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Raman Spectroscopy: A Process Analytical Technology (PAT) Tool?

It’s been thirteen years since FDA published its Guidance for Industry PAT — A Framework for Innovative Pharmaceutical Development, Manufacturing, and Quality Assurance. The goal, however, is to identify process analytical technologies that will improve process control. Most would agree that PAT implementation has been slow in the biopharma industry despite pressures to lower costs, improve quality, and move toward continuous processes.

Applying new tools for Process Analytical Technology (PAT) that cross the space between industrial and biopharma were presented at the October 28 – November 1, 2017, RAFT (Recent Advances in Fermentation Technology) conference.

At the conference, a number of companies gave presentations and posters on how they were using the Raman Technology in their organizations in the process development and manufacturing space. These projects involved in situ, real-time monitoring of microbial and mammalian cell processes.

As we know, processes involving microbial and mammalian cells are complex solutions/suspensions, containing living organisms and sparged gases. Due to this complexity, Raman spectroscopy instruments require the use of “training sets” to define what constitutes “normal” process conditions during manufacturing.

 

  • What is Raman Spectroscopy?

Raman spectroscopy uses visible, near infrared, or near ultraviolet monochromatic laser light to cause molecular vibrational excitation in the system and then measures the wavelength shift of the scattered photons.  This shift in photon energy provides structural identification of specific molecules of interest. Raman spectroscopy is used for process control in the manufacture of small molecule pharmaceuticals where the process streams are “cleaner.”

 

  • What are some applications being explored using Raman Spectroscopy?

GSK reported using Raman spectroscopy to monitor mature and platform processes, where “normal” is well understood. Preliminary characterization of this platform was performed by measuring multiple bioprocess metabolites and changes in key nutrients in situ using real-time Raman spectroscopy.   They also did early characterization of processes that produced the molecule of interest in Pichia pastoris and looked at changes in key nutrients using Raman spectroscopy in-situ.

Lonza Biologics reported on using multivariate software paired with in-line Raman to establish a predictive model for critical process parameters. They developed a generic model within their GS -CHO platform to monitor critical process parameters and also confirmed the model with a third-party GS-CHO cell line. Whether the approach works for a non-GS-CHO cell line was not discussed. If the answer is YES, then Raman and the software would be of additional interest to the community as it would increase the portability of the technology.

The quest for predictive inline tools to monitor and finally control processes in new ways allows engineers and scientist to know more, earlier whether it is in development or manufacturing. Raman is an example of a tool that is being explored in both the microbial and mammalian communities and not just for biopharma but also in the industrial fermentation space, for example, BASF reported developing small-scale models for Pichia. The industrial cell culture market is regulated differently than the biopharma cell culture market, so they are often able to implement and optimize new tools and software faster due to differences in regulatory and often cycle times and number of batches of product x or y.

Will Raman be fully implemented to deliver on PAT initiatives or will another technology? Only time will tell…

Blog article by: Tiffany D. Rau

The following presentations by my colleagues address other issues related to continuous processing where PAT and measurement instrumentation will be critical.

Opportunities for Continuous Manufacturing in Biopharmaceutical Production

Perspectives on Continuous Processing