Always an important consideration in late-stage development for QC and release testing, comparability is now even more of a concern particularly with ADCs and other complex multi-component, combination products, where batch-to-batch comparability poses a huge challenge. In addition, more and more biosimilars are expected to enter the foray of drug approvals in the coming years, giving more angst to companies trying to ensure analytical comparability of their biosimilars to the originators.

The Comparability and Biosimilarity conference aims to open up communication within the industry to discuss the expectations, requirements, acceptable criteria, methodologies and reality concerning analytical comparability and biosimilarity, particularly on protein higher-order structure analysis and interpretation, forced degradation and stability testing, as well as comparability assessment for the heterogeneous antibody-drug conjugates.

THURSDAY, MARCH 17

7:30 am Registration and Morning Coffee

8:30 Chairperson’s Opening Remarks

John P. Gabrielson, Ph.D., President, Elion Labs

ESTABLISHING REFERENCE STANDARDS FOR ANALYTICAL REGULATORY COMPLIANCE

9:10 Strategies for Establishing Reference Standards throughout a Product’s Lifecycle

Susan Park, Ph.D., Senior QC Scientist, Global Biologics QC, Genentech, a member of the Roche Group

Reference standards are a critical component of a product’s development history by providing a link to clinical experience, confirming suitability of methods that assess critical quality attributes and calibrating biological activity, such as in cell-based potency assays. Therefore, a well-characterized reference standard at the time of licensure and a robust maintenance standard provide an important thread of continuity throughout a product’s lifecycle. Strategies for establishing reference standards during late stage phase III through post- approval changes will be presented.

9:40 Higher Order Structure, A Key Quality Attribute to Consider in the Design of Comparability Studies

Íñigo Rodríguez-Mendieta, Ph.D., Manager Biophysical Group, SGS Life Science Services

The testing requirements of biosimilar drug manufacturers aiming to provide technical comparability data, recognized biophysical analysis as a valuable analytical tool. The result is that biophysical analysis is becoming more streamlined to industry requirements. It is no longer simply of academic interest and industry is opting in to this rapidly developing area of analysis in support of biopharmaceutical product development.

9:55 Sponsored Presentation (Opportunity Available)

10:10 Coffee and Pastry Break in the Exhibit Hall with Poster Viewing

HIGHER ORDER STRUCTURE ANALYSIS FOR COMPARABILITY AND BIOSIMILARITY

10:40 Choosing the Right Tools for the Job: Higher Order Structure Methods for Comparability and Biosimilarity

John P. Gabrielson, Ph.D., President, Elion Labs

Higher order structure (HOS) comparisons of protein therapeutics are important components of both analytical comparability and analytical biosimilarity studies, but the methods used to characterize HOS are not always sufficiently sensitive, fit for purpose, or consistently applied. This presentation will explore what fit for purpose means in the context of HOS methods for comparability and biosimilarity and then present a framework upon which different HOS methods may be quantitatively compared to gauge their usefulness for various biopharmaceutical development studies.

11:10 Application of NMR and Biophysical Techniques to Higher Order Structure Comparability Studies

Desiree Tsao, Ph.D., Associate Director, Analytical Development, Momenta Pharmaceuticals

With an increase in size and complexity in the molecules, HOS characterization is increasingly challenging and additional complementary techniques are emerging. Here we present a study where HOS of a brand and biosimilar antibody are compared, utilizing both traditional methods including CD, differential scanning calorimetry, DLS, fluorescence spectroscopy and novel NMR methods. NMR probes directly into the three dimensional structure of a protein, and a suite of experiments was developed to help demonstrate HOS comparability between the brand and biosimilar.

11:40 Assessment of Higher Order Structure Techniques (CD, FTIR and NMR) for Characterization and Comparability of Monoclonal Antibodies

Jasper Lin, Ph.D., Technical Development Scientist, Late Stage Pharmaceutical Development, Genentech, a Member of the Roche Group

Spectroscopic techniques such as circular dichroism (CD) and Fourier transform infrared spectroscopies (FTIR) are widely used to characterize the higher order structure (HOS) of proteins. Additionally, the use of nuclear magnetic resonance (NMR) “fingerprint spectra” has become a viable option to compare samples. Though the characterization of the HOS is important, the sensitivity of these techniques must be evaluated for comparability testing especially of large proteins.

12:10 pm Enhanced Comparability Assessment of Biotherapeutics Using Chemometrics

Robert Kutlik, MSc, Scientist, Biotherapeutics Analytical R&D, Pfizer, Inc.

Higher order structure (HOS) characterization and comparability assessments are an integral part of regulatory filings for biotherapeutics, and typically involve biophysical analyses such as circular dichroism (CD). Effort has been made to enhance the spectral comparison process using orthogonal methods, statistical analysis, chemometrics, and perturbation studies, in addition to visual inspection. Here we describe the sensitivity of several chemometric methods by testing them against a number of different perturbation studies.

12:40 Luncheon Presentation (Sponsorship Opportunity Available) or Lunch on Your Own

1:25 Session Break

2:00 Chairperson’s Remarks

Fouad Atouf, Ph.D., Director, Global Biologics, U.S. Pharmacopeia (USP)

ADVANCED AND HIGH THROUGHPUT METHODS FOR POTENCY AND STABILITY COMPARABILITY

2:35 Comparability of Biologics – A Stability Perspective

Nila Das, Ph.D., Senior Research Investigator, R&D, Bristol-Myers Squibb

Changes in stability of biologics may be in the form of changes to protein folding and 3-dimensional structures. Several changes in manufacturing site, scale or process may occur through the product development. Comparative stability studies are essential to understand how these changes influence the CQAs of both drug substances and products, and eventually support their shelf-life statements. Case studies will be presented to highlight the challenges associated with the stability of biologics from the IND stage through their approval for commercialization.

