The Bioprocessing Summit

Cambridge Healthtech Institute’s Third Annual
High-Concentration Protein Formulations
Overcoming Challenges in High Viscosity, Aggregation and Stability
Part of CHI’s 6th Annual The Bioprocessing Summit

August 20-21, 2014 | Renaissance Waterfront Hotel | Boston, Massachusetts


At higher concentrations, proteins or antibodies exhibit characteristic problems including aggregation, precipitation, gelation, and increased viscosity. Development of these high concentration protein formulations results in several manufacturing, stability, analytical, and delivery challenges. Thus, development of formulations for protein drugs requiring high dosing requires specific strategies. This popular annual conference will feature informative, high-quality case studies and successful strategies to overcome the problems you are facing in the rapidly changing biotherapeutic landscape.


Day 1 | Day 2 | Short Courses | Download Brochure | Speaker Bios 

Wednesday, August 20

7:00 am Registration and Morning Coffee


PROTEIN ASSOCIATION AND AGGREGATION

8:05 Chairperson’s Remarks

DeanRippleDean Ripple, Ph.D., Leader, Bioprocess Measurements Group, National Institute of Standards and Technology

 

 

 

KEYNOTE PRESENTATIONS

8:15 Mechanisms of Protein Association and Aggregation

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

The same forces underlie protein stability, protein-protein interactions and protein aggregation. In addition to viewing the thermodynamics of these processes, it is worthwhile to consider their kinetic aspects. A kinetic view of these processes is particularly revealing with respect to hydrophobic interactions. Considering hydrophobic interactions as a two-step process that first involves de-solvation, then dispersion-energy stabilization leads to the conclusion that flanking hydrophobic regions with anionic groups should reduce hydrophobically-driven aggregation.

9:00 Liquid-Liquid Phase Separation as a Quantitative Colloidal Stability Assay for Monoclonal Antibodies

Ramil LatypovRamil F. Latypov, Ph.D., Principal Scientist, Process & Product Development, Amgen, Inc. - Read Recent Interview 

Colloidal stability is an important consideration in formulation development of therapeutic antibodies. In a protein solution, different pathways including crystallization, aggregation and liquid-liquid phase separation (LLPS) can lead to the formation of precipitates and particles. Polyethylene glycol (PEG) induces LLPS in antibody solutions and can be used to compare colloidal stability of antibodies in different conditions. Our analysis defines the binding energy in the PEG-induced condensed phase to quantitatively measure attractive interactions between antibody molecules.


9:30 Structural and Surface Characteristics of a Protein that Impact its Opalescence in Solution

RaviChariRavi Chari, Ph.D., Senior Scientist, Pharmaceutics, AbbVie Bioresearch Center

In this study we investigated the underlying properties of a protein that led to its opalescence in solution. Initial formulation studies led to the hypothesis that hydrophobic interactions governed this behavior. Computer modeling was then performed to identify hydrophobic residues and surfaces of the protein that could be targeted for mutational studies to test the hypothesis. The results suggest that the degree and nature of hydrophobicity impacted opalescence.

10:00 Coffee Break in the Exhibit Hall with Poster Viewing

10:45 Monoclonal Antibody Self-Association, Rheology, and Phase Behavior at High Concentrations

WenhuaWangWenhua Wang, Ph.D., Postdoctoral Fellow, Late Stage Pharmaceutical Development, Genentech, Inc.

Therapeutic protein intermolecular interactions at high concentrations often lead to manufacturing problems including high viscosity, turbidity, and aggregation. Here, we presented our work on the correlation of monoclonal antibody (mAb) self-associating dimer and oligomer structural information to their rheology and phase behaviors. A better understanding of mAb self-association behaviors from this research is insightful not only for overcoming challenges in high-concentration protein formulations, but also for comprehending the mechanisms of protein gelation or crystal formation.

11:15 CMC Challenges in Development of High Concentration Protein Formulation

JamieTsungJamie Tsung, Ph.D., Principle Scientist, Momenta Pharmaceuticals, Inc.

Highly concentrated therapeutic proteins are prone to be viscous and aggregate posing developmental and CMC challenges in purification, formulation, analytical development, manufacturing, product stability, syringeability and injectability.  This talk provides a review of current strategies and technologies used in product development to overcome these CMC challenges and minimize the impact on product quality. 
 

