Well Characterized Biologicals 
Event Information
Document Title
Agenda
| Day One Monday, November 10, 2008 | DAY ONE | DAY TWO | DAY THREE | | ||||
| 7:00 | Registration and Coffee | |||
| 8:00 | Chairperson's Opening Remarks Michael G. Mulkerrin, Ph.D., Vice President, Process Development, OncoMed Pharmaceuticals | |||
| Characterization of Approved Products | ||||
| 8:15 |
A cluster of adverse clinical reactions toward Baxter Heparin Sodium USP was first detected in late December 2007, leading to a recall of vial products in early 2008. The subsequent investigation identified the hypotensive agent as fully sulfated chondroitin sulfate present in the heparin API sourced from China. This investigation and the characterization conducted for product remediation will be discussed. Edward K. Chess, Ph.D., Senior Director, Physical and Chemical Sciences, Technology Resources, Baxter Healthcare Corporation | |||
| 8:45 | Characterization of Oversulfated Chondroitin Sulfate in Heparin and its Association with Adverse Clinical Events Ali Al-Hakim, Ph.D., Branch Chief, Division of New Drug Quality Assessment, CDER, US FDA | |||
| 9:15 | Heparin Monograph and Standards - Current and Future Developments from the USP Tina S. Morris, Ph.D., Director, Biologics and Biotechnology, Department of Standards Development, U.S. Pharmacopeia | |||
| 9:45 | Networking Refreshment Break in Exhibit and Poster Hall | |||
| 10:15 |
Licensed vaccines can have a commercial life of several decades. This can pose a challenge to manufacturers and regulators in that new, relevant analytical technology may allow better characterization and control of established products. This talk will focus on considerations for when, why and how these legacy products should be evaluated for updating. John P. Hennessey, Jr., Ph.D., Independent Consultant (formerly Senior Director, Bioprocess Research and Development, Merck & Co., Inc.) | |||
| 10:45 | Necessity of Change for Plasma and Recombinant Products Roman T. Drews, Ph.D., Regulatory Scientist, Division of Hematology, CBER, US FDA | |||
| 11:15 |
Proteins from human plasma are well-recognized therapeutics, but they are not classified as "Well-Characterized or Specified". The reasons include the undefined nature of the starting material, low purity, complexity and heterogeneity of the products, as well as the history of viral transmission. Advances in process development and analytical methods have considerably improved viral safety and purity of the products. This presentation will address industry's effort and regulator's role in facilitating new technologies for plasma-derived product's quality, safety and efficacy. Case studies will be presented. Andrew C. Chang, Ph.D., Executive Director, PharmaNet Consulting, PharmaNet Development Group, Inc. | |||
| Regulatory Keynote Address | ||||
| 11:45 | Using Quality by Design (QbD) for Biotechnology Products - What are the Unique Considerations and How can QbD Enhance the Development of Biotechnology Products? Steven Kozlowski, Ph.D., Director, Office of Biotechnology Products, OPS, CDER, US FDA | |||
| 12:30 | Luncheon in Exhibit and Poster Hall | |||
| 1:45 | Afternoon Chairperson's Remarks Donald S. Neblock, Ph.D., Senior Director, BioProcess Technology Department, Worldwide Technical Operations, Global Biologics Supply Chain, L.L.C. | |||
| Assessing Structure/Function Relationships | ||||
| 2:00 |
Recent findings have shown that the human IgG2 subclass exists as an ensemble of distinct isoforms, designated IgG2-A, -B and -A/B, which differ by the disulfide connectivity at the hinge region. Data will be presented on the structural and functional properties of the IgG2 disulfide isoforms and techniques to enrich and control them. Thomas M. Dillon, Senior Associate Scientist, Formulation & Analytical Resources, Amgen Inc. | |||
| 2:30 |
Aparna Deora, Ph.D., Senior Principal Scientist, Pfizer Inc. | |||
| 3:00 | Networking Refreshment Break in Exhibit and Poster Hall | |||
| How Hard will it be to Produce Biosimilars? | ||||
| 3:30 |
