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24 | SEPTEMBER 1, 2016 | GENengnews.com | Genetic Engineering & Biotechnology News See Sensor Awareness on page 26 "PAT methods may form part of a QbD approach to the development of bioprocess control strategies," says Nick Hutchinson, Ph.D., technical content manager for biopro- cess solutions at Sartorius Stedim Biotech. Moreover, the adoption of disposable processing tech- nologies by contractors and innovator firms spurred develop- ment of sensors in single-use formats. "Initially this presented something of a challenge," Dr. Hutchinson continues. "How- ever, novel single-use sensors are becoming increasingly avail- able for both upstream and downstream applications." For example, the integration of in-line biomass sensors into single-use bioreactors leads to enhanced monitoring and control strategies while in-line disposable UV sensors can monitor protein concentration to support control of down- stream ultrafiltration steps. "By linking process measurements to advanced automa- tion strategies," explains Dr. Hutchinson, "we can not only increase consistency and process robustness, but also ensure we control processes within design spaces that deliver prod- uct with the required quality attributes." Scientists at Amgen have recently shown how the col- lection of chromatography pools based on purity measure- ments via online HPLC helps prevent lot rejection. Similarly, monitoring of nutrients and metabolites in cell cultures al- lows for the fully automated control of glucose feeds in real time by connecting the analysis system to local automation such as programmable logic control (PLC) and supervisory control and data acquisition (SCADA) systems. "Integrating sensors with automation platforms to ensure process consistency will greatly expedite the adoption of con- tinuous processing by the biopharmaceutical industry," Dr. Hutchinson predicts. "The drive to accomplish this is likely to herald a new wave of innovation in sensor technology." More sensors equals greater complexity and, inevitably, more information streaming from processes to analysis and control systems. Multivariate data analysis techniques help make sense of bioprocess data generated across scales, and converts that information into process knowledge and under- standing. Bioprocess engineers must be able to retrieve data reliably from both miniaturized experiments (for example, from the Sartorius ambr ® systems and others) that today's developers use to define design space and to predict perfor- mance of process runs at intermediate to commercial scales. "This is a significant 'big data' challenge," notes Dr. Hutchinson. "Currently, it is being addressed by the industry through knowledge management tools." Biomass Monitoring at Scale At-scale operation, however, has been an issue. Capacitive biomass sensors from Aber Instruments have been adopted by GlaxoSmithKline, Xpand Biotechnology, and Aachen University, but as reported by Aber's marketing director John Carvell, Ph.D., these installations were at sub-25 L scale. Sensors that reliably operate across scales, including "de- sign of experiment" (DOE) volumes of parallel micro- and mini-bioreactors, will become increasingly relevant. For ex- ample, Aquila Biolabs' Cell Growth Quantifier for microbial fermentations measures biomass in specially designed shake flasks. The system uses an optical sensor that reads cell density through the bottom of the flask. Conventional biomass mea- surements employ lengthy manual sampling and photometric optical density measurements. Even simpler is a handheld biomass sensor from BugLab, which according to company literature measures cell density in six seconds at up to 30 optical density units. For cell culture biomass determinations, options include the Countstar system from Aber (and sold by Applikon Bio- technology). The company has published data showing a greater than 99% correlation between Countstar measure- ments and conventional determinations of CHO biomass through hemocytometry. Countstar is also available for mi- crobial cultures. Other companies, including Hamilton (through its ac- quisition of Fogale Nanotech), provides sensors suitable for measuring viability of small-scale cell cultures used in bio- medical research. Online Sensing and the Bottom Line The integration and application of sensing technologies is becoming critical to bioprocessors. "Companies are driven by QbD," says Ken Clapp, senior manager for applications, inte- gration, and technology, GE Healthcare Life Sciences. "As a consequence, they apply sensors to help achieve that quality, lower costs, and improve their bottom lines and the availability of drugs." Ultimately, it matters little whether a clean-in-place or plastic platform is used. "The need," Clapp insists, "is the See the Bioprocess, Be the Bioprocess Angelo DePalma, Ph.D. In 2004, the U.S. Food and Drug Administration issued an official guidance on process analytic technology (PAT), to encourage its voluntary adoption as a means of achieving quality by design (QbD). In theory, PAT and related instrumentation facilitate the design and development of well-understood and -controlled manufacturing processes resulting in predefined product quality. BIOPROCESSING Single-use sensors are built into disposable process containers, which together are gamma-irradiated and delivered to the customer as a sterile system. Challenges for single-use sensors include reliability, standardization, and consistency. According to Thermo Fisher Scientific, a producer of single-use sensors, research into quality gaps could help to deliver an ideal product to the market.