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Article CommentaryCommentary

Implementation of Plate Imaging for Demonstration of Monoclonality in Biologics Manufacturing Development

Kyle Zingaro, David Shaw, Jerry Carson, Anke Mayer-Bartschmid, Christian Bender, Christina Alves, Duncan Mcvey, Nan-Xin Qian, Qingxiang Wei, Michael W. Laird, Yuan Zhu, Robyn Emmins, John A. Follit, Alison Porter, Andrew J. Racher, Sarah Milne, Ivan Carubelli, Zhimei Du, Ankita Khatri, Marilyne Failly, Hervé Broly, Frank Lee, Matthew Reeser, Jared Spidel, Karin Anderson, Christine Demaria, Jennifer Di-Carlo, John Gill, Amie Lundquist, Sampath R. Kumar and Tony Gill
PDA Journal of Pharmaceutical Science and Technology July 2018, 72 (4) 438-450; DOI: https://doi.org/10.5731/pdajpst.2018.008789
Kyle Zingaro
1Alexion Pharmaceuticals, Inc., New Haven, CT, USA;
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  • For correspondence: kyle.zingaro@gmail.com david.shaw@gene.com
David Shaw
2Genentech, Inc., South San Francisco, CA, USA;
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  • For correspondence: kyle.zingaro@gmail.com david.shaw@gene.com
Jerry Carson
3AbbVie Bioresearch Center, Worcester, MA, USA;
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Anke Mayer-Bartschmid
4Bayer AG, Pharmaceuticals, Research and Development, Cell and Protein Sciences, Wuppertal, Germany;
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Christian Bender
4Bayer AG, Pharmaceuticals, Research and Development, Cell and Protein Sciences, Wuppertal, Germany;
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Christina Alves
5Biogen, Cell Culture Development, Cambridge, MA, USA;
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Duncan Mcvey
6Bristol-Myers Squibb, Pennington, NJ, USA;
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Nan-Xin Qian
7Bristol-Myers Squibb, Devens, MA, USA;
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Qingxiang Wei
8Celgene Corporation, Summit West, Summit, NJ, USA;
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Michael W. Laird
2Genentech, Inc., South San Francisco, CA, USA;
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Yuan Zhu
9GSK, King of Prussia, PA, USA;
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Robyn Emmins
10GSK, Stevenage, UK;
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John A. Follit
11ImmunoGen, Inc., Waltham, USA;
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Alison Porter
12Lonza Biologics plc, Slough, UK;
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Andrew J. Racher
12Lonza Biologics plc, Slough, UK;
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Sarah Milne
12Lonza Biologics plc, Slough, UK;
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Ivan Carubelli
12Lonza Biologics plc, Slough, UK;
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Zhimei Du
13Merck & Co., Inc., Kenilworth, NJ, USA;
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Ankita Khatri
13Merck & Co., Inc., Kenilworth, NJ, USA;
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Marilyne Failly
14Merck Biodevelopment, Martillac, France;
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Hervé Broly
15Merck Serono S.A., Fenil-sur-Corsier, Switzerland;
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Frank Lee
16Morphotek, Inc., Exton, PA, USA;
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Matthew Reeser
16Morphotek, Inc., Exton, PA, USA;
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Jared Spidel
16Morphotek, Inc., Exton, PA, USA;
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Karin Anderson
17Pfizer BioTherapeutics Pharmaceutical Sciences, Andover, MA, USA;
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Christine Demaria
18Sanofi Biopharmaceutics Development, Framingham, MA USA;
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Jennifer Di-Carlo
19Sanofi Biopharmaceutics Development, Vitry-sur-Seine, France;
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John Gill
20Shire, Lexington, MA, USA;
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Amie Lundquist
20Shire, Lexington, MA, USA;
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Sampath R. Kumar
21Takeda Pharmaceuticals International Co., Cambridge, MA, USA; and
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Tony Gill
22BioPhorum Development Group, Sheffield, UK
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Abstract

Monoclonality of mammalian cell lines used for production of biologics is a regulatory expectation and one of the attributes assessed as part of a larger process to ensure consistent quality of the biologic. Historically, monoclonality has been demonstrated through statistics generated from limiting dilution cloning or through verified flow cytometry methods. A variety of new technologies are now on the market with the potential to offer more efficient and robust approaches to generating and documenting a clonal cell line.

