Heat stabilization of therapeutic proteins in biomanufacturing and storage.

Therapeutic preparations of blood clotting factors are absolutely essential for haemophiliac patients. Although haemophilia is a relatively rare, sex linked disorder affecting males, it occurs in all races and ethnic groups. It is a major world health issue and it has a huge economic impact as well as health and welfare impact on the lives of sufferers and their families. The safety of the clotting factors has been improved considerably in the last two decades by introduction of so-called recombinant laboratory-produced factors that replaced the previously used materials derived from blood extracts. This reduced markedly the risk of infection by virally contaminated preparations. However, there is no doubt that there is still a great need to improve the performance of the blood clotting factors; in particular, there is an urgent requirement to improve their stability, and to reduce the cost of their production. Blood clotting factors are complex proteins that are inherently very unstable. Consequently, these therapeutically important proteins must be produced in a dried or lyophilized form and stored refrigerated. The instability has a marked effect on the cost of their production and also limits their subsequent storage and use to applications where refrigeration is available. Insense Ltd has developed a novel method to stabilize proteins in aqueous (water-based) solutions, and demonstrated this technology with remarkable results using a wide range of commercially relevant proteins which would otherwise deteriorate readily at room temperature in aqueous solution. The stabilization is achieved using unique principles that in many ways contradict the conventional teaching regarding protein formulation. It has been shown repeatedly by Insense Ltd that such unconventional formulations result in markedly improved protein shelf life. Formulations of clotting factors with markedly improved storage stability would be a major innovation arising from this project. The overall aims of this project, which is a collaboration between Insense Ltd, the University of Kent, and the National Institute for Biological Standards and Control (NIBSC), are two-fold. Firstly, the Insense Ltd protein stabilization technology will be applied to a range of commercially available blood clotting factors to improve storage stability, and to identify the most effective formulations. The stabilizing formulations developed in the first part of the project will be incorporated into the recombinant protein production process - using mammalian cells grown in the laboratory - that will be developed at the University of Kent. This in-process stabilization approach is thought to be unique, and if proved to be effective it would clearly have potential to transform the way biopharmaceutical production is conducted, leading directly to innovative process design for the clotting factors. The key advantage of such novel process design will be in minimizing the time between protein production and its transfer into the stabilizing medium. In the case of very unstable proteins, such as clotting factors, this delay, even if relatively short, will result in protein breakdown, and will therefore have a considerable effect on production quality, yield and efficiency. Importantly, the knowledge and expertise accumulated within this project will be directly applicable to other kinds of unstable proteins, and could significantly reduce their production costs, with an associated reduction in expense incurred by the National Health Service.