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Research ArticleResearch

Kinetic Modeling of the Release of Ethylene Oxide from Sterilized Plastic Containers and its Interaction with Monoclonal Antibodies

Bryan Lei Yu, Jun Han, Matthew Hammond, Xuemei Wang, Qingchun Zhang, Andrew Clausen, Ronald Forster and Mingda Eu
PDA Journal of Pharmaceutical Science and Technology January 2017, 71 (1) 11-19; DOI: https://doi.org/10.5731/pdajpst.2015.005819
Bryan Lei Yu
4Device Technologies, Process Development, Amgen Inc., Thousand Oaks, CA
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  • For correspondence: Bryan.yu@amgen.com
Jun Han
3Attribute Sciences, Process Development, Amgen Inc., Thousand Oaks, CA;
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Matthew Hammond
3Attribute Sciences, Process Development, Amgen Inc., Thousand Oaks, CA;
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Xuemei Wang
3Attribute Sciences, Process Development, Amgen Inc., Thousand Oaks, CA;
1Current affiliation: Kythera Biopharmaceuticals, Westlake, CA;
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Qingchun Zhang
3Attribute Sciences, Process Development, Amgen Inc., Thousand Oaks, CA;
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Andrew Clausen
3Attribute Sciences, Process Development, Amgen Inc., Thousand Oaks, CA;
2Current affiliation: Snapdragon Chemistry, Cambridge, MA;
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Ronald Forster
4Device Technologies, Process Development, Amgen Inc., Thousand Oaks, CA
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Mingda Eu
4Device Technologies, Process Development, Amgen Inc., Thousand Oaks, CA
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Abstract

Ethylene oxide (ETO) is commonly used to sterilize plastic containers, but the effects of residual amounts left after sterilization on protein therapeutics are still not well understood. Here we focus primarily on the factors that influence concentrations of ETO migrating from ETO-treated plastic containers into aqueous solution. A study was designed to investigate the kinetics of this process at various temperatures, and the kinetic data could be fit with a model based on a combination of Fickean diffusion and first-order chemical reaction (to account for observed hydrolysis of ETO). The diffusion and reaction rate constants thus obtained obey Arrhenius-like temperature dependence. These results indicate that for analytical methods involving extraction into water, measurements of residual ETO in a container must account for the effects of ETO hydrolysis. Further, the effects of salt concentration and pH of the fluid in the container on accumulated ETO levels were explored. Finally, interactions of ETO with anti-streptavidin (AntiSA) Immunoglobulin G1 (IgG1) and IgG2 antibodies were studied, with ETO adducts found on all methionine residues when incubated in solutions spiked with ETO at concentrations that could be reached (based on the kinetic studies) in ETO-treated plastic vials. Overall, the likelihood of observable ETO-protein modifications upon storage in ETO-sterilized containers will depend on a complex interplay of protein properties, formulation details, storage conditions, and amount of residual ETO initially in the container.

LAY ABSTRACT: Ethylene oxide (ETO) is commonly used to sterilize plastic containers, but the effects of residual amounts left after sterilization on protein therapeutics are still not well understood. Here we describe experiments exploring the factors that influence concentrations of ETO migrating from ETO-treated plastic containers into aqueous solution over time. Additionally, interactions of ETO with model antibodies were studied, with ETO adducts found on all methionine residues when incubated in solutions spiked with ETO at concentrations that could potentially be reached in ETO-treated plastic vials. Overall, the likelihood of observable ETO-protein modifications upon storage in ETO-sterilized containers will depend on a complex interplay of protein properties, formulation details, storage conditions, and amount of residual ETO initially in the container.

  • Ethylene oxide
  • Plastic container
  • Headspace–gas chromatography
  • Mass spectrometry
  • Antibody
  • Chemical modification
  • © PDA, Inc. 2017
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PDA Journal of Pharmaceutical Science and Technology: 71 (1)
PDA Journal of Pharmaceutical Science and Technology
Vol. 71, Issue 1
January/February 2017
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Kinetic Modeling of the Release of Ethylene Oxide from Sterilized Plastic Containers and its Interaction with Monoclonal Antibodies
Bryan Lei Yu, Jun Han, Matthew Hammond, Xuemei Wang, Qingchun Zhang, Andrew Clausen, Ronald Forster, Mingda Eu
PDA Journal of Pharmaceutical Science and Technology Jan 2017, 71 (1) 11-19; DOI: 10.5731/pdajpst.2015.005819

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Kinetic Modeling of the Release of Ethylene Oxide from Sterilized Plastic Containers and its Interaction with Monoclonal Antibodies
Bryan Lei Yu, Jun Han, Matthew Hammond, Xuemei Wang, Qingchun Zhang, Andrew Clausen, Ronald Forster, Mingda Eu
PDA Journal of Pharmaceutical Science and Technology Jan 2017, 71 (1) 11-19; DOI: 10.5731/pdajpst.2015.005819
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Keywords

  • ethylene oxide
  • plastic container
  • Headspace–gas chromatography
  • Mass spectrometry
  • Antibody
  • Chemical modification

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