GAMUNEX-C is a ready-to-use sterile solution of human
immune globulin protein for intravenous and subcutaneous (PI indication only)
administration. GAMUNEX-C consists of 9%–11% protein in 0.16–0.24 M glycine.
Not less than 98% of the protein has the electrophoretic mobility of gamma globulin.
GAMUNEX-C contains trace levels of fragments, IgA (average 0.046 mg/mL), and
IgM. The distribution of IgG subclasses is similar to that found in normal
serum. GAMUNEX-C doses of 1 g/kg correspond to a glycine dose of 0.15 g/kg.
While toxic effects of glycine administration have been reported, the doses and
rates of administration were 3–4 fold greater than those for GAMUNEX-C. In
another study it was demonstrated that intravenous bolus doses of 0.44 g/kg
glycine were not associated with serious adverse effects.  Caprylate is a
saturated medium-chain (C8) fatty acid of plant origin. Medium chain fatty
acids are considered to be essentially non-toxic. Human subjects receiving
medium chain fatty acids parenterally have tolerated doses of 3.0 to 9.0
g/kg/day for periods of several months without adverse effects.  Residual
caprylate concentrations in the final container are no more than 0.216 g/L (1.3
mmol/L). The measured buffer capacity is 35 mEq/L and the osmolality is 258
mOsmol/kg solvent, which is close to physiological osmolality (285-295
mOsmol/kg). The pH of GAMUNEX-C is 4.0–4.5. GAMUNEX-C contains no preservative and
GAMUNEX-C is made from large pools of human plasma by a
combination of cold ethanol fractionation, caprylate precipitation and
filtration, and anion-exchange chromatography. Isotonicity is achieved by the
addition of glycine. GAMUNEX-C is incubated in the final container (at the low
pH of 4.0–4.3). The product is intended for intravenous administration and may
be administered subcutaneously in treatment of PI.
The capacity of the manufacturing process to remove
and/or inactivate enveloped and non-enveloped viruses has been validated by
laboratory spiking studies on a scaled down process model, using the following
enveloped and non-enveloped viruses: human immunodeficiency virus, type I
(HIV-1) as the relevant virus for HIV-1 and HIV–2; bovine viral diarrhea virus
(BVDV) as a model for hepatitis C virus; pseudorabies virus (PRV) as a model for
large DNA viruses (e.g., herpes viruses); Reo virus type 3 (Reo) as a model for
non-enveloped viruses and for its resistance to physical and chemical
inactivation; hepatitis A virus (HAV) as relevant non-enveloped virus, and
porcine parvovirus (PPV) as a model for human parvovirus B19. Overall virus
reduction was calculated only from steps that were mechanistically independent
from each other and truly additive. In addition, each step was verified to
provide robust virus reduction across the production range for key operating
Table 12: Log10 Virus Reduction
||Log10 Virus Reduction
|Caprylate Precipitation/ Depth Filtration
|| ≥ 3.5
|| ≥ 3.6
|| ≥ 4.5
|| ≥ 4.6
|| ≥ 4.5
|| ≥ 4.3
|| ≥ 2.0
|| ≥ .0 .3
|| ≥ .3. 3
|| ≥ 4.0
|| ≥ 1.4
|Low pH Incubation
|| ≥ 6.5
|| ≥ 14.0
|| ≥ 12.2
|| ≥ 16.3
|| ≥ 7.5
|| ≥ 5.0
|a C/I - Interference by caprylate precluded
determination of virus reduction for this step. Although removal of viruses is
likely to occur at the caprylate precipitation/depth filtration step, BVDV is
the only enveloped virus for which reduction is claimed. The presence of
caprylate prevents detection of other, less resistant enveloped viruses and
therefore their removal cannot be assessed.
b Not Applicable – This step has no effect on non-enveloped viruses.
c CAP - The presence of caprylate in the process at this step
prevents detection of enveloped viruses, and their removal cannot be assessed.
d Some mechanistic overlap occurs between depth filtration and other
steps. Therefore, Grifols Therapeutics Inc. has chosen to exclude this step
from the global virus reduction calculations.
Additionally, the manufacturing process was investigated
for its capacity to decrease the infectivity of an experimental agent of
transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD
and CJD agents. [22-26]
Several of the individual production steps in the
GAMUNEX-C manufacturing process have been shown to decrease TSE infectivity of
that experimental model agent. TSE reduction steps include two depth
filtrations (in sequence, a total of ≥ 6.6 logs). These studies provide
reasonable assurance that low levels of CJD/vCJD agent infectivity, if present
in the starting material, would be removed.
1. Cayco AV, Perazella MA, Hayslett JP. Renal
insufficiency after intravenous immune globulin therapy: a report of two cases
and an analysis of the literature. J Am Soc Nephrol, 1997. 8(11): p. 1788-94.
20. Tai VM, M.E., Lee-Brotherton V, Manley JJ, Nestmann
ER, Daniels JM. Safety Evaluation of Intravenous Glycine in Formulation
Development. In J Pharm Pharmaceut Sci. 2000.
21. Traul KA, et al. Review of the toxicologic properties
of medium-chain triglycerides. Food Chem Toxicol, 2000. 38(1): p. 79-98. Secondary
Endpoint p-valuea Randomized Withdrawal Period Time to Relapse p= 0.011
22. Stenland CJ, Lee DC, Brown P, et al. Partitioning of
human and sheep forms of the pathogenic prion protein during the purification
of therapeutic proteins from human plasma. Transfusion 2002. 42(11):1497-500.
23. Lee DC, Stenland CJ, Miller JL, et al. A direct
relationship between the partitioning of the pathogenic prion protein and
transmissible spongiform encephalopathy infectivity during the purification of
plasma proteins. Transfusion 2001. 41(4):449-55.
24. Lee DC, Stenland CJ, Hartwell RC, et al. Monitoring
plasma processing steps with a sensitive Western blot assay for the detection
of the prion protein. J Virol Methods 2000. 84(1):77-89.
25. Cai K, Miller JL, Stenland CJ, et al. Solvent-dependent
precipitation of prion protein. Biochim Biophys Acta 2002. 1597(1):28-35.
26. Trejo SR, Hotta JA, Lebing W, et al. Evaluation of
virus and prion reduction in a new intravenous immunoglobulin manufacturing
process. Vox Sang 2003. 84(3):176-87.
Last reviewed on RxList: 1/14/2013
This monograph has been modified to include the generic and brand name in many instances.