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9:00am - 9:15am 15 mins
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Workshop 1: Technology for Analytical Characterization: Formulation and Common Challenges
Chairperson's Remarks
  • Julia Ding, Ph.D. - Associate Director, Bristol-Myers Squibb

Workshop Overview

This multi-speaker workshop will begin with an introduction to an array of analytical technologies currently used. Attendees will then hear a diverse range of case studies and unpublished data discussing these relevant and useful analytical technologies for characterization.

9:00am - 5:00pm 480 mins
Info
Workshop 2: Statistical Analysis, Views and Practical Concepts to Build Understanding and Improve Biological Assay Development - A Modular Approach
Statistical Analysis, Views and Practical Concepts to Build Understanding and Improve Biological Assay Development - A Modular Approach
  • David Lansky, Ph.D. - President and Principal Statistician, Precision Bioassay, Inc.

This course will introduce the statistical concepts needed for design and analysis of biological assays, then show how exploiting these, combined with practical considerations, lead to better bioassays. This course is intended for those who are developing, performing, analyzing, managing, or validating biological assays.

Biological assays are complex procedures with many practical constraints. The statistical ideas behind bioassay are, at their core, quite simple; but: 1) there are enough differences between bioassays and other common assays that it is not simple to transfer general design and analysis knowledge to bioassays, 2) there are many statistical ideas used in the design and analysis of modern bioassays, and 3) many challenges in using statistical methods strategically for biological assays. This course will focus on key concepts and practical strategies for assay development, qualification, validation, routine use, monitoring, and assay improvement.

Course agenda:

  • Introduction
  • Statistical Ideas

    • Randomization and Experimental Units
    • Blocking
    • Common Statistical Assumptions & Dealing with Violations
    • Equivalence Tests
    • Design of Experiments (DOE)
  • Properties of and Design of Bioassays

    • Terminology
    • Common Designs and Improved Designs
    • Analysis
    • Using DOE for Bioassay Development
    • Using DOE for Qualification/Validation
  • Strategy: A Modular Approach to Bioassay

    • Analytic Target Profile from Clinical Needs
    • Bias Reduction
    • Assay Throughput
    • Modules
  • Summary & Discussion


Workshop Schedule:

9:00am Start of Workshop

10:45am-11:15am - Morning refreshment break

12:00pm-1:30pm – Luncheon

3:00pm-3:30pm - Afternoon refreshment break

5:00pm Close of Workshop

9:00am - 5:00pm 480 mins
Info
Workshop 3: Taking it to Another Level: Phase Appropriate Validation of Bioassays
Taking it to Another Level: Phase Appropriate Validation of Bioassays
  • Michael Sadick, Ph.D. - Principal Scientist, Catalent Pharma Solutions
  • Michael Merges - Director of Strategic Growth, Biologics Analytical Services, Catalent Pharma Solutions
  • What Phase Appropriate Validation is, how it applies
    to your bioassay, and how does it differ, if at all, from
    Qualification.
  • Guidance for validation work is provided by ICH guidelines
    and USP guidelines. How are they similar, and how
    do they differ?
  • Reliable success of your validation program/efforts will be
    greatly improved if pre-validation activities are done for all
    phase appropriate validation activities.
9:15am - 10:15am 60 mins
Workshop 1: Technology for Analytical Characterization: Formulation and Common Challenges
Hydrogen-Deuterium Exchange Mass Spectrometry Measurements of a mAb Therapeutic: a Multi-national Interlaboratory Comparison
  • Jeffrey Hudgens, Ph.D. - Research Chemist, IBBR Fellow, IBBR/NIST
10:15am - 10:45am 30 mins
Info
Workshop 1: Technology for Analytical Characterization: Formulation and Common Challenges
Practical challenges and technologies for formulation development of ultra-high protein concentration
  • Zhenyu Gu - Scientist III, Global Analytical and Pharmaceutical Development, Alexion Pharmaceutical

The demand for ultra-high protein concentration formulation has been on the continuous rise due to the increasing popularity of self-administrated devices that bring unparalleled convenience to patients. However, the challenges to manufacture, formulation and analysis of ultra-high protein solution increase unproportionally once the concentration surpasses 150 mg/mL. In order to formulate a protein at ultra-higher concentrations at scale, a strategy should be put into place through the molecule screening phase to the late stage development by holistically considering many contributing factors at high protein concentrations. These aspects include but are not limited to concentratability, stability, viscosity, osmolality and assay feasibility during screening, development and pre or post formulation. First and foremost, it is imperative that appropriate theoretical models or evaluation techniques are introduced to select the right molecules that are stable and amenable at ultra-high concentration during the discovery phase. Subsequently, purification, formulation and release testing need to be developed and executed at a manufacturing setup for ultra-high protein solution. In this presentation, practical challenges to selection, formulation and analysis of the right molecule and formulation for ultra-high protein concentration will be discussed. A phase appropriate developability, formulation and testing activities will be introduced for the development of ultra-high protein concentration formulation.

