eBriefing

Follow-on Biologics Workshop

Follow-on Biologics Workshop
Reported by
Angelo DePalma

Posted July 01, 2009

Presented By

New York Academy of Sciences and the U.S. Food and Drug Administration, in collaboration with the National Institute of Standards and Technology (NIST)

Overview

The New York Academy of Sciences, in conjunction with the FDA and the National Institute for Standards and Technology (NIST), held a workshop on December 12–14, 2005 that focused on the scientific issues involved in assessing the similarity of follow-on protein products. At the conference, scientists from academe, industry, and government surveyed the scientific issues surrounding protein structure and function, focusing on specific analytical methodologies for characterizing protein products.

The first half of the conference focused on the challenges posed by the complexities of protein structure. Day one covered primary, secondary, and tertiary structure, and analytical methods for characterizing those structures. On the first half of day two, speakers discussed quaternary structure, protein-protein interactions, and protein aggregates. Speakers from FDA and NIST introduced these sessions, laying out the scientific and regulatory challenges presented by each protein structure element. During the second half of day two, several speakers discussed the impact of processing on protein properties.

Web Sites

Biotechnology Industry Organization (BIO)
BIO has collected their comments on follow-on biotechnology product regulation as full-text pdf files here.

EMEA/DIA Joint Workshop on EMEA New Guidelines for Development and Approval of Biosimilars
Program for a December 2005 conference on European regulation of follow-on biologics (PDF, 368 KB).

European Medical Association Guidelines
Emerging Biopharmaceutical Enterprises, an organization of European pharmaceutical companies, has posted documents from the European Medical Association here related to the regulation of follow-on biologics, called "biosimilars" in Europe. See in particular:

FDA Center for Biologics Evaluation and Research
Web site of the FDA division responsible for regulating blood-derived biological products.

FDA Center for Drug Evaluation and Research
Web site of the FDA division responsible for regulating most protein products.

The Law of Off-Patent Biopharmaceuticals
A statement by Senator Orrin Hatch on steps Congress must take to provide the regulatory framework for follow-on biologics.

PhRMA Comments to the FDA on follow-on biologics (PDF, 805.1 KB)
PhRMA (The Pharmaceutical Research and Manufacturers of America) advocates for public policies on behalf of pharmaceutical/biotechnology research companies.

Scientific Considerations Related to Developing Follow-On Protein Products (February 2005)
Collected slide presentations for a February 14-16, 2005, FDA Meeting

Scientific Considerations Related to Developing Follow-On Protein Products (September 2004)
Slide presentations for the earlier, September 14-15, 2004 FDA Meeting. This online docket also contains a transcript of the meeting.


Journal & Magazine Articles

Ashline, D., S. Singh, A. Hanneman & V. Reinhold. 2005. Congruent strategies for carbohydrate sequencing. 1. Mining structural details by MS(n). Anal. Chem. 77: 6250-6262.

Baneyx, F. & M. Mujacic. 2004. Recombinant protein folding and misfolding in Escherichia coli. Nat. Biotechnol. 22: 1399-1408.

Baneyx, F. 2004. Keeping up with protein folding. Microb. Cell Fact. 3: 6. Full Text

Bristow, A., P. Berger, J. M. Bidart, et al. 2005. Establishment, value assignment, and characterization of new WHO reference reagents for six molecular forms of human chorionic gonadotropin. Clin. Chem. 51: 177-182. Full Text

Bunk, D. M. & M. J. Welch. 2006. Characterization of a new certified reference material for human cardiac troponin I. Clin. Chem. 52: 212-219.

Chamberlain, P. 2004. Biogenerics: Europe takes another step forward while the FDA dives for cover. Drug Discov. Today 9: 817-820.

Charles, S. A. 2005. SuperGenerics: a better alternative for biogenerics. Drug Discov Today. 10: 533-535.

Chi, E. Y., S. Krishnan, T. W. Randolph & J. F. Carpenter. 2003. Physical stability of proteins in aqueous solution: mechanism and driving forces in nonnative protein aggregation. Pharm. Res. 20: 1325-1336.

Clark, K. J., F. W. Chaplin & S. W. Harcum. 2004. Temperature effects on product-quality-related enzymes in batch CHO cell cultures producing recombinant tPA. Biotechnol. Prog. 20: 1888-1892.

Combe, C., R. L. Tredree & H. Schellekens. 2005. Biosimilar epoetins: an analysis based on recently implemented European medicines evaluation agency guidelines on comparability of biopharmaceutical proteins. Pharmacotherapy. 25: 954-962.

