Part Two: Characterization & Compliance


Characterization and Compliance focuses on application of advanced analytical technologies throughout development. It presents characterization of the complex heterogeneity of ADCs by means of sophisticated technologies such as new inductively-coupled plasma mass-spec ICP-MS, capillary electrophoresis and protein mass spectrometry. A range of technologies for aggregate characterization will also be presented together with an FDA study on pathways that lead to aggregation.  Because host cell proteins have become very hot, we have included a presentation (and short course) on the most advanced technologies for their characterization. Practical case studies on control and monitoring of Critical Quality Attributes and on phase-specific characterization will be presented.Reference standards for product quality and manufacturing consistency will be presented by the FDA and backed up with examples from NIST and a case study from the industry. Regulatory issues are further addressed by regulatory and FDA on concerns such as reference standards, product comparability and the new topic of mycoplasma detection.

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Tuesday, March 10

12:30 pm Registration


CHARACTERIZATION OF SPECIFIC PRODUCTS

1:30 Chairperson’s Opening Remarks

Ned Mozier, Ph.D., Senior Director, Analytical R&D, Biotherapeutics Pharmaceutical Sciences, Pfizer, Inc.


1:35 KEYNOTE PRESENTATION:
New Approaches to Characterization of Biopharmaceutical Products

Igor A. KaltashovIgor A. Kaltashov, Ph.D., Professor, Chemistry, University of Massachusetts, Amherst

Quantitation of biotherapeutics in biological matrices remains a challenging problem in PK studies. One additional complication that is encountered frequently is the close similarity of the biopharmaceutical product and abundant endogenous proteins (e.g., transferrin- or albumin-based drug conjugates). We will discuss the application of traditional isotope labeling techniques (e.g., based on O18 labeling) and new approaches developed in our lab that utilize metal tagging protein therapeutics and their detection, quantitation and imaging based on inductively-coupled plasma mass spectrometry (ICP MS).


2:05 Overcoming Analytical Challenges in Characterization of Heterogeneities of Antibody-Drug Conjugates

April XuApril Xu, Senior Principle Scientist, BioTx – Analytical R&D, Pfizer, Inc.

An antibody drug conjugate exhibits additional heterogeneity compared to the corresponding monoclonal antibody. In this presentation, a case study will be presented on how heterogeneity in an antibody-drug conjugate is characterized. In particular, the application of improved analytical techniques using capillary electrophoresis and protein mass spectrometry are applied to characterize the heterogeneities due to drug load distribution.

2:35 Exploring the Structure and Flexibility of Dual Variable Domain Immunoglobulins Alone and with Bound Antigens

Czeslaw Radziejewski, Ph.D., Associate Director, Analytical Development, Process Sciences, AbbVie, Inc.

3:05 Development of Mass Spectrometry-Based Approaches to Study the Dimerization of Therapeutic Monoclonal Antibodies

Shunhai WangShunhai Wang, Ph.D., Scientist, Analytical Chemistry, Regeneron Pharmaceuticals, Inc.


 


 

Bruker3:35 Epitope Mapping Enabled with Fast Photochemical Oxidation of Proteins Approach

Yuan Cao, Ph.D., Protein Analytics, Adimab, LLC

Characterization of the antibody/antigen interaction (epitope mapping) provides the fundamental understanding for rational design of therapeutic mAbs. Fast Photochemical Oxidation of Proteins (FPOP) has recently been developed in academic labs as an alternative method for HDX MS method. Here, we designed an adapted FPOP approach coupled with affinity precipitation and LC-MS/MS. As a result, we profiled the conformational epitope of target of interest #1 and #2 against commercialized mAbs and mAb leads from Adimab workflow.

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


CHARACTERIZATION AND CONTROL OF
SUB-VISIBLE PARTICLES AND AGGREGATES

4:45 Assessing Aggregation of Therapeutic Proteins in Human Plasma

Shen LuoShen Luo, Ph.D., Senior Staff Fellow, Division of Therapeutic Proteins, Office of Biotechnology Products, CDER/FDA

The formation of aggregates in therapeutic proteins could adversely impact product safety and efficacy. Therefore, the levels of aggregate must be adequately controlled throughout the formulation and clinical administration procedures. We are interested in understanding product aggregation under conditions mimicking clinical settings, which involve the active pharmaceutical ingredient, formulation excipients, diluent, and plasma components. This presentation describes our findings about the pathways leading to protein product aggregation in human plasma.

