Abstract
Chemotherapy has grown, from chemotherapeutic agents discovered in the 1940s still used today, such as vincristine, to antibody therapies developed in the 1990s such as trastuzumab. Antibody drug conjugates (ADCs) are a class of drug that have been theorized about since the turn of the 20th century, they are a potent cytotoxic drug and an antibody combined. Trastuzumab emtansine, licensed in 2013, has broken headlines, as it outperforms current gold standard therapies, but costs £90K per patient a year.Stability studies performed on aseptically prepared biopharmaceuticals, conforming to the requirements set out in the NHS’s ‘A Standard Protocol for Deriving and Assessment of Stability. Part 2’ allow the shelf life of products prepared under a Section 10 exemption or a Specials License to be extended beyond their summary of products characteristics shelf life (typically 24-48 hours). Shelf life extensions have many benefits e.g. reducing logistics issues for product storage and transportation, a safety net of time in case a product cannot be administered, batch production minimising drug wastage, which allows prices of medicines to be reduced.
The work herein details research dedicated to enabling a stability study to be performed on the ADC, trastuzumab emtansine. We identified and validated many techniques for characterisation of the biopharmaceutical infliximab and published an NHS compliant stability study. A 7-day shelf life can be applied to infliximab by all UK hospitals. These techniques were then evaluated by their ability to characterise trastuzumab emtansine and if they remained stability indicating, a minimum requirement for a stability study.
Where necessary, methods were optimised or developed anew, to enable full characterisation of the ADC trastuzumab emtansine. This involved validation of a new chromatography method, the design, construction and validation of an infrared spectroscopy method, and creative thinking to overcome low sensitivity of intact LC-MS. This allowed a stability study to be performed and a shelf life extension for trastuzumab emtansine was achieved. Furthermore, some preliminary work regarding ADC in use safety and the applicability of the developed methods regarding differently designed ADCs, such as brentuximab vedotin was carried out.
| Date of Award | 19 Jun 2019 |
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| Original language | English |
| Awarding Institution |
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| Sponsors | Qualasept Ltd |
| Supervisor | Andrew Watts (Supervisor), Randy Mrsny (Supervisor) & Malcolm L Watson (Supervisor) |