Spectroscopy integration to miniature bioreactors and large scale production bioreactors-Increasing current capabilities and model transfer.

Spectroscopy techniques are being implemented within the biopharmaceutical industry due to their non-destructive ability to measure multiple analytes simultaneously, however, minimal work has been applied focussing on their application at small scale. Miniature bioreactor systems are being applied across the industry for cell line development as they offer a high-throughput solution for screening and process optimization. The application of small volume, high-throughput, automated analyses to miniature bioreactors has the potential to significantly augment the type and quality of data from these systems and enhance alignment with large-scale bioreactors. Here, we present an evaluation of 1. a prototype that fully integrates spectroscopy to a miniature bioreactor system (ambr®15, Sartorius Stedim Biotech) enabling automated Raman spectra acquisition, 2. In 50 L single-use bioreactor bag (SUB) prototype with an integrated spectral window. OPLS models were developed demonstrating good accuracy for multiple analytes at both scales. Furthermore, the 50 L SUB prototype enabled on-line monitoring without the need for sterilization of the probe prior to use and minimal light interference was observed. We also demonstrate the ability to build robust models due to induced changes that are hard and costly to perform at large scale and the potential of transferring these models across the scales. The implementation of this technology enables integration of spectroscopy at the small scale for better process understanding and generation of robust models over a large design space while facilitating model transfer throughout the scales enabling continuity throughout process development and utilization and transfer of ever-increasing data generation from development to manufacturing.

ambr® 15 Microbioreactors for CHO Cell Cultivation.

The ambr 15 has become the industry's standard automated microbioreactor system for mammalian cell culture. It has applications throughout the industry, most commonly for cell line screening and media/feed development. On each ambr 15 workstation, conditions in up to 48 × 15 mL bioreactors can be individually controlled while a liquid handler enables automated addition and removal of liquids during the process. Integrated cell counting, metabolite analysis and pH offset correction are also possible thereby reducing the operator interactions that are required. Extensive user and software manuals are supplied by the manufacturer, but in this chapter we describe additional ways of working that we have implemented in routine cell line screening using the ambr 15.

Microbioreactors and scale-down models: growth of CHO cells using the Pall Micro24 MicroReactor system.

Microbioreactors are increasingly used within animal cell biotechnology to grow mammalian cells for cell line screening and to facilitate process development. Many such devices have been reported in the literature, but only a small number are available commercially. Microbioreactors range in complexity from simple plate-based systems to complex automated parallel bioreactors designed to enable the meaningful scale-down of conventional bioprocesses. The Micro24 MicroReactor system (Pall Life Sciences) fits between these extremes providing 24× 7 mL parallel "bioreactors" with individual monitoring and control of temperature, pH, and dissolved oxygen. Inoculation, sampling, and feed additions are carried out manually in a Biological Safety Cabinet. In this chapter we describe the use of the Micro24 system to carry out screening or process development experiments with CHO cells.