Flow-Based Tools for Assessment of Aggregation Propensity of Protein Based Pharmaceutical Products
Lead Research Organisation:
University of Leeds
Department Name: Mechanical Engineering
Abstract
This project addresses the important issue of how proteins behave under flow. The proteins under consideration within this project are bio-pharmaceuticals - these are proteins that have medicinal value and are a growing class of medicines used to treat patients. The protein molecules are manufactured biologically - e.g. from cells - and have to go through a complex series of steps before being formulated into the final medicine. Each of these steps, e.g. filtration to remove virus particles, is carried out under flow, and this project is to assess how flow affects the stability of the protein molecule. Stability is important as forces exerted on the protein can cause it to clump together or aggregate and lose its medicinal function. These aggregated proteins can also induce an immunogenic response - ie triggering an immune response to the aggregate within the human body. By better understanding the role of flow on protein stability allows more robust medicines to be designed and therefore make therapies available to patients in a shorter timeframe.
The aim of this project is to develop understanding of how flow and protein stability are linked. This will be carried out using tools drawn from across engineering and biology. A series of flow paths that exert force on the protein molecules will be designed using computational fluid dynamics simulations. This allows a full description of the conditions that the protein experiences under flow to be established - for example the force exerted by the flow on the protein. These flow-paths will be manufactured before being used to stress the protein through a series of experiments. A range of protein systems will be studied including those provided by our industrial partners (MedImmune) which will include Immunoglobulin Gs since this is a common protein on which biopharmaceuticals are based. By carrying out the research in this way allows the flow conditions to be linked with the ultimate aggregation propensity of the protein. This, together with details of the protein structure, then starts to allow a link to be made between the fundamental design of the protein and its stability under flow. The outcome of this work allows a deeper understanding of the science of aggregation, as well as providing tools that can be used during the development of protein based medicines.
The work fits directly into the remit of Industrial Biotechnology within the BBSRC portfolio "the synthesis and manufacture of advanced biological products for the pharmaceutical industry, such as biologics (e.g. proteins or other high molecular weight chemicals)".
The work is carried out through a multi-disciplinary team drawn from Engineering (Kapur) and the Astbury Centre (Radford, Brockwell, Ashcroft) at the University of Leeds, and is in partnership with MedImmune, a leading global biologics company. By working with MedImmune ensures the research is relevant to the industry it supports.
The aim of this project is to develop understanding of how flow and protein stability are linked. This will be carried out using tools drawn from across engineering and biology. A series of flow paths that exert force on the protein molecules will be designed using computational fluid dynamics simulations. This allows a full description of the conditions that the protein experiences under flow to be established - for example the force exerted by the flow on the protein. These flow-paths will be manufactured before being used to stress the protein through a series of experiments. A range of protein systems will be studied including those provided by our industrial partners (MedImmune) which will include Immunoglobulin Gs since this is a common protein on which biopharmaceuticals are based. By carrying out the research in this way allows the flow conditions to be linked with the ultimate aggregation propensity of the protein. This, together with details of the protein structure, then starts to allow a link to be made between the fundamental design of the protein and its stability under flow. The outcome of this work allows a deeper understanding of the science of aggregation, as well as providing tools that can be used during the development of protein based medicines.
The work fits directly into the remit of Industrial Biotechnology within the BBSRC portfolio "the synthesis and manufacture of advanced biological products for the pharmaceutical industry, such as biologics (e.g. proteins or other high molecular weight chemicals)".
The work is carried out through a multi-disciplinary team drawn from Engineering (Kapur) and the Astbury Centre (Radford, Brockwell, Ashcroft) at the University of Leeds, and is in partnership with MedImmune, a leading global biologics company. By working with MedImmune ensures the research is relevant to the industry it supports.
| Description | Throughout the complex manufacturing process of biopharmaceuticals, molecules are exposed to forces under flow conditions in combination with the surface interaction through the whole process. Surfaces including bioreactors, filters, syringes, vials etc interact with the molecules thought the manufacture, fill-finish and administration of the final product. A key outcome of the project was that the surface affects significantly into how the molecules behave under these flow conditions and highly influence their propensity to aggregate. |
| Exploitation Route | The identification of surfaces that protect molecules from aggregating is highly applicable in practical perspective. Equipment surfaces, filters, syringes, vials can be treated with the surfaces that are found to be protective in avoiding impacting the biological value of the molecule before reaching to patients. |
| Sectors | Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Description | Surfactant study |
| Organisation | AstraZeneca |
| Department | Research and Development AstraZeneca |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Our previously developed extensional flow device is used to characterise the response of a range of surfactant molecules exposed to extensional flow fields found in the biologics production line. The effect of surfactant is also investigated using analytical methods to determine the best surfactant candidate that could be suitable as a formulation additive. |
| Collaborator Contribution | The collaboration is based on the sharing of model proteins and a range of surfactant molecules (shared by the collaborators) that are used for the conduction of the current study. |
| Impact | This collaboration highlights the importance of interfaces in which biomolecules interact through their manufacture. The combination of interfaces and formulation additives is also commonly found throughout the whole manufacturing process indicating the synergy between interfaces and formulation additives in the protection of the misfolding events of biopharmaceuticals. Some of the interfaces in combination with the formulation additives are found to be important in protecting the structure of these biomolecules. |
| Start Year | 2020 |