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Advancing Biologics Development Programs with Legacy Cell Lines: Advantages and Limitations of Genetic Testing for Addressing Clonality Concerns Prior to Availability of Late Stage Process and Product Consistency Data

Paul Wu, Taymar Hartman, Louise Almond, Jennitte Stevens, John Thrift, Juhi OJha, Christina Alves, David Shaw, Michael W Laird, Robyn Emmins, Yuan Zhu, Ren Liu, Zhimei Du, Rolf Koehler, Thomas Jostock, Karin Anderson, Chris Campbell and Howard Clarke
PDA Journal of Pharmaceutical Science and Technology September 2019, pdajpst.2018.009316; DOI: https://doi.org/10.5731/pdajpst.2018.009316
Paul Wu
1 Bayer HealthCare LLC, Berkeley, CA, United States 94710;
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Taymar Hartman
2 Abbvie Biotherapeutics Inc., Redwood City, CA, United States 94063;
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Louise Almond
2 Abbvie Biotherapeutics Inc., Redwood City, CA, United States 94063;
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  • For correspondence: louise.almond@allergan.com
Jennitte Stevens
3 Amgen Inc, Thousand Oaks, CA United States 91320;
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  • For correspondence: jennitte@amgen.com
John Thrift
1 Bayer HealthCare LLC, Berkeley, CA, United States 94710;
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Juhi OJha
1 Bayer HealthCare LLC, Berkeley, CA, United States 94710;
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  • For correspondence: juhi.ojha@bayer.com
Christina Alves
4 Biogen Inc, Cambridge, MA, United States 02141;
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  • For correspondence: christina.alves@biogen.com
David Shaw
5 Genentech Inc, South San Francisco, CA, United States 94080;
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  • For correspondence: david.shaw@gene.com
Michael W Laird
5 Genentech Inc, South San Francisco, CA, United States 94080;
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  • For correspondence: laird.michael@gene.com
Robyn Emmins
6 GSK, King of Prussia, PA, United States 19406; Stevenage, United Kingdom;
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  • For correspondence: robyn.a.emmins@gsk.com
Yuan Zhu
6 GSK, King of Prussia, PA, United States 19406; Stevenage, United Kingdom;
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  • For correspondence: yuan.zhu@gsk.com
Ren Liu
7 Merck & Co., Inc., Kenilworth, NJ, United States 07033;
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  • For correspondence: ren.liu@merck.com
Zhimei Du
7 Merck & Co., Inc., Kenilworth, NJ, United States 07033;
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Rolf Koehler
8 Novartis Pharma AG, 4056 Basel, Switzerland;
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Thomas Jostock
8 Novartis Pharma AG, 4056 Basel, Switzerland;
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Karin Anderson
9 Pfizer Inc, Andover MA, United States 01810;
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Chris Campbell
10 Takeda Pharmaceuticals, Cambridge MA, United States 02039;
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  • For correspondence: norbert.schuelke@takeda.com
Howard Clarke
11 Seattle Genetics Inc, Bothell, WA, United States 98021
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  • For correspondence: hclarke@seagen.com
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Abstract

The bioprocessing industry uses recombinant mammalian cell lines to generate therapeutic biologic drugs. To ensure consistent product quality of the therapeutic proteins it is imperative to have a controlled production process. Regulatory agencies and the biotechnology industry consider cell line ″clonal origin″ an important aspect of maintaining process control. Demonstration of clonal origin of the cell substrate, or production cell line, has received considerable attention in the past few years and the industry has improved methods and devised standards to increase the probability and/or assurance of clonal-derivation 1-4. However, older production cell lines developed before the implementation of these methods, herein referred to as ″legacy cell lines″, may not meet current regulatory expectations for demonstration of clonal-derivation. In this article, the members of the IQ Consortium ″Working Group on Clonality″ present our position that the demonstration of process consistency and product comparability of critical quality attributes (CQAs) throughout the development life cycle should be sufficient to approve a license application without additional genetic analysis to support clonal origin, even for legacy cell lines that may not meet current day clonal-derivation standards. With this commentary we discuss advantages and limitations of genetic testing methods to support clonal-derivation of legacy cell lines and wish to promote a mutual understanding with the regulatory authorities regarding their optional use during early drug development, subsequent to IND application and prior to demonstration of product and process consistency at BLA submission.

  • CHO cell culture
  • MCB
  • WVB
  • cell line development
  • clonality
  • genetic characterization
  • Received September 7, 2018.
  • Accepted August 22, 2019.
  • Copyright © 2019, Parenteral Drug Association

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PDA Journal of Pharmaceutical Science and Technology: 75 (1)
PDA Journal of Pharmaceutical Science and Technology
Vol. 75, Issue 1
January/February 2021
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Advancing Biologics Development Programs with Legacy Cell Lines: Advantages and Limitations of Genetic Testing for Addressing Clonality Concerns Prior to Availability of Late Stage Process and Product Consistency Data
Paul Wu, Taymar Hartman, Louise Almond, Jennitte Stevens, John Thrift, Juhi OJha, Christina Alves, David Shaw, Michael W Laird, Robyn Emmins, Yuan Zhu, Ren Liu, Zhimei Du, Rolf Koehler, Thomas Jostock, Karin Anderson, Chris Campbell, Howard Clarke
PDA Journal of Pharmaceutical Science and Technology Sep 2019, pdajpst.2018.009316; DOI: 10.5731/pdajpst.2018.009316

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Advancing Biologics Development Programs with Legacy Cell Lines: Advantages and Limitations of Genetic Testing for Addressing Clonality Concerns Prior to Availability of Late Stage Process and Product Consistency Data
Paul Wu, Taymar Hartman, Louise Almond, Jennitte Stevens, John Thrift, Juhi OJha, Christina Alves, David Shaw, Michael W Laird, Robyn Emmins, Yuan Zhu, Ren Liu, Zhimei Du, Rolf Koehler, Thomas Jostock, Karin Anderson, Chris Campbell, Howard Clarke
PDA Journal of Pharmaceutical Science and Technology Sep 2019, pdajpst.2018.009316; DOI: 10.5731/pdajpst.2018.009316
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Keywords

  • CHO cell culture
  • MCB
  • WVB
  • Cell line development
  • Clonality
  • Genetic characterization

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