Optimising the formulation and processing of freeze dried biopharmaceuticals

Freeze drying, also commonly known as lyophilisation, is a widely used manufacturing method used in the final stages of production of many biopharmaceuticals, especially those whose solution stability is poor. It is a physical drying process in which an aqueous based solution containing the active protein (as well as other stabilisers) is frozen, and then the frozen water is sublimed and desorbed away from the solution under vacuum, leaving a glassy solid cake of the active product behind. Biopharmaceutical solutions themselves can have short shelf lives, primarily due to protein degradation in solution, whereas freeze dried formulations can provide improved stability and long term storage life. Despite the importance of this area, there is a dearth of academic research and expertise in the UK on freeze drying, especially of biopharmaceuticals. It is also commonly accepted that freeze drying is non-optimised, with consequently poor product control and thus a limited understanding of how to optimise both product and process with regard to product quality and economic and energy-efficient processing. These problems result in a significant environmental and cost burden, including increased times of product to market. In this study the effects of various aspects of formulation and the freeze-drying process on biopharmaceutical materials in terms of their structure, function, activity, and other aspects of product quality, including the level of residual water and its distribution within the freeze-dried material, will be investigated. While a number of publications exist that describe studies carried out by a number of workers in the field, such publications have tended to limit themselves to describing individual studies on single products, or single-variable studies for a small number of 'model' products - often with the risk of over-extrapolating the significance and meaning of the data produced. Other studies have concentrated on the mathematical modelling of issues such as heat and mass transfer during the freeze-drying process - usually for ice alone, or a single model solution - which may bear no relation to what would happen for a real product being processed. The opportunity here is to undertake a multi-variable, multi-product study in the field of lyophilisation therefore exists, to help bridge the knowledge gap that currently persists, which is relevant to the biopharmaceutical, vaccine, bio-products and diagnostics industries. Specifically in this project, the relationship between a number of key input and output variables needs to be identified and understood for real products. Input variables would typically comprise: formulation excipients, total solute concentration, pH, solution-state stability, container design and dimensions, fill depth, cooling rate, initial freezing temperature, presence or absence of an annealing step, primary drying (sublimation) temperature and pressure. Output variables currently studied include: product appearance (including surface anomalies and visible heterogeneity), residual water content, activity/potency, molecular integrity, surface area, porosity, crystal/polymorphic form of active ingredient and/or excipients, thermal properties (such as glass transition temperature, crystallisation events, relaxation), stability, degradation product levels, process economics and scale-up issues. Additionally, there are a number of in-process variables that would be studied (eg local temperatures, vial concentrations, rates of water loss from vials etc) in order to further the understanding of the product during the freezing, sublimation and desorption processes as well as examining the final lyophilised product. In conclusion it is expected that this project will inform on the rational and optimised design of industrial biopharmaceuticals which use freeze drying manufacturing operations.