Coon, J. J., B. Ueberheide, J. E. Syka, et al. 2005. Protein identification using sequential ion/ion reactions and tandem mass spectrometry. Proc. Natl. Acad. Sci. USA 102: 9463-9468. Full Text

Defelippis, M. R. & F. S. Larimore. 2005. The role of formulation in insulin comparability assessments. Biologicals (not yet in print).

Donohue, M. J., M. B. Satterfield, J. J. Dalluge, et al. 2005. Capillary electrophoresis for the investigation of prostate-specific antigen heterogeneity. Anal. Biochem. 330: 318-327.

Eyles, S. J. & I. A. Kaltashov. 2004. Methods to study protein dynamics and folding by mass spectrometry. Methods 34: 88-99.

Feldbaum, C. B. BIO and biogenerics. Nat. Biotechnol. 23: 17.

Freedberg, D. I., R. M. Venable, A. Rossi, et al. 2004. Discriminating the helical forms of peptides by NMR and molecular dynamics simulation. J. Am. Chem. Soc. 126: 10478-10484.

Fromell, K. M. Andersson, K. Elihn & K. D. Caldwell. 2005. Nanoparticle decorated surfaces with potential use in glycosylation analysis. Colloids Surf. B. Biointerfaces 46: 84-91.

Gale, B. K., K. D. Caldwell & A. B. Frazier. 1998. A micromachined electrical field-flow fractionation (mu-EFFF) system. IEEE Trans. Biomed. Eng. 45: 1459-1469.

Garcia, B. A., C. M. Barber, S. B. Hake, et al. 2005. Modifications of human histone H3 variants during mitosis. Biochemistry 44: 13202-13213.

Griffiths, S. 2004. Betting on biogenerics. Nat. Rev. Drug Discov. 3: 197-198.

Hake, S. B., B. A. Garcia, E. M. Duncan, et al. 2006. Expression patterns and post-translational modifications associated with mammalian histone H3 variants. J. Biol. Chem. 281: 559-568.

Herrera, S. 2004. Biogenerics standoff. Nat. Biotechnol. 22: 1343-1346.

Hitchens, K. 2003. Push for generic biologics gaining momentum. Drug Topics (August 1). Full Text

Hoerner, J. K., H. Xiao & I. A. Kaltashov. 2005. Structural and dynamic characteristics of a partially folded state of ubiquitin revealed by hydrogen exchange mass spectrometry. Biochemistry 44: 11286-11294.

Issaq, H. J., K. C. Chan, G. M. Janini, et al. 2005. Multidimensional separation of peptides for effective proteomic analysis. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 817: 35-47.

Johnson, K. A., B. A. Shira, J. L. Anderson & I. J. Amster. 2001. Chemical and on-line electrochemical reduction of metalloproteins with high-resolution electrospray ionization mass spectrometry detection. Anal. Chem. 73: 803-808.

Johnson, L. S. Mollah, B. A. Garcia, et al. 2004. Mass spectrometry analysis of Arabidopsis histone H3 reveals distinct combinations of post-translational modifications. Nucleic Acids Res. 32: 6511-6518.

Kawanishi, T. 2005. Regulatory perspectives from Japan: comparability of biopharmaceuticals. Biologicals (not yet in print).

Lapadula, A. J., P. J. Hatcher, A. J. Hanneman, et al. 2005. Congruent strategies for carbohydrate sequencing. 3. OSCAR: an algorithm for assigning oligosaccharide topology from MS(n) data. Anal. Chem. 77: 6271-6279.

Louet, S. 2003. Lessons from Eprex for biogeneric firms. Nat. Biotechnol. 21: 956-957.

Nieminen, O. & K. Nordstrom. 2004. Regulation of biogenerics: a survey of viewpoints. BioDrugs. 18: 399-406.

Rafferty, B., P. Maile, P. Rigsby, et al. 2001. International Standards for hepatocyte growth factor/scatter factor: initial assessment of candidate materials and their evaluation by multicentre collaborative study. J. Immunol. Methods 258: 1-11.

Schachter, H., S. Chen, W. Zhang, et al. 2002. Functional post-translational proteomics approach to study the role of N-glycans in the development of Caenorhabditis elegans. Biochem. Sox. Symp. 69: 1-21.

Schellekens, H. 2005. Follow-on biologics: challenges of the "next generation." Nephrol. Dial. Transplant. 20 Suppl 4: iv 31-36.

Thienpont, L. M., K. Van Uytfanghe, J. Marriott, et al. 2005. Feasibility study of the use of frozen human sera in split-sample comparison of immunoassays with candidate reference measurement procedures for total thyroxine and total triiodothyronine measurements. Clin Chem. 51: 2303-2311.

Tsumoto, K., D. Ejima, Y. Kita & T. Arakawa. 2005. Why is arginine effective in suppressing aggregation? Mini Rev. Med. Chem. 5: 613-619.

