Kaiser Optical Systems, Inc

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This application note shows the utility of Kaiser Raman for real-time monitoring of polymorphic transformation under various process conditions within a cGMP environment. 

In Situ Monitoring of Polymorphic Transformation of Active Pharmaceutical Ingredients

This application note demonstrates the utility of Kaiser Raman to rapidly measure taste, color, and texture attributes of salmon meat in the laboratory or plant. 

Multi-Attribute Salmon Quality Monitoring using Kaiser Raman

Sampling flexibility of Raman enables in-process analysis of solids, turbid media, liquids, and gases

Large volumetric Raman provide representative sampling of heterogenous solids 

	Raman spectroscopy is an analysis technique that provides a "molecular fingerprint" of the sample, enabling analysis of chemical composition and molecular structure without sample preparation. As a measurement technique, Raman imparts application and financial benefits from laboratory discoveries to feedback-control in manufacturing. In situ real-time analysis, compatibility with aqueous systems, nondestructive nature, and high chemical specificity means that a Raman-analyzed sample is representative of the process. Because Raman is a nondestructive technique, the same sample measured by Raman can also be measured by other analytical techniques. These well-known features have been harnessed in pharmaceutical, chemical, polymer, and bioprocessing industries.

	Fiber optic sampling probes enable real-time Raman measurements outside the laboratory. For process or in-line sampling applications, fiber optic probes can be inserted directly in the process. Figure 1 shows variants of fiber-optic probes used in Raman spectroscopy. The sampling flexibility imparted by fiber optic probes means that Raman spectroscopy can be applied to real-time in situ analysis of a variety of materials for applications from early development to manufacturing. The design of fiber optic probes for process environments takes into account additional considerations of the material's phase, the ability to be immersed in corrosive or hazardous environments, and laser safety.


	Figure 1: Raman measurements outside of a laboratory setting is achieved through fiber optic sampling probes. Sampling probes for Raman spectroscopy enable offset analysis of solids, thin films, and raw materials, or immersion analyses in liquids or gases without needing to customize process hardware. 

In-process Raman in Solids and Turbid Media

	For processes that involve solids or turbid media, optical scattering is an important material property that needs to be considered. Understanding the effects of optical scattering on Raman signal recovery will guide the selection of a fiber-optic probe, because there are applications in which optical scattering can be harnessed to maximize sampling volume and there are other applications in which the effects of optical scattering should be minimized. In a recent example of Raman-based control in a process with solid materials, a large volumetric Raman probe was used to acquire information on critical quality attributes of pharmaceutical granules during a continuous blending and tableting process (1). Raman data were acquired quickly and nondestructively and with great chemical specificity, showing that Raman provides detailed in situ

process knowledge needed for real-time process understanding.

	Sampling flexibility is a significant benefit of Raman spectroscopy. The use of fiber-optic probes expands the capability of an analyzer to meet current and future application needs. Raman provides detailed chemical information without sample homogenization, enabling bulk or cross-sectional analysis during the process. Raman spectroscopy approaches to measuring layered samples may be applied to pharmaceutical tablets, copolymers, or biological materials such as cells or engineered scaffolds. Scientifically and financially successful Raman applications have been demonstrated at all scales, from the laboratory to on-line in manufacturing in PAC and PAT environments. Examples of processes benefiting from Raman spectroscopy include:

		Pharmaceutical formulations: blending, granulation, coating, drying, tableting, content uniformity

		Pharmaceutical API: reaction chemistry, yield, polymorph form identification, crystallization

		Polymer: polymerization blending, extrusion monitoring, crystallinity, density, copolymers

		Bioprocessing: cell culture, fermentation

	(1) B. Nagy et al., "In-line Raman spectroscopic monitoring and feedback control of a continuous twin-screw pharmaceutical powder blending and tableting process," 


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Sampling flexibility is a significant benefit of Raman spectroscopy.

Sampling Flexibility for Raman Spectroscopy

	Raman spectroscopy is an analysis technique that provides a "molecular fingerprint" of the sample, enabling analysis of chemical composition and molecular structure without sample preparation. As a measurement technique, Raman imparts application and financial benefits from laboratory discoveries to feedback-control in manufacturing. 

 real-time analysis, compatibility with aqueous systems, nondestructive nature, and high chemical specificity means that a Raman-analyzed sample is representative of the process. Because Raman is a nondestructive technique, the same sample measured by Raman can also be measured by other analytical techniques. These well-known features have been harnessed in pharmaceutical, chemical, polymer, and bioprocessing industries.

