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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - CELLUP (Innovative in-line Raman analytical sensor for new upstream cell culture monitoring and qualitycontrol)

Teaser

Summary

CellUp business innovation project had the global objective to fix well-known key issues for the biopharmaceutical industry: costly batch failures, long lead times and associated costs for the development of complex processes and transfer to production, need for increasing productivity and capacity and too long batch release.
Currently, conventional methods are lacking: Upstream cell cultures growing in bioreactors are generally controlled in real-time only with measurements of a few process parameters, particularly temperature, pH, and DO. Current feeding strategies (nutrient supply) in mammalian cell cultures are commonly based on manual sampling once or twice per day. Downstream processes are controlled by multiple, complex, and long-lead off-line methods.
This way of proceeding, based on these conventional methods only, suffers from key disadvantages:
- Inaccurate (neither real-time nor in-situ) sampling and manual feeding introduces risk of contamination
- Routine use of off-line analytical instruments is expensive (e.g. consumables, personnel) and generally leads to long lead times, especially in DSP
- Weakness of batch monitoring makes comparison, improvement, process control, process transfer, and investigations difficult due to poor data record.
These disadvantages relate to major issues of the biopharmaceutical industry to offer reliable medicines at acceptable price whereas they mainly concern serious diseases. Improving the analytical control and automation of bioprocesses from cell cultures to formulation on the entire product cycle will have a very significant impact on this issue. This is why the major national drug agencies, such as EMA and FDA, are actively promoting the Process Analytical Technology initiative, in which CellUp intends to provide a major output.
The main objective of the CellUp business innovation project was to develop and commercialize this new disruptive in-line analytical solution for bioprocesses that the biopharmaceutical industry needs for quality and process control during the phases of process development, scale-up and manufacturing of vaccines, antibodies and cell therapies for human medicines.
This in-line analytical solution, called ProCellicsâ„¢, is based on Raman spectroscopy. In terms of technological development, the above global objective of CellUp was achieved thanks to the development of a GMP (Good Manufacturing Practice) integrated hardware suite and of a GxP compliant software enabling to implement an easy, efficient and robust methodology for multivariate calibration. These capabilities were missing in the other Raman existing systems, creating a serious brake for its use in process development and for automation and preventing to be realistically used in production.
The assessment, dissemination and enrollment of the industry with CellUp ProCellicsâ„¢ solution was another major successful activity of the CellUp project, with various experiments in our Upstream application lab and adoption by the development teams of major biopharmaceutical companies.

Work performed

During the CellUp project, a complete flexible hardware suite of analyzers for process development and production, oriented toward Quality Control or pure automation, has been developed and evaluated. In particular, a multi-channel unit (MCU) can be released as an add-on to fast by 4 times the generation of calibration data and to monitor up to 4 setups at the same time. A ProCellicsâ„¢2 unit using breakthrough technologies has been developed in order to propose a very compact analyzer mainly dedicated to cell culture process automation.
About 20 cell cultures batches have been performed in our application lab. They have generated a large amount of data with different user cases which have been used to develop and assess the new method of calibration and the new hardware. The CellUp project has also been the opportunity to conduct experiments with 14 different partners for upstream or downstream applications. Thanks to these experiments, we have produced with our partners top-notch results such as first monitoring of specific downstream processes, very stable closed loop nutrient feeding or early contamination detection, to name but a few.
An extended data analysis work based on the data generated in our application lab has conducted to progressively confirm an optimal and realistic method for multivariate calibration in the context of industrial usage. We have elaborated a whole methodology covering the case of new processes up to model maintenance: on the hardware side, the development of the Multi-Channel Unit was a key and proven element of this methodology. On the software side, this new method of calibration has been implemented in ProCellicsâ„¢ Software 3.0, including a Chemometric Module, with other improvements and new features to achieve the compliance with CFR 21 part 11 (data integrity).
Partnerships with biopharmaceutical companies or labs, such as the MIT, have been set up in order to provide a wide stream of feedback to better implement bioprocess Raman monitoring. The non-confidential outputs of CellUp project have been regularly presented at conferences, workshops or in articles in professional reviews.
As an overview of CellUp project results, we can list the following main major contributions to bioprocessing:
- A compact and GMP ProCellicsâ„¢ analyzer hardware suite including a Multi-Channel Unit and an ultra-compact, affordable version of the analyzer, dedicated to automation of nutrients feeding
- Demonstrated methodology to very efficiently manage multivariate calibration necessary to generate models which translate Raman spectra into set of quantified parameters: parallel batch management, calibration transfer from one analyzer to another and robust maintenance, fast model building based on a Local Model Selection in a Generic Dataset
- A ProCellicsâ„¢ Software suite, implementing this methodology and compliant with CFR 21 part 11
- An extensive range of results performed in Upstream and Downstream, internally and by numerous blue-chip users
- A corpus of user documentation and publications to assess ProCellicsâ„¢ CellUp solution and provide information for its implementation, reflecting a deep knowledge of bioprocessing challenges.

Final results

Following the CellUp project, ProCellicsâ„¢ bioprocess in-line and real-time analyzer is a very mature solution and a step forward in terms of integration and easiness to use with regards to other existing solutions. ProCellicsâ„¢ advantages are the following:
- In-situ non-destructive sampling
- Real-time/fast multi-parameter control
- Compact GMP hardware
- Multivariate analysis in one, integrated and GMP solution
This is a unique GMP ready PAT tool for bioprocessing, which has been adopted by blue-chip customers during the CellUp project and which is already implemented in processes currently transferred to production.
Thanks to the CellUp project, RESOLUTION Spectra Systems is now a market-leader and premium developer of a scalable platform for bioprocessing analytical instrumentation, coming with a deep understanding of bioprocessing and competencies in automation â€“ highly differentiated products and capabilities years ahead of competitorsâ€™ solutions.