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Case ReportCase Studies

Identification and Root Cause Analysis of Cell Culture Media Precipitates in the Viral Deactivation Treatment with High-Temperature/Short-Time Method

Xiaolin Cao, Gregory Stimpfl, Zai-qing Wen, Gregory Frank and Glenn Hunter
PDA Journal of Pharmaceutical Science and Technology January 2013, 67 (1) 63-73; DOI: https://doi.org/10.5731/pdajpst.2013.00894
Xiaolin Cao
1Department of Drug Product Development, Amgen Inc., Thousand Oaks, CA 91320 and
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  • For correspondence: xiaolinc@amgen.com
Gregory Stimpfl
2Department of Pilot Plant Operations, Amgen Inc., Thousand Oaks, CA 91320
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Zai-qing Wen
1Department of Drug Product Development, Amgen Inc., Thousand Oaks, CA 91320 and
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Gregory Frank
2Department of Pilot Plant Operations, Amgen Inc., Thousand Oaks, CA 91320
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Glenn Hunter
2Department of Pilot Plant Operations, Amgen Inc., Thousand Oaks, CA 91320
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Abstract

High-temperature/short-time (HTST) treatment of cell culture media is one of the proven techniques used in the biopharmaceutical manufacturing industry for the prevention and mitigation of media viral contamination. With the HTST method, the formulated media is pasteurized (virus-deactivated) by heating and pumping the media continuously through the preset high-temperature holding tubes to achieve a specified period of time at a specific temperature. Recently, during the evaluation and implementation of HTST method in multiple Amgen, Inc. manufacturing facilities, media precipitates were observed in the tests of HTST treatments. The media precipitates may have adverse consequences such as clogging the HTST system, altering operating conditions and compromising the efficacy of viral deactivation, and ultimately affecting the media composition and cell growth. In this study, we report the identification of the composition of media precipitates from multiple media HTST runs using combined microspectroscopic methods including Raman, Fourier transform infrared spectroscopy, and scanning electron microscopy with energy-dispersive X-ray spectroscopy. The major composition in the precipitates was determined to be metal phosphates, including calcium phosphate, magnesium phosphate, and iron (III) phosphate. Based on the composition, stoichiometry, and root-cause study of media precipitations, methods were implemented for the mitigation and prevention of the occurrence of the media precipitation.

LAY ABSTRACT: Viral contamination in cell culture media is an important issue in the biopharmaceutical manufacturing industry and may have serious consequences on product quality, efficacy, and safety. High-temperature/short-time (HTST) treatment of cell culture media is one of the proven techniques used in the industry for the prevention and mitigation of media viral contamination. With the HTST method, the formulated media is pasteurized (virus-deactivated) by heating at preset conditions. This paper provides the identification and root-cause study of the media precipitates that adversely affected the HTST process and discusses the possible solutions to mitigate the precipitation problem.

  • Cell culture media
  • Viral contamination mitigation
  • High-temperature/short-time (HTST)
  • Media precipitation
  • Metal phosphates
  • Root cause analysis
  • © PDA, Inc. 2013
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PDA Journal of Pharmaceutical Science and Technology: 67 (1)
PDA Journal of Pharmaceutical Science and Technology
Vol. 67, Issue 1
January/February 2013
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Identification and Root Cause Analysis of Cell Culture Media Precipitates in the Viral Deactivation Treatment with High-Temperature/Short-Time Method
Xiaolin Cao, Gregory Stimpfl, Zai-qing Wen, Gregory Frank, Glenn Hunter
PDA Journal of Pharmaceutical Science and Technology Jan 2013, 67 (1) 63-73; DOI: 10.5731/pdajpst.2013.00894

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Identification and Root Cause Analysis of Cell Culture Media Precipitates in the Viral Deactivation Treatment with High-Temperature/Short-Time Method
Xiaolin Cao, Gregory Stimpfl, Zai-qing Wen, Gregory Frank, Glenn Hunter
PDA Journal of Pharmaceutical Science and Technology Jan 2013, 67 (1) 63-73; DOI: 10.5731/pdajpst.2013.00894
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Keywords

  • Cell culture media
  • Viral contamination mitigation
  • High-temperature/short-time (HTST)
  • Media precipitation
  • Metal phosphates
  • Root cause analysis

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