	Fiber optic sampling probes enable real-time Raman measurements outside the laboratory. For process or in-line sampling applications, fiber optic probes can be inserted directly in the process. Figure 1 shows variants of fiber-optic probes used in Raman spectroscopy. The sampling flexibility imparted by fiber optic probes means that Raman spectroscopy can be applied to real-time 

 analysis of a variety of materials for applications from early development to manufacturing. The design of fiber optic probes for process environments takes into additional considerations of the material's phase, ability to be immersed in corrosive or hazardous environments, and laser safety.


	Figure 1: Raman measurements outside of a laboratory setting is achieved through fiber optic sampling probes. Sampling probes for Raman spectroscopy enable offset analysis of solids, thin films, and raw materials, or immersion analyses in liquids or gases without needing to customize process hardware.

	For processes that involve solids or turbid media, optical scattering is an important material property that needs to be considered. Understanding the effects of optical scattering on Raman signal recovery will guide the selection of a fiber-optic probe, because there are applications in which optical scattering can be harnessed to maximize sampling volume and there are other applications in which the effects of optical scattering should be minimized. In a recent example of Raman-based control in a process with solid materials, a large volumetric Raman probe was used to acquire information on critical quality attributes of pharmaceutical granules during a continuous blending and tableting process (1). Raman data were acquired quickly and nondestructively and with great chemical specificity, showing that Raman provides detailed 

Sampling flexibility of Raman enables cross-sectional and /or bulk product analysis

Large volumetric measurements provide data on subsurfaces in layered samples

Enhanced reflection improves Raman sensitivity for in-process measurements

	Materials such as pharmaceutical tablets or graft copolymers are chemically and spatially heterogeneous materials. Chemical analysis of these materials requires non-destructive techniques in order to also capture the spatial heterogeneity of the layers or bulk product. Optical spectroscopy, such as Raman spectroscopy, is widely used to analyze heterogeneous samples. Raman provides detailed chemical information and requires no sample homogenization: enabling bulk or cross-sectional analysis in a spatially heterogeneous sample.

	Raman spectroscopy approaches to measuring layered samples may be applied to pharmaceutical tablets, copolymers or biological materials such as cells or engineered scaffolds. The sampling principles have been also applied to axially heterogeneous polymers (1). Three techniques: backscattered Raman, large volumetric Raman (also called wide area Raman) and enhanced reflection Raman are highlighted.

	Figure 1 shows variants of reflectance-based Raman spectroscopy techniques using fiber-optic probes. A commonly used approach is backscattered Raman (left), where incident and Raman-scattered light share the same optical path, or one that is minimally offset. Large volumetric Raman (middle) uses a wide laser beam and multiple collection fibers to obtain data from surface and subsurface layers. Enhanced reflection is an option for processes needing additional sensitivity (2). Inclusion of a reflectance standard such as barium sulfate or a fluoropolymer into the wide volumetric geometry is called enhanced reflection (right). Metalized mirrors or dielectric mirrors are other enhanced reflection materials and they offer minimal Raman signatures. Large volumetric or enhanced reflection are useful tools for in-process measurements of content uniformity or processing solids or turbid media. Another configuration of note is Raman microscopy. The high spatial resolution of Raman microscopy can provide detailed information on inter-layer mixing or verification of polymorphic form in the API layer during a cross-sectional analysis of tablets. These four variants provide sampling flexibility from early development to manufacturing, in applications from laboratory QA to in-process monitoring, testing, or control.

	Sampling flexibility is a significant benefit of Raman spectroscopy. The use of fiber-optic probes and microscopes enables fast switching between scenarios. This attribute contributes to good method transferability across instruments and across scales.

	Enhanced reflectance Raman is a process friendly option that can be used to obtain spectral information from throughout the bulk of the sample, with applications commonly used in pharmaceutical processing. While depth profiling is also possible using transmission Raman, enhanced reflection spectroscopy provides similar information without the experimental complexity because it can be integrated into processes using existing equipment such as non-transmissive belts.

	(1) N. Brun, M.-C. Chevrel, L. Falk, S. Hoppe, A. Durand, D. Chapron, et al., 

	(2) D. Oelkrug, E. Ostertag, R.W. Kessler, 

Kaiser Optical Systems, Inc

Articles

In Situ Monitoring of Polymorphic Transformation of Active Pharmaceutical Ingredients

Multi-Attribute Salmon Quality Monitoring using Kaiser Raman

Sampling Flexibility for Raman Spectroscopy

Sampling Flexibility for Raman Spectroscopy

In-Process Raman Spectroscopy of Layered Materials