Cambridge Healthtech Institute's 11th Annual

Protein Aggregation and Stability in Biopharmaceuticals

( 生物制药的蛋白质聚集与稳定性 )

Understanding and Controlling Protein Aggregation from Early Development through Scale-Up and Clinical Production

2018年5月3-4日 | World Trade Center | 马萨诸塞州波士顿


The phenomenon of protein aggregation is a complex conundrum that impacts biopharmaceutical development at virtually every stage. All mechanisms of aggregation are not conclusively known, but the industry must use every effort to characterize and control these conditions, applying a rapidly changing landscape of assays, instrumentation, formulation strategies and process steps. The PEGS Protein Aggregation and Stability in Biopharmaceutical Products offers important scientific updates and a forum for dialog among the stakeholders in this challenging arena.

Final Agenda

Recommended Short Course(s)*

SC8: Introduction to Biophysical Analysis for Biotherapeutics: Discovery & Development Applications

*Separate registration required.



12:00 pm Registration

12:35 Luncheon in the Exhibit Hall with Poster Viewing

1:40 Chairperson's Remarks

David Brockwell, PhD, Associate Professor, School of Molecular and Cellular Biology, University of Leeds, United Kingdom

1:50 Emerging Approaches for Understanding Early Aggregation Transients

Arun Alphonse Ignatius, PhD, Principal Scientist, Pfizer

Monoclonal antibodies could be susceptible to aggregation, especially at concentrations relevant to pharmaceutical formulations. (>100 mg/ml). Although conventional low resolution biophysical methods probe conformational stability of mAbs in relation to aggregation, molecular origins of aggregation are largely elusive. Nuclear magnetic resonance (NMR) studies on mAb and mAb fragments provide structural fingerprinting at an atomic resolution that can be potentially correlated to aggregation propensities of mAbs.

2:20 Protein Aggregation and Gelation - Insight from Combining Scattering, Rheology and Computer Simulations

Peter Schurtenberger, PhD, Professor, Physical Chemistry, Lund University, Sweden

Understanding and avoiding protein aggregation and gelation is essential in formulating biopharmaceuticals. We show how we can use a combination of advanced characterization techniques such as small-angle neutron (SANS) and X-ray scattering (SAXS), neutron spin echo measurements and microrheology experiments, combined with the theoretical toolbox from colloid physics and state-of-the-art computer simulations, to assess and predict aggregation and gel formation in concentrated solutions of biopharmaceuticals.

2:50 KEYNOTE PRESENTATION: Complement Activation in Human Serum by Protein Particles Is Influenced by Interactions with Containers

Theodore W. Randolph, PhD, Professor, Chemical & Biological Engineering, University of Colorado, Boulder

Acute immune responses to therapeutic proteins include anaphylactic shock, which may result from activation of the complement cascade. Container materials may affect the number of particles formed following freeze-thawing or agitation of protein formulations. Testing of these formulations in human serum shows that levels of activation of Bb, C3a and C5a, all critical intermediates on the complement activation cascade, are strongly correlated with levels of particles within antibody formulations.


3:20 Presentation to be Announced

3:50 Networking Refreshment Break

4:20 Assessing the Aggregation of Biopharmaceuticals in vitro and in vivo

David Brockwell, PhD, Associate Professor, School of Molecular and Cellular Biology, University of Leeds, United Kingdom

Protein-based biopharmaceuticals are susceptible to unfolding, mis-folding and aggregation by environmental perturbations that include hydrodynamic flow. Aggregation thus poses an enormous challenge to biopharmaceutical development, production, formulation and storage. To address this problem, we describe an in vivo method to rapidly assess candidates for developability and an in vitro method to assess candidate manufacturability or process suitability for the manufacture of aggregation-prone biopharmaceuticals.

4:50 Combining Viral Particle Counting, Biological Characterization and Advanced Kinetics to Predict Vaccine Stability

Didier Clenet, PhD, Research Scientist, Formulation & Stability, Sanofi Pasteur, Canada

In-depth characterization of a purified rabies vaccine was performed in term of virus counted, aggregation state, and antigenic and genomic titer. Agreement between results from NTA (nanoparticle tracking analysis) and ELISA was assessed. Additionally, forced degradation study was combined with modern kinetic-based modeling approach to delimitate a time-temperature stability domain into which the vaccine would be kept antigenic. Based on a kinetic model, 3 years of vaccine stability was predicted at 5°C.

5:20 End of Day

5:20 Registration for Dinner Short Courses

Recommended Dinner Short Course(s)*

SC11: Strategic/Modular Bioassay Design and Analysis

*Separate registration required.


8:00 am Morning Coffee


8:30 Chairperson's Remarks

Neal Whitaker, PhD, Associate Researcher, Macromolecule and Vaccine Stabilization Center, Pharmaceutical Chemistry, The University of Kansas School of Pharmacy

8:35 Chemical Stability Screening in Early Stage Discovery: New Isomerization and Deamidation Datasets

Yingda Xu, PhD, Director, Protein Analytics, Adimab

Isomerization and deamidation of therapeutic leads can often delay development timelines and provide challenge and risks for downstream process. Sequence-based prediction to scan for NG and DG can often lead to false positive results. Here we report the chemical liability analysis of ~140 clinical stage antibodies, under forced degradation conditions.

9:05 FEATURED PRESENTATION: Methods for Identifying Monoclonal Antibodies with Drug-Like Properties

Peter M. Tessier, PhD, Professor, Pharmaceutical Sciences and Chemical Engineering, University of Michigan

The success of antibody therapeutics is dependent not only on their specific bioactivities but also on their physiochemical properties. Here we report the development of methods for identifying antibodies with drug-like properties based on their chemical compositions and biophysical properties.

