Immune Globulin Intravenous (Human) - Gamimune
Status: approved; phased out in 2004
Organizations involved:
Talecris Biotherapeutics Inc. – Manuf.; Tech.; USA mark.
Instituto Grifols, S.A. - Parent
NPS Pharmaceuticals Inc – Former
Bayer Schering Pharma AG – Intl. mark.
Bayer Corp. – R&D.; Former
New York Blood Center, Inc. – Tech.
Cross ref: See the Immune Globulin Products entry (#743). See the entry above for Gamunex from Talecris, which recently replaced this product.
Description: Immune Globulin Intravenous (Human) or Gam-imune N S/D refers to aqueous formulations of highly refined immune globulin obtained from pooled Plasma from paid (presumably, plasmapheresis) donors, with viral inactivation using heat (pasteurization), the solvent detergent (S/D) process, and processing at low pH. The ‘N’ in the trade name refers to the native or unmodified characteristics of the IgG in the product. Over 98% of the protein is IgG, of which ≥ 90% is monomeric. The distribution of IgG subclasses in Gam-imune N is similar to that found in normal serum.
Gamimune N 10% consists of 9-11% protein in 01.6-0.24 M glycine. Gamimune N S/D is available as 5% and 10% solutions. IgG content is ≥ 98%, with monomeric (non-polymerized) IgG ≥ 95%. IgG subclass content includes IgG1 59%, IgG2 29%, IgG3 6% and IgG4 5%. IgA content in the 5% solution is less that 270 µg/ml. A trace of IgM is present. Glycine (about 10%) is used to adjust isotonicity. The solutions are stored at 2-8˚C (refrigerated), with the 5% solution having a shelf life of 36 months and the 10% solution having a shelf life of 27 months.
Nomenclature: Immune Globulin (IGIV)/Talecris [BIO]; Gamimune N S/D [TR]; Immune Globulin Intravenous (Human) [FDA]; Polyglobin N S/D [TR outside U.S.]; gamma globulin, intravenous [SY]; immune globulin, intravenous [SY]; IVIG [SY]; intravenous immune globulin (IVIG) [SY]; NDC 0026-0648-12; NDC 0026-0648-20; NDC 0026-0648-71; NDC 0026-0648-24 [NDC]
History: Gamimune from Cutter Labs. (later Miles Labs. and Bayer Corp.; now Talecris Biotherapeutics) was the first conventional IGIV, launched in the U.S. in 1981. Manufacturing included alkylation (chemical modification) with iodoacetamide and reduction with dithiothreitol (DTT) to reduce/eliminate IgG fragmentation, aggregation, and anticomplement activity. The manufacturing process was changed in 1986 to eliminate these chemical modifications and provide unmodified IgG.
Companies.: Gamimune N S/D (and Polyglobin N S/D) was developed and manufactured by Bayer Corp., FDA CBER est. no. 0008, a subsidiary of Bayer AG, at facilities in Clayton, NC. Gamimune was marketed in the U.S. by Bayer Corp., and internationally by Bayer AG affiliates. In April 2005, Talecris Biotherapeutics Inc., a subsidiary of NPS Pharmaceuticals Inc., acquired the blood/plasma products business of Bayer AG, including manufacturing and U.S marketing, with Bayer AG, now Bayer Schering Pharma AG, retaining international marketing.
In Feb. 2011, Grifols S.A./Instituto Grifols acquired Talecris Biotherapeutics.
