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GAMMAGARD LIQUID Immune Globulin Intravenous (Human), 10% is a ready-for-use sterile, liquid preparation of highly purified and concentrated immunoglobulin G (IgG) antibodies. The distribution of the IgG subclasses is similar to that of normal plasma.^1,2 The Fc and Fab functions are maintained in GAMMAGARD LIQUID. Pre-kallikrein activator activity is not detectable. GAMMAGARD LIQUID (immune globulin intravenous human 10%) contains 100 mg/mL protein. At least 98% of the protein is gammaglobulin, the average immunoglobulin A (IgA) concentration is 37µg/mL, and immunoglobulin M is present in trace amounts. GAMMAGARD LIQUID (immune globulin intravenous human 10%) contains a broad spectrum of IgG antibodies against bacterial and viral agents. Glycine (0.25M) serves as a stabilizing and buffering agent, and there are no added sugars, sodium or preservatives. The pH is 4.6 to 5.1. The osmolality is 240-300 mOsmol/kg, which is similar to physiological osmolality (285 to 295 mOsmol/kg).³

GAMMAGARD LIQUID is manufactured from large pools of human plasma. Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. Each individual plasma donation used in the manufacture of GAMMAGARD LIQUID (immune globulin intravenous human 10%) is collected only at FDA approved blood establishments and is tested by FDA licensed serological tests for Hepatitis B Surface Antigen (HBsAg), and for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, mini-pools of the plasma are tested for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT) and found negative. IgGs are purified from plasma pools using a modified Cohn-Oncley cold ethanol fractionation process, as well as cation and anion exchange chromatography.

To further improve the margin of safety, three dedicated, independent and effective virus inactivation/removal steps have been integrated into the manufacturing and formulation processes, namely solvent/detergent (S/D) treatment,^4,5 35 nm nanofiltration,^6,7 and a low pH incubation at elevated temperature.^8,9 The S/D process includes treatment with an organic mixture of tri-n-butyl phosphate, octoxynol 9 and polysorbate 80 at 18°C to 25°C for a minimum of 60 minutes. In vitro virus spiking studies have been used to validate the capability of the manufacturing process to inactivate and remove viruses. To establish the minimum applicable virus clearance capacity of the manufacturing process, these virus clearance studies were performed under extreme conditions (e.g., at minimum S/D concentrations, incubation time and temperature for the S/D treatment). Virus clearance studies for GAMMAGARD LIQUID (immune globulin intravenous human 10%) performed in accordance with good laboratory practices (Table 1) have demonstrated that:

•  S/D treatment inactivates the lipid-enveloped viruses investigated to below detection limits within minutes.
•  35 nm nanofiltration removes lipid-enveloped viruses to below detection limits and reduces the non-lipid enveloped viruses HAV and B19V As determined by a polymerase chain reaction assay nanofiltration reduced B19V by a mean log₁₀ reduction factor of 4.8 genome equivalents.
•  Treatment with low pH at elevated temperature of 30°C to 32°C inactivates lipid-enveloped viruses and encephalomyocarditis virus (EMCV, model for HAV) to below detection limits, and reduces mice minute virus (MMV, model for B19V).

Table 1: Three Dedicated Independent Virus Inactivation/Removal Steps
Mean Log₁₀ Reduction Factors ^a (RFs) For Each Virus and Manufacturing Step

REFERENCES

1. Skvaril F. Qualitative and quantitative aspects of IgG subclasses in i.v. immunoglobulin preparations. In: Nydegger UE, ed. Immunotherapy. London: Academic Press; 1981:118-122.

2. French M. Serum IgG subclasses in normal adults. Monogr Allergy. 1986;19:100-107.

3. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Appendix: Abbreviations and Measurements. Drug Information Handbook. Lexi-Comp; 1999:1254.

4. Horowitz B, Prince AM, Hamman J, Watklevicz C. Viral safety of solvent/detergent-treated blood products. Blood Coagul Fibrinolysis. 1994;5 Suppl 3:S21-S28.

5. Kreil TR, Berting A, Kistner O, Kindermann J. West Nile virus and the safety of plasma derivatives: verification of high safety margins, and the validity of predictions based on model virus data. Transfusion. 2003;43:1023-1028.

6. Hamamoto Y, Harada S, Kobayashi S, et al. A novel method for removal of human immunodeficiency virus: filtration with porous polymeric membranes. Vox Sang. 1989;56:230-236.

7. Yuasa T, Ishikawa G, Manabe S, Sekiguchi S, Takeuchi K, Miyamura T. The particle size of hepatitis C virus estimated by filtration through microporous regenerated cellulose fibre. J Gen Virol. 1991 ;72 (Pt 8):2021 -2024.

8. Kempf C, Jentsch P, Poirier B, et al. Virus inactivation during production of intravenous immunoglobulin. Transfusion. 1991;31:423-427.

9. Louie RE, Galloway CJ, Dumas ML, Wong MF, Mitra G. Inactivation of hepatitis C virus in low pH intravenous immunoglobulin. Biologicals. 1994;22:13-19.

Last reviewed on RxList: 9/9/2008
This monograph has been modified to include the generic and brand name in many instances.