Part Three: Comparability for Biologics


In the lifecycle of a biotech product, manufacturing changes (process, site, equipment) to the drug substance or drug product are to be expected. When such changes occur, manufacturers need to demonstrate sufficient and appropriate comparability between pre-change and post-change to ensure that the safety and efficacy of the product remains intact. The biggest challenge therein, lies in what constitutes “sufficient” and “appropriate”? How do you know what may/may not be affected and what needs to be tested? When do you need to conduct such assessments? How much information is sufficient? What techniques should you use to obtain the best possible comparison? These and many other questions are on the minds of many analytical scientists as the products move along the development pathway, from early stage to formulation.

The Comparability for Biologics conference brings together scientists and engineers from core analytical lab, drug development, process sciences, formulation, manufacturing, QA/QC and regulatory affairs to share strategies, approaches and technologies that will help overcome these comparability questions and challenges.

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Thursday, March 12

7:30 am Registration and Morning Coffee


REGULATORY PERSPECTIVES ON
COMPARABILITY ASSESSMENTS

8:30 Chairperson’s Opening Remarks

Methal Albarghouthi, Ph.D., Senior Scientist, Regulatory Sciences & Strategy, MedImmune, Inc.


8:35 KEYNOTE PRESENTATION: An FDA Perspective on Risk-Based and Phase Appropriate Comparability

Marjorie ShapiroMarjorie Shapiro, Ph.D., Chief, Laboratory of Molecular and Developmental Immunology, Division of Monoclonal Antibodies, CDER, FDA

It can be challenging to distinguish the expectations for post-marketing comparability studies from those during development. As clinical development progresses from Phase 1 through Phase 3, regulatory expectations increase; however, there may be limited numbers of pre- and post-change lots. This talk will provide case studies from different stages of the product development lifecycle and discuss FDA expectations for development of novel and biosimilar therapeutic products.


9:05 An Industry Regulatory Affairs Perspective on Managing Complex Changes

Allison WolfAllison Wolf, Senior Research Scientist, Regulatory Affairs CMC Biotechnology, Eli Lilly and Company

Manufacturing changes are often unavoidable during clinical development and commercialization. Implementing complex changes including multiple changes at the same time creates risk that needs to be managed. This presentation will include several examples involving complex changes and will highlight the approach taken to demonstrate comparability and to effectively communicate these changes to regulators.


RISK ASSESSMENT AFTER
MANUFACTURING CHANGES

9:35 Risk-Based Comparability Assessment of Post-Manufacturing Process Change during Early Clinical Development Stage of a Monoclonal Antibody: General Considerations and Case Study

Veronique BaillyVeronique Bailly, Ph.D., Bioprocess Development CMC Team Leader, Biogen Idec

Comparability assessments at early stage of clinical development usually face limited manufacturing history and high uncertainty on the potential impact of attributes such as aggregates, acidic species and N-glycans on efficacy and safety. We will present a case study describing the comparability assessment after changes in the manufacturing process of a monoclonal antibody between phase 2a and phase 2b, as well as after a change in a raw material impurity.

10:05 Primary and Higher Order Structural Characterization Strategies for Biosimilarity Assessment

Fiona GreerFiona Greer, Ph.D., Global Director, Biopharma Services Development, Life Science Services, SGS

Biosimilar development requires comprehensive physicochemical characterization at many stages. Initially, intensive characterization of multiple originator batches determines variability of the target quality attributes for the biosimilar. Subsequently, side-by side comparison is carried out with the originator to demonstrate “Biosimilarity”. Strategies for comparability will be discussed particularly for antibodies where their size and complexity requires orthogonal approaches.

 

10:20 Sponsored Presentation (Opportunity Available, please contact Jon Stroup, jstroup@healthtech.com)

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

11:05 Risk-Based Comparability Strategy for Clinical Development of Therapeutic Proteins

Methal AlbarghouthiMethal Albarghouthi, Ph.D., Senior Scientist, Analytical Biotechnology, MedImmune, Inc.

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 managing variation in quality attributes levels in clinical trial material to represent long term manufacturing variability will be discussed.

11:35 Comparability Approaches during Clinical Development and Post-Approval

Matthew KaloMatthew Kalo, Ph.D., Senior Group Leader, Protein Analytical Chemistry, Genentech, Inc.

