Protein Aggregation and Stability in Biopharmaceutical Products


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7:00 am Registration and Morning Coffee


Understanding the Mechanics of Aggregation 

8:30 Chairperson’s Opening Remarks

Thomas Laue Thomas Laue, Ph.D., Professor, Biochemistry and Molecular Biology; Director, Biomolecular Interaction Technologies Center (BITC), University of New Hampshire


8:40 Addressing Particulate and Aggregation Issues of Therapeutic Protein Products

Li Shi Li Shi, Ph.D., Senior Director, BioAnalytics and Formulation, CPD, Genzyme

Biological product quality control is a critical effort in ensuring the success of the manufacturing, final product safety and efficacy, and process consistency. In addition to process control, formulation design and formulation/fill/finish process development are also responsible for the final product’s critical quality attributes. One of the common challenges of protein biopharmaceutical quality evaluation is the aggregation during process, handling, and under the situation of process deviation. In addition, the presence of foreign particles in parenteral protein products is often a manufacturing process and product release challenge. This presentation will review related expectation and elaborate general strategies and scientific approaches used in addressing those protein aggregation and particulate issues.

9:10 Mechanistic Understanding of Reversible Self Association in Therapeutic Monoclonal Antibodies

Sathish Hasige Sathish Hasige, Ph.D., Senior Scientist, Formulation Sciences, MedImmune


Sponsored by
Malvern small
9:40 The Importance of Protein Surface Charge on Biological Activity, Inherent Structural Stability, and Formulation Shelf Life

Kevin Mattison Kevin Mattison, Ph.D., Principal Scientist, Bioanalytics, Malvern Instruments

There is a growing interest in the measurement of protein charge, as a means of predicting formulation characteristics. A common technique for measuring protein charge is electrophoretic light scattering (ELS). Historically, the low scattering of proteins have made ELS measurements somewhat challenging. Recent advances in ELS technology however, have led to significant reductions in both the minimum sample volume and the experimental limitations under which protein samples can be measured. This paper highlights these improvements using a series of antibody formulations.

10:10 Coffee Break in the Exhibit Hall with Poster Viewing

11:10 Amyloidogenic Regions and Interaction Surfaces Overlap in Globular Aggregating Proteins

Salvador Ventura Salvador Ventura, Ph.D., Group Leader, Institut de Biotecnologia i Biomedicina, Universitat Autonoma de Barcelona

Protein aggregation underlies a wide range of human disorders. The polypeptides involved in these pathologies might be intrinsically unstructured or display a defined 3D-structure. Little is known about how globular proteins aggregate into toxic assemblies under physiological conditions, where they display an initially folded conformation. Protein aggregation is, however, always initiated by the establishment of anomalous protein-protein interactions. Therefore, in the present work, we have explored the extent to which protein interaction surfaces and aggregation-prone regions overlap in globular proteins associated with conformational diseases.


Orthogonal Characterization Tools and Physiological Effects 

11:40 Aggregates, Particulates: Why is there a Need for Orthogonal Characterization Tools and What are the Adverse Physiological Effects

Joel Richard Joel Richard, Ph.D., Vice President, Drug Product Development, Pharmaceutical Development, Ipsen

A major critical quality attribute for liquid formulations of biologics is the level of aggregates and particulates. Their key features (size, morphology, reversibility) have to be characterized, in order to anticipate potential related safety issues. For this purpose, orthogonal characterization methods have to be implemented so as to get a comprehensive mapping of the characteristics of aggregates and particulates. Practical approaches based on appropriate combination of analytical tools for the in-depth characterization of aggregates and particulates will be highlighted. The adverse physiological effects related to their presence in the formulations, e.g. induction of immune response, will also be discussed.

12:10 pm Luncheon Presentations (Sponsorship Opportunities Available) or Lunch on Your Own

1:10 Break


Detecting and Predicting Aggregation 

1:30 Chairperson’s Remarks

Robert Forbes, Ph.D., Professor of Biophysical Pharmaceutics, School of Pharmacy, University of Bradford

1:35 Novel Approaches to Predicting Aggregation Rates

Christopher RobertsChristopher Roberts, Ph.D., Associate Professor, Chemical Engineering, University of Delaware

This presentation will focus on new approaches to rapidly and quantitatively estimating real-time aggregation rates based on accelerated data and/or biophysical properties. Comparison with conventional methods for different proteins as a function of pH and excipient concentrations shows predictability across a range of systems, with reduced time and material consumption. The methods also provide useful data for mechanistic modeling of aggregation pathways.