Manufacture: As described in a process flow chart at www.gamunex.com, processing starting with suspended Cohn Fraction II+III involves cold ethanol fractionation and centrifugation; another cycle of cold ethanol fractionation and centrifugation; depth filtration; ultrafiltration/diafiltration; solvent-detergent viral inactivation (incubation with solvent and detergent); depth filtration; ultrafiltration/diafiltration; hydrophobic interaction chromatography (HIC; liquid ion-exchange chromatography to separate proteins based on their hydrophobicity), bulking (adjustment of fluid content); and incubation at low pH of 4.25 (secondary viral inactivation; also stabilizes IGIV, avoiding the use of sugar stabilizers.). The fragile immunoglobulin stays in solution during the entire production process, allowing a gentler treatment that preserves biological activity. Pooled human Plasma from paid donors is fractionated using the Cohn-Oncley cold-ethanol process (methods 6 and 9). Filtrate (Effluent) III is adjusted to a pH of 4.25 at a low salt concentration. This is subjected to ultrafiltration and diafiltration (dialysis). Maltose is added as an excipient and the product is sterile filtered (depth filtration). The solution is adjusted to 0.3% tri-n-butyl phosphate (TNBP; a solvent) and 0.2% sodium cholate (a detergent), and heated and maintained at 30˚C for at least six hours (for solvent-detergent virus inactivation; primarily effective against enveloped viruses). The solvent and detergent are removed by precipitation, filtration, diafiltration, and ultrafiltration. The final containers are filled and incubated at a low pH of 4.25 at 24˚±3˚C (68˚F; wet heat) for 21 days, with the low pH and heat resulting in significant inactivation of enveloped viruses. This low pH (acidity) adjustment also eliminates undesired anticomplement activity (from aggregation of IgG). This low pH viral inactivation condition is maintained as the product is filled and packaged in the final container. Prior to filling, plasma is sterile-filtered through a 0.2 micron filter (to remove and bacteria, fungi, and particulates). Solvent/detergent (S/D) viral inactivation was added to the manufacturing process in 1997.
Total reduction of viruses by the Gamimune manufacturing process is >20.8 log10 for HIV-1, >11.8 for bovine viral diarrhea virus (BVDV; a model for hepatitis C virus), >18.6 log for pseudorabies virus (PRV; a model for hepatitis B virus), ≥9.7 log for reovirus 3 (a model for viruses resistant to physico-chemical agents), ≥8.3 log for hepatitis A virus (HAV), and ≥9.2 log for porcine parvovirus (PPV; a model for human parvovirus B19). Cohn-Oncley fractionation reduces HIV-1 by ≥5.9 log, BVDV by 3.2 log, PRV by ≥4.1 log, reovirus 3 by ≥5.2 log, HAV by ≥4.4 log, and PPV by ≥4.8 log. Depth filtration reduces HIV-1 by ≥5.3 log, BVDV by <1.0 log, PRV by ≥3.8 log, reovirus 3 by ≥4.5 log, HAV by ≥3.9 log, and PPV by ≥4.4 log. Solvent/detergent (SD) treatment reduces HIV-1 by ≥5.2 log, BVDV by 4.4 log, and PRV by ≥4.6 log (each enveloped viruses), with no activity against the non-enveloped viruses (reovirus 3; HAV; PPV). The low pH process reduces HIV-1 by ≥4.5 log, BVDV by ≥4.4 log, and PRV by ≥6.1 log, with no activity against the non-enveloped viruses. In April 2003, Bayer announced that Gamimune manufacturing processes “successfully inactivate vaccinia,” eliminating the risk of vaccinia virus infection from plasma donors having received smallpox virus vaccination.
FDA class: Biologic PLA
CBER class: Blood and Blood Derivatives
Approvals: Date = 19810911; first approval for IGIV from Cutter Labs.
Date = 19860000; PLA supplement; Indication = manufacturing changes to methods providing unmodified IgG, resulting in Gamimune (current product)
Date = 19931227; PLA supplement; orphan designation (granted 02/18/1993; expired 12/27/2000); Indication = infection prophylaxis in HIV-infected pediatric patients
Date = 19970000; PLA supplement; Indication = addition of solvent-detergent viral inactivation manufacturing process [exact date unavailable; perhaps, included in Feb. 1997 approval for ITP/BMT]
Date = 19970221; PLA supplement; Indication =use with idiopathic thrombocytopenic purpura (ITP) and/or bone marrow transplants (BMT)
Date = 20030423; BLA supplement; Indication = approval of new sterile Clayton, NC, filling facilty
Indications: [portions of the "INDICATIONS AND USAGE” section from consumer version of product insert/labeling; This section extends multiple pages]:
Primary Humoral Immunodeficiency: Efficacious in the treatment of primary immunodeficiency states in which severe impairment of antibody forming capacity has been shown, such as: congenital agammaglobulinemias, common variable immunodeficiency, Wiskott-Aldrich syndrome, x-linked immunodeficiency with hyper IgM, and severe combined immunodeficiencies.
