Cambridge Healthtech Institute’s 5th Annual
High-Concentration Protein Formulations
Formulation, Manufacturing, Analytics, High Viscosity, Aggregation, Devices and Delivery
Part of CHI's 8th Annual The Bioprocessing Summit

August 18-19, 2016 | Westin Boston Waterfront | 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. The popular High-Concentration Protein Formulations conference will feature informative, high quality case studies and successful strategies to overcome the problems you are facing with development and delivery of high-concentration formulations.

Final Agenda

Thursday, August 18

11:30 am Registration Opens

12:15 pm Lunch Available for Purchase in the Exhibit Hall

1:15 Dessert Refreshment Break in the Exhibit Hall with Poster Viewing


1:55 Chairperson’s Opening Remarks

Atul Saluja, Ph.D., Senior Research Investigator II, Drug Product Science & Technology, Bristol-Myers Squibb


2:00 Correlating Protein-Protein Interactions and Aggregation Rates over Broad Concentration Range: Misconceptions, Challenges and Promising Approaches

Atul Saluja, Ph.D., Senior Research Investigator II, Drug Product Science & Technology, Bristol-Myers Squibb

Protein–protein interactions (PPI) and rates of aggregation (kagg) were quantified systematically for a monoclonal antibody (MAb) across a broad range of concentration in presence and absence of excipients. Hypotheses based on thermodynamic activity and fluctuation theory were inconsistent with experimental kagg and scattering data. However, arguments based on surface contact probabilities were reasonably successful in providing a semi-quantitative correlation. Challenges and opportunities for such an approach are further discussed.

2:45 Applications of AU-FDS to High- Concentration Antibody Interactions

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

Will discuss two applications of AU-FDS. First, high-concentration antibody solutions may exhibit excessive viscosity due to weak interactions between proteins. A case will be built that they are a consequence of a balance between attractive electrostatic energies and repulsive desolvation energies. Second, how does a high-concentration protein background influence an IgG-antigen interaction? Here, both the IgG and the antigen are multi-valent, which leads to very large networks being formed in dilute solution. Are these large structures observed in serum?

3:15 Use of Viscosity Surrogate Solutions to Identify Equipment Operating Conditions in Fill-Finish Process for High Concentration Biologic Drug Product

Zach_ZhuZach Zhu, Ph.D., Scientist II, Pharmaceutical Operations & Technology, Biogen

A platform approach was applied to the development of several fill-finish process unit operations for a highly concentrated biologic drug product. The approach utilized viscosity surrogate solutions to identify operational parameters for a scaleable single-use system (SUS), which is applied for mixing, pooling, and filtration steps in the manufacturing operation. Accordingly, at-scale equipment operating conditions were successfully identified, leading to a significant reduction in characterization of the commercial-scale process using active product. A GMP production run of active drug product further confirmed the suitability of process parameters identified from the surrogate solutions.

3:45 Selected Poster Presentation: Evaluation Methods of Antibody Therapeutic's Viscosity at Lead Optimization Stage

Momoko Okuda, Ph.D., Researcher, Research Division, Chugai Pharmaceutical Co., Ltd., Japan

Selection of clinical candidate with low viscosity is one of the pivotal factors in developing subcutaneous-injectable therapeutic antibody. To evaluate viscosity, we routinely use two methods for different purposes. One method examines the viscosity of a clinical candidate directly with minimum labor while the other method involves viscosity prediction of multiple variants with small amount of protein. We will introduce key features of each method alongside with some case studies.

4:00 Refreshment Break

4:15 Breakout Discussions

Table 1: Understanding and Controlling Protein Aggregation and New Modalities

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

  • What features of new protein modalities influence aggregation?
  • What are tools can be used to study these interactions?
  • Importance of comparability studies
  • How aggregation in new modalities can be controlled of mitigated


Table 2: Pros and Cons of Platform Approach for Protein Formulation Development

Mark Yang, Ph.D., Director, Fill Finish Development, Sanofi Genzyme

  • What are the commonly used platform approaches for high concentration protein formulation?
  • What the are challenges faced when using single platform approach for various formulations
  • What are the common issues and how can they be overcome


5:15 End of Day

5:15 Registration for Dinner Short Course

Friday, August 19

8:00 am Registration Opens and Morning Coffee


8:25 Chairperson’s Remarks

Mark Yang, Ph.D., Director, Fill Finish Development, Sanofi Genzyme

8:30 Detection and Management of Protein Aggregates during Downstream Processing

Danny_ChouDanny Chou, Ph.D., President and Founder, Compassion BioSolution; Former Senior Research Scientist, Biologics Development, Gilead Sciences

It is known that protein aggregation is a significant bottleneck in the development of efficient and cost-effective biologics purification process. The goal of this presentation is to use a case study to illustrate how one may detect the “seeds” of protein aggregate that occur early in the process in order to reduce the formation of larger particulate in the final drug product and reduce processing cost.