Comparability assessments ensure drug product after manufacturing changes is not adversely impacted due to the change. Two key questions arise during the risk assessment of the change. Is the drug product generated by the changed process or at a new facility highly similar or different? If the material is different, what are the potential impacts to patients? Case studies and strategies from clinical development and after approval will be provided.


 

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


ANALYTICAL TOOLS AND APPROACHES
FOR COMPARABILITY STUDIES

1:40 Chairperson’s Remarks

Elizabeth Higgins, Ph.D., Founder & CEO, GlycoSolutions Corporation

1:45 New Analytical Approaches to Probe the Interrelationships between Protein Higher-Order Structure and Pharmaceutical Stability as Applied to Comparability Assessments

David B. VolkinDavid B. Volkin, Ph.D., Takeru and Aya Higuchi Distinguished Professor;Director, Macromolecule and Vaccine Stabilization Center, Department of Pharmaceutical Chemistry, University of Kansas

This presentation will examine new analytical approaches to assess protein physical stability profiles and their applicability for comparability assessments. Illustrative case studies will include (1) high-throughput biophysical analysis examining the conformational stability of different IgG1-Fc glycoforms, and (2) H/D exchange mass spectrometry to correlate local flexibility and IgG1-mAb physical stability in presence of different salts and excipients.

2:15 Application of Spectral Similarity Analysis for Product Comparability Exercise

Thomas LerchThomas Lerch, Ph.D., Senior Scientist, Analytical R&D, Pfizer, Inc.

Biophysical tools, including circular dichroism spectroscopy, have often been used to provide qualitative assessment of the similarity in higher order structure for biological molecules through visual inspection of the characteristic spectral overlay. It is desirable to include quantitative analysis for more rigorous comparison and easier presentation of results. This presentation will focus on application of spectral similarity analysis in evaluating the similarity of spectra for lot-to-lot comparison and for sample stability analysis.

2:45 Characterization of Fusion Proteins by Mass Spectrometry: Challenges to Analysis and Data Interpretation

James BourellJames Bourell, MSc., Senior Scientist, OncoMed Pharmaceuticals

Current efforts at Oncomed to develop novel cancer therapeutics have generated a significant increase in the number of protein conjugates. The recombinant expression and subsequent protein analysis of protein conjugates can be more challenging due to the complexity of protein folding, N- and O-linked glycosylation sites, and other required posttranslational modifications. This talk will focus on efforts to modify sample preparation schemes and to apply different LC-MS and LC-MS/MS techniques to meet these challenges.

3:15 Refreshment Break in the Exhibit Hall with Poster Viewing

3:45 Quantitative Analysis of Site-Specific Glycosylation of Recombinant Therapeutic Glycoprotein as A Tool to Support Drug Development

Joanne Cotton, Staff Scientist I, Genzyme Corp.

4:15 Demonstrating Glycosylation Comparability – Assay Selection

Elizabeth HigginsElizabeth Higgins, Ph.D., Founder & CEO, GlycoSolutions Corporation

One of the challenges in analyzing the glycosylation of a biotherapeutic is deciding on how many and which assays are necessary. For release testing, oligosaccharide profiling by HPLC is often sufficient to demonstrate lot-to-lot consistency. However, sometimes it is important to add additional assays for characterization and comparability testing, such as tests for specific monosaccharides, for certain carbohydrate epitopes or for O-glycosylation. A strategy will be presented for selecting the optimal mix of assays.


4:45 Breakout Discussions

Table 1: Biologics Higher Order Structure Analysis Technologies

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

  • What are the technologies out there for Biologics Higher Order Structure Analysis?
  • Is there a gap between required HOS characterization and what the technologies can offer?
  • Can we define an HOS impurity profile?
  • How to link HOS impurity to immunogenicity and other properties of Biologics?

Table 2: Considerations for Pre-Approval and Post-Approval Comparability for Biosimilars

Moderator: Jennifer Liu, Ph.D., Director, Analytical Sciences, Biosimilars Process Development, Amgen Inc.

  • What are the challenges in managing comparability and similarity after process changes during biosimilar development
  • Are there unique issues for managing comparability post-approval for biosimilar products
  • Should comparability be considered a stand-alone exercise for approved biosimilars

Table 3: Analytical Strategies For Comparability

Moderator: Thomas Lerch, Ph.D., Senior Scientist, Analytical R&D, Pfizer, Inc.