We compared the biophysical properties of purported rHuEPO products manufactured from Asia and Latin America with the innovator product Epogen® (Epoetin alfa). We analyzed glycoforms, conformational similarity, bioactivity, covalent aggregates, and cleavage products using established methods. All tested rHuEPO products were different from Epogen® (Epoetin alfa). Concentrations varied and did not always match the information provided on the product's label. SungAe Suhr Park, Ph.D., Senior Scientist, Formulation and Analytical Resource Group, Product and Process Development, Amgen Inc. | |||
| 4:00 | FDA's Perspective on Demonstrating Comparability for Biosimilar Products Emily Shacter, Ph.D., Chief, Laboratory of Biotechnology, Division of Therapeutic Proteins, Office of Biotechnology Products, CBER, US FDA | |||
| Industry Keynote Address | ||||
| 4:30 | The Biosimilar Dilemma - A Global Perspective The Biotechnology Industry after a quarter century of incredible successes is poised to face the challenge of low cost biogeneric competition. The need for low cost biosimilars coupled with the patent expiration of many of the block buster biotechnology products paves the way for the emergence of a 20-40 billion dollar biogeneric industry. Nevertheless, there are significant scientific issues that the legislators, public and regulatory authorities will need to resolve. Unlike generic copies of small molecule drugs, the regulatory approval of biosimilars will need to be based on a combination of analytical characterization, in vitro biological activity measurements and potentially human clinical trials, in order to answer important public health questions about efficacy, safety and immunogenicity. This presentation will describe the regulatory and legal issues facing the development of biosimilars as well as present some scientific evidence of the hurdles which must be surmounted. Finally, the talk will conclude with some analytical considerations about the possible detection of contaminated biosimilars outsourced from third world countries. Robert L. Garnick, Ph.D., Senior Vice President, Regulatory, Quality and Compliance, Genentech, Inc. | |||
| 5:15-6:30 | Exhibit and Poster Hall Networking | |||
| Day Two Tuesday, November 11, 2008 | DAY ONE | DAY TWO | DAY THREE | | ||||
| 7:30 | Coffee | |||
| 8:00 | Chairperson's Opening Remarks Nadine M. Ritter, Ph.D., Senior CMC Consultant, Biologics Consulting Group, Inc. | |||
| Process and Product-Related Impurities | ||||
| 8:15 | Product and Process-Related Impurities and their Impact on Product Quality - An FDA Perspective and Recommendations The manufacture and testing process of biotechnology products must provide sufficient control over product- and process-related impurities and process contaminants. Product-related impurities are molecular variants arising during the manufacture and/or storage, which do not have properties comparable to those of the desired product. Process-related impurities are those impurities derived from the manufacturing process, cell culture or downstream processing. Contaminants are adventitiously introduced materials not intended to be part of the manufacturing process. Impurities/contaminants can affect the safety and efficacy of drug products. Characterization of, and control over, impurities can take a graded approach over the course of clinical development. Dr. Rellahan will discuss the types of impurities and contaminants, and regulatory expectations related to control of these substances over the course of clinical development and for licensure. She will also present information on the use of commercial and process-specific assays for host cell protein detection. Barbara Rellahan, M.S., Ph.D., Product Quality Team Leader, Division of Monoclonal Antibodies, Office of Biotechnology Products, CDER, US FDA | |||
| 8:45 | Acidic Variants of Monoclonal Antibodies: Origins, Characteristics, and Impact on Pharmacokinetics The impact of manufacturing processes, characteristics, and pharmacokinetics of antibody acidic variants was examined. Acidic variant formation was mainly caused by exposure to cell culture media components. Acidic variants included glycated, deamidated, reduced, sialylated, and fragmented forms. Pharmacokinetics of acidic variants and starting material were comparable. Although acidic variants are chemically different from the desired product, they are pharmacokinetically equivalent. Paul Motchnik, Ph.D., Senior Scientist, Protein Analytical Chemistry, Genentech, Inc. | |||