5:15 Reversible Self-Association and Stability in a Monoclonal Antibody

Julie Wei, Ph.D., Scientist II, Protein Pharmaceutical Development, Biogen Idec, Inc.

This work is a biophysical characterization study of a monoclonal antibody that displays reversible self-association and poor stability. A possible connection between the protein’s self-association with poor stability has been investigated by a suite of biophysical methods including AUC, FTIR, thermal and chemical denaturation, and HDX-MS, as well as molecular modeling. A structural basis for the reversible self-association and poor stability is proposed.

5:45 Close of Day / Short Course Registration



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Wednesday, March 11

7:30 am Morning Coffee


REGULATORY PERSPECTIVES AND
PHASE SPECIFIC REQUIREMENTS

8:00 Chairperson’s Remarks

Martin Vanderlaan, Ph.D., Director, Analytical Operations, Genentech, Inc.


8:05 KEYNOTE PRESENTATION:
Perspectives on FDA Expectations for Phase Specific Product Characterization

Emily ShacterEmily Shacter, Ph.D., Consultant ThinkFDA LLC

When do you have to do what in order to meet FDA expectations for the development and approval of protein products for clinical and commercial use? This talk is aimed at helping you understand regulatory expectations on many of the questions that arise during product development, including the extent of analytical characterization studies, method validation, bioactivity, CQA assessment, and process control required at each stage of development.


8:35 Integration of Product Comparability into Process Development Strategies to Ensure Regulatory Approval

Alain BernardAlain Bernard, Ph.D., Vice President, Technical Operations GPS, UCB Pharma

We will demonstrate how appropriately and safely implemented process changes have effectively improved product quality and how some changes can contribute significantly to major progress in process and product understanding with positive impacts for the patients. We will exemplify how an extensive array of analytical tools, including some low-throughput but highly indicative quality tests can be used to increase chances of success with the comparability exercise.

9:05 Case Study on Early and Late Stage Characterization of an HSA Fusion Protein to Align with Clinical Phases

Ping FengPing Feng, MSc, Director, Analytical Sciences, Biological CMC, Teva Pharmaceuticals, Inc.

The focus of early stage characterization is evaluation of product biological activity and overall purity profile, including assessment of primary degradation pathways, and PTMs to support initiation of early clinical studies (I&II) and setting-up a baseline for future comparability. Late stage characterization includes a full understanding of the purity/impurity profile, and compatibility and product stability to support drug licensure. A case study will be presented on variant characterization of an HSA fusion protein.


9:35 Breakout Discussions

Table 1: Practical Application of New Mass Spectrometry Technology

Moderator: Igor A. Kaltashov, Ph.D., Professor, Chemistry, University of Massachusetts, Amherst

  • Range of mass spec approaches for analytical characterization
  • Potential applications of mass spec: sequence errors, glycoforms,etc.
  • Application of mass spec for ADCs and bispecific antibody characterization
  • Applications for comparability and routine structural assessments

Table 2: Aggregation: Factors that Give Rise to Aggregation and Means of Characterizing Aggregates

Moderator: Shunhai Wang, Ph.D., Scientist, Analytical Chemistry, Regeneron Pharmaceuticals, Inc.

  • Aggregate heterogeneity and challenges for analytical characterization
  • Discussion on contributory factors to aggregation
  • Strategies for aggregate characterization
  • Additional challenges with aggregates

Table 3: Appropriate Use of Functional Assays to Support Product Characterization

Moderator: Tamer Eris, Principal Scientist, Attributes Sciences, Amgen, Inc.