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Zhang, H., S. Singh & V. N. Reinhold. 2005. Congruent strategies for carbohydrate sequencing. 2. FragLib: an MS(n) spectral library. Anal. Chem. 77: 6263-6270.

Organizers

Kurt A. Brorson, PhD

FDA Center for Biologics Evaluation and Research
email | web site | publications

Kurt Brorson is a staff scientist in CDER's division of monoclonal antibodies, Office of Biotech Products. Kurt Brorson received a BA in biology from the University of Chicago in 1984 and PhD in molecular biology from the California Institute of Technology in 1990. After a two-year postdoctoral fellowship at the NIH, he joined the FDA in 1992 as a staff fellow and was converted to a staff scientist in 1999. In addition to review and policy activities, he conducts research on viral safety issues associated with biotechnology products.

David Bunk, PhD

National Institute of Standards and Technology
email | publications

David Bunk received his doctorate in chemistry from Texas A&M University in 1992. He then was awarded a National Research Council Postdoctoral Fellowship at the National Institute of Standards and Technology. After finishing his postdoctoral fellowship, he continued his research at NIST in the analytical chemistry division.

His research interests at NIST focus on the application of chromatographic and mass spectrometric techniques to the analysis of proteins. Recently he has been investigating the use of proteomics method for the quantification of clinically-relevant proteins in serum, specifically cardiac troponin I, c-reactive protein, and B-type natriuretic peptide.

Bunk is a member of the American Society for Mass Spectrometry and the American Association for Clinical Chemistry and actively serves on committees for the American Association for Clinical Chemistry, the International Federation of Clinical Chemistry, and the Clinical Laboratory Standards Institute.

Barry W. Cherney, PhD

FDA Center for Drugs Evaluation and Research
email | web site | publications

Barry Cherney is deputy director at the division of therapeutic proteins in the office of biotechnology products at FDA's Center for Drugs Evaluation and Research (CDER). His regulatory duties have included oversight of reviews for INDs and BLAs for recombinant and naturally derived proteins, product reviewer training, and development of regulatory guidance to address scientific issues related to characterization, manufacture, and control of specified and naturally derived protein products.

Cherney obtained his PhD in biology from Case Western Reserve University. His dissertation work involved the purification and characterization of the nuclear enzyme, Poly (ADP-ribose) synthetase. In 1986, he began postdoctoral training in the department of biochemistry and molecular biology at Georgetown University where he worked on molecular approaches toward defining the structure/function of this enzyme. He joined CBER in 1991 as a senior staff fellow in the division of hematological products and in addition to his regulatory duties, conducted research on the molecular mechanisms leading to tumorigenesis. Since 1998, Cherney has held positions as a full time regulatory reviewer, an expert biologist and became deputy director of the division of therapeutic proteins in March 2001. He was FDA's topic lead expert on ICH Q5E for comparability of biotech products and has been involved with issues concerning the comparison of protein products throughout his FDA career.

Curtis Meuse, PhD

National Institute of Standards and Technology
email | publications

Curtis Meuse is a scientist in the biochemical science division of Chemical Science and Technology Laboratory at the National Institute of Standards and Technology (NIST). He received his PhD in chemistry at the University of Massachusetts, Amherst studying ultra-thin polymer layers using infrared spectroscopy. As a postdoctoral fellow in the Laboratory of Chemical Physics at the National Institutes of Health, he synthesized specifically fluorinated phospholipids and studied their nano-domain structure using Raman spectroscopy. In 1995, he was hired as part of a NIST-wide initiative to develop expertise in the development and characterization of new biomimetic materials. In the Biomolecular Materials Group, he developed methods and models for the characterization of the molecular structure of cell membrane components organized on surfaces using neutron reflectivity and optical techniques. In addition, a state-of-the-art infrared spectroscopic ellipsometer was built and methods for the analysis of spectroscopic data to determine the thickness, optical constants and molecular structure of various cell monolayer and bilayer constructs were developed.

Currently in the biospectroscopy group, Meuse’s work is focused on protein conformation measurements. The goals of his work are to develop and standardize methods to characterize the biologically active state, to allow the measurement of structural changes, and to characterize physical processes that contribute to biological inactivation of proteins such as aggregation and macromolecular association/dissociation. For example, infrared methods have been developed to quantify protein structural stability and protein binding interactions by quantifying the extent of the exchange of deuterium for hydrogen in the amide bonds of proteins in solutions, as solids, in membranes or immobilized on surfaces. In addition, collaborations with the United Kingdom’s National Physics Laboratory are underway on a pilot study for the standardization of biomolecular circular dichroism measurements under the auspices of the International Committee for Weights and Measures.

