Cambridge Healthtech Institute’s 4th Annual
High-Concentration Protein Formulations:
Formulation, Manufacturing, Analytics, High Viscosity, Aggregation, Devices and Delivery
August 5-6, 2015
Part of CHI's 7th Annual The Bioprocessing Summit
August 3-7, 2015 | Westin Copley Place 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. 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. We invite you to attend to learn from and network with the leading experts from around the world.

Tuesday, August 4

Wednesday, August 5

7:00 am Registration and Morning Coffee

PROTEIN-PROTEIN INTERACTIONS & DEALING WITH VISCOSITY

8:00 Chairperson’s Remarks

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

8:55 Viscosity in High-Concentration Protein Formulations

Thomas Palm, Ph.D., Senior Research Investigator II, Drug Product Science and Technology, Bristol-Myers Squibb Co.

At high protein concentration, small changes in concentration or pH that are within the typical specification range can have a significant impact on product viscosity. Likewise, product viscosity is significantly higher at storage temperature of 2-8 °C than it is at ambient temperature. Viscosity ranges of a model antibody and implications for formulation development, manufacturing, and device development will be discussed.

9:25 Cluster Formation in Dense Protein Solutions and Its Implications to Solution Viscosity

Yun Liu, Ph.D., Research Associate Professor/Instrument Scientist, Chemical & Bimolecular Engineering/Center for Neutron Research, University of Delaware/National Institute of Standards and Technology

Protein cluster formation in solutions is of fundamental interest for both academics and industries, and is very important for solution viscosity control in concentrated protein solutions. We will present our recent research efforts to directly identify the structures of small reversible protein clusters in monoclonal antibody solutions. The fundamental physical mechanisms of high viscosity in monoclonal protein solutions will be discussed within the context of our research examples.

9:45 High-Concentration Protein Analysis via Slope Spectroscopy and Variable Pathlength Technology

Joe Ferraiolo, Senior Product Specialist, C Technologies

The traditional method for measuring highly concentrated protein solutions typically requires the sample to be diluted prior to analysis in a fixed pathlength spectrophotometer. The time, error and costs associated with dilutions impacts analysis from formulation through in-process and release testing. This talk focuses on the Slope Spectroscopy technique which enables measurements on neat samples with concentrations ranging up to 300 mg/ml by increasing the linear range of the instrument through dynamic optimization of the measurement pathlengths.

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

FORMULATION & CMC CHALLENGES OF HIGH-CONCENTRATION PROTEIN FORMULATIONS

10:45 Preformulation Screening for Risk Mitigation during the Development of Biopharmaceuticals

Randall Mauldin, Ph.D., Scientist II, Protein Formulation and Process Development, Biogen Idec

In order to address unmet patient needs, drug candidates are becoming more complex and delivered at higher concentration than ever before. Furthermore, aggressive CMC timelines necessitate the need for a rigorous assessment of early-stage drug candidates to de-risk future development. This talk will provide an overview of the challenges and strategies for characterizing the multidimensional formulation space of novel biopharmaceuticals with limited sample availability.

11:15 HESylation® - A Versatile Polymer Modification Technology Enabling High-Concentration Protein Formulations

Thomas Hey, Ph.D., Director, Biochemistry, Innovation Center Complex Formulations, Fresenius Kabi Deutschland GmbH

The attachment of the biodegradable and poorly immunogenic polymer hydroxyethyl starch (HES) to biologicals leads to increased efficacy by stabilization of the protein and prevention of renal excretion. The resulting conjugates show high solubility, but comparably low viscosity, allowing s.c. administration of highly concentrated solutions. In addition, HESylation® was used to develop next-generation ADCs allowing site-specific conjugation and higher payload density while maintaining excellent binding activity with the target protein and cancer cells.

11:45 Designing a Unique Drug Delivery Device for Viscous Drug Products with Novel Needle Technology and Polymer Syringes

Kevin Constable, Director, Technology Development, Terumo- Global Pharmaceutical Solutions

New drug products being developed today are often created as concentrated proteins which can result in a viscous solution that may require novel devices for drug delivery. Using a systems approach to device design, we will explore how the combination of a silicone oil free polymer syringe system with a tapered needle can be combined to reduce the force of injection, improve functionality, and reduce the potential degradation of these complex protein based formulation.

12:15 pm Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:30 Session Break

FORMULATION & CMC CHALLENGES OF HIGH-CONCENTRATION PROTEIN FORMULATIONS (cont.)

1:55 Chairperson’s Remarks

Thomas Palm, Ph.D., Senior Research Investigator II, Drug Product Science and Technology, Bristol-Myers Squibb Co.

2:00 Drug Product Design and High Concentration Formulation Development

Bruce Kerwin, Ph.D., Head, Drug Product Design, Just Biotherapeutics, Inc.

Protein formulation development is an evolving field that now encompasses the concept of drug product design rather than focusing solely on stabilization and concentration of the protein. Increasingly, an integrated approach to drug product design encompasses in silico tools, high throughput screening and development of predictive tools that integrate with the commercialization process. At this meeting examples and ideas will be combined to provide a vision of the future as it evolves into the field of drug product design.

2:30 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.

3:00 Aromatic Amino Acid Salts Rescue the Solubility of a Poorly Soluble Multivalent Protein

Yu (Eunice) Tang, Ph.D., Principal Scientist, Drug & Combination Product Development Group, Shire HGT

A multivalent protein demonstrates poorly solubility across wide pH range with temperature dependency. Conventional “salt in” ions further facilitate the precipitation of the protein. Interestingly, aromatic amino acid salts successfully rescue the protein solubility. A systemic investigation was performed to reveal the cause of the poor solubility and the mechanism of solubility enhancement by aromatic amino acid salts.