9:00 Case Study: Formulation pH Shift Caused by Protein Concentration Increase

Mark Yang, Ph.D., Director, Fill Finish Development, Sanofi Genzyme

In this new case study, it has been observed that the formulation pH decreases as its protein concentration increases. This pH shift becomes more pronounced in the high concentration formulations or in the diafiltration step where protein gets concentrated. The underlining mechanisms responsible for this pH shift, along with mitigation strategies, will be discussed.

9:30 Impact of Charge Isoforms on Stability of Antibody Formulations Manufactured Using High Titer Bioprocess

Jason_FernandezJason Fernandez, M.Sc., Scientist, Protein Pharmaceutical Development, Biogen

This presentation will cover how molecular charge isoforms from upstream drug substance process influence protein stability in the downstream drug product. Particular post-translational modifications and chemical degradation will be discussed that lead to charge isoform impacting protein aggregation. Further, isoform fractionation approaches and novel stability study designs will be presented that help elucidate the impact of isoform species in high titer and high concentration biopharmaceuticals.

10:00 Networking Coffee Break


10:30 Co-Formulation Development of Monoclonal Antibodies and Recombinant Human Hyaluronidase (rHuPH20) – A Case Study

Claudia Mueller, Ph.D., Senior Scientist, Group Leader, Late-Stage Pharmaceutical and Process Development, F. Hoffmann-La Roche Ltd.

Subcutaneous application faces limitations with regards to the drug volume that can be administered. To enable delivery of the necessary doses, increase in the concentration of the drug and/or temporary enlargement of the interstitial space at the injection site, e.g. by using rHuPH20, are potential strategies to face this challenge. This presentation highlights the drug product development of co-formulations consisting of highly concentrated monoclonal antibodies and rHuPH20. The talk will focus on formulation and process development challenges arising from combination of two very different proteins in order to maintain both stable and active within one formulation.

11:00 Formulation Strategies for High-Concentration, Low-Volume Injectables

Charles Wescott, Ph.D., Vice President, Research and Development, Protein Formulation, Arsia Therapeutics

At concentrations exceeding 100 mg/mL, many biologics are highly viscous, and can suffer reduced colloidal stability. Formulation designs targeting the protein-protein interactions mediating these problems can produce highly-concentrated drug products with good stability, syringeability, and injectability characteristics. These advanced high-concentration formulations allow biologics that would otherwise be dosed by i.v. infusion to be administered by s.c. injection, or delivered by low-volume devices.

11:30 Building a Better Bridge: Biophysical Tools to Better Understand the Complexities of High Concentration Biotherapeutics

Michael_MarlowMike Marlow, Ph.D., Senior Staff Scientist, Protein Biochemistry, Regeneron Pharmaceuticals, Inc.

The thermodynamic interactions that govern a variety of protein therapeutic and solution properties are distinctly protein concentration dependent. Manufacturing and dosing of therapeutic monoclonal antibodies frequently calls for high protein concentration solutions and the resulting non-ideality complicates reliable estimation of critical properties from measurements under dilute conditions. We illustrate the utility of different biophysical tools in bridging the dilute - high concentration gap by characterizing two antibodies that exhibit contrasting concentration-dependent behavior.

12:00 pm Sponsored Presentations (Opportunities Available)

12:30 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:15 Session Break


1:25 Chairperson’s Remarks

Jan Jezek, Ph.D., CSO, Research & Development, Arecor Ltd.

1:30 Strategies for Overcoming Long Reconstitution Times of Lyophilized Highly Concentrated Protein Formulations

Robin_BognerRobin Bogner, Ph.D., Associate Professor, Pharmaceutical Sciences, University of Connecticut

High protein concentration is often accompanied by unacceptably long reconstitution times of 40-60 minutes. Formulation and lyophilization cycles have been found to influence the time to achieve complete reconstitution. In addition, there are an increasing battery of methods to assess the potential for long reconstitution times. Several strategies, some of which may be counterintuitive, can be used to reduce the reconstitution times of challenging formulations.

2:00 Product Differentiation through Formulation and Device

Jan_JezekJan Jezek, Ph.D., CSO, Research & Development, Arecor, Ltd.

In the increasingly competitive biopharmaceutical market, convenience of use has become an essential feature for a product to succeed. Convenience can be achieved by smart devices as well as formulations that enable high protein concentration or use of the product outside the cold chain. This talk will focus on unique formulation strategies for stable concentrated products as well as related device choices that enable development of competitive biopharmaceuticals.

2:30 Mitigation of High Concentration Formulation Issues of a Human IgG1 Monoclonal Antibody via Rational, Structure- Guided Protein Engineering

Reza Esfandiary, Ph.D., Scientist II, Department of Formulation Sciences, MedImmune

High concentrations can add significant challenges during development of mAb therapeutics. Although a global mechanistic understanding might be sufficient to develop robust formulation controls, mitigation approaches via protein engineering requires knowledge of the molecular hotspots. Here, we have integrated experimental and in silico methods to systematically identify the molecular hotspots responsible for high concentration issues of a model mAb and have engineered variants with improved high concentration developability properties.

3:00 CMC Strategies on Scaling Up and Down for High-Concentration Protein Formulations

Jamie Tsung, Ph.D., Principal 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.

3:30 Close of Conference