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):
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.