| 9:15 | Platform (Generic) Versus Process Specific HCP ELISA The successful development of a CHO Host Cell Protein (HCP) ELISA depends on balancing scientific issues with pragmatic application. The ELISA must be capable of measuring the wide spectrum of HCP potentially present in the process samples. A host specific platform or generic method is viable for multiple products from that host. The development of a CHO HCP platform ELISA will be described. Patrick Dunlap, Research Scientist, Bioproduct Research and Development, Eli Lilly and Company | |||
| 9:45 | Networking Refreshment Break in Exhibit and Poster Hall | |||
| 10:15 | Multi-Product Host Cell Protein Impurity Assays Provide Superior Means of Monitoring Manufacturing Consistency Martin Vanderlaan, Ph.D., MBA, Director, Analytical Operations, Genentech, Inc. | |||
| 10:45 |
The challenge of process development requires attention to the development of comprehensive analytical tools to monitor residual host impurities. A case study is provided where problematic host proteins were isolated, identified and characterized in order to enable a robust production as well as improve product quality. Along the way, further means of monitoring unique species were developed. Ned Mozier, Ph.D., Director, Analytical Sciences, Global Biologics, Research and Development, Pfizer, Inc. | |||
| Technology Workshop | ||||
| 11:15 |  Electrochemiluinescence-Based Imunoassays for Biotherapeutic ApplicationsBiotherapeutics push the limits of traditional methods for immunoassays (e.g. ELISA, RIA). Complex matrices, widely ranging concentrations of analytes and limited sample can make assays intractable. Electrochemiluminescence-based immunoassays improve sensitivity, expand the dynamic range, enable measurement of multiple analytes from a single sample (i.e. multiplexing), work well in difficult sample media and have proven well-suited for use in validated work environments Pankaj Oberoi, Ph.D., Director of Scientific Services, Meso Scale Discovery | |||
| 11:45 | Luncheon in Exhibit and Poster Hall | |||
| 1:15 | Afternoon Chairperson's Remarks Joseph Kutza, Ph.D., Associate Director, CMC Regulatory Affairs, MedImmune | |||
| Strategies to Assure Potency Assays are Measuring the Right Things | ||||
| 1:30 |
Simultaneous development of multiple protein products on shortened timelines dictates rapid assay development and leaves limited time for assessment and selection of an appropriate assay format. This presentation will focus on the phased approach to the potency assay selection based on the stage of the product development. Svetlana Bergelson, Ph.D., Principal Scientist, Analytical Development, Biogen Idec | |||
| 2:00 |
The presentation will discuss the strategy in developing potency assays for a large portfolio of therapeutic antibodies, for early and late stage clinical development. Case studies will be given to show the approach for selecting potency methods mimicking the mechanism of action, as well as being suitable for QC lot release. Binding assays can be good alternatives if proper justification is provided. Yongjian Wu, Ph.D., Scientist, Biological Technologies, Quality Bioanalytical Development, Genentech, Inc. | |||
| 2:30 |
The use of ADDC as a functional bioassay for release testing is impractical. Donor to donor variability and the use of radioactive isotope prohibit its use in a QC setting. We have developed a CD16 binding assay that can be used, in addition to a CDR binding assay, as a surrogate for the ADCC assay. A correlation between these assays and the ADCC assay will be discussed. Laurent J. Fanget, M.Sc., Senior Manager, Bioanalytical Development and Quality Control, Product Operations, PDL BioPharma, Inc. | |||
| 3:00 | Networking Refreshment Break and Last Chance for Exhibit and Poster Hall Viewing | |||
