Q&A WITH SPEAKERS - THE BIOPROCESSING SUMMIT
An exclusive interview with Ramil F. Latypov, the keynote speaker at the 3rd Annual High-Concentration Protein Formulations conference
In a preview of his upcoming keynote, Ramil F. Latypov, Ph.D., Principal Scientist, Process & Product Development, Amgen, Inc., recently spoke with Cambridge Healthtech Institute's Nandini Kashyap about the major challenges in development of high concentration protein formulations, and where the field is headed. All will be covered in his upcoming keynote address, "Liquid-Liquid Phase Separation as a Quantitative Colloidal Stability Assay for Monoclonal Antibodies."
What are the major challenges in development of high concentration protein formulations?
Viscosity and aggregation are the main challenges in high concentration protein formulation development. Although both are the result of inter-protein interaction, they differ greatly in the strength of such interaction. Viscosity is governed by relatively weak and transient interactions, which may or may not result in formation of specific complexes or associates. In contrast, aggregation is specifically defined as formation of protein complexes that are discrete and relatively more stable. At high protein concentrations the probability of protein-protein interaction increases because of proximity of protein molecules and can manifest itself as changes in viscosity or aggregation.
How is the better understanding of aggregation mechanisms being applied to help resolve the challenges posed by viscosity and aggregation?
Detailed understanding of aggregation mechanisms allows a more targeted implementation of protein engineering and formulation approaches. For example, identification of aggregation-prone regions can drive mutational efforts to improve protein stability and solubility. In the case of a well-defined and highly localized aggregation-prone region it is also possible to apply computational tools for selecting stabilizing excipients in silico.
Where do you think this field is headed?
The field is headed towards applying QbD principles into molecule engineering and selection with the goal of designing the most efficacious yet stable and soluble molecules. Such molecules pose less difficulty in manufacturing and can be presented in the most attractive way from commercialization and marketing perspectives. Ease of manufacturing is needed to reduce the COGs, while a more convenient dosage form may improve patient compliance and increase competitiveness. Molecule engineering and selection rely on the development of predictive experimental and computation approaches for drug design and formulation. Availability of such tools determines how attainable QbD can be.
You will be delivering a keynote presentation on Liquid-Liquid Phase Separation as a Quantitative Colloidal Stability Assay. What can audience expect from it?
The audience will be presented with a quantitative way of measuring protein stickiness using PEG-induced liquid-liquid phase separation. Colloidal stability of antibody solutions is an important consideration in formulation development which reflects the propensity of such solutions to form aggregates. In order to avoid aggregation problems, it is desirable to have an early stage solubility screening method to eliminate molecules or formulations that may present challenges in development. However, due to the diversity of antibody molecules and the various forms of aggregation, standard solubility tests are not yet available in the biopharmaceutical industry. Our method calculates a binding energy in the precipitate which is a measure of attractive interactions between antibody molecules and can be used for quantitative characterization of the colloidal stability of antibody solutions. The method requires only microgram protein quantities and can be readily applied to high-throughput screening.
Are there any particular speakers or talks that you are looking forward to at the conference?
I'm looking forward to all of the presentations from industry and academia. The technical and scientific issues with viscosity and aggregation that we're facing are very complex. It is therefore important that groups from industry and academia work in the most connected way.
By bringing industry and academia together, the High-Concentration Protein Formulations conference sessions foster information exchange that benefits the field.
Ramil F. Latypov, Ph.D., Principal Scientist, Process & Product Development, Amgen, Inc.
I received my Ph.D. in Biophysics from the Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences. Subsequently, I spent three years as a post-doc in the group of Heinrich Roder at the Fox Chase Cancer Center in Philadelphia (USA). There I studied structural, thermodynamic and kinetic aspects of protein folding and denaturation. After completing post-doctoral training, I joined Amgen in 2003 as a protein formulation scientist. I am an expert in biophysical analysis of biomolecules and in the formulation of protein therapeutics. I made contributions to the understanding of aggregation and liquid-liquid phase separation of immunoglobulins and developed assays to measure aggregation propensity of multiple different Ab samples subjected to the same stress. I have worked on a variety of drug development projects including single domain proteins, peptibodies, Fc-fusion proteins, as well as monoclonal antibodies. Currently, I am contributing to the development of engineering and formulation technologies for poorly behaving therapeutic candidates.