  • Product dependent effector function characterization strategies
  • Understanding product quality attribute impact on effector function activity
  • Tools, technologies and assay formats, e.g. challenges with CDC, ADCC, binding assays, potency assays, surrogate assays

Table 4: Building an In-House Reference Standard System

Moderator: Baolin Zhang, Ph.D., Senior Investigator, Division of Therapeutic Proteins, Office of Biotechnology Products, CDER/FDA

  • Interpretations of the primary reference standard and the working reference standard
  • Discussion of when to do what (BLA stage, before process validation and/or after tech transfer)
  • Forward planning required to ensure there is enough reference material at every stage
  • Analytical testing that needs to be standardized
  • Comparing current reference standards with previous ones
  • Challenges with bioassays regarding reference standards

Table 5: Detection and Characterization of Process-Related Impurities

Maura Kibbey, Ph.D., Senior Scientist Liaison, Biologics and Biotechnology, USPharmacopeia

  • Importance of ensuring that most HCPs are detected and appropriate methods for doing this
  • Besides residual HCP and DNA, what are the other process-related impurities that are hot topics?
  • Comments on USP activities related to residual HCP and DNA detection
  •  
 

10:35 Coffee Break in the Exhibit Hall with Poster Viewing


PRODUCT-RELATED IMPURITIES

11:05 A Regulatory Perspective on the Detection of Mycoplasma in Biotechnology Products

Laurie GrahamLaurie Graham, Ph.D., Product Quality Reviewer, Division of Monoclonal Antibodies FDA/CDER



 


 11:35 Case Study of Development of Host Cell Protein Specific ELISAs to Monitor Process Development 

Chris FongChris Fong, Senior Supervisor, Analytical Operations, Genentech, Inc.

Specific chaperones can be over-expressed in host cells to increase product titer. Chaperone specific ELISAs may be necessary if the chaperones are not detected in the platform HCP ELISA. Chaperone clearance can be monitored by chaperone specific ELISA methods. Strategies for integrating Process Validation clearance data with GMP lot release testing will be discussed.

12:05 pm Sponsored Presentation (Opportunity available, please contact Jon Stroup, jstroup@healthtech.com)

12:35 Luncheon Presentation (Sponsorship Opportunity Available, please contact Jon Stroup, jstroup@healthtech.com)
or Lunch on Your Own


REFERENCE STANDARDS

2:00 Chairperson’s Remarks

Baolin Zhang, Ph.D., Senior Investigator, Division of Therapeutic Proteins, Office of Biotechnology Products, CDER/FDA

2:05 Regulative Perspectives on the Use of Reference Standards in the Development of Therapeutic Proteins

Baolin ZhangBaolin Zhang, Ph.D., Senior Investigator, Division of Therapeutic Proteins, Office of Biotechnology Products, CDER/FDA

Many therapeutic proteins are new molecular entities lacking relevant international or national reference standards, which require the development of in-house reference standards from representative(s) of the actual product lots. When adequately qualified, reference standards ensure the assay performance and validity of testing results regarding product quality and manufacturing consistency. This presentation will focus on regulatory expectations on the use and qualification of in-house reference standards for novel therapeutic protein products.

2:35 The NIST mAb: A Reference Material to Supplement Biopharmaceutical Characterization and Compliance

John E. SchielJohn E. Schiel, Ph.D., Research Chemist, Biomolecular Measurement Division, National Institute for Science and Technology

This presentation will discuss the establishment of an IgG1k Reference Material expected to more firmly underpin regulatory decisions and facilitate the development of originator and follow-on biologics. The RM is intended for a variety of uses including, but not necessarily limited to: system suitability tests, establishing method or instrument performance and variability, comparing changing analytical methods, assisting in method qualification, etc.

3:05 Sponsored Presentation (Opportunity available, please contact Jon Stroup, jstroup@healthtech.com)

3:35 Refreshment Break in the Exhibit Hall with Poster Viewing

4:05 Strategy for Building an In-House Reference Standard System for Early Development through to Commercialization

Michael Huang, Ph.D., Senior Scientist, Analytical Technology, MedImmune, Inc.


CHARACTERIZATION STRATEGY TO SUPPORT CRITICAL QUALITY ATTRIBUTES

4:35 Case Study on Control and Monitoring of Critical Quality Attributes during Process and Product Development

Tamer ErisTamer Eris, Principal Scientist, Attributes Sciences, Amgen, Inc.

Development of biotherapeutic molecules requires in-depth knowledge of the product quality attributes critical for the safety and efficacy of the drug candidate. Consequently, appropriate understanding and assessment of these critical attributes is necessary to develop robust manufacturing processes that deliver consistent product quality and yield. Strategies for control and monitoring of biologically relevant attributes for a monoclonal antibody process will be presented and discussed.

5:05 Networking Reception in the Exhibit Hall with Poster Viewing

6:05 Close of Part Two - Stay on for Part Three: Comparability for Biologics 



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