11:45 Selected Poster Presentation: Opalescence in a Monoclonal Antibody Solution and Its Correlation with Intermolecular Interactions in Dilute and Concentrated Solutions

Ashlesha S. Raut, Ph.D. Candidate, Department of Pharmaceutical Sciences, University of Connecticut

Monoclonal antibody molecule studied, shows a unique property of high opalescence due to liquid-liquid phase separation. Results indicate that high opalescence and phase separation are due to the attractive interactions in solution as measured using light scattering and rheology, however, presence of attractive interactions do not always imply phase separation. Temperature dependence of opalescence, suggests that Tcloud can be utilized as a potential tool to assess attractive interactions in solution.

12:00 pm Enjoy Lunch on Your Own

1:30 Session Break


OVERCOMING AGGREGATION & VISCOSITY CHALLENGES

1:55 Chairperson’s Remarks

Ramil Latypov

Ramil F. Latypov, Ph.D., Principal Scientist, Process & Product Development, Amgen, Inc.

 

 

 

2:00 Multimer Protein Cluster Structure at High-Concentration: Dynamic Modeling of Stability and Viscosity

JohnTsavalasJohn Tsavalas, Ph.D., Assistant Professor of Materials Science, University of New Hampshire

In this work, a dynamic model is presented that can evaluate and predict this behavior of proteins in concentrated solutions as a function of their charge, charge distribution, and resultant interaction potential. In particular, the viscosity response to the stability of the proteins in solution is discussed with emphasis on the effective hydrodynamic radius due to the high aspect ratio of a mAb exacerbated by weak clustering of multiple mAbs during concentration.

2:30 Understanding and Addressing Viscosity in the Development of High-Concentration Protein Formulations

RobertWaltersRobert H. Walters, Senior Scientist, Biotherapeutics Pharmaceutical R&D, Pfizer, Inc.

High-concentration formulations of therapeutic proteins are beneficial as they reduce storage costs of biotherapeutics and can enable more patient friendly administration options, such as subcutaneous dosing. However, development of high-concentration formulations remains challenging. High viscosities associated with high-concentration protein formulations can negatively impact manufacturability and injectability of the product. This talk will focus on understanding the sources of elevated viscosity in high-concentration protein formulations and suggest strategies for viscosity reduction.

3:00 Instrument Biases for Counting and Sizing of Particles in High-Concentration Formulations

DeanRippleDean Ripple, Ph.D., Leader, Bioprocess Measurements Group, National Institute of Standards and Technology

Characterization and sizing of protein particles is necessary for assuring the quality of drug products. High-concentration formulations lead to reduced optical contrast of particles, leading to errors for the most common optical methods of particle detection. This talk discusses biases between methods in common use, as identified by the NIST round robin comparison on subvisible particles, and then considers the impact of either high protein or high excipient concentrations on these biases.

3:30 Refreshment Break in the Exhibit Hall with Poster Viewing


EMERGING BIOPHYSICAL TECHNIQUES FOR HIGH-CONCENTRATION FORMULATIONS

4:15 Orthogonal Toolbox for Screening and Identification of High-Concentration mAb Formulations

Yunsong “Frank” Li, Ph.D., Associate Principal Scientist, Bioprocess Development, Merck Research Laboratories

In this study, we focused on the evaluation of several techniques for understanding of high-concentration mAb solution properties. We observed good correlations between turbidity, relative solubility and the second viral coefficient (B22) value which are indicative of protein colloidal stability. We have demonstrated the ability of DSF to test high-concentration protein formulations and comparison between classical formulation stability studies and new toolbox will also be presented for 150 mg/mL mAb formulations.  

4:45 Extended Q&A with Speakers  

 

5:15 Networking Reception in the Exhibit Hall with Poster Viewing




6:30 End of Day


Suggested Short Course*:

Bioprocess Development: Considerations for the Quality and Safety of Materials in Contact with Biologics 

Thursday, August 21, 6:30 - 9:00 pm


*Separate registration required


Day 1 | Day 2 | Short Courses | Download Brochure | Speaker Bios