Worsham, Robert D; (2024) Continuous Manufacturing of Liposomal Drug Products. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Over the last several years, continuous manufacturing of pharmaceuticals has evolved from bulk APIs and solid oral dosages into the more complex realm of biologics. The development of continuous downstream processing techniques has allowed biologics manufacturing to realize the benefits that come with continuous processing (e.g. improved economics, more consistent quality). If relevant processing techniques and principles are selected, the opportunity arises to develop continuous manufacturing designs for additional pharmaceutical products including liposomal drug product formulations. Liposome manufacturing has some inherent aspects that make it favorable for a continuous process. Other aspects such as formulation refinement, materials of construction, and aseptic processing need development, but present an achievable challenge. This thesis aims to explore the feasibility, challenges and economic benefits of continuous manufacturing of liposomal drug products. Liposomal drug product manufacturing has evolved into a commercial scale batch process. A commercial liposomal drug product batch process for a formulation delivering amikacin through a nebulized inhalation suspension (Arikayce®) was assessed for specific considerations and requirements in order to convert the design to a continuous process. Continuous process options for specific unit operations (liposome generation, diafiltration) were evaluated with detailed characterisation of the impact of key process parameters on the performance. The most significant of these was the impact of retentate ethanol concentration on hollow fiber permeability and overall diafiltration efficiency. Retentate ethanol concentration directly impacted the morphology of the hollow fiber filters, decreasing their permeability and permeate flux. The findings determined that dilution of the retentate offset the impact to hollow fiber permeability allowing for a continuous diafiltration design with minimal stages (5% retentate ethanol concentration requiring 7 ILDF stages) and buffer consumption that is competitive with the batch process. These experimental findings fed into an economic assessment of the continuous process as compared to the batch showing the continuous option to be advantageous in drivers such as cost of goods when demand surpasses a certain threshold (<5M annual doses/vials). A convertible process is proposed to leverage both batch and continuous economic and capacity advantages as a function of demand. The work in the thesis demonstrates that using a continuous process for the manufacture of liposomal drug products is feasible, can be significantly optimized, and has benefits that allow the design to compete with or surpass a batch process design.

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