Bioprocessing, as in the manufacturing of chemical substances using living cells or enzymes as highly efficient catalysts, has long become mainstream in pharmaceutical production. On an industrial scale, this energy-efficient and environmentally friendly approach is now employed in the production of pharmaceuticals, foods, flavours, cosmetics, fuels, and specialty chemicals in a bioreactor. Downstream processing involves the removal of impurities, bulk-volume reduction, and concentration of the product from the bioreactor. Upstream processing relates to the growth of a host organism to produce a bioproduct. New bioprocessing technologies emerge based on the cultivation of mammalian, insect, yeast, bacterial and even plant cells. The gradually commercialised biofuels, biobased chemicals and polymers have the potential to become true game changers in the “Green industrial revolution”.
With bioprocessing in single-use bioreactors (S.U.B.) and, downstream processing relying increasingly more on single-use components, smartly tuned sensor devices are critical not only for cost-effective operation, but for ensuring fail-safe, contamination-free production. And, it is precisely in bioprocessing that environmental and biological sensors help enable this new bio functionality.
In-vitro cell growing
In recent years high effort was put on growing meat not from livestock but from single (stem) cells of animals. This branch of cellular agriculture will revolutionize the food industry making meat production less resource intensive and more animal friendly. The in vitro cell growth process will help to make the human food supply more sustainable by providing an alternative to mass animal stock farming.
The production technology for cell-cultured meat sets high demands on process control for cell growth in proliferation as well as in differentiation stages. Mainly myosatellites are cultured, stem cells, which are responsible for muscle regeneration after an injury. For cell differentiation and growth, tight glucose monitoring leads to higher yield and faster production cycles. Monitoring of the crucial metabolic factor lactate brings additional benefits, especially during the exponential growth phase. With expensive growth factors and hormones being the foundation for the cultivation process routes, re-use and multiparametric monitoring of glucose, lactate and amino acids like glutamine is needed.
Biosensors for glucose monitoring
IST AG’s biosensor portfolio can be used in single small-scale bioreactors, making use of its unique, continuous monitoring capability for glucose, lactate as well as glutamine and glutamate. The small size and low cost of our B.LV5 sensor and SIX transmitter enable parallel monitoring of multiple cultures without having to purchase highly expensive desktop devices. With our measurement system, continuous media surveillance and feedback-controlled bioreactors contribute to fast development cycles in cellular agriculture. The recording of multi-parametric data with high temporal resolution gives valuable insights for the optimization of cell grown meat for researchers as well as production.
Instant metabolic monitoring
For improved quality and productivity in manufacturing, the industry is moving toward increasing use of bioreactor systems with real-time integrated monitoring and advanced analytics that can enable automation, drive performance, and improve data-rich quality control. Multiple options emerge for sensors and technologies that monitor important cell-culture variables or critical process parameters.
Whether in cGMP production or during process characterisation in the laboratory, real-time evaluation of nutrient and metabolite contents in the cultivation medium present invaluable information on the process status. This is because they can be directly correlated to the metabolic activity of the cells and indirectly to the production of the manufactured biomolecules. Instant metabolic monitoring can facilitate process fingerprinting or act as a basis for real-time feedback control.
Monitoring of glucose, lactate, glutamine, glutamate concentrations
IST AG biosensors enable continuous analysis of the glucose and lactate, as well as glutamate and glutamine concentrations. Integrated into at-line process analysers with automated sampling, a microfluidic biosensor array can operate with no sample preparation and within seconds extract valuable process data from microliters of the cultivation media.
Suitable for easy sample delivery, automatic calibration systems, the compact peristaltic micropumps complement the metabolite biosensors, and together with a ready-to-use OEM transmitter, form the building blocks for an adaptive measuring system.
Recent years have seen huge progress in cell-based therapeutics, including cartilage repair products; tissue-engineered skin; organ printing; and personalized, cellular immunotherapy for cancer. Still, the commercial cultivation of patient-specific, autologous stem cells has proven a challenging technological undertaking also due to high process variability. Instead of experimental process characterisation and careful up-scaling, de-risking continuous process control has been identified as a prerequisite for the adoption and commercialization of cell therapy production.
In-line or at-line measurement
In-process measurements and control of living cell-based pharmaceuticals present several unique challenges, notably cell monitoring and control, sampling, and dosing. Parallel cultivation in multiple small-volume cell bioreactors require a high level of automation, starting with bioreactor set-up, gas exchange for aeration, and pH control to de-stress feeding strategies based on continuous metabolic monitoring.
Novel, innovative biosensors from IST AG that measure concentrations of Glucose, Lactate, Glutamine and Glutamate (in-line or at-line) and peristaltic actuators from Jobst Technologies suitable for liquids (incl. cell culture) or gas up to 2 bar using continuous, remote monitoring, with low drift & and minimal biofouling risk, are now employed to bring cell therapies to commercial success.
Downstream processing is employed for the control of process- and product-related impurities in biomanufacturing to effectively separate and purify biomolecules analytics for measuring process-related impurities such as host cell proteins and nucleic acids are pushing the limits of the current measurement technology. Modern automation strategies targeting optimalisation for processing & manipulation time, energy consumption and purification level rely heavily on reliable in-line monitoring.
Accurate monitoring and measurement of product-related impurities, including higher molecular weight and lower molecular weight species is critical for product safety, Quality processes demand critical process steps such as virus inactivation.
Compact conductivity, temperature, and flow sensors from IST AG with custom packaging and assembly solutions, are used for process control measurements, and are easily integrated in-site with minimal dead volume. Suitable for single-use systems and compatible with variable sterilisation and clean-in-place (CIP) procedures. Biocompatible materials and compatibility with most common CIP & sterilisation procedures simplify initial qualification.