Cambridge Healthtech Institute’s 7th Annual

High-Concentration Protein Formulations

New Technologies, Devices, Analytics, Case Studies and New Research Highlights

August 15-16, 2018


At higher concentrations, proteins or antibodies exhibit characteristic problems including aggregation, precipitation, gelation, and increased viscosity. Development of the high-concentration protein formulations for traditional and novel biologic products can be challenging during manufacturing, storage, and delivery. 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 protein formulations.


Final Agenda

Tuesday, August 14

6:00 - 8:30 Recommended Short Course*

SC6B: Protein Aggregation: Mechanism, Characterization and Consequences

Instructors: Thomas Laue, PhD, Professor Emeritus, Molecular, Cellular and Biomedical Sciences, University of New Hampshire

Matthew Brown, PhD, Applications Manager, Bioscience, Malvern PANalytical

* Separate registration required.

Wednesday, August 15

7:00 am Registration Open and Morning Coffee

MANUFACTURING AND PROCESS CHALLENGES

8:05 Chairperson’s Remarks

Jean-René Authelin, PhD, Global Head of Pharmaceutical Engineering, Pharmaceutical Sciences, Sanofi France


8:15 KEYNOTE PRESENTATION: Challenges in Industrial-Scale Fill & Finish Operations for High-Concentration Proteins Formulations

Jean-René_AuthelinJean-René Authelin, PhD, Global Head of Pharmaceutical Engineering, Pharmaceutical Sciences, Sanofi France

High-concentration protein formulations are more and more required to administer proteins, especially mAbs. However, due to their high viscosity, propensity to aggregate or to form gel by drying, there are many hurdles to develop a robust commercial fill & finish process. The role of product development studies, which will be shared during this talk, is to anticipate the main difficulties and to adapt the process to the product by setting up a de-risking methodology, based on downscaled models and the use of well-designed surrogates.

9:00 Time-Pressure Filling of Concentrated mAbs Solutions: Understanding the Temperature Impact to Better Control the Filling Step (A Case Study)

Charlotte_PelletCharlotte Pellet, PhD, Pharmaceutical Sciences Operations, Sanofi, France

Fill & finish process for parenteral products includes a filling step crucial to obtain accurate and reproducible doses in syringes. It becomes a great technical challenge for concentrated mAbs solutions of high viscosity, strongly dependent on concentration and temperature. Understanding both rheology and complex machine automatism is the key. I will present a study case in which we rationalized and modeled the impact of very small temperature effects on filling accuracy.

9:30 PANEL DISCUSSION: Managing the Manufacturing and Process Challenges Posed by High Viscosity

  • Challenges in scaling up high-concentration protein formulations
  • New techniques and tools for processing at high concentrations
  • Share your own experiences and problems when processing high-concentration formulations and how the problem was approached and solved
  • What’s in the future?

Moderator:

Thomas Laue, PhD, Professor Emeritus, Molecular, Cellular and Biomedical Sciences, University of New Hampshire

Panelists:

Jean-René Authelin, PhD, Global Head of Pharmaceutical Engineering, Pharmaceutical Sciences, Sanofi France

Devin Tesar, PhD, Scientist, Drug Delivery, Genentech, Inc.

Robin Bogner, PhD, Professor, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut

William Callahan, MSc, Senior Scientist, Process Development, Amgen

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

LYOPHILIZATION & ALTERNATIVE DRYING TECHNIQUES FOR HIGH-CONCENTRATION PROTEIN FORMULATIONS

10:45 Single Step Drying: Challenges and Considerations for Freeze-Drying High Concentration Protein Formulations

Swapnil Pansare, Associate Scientist II, Dosage Form Design & Development, MedImmune

Lyophilization process optimization enables reduced cost and increased Drug Product manufacturing throughput. Typically, drying is performed below the collapse temperature to produce an elegant product appearance. Here, drying above the collapse temperature was performed in a single step by combining primary and secondary steps, without impacting product appearance. A case study is presented to assess the impact of single step drying on product quality, process efficiency and scale up.

11:15 Factors Governing the Reconstitution Time of High-Concentration Lyophilized Protein Formulations

Robin_BognerRobin Bogner, PhD, Professor, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut

Co-Presenter: Shreya Kulkarni, PhD Candidate, Pharmaceutical Sciences, University of Connecticut

A major challenge to the development of high-concentration lyophilized protein formulations is slow and variable reconstitution times, sometimes exceeding 1 hour. Long reconstitution times are especially undesirable for self-administered products. As biosimilars and additional protein products come to market, reduced reconstitution time is expected to be a differentiating factor. The overall goal of our research is to offer a fundamental understanding of the variables governing reconstitution in both amorphous and partially crystalline freeze-dried cakes and to identify the key cake attributes predictive of reconstitution time.

