MEDPROT- Development of new production technologies for biopharmaceuticals

The project focus has been to develop new competence and better production methods with the aim of developing commercial manufacturing of biologics (medical drug produced by a living organism) in Norway. Now, at the end of the project, a commercial production line for a new biologics is very close to be finalized and an application for medical treatment will during 2022 be finalized and submitted for regulatory approval. The work to establish this has been much more extensive than anticipated when the project started and has resulted in large organisation changes to Diatec with about a threefold increase in the number of employees. The process validation is now being completed which consisted of four full scale process runs according to a predefined control strategy. This concludes the major goal of the project, demonstrating that we have been able to establish a highly optimized production method with our fibre based bioreactor systems using hybridoma producer cells. Much work in the project has also included optimizing CHO cells productivity which was performed at SINTEF, UiO and at Diatec. Modified CHO cells are commonly used in biologics production lines and the cell line investigated are intended for manufacturing of a next generation cancer therapeutic product. At SINTEF, feeding components in microscale to improve CHO cells productivity, was tested, as well as evaluating the effect of a temperature shift and cell seeding densities. An in silico metabolic model was also established, and cell antibody and process data from experiments were integrated and the model was used to optimize the process. Furthermore, a new IgG analytical method based on polarization was recently established for rapid quantification which facilitates the screening work to optimize productivity. Cell seeding density and temperature shift was also demonstrated in scaled-up cultures in a bioreactor for the selected IgG-producing CHO cell line. As a result of the work it has now been demonstrated that the optimal process in terms of media, feeds, feeding strategy and temperature may give a good product yield of > 1g/L, 10x the yield expected from the starting point in MEDPROT. The bioreactor process was described in detail in regard to central metabolites, amino acids and all continuous measured process parameters. At Diatec the good result from testing at SINTEF was followed up through implementation in a larger scale using a newly developed bioreactor system and the testing is currently ongoing. A goal for the MEDPROT project was also to establish new production technologies enabling competitive process development and manufacturing for radiopharmaceuticals. IFE`s focus was on developing a prototype automated production unit by integrating commercially available components for radiopharmaceutical production in a proposed modular design. Activities and geometries that were most likely to be handled in radiopharmaceutical production line were used. This included 3D modelling of existing possible components of the production line, development of specialized features (functionalities) for the simulation platform e.g. simulation of the (or possible alternative) robotic equipment and 3D design of required new/specialized components. Based on the 3D simulation platform, alternative production lines and thus feasibility evaluation and comparison of these alternatives were also assessed, including process flow analysis using the 3D platform and evaluation of alternative robot arms and production unit designs (component configurations). Using the design obtained from the activities above a prototype was developed, focusing on the development of a simple and one more complex gripping system for handling of glass vials, on an interface between robot/ dispensing modules / dose calibrator / other visualized equipment (autoclave) and testing of sensor systems for autonomous robot operation, and also a system for data recording. A short literature evaluation of radiation hardening for the robotic equipment and other sensitive electronics was conducted. Dose estimation to humans based on human operator using fully interactive, input error checking deterministic radiation transport models such as MicroShield and VRDose tool kit were performed. For the visual inspection process both semi-automated and automated inspection methods, based on the optical characteristics of filled units, were considered. Development / implementation / testing of camera/sensor systems for automatic visual inspection was a joint effort between SINTEF and IFE DS. IFE selected to investigate how AI can be used to help the operators with visual product inspection. However, to conclude on this, further tests would be required. All in all the project has been successful and gives a foundation for new business opportunities and further commercial growth.

MEDPROT prosjektet har fungert som et springbrett til å kunne utvikle kommersiell biofarmasøytisk produksjon i Norge (produksjon av legemidler basert på dyrkning av levende celler). FoU resultatene har lagt grunnlag for at det nå kan sendes inn søknad om kommersiell fremstilling av et nytt biologisk legemiddel. Det er også oppnådd gode resultater og ny kunnskap i forhold til å optimalisere produksjonsevnen til celler (CHO) som kan benyttes i fremtidig produksjoner. Utvikling av robotteknologi til produsere radioaktive legemidler har også gitt gode resultater og gir grunnlag for kommersiell bruk i fremtiden. Generelt har kompetansehevningen og utvikling av infrastruktur i regi av prosjektet gitt oss et nytt ståsted for å kunne utvikle og realisere produksjon av nye biologiske legemidler i fremtiden.

Biotherapeutics make up a class of drugs including proteins and peptides, which are generally produced in living organisms and used for treatment of a wide variety of diseases including cancer, diabetes, and rheumatoid arthritis. These products also provide genuinely new strategies against infectious agents and orphan diseases alike. Despite the wide and highly increasing use of biotherapeutics and their commercial and economic value there is currently no established commercial manufacturing of biotherapeutics in Norway. Biotherapeutics may be further processed to radiopharmaceuticals consisting of radiolabeled conjugates used for diagnostic or treatment purposes. The overall goal for this R&D-project is to establish new production technologies enabling competitive process development and manufacturing for protein based pharmaceuticals, including radiopharmaceuticals. As a necessary approach the aim of this R&D-project will be to develop improved bioreactor upstream processes, improved analytical methods for better product characterization and new production process automatization including use of robotics during radioisotope handling. Furthermore, the project will include set-up of new test facilities based on method transfer and development for both new GMP upstream and downstream processes. The project will be a collaboration between different scientific and technical partners with expertise within cell cultivation, bioanalytical methods, biopharmaceutics process manufacturing (upstream and downstream), process sensor technologies, manufacturing of radiopharmaceuticals, automatization and robotics. The current project aims to be an initiator for the Norwegian pharmaceutical industry through stimulating and enabling the building of new competitive biopharmaceutical business on a large scale within a highly promising area.