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Soluble tungsten in syringes seen as possible root cause of unwanted epo immunogenicity | BioQuality.biz

Tungsten-induced denaturation and aggregation of epoetin alfa during primary packaging as a cause of immunogenicity, Pharm Res. 2012 Jun;29(6):1454-67. Epub 2011 Nov 18., Seidl A, Hainzl O, Richter M, Fischer R, Böhm S, Deutel B, Hartinger M, Windisch J, Casadevall N, London GM, Macdougall I., Sandoz Biopharmaceuticals, Hexal AG, Keltenring 1 + 3, 82041, Oberhaching, Germany, andreas.seidl@sandoz.com.

Overview of the paper

  • Two cases were noted of neutralizing antibodies to epoetin alfa in an investigational clinical study
  • During the investigation of this unwanted immunogenicity, a small number of individual syringes of two drug product batches were found to contain unusually high levels of aggregation at the end of the clinical trial
  • The scientists thus undertook an extensive analytical investigation to determine the root-cause of the increased aggregation in the affected batches
  • They found soluble tungsten in the syringes, most likely derived from the pins used to manufacture the syringes
    • Spiking of epoetin alfa with sodium polytungstate or an extract of tungsten pins used to manufacture the syringes induced the formation of aggregates:
      • the agrregated contained both dimers that appeared to be covalently linked by disulphide bonds as well as higher-order aggregates
    • Sodium polytungstate had also a strong denaturing effect on the protein
  • In conclustion, the authors propose that tungsten-mediated unfolding and aggregation of epoetin alfa in pre-filled syringes is a potential root cause for increased immunogenicity.
  • They also state that this finding may be more broadly applicable to this and other classes of therapeutic proteins

To see the Abstract, and a link to obtain this paper: http://www.ncbi.nlm.nih.gov/pubmed/22094831

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