Day 1 | Day 2
13:00 Dessert Break in the Exhibit Hall with Poster Viewing
13:30 Chairperson's Opening Remarks
Paul Dalby, MA, Ph.D., FRSC, AMIChemE, Deputy Head of Department (Research),
Biochemical Engineering, University College London
13:35 Microscopic Mechanisms Underlying the Effect of Surfaces and Mechanical Agitation on Protein Aggregation
Paolo Arosio, Ph.D., Professor, Institute of Chemical and Bioengineering, ETH Zurich
Despite the fact that empirical effects of surfaces and mechanical forces on protein aggregation are well documented, the molecular details of the mechanisms underlying this behaviour are still largely elusive. In this work, we design an experimental assay based on nanoparticles to investigate independently the effect of surfaces and mechanical forces on the formation of amyloid fibrils from human insulin, and we apply a chemical kinetic platform to analyse the molecular mechanisms at the origin of this effect.
14:05 Review on Silicone as Source for Subvisible/Visible Particles and Potential Protein Aggregation Promoter
Karoline Bechtold-Peters, Ph.D., Senior Strategy & Technology Leader, Pharmaceutics, Biologics Technical Development & Manufacturing, Novartis
While silicone is toxicologically safe, the use of silicone as a lubricant in packaging materials for injection purposes is associated with the increase of subvisible as well as visible particles and is also described as a source of protein aggregation for biologics. The talk will discuss various published studies and describe analytical methods to characterize silicone layers, which can be used within the context of a control strategy.
14:35 Presentation to be Announced
15:05 Refreshment Break in the Exhibit Hall with Poster Viewing
15:50 KEYNOTE PRESENTATION: Regulatory Perspective in New Analytical Methods for Protein Aggregates Quantification and Characterization
Ewa Marszal, Ph.D., CMC Reviewer, Plasma Derivatives Branch, Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, US FDA
16:20 A Semi-Quantitative Method for Visible Particles in Biotechnological Solutions - Why Do We Care?
Patricia Winter Cash, Ph.D., Independent Consultant
Presence of particulates is a common reason for Product Recalls. Formation of protein particles is recognized as an inherent quality attribute. All proteins contain particles. There is an industry-wide need for particle standards so biopharmaceutical manufacturers can monitor and control the presence of particles in their protein products. This talk will explain the need for particle standards, describe one method for estimating particles and introduce new particle standards in development.
16:50 End of Day
17:00 Dinner Short Course Registration
17:30-20:30 Recommended Dinner Short Course*
*Separate registration required
Day 1 | Day 2
08:00 Registration and Morning Coffee
08:30 Chairperson's Remarks
Vasco Filipe, Ph.D., Unit Head, Formulation Development of Biopharmaceuticals,
08:35 KEYNOTE PRESENTATION: Approaches to Predict Protein-Protein Interactions, and Their Impact on Product Properties
Christopher J. Roberts, Ph.D., Professor, Chemical & Biomolecular Engineering, University of Delaware
There is increasing interest in the development of experimental approaches and computational models to predict product properties such as high solution viscosity, solubility limits, and aggregation rates from low- to high-concentration conditions. This presentation focuses on a combination of experimental and modeling approaches to predict protein-protein interactions and their impact on stability and viscosity for monoclonal antibody products, illustrating both successes and outstanding challenges.
09:05 Combining Stability and Surface Aggregation Predictions to Design Protein Solubility
Salvador Ventura, Ph.D., Chair, Professor of Biochemistry & Molecular Biology, Institute of Biotechnology and Biomedicine, Universitat Autonoma de Barcelona
Mutations that increase protein stability usually result in reduced aggregation-propensity. The same effect can be attained with amino acid changes that increase the solubility of structural surfaces. Very often these changes result in decreased protein stability or even a gain in protein aggregation-propensity. AGGRESCAN3D is a software that is able to forecast simultaneously these two effects and to select protein variants with higher probabilities to be evolved into soluble drugs.
09:35 A New Strategy to Assess Ligand or Solution-Based Stability of Aggregation-Prone Proteins Using an Automated Chaperonin Biolayer Interferometry Platform
Mark T. Fisher, Ph.D., Professor, University of Kansas Medical Center
Stabilizing the folded state of metastable and/or aggregation-prone proteins through ligand binding is an appealing strategy to decrease disease pathologies brought on by deleterious protein folding defects. This presentation describes an automated GroEL chaperonin-based biolayer interferometry (BLI) denaturant-pulse platform for assessing the kinetic stability of aggregation prone proteins and allows us to validate the effects of ligand stabilization or destabilization of these kinetically unstable proteins.
10:05 Coffee Break with Poster Viewing
10:35 Aggregation of Monoclonal Antibodies: Causes, Bioavailability and Immunogenicity
Vasco Filiipe, Ph.D., Unit Head, Formulation Development of Biopharmaceuticals, Sanofi
The mechanisms and factors influencing protein aggregation will be reviewed. Some examples and interesting cases from Sanofi and literature will be shown. A review of the current knowledge and ongoing initiatives on aggregate-induced immunogenicity will be presented.
