NISTmAb Common Technical Document Case Study · PDF file2018-04-02 · NISTmAb...

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  • NISTmAb Common Technical Document Case Study

    In order to provide attendees with an opportunity to evaluate real world data, we have assembled a mock IND filing for NISTmAb RM 8671, a humanized monoclonal antibody (IgG1) Reference Material (RM). NISTmAb RM 8671 embodies the quality and characteristics of a biopharmaceutical product, is widely available to the biopharmaceutical community, and is an open innovation tool for technology development and dissemination of results. The public nature of information pertaining to the NISTmAb product quality attributes presents a unique opportunity for cross-community discussion on best practices. The mock common technical document is a summation of NISTmAb data measured by numerous collaborators and formatted to model an elucidation of structure section of the ICH common technical document M4Q(R1). The case study is not intended to be a template for mAb filings, instead it should serve as a foundation upon which to build discussions on current best practices and potential innovative approaches to analytical and biophysical data submission.

    Disclaimers:

    RM 8671 is intended for research use only. RM 8671 is NOT intended for animal or human consumption, clinical testing, or therapeutic use.

    RM 8671 users should always refer to the official NIST Report of Investigation for their specific material lot to obtain NIST Reference Values and uncertainty ranges. Values and specifications reported herein are based on measurements performed on the NISTmAb Primary Sample 8670 and RM 8671 (other than potency), however they do not necessarily represent NIST Reference and/or Certified Values.

    This presentation/article reflects the views of the author(s) and should not be construed to represent FDAs views or policies.

    Certain commercial equipment, instruments, or materials are identified to adequately specify the experimental procedure. Such identification does not imply recommendation or endorsement by the National Institute of Standards and Technology, nor does it imply that the materials or equipment identified are necessarily the best available for the purpose.

  • Document Organizers and Contact Information:

    John Schiel, National Institute of Standards and Technology, [email protected]

    Christina Vessely, Biologics Consulting, Inc., [email protected]

    Contributing Authors

    Contributors Organization John Schiel Marco Blanco Trina Formolo Abigail Turner Curtis Meuse Luke Arbogast Robert Brinson Katharina Yandrofski Srivalli Telikepalli

    National Institute of Standards and Technology Institute for Bioscience and Biotechnology Research

    Christina Vessely Biologics Consulting, Inc. David Hayes David Feder Boehringer Ingelheim

    Iain Campuzano Amgen Brandon Ruotolo Yumie Tian University of Michigan

    Doug Marshall Bernard Costello Applied Photophysics

    TABLE OF CONTENTS

    3.2.S.1 GENERAL INFORMATION

    3.2.S.2 MANUFACTURE 3.2.S.3 CHARACTERIZATION

    mailto:[email protected]:[email protected]

  • NIST 00001234 Humanized IgG1 monoclonal antibody, RM 8671 0000

    3.2.S.1 General Information [Humanized IgG1 Monoclonal Antibody, NIST], Page 1

    3.2.S.1 GENERAL INFORMATION [Humanized IgG1 monoclonal antibody, NIST]

    3.2.S.1.1 NOMENCLATURE

    Chemical Name(s) NISTmAb humanized IgG1 monoclonal antibody

    Company or Laboratory Code RM 8671

  • NIST 00001234 Humanized IgG1 monoclonal antibody, RM 8671 0000

    3.2.S.1 General Information [Humanized IgG1 Monoclonal Antibody, NIST], Page 2

    3.2.S.1.2 STRUCTURE The NISTmAb is an ~150 homodimer of two light chain and two heavy chain subunits linked through both inter- and intra-chain disulfide bonds kDa (theoretical molecular mass of 148199.3 Da for the G0F/G1F glycoform). The amino acid sequence for the NISTmAb heavy and light chains, as deduced from the cDNA sequence and confirmed by ultrahigh performance liquid chromatography coupled with UV-Visible absorbance and tandem mass spectrometry detection (LC-UV-MS/MS peptide mapping) as well as intact mass spectrometry is shown in Section 01.

    3.2.S.1.2.1 NISTmAb Sequence Summary Variable FabConstant Fab Hinge Constant Fc-secretory tail NISTmAb Heavy Chain AA QVTLRESGPALVKPTQTLTLTCTFSGFSLSTAGMSVGWIRQPPGKALEWLADIWWDDKKHYNPSLKDRLTISKDTSKNQVVLKVTNMDPADTATYYCARDMIFNFYFDVWGQGTTVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK NISTmAb Light Chain DIQMTQSPSTLSASVGDRVTITCSASSRVGYMHWYQQKPGKAPKLLIYDTSKLASGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCFQGSGYPFTFGGGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC The 3 complementarity-determining regions (CDRs) in each chain are bolded and underlined. The N-linked glycosylation site (Asn300) is marked in bold and italic. The Glu residue at position 1 of the heavy chain and the Asp residue at position 1 of the light chain constitute the N-termini of the mature chains.