Emily Shacter, PhD

FDA Center for Biologics Evaluation and Research
email | publications

Emily Shacter is chief of the laboratory of biochemistry in the division of therapeutic proteins of the Office of Biotechnology Products, Office of Pharmaceutical Science, CDER. She received her PhD in biochemistry from Johns Hopkins University in 1982, carried out basic cell regulation and cancer research at the National Institutes of Health for 12 years, and then joined the FDA in 1994.

Shacter oversees the review of INDs and BLAs for novel therapeutic proteins covering a wide range of clinical indications, including cancer, hematopoiesis, tissue repair and remodeling, thrombosis and thrombolysis, inflammatory disease, and bioterrorism. She is engaged in establishing CDER policy regarding product manufacture and characterization and performs inspections of biotechnology manufacturing facilities.

Shacter also runs an active laboratory research program to support the scientific review of therapeutic proteins that have wide-ranging mechanisms of action and unique biological and physicochemical characteristics. Her laboratory research focuses on studying the cytotoxic mechanisms of cancer chemotherapy drugs and understanding how elements of the immune system, such as oxidants and activated phagocytes, influence killing and clearance of dying cells. Her research expertise in the area of protein oxidation is applied regularly to the review of protein therapeutics.


Speakers

Jon Amster, PhD

University of Georgia
Department of Chemistry
email | web site | publications

François Baneyx, PhD

University of Washington
Department of Chemical Engineering
email | web site | publications

Adrian Bristow, PhD

National Institute for Biological Standards and Control
email | publications

Karin D. Caldwell, PhD

Uppsala University
Center of Surface Biotechnology
email | web site | publications

John F. Carpenter, PhD

University of Colorado Health Sciences Center
Center for Pharmaceutical Biotechnology
email | web site | publications

Kathleen A. Clouse, PhD

Food and Drug Administration
Office of Biotechnology Products
email | publications

Charles Cooney, PhD

Massachusetts Institute of Technology
Department of Chemical Engineering
email | web site | publications

Steve Cramer, PhD

Rensselaer Polytechnic Institute
Department of Chemical and Biological Engineering
email | web site | publications

Erik J. Fernandez, PhD

University of Virginia
Department of Chemical Engineering
email | web site | publications

Ewa Folta-Stogniew, PhD

Yale University School of Medicine
W.M. Keck Foundation Biotechnology Resource Laboratory
email | publications

Daron I. Freedberg, PhD

U.S. Food and Drug Administration
Center for Biologics Evaluation and Research
email | publications

William Hancock, PhD

Northeastern University
Department of Chemistry and Chemical Biology
email | web site | publications

Sarah W. Harcum, PhD

Clemson University
Department of Bioengineering
email | web site | publications

Donald Hunt, PhD

University of Virginia
Department of Chemistry
email | web site | publications

Igor Kaltashov, PhD

University of Massachusetts
Department of Chemistry
email | web site | publications

Steven Kozlowski, MD

Food and Drug Administration
Office of Biotechnology Products
email

Tom Laue, PhD

University of New Hampshire
Department of Biochemistry and Molecular Biology
email | web site | publications

Laureen Little, PhD

Bioquality
email | web site

Roger E. Marchant, PhD

Case Western Reserve University
Department of Biomedical Engineering
email | web site | publications

Russ Middaugh, PhD

University of Kansas
Department of Pharmaceutical Chemistry
email | web site | publications

Keith Oberg, PhD

Alfred Mann Foundation
publications

Vernon Reinhold, PhD
University of New Hampshire
Department of Chemistry
email | web site | publications

Nadine M. Ritter, PhD
Biologics Consulting Group, LLC
email | web site | publications
C. Jane Robinson, PhD

National Institute for Biological Standards and Control
Division of Immunology and Endocrinology
email

Amy Rosenberg, MD

Food and Drug Administration
Division of Therapeutic Proteins
email

Frederick Schwarz, PhD

National Institute of Standards and Technology
Center for Advanced Research in Biotechnology
email | web site | publications

Tim D. Veenstra, PhD

SAIC-Frederick, Inc.
email | web site | publications

Keith Webber, PhD

U.S. Food and Drug Administration
Center for Biologics Evaluation and Research
email | web site | publications


Angelo DePalma

Angelo DePalma is a freelance writer based in Newton, New Jersey. In 1984, he received a PhD in chemistry from the State University of New York, Stony Brook. His work appears in a dozen pharmaceutical industry trade magazines, and he is the author of a bestselling book on vitamins and supplements.

Presented by the New York Academy of Sciences and the U.S. Food and Drug Administration, in collaboration with the National Institute of Standards and Technology (NIST)