Here we present an industry perspective on approaches for the application of imaging and integration of that information into a regulatory submission to support a monoclonality claim. These approaches represent the views of a consortium of companies within the BioPhorum Development Group and include case studies utilising imaging technology that apply scientifically sound approaches and efforts in demonstrating monoclonality. By highlighting both the utility of these alternative approaches and the advantages they bring over the traditional methods, as well as their adoption by industry leaders, we hope to encourage acceptance of their use within the biologics cell line development space and provide guidance for regulatory submission using these alternative approaches.

LAY ABSTRACT: In the manufacture of biologics produced in mammalian cells, one recommendation by regulatory agencies to help ensure product consistency, safety, and efficacy is to produce the material from a monoclonal cell line derived from a single, progenitor cell. The process by which monoclonality is assured can be supplemented with single-well plate images of the progenitor cell. Here we highlight the utility of that imaging technology, describe approaches to verify the validity of those images, and discuss how to analyze that information to support a biologic filing application. This approach serves as an industry perspective to increased regulatory interest within the scope of monoclonality for mammalian cell culture–derived biologics.

  • Monoclonality
  • Cell cloning
  • Clonally derived
  • Limited/limiting dilution
  • Plate-based imaging
  • Single-cell imaging
  • CHO
  • © PDA, Inc. 2018
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PDA Journal of Pharmaceutical Science and Technology: 72 (4)
PDA Journal of Pharmaceutical Science and Technology
Vol. 72, Issue 4
July/August 2018
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Implementation of Plate Imaging for Demonstration of Monoclonality in Biologics Manufacturing Development
Kyle Zingaro, David Shaw, Jerry Carson, Anke Mayer-Bartschmid, Christian Bender, Christina Alves, Duncan Mcvey, Nan-Xin Qian, Qingxiang Wei, Michael W. Laird, Yuan Zhu, Robyn Emmins, John A. Follit, Alison Porter, Andrew J. Racher, Sarah Milne, Ivan Carubelli, Zhimei Du, Ankita Khatri, Marilyne Failly, Hervé Broly, Frank Lee, Matthew Reeser, Jared Spidel, Karin Anderson, Christine Demaria, Jennifer Di-Carlo, John Gill, Amie Lundquist, Sampath R. Kumar, Tony Gill
PDA Journal of Pharmaceutical Science and Technology Jul 2018, 72 (4) 438-450; DOI: 10.5731/pdajpst.2018.008789

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Implementation of Plate Imaging for Demonstration of Monoclonality in Biologics Manufacturing Development
Kyle Zingaro, David Shaw, Jerry Carson, Anke Mayer-Bartschmid, Christian Bender, Christina Alves, Duncan Mcvey, Nan-Xin Qian, Qingxiang Wei, Michael W. Laird, Yuan Zhu, Robyn Emmins, John A. Follit, Alison Porter, Andrew J. Racher, Sarah Milne, Ivan Carubelli, Zhimei Du, Ankita Khatri, Marilyne Failly, Hervé Broly, Frank Lee, Matthew Reeser, Jared Spidel, Karin Anderson, Christine Demaria, Jennifer Di-Carlo, John Gill, Amie Lundquist, Sampath R. Kumar, Tony Gill
PDA Journal of Pharmaceutical Science and Technology Jul 2018, 72 (4) 438-450; DOI: 10.5731/pdajpst.2018.008789
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    • Abstract
    • Introduction
    • Considerations for Implementation of Plate Imaging
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    • Approaches to Addressing Regulatory Requirements for Clonal Cell Lines
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Keywords

  • monoclonality
  • cell cloning
  • clonally derived
  • limited/limiting dilution
  • Plate-based imaging
  • Single-cell imaging
  • CHO

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