9:35 Sponsored Presentation (Opportunity Available)

10:05 Networking Coffee Break

10:35 Developing a Screening Platform for Novel Biotherapeutics

Zhi (Jay) Guo, PhD, Senior Scientist, Global Protein Sciences, AbbVie Bioresearch Center

Novel bi-functional biologics with a variety of formats to choose from (scFv, Fab, mAb, etc.) and fused to different payloads (cytokines, growth factors, a different scFv, etc.) is of immense interest for targeted delivery and improved efficacy. Payloads can be fused at different positions and spacer lengths and it is now apparent that payloads dominate production and stability of biologics; thus, confounding drug-like properties (DLPs). To better understand structure-function relationship and rapidly advance candidates with good DLPs we will discuss our throughput screening process.


11:05 Characterization of Aggregates That Are Concentration-Dependent

Neal Whitaker, PhD, Associate Researcher, Macromolecule and Vaccine Stabilization Center, Pharmaceutical Chemistry, The University of Kansas School of Pharmacy

High protein concentrations in biopharmaceutical drug products (>100 mg/ml) can lead to colloidal instability and elevated levels of aggregation. Numerous analytical techniques are required to characterize these aggregates, from small soluble aggregates, to submicron and subvisible particles to larger visible particles. This talk will present several case studies utilizing these methods with the aim of reducing the propensity of aggregate formation as part of the development of stable protein formulations.

11:35 Optimizing Cryoprotectant to mAb Ratios to Mitigate Aggregation

Tom Crowley, PhD, Principal Scientist, Pharmaceutical R&D, Pfizer, Inc.

The use of disaccharides such as sucrose and trehalose as cryoprotectants in monoclonal antibody formulations is a well-established strategy in protecting against freeze thaw induced aggregation. This work explores the impact of varying the ratio of cryoprotectant to antibody to meet the challenges of ensuring protein stability, controlling viscosity, and maintaining isotonicity for high concentration dosage forms.

12:05 pm Challenges and Opportunities in the Use of Surfactants in Protein Drug Products

Christoph Grapentin, PhD, Postdoctoral Fellow, Pharmaceutical Development, F. Hoffmann-La Roche Ltd., Switzerland

Poloxamer 188 (P188) is a valuable alternative surfactant for parenteral use, due to the widely known issues regarding polysorbate degradation and lack of clinical experience with other surfactants. An increased understanding of P188's stabilization mechanism, its interplay with pharmaceutically relevant interfaces (e.g. air, silicone oil), mAbs and complex protein formats is desirable to increase efficiency and confidence during formulation development. In our studies, we combined advanced analytical methods to better correlate and understand real-time formulation data.

12:35 Luncheon Presentation (Sponsorship Opportunity Available) or Enjoy Lunch on Your Own

1:05 Networking Refreshment Break


1:35 Chairperson's Remarks

Zhi (Jay) Guo, PhD, Senior Scientist, Global Protein Sciences, AbbVie Bioresearch Center

1:40 Rapid, High-Resolution Analysis of Monoclonal Antibody Aggregates Using Chip LFMC

Raja Ghosh, PhD, Professor, Chemical Engineering, McMaster University, Canada

Laterally-fed membrane chromatography (LFMC) has been shown to be suitable for high-speed, high-resolution separation and analysis of biologicals such as monoclonal antibodies. A scaled-down Chip LFMC device suitable to rapid and high-resolution analysis of monoclonal antibody aggregates will be discussed. The typical separation time with Chip LFMC is of the order of a couple of minutes, which is significantly faster than UPLC. Also, the separation can be carried out using inexpensive low-pressure liquid chromatography systems.

2:10 Product Quality Control Strategy Development for Non-mAb Complex Modalities by Using Combinatorial Cell Engineering and OMICS Screening Tools

Zhimei Du, PhD, Head, Cell Line Development, Merck & Company, Inc.

New product-related impurities have been found to accompany non-mAb complex modalities, which usually don't exist in standard mAb production. Many of these PQAs are related to protein folding and assembly efficiency inside the cell, which impact post-translational modifications directly or indirectly. Our presentation will illustrate the importance of selecting appropriate cell/upstream conditions through screening and/or engineering, as part of quality control strategy to obtain the desired recombinant protein PQA profile.

2:40 Process Control Challenges in Controlling Aggregation

Jason Fernandez, Scientist, Protein Pharmaceutical Development, Biogen

Control of aggregation is a common goal across biopharmaceutical manufacturing processes, from the bioreactor through fill finish operations. As process controls vary along the manufacturing process, with each processing operation having unique challenges to aggregation control, an end-to-end process control strategy is important in minimizing the ultimate aggregate level in finished products. This talk will highlight the concept and challenges of end-to-end process control of aggregation.

3:10 Evaluation of Sub-Visible Particle Technologies Used to Characterize Particles from Packaging Components

John Rech, Technology Manager, Particle Testing, Analytical Laboratory, West Pharmaceutical Services

Measurement and control of sub-visible particles (SVP) in injectables is a growing concern in pharma because of potential to cause patient harm. Global compendia have specifications in the final drug product for particles >100µm and >10µm, but current methods can measure below 10µm and into the submicron range. To better understand SVP contribution, particularly from silicone-treated stoppers, a study was designed to determine optimal methods to measure and identify SVP.

3:40 End of Conference

* 活动内容有可能不事先告知作更动及调整。

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