  • What are the key strategic differences between comparability and biosimilarity exercises?
  • What is the the right assay for a given process change?
  • What are the similarity criteria for non-quantitative assays?  

 

5:45 Close of Day and Short Course Registration



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Friday, March 13

8:00 am Morning Coffee


ANALYTICAL TOOLS AND APPROACHES FOR COMPARABILITY STUDIES (CONT’D)

8:30 Chairperson’s Opening Remarks

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

8:35 State-of-the-art Analytical Tools for Comparability and Biosimilarity Assessment

Horst BierauHorst Bierau, Ph.D., Scientific Advisor and Relation Manager, Pharmaceutical & Analytical Development, Biotech Products, Merck Serono

Detailed knowledge of the intactness, the structure, and post-translational modifications of a protein is a prerequisite for the development of biopharmaceuticals. The primary structure, the conformation, as well as modifications of a protein determine its function. This talk presents case studies on the characterization of biopharmaceuticals by state-of-the-art analytical techniques in order to ensure comparability of samples, e.g. manufactured by different processes.

9:05 LC-MS/MS for Glycan Analysis

Jianjun LiJianjun Li, Ph.D., Director, Institute of Biological Sciences, National Research Council, Canada

Protein N-glycosylation modulates the physical, chemical and biological properties of proteins. Alteration of the glycan structures can take on several forms including different monosaccharide compositions, changes in connectivity (sequence), and most interestingly, changes in the types of linkages between monosaccharides. In this presentation, I will discuss LC-MRM based strategy for quantification of N-glycans, which enables sensitive and consistent identification and quantification of diverse glycans across multiple samples.

9:35 Higher Order Structure Analysis for Novel and Biosimilar mAb Conformational Comparability

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

Using antibody arrays, we’ve developed a novel technology that provides a sensitive, systematic and high-throughput approach for mAb Higher Order Structure comparability analysis, generating valuable information for cell line selection, process development and formulation development. Examples will be presented to demonstrate the application of the antibody array in biosimilar as well as novel mAb development and its complementary value to the bioassays and other analytical technologies.

10:05 Networking Coffee Break


ESTABLISHING BIOSIMILARITY

10:30 Current Regulatory and Scientific Issues with Biosimilars in the US

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

Sponsors still have many questions regarding the analytical, non-clinical, and clinical studies required to license their biosimilar products in the US. In this talk, we will discuss FDA’s latest guidance and perspectives on how biosimilarity can be demonstrated and how it will be evaluated by the FDA reviewers, with emphasis on the fundamental role of the analytical similarity studies.

11:00 How Similar Does a Biosimilar Have to Be?

Christopher HollowayChristopher Holloway, Ph.D., Group Director, Regulatory Affairs & CSO, ERA Consulting Group


 


 


 

  • Biosimilars do not need to be “identical” but they should be as “similar” as possible – what does this mean?
  • For parameters that differ from the reference product, what has to be done to support the biosimilarity claim?
  • What are the “deal breakers” in the biosimilar paradigm?
  • What can we learn from past experience in failure of purported biosimilar products?

11:30 Demonstrating Biosimilarity from the Aspects of Functional Characterization

Patrick LiuPatrick Liu, M.D., Ph.D., Senior Director and Global Head, Bioassays and Technology, Teva Pharmaceuticals

Functional assays are essential for biosimilar development, and characterization of molecular functionality is one of the most critical elements to demonstrating biosimilarity. This presentation will cover:


 

  • Product critical quality attributes (CQA) and target product profile (TPP)
  • Functional assays and product characterization
  • Similarity range establishment
  • Issues and challenges on functional similarity demonstration

12:00 pm Establishing Biosimilarity and Comparability with Process and Manufacturing Changes

Jennifer LiuJennifer Liu, Ph.D., Director, Analytical Sciences, Biosimilars Process Development, Amgen, Inc.

During the development life-cycle of biological products, refinement of the manufacturing processes and changes in the production facilities are inevitable in order to support registration and commercialization. Managing comparability while establishing biosimilarity can be a challenge. Appropriate analytical strategies based on the type of changes introduced and stages of product development should be applied to ensure safety and efficacy of the biosimilar product during development and post approval.

12:30 Close of Part Three



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