the composition of subsequent samples. In addition, several components within a mixture can be determined simultaneously
from just one spectrum.
The power of NIR in a PAT environment is that it provides crucial comprehensive information about a process in real time while
the material is being manufactured. Other spectroscopic, electrochemical, chromatographic, or wet-chemistry techniques require
samples to be drawn off and sent to the laboratory for analysis, which, in addition to the cost in labor and time, necessitate
the destruction of valuable samples. Analysis of multiple components in a mixture also requires several analytical techniques
that invariably add to the cost. Most importantly, the information obtained by these off-line techniques may be several hours
or days old, which is too long to maintain adequate control over the process.
Once in place, NIR largely replaces these off-line analytical techniques, and the speed with which NIR can nondestructively
determine multiple components in a mixture allows critical decisions and adjustments to be made before the material falls
out of specification and becomes unsalvageable. Batches of active pharmaceuticals may easily be valued in excess of $1 million,
which is an expensive loss if out-of-specification material is discovered during final quality checks simply because the process
was not tightly controlled using PAT.
