Current PAT and QbD initiatives are driving the need for a more comprehensive understanding of cell culture processes. The objective of these initiatives is to ensure product quality and performance through the design of effective and efficient manufacturing processes. This can be achieved with a detailed understanding of how various process factors and their interactions affect the product.
The challenge for bioprocess development lies in the limited experimental capacity provided by traditional scale-down models. Simpler models such as shake flasks and well plates do not provide the measurements and controls required to accurately predict the full-scale manufacturing process. As a result, these platforms offer limited applicability for exploring the knowledge space and identifying critical process parameters.
Bench-scale bioreactors are the tried and true scale-down model but have economic and throughput limitations. Characterization of the design space is often left to the final stages of process development, after clone and media selection have already occurred. Therefore, the best clone at manufacturing scale may have been prematurely eliminated, and critical interactions between factors may still be unknown due to limited experimental designs.
In order to fully recognize the benefits of PAT and QbD, a higher throughput scale-down model is required. Such a scale-down model should have measurement and control capabilities similar to bench-scale and larger bioreactors in order to accurately predict performance in the manufacturing process. Seahorse Bioscience has developed the SimCell platform, which is capable of performing hundreds of bioreactor-relevant fed-batch experiments with measurement and control of temperature, pH, dissolved oxygen (DO), and glucose.
The core technology of the SimCell platform is the Bioreactor Card. Each card contains six microbioreactors, each with a working volume of approximately 700 microliters. Each microbioreactor contains immobilized sensors for the noninvasive measurement of pH and DO. Total cell density is measured via forward light scattering.
Bioreactor Cards are constructed of gas-permeable membranes for the exchange of culture gasses (e.g., O2 and CO2) with the incubator environment. Cards are manipulated by a robotic system for automatic inoculation, incubation, mixing, sampling, feeding, and process monitoring and control. Comprehensive software tools enable multifactor experimental designs to be implemented across hundreds of microbioreactors with real-time data tracking. On-line and off-line data sets can be combined for each microbioreactor and analyzed to identify significant trends.