By Agnes Shanley
The International Forum for Process Analytical Technology (IFPAC) is often seen more as a networking event for those working on PAT and QbD, rather than a groundbreaking conference displaying radical innovations. Last month, IFPAC 2011 in Baltimore brought some of the same old presentations, but also a few surprises, including an emphasis on biopharmaceutical PAT and more practical case studies showing what is, rather than what may, be done with PAT and QbD.
Coincidentally, the week after IFPAC, FDA published its new guidance on process validation, which may spur increased use of process monitoring and control. Clearly, the technologies available to help manufacturers do this are smaller, simpler and less expensive than ever.
Evolution rather than revolution was the theme on the show floor this year, notes Pedro Hernandez, PAT consultant who led PAT and QbD teams at Wyeth and Pfizer. “It was good to see a number of more mature Light Induced Fluoresence (LIF) instruments this year,” he said.
I recall first hearing about LIF around 2003, in a presentation byMIT professor G.K. Raju summarizing research done at MIT. Recently, formulation specialist, Das Debanjan recently reviewed the technology as one solution to powder blend monitoring.
LIF is a sensitive technique, Hernandez says. If there is no interference from analytes, he says, it allows for monitoring and control without the need for the chemometric models that NIR requires.
A number of companies already offer LIF , and there have been some recent product introductions in this area. Natoli Engineering, for instance, now offers an LIF sensor to help users monitor the tableting process. At IFPAC, Expo’s LIF platform for PAT was exhibited and discussed in some technical presentations, while Custom Sensors and Technology is also supplying LIF sensors.
What consultant John Coates, summarized recently as “game-changing spectral sensors” were also on display. The “next wave” in process monitoring and analytics was also seen in a few exhibits, notably Stratophase’s SpectroSens sensor, a commercial spinoff of work done at the University of Southampton’s ORC (Optoelectronics Research Centre). Stratophase uses a UV laser to write integrated optical circuits directly on glass substrates. The process is said to be much less expensive than traditional photolithography.
Based on a Bragg grating design, the sensor measures the change in the refractive index of a process liquid as it passes across the surface of the optical chip, Its developers say it offers a precision better than one part in one million. It can reportedly detect chemicals, but, when pretreated with antibodies, it can also detect viruses, proteins and biologics.
From Ireland, we saw Innopharma Labs’ PAT monitoring systems designed for blending, granulation, roller compaction and milling and compression. Heading the new Dublin-based company is Ian Jones, who once worked for Wyeth, before the Wy- Pfi merger.
Driving the company’s technology base, developed in conjuction with VTT of Finland, using VTT’s piezoelectronics and NIR knowho had developed for other industries and an alternative calibration system first discussed by Ralf Marbach, is an imaging system that utilizes new piezoelectronics, in the form of Fabry Perot interferometers, LEDs, cameras and algorithms that allow the three-dimensional visualization of particles, and particle-size distribution, in real time.
The eyecon system, based on technology first developed for pulp and paper manufacturing, uses a camera and LED light to image particles, while eyemap uses NIR to image the API ingredient in tablets after compression.
Biopharm had a much more prominent role in this year’s program, according to consultant Gary Ritchie, who saw two key trends:
- Existing measurement technologies such as Raman and Mid-IR spectroscopy are being used in whole new ways, while advanced bioanalyzers are being introduced to detect contaminants and monitor nutrients and products.
- Control systems, including predictive types, are being introduced to biopharma, including control systems designed to maintain a steady state (for attributes like glycosylation), but then allow correction to be applied at the frequency that the attribute can be monitored (around 12 hours in the case of glycosylation
The Plenary Session focusing on biotechnology, Use of Analytics with QbD, was well attended and received, Ritchie said. Dr. Mary Cromwell of Genentech gave a very broad overview of the particular issues and advances in analytical chemistry/biochemistry that she is dealing with at Genentech, representing what biotech as a whole is dealing with in trying to apply PAT and QbD principles to manufacture their products.
For instance, in order to close the process control loop, Cromwell said, analysis times had to be shortened, Ritchie reported. To accomplish this, her team is working with a newer type of bioanalyzer combining UV, fluorescence and capillary electrophoresis. So far, this analyzer has reduced analysis time from 10 samples in 10 hours to the same number in 10 minutes.
Genentech can now take measurements in or at line, allowing for real-time or near real-time analysis and control. The company is using this bioanalyzer to eliminate product loss by closer monitoring and controlling the critical cell harvesting step. During harvesting, lysing enzymes can destroy product, by cleaving to protein disulfide bonds. By monitoring lytic enzymes, and taking action to eliminate them from the product rich broth, Genentech is using process control and optimization to stop product loss.
Dr. Seongkyu Yoon (Univ. of Massachusetts, Lowell), in his talk, “Characterization of Critical Raw Material Impact on Mammalian Cell-culture Performance and Product Quality Attributes,” pointed out several factors that biopharmaceutical manufacturers are facing, Ritchie reported, due to lot-to-lot variations of critical raw material, lack of appropriate measurements of intermediate process parameters, and even inappropriate analytical test methods of final product quality attributes.
Dr. Yoon gave examples on how to characterize raw material variations and its impact in a cell culture process by using advanced analytical instruments (NIR/Raman spectroscopy) with a multivariate modeling framework.
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