    1 Formolo, T.; Ly, M.; Levy, M.; Kilpatrick, L.; Lute, S.; Phinney, K.; Marzilli, L.; Brorson, K.; Boyne, M.; Davis, D.; Schiel, J., Determination of the Nistmab Primary Structure. In State-of-the-Art and Emerging Technologies for Therapeutic Monoclonal Antibody Characterization Volume 2. Biopharmaceutical Characterization: The Nistmab Case Study, American Chemical Society: 2015; Vol. 1201, pp 1-62.

  • NIST 00001234 Humanized IgG1 monoclonal antibody, RM 8671 0000

    3.2.S.1 General Information [Humanized IgG1 Monoclonal Antibody, NIST], Page 3

    3.2.S.1.3 GENERAL PROPERTIES The physical and chemical properties of RM 8671 are provided in Table 1.

    Table 1: General Properties of RM 8671

    Physical/Chemical Properties Description Physical form and appearance RM 8671 drug substance is an aqueous solution stored

    frozen at -70 C at a concentration of approximately 10 mg/mL in (12.5 mmol/L L-histidine, 12.5 mmol/L L-histidine HCl. The drug substance is a clear to opalescent solution, colorless to slightly yellow.

    pH RM 8671 is formulated at a target pH of 6.0

    pI The isoelectric point of RM 8671 was measured as 9.18 ( 0.01)

  • NIST 00001234 Humanized IgG1 monoclonal antibody, RM 8671 0000

    3.2.S.2 Manufacture [Humanized IgG1 Monoclonal Antibody, {Manufacturer}], Page 1

    3.2.S.2 MANUFACTURE [Humanized IgG1k monoclonal antibody, NIST]

    3.2.S.2.1 MANUFACTURER(S) Table 1: Manufacturer Information

    Facility Responsibility

    National Institute of Standards and Technology Institute for Bioscience and Biotechnology Research National Institute of Standards and Technology 9600 Gudelsky Dr. Rockville, MD 20850 John Schiel

    Manufacture of reference standard Release testing Extended Characterization Testing

    3.2.S.2.2 DESCRIPTION OF MANUFACTURING PROCESS AND PROCESS CONTROLS

    This NISTmAb was received as a bulk substance prepared using mammalian cell culture and downstream processing representative of industry state-of-the-art. The manufacturing process is proprietary and therefore will not be presented as part of this case study. This includes the description of in-process controls, control of materials (raw material and starting material specifications, and analytical methods for analysis of the materials, compendial grade of materials, etc), control of critical steps and intermediates, process validation and process development. Comparability assessments associated with process changes that occurred over the course of the development of the drug substance will also be excluded from of this document.

    The drug substance that was filled as the primary reference standard (PS 8670) was manufactured in alignment with the scaled process. PS 8670 was prepared from a single lot of drug substance which was diluted 10 fold in USP grade formulation buffer (12.5 mmol/L L histidine, 12.5 mmol/L L-histidine HCl, pH 6.0) and 800 L aliquots placed into internally threaded screw top. Vials were placed in racks of 96 units each for storage at 80 C. Sample processing was completed in a sterile environment using pre sterilized single-use equipment and/or in a class 100 000 cleanroom environment. The drug substance that was filled as the working reference standard (RM 8671) was manufactured for NIST according to the commercial process. RM 8671 was prepared by first homogenizing multiple bulk substance containers to form the 14HB batch. Aliquots of 1 L each were made from the homogenized bulk and designated as individual lots. A single lot (14HB-002) was then diluted 10 fold in USP grade formulation buffer (12.5 mmol/L L histidine, 12.5 mmol/L L-histidine HCl, pH 6.0) and 800 L aliquots placed into internally threaded screw top. Vials were placed in racks of 96 units each for storage at 80 C. Sample processing was completed in a sterile environment using pre sterilized single-use equipment and/or in a class 100000 cleanroom environment.

  • National Institute of Standards and Technology 00001234 Humanized IgG1 monoclonal antibody, RM 8671 0000

    3.2.S.3 Characterization [Humanized IgG1 Monoclonal Antibody, NIST], Page 1

    3.2.S.3 CHARACTERIZATION [NISTmAb, National Institute of Standards and Technology]

    TABLE OF CONTENTS 3.2.S .3.1 ELUCIDATION OF S TRUCTURE AND OTHER

    CHARACTERIS TICS ...............................................................................................4 3.2.S.3.1.1 Introduction .............