| 3:30 | An FDA Perspective on the Development of Appropriate Potency Assays for Biopharmaceutical Products Understanding a biopharmaceutical's mechanism of action (MOA) is a significant challenge. Potency is defined in 21 CFR 600 as the "...capacity of the product...to effect a given result". Therefore, a major goal in the drug development process includes understanding how the biopharmaceutical interacts with and/or modifies the proposed target to beneficially alter the course of the pathology to be treated. This information is important when developing a robust in vitro model to assess the biopharmaceutical's MOA. ICH Q6b (Specifications: Test Procedure and Acceptance criteria for Biotechnological/Biological Products) states that "Assessment of the biological properties constitutes and equally essential step in establishing a complete characterization profile..." and that "A valid biological assay to measure the biological activity should be provided by the manufacturer". Regulatory considerations associated with the development of potency assays for biopharmaceuticals will be discussed. Carla S. Lankford, M.D., Ph.D., Quality Reviewer, Division of Monoclonal Antibodies, Office of Biotechnology Products, CDER, US FDA | |||
| Advances in Stability Indicating Methods | ||||
| 4:00 | Structure and Stability Changes of Human IgG1 Fc as a Consequence of Methionine Oxidation Dingjiang Liu, Principal Scientist, Protein Formulation, Amgen Inc. | |||
| 4:30 |
Mary Cromwell, Associate Director, Protein Analytical Chemistry, Genentech, Inc. | |||
| 5:00 | Close of Day Two | |||
| Day Three Wednesday, November 12, 2008 | DAY ONE | DAY TWO | DAY THREE | | ||||
| 7:30 | Coffee | |||
| 8:00 | Chairperson's Opening Remarks Ned Mozier, Ph.D., Director, Analytical Sciences, Global Biologics, Research and Development, Pfizer, Inc. | |||
| Analysis of Protein Glycosylation | ||||
| 8:15 | Overview of CMC Strategy Forum on Glycosylation of Biotechnology Products Nadine M. Ritter, Ph.D., Senior CMC Consultant, Biologics Consulting Group, Inc. | |||
| 8:45 | What is the Industry Trending Towards for Glycosylation Analysis? The glycosylation pattern of recombinant proteins is defined by expression system and process conditions due to the characteristics of the biosynthetic mechanism of complex glycans. Monitoring critical structural features of glycans since early stages of process development can be a powerful tool. The talk will focus on the use of glycosylation analysis for product control. Adriana E. Manzi, Ph.D., President and CEO, Atheln | |||
| 9:15 | Characterization of a Recombinant NGAL, a New Diagnostic Marker for Acute Kidney Injury Neutrophil Gelatinase Associated Lipocalin (NGAL) levels in urine have been shown to increase in association with acute kidney injury. We have characterized a highly purified recombinant human NGAL produced in CHO cells for use as a standard for quantitation in an immunodiagnostic assay. We utilized a multi-technique analytical approach for characterization including classical bioanalytical and mass spectrometric techniques. In addition to immunoreactivity and purity, we examined glycan heterogeneity, peptide mapping, isoform distribution, and saccharide composition of multiple lots at various stages of research and development. Kevin R. Rupprecht, Ph.D., Principal Molecular Biologist, Analytical Chemistry, Diagnostics Divisional R&D, Abbott Laboratories | |||
| 9:45 | Networking Refreshment Break | |||
| 10:15 |
MAb product quality is one of the key parameters to consider in selecting a cell-line clone. This presentation decscribes an LC-MS-based method for confirmation of mAb primary structure and high-throughput glycan profiling. This method utilizes LCMS to measure the mass of intact and reduced mAbs. Unpurified media can be analyzed directly and at very early stage. The total analysis time is less than an hour, compared to weeks for cell culture scale up, protein purification, 2-AB sample preparation, and the analysis step. Wenjun (David) Mo, Ph.D., Senior Scientist, Analytical Biochemistry, MedImmune, Inc. | |||
| 10:45 | Effects of O-Linked Sialylation on the Pharmacokinetics and Biodistribution of Proteins BR3-Fc is an IgG1-receptor dimeric fusion protein that has multiple O-linked glycosylation sites. Studies in mice with BR3-Fc demonstrated a relationship between the degree of sialylation on these O-linked sites and clearance of BR3-Fc. The results of our studies suggest there is an ASGP-like receptor on Kupffer cells that internalizes and degrades BR3-Fc bearing terminal O-linked Gal and/or GalNAc. Eric G. Stefanich, Associate Scientist, Pharmacokinetic and Pharmacodynamic Sciences, Genentech, Inc. | |||
