On August 1, 2020 the United States Pharmacopeia’s (USP) Raman chapters USP <858> Raman Spectroscopy and USP <1858> Raman Spectroscopy – Theory and Practice went into effect, replacing USP <1120> Raman Spectroscopy.
USP chapters numbered <1000 indicate that this is mandatory if it is called for in a monograph, and is generally considered enforceable. Chapters numbered >1000 are informational and do not represent official standards. The U.S. Food and Drug Administration (FDA) enforces compliance with these regulations. The introduction of USP <858> demonstrates Raman spectroscopy’s growing importance in the pharmaceutical sector.
USP<858> separates qualification of Raman spectrometers into three components: installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ). IQ demonstrates that hardware and software are properly installed in the user’s desired location. OQ demonstrates that the instrument meets fit for purpose criteria and may depend on user and application. USP <858> provides acceptance criteria for wavelength accuracy and photometric precision for OQ. PQ proves that the instrument is working within specified limits for wavelength accuracy and photometric precision on a continuing basis. IQ/OQ/PQ documentation is available for B&W Tek instruments designed for raw material identification.
Raman shift standards such as polystyrene, cyclohexane, and acetaminophen can be used to determine the wavelength accuracy of the instrument. Unlike the European Pharmacopeia (EP) and Japanese Pharmacopeia (JP) Raman chapters, USP <858> divides the published accepted wavelength accuracy criteria into quantitative and qualitative applications. For qualitative Raman, the acceptance criteria are ± 3.0 cm-1 for all specified Raman shifts of polystyrene, cyclohexane, and acetaminophen. Table 1 shows the USP<858> Raman wavelength accuracy criteria for polystyrene compared with the criteria from JP 2.26 and the EP 2.2.48, as well as the USP <858> criteria for quantitative Raman analysis. The USP <858> qualitative requirements are broader than the requirements for handheld Raman set forth by the EP and JP.
NanoRam and NanoRam-1064 systems for qualitative raw material identification (RMID) analysis are calibrated to be compliant with the wavelength accuracy criteria for qualitative Raman measurements set forth by all global pharmacopeias, including the new USP <858> chapter. The system software of the NanoRam and NanoRam-1064 also includes performance validation testing using Raman shift standard materials as defined by ASTM E1840 Standard Guide for Raman Shift Standards for Spectrometer Calibration. Figure 1 shows the performance validation report from the NanoRam system when measuring with a polystyrene cap. The report shows that the Raman shifts measured during the validation are within the specification for the tolerances for polystyrene set forth by the USP, EP, and JP Raman chapters.
The photometric precision of the instrument can change with respect to variation of photons emitting from the laser from one measurement to the next. USP <858> sets a tolerance of 10% for the photometric precision of the measurements of reference materials. This tolerance is relatively loose because it is difficult to separate laser variations from sample variations. The performance validation report in Figure 1 shows the relative intensity precision calculated for the polystyrene peaks using the peak at 1001.4 cm-1 as the standard. The peak intensity ratios for the other three polystyrene peaks (620.9 cm-1, 1031.8 cm-1, and 1602.3 cm-1) are calculated against the reference peak. Two sets of ratios are calculated in the software; the first compares the performance validation measurement to the previous performance validation measurement, and the second compares the performance validation scan to the validation reference file. The tolerance for all peak ratios is ±10%. Absolute intensity of the 1001.4 cm-1 polystyrene peak is also measured with a tolerance of ±50%, though this is not required by the USP.
1. ASTM E1840-96(2014), Standard Guide for Raman Shift Standards for Spectrometer Calibration, ASTM International, West Conshohocken, PA, 2014, www.astm.org