Berinert is a human plasma-derived, purified, pasteurized, lyophilized concentrate of C1 esterase inhibitor to be reconstituted for intravenous administration. Berinert is prepared from large pools of human plasma from US donors. One standard unit of C1 esterase inhibitor concentrate is equal to the amount of C1 esterase inhibitor in 1 mL of fresh citrated human plasma, which is equivalent to 270 mg/L or 2.5 ?M/L. No international laboratory standard for quantifying C1 esterase inhibitor exists. An in-house standard is used to assure lot-to-lot consistency in product potency.

C1 esterase inhibitor is a soluble, single-chain glycoprotein containing 478 amino acid residues organized into three beta-sheets and eight or nine alpha-helices.3 The heavily glycosylated molecule has an apparent molecular weight of 105 kD, of which the carbohydrate chains comprise 26% to 35%.4

Each vial of Berinert contains 500 units C1 esterase inhibitor, 50 to 80 mg total protein, 85 to 115 mg glycine, 70 to 100 mg sodium chloride, and 25 to 35 mg sodium citrate.

All plasma used in the manufacture of Berinert is obtained from US donors and is tested using serological assays for hepatitis B surface antigen and antibodies to HIV-? and HCV. Additionally, the plasma is tested with Nucleic Acid Testing (NAT) for HCV and HIV-1 and found to be non-reactive (negative). In addition, the plasma is tested by NAT for HAV and Human Parvovirus B19. Only plasma that has passed virus screening is used for production, and the limit for Parvovirus B19 in the fractionation pool is set not to exceed 104 IU of Parvovirus B19 DNA per mL.

The manufacturing process for Berinert includes multiple steps that reduce the risk of virus transmission. The virus inactivation/reduction capacity consists of three steps:

  • Pasteurization in aqueous solution at 60°C for 10 hours,
  • Hydrophobic interaction chromatography, and
  • Virus filtration (also called nanofiltration) by two filters, 20 nm and 15 nm, in series.

This was evaluated in a series of in vitro spiking experiments. The total mean cumulative virus inactivation/reduction is shown in Table 5.

Table 5: Mean Virus Inactivation/Reductions in Berinert

Virus Studied Pasteurization [log10] Hydrophobic Interaction Chromatography [log10] Virus Filtration [log 10] Total Cumulative [log10]
Envelope d Viruses
  HIV-1 6.6 4.5 5.1 16.2
  BVDV 9.2 4.7 5.3 19.2
  PRV 6.3 6.5 7.1 19.9
  WNV 7.0 ND 8.0 15.0
Non-Enveloped Viruses
  HAV 6.4 2.8 5.3 14.5
  CPV 1.4 6.4 7.2 15.0
  B19V 3.9 ND ND NA
HIV-1, Human immunodeficiency virus type 1, a model for HIV-1 and HIV-2
BVDV, Bovine viral diarrhea virus, a model for HCV
PRV, Pseudorabies virus, a model for large enveloped DNA viruses
WNV, West Nile virus
HAV, Hepatitis A virus
CPV, Canine parvovirus
B19V, Human Parvovirus B19
ND, Not determined
NA, Not applicable

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