| Aggregates: Audience Interactive Panel Discussion | ||||
| 11:15 | Which Analytical Method(s) for this Aggregate Sample? One Size does not Fit All Moderator: Stephen Raso, Ph.D., Principal Research Scientist I, Analytical Biochemistry and Biophysics, Wyeth BioPharma Panelists: Michelle Frazier-Jessen, Ph.D., Associate Director, Regulatory Affairs, MedImmune, Inc. Allen Minton, Ph.D., Chief, Section on Physical Biochemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health Jamie M. Moore, Ph.D., Scientist and Group Leader, Early Stage Pharmaceutical Development, Genentech, Inc. Peter Schuck, Ph.D., Chief, Protein Biophysics Resource, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health | |||
| 12:15 | Lunch on your Own | |||
| 1:45 | Afternoon Chairperson's Remarks Richard Strong, Ph.D., Scientist II, Analytical Development, Biogen Idec | |||
| Featured Presentation | ||||
| 2:00 | Reduced Virus Safety Package for IMPs in Europe Hannelore Willkommen, Ph.D., Consultant, CEO, Regulatory Affairs & Biological Safety Consulting, Germany | |||
| Advances in Development and Implementation of Analytical Technologies | ||||
| 2:30 | Novel Methodology for Determination of the Complete Connectivity of IgG2 Disulfide Variants The detection and characterization of unexpected disulfide-mediated structural variants of human IgG2 antibodies was recently the subject of two co-publications. In this report, we present data to confirm the previously reported structures, and elucidate the complete disulfide connectivity of each variant through the application of a novel analytical methodology. In this manner, the data illustrates the presence of five structural variants, including the classical structure with independent Fab domains and hinge region. Two sub-variants of the IgG2-B structure are identified; the first presents a symmetrical distribution of linkages between the two Fab arms and the hinge region, whereas the second sub-variant possesses an asymmetric disulfide bonding arrangement. Furthermore, the detection and characterization of an additional previously unreported variant is discussed. This species is determined to include cross-domain disulfide linkages, as the net structure contains single copies of the hinge peptide, and each of the light chain and heavy chain peptides from the Fab domain. The absence of "half-molecule" species is used to infer the cross-domain linkage geometry. The results presented in this paper reveal that the population of disulfide structural variants is yet more complex than recently reported. Steven Cockrill, Ph.D., Senior Scientist, Analytical Sciences, Amgen Inc. | |||
| 3:00 | Networking Refreshment Break | |||
| 3:30 | Development of a CE Charge Heterogeneity Method for a Challenging Protein Bruce Tangarone, Senior Research Scientist II, Wyeth Biopharma | |||
| 4:00 | Analytical Strategies for Streamlined Validation and Testing of Early Stage Clinical Candidates A streamlined approach for development and validation of analytical procedures is possible with the recent technological advance and refinements of existing analytical techniques. Furthermore, establishment of generic methods for similar classes of molecules have shortened the validation time and simplified transfer of these methods for clinical testing. Examples of generic analytical procedures and the streamlined validation approach will be presented. Amir Malek, Ph.D., Group Leader, Protein Analytical Chemistry, Genentech, Inc. | |||
| 4:30 | Characterization of Immunoconjugates by Mass Spectrometry Antibodies conjugated with potent cytotoxic molecules are promising therapeutic agents used in the fight against cancer. The presentation will describe the characterization of immunoconjugate products using size-exclusion chromatography directly coupled to mass spectrometry. The effect of several parameters on the mass spectrometric analysis of immunoconjugates will also be discussed. Alex Lazar, Ph.D., Senior Scientist, Analytical and Pharmaceutical Sciences Department, ImmunoGen, Inc. | |||
| 5:00 | Close of Conference | |||
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