2:05 Fast Assessment and Prediction of Protein Aggregation Trends

Andreas Bommarius Andreas Bommarius, Ph.D., Professor, Chemical & Biomolecular Engineering and Chemistry & Biochemistry, Georgia Institute of Technology

In the present work, diffusion and aggregation kinetics of the globular model proteins lysozyme and BSA were studied in sodium-salt solutions of different composition and ionic strength using dynamic light scattering. We find a strong correlation between the concentration dependent protein diffusivity in stable solutions and the kinetics of protein aggregation in unstable solutions of similar composition but higher salt content. Our findings suggest a fast and convenient new way to assess a protein’s specific tendency to aggregate in different types of electrolytes and buffer solutions.

2:35 Sponsored Presentations (Opportunities Available)

3:05 Refreshment Break in the Exhibit Hall with Poster Viewing


3:50 Problem Solving Breakout Sessions 

Concurrent Problem Solving Breakouts are interactive sessions hosted by a moderator to discuss a topic in depth. They are open to all attendees, sponsors, exhibitors, and speakers and provide a forum for discussing key issues and meeting potential partners. Please pick a topic of your choice and join in. 

TABLE 7: Engineering Proteins to Improve Solubility and Reduce Aggregation 

Moderator:  Tom Laue, Ph.D., Professor, Biochemistry and Molecular Biology, Director, Biomolecular Interaction Technologies Center (BITC), University of New Hampshire 

• What protein properties cause of solubility, viscosity and aggregation problems?
• What role can the solvent play in mitigating these problems?
• What measurements can you make that will help guide your solution development?

TABLE 8: Strategies and Computational Methods to Improve Prediction and Selection 

Moderator:  Salvador Ventura, Ph.D., Group Leader, Institut de Biotecnologia/Biomedicina, Univsersitat Autonoma de Barcelona 

• Protein sequence based prediction methods
• The influence of the three-dimensional structure
• The influence of the solution conditions.
• Prediction of the aggregation properties of complete proteomes

TABLE 9: Predictive Techniques and Methods in Biopharmaceutical Development – Challenges, Current Trends and Future Potential 

Moderator:  Sathish Hasige, Ph.D., Senior Scientist, Formulation Sciences, MedImmune 

• Recent advances in verified and validated techniques to predict therapeutic protein degradation
• Challenges associated in predicting behavior of large multi-domain monoclonal antibodies
• Collaboration between Industry and Academia

TABLE 10: Detecting and Characterizing of Soluble and Insoluble Protein Aggregates: Novel Methods; Complementary/Orthogonal Analytical Tools 

Moderator:  Joel Richard, Ph.D., Senior Director, Head, Drug Product Development, Pharmaceutical Development, Ipsen. 

• Methods to detect and characterize soluble aggregates - Reliability and performance of the methods - How to cross-check the data? Do we still need improvements of the methods and/or new methods?
• Methods to detect and characterize insoluble aggregates - Specific features and performances of the methods - What selection/association of methods should be recommended and what is the rationale?
• Impact of soluble and insoluble aggregates - Do they present the same risk? What risk assessment should we perform and should we address the issue differently, depending on the nature of the aggregates?

TABLE 11: Protein Aggregates and Particulates 

Moderator:  Arvind Srivastava, Ph.D., Director, Formulation Development, ImClone Systems, a wholly owned subsidiary of Eli Lilly & Co.  

• Mechanism of formation
• Measurement
   a. Measurement of solution aggregates
   b. Measurement of smaller than 10µm particles
   c. Measurement of larger than  10µm particles
• Safety concern
• Regulatory concern
• Formulation challenges

TABLE 12: Understanding and Characterizing Aggregation in High-Concentration Protein Solutions 

Moderator:  Vineet Kumar, Ph.D., Senior Research Scientist, Global Formulation Sciences, Parenterals, Abbott
Moderator:  Devendra (Davy) S. Kalonia, Ph.D., Professor of Pharmaceutics, Department of Pharmaceutical Sciences, University of Connecticut

• Impact of short range hydrophobic interactions on aggregation at high concentration
• Impact of polyol and sugar excipients on aggregation at high concentrations
• Engineering surface exposed hydrophobic residues to minimize aggregation propensity
• Discrete aggregates
• Transient networks
• Gel formation

TABLE 13: Understanding the Role of Aggregates in Immunogenicity 

Moderator:  Melody Sauerborn, Ph.D., Utrecht Institute for Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht University 

Moderator:  Wim Jiskoot, Ph.D., Professor, Drug Delivery Technology, Leiden University 

• Why aggregates are immunogenic from a theoretical point of view
• How can we verify the theory
• Risk factors for immunogenicity - beyond aggregates

4:50 Reception in the Exhibit Hall with Poster Viewing

6:00 End of Day

Recommended Short Course 

SC9 – Characterization Techniques for Protein Therapeutics – Orthogonal vs. Complimentary  

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