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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

Periodic Reporting for period 2 - BIOSIM (Accelerating the commercialisation of a disruptive analytical technology which enables thebiopharmaceutical industry to manufacture drugs faster, cheaper and with greater regulatoryconfidence)

Reporting period: 2018-08-01 to 2019-05-31

A new generation of biological medicines holds the promise for breakthrough treatments for cancer, cardiovascular & rare diseases for which treatment currently does not exist. The high cost of these new drugs has presented major challenges for European governments who wish to support innovation in European biopharmaceutical industry but are working within limited healthcare budgets. This has resulted in many patients in Europe having no access to these new drugs while patients in other countries enjoy the benefits.

A major contributor to the high cost is the complexity of manufacturing these large molecule drugs which are produced using bioengineered cells and the high costs associated with poor cell selection in determining which cell to use in the manufacturing process. Valitacell can rebalance the cost benefit equation for these drugs by reducing the cost of manufacturing these drugs and reducing the time to get them to market. As companies bring drugs to market faster they reduce their development and manufacturing cost and also increase their time on the market without competition. (One month early on the market can be worth $250m in sales for a top 20 biologic drug with some drugs achieving $14bn in annual sales based on IMS data). Improved manufacturing process also enables more biosimilar drugs to be brought to market at lower costs.

In addition, preferential roll out of Valitacell technology in Europe will enable the European pharmaceutical sector, which currently employs over 725,000 people (EFPIA Facts and Figures 2017), to become more competitive in producing these new drugs and therefore gain an advantage in the international market and preventing loss of market share and jobs to lower cost manufacturing countries. This will contribute to the European economy by keeping biopharmaceutical manufacturing in Europe and so contributing to local European economies.
The project sought to validate the use of ChemStress technology as an analytical tool in selecting the host cell to be used in the manufacturing of biologic drugs. This was successfully achieved in the BIOSIM project following validation at seven industry sites with all Deliverables successfully completed.

The manufacturing of the ChemStress plates was outsourced following EU procurement guidelines. Detailed Final Plate Specification (D2.1) was achieved and plates were produced achieving the targeted manufacturing cost (D2.2). These plates were then used in a series on industry validation studies (D3.1). The industry partners who participated in the project include; GSK Stevenage UK, Fujifilm Diosynth Billingham UK, GE Healthcare Upsalla SWEDEN, Alexion Pharma NewHaven USA, Canadian National Research Council Montreal CANADA, Allergan Pharma Liverpool UK, Pfizer Penzberg GERMANY, Danish Technological University Copenhagen DENMARK.

Based on the experience of working with industry staff a End User Working Protocol (Instruction For Use) was developed (D4.1). It also became clear that there was no necessity to develop an Enterprise version of the ValitaApp (D4.2) software as the standalone software used in the product was deemed adequate and better suited to local industry security requirements. Analysis and sharing of the results (D6.1) led to a number of changes in the preparation for the first ChemStress product launch. These included; modification of original shipping guidelines to require product to be shipped and stored at temperature between 2-8C following the Validation, Stability and Shipping testing (D5.1) product will not carry a CE Mark as it is Research Use Only (RUO) and therefore does not fall within CE applicability (D5.2). In place of a CE Mark a Product Quality File has been developed and submitted as a deliverable.

The original expectation of the BIOSIM project was that the ability of ChemStress technology to assess cell stability would be demonstrated by correlating ChemStress results against the existing measures used to determine stability. The results of the project proved that this was not possible as stability is currently determined based on simple product titre (amount of drug produced) not falling off by more than a fixed percentage. What ChemStress showed was that many cells that would be determined to be stable under current approach (product produced did not fall significantly) displayed exaggerated responses in terms of either growth or productivity. Large increases in productivity compensated for large fall off in growth and vice versa. These cells were not in fact stable and should not be brought further in development as they are more likely to fail in full scale up.

The results formed the basis of two Peer Review publications (D6.2) 14 oral presentations and 11 poster presentations at industry conferences. In addition results have been communicated in a Webinar (with industry partner) and on company website.
"The current methods by which biopharmaceutical companies select cells on which to manufacture biologic drugs take significant time and often lead to projects which fail at a late stage due to cell instability. The current methods to select for cell instability is based on culturing cells out for many generations (up to 160 days) and measuring at certain time points whether there is any drop off in the amount of drug produced by the cell. Feedback from biopharmaceutical companies suggests that the current method of selection is resulting in significant number of cells being falsely classified as ""stable"" as when they reach the bioreactor they no longer behave in a predictable fashion.

Results from the Demonstration Projects show that ChemStress can profile the functional response of cells to the chemical stressors revealing changes in underlying metabolic pathways. We have observed cells in which growth has fallen significantly but in which product production has significantly increased at an individual cell level to such an extent that the overall level of product produced does not fall. These cells are determined as being STABLE using current methods despite their exaggerated behaviour. Industry partners have indicated that they would not wish to take such cells any further in the development process and believe that this insight helps explains some unexplained manufacturing failures. Thus ChemStress technology allows the identification of ""false stable"" cells which are more likely to be prone to failure when brought forward to the full manufacturing process.

The outcome is that not only can stability be determined at an earlier stage, but that it can also be determined more accurately removing the number of late stage failures.

The impact of this discovery is that the time and cost of bringing these high tech drugs to market will fall, allowing the drugs to be brought to market quicker and at a lower price. This will facilitate more patients accessing more of these breakthrough drugs earlier."
Generated ChemStress Fingerprint
ChemStress Workflow
ChemStress Fingerprint
ChemStress Technology Platform
Chemicals in ChemStress
Comparison of traditional and biologic drugs
ChemStress plate