Moderator: Michael Tovey, Ph.D., INSERM Director of Research, Laboratory of Biotechnology & Applied Pharmacology, Ecole Normale Superieure de Cachan

4:05 Refreshment and Cookie Break in the Exhibit Hall with Poster Viewing

4:35 Application of Differential Scanning Calorimetry in Biotherapeutic Comparability Analysis

Simon Yeung, MSc, Research Associate II, Protein Biochemistry, Regeneron Pharmaceuticals, Inc.

Differential Scanning Calorimetry (DSC) is a sensitive technique commonly used to define protein thermal unfolding transitions, assess relative thermal stability, and compare high order structural content. Multiple characteristic unfolding transitions are often observed, making the method amenable for both establishing identity and the estimation of impurities. Thermodynamic properties such as Tm, enthalpy, and heat capacity were evaluated as indicators of structural similarity and purity.

5:05 mAb Higher Order Structure Comparability Analysis with A Novel Luminex Platform

Xing Wang, Ph.D., President, R&D, Array Bridge, Inc.

Protein conformational array was adapted to the Luminex platform and has demonstrated advantage in large dynamic range, higher sensitivity, increased throughput in the systematic characterization of mAb higher order structure. The adaptation to the new platform with high automation and high throughput will provide a new alternative in mAb higher order structure comparability analysis.

5:35 Close of Day

FRIDAY, MARCH 18

8:00 am Morning Coffee

8:30 Chairperson’s Remarks

Kenneth R. Miller, Ph.D., Senior Scientist, Analytical Biotechnology, Biopharmaceutical Development, MedImmune

BIOSIMILARS – ANALYTICAL REQUIREMENTS AND ROLE OF STATISTICS

8:40 Analytics for Biosimilars: The Inverted Rhino Paradigm

Nadine M. Ritter, Ph.D., President and Senior Analytical Advisor, Global Biotech Experts, LLC.

Analytical characterization efforts for biopharmaceutical products has traditionally ramped up in the later phases of product development. However, biosimilar products have inverted this lifecycle paradigm by requiring extensive analytical characterization before even being allowed to enter the clinic. The nature and degree of testing applied sooner rather than later, can present a substantial challenge to product development teams for timelines and resources, as well as affect the expectations of upper management when considering CMC milestones.

9:10 Forced Degradation Study of a Therapeutic Protein and Reference Product: Comparability Assessment in Support of Biosimilarity

James Prescott, Ph.D., Associate Director, Analytical Development, Momenta Pharmaceuticals

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) created an abbreviated approval pathway for biologic products demonstrated to be “biosimilar” to approved biological products. Forced degradation studies are an important part of the similarity assessment. Quantitative characterization data are presented for a study comparing a recombinant therapeutic protein and the corresponding reference product following exposure to multiple stress conditions. The totality of these data provides a framework for assessing biosimilarity.

9:40 The Role of Statistics in Biosimilarity Evaluation

Harry Yang, Ph.D., Senior Director, R&D, MedImmune

10:10 Networking Coffee Break

COMPARABILITY OF ANTIBODY-DRUG CONJUGATES

10:40 Analytical Characterization and Comparability of an Antibody-Drug Conjugate and Its Parent Antibody Intermediate in Support of Manufacturing Process and Site Changes

Adam Fung, Ph.D., Principal Scientist, Analytical Development, Agensys, Inc.

Consistent with regulatory expectations, analytical characterization of physiochemical and biological properties must be performed throughout the course of development. In addition, product comparability exercises must be performed when changes in manufacturing are encountered to ensure no adverse effects on product safety, efficacy, and immunogenicity. Analytical comparability of an antibody-drug conjugate and its parent antibody intermediate was recently completed to support changes in the manufacturing process, including a site change. The approach and results from the assessment of product comparability will be presented.

11:10 Risk-Based Comparability Strategy for ADCs in Early-Stage Development

Kenneth R. Miller, Ph.D., Senior Scientist, Analytical Biotechnology - Sciences and Strategy, MedImmune, a Member of the AstraZeneca Group

Manufacturing process changes during the course of development for therapeutic proteins should be evaluated for the potential impact to safety and efficacy. A risk-based comparability strategy for pre- and post-change material can be designed based on the extent of the manufacturing process changes, knowledge of product quality attributes, and phase of clinical development. Considerations for comparability studies in early-stage development of ADCs will be discussed.

11:40 Strategies and Challenges for Demonstrating Biological Activity Comparability for ADCs

Jodi A. Pegg, Ph.D., Scientist, Pfizer

A relatively new class of therapeutic compounds for oncology is antibody drug conjugates (ADCs), in which a cytotoxic drug is covalently conjugated to a mAb.  ADCs are designed to facilitate the targeted delivery of cytotoxic drugs to tumors while minimizing systemic toxicity.  Each component of an ADC is important to achieve efficacy with minimal toxicity so the ability to evaluate the potency of this multi-component compound in bioassays is critical.  The complex structure and mechanism of ADCs requires a strategy that involves bioassay approaches for both the mAb (target binding) and the drug (cytotoxic activity).  Studies to evaluate process changes or reference material changes are performed to demonstrate analytical comparability between batches.  Bioassay evaluation is just one component of the overall comparability package, but is critical to understand the impact on biological activity.  Using a case study, this presentation will describe the strategies and challenges for demonstrating biological activity comparability for ADC drug product batches. 

 12:10 pm End of Conference