11:05 Probing Protein Aggregation and Immunogenicity by Epitope Profiling
Tim Eyes, Ph.D., Research Associate, Immunology and Biotechnology, University of Manchester
Aggregation is thought to be a significant risk factor in promoting the unwanted immunogenicity of therapeutic protein products. Our work has examined the relationship between oxidation, aggregation and the influence of heat shock proteins, as prominent HCPs, on the quality and vigor of the immune response to selected model biotherapeutic proteins. More recently we have demonstrated how B-cell epitope profiling can shed light on how antibodies specifically target protein aggregates.
11:35 Mechanisms Behind Immunogenicity Risk due to Aggregates and Impurities during Biologics Development
Vibha Jawa, Ph.D., Director, Biologics & Vaccines Bioanalytics, Merck & Co., Inc.
Human immune system is not exposed to aggregated proteins endogenously. There is an uncertainty around potential risk of aggregates associated with biologics in clinic as there are confounding factors like dose, frequency, route that can also contribute to risk. To address this uncertainty, it is important to identify attributes that can cause a clinically relevant response, establish the threshold of activation of such a response that will support establishing ranges and understand the extent and nature of the response and how close it is to physiological relevance.
12:05 Combining an Analytical Toolbox with in vitro Assays to Assess Immunogenicity of Aggregated Nivolumab & Trastuzumab
Sofie Pattijn, CTO, ImmunXperts
Aggregated therapeutic protein species can induce immunogenicity in patients. Nivolumab (OPDIVO®) and Trastuzumab (Herceptin®) aggregates were extensively characterized with an analytical toolbox and triggered PBMCs to produce specific cytokines, altered the maturation of dendritic cells and enhanced IL-8 production in whole blood. The screening approach presented here could contribute to improved product design and manufacturing processes during drug development in order to reduce the potential safety and efficacy issues related to aggregates.
12:35 Problem-Solving Breakout Discussions with a Light Snack in the Foyer*
*See website for more details
13:35 Session Break
14:00 Chairperson's Remarks
Christopher J. Roberts, Ph.D., Professor, Chemical & Biomolecular Engineering, University of Delaware
14:05 Impact of Protein Mutational Variability upon Formulation Designs
Paul Dalby, MA, Ph.D., FRSC, AMIChemE, Deputy Head of Department (Research), Biochemical Engineering, University College London
Protein stability is a critical factor for the successful development of non-aggregating biopharmaceuticals. Routes to predictably engineer protein stability are therefore crucial. We have used a wide range of biophysical analyses to characterise the aggregation landscape of proteins, and used this understanding to inform both better formulation design strategies, and improved protein engineering strategies. The relationships between the conformational stabilities imparted by protein engineering and formulation excipients will be discussed.
14:35 Tackling "Tornado-Like" Particle Formation Issues with an IgG1 Molecule by Formulation Optimisation
Peng Ke, Ph.D., Scientist I, Formulation Sciences, MedImmune, a member of the AstraZeneca Group
During formulation development of an IgG1 molecule, "tornado-like" particles were observed in the solutions after storage for a certain period of time. The onset of particle formation was variable and difficult to predict using common analytical techniques. Therefore, significant formulation development challenges were presented and in order to solve the particle issues, systematic investigational works and formulation optimisation were conducted.
15:05 The Role of Poloxamer 188 in Protecting Protein Formulations
Christoph Grapentin, Ph.D., Postdoctoral Fellow, Pharmaceutical Development & Supplies, PTD Biologics Europe, (PTDE-P), F. Hoffmann-La Roche, Ltd.
The liabilities of polysorbates have become a hot industry topic recently. Attention has been enhanced to the use of alternative surfactants like poloxamer 188 (P188). The presentation will evaluate a range of state-of-the-art techniques to study the interplay of P188 and proteins at interfaces (air, silicone oil) plus the characteristics of P188 in solution (i.a. dilation rheology, small angle x-ray scattering). Similarities and differences of P188 to polysorbates will be discussed.
15:35 Reviving Otherwise Hard-to-Stabilize Biopharmaceuticals through Protein Co-Formulation
Elenora Cerasoli, Ph.D., Senior Research Scientist, Bioprocess Characterisation Albumedix
Aggregation and depletion of biopharmaceuticals is a source of both dosage form and storage instability, compromising safety and efficacy. Human serum albumin is well known to stabilize proteins preventing adsorption, aggregation and oxidation due to its natural roles and inherent properties. Recombinant human albumin is therefore a promising stabilizer for hard-to-formulate biopharmaceuticals. We will present data on the use of Albumedix' Recombumin® as a stabilizing agent for model biopharmaceuticals and elucidate on potential mechanisms.
16:05 A Rational Strategy for the Reduction of Protein Aggregation in Mammalian Cell Cultures
Friedemann Hesse, Ph.D., Professor, Institute for Applied Biotechnology, Biberach University of Applied Sciences
Although protein aggregation is a well-known quality issue in the production of recombinant biopharmaceuticals which can already occur in early stages of the manufacturing process, only few studies address protein aggregation during upstream processing. Therefore, this study was performed in order to establish a rational approach for the optimization of upstream bioprocesses to reduce protein aggregation in mammalian cell cultures.
16:35 End of Conference