Idiopathic Thrombocytopenic Purpura (ITP): To rapidly increase the platelet count to control bleeding or to allow a patient with ITP to undergo surgery administration of Gamimune N should be considered.
Bone Marrow Transplantation (BMT): To decrease the risk of septicemia and other infections, interstitial pneumonia of infectious or idiopathic etiologies, and acute graft-versus-host disease (AGVHD) in bone marrow transplant patients 20 years of age or over during the first 100 days post-transplant. Gam-imune N is not indicated for BMT patients under 20 years of age.
Pediatric HIV Infection: To decrease the frequency of serious and minor bacterial infections (laboratory-proven and clinically diagnosed), decrease the frequency of hospitalization, and increase the time free of serious bacterial infection (especially primary bacteremia and acute pneumonia).
Status: Bayer filed a BLA supplement in Sept. 2002 for approval for treatment of primary immunodeficiency.
Gamimune was phased out in mid-2004, and replaced by Gamunex from Bayer, now Talecris (see entry #760).
Tech. transfer: The product insert cites U.S. 4,396,608, “Intravenously injectable immune serum globulin,” August 2, 1983, assigned to Cutter Labs./Bayer (now Talecris Biotherapeutics), covering the low pH processing of Gamimune. The patent describes high yield methods for manufacture and formulation of intravenously injectable immune globulin with an ionic strength and low pH to maintain high monomer content (>90%). The product is substantially free of actual and latent anticomplement activity and polymeric material or “aggregates”
In Dec. 2002, Bayer agreed to license technology for the production of intravenous immune globulin (IVIG) 5% S/D (Gamimune) to the Japanese Red Cross Society (JRS), which will build its own manufacturing facility. Bayer Yakuhin Ltd.. will co-market the product in Japan, with launch expected in late 2006.
Solvent detergent viral inactivation technology was developed by and nonexclusively licensed from the New York Blood Center, e.g,. U.S. patent 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma) (#799) for further information about solvent detergent viral inactivation, used primarily for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).
Market: Gamimune sales in the first half of 2003 were about $162 million (equivalent to ~$324 million/year).
Gamunex was phased-in and replaced Gamimune N from Bayer/Talecris in mid-2004.
The 2004 Average Wholesale Price (AWP) for Gamimune N 10% was $97.20/10 mL; $243.00/25mL; $486.00/50 mL; $972.00/100 mL; and $1,944.00/200 mL (Red Book, 2004) (the same as for Gamunex at the time).
Companies involvement:
Full monograph
765 Immune Globulin (IGIV)/Talecris
Nomenclature:
Immune Globulin (IGIV)/Talecris [BIO]
Gamimune N S/D [TR]
Immune Globulin Intravenous (Human) [FDA]
gamma globulin, intravenous [SY]
immune globulin, intravenous [SY]
intravenous immune globulin (IVIG) [SY]
IVIG [SY]
Polyglobin N S/D [TR ex-U.S.]
NDC 0026-0648-12; NDC 0026-0648-20; ; NDC 0026-0648-71; NDC 0026-0648-24 [NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1981
Date of 1st FDA approval = 19810911
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
blood products
human materials used<!-- humansource -->
immune globulins, human <!-- immunoglobulins -->
dithiothreitol (DTT)
ethanol
Filtrate (Effluent) III
glycine
heat treatment (pasteurization)
iodoacetamide
maltose
Plasma (Human)
sodium cholate
tri-n-butyl phosphate (TNBP)
viral inactivation, acid (low pH)
viral inactivation, solvent detergent
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
North American coral snake
North American coral snake
orphan status
EU011 Approved Formerly in EU/withdrawn
UM999 Not Available/Not Marketed in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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