10:45am - 11:15am 30 mins
Workshop 1: Technology for Analytical Characterization: Formulation and Common Challenges
Networking and Refreshment Break
11:15am - 12:00pm 45 mins
Info
Workshop 1: Technology for Analytical Characterization: Formulation and Common Challenges
New Applications for NMR in the Characterization of Biopharmaceuticals
  • Mats Wikström, Ph.D. - Principal Scientist, Group Leader, Higher Order Structure, Amgen

Nuclear magnetic resonance (NMR) has unique capabilities to provide information of the structure and dynamics of proteins including primary, secondary, tertiary, and quaternary structure. In this presentation I will discuss two new applications of NMR for the characterization of biopharmaceuticals.
The first application relates to the assessment of higher order structure in comparability and similarity exercises for innovator and biosimilar products. We have compared 1D NMR methods with established methods for higher order structure (HOS); FTIR and far UV CD for secondary structure, and intrinsic fluorescence and near UV CD for tertiary structure, using a sample set based on two monoclonal antibodies (one IgG1 and one IgG2), with samples of IgG1 spiked with IgG2 and vice versa. Our results show that NMR has the potential to distinguish between a larger set of samples as compared to the traditional HOS methods, and therefore has superior ability to address subtle differences in HOS, a feature that could be directly applicable in comparability and similarity assessments.
In the second application we will show results from a newly developed method to assess hydrodynamic properties by NMR, with the ability to provide a hydrodynamic profile for formulated biologics. In addition, recent developments of this method have provided a novel approach to determine the concentration of excipient for formulated biopharmaceutics. Here we present this new method which can accurately estimate the concentration of polysorbate 80 (PS80) in intact pharmaceutical samples of an arbitrary formulation applied to a formulated antibody with variable levels of PS80.

12:00pm - 1:30pm 90 mins
Workshop 1: Technology for Analytical Characterization: Formulation and Common Challenges
Networking Lunch
1:30pm - 2:15pm 45 mins
Info
Workshop 1: Technology for Analytical Characterization: Formulation and Common Challenges
Intact mass analysis for highly heterogeneous systems: combination of gas phase chemistry and in-line chemical processing in LC/MS
  • Igor Kaltashov, Ph.D. - Professor, UMass Amherst

Intact mass analysis is becoming a commonly accepted tool for the analysis of protein therapeutics. However, its application to highly heterogeneous systems is fraught with problems. In this presentation we will review various experimental strategies that allow meaningful information to be extracted at the intact protein level.

2:15pm - 3:00pm 45 mins
Info
Workshop 1: Technology for Analytical Characterization: Formulation and Common Challenges
Advancing CE-SDS Technology in Biologic Analysis Through the Implementation of Novel Surfactant
  • Julia Ding, Ph.D. - Associate Director, Bristol-Myers Squibb

CE-SDS separation has been widely applied to replace the traditional SDS-PAGE gel assay for protein fragmentation, purity and impurity analysis. The majority of CE-SDS users develop the assays based on a set of commercial reagents from Sciex, For proteins with specific biophysical characteristics, applying Sciex commercial reagents had result poor assay performance and assay induced aggregation artifacts. A few case studies are presented showing how we solve these issues using an unconventional surfactant. They are: • With an invention of a novel CE gel matrix, where an unconventional surfactant was applied, we demonstrated significant improvement in product quality analysis for a fusion protein and monoclonal antibody cases. • Assay induced aggregation can be minimized by applying an unconventional surfactant in CE-SDS separation. In both cases, sample denaturing conditions were shown to contribute to the poor assay performance and formation of aggregate artifacts in CE-SDS separation.

3:00pm - 3:30pm 30 mins
Workshop 1: Technology for Analytical Characterization: Formulation and Common Challenges
Networking and Refreshment Break
3:30pm - 4:00pm 30 mins
Info
Workshop 1: Technology for Analytical Characterization: Formulation and Common Challenges
In-depth characterization of the higher order structures of monoclonal antibodies: a single-labeling FPOP strategy
  • Yuetian Yan, Ph.D. - Scientist, Regeneron Pharmaceuticals

Understanding the mAb aggregation mechanism is of great importance to control aggregate formation in the production of mAb biologics.  However, mapping the dimerization interface in mAb molecule remains challenging, due to the complexity and heterogeneity of mAb dimers. Here, we demonstrated the successful mapping of  the heterogeneous dimer interfaces of a mAb molecule, utilizing a combined approach of native SEC-MS and a novel single-labeling hydroxyl radical footprinting method.

4:00pm - 4:30pm 30 mins
Info
Workshop 1: Technology for Analytical Characterization: Formulation and Common Challenges
Electrophoretic Methods Employed for Deep Characterization of Complex Fc Fusion Therapeutic Proteins
  • Francesco Cristofaro, Ph.D. - Junior Researcher, EMD Serono

Capillary Electrophoresis methods are routinely used to monitor several productrelated
impurities. Here, electrophoretic methods are employed for deep characterization of complex Fc fusion therapeutic proteins. The work extends the use of a fractionator system and demonstrates the high potential of combing different electrophoretic techniques to elucidate a complete characterized profile.

4:30pm - 5:00pm 30 mins
Info
Workshop 1: Technology for Analytical Characterization: Formulation and Common Challenges
Characterization and Release Assays for Antibody-Drug Conjugates
  • Alvaro Amor, Ph.D. - Scientist, Charles River Laboratories

Understanding the molecular-level impact of a therapeutic is important in designing assays to assess bioactivity in a given formulation over time, which can be mapped through the complimentary approaches of cell-based bioassays and kinetic surface plasmon resonance (SPR) studies. The former provides an in vivo look as to how the drug is affecting a given cell lineage or immune pathway, whereas SPR provides in vitro insight as to how fast and how well the underlying reactions are occurring at the level of protein-protein noncovalent interactions. Antibody-drug conjugate (ADC) characterization benefits from such two-pronged studies, where the ability to specifically destroy cells of interest hinges on binding a target-specific receptor while not causing major immunogenic response. A body of data is presented here, such as SPR profiles of an ADC binding to receptors such as FcRn, FcγR, or the C1q complex, as well as the nature of the affinities underlying these reactions and the connection to information gleaned from bioassays. The assays presented here can be used to monitor stability of a therapeutic drug to understand bioactivity over a period of time, and may be crucial to drug development efforts when considering the poor stability of an ADC as shown in this case study.

5:00pm - 5:05pm 5 mins
Close of Workshops