Raman’s role in the production line

17th June 2016

Posted By Paul Boughton

A PhAT Raman interface for a batch coating (top) and a continuous coater (bottom)
Comparison of a reaction design space using a fixed post-reaction age (a) and a variable reaction age (b) based on a Raman-defined endpoint. In-process Raman measurements enabled real-time control of the reaction, resulting in a more robust process

Karen Esmonde-White on Raman spectroscopy as a process analytical technology for batch or continuous manufacturing

An important consideration in successful continuous or batch manufacturing is integrating analytical tools into the reaction flow. On-line, in-line and at-line analyses enable Quality by Design (QbD) and ensure efficient operations. Raman spectroscopy is uniquely suited for this task and has been proven to: facilitate continuous processing/manufacturing approaches; provide robust method transferability from laboratory to manufacturing; reduce cycle times; and prevent reject product and waste.

Scientifically and financially successful Raman applications have been demonstrated at all scales, from at-line in the laboratory to on-line in manufacturing in PAC and PAT environments. Examples in continuous manufacturing and pharmaceutical reaction control highlight the advantages of in-process Raman spectroscopy.

Continuous manufacturing

There is a clear need for rugged and validated analytical tools that will meet the specific needs for continuous reaction monitoring. Kaiser Optical Systems’ process Raman solutions feature a fibreoptic technology platform that provides sampling versatility, remote monitoring with excellent scalability and model transferability. The company’s systems are compatible with microreactor, laboratory, scale-up, and pilot-plant to GMP/GLP production settings. These features can be exploited to control flow processes involving solids or liquids in real time. Two examples illustrate the advantage of Raman spectroscopy in continuous reaction monitoring and controlling continuous solids processing.

Chemical reaction monitoring

Kaiser is well versed in monitoring reactions under the intense conditions found in continuous manufacturing within the chemical and petrochemical industries. In one application, Raman spectroscopy was used to measure the continuous reaction between phosphorus and chlorine to produce phosphorus trichloride. Owing to the corrosive intermediates and reaction products, an in-line reaction analysis tool was needed to replace off-line measurements. Raman spectroscopy was chosen because it was able to directly measure all components of interest throughout the reaction, was sensitive to better than 1% for reactants and products and provided fast feedback. Within the pharmaceutical industry, customer applications have demonstrated the practicality of Raman measurements in an esterification reaction and flow synthesis of an oligonucleotide(1), (2) In these examples, many benefits were cited, including: reduced cost of goods and production losses; remote monitoring in hazardous reaction conditions; ability to control the reaction based on real-time analytics and improved process robustness.

Pharmaceutical tablet coating

Kaiser has addressed continuous solids monitoring and solid phase unit operations including in situ control of crystallisation and polymorphism, process-induced transformations, low-dose formulations and tablet coating. In a representative application, Kaiser’s PhAT probe was used to monitor an active coating process for pharmaceutical tablets. Active coating process studies in the laboratory showed that Raman spectroscopy was robust to variations in the probe working distance, enabling representative sampling without focusing the probe. In-process Raman provided a non-invasive measurement without hardware modification, insight into the chemistry of the coating process and could be used for control from on-line measurements that determine optimal coating time. Raman spectroscopy for active coating monitoring has been demonstrated successfully in continuous and batch manufacturing. 

Raman spectroscopy within a QbD approach

A customer webinar shows practical examples of integrating Raman spectroscopy into a process environment.(3) One example demonstrated coupling in-line Raman spectroscopy with a QbD approach to improving a process reaction. Reaction age post-completion was determined to be a critical process parameter to avoid product degradation and build-up of side products. Based on experience, it was known that the reaction needed to be cooled to < 25◦C within five hours of the reaction completion. Raman spectroscopy was proposed as an in-line PAT method because the reaction conditions required in line monitoring. The Raman method was tested on multiple Raman instruments and using different probes to create a robust calibration set. Scale-up performance was tested at limits of the initial design space to address questions regarding scale dependency.

Kaiser shows Raman spectroscopy as a valuable technique for process monitoring and control, with applications in continuous manufacturing and pharmaceutical reaction monitoring. Raman spectroscopy provides increased process knowledge that enables advanced process monitoring and real-time process control.

For more information, visit

Karen Esmonde-White is with Kaiser Optical Systems


1. Hart, R. J.; Pedge, N. I.; Steven, A. R.; Sutcliffe, K. Org. Process Res. Dev. 2015, 19 (1), 196–202.

2. Rydzak, J. W.; White, D. E.; Airiau, C. Y.; Sterbenz, J. T.; York, B. D.; Clancy, D. J.; Dai, Q. Org. Process Res. Dev. 2015, 19 (1), 203–214.

3. Wasylyk, J.; Wethman, R. From Development to Plant Implementation of Raman Methods: Strategy, Challenges, and Solutions; Raman Spectroscopy in the Pharmaceutical Industry.





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