The commercial advantages of Raman

15th December 2015

Posted By Paul Boughton

A laboratory-scale reactor analysed by a Kaiser MR probe
On-line monitoring of a pilot plant process by the Kaiser Pilot probe
Bioreactor processing is analysed for control using the Kaiser Bio-Pro

Linking laboratory and process line with optimised Raman solutions. By Lisa Ganster

Industrial process development begins in the laboratory and ends in the manufacturing plant. Process development is iterative, complex and can take a long time if not properly controlled. There are numerous challenges as the process is scaled up from the laboratory to the pilot plant to manufacturing. A significant challenge is to understand the physical and chemical properties of the process at each scale. Once a process is understood it can become optimised, effectively scaled and properly controlled. There are multiple steps involved in understanding a process including: analysing the process, understanding critical process parameters (CPPs) and what chemical or physical factors affect them, and controlling those process dependent factors.

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

* 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.(1)

Examples of Kaiser Optical Systems’ customers’ processes benefitting from Raman spectroscopy include:

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

* Pharmaceutical API: reaction chemistry, yield, polymorph form identification, crystallisation

* Polymer: polymerisation blending, extrusion monitoring, crystallinity, density, copolymers

* Biologics/bioprocessing/biopharmaceutical/biotech: cell culture, fermentation

Two customer examples illustrate the advantages of Raman spectroscopy in pharmaceutical bioprocessing and polystyrene polymerisation processes.

Pharmaceutical bioprocessing

Recent successes of biopharmaceuticals and bioprocessing have driven the development of novel therapeutics in the pharmaceutical industry. Recent FDA process analytical technologies (PAT) and quality by design (QbD) initiatives support bioprocessing and emphasise the importance of real-time analysis in the bio/pharmaceutical industry. Real-time analysis of complex bioprocesses must consider many interrelated parameters, all of which need to be optimised. Raman spectroscopy of bioprocesses provides chemically specific data, exhibits excellent model transferability and can be performed continuously and directly in the reaction vessel or consumable. Traditional bioprocess analytics provide general reaction parameters such as temperature, agitation rate, pH and dissolved oxygen levels. Raman can monitor general reaction parameters and data on specific CPPs such as nutrients, metabolite waste production, total cell count and viable cell count.

In one representative study, Berry et al.(2) used Raman spectroscopy to analyse a Chinese hamster ovary (CHO) bioprocess at the laboratory (3 L), pilot (200 L), and manufacturing (2000 L) scales. Raman data from the laboratory, pilot and manufacturing scale were used to develop partial least squares (PLS) prediction models for predicting manufacturing batch output. They demonstrate simultaneous measurement of important CPPs at all three scales. PLS predictions of CPPs correlated closely to externally measured values at all three scales.

Polystyrene polymerisation

Polymerisation processes involve monitoring hierarchical phenomena ranging in scale from molecules to reactors. Molecular and rheological properties can significantly affect monomer consumption and bulk polymerisation. As a polymerisation reaction proceeds it is useful to have information from all scales, including the molecular characteristics of the growing macromolecules, the shapes and sizes of colloidal particles, and bulk rheological properties. Method transferability is another important aspect in developing analytical methods for these types of polymerisation reactions in order to ensure that the analytical data can scale with the reaction. Additional considerations are the ability to obtain in-process data without the need to remove samples from the reactor or consumable, and if the spectra provide enough data to ensure a robust analytical method.

Raman spectroscopy addresses all of these concerns. Brun et al.(3) investigated bulk, emulsion and mini-emulsion polystyrene polymerisation processes and found that rich process information could be generated in all processes. In addition, Raman coupled with rheometry enabled simultaneous real-time monitoring of monomer consumption and reaction medium viscosity, which are important parameters in understanding scale up and gel effect.


Raman is a proven technique in the world of process development. Kaiser is at the forefront with its phase-optimised Raman solutions, implementable across all scales, with demonstrated transferability.

For more information, visit

Lisa Ganster is with Kaiser Optical Systems.

References: (1.) Lewis, I. R. & Edwards, H. G. M. Handbook of Raman Spectroscopy: From the Research Laboratory to the Process Line. (CRC Press, 2001); (2.) Berry, B., Moretto, J., Matthews, T., Smelko, J. & Wiltberger, K. Cross-scale predictive modeling of CHO cell culture growth and metabolites using Raman spectroscopy and multivariate analysis. Biotechnol. Prog. 31, 566–577 (2015); (3.) Brun, N. et al. In situ monitoring of styrene polymerization using Raman spectroscopy. Multi-scale approach of homogeneous and heterogeneous polymerization processes. J. Raman Spectrosc. 44, 909–915 (2013).




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