11:45 Delivery of High-Concentration Protein Suspensions

Deborah Bitterfield, PhD, CEO and Founder, Lindy Biosciences, LLC

12:00 pm Sponsored Presentation (Opportunity Available)

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

1:00 Session Break

PREDICTION & MEASUREMENT OF PROTEIN-PROTEIN INTERACTIONS, VISCOSITY & SOLUBILITY

1:45 Chairperson’s Remarks

Robin Bogner, PhD, Professor, Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut

1:50 Biotherapeutic Protein Size and Charge and Colloidal Stability

Thomas_Laue_2Thomas Laue, PhD, Professor Emeritus, Molecular, Cellular and Biomedical Sciences, University of New Hampshire

Good colloidal stability is required to develop low-viscosity, stable high-concentration protein solutions. Charge and charge distribution are major contributors to protein solubility and rheology. Data are presented to show that the amount of charge needed for good colloidal solubility increases with the square of the Stokes radius. This means that a bispecific mAb of 7 nm radius will require nearly twice the charge to achieve the same solubility as a 5 nm mAb. Protein charge cannot be calculated, and importance of measuring the charge will be emphasized.

2:20 Solubility Theory and Relevance to Protein-Protein Interactions Underlying Viscosity in High-Concentration Protein Formulations

William_CallahanWilliam Callahan, MSc, Senior Scientist, Process Development, Amgen

At high protein concentration, many proteins are viscous, resulting in formulations that cannot be administered via parenteral injection. In this work, we demonstrate that for water miscible solvents, common properties of these solvents may be important in minimizing viscosity. These properties include dispersion forces, polar forces and hydrogen bonding. A case example will show how evaluating solubility parameter space is relevant in mitigating the effects of solution viscosity at high concentration.

2:50 Applying Modified Colloidal Theories to Model Protein Solutions from Low to High Protein Concentrations

Cesar_Calero-RubioCesar Calero-Rubio, PhD, Scientist, Formulation Development, Global Pharmaceutical Development Biologics, Sanofi

Several experimental and computational methodologies are combined at low protein concentrations (c2) to model protein self-interactions. Scattering techniques are used to measure self-interaction parameters of protein solutions as a function of solution formulation. Molecular scale simulations are used to predict protein self-interactions at high c2 based on low-c2 measurements. The results show the viability and limitations of using simplified molecular models to predict protein self-interactions.

3:20 Thermodynamics of Osmolyte-mAb Interaction in Aqueous Solutions

Chaitanya_SudrikChaitanya Sudrik, Postdoctoral Associate, Chemical Engineering, Massachusetts Institute of Technology

We have investigated via vapor pressure osmometry the interactions of osmolytes in 3 antibodies with different properties. The transfer free energy (0.5-0.9 kJ/mol per 1000 Ao2 of protein-water interface, for 200 mM osmolyte) follows the trend: trehalose and sucrose> sorbitol and is not affected by a change in solution pH from 5.5 to 7.2 or change in the buffer from 25 mM Na-acetate to 25 mM Histidine.HCl.


3:50 Refreshment Break in the Exhibit Hall with Poster Viewing


4:45 Plenary Keynote Session

The Next 10 Years: Looking Ahead to Next-Gen Bioprocessing

4:45 pm Chairperson’s Remarks

John Sterling, Editor in Chief, Genetic Engineering & Biotechnology News (GEN)

 

Murray_Jerry4:50 Digital Transformation to Advance Next-Generation Biomanufacturing through Data Integration and Analytics

Jerry Murry, PhD, Senior Vice President, Process Development, Amgen

Hundreds of millions of data points are currently generated through the development and execution of biopharmaceutical processes. It is expected that the volume and complexity of biomanufacturing data is set to grow exponentially as developers and manufacturers integrate novel sensors, smart materials, process analytical technologies and process automation into laboratories and manufacturing plants. This presentation will describe the value associated with a comprehensive digital strategy incorporating a structured data integration and analytics platform inclusive of AI, predictive modeling and visualization, and how digital transformation can advance next-generation biomanufacturing.

5:20 Driving Change in Biomanufacturing through Innovation in Processes, Technologies and Operations

Eliana Clark, PhD, Vice President, International Manufacturing Operations, Biogen

A critical step in meeting the demand of biologic production worldwide involves implementing disruptive manufacturing technologies, processes and capabilities. This talk will use Biogen’s new manufacturing site in Switzerland, due to go online in 2019, as an example to demonstrate the new processes, operational models and technologies being adopted to drive value through innovation and deliver new medicines in areas such as Alzheimer’s.