3:30 Simplest Concepts and Measurements May Become Challenges at High Protein Concentration

Erinc Sahin, Ph.D., Sr. Research Investigator, Drug Product Science & Technology, Bristol-Myers Squibb Co.

4:00 Refreshment Break in the Exhibit Hall with Poster Viewing

PLENARY SESSION

4:45 Chair’s Remarks

Sam Ellis, Vice President, Biochemist, Thomson Instrument Co.

5:20 INTERACTIVE PANEL DISCUSSION:

How to Innovate Product Development

• Technologies
• Strategies
• Cutting Costs
• Meeting needs
• Utilizing creativity
• Lessons Learned

Panelists:

Joanne T. Beck, Ph.D., Senior Vice President, Pharmaceutical Development, Shire Pharmaceuticals
Wayne Froland, Ph.D., Associate Vice President, Center for Biopharmaceutical Manufacturing Sciences, Merck Manufacturing Division
Stefan Schmidt, Ph.D., M.B.A., Vice President, Process Science & Production, Rentschler Biotechnologie GmbH
Haripada Maity, Ph.D., Research Advisor, Eli Lilly and Company

6:00 Networking Reception in the Exhibit Hall with Poster Viewing

7:00 End of Day

Thursday, August 6

8:00 am Registration and Morning Coffee

ANALYTICAL STRATEGY FOR HIGH-CONCENTRATION PROTEIN FORMULATIONS

8:25 Chairperson’s Remarks

Bruce Kerwin, Ph.D., Head, Drug Product Design, Just Biotherapeutics, Inc.

8:30 Building a Better Bridge: Biophysical Tools to Better Understand the Complexities of High Concentration Biotherapeutics

Michael S. 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.

9:00 Challenges with Measuring Detergents and Excipients Used in Biopharmaceuticals

Shiranthi Jayawickreme, Ph.D., Associate Director, Analytical Development, Biogen Idec

A variety of detergents are used for solubilization, viral-inactivation, and as excipients in Biopharmaceutical drug substances and products. Lack of chromaphores in many of these detergents poses a challenge for the detection and quantitation of these components during process development and quality control. Current methods available for the determination of low levels of polysorbates in high concentration drug substances and drug products will be presented. Sensitivity and robustness of three different methods will be discussed.

9:30 Characterization of and Relationship between Soluble and Insoluble Aggregate Populations

Ronald Maurer, Ph.D., Scientist, Process Development – Downstream, Bristol-Myers Squibb Co.

Protein aggregation presents serious challenges in all stages of biotherapeutic development, compromising both product yield and patient safety. However, many fundamental aspects of aggregation are poorly described and prevent robust characterization and prediction of aggregation behavior. In this work, we investigate the relationship, if any, between soluble and insoluble protein particle formation and correlate their growth and stability to experimentally-tenable biophysical properties.

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

DELIVERY & DEVICE APPROACHES IN HIGH-CONCENTRATION / HIGH-VOLUME PROTEIN FORMULATIONS

10:45 Device & Formulation – Two Inseparable Aspects of a Successful Product

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

The biologics market is becoming increasingly competitive with multiple products competing for the same indication and a number of biosimilars in development. Therefore, there is a strong pressure for product differentiation offering distinct advantages over other products. Stability together with a convenient injection device are two key aspects of successful products. This talk will focus on unique formulation strategies and related device choices that enable development of competitive biopharmaceuticals.

11:15 Reconstitution of Highly Concentrated, Dried Proteins: What Have We Learned in the Past 5 Years?

Bakul Bhatnagar, Ph.D., Principal Scientist, Formulation & Process Development, Pfizer, Inc.

The reconstitution time of lyophilized biopharmaceuticals is a quality attribute where it is desirable and often critical to achieve fast reconstitution (for example, in an emergency environment) without compromising the product quality. The reconstitution times of highly concentrated freeze-dried proteins can be often quite long. The presentation will address recent advances in our understanding of the dissolution behavior and will cover aspects of mechanisms contributing to reconstitution, strategies to obtain rapid reconstitution, and methods to determine the end of reconstitution.

11:45 Adocia Viscosity Reducers (AVRs®) – A New Alternative to Reduce the Viscosity of Highly Concentrated mAb Formulations

Emmanuel Dauty, Ph.D., Head of the Physico-Chemistry Department, Department: Physico-Chemistry, Adocia

Highly concentrated monoclonal antibody (mAb) formulations are often highly viscous, which poses manufacturing and administration challenges. Adocia has developed two distinct families of small molecules that have impressive viscosity-reduction properties in highly concentrated mAb formulations – Adocia Viscosity Reducers (AVR®). Through low-affinity electrostatic and hydrophobic interactions, AVR® excipients are capable of disrupting the mAb-mAb interaction network responsible for the high viscosity of highly-concentrated mabs, resulting in significant viscosity reduction.

12:15 pm Crystalomics – A Strategy for High-Concentration Protein Formulation

Tan Leminh, MBA, Director, Technology Transfer, Althea

Crystalomics® is a technology platform that offers a formulation solution for protein therapies that must be delivered at high concentrations or as sustained release formulations. The technology can be used to formulate antibodies to up to 350 mg/ml, allowing IV infusions to be converted to SC injections. Crystalomics® is an ideal technology to formulate “BioSuperior” biologics that deliver superior dosing regiments and expanded patent protection for established protein therapeutics.

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

1:15 Close of Conference