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.
Thursday, March 12
7:30 am Registration and Morning Coffee
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 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 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.
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 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 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.
10:35 Coffee & Pastry Break in the Exhibit Hall with Poster Viewing
11:05 Risk-Based Comparability Strategy for Clinical Development of Therapeutic Proteins
Methal 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 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
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. 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 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 Quantitative Analysis of Site-Specific Glycosylation of Recombinant Therapeutic Glycoprotein as A Tool to Support Drug Development
Joanne Cotton, Staff Scientist I, Genzyme Corp
3:15 Refreshment & Cookie Break in the Exhibit Hall with Poster Viewing
3:45 Demonstrating Glycosylation Comparability – Assay Selection
Elizabeth 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.
4:15 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?
5:15 Close of Day and Short Course Registration
Friday, March 13
8:00 am Morning Coffee
8:30 Chairperson’s Opening Remarks
Emily Shacter, Ph.D., Consultant, ThinkFDA, LLC.
8:35 LC-MS/MS for Glycan Analysis
Jianjun 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.
9:05 Higher Order Structure Analysis for Novel and Biosimilar mAb Conformational Comparability
Xing 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.
9:35 Oral Poster
Presentation
Comparison of
N-Glycans in Innovator and Biosimilar Erythropoietin Preparations Using the
GlycanMap® Assay Based on BlotGlyco® Bead Technology
Anju Dang, Director, Business
Development, S Bio
Detailed characterization of glycans
on glycoproteins remains an important challenge in the development of
biotherapeutics. With the growing need to evaluate glycan differences
amid innovator products and “biosimilars”, we choose Erythropoietin to analyze
for its complex N-glycan characteristics in innovators (Eprex® /Erypro®,
Biopoin®, and NeoRecormon®) and their biosimilars (Silapo® and
Binocrit®). The GlycanMap® assay revealed some features in
glycan modification including phosphorylation, O-acetylation, antennary
fucosylation, N-acetyllactosamine (LacNAc) structures, “extra”
sialylation, and terminal galactosylation.
9:50 Networking Coffee Break
10:15 Current Regulatory and Scientific Issues with Biosimilars in the US
Emily 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.
10:45 How Similar Does a Biosimilar Have to Be?
Ashvin Patel, Ph.D., Director, Regulatory Affairs (CMC Biologics), ERA Consulting (UK) Ltd.
- 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?
11:15 Establishing Biosimilarity and Comparability with Process and Manufacturing Changes
Jennifer 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.
11:45 Close of Part Three