5:50 End-to-End Solutions Considering New Trends in Biomanufacturing

Guillaume Plane, MSc, MBA, Manager, Global Development, Biodevelopment Solutions, MilliporeSigma

The presentation will get into the current state of biomanufacturing, from DNA to market approval, considering the way a key supplier can support drug makers to the fullest, thanks to a deep understanding of the trends that could affect our industry in the midterm, including growth of the pipelines, strengthening of regulations, and acceleration of timelines, for development as well as for the set-up of capabilities. Some thoughts and ideas will be proposed to consider commercial manufacturing with single-use equipment.

6:25 Close of Plenary Keynote Session

6:25 Networking Reception in the Exhibit Hall with Poster Viewing

7:30 End of Day

Thursday, August 16

8:00 am Registration Open and Morning Coffee

PREDICTION & MEASUREMENT OF PROTEIN-PROTEIN INTERACTIONS, VISCOSITY & SOLUBILITY (CONT.)

8:25 Chairperson’s Remarks

Jan Jezek, PhD, CSO, Research & Development, Arecor, Ltd.

8:30 Weak IgG Self- and Hetero-Association Characterized by Fluorescence Analytical Ultracentrifugation

Danlin_YangDanlin Yang, PhD, Senior Scientist, Biotherapeutics Discovery, Boehringer Ingelheim

Weak protein-protein interactions may be important to binding cooperativity. A panel of 7 fluorescently labelled tracer IgG antibodies, differing in variable (V) and constant (C) region sequences, were sedimented in increasing concentrations of unlabeled IgGs of identical, similar, and different backgrounds by analytical ultracentrifuge fluorescence detection. Weak IgG:IgG attractive interactions were detected and characterized by global analysis of the hydrodynamic nonideality coefficient, ks.

FORMULATION DESIGN, DRUG DELIVERY AND SMART DEVICES

9:00 Successful High-Concentration Products – Creative Formulation and Device Choice

Jan_Jezek_2Jan Jezek, PhD, CSO, Research & Development, Arecor, Ltd.

Developing stable, low-viscosity therapeutic protein products is extremely challenging and requires a number of good decisions to be made along the development process with respect to the product concept, formulation, delivery device. The talk will describe innovative formulation approaches enabling differentiated product concepts, as well as examples of intellectual property considerations that have to be taken into account during the development.

9:30 Sponsored Presentation (Opportunity Available)

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

10:45 Identification and Characterization of Excipients and Excipient Mixtures Based on Thermodynamic Models and Advanced Analytics

Christoph Brandenbusch, PhD, Group Leader, Department of Biochemical and Chemical Engineering, Laboratory of Thermodynamics, Technical University of Dortmund

Classically, excipients and excipient mixtures are identified based on heuristic or “trial-and-error” based approaches. However, it is unlikely that this results in optimal formulations. It is thus desired to develop a physically-sound method to identify excipients and excipient mixtures based on modeling/predicting the intermolecular interactions in solution. This allows to access the suitability of multi-excipient systems and to determine the optimal excipient mixture in an early stage, circumventing cost-intensive screening methods.

11:15 Engineering Proteins for Long-acting Ocular Delivery

Devin Tesar, PhD, Scientist, Drug Delivery, Genentech, Inc.

Ocular delivery of protein therapeutics often requires favorable viscosity properties to support high concentration formulations. Using structure-based design we generated high-affinity mutants of a backup Fab which exhibited superior viscosity properties but inferior target binding and inhibition as compared to the lead candidate. Two of these mutants, FM1 and FM2, exhibit binding and target inhibition equal or superior to that of the lead molecule, while retaining the superior viscosity profile.

11:45 A Virtual Formulation Screening Tool for High Concentration Antibodies: Formulations with Reduced Viscosity

Sarah Altinoglu, PhD, Post-Doctoral Scientist, Bioproduct Research and Development, Eli Lilly and Company

Development of high concentration antibody formulations (>150mg/ml) require consideration of product viscosity, leading to additional conditions to evaluate and compounding the already high material and time requirements to develop the proper formulation. A virtual tool to aid in screening out formulation conditions with the highest likelihood of high viscosity was built based on the correlation analysis of antibody molecular properties and formulation viscosity responses..

12:15 pm Enjoy Lunch on Your Own

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

1:55 End of Conference


6:00 - 9:00 Recommended Short Course*

SC11C: Development of Innovative and Competitive Biologic Formulations in Complex Patent Landscape

Instructor: Jan Jezek, PhD, CSO, Research & Development, Arecor, Ltd.

* Separate registration required.


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Premier Sponsors:

Millipore Sigma

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