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Accelerating the commercialisation of a disruptive analytical technology which enables the biopharmaceutical industry to manufacture drugs faster, cheaper and with greater regulatory confidence

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Cell function profiling to assess clone stability in drug bioreactors

Biopharmaceutical companies need to speed up the development and manufacture of novel, complex and difficult to produce medicines to meet healthcare demands. The ChemStress® cell function profiling array directly measures multiple bioprocess-relevant cell functions in one simple, rapid assay.

Industrial Technologies
Health

Biological drugs hold great promise for breakthrough treatments for cancer, cardiovascular and rare diseases. Central to the production of these drugs is selecting the host cell that will produce the therapeutic molecule in sufficient quantity and quality. Engineered cells however display genetic variability which may lead to unpredictable behaviour including loss of productivity. It is therefore critical to identify and understand the mechanisms that drive bioprocess performance. At the same time, the high production cost of these new drugs poses a significant challenge for countries with limited healthcare budgets.

An innovative technology for assessing cellular stress

The EU-funded BIOSIM project developed a platform technology that offers rapid profiling of cell-based manufacturing systems. The ChemStress Fingerprinting technology was developed by the Irish SME Valitacell. “In order to have a better, more controllable manufacturing system – particularly for more complex molecules, it is critical that we identify and understand the changes to the cellular machinery driving bioprocess performance – ChemStress has been developed to provide that deep, functional, cellular analysis,″ explains project coordinator and Valitacell CEO, Jerry Clifford. ChemStress® is a 96-well plate containing multiple chemicals selected for their ability to challenge key cellular pathways driving production or to emulate major bioprocess stresses. Static cell culture on ChemStress® plates for three days allows time for the chemicals to challenge the cells. Cellular responses to these challenges are assayed for end-user specific outputs such as viable cell density. Taken together, the output responses to the different chemicals constitute characteristic fingerprints of deep cell function.

ChemStress performance and future directions

BIOSIM has collaborated with four companies to validate the ChemStress technology results against cell performance observed using traditional methods. Results suggest that traditional methods which focus upon high-level attributes can mask profound underlying cellular changes thus leading to unstable clones mistakenly being chosen for production. ChemStress® profiling was used to assess cell function similarity and rank cell clones based on function stability. Top-ranked clones had the most consistent cell function fingerprints providing a novel, orthogonal stability metric that looks deeper into cell function than titre alone. This approach offers a rational basis for removing unstable clones early in trials to reduce the cell culture burden. “BIOSIM funding has been paramount for Valitacell to engage in the global biopharma market,″ emphasises Clifford. Through an early adopter programme, the company has started selling the product until it has a number of specific end users and application notes for full launch. ChemStress constitutes a rapid assay for assessing cell fitness for bioprocessing by exploiting the cell’s response to a stressful environment. Additional ChemStress® applications within the area of biologics manufacturing include cell culture media and cell line quality control, functional assessment of cell engineering as well as cell culture media design. Given the strict regulatory requirements of drug discovery and cell line development, Clifford is confident that “bringing ChemStress to the market will facilitate the detailed functional profiling of cell engineering.″

Keywords

BIOSIM, stress, ChemStress, cell line, assay

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