title: Pathogen safety of human C1 esterase inhibitor concentrate.
abstract: BACKGROUND
  Human plasma-derived products--such as C1 esterase inhibitor (C1-INH) concentrate, used to treat hereditary angioedema--carry with them the risk of transmitting blood-borne viruses and, theoretically, prion proteins. To minimize this risk, three complementary approaches are implemented: selection and testing of plasma donations for the absence of pathogenic blood-borne viruses, similarly testing and releasing the plasma pool for fractionation, and ensuring that the manufacturing process includes validated steps for pathogen inactivation and removal.
  
  
  METHODS
  This article describes the selection of plasma for the production of C1-INH and the studies used to confirm the pathogen reduction capacity of the manufacturing process: three independent virus reduction steps--pasteurization, hydrophobic interaction chromatography (HIC), and virus filtration--and two prion reduction steps. Samples of product intermediates from the manufacturing steps were spiked with a panel of enveloped and nonenveloped viruses and two prion preparations and subjected to a valid scaled-down version of the respective manufacturing steps resulting in the quantification of the pathogen reduction factors.
  
  
  RESULTS
  Validation studies demonstrated overall virus reduction factors for all viruses of more than 15 log, considerably exceeding the potential amount of virus present in a plasma pool for fractionation. Prion proteins were also efficiently removed by the manufacturing process, as currently determined in evaluating the prion removal capacity of the ammonium sulfate precipitation and HIC steps.
  
  
  CONCLUSIONS
  The pathogen reduction capacity demonstrated here indicates that the manufacturing process of the C1-INH Berinert is highly effective for reducing enveloped and nonenveloped viruses and prion proteins.
authors.affiliation: Department of Pathogen Safety, CSL Behring, Marburg, Germany.
authors.forename: Albrecht
authors.initials: A
authors.lastname: Gröner
authors.forename: Thomas
authors.initials: T
authors.lastname: Nowak
authors.forename: Wolfram
authors.initials: W
authors.lastname: Schäfer
mesh_terms: D000818:Animals; D054316:Biomarkers, Pharmacological; D017848:Blood-Borne Pathogens / Q000187:drug effects; D002460:Cell Line / Q000821:virology; D005591:Chemical Fractionation / Q000379:methods; D002853:Chromatography, Liquid / Q000379:methods; D050718:Complement C1 Inhibitor Protein / Q000009:adverse effects / Q000302:isolation & purification / Q000592:standards* / Q000627:therapeutic use; D046148:Donor Selection; D004340:Drug Contamination / Q000517:prevention & control*; D056829:Hereditary Angioedema Types I and II / Q000188:drug therapy; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D021141:Nucleic Acid Amplification Techniques; D061352:Pasteurization; D010949:Plasma; D010956:Plasmapheresis; D011328:Prions / Q000097:blood*; D014462:Ultrafiltration; D019562:Viral Load; D038301:Virus Inactivation; D014780:Viruses / Q000302:isolation & purification
chemical_list: D054316:Biomarkers, Pharmacological; D050718:Complement C1 Inhibitor Protein; D011328:Prions