Adaptive bioprocess control

23rd January 2018

The Stratophase Ranger sensor in situ
Stratophase offers Ranger as part of a rapid process development service to accelerate upstream process development
The process protocol uses a number of bioreactor runs with up to four cultures running in parallel
Fig 1. Process Trend Index (PTI) and Metabolic Rate Index (MRI) profiles for cell culture process pre and post temperature optimisation. Table shows performance characteristics for both cultures demonstrating improved metabolic activity and performance associated with process optimisation

The escalating cost of new biologics, particularly advanced therapies, has resulted in treatments that are unaffordable for many potential patients. Ultimately, this could limit the market size for such products or limit their commercial viability.

To reduce the cost of manufacturing biologics, the biopharma industry is adopting a flexible approach to process development and manufacturing platform design. Where possible, it is also seeking to integrate continuous upstream and downstream processes.

To meet both these objectives there is an increasing demand for bioprocesses, such as cell culture, to be better automated and to employ approaches such as quality-by-control. In the extreme, advanced therapies such as autologous CAR-T therapies may require complete enclosure, integration and automation of processing steps in a highly scalable, distributable and de-skilled manufacturing platform suitable for manufacturing patient-specific therapies at or near the clinic.

One area set to revolutionise bioprocessing is the use of adaptive process control: to optimise conditions during process development and to maintain process performance and quality during manufacturing. In the case of cell culturing, adaptive control is realised by implementing techniques to rapidly determine the process performance and/or product quality combined with providing the bioreactor system with the freedom and intelligence to change the culture conditions as required to maintain performance and quality.

One proven technology is Stratophase’s Ranger, which enables real-time process optimisation by continually scanning process parameters and dynamically controlling nutrient feed addition rates from single or multiple nutrient sources.

Adaptive control technology

The product’s ability to adaptively control a cell culture stems from the use of a real-time measure for metabolic activity, which is indicative of a process’s performance. The metabolic activity of a cell culture, and more importantly, changes in the metabolic activity of a culture, are derived from changes in the relative refractive index of the culture medium via an in-situ probe. Any changes to the medium composition due to cellular activity are observed as changes in the relative refractive index. The rate at which the refractive index changes during a cell culture process, therefore infers the rate at which cellular activity is occurring, thereby rapidly determining the metabolic activity of a cell culture.

Using a real-time indicator for process performance allows Ranger to implement a probing control strategy, in which a non-specific and holistic measure for process performance enables specific control by observing the effect on performance that results from specific changes to the process conditions. By using probing control Ranger is able to dynamically control the feed addition rate by observing changes to the metabolic activity that occur directly following finite feed additions and the subsequent onset of ‘low’ nutrient conditions and to screen process parameters such as temperature, pH and dissolved oxygen to determine optimum setpoints. In both cases, the system identifies optimum cell culture conditions while the cell culture is running, either as part of a semi-automatic process optimisation protocol or as fully automated adaptive process control.

Stratophase offers Ranger as part of a rapid process development service to accelerate upstream process development. A combination of the firm’s contract process development expertise and the rapid process optimisation allows considerable reductions in the timelines and risk associated with producing robust and high-performance cell culture processes.

Case study:  use of metabolic activity during cell culture temperature optimisation

The nature of the changes in metabolic activity that occur during dynamic feeding control and during real-time process parameter screening, have been shown to enable significant improvements in a cell cultures performance. Typically, the Ranger process development protocol uses a number of bioreactor runs with up to four cultures running in parallel. During the protocol, the process is initially screened using a range of set-points for the key parameters (e.g. temperature, pH, dissolved oxygen, etc.) allowing the parameter-space to be coarsely mapped. Subsequent runs are then used to fine-tune the key parameters if necessary and to optimise feeding strategy. Finally, a set of cultures is run to verify the relative performance benefits associated with the optimised and adaptively controlled process.

Fig. 1 shows an example of a typical CHO cell culture used to demonstrate the benefits of optimising temperature. Both cultures were run with the same cell line and with automatic dynamic feeding control using the same single complete medium feed, such that nutrient conditions are optimised within the limitation of the fixed composition of the feed. The Process Trend Index (PTI) and Metabolic Rate Index (MRI) are shown for both for the pre-optimisation culture and the post-optimisation culture.

As is typical for cell cultures, the PTI and MRI profiles generated are not consistent throughout the process due to the various phases that a fed-batch culture undergoes. Cell culture processes can generate MRI profiles that are either positive or negative, depending upon whether metabolite/product accumulation or nutrient consumption is dominating the relative refractive index signal. However, in both cases, the absolute MRI is representative of the metabolic activity of the process at that moment in time. In this case, the growth-phase shows a broadly negative MRI and the production-phase a positive MRI. Comparing the pre-optimisation and post-optimisation cell cultures it is clear that optimising the temperature has improved the metabolic activity during the growth-phase resulting in higher peak Viable Cell Counts (VCC) and improved the metabolic activity during the production-phase resulting in higher product titre.

The ability to rapidly identify the processing conditions required for a robust and high-performance cell culture, via the Ranger contract services, enables process development activities to be significantly streamlined and throughput increased.

Adaptive process control techniques, such as that enabled by the Ranger technology, promise a game-changing approach to process development by offering a rapid, flexible processing platform, and a route to a flexible manufacturing platform and a quality-by-control approach for GMP. In the case of advanced therapies, there is the potential to blur the lines between process development and manufacturing by offering self-optimising intelligent processes that can tailor themselves to an individual patient’s therapy.

As biologics become more diverse and the timelines between discovery and commercialisation are required to become shorter, cost-effective adaptive process control is expected to have much to offer.

Sam Watts is co-founder of






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