Infrared (IR) radiation is electromagnetic radiation whose wavelength is longer than that of visible light (400-700 nm) in the electromagnetic spectrum and covers the wavelengths from 780 nm to 2500 nm. Near-infrared spectroscopy (NIRS) is an analytical technique based on absorption measured in this near-infrared region that measures different types of inter-atomic bond vibrations at different frequencies. This technique is fast becoming a key tool in the precise analysis of pharmaceutical components and the prediction of functionality parameters. The OH, CH, NH, and SH bonds have the strongest overtone absorbances in the NIR region. NIR is being used effectively for the qualitative and quantitative measurements from the inspection of incoming raw materials to the final testing of manufactured products. The use of NIRS has become viable due to technological advances in instrumentation and software and involves the multidisciplinary approaches of the analytical chemist, statistician, and computer programmer. It is the discipline of chemometrics which refers to the application of mathematical or statistical methods to measurements made on chemical systems of varying complexity which permits the application of formal logic to design and the selection of optimal measurement procedures and experiments to provide maximum relevant chemical information by analyzing chemical data. It is the relative variability of physiochemical parameters which provides valuable information which can be acted upon earlier rather than later. Batch end points can be over-layed to illustrate repeatability through three dimensions. NIRS is a measurement technique arising from a growing focus on Process Analytical Technology (PAT). This technique is applied following assessments of critical quality attributes which pose as substantial risks in terms of safety or efficacy of the product for the patient and on the basis that such variables can be managed via measurable control i.e. product/intermediate specifications, in process and finished product testing and controls. This initiative merges a science-based risk management approach into the quality system. Quality and material attributes and process parameters are assessed from a risk prioritization perspective and the results drive the use of PAT in specific areas on the basis that all share a design space and interact together or impact on each other. NIRS permits real time data to be obtained which in turn reduces variability in the process and increases uniformity and consistency of results and fits nicely with the Right First Time (RFT) concepts and indeed lean and six sigma drivers.
Currently the US Pharmacopeia monograph requires content uniformity tests to be performed on solid-dosage form samples at a frequency of 10 per batch. The FDA asserts that “quality cannot be tested into products, it should be built in or should be by design”.(1) The FDA defines “analytical” broadly to include chemical, physical, mathematical, and other analyses used in an integrated way. However, in order to ascertain the critical parameters, the variables need to be determined by analysis of validation data. Internal multidisciplinary communication and in-depth literature reviews to ensure that a robust “Proof of Concept” is established are needed. A full review and understanding of the process is required. PAT implementation may reduce the requirements for Quality Control testing, and increase product yields. However, financial assessment must consider savings associated with testing reductions, speed of results, less rejections and findings and increased yields, whilst considering the costs associated with the installation and qualification of analytical technologies and Part II compliant software, as well as the time and resource required to produce correlations of NIR results versus the current methods such as disintegration, dissolution and friability as part of release testing.
A reference method is required to determine the reference component values that are to be used in the NIR calibration in order to obtain an appropriate mathematical expression. Laboratory methods for tablet assay and content uniformity are usually time-consuming because they routinely are done by high-performance liquid chromatography (HPLC), which requires lengthy calibration runs, the mixing of buffers, and the procurement and disposal of volatile solvents. NIR real time testing can ensure that assay and content-uniformity out of trends can be detected before they go out of specification. However, many factors can contribute to the variations in NIR spectra, such as detector noise, environmental conditions, and different sample preparation. Often the largest variations come from the constituent or concentration differences. Using this knowledge, chemometric techniques such as principal axis transformation can be used to interpret complex overlapping spectra. Proper probe placement for best sample spectrum, keeping the probe clean, the ability to get samples for calibration, robust calibration method/good reference method and seamlessly transferable calibrations are required. Personnel and technicians with an adequate technological skill set are also difficult to find for new evolving techniques.
Concerns about changes to such a highly regulated environment, steep initial investments, and unfamiliarity have slowed its adoption. In addition, technical shortcomings also made initial adoption slow. Among these shortcomings were difficult calibrations, lack of robustness, and results that were hard to interpret. However, improvements in chemometric software made calibration and analyses of results easier, while new, more rugged probes and flow through cells have made sampling and process control easier and more sensitive. Yet concerns about validation, methods transferability and regulatory acceptance remain. The European pharmacopeia published NIR guidance in 1997, though it was limited. The US Pharmacopeia’s recently published revisions to Chapter 1119 includes qualification and verification information for NIR and guidelines for validation. However, these changes are new and adoption will take time. There is still a lag in the acceptance of NIR for on-line analysis. This will become easier in the future with the improved general acceptance of NIR (USP Chapter 1119). As new production lines are implemented new and innovative NIR methods for assay and uniformity of content testing will be established.
References
1. US FDA Guidance for Industry “PAT- A Framework for Innovative Pharmaceutical
Development, Manufacturing and Quality Assurance”, September 29, 2004