Intravenous Immune Globulin (IGIV) - Carimune NF; Sandoglobulin
Status: approved; marketed
Organizations involved:
CSL Bioplasma, Inc. – USA mark.
CSL Bioplasma AG – Manuf.; R&D; Tech.; Intl. mark.; Parent co.
CSL Ltd. – Parent co.
Baxter Hyland Immuno – Manuf. other
American National Red Cross (ARC) – Former
Central Lab. Blood Transfusion Service, Swiss Red Cross – R&D; Tech.; Former inv.
Sandoz Corp./AG – Former inv.
Novartis Pharmaceutical Corp. – Former inv.
Cross ref: See the Immune Globulin Products entry (#743) and the entries for other IGIV products. See also Panglobulin (#762), which is substantially similar or identical to Carimune.
Description: Immune Globulin Intravenous (Human) or Carimune NF (formerly Sandoglobulin) is a lyophilized (freeze-dried) formulation of highly refined immune globulin obtained from pooled fractionated Plasma, with manufacture including a viral inactivation step involving porcine (pig) pepsin digestion at low (acid) pH and nanofiltration for virus removal. Carimune is derived from plasma obtained from unpaid volunteer U.S. donors (indicating that the Plasma is collected by the American National Red Cross Carimune NF was the first IGIV product in the U.S. to employ the use of nanofiltration in addition to virus inactivation steps.
Carimune is packaged in vials containing 6 grams of protein with 1.67 gram sucrose/gram protein and less than 20 mg sodium chloride/gram protein. Prior to use, Carimune may be reconstituted with either Sterile Water for Dilution, 5% Dextrose, or 0.9% Sodium Chloride Injection USP (saline) to form solutions with protein concentrations ranging from 3%-12%. The concentration used (osmolality) depends on variables including patient’s fluid and electrolyte levels, caloric requirements, and renal function. After reconstitution, it has a pH of 6.6 ± 0.2. Carimune contains no preservatives. Sucrose is used as a stabilizer. Carimune should be stored at or below 30˚C (86˚F), with a shelf life of 36 months.
The IgG content of Carimune is ≥ 96%. Most of the immune globulins are monomeric (unpolymerized) 7S IgG. The remainder consists of dimeric IgG and a small amount of polymeric IgG, traces of IgA and IgM, and immunoglobulin fragments. It has been reported that monomeric (non-polymerized) IgG content is > 92%. IgG subclass content matches that of pooled normal serum (reported by one source as IgG1 61%, IgG2 30%, IgG3 7% and IgG4 3%). IgA content is reported to less that 970 µg/ml. IgM is reported to be present at < 20 µg/ml. Carimune, among all marketed IGIV products, has the highest level of IgG4. The clinical significance of this has not been determined, but IgG4 is known to be involved in protecting the respiratory tract, and IgG4 deficiency has been associated with severe recurring respiratory tract infections and bronchiectasis.
Nomenclature: Immune Globulin (IGIV)/Carimune [BIO]; Carimune [TR]; Sandoglobulin [TR former; reg. to Sandoz/Novartis]; Immune Globulin Intravenous (Human) [FDA]; gamma globulin [SY]; intravenous immune globulin (IVIG) [SY]; immune globulin, intravenous [SY]; IGIV [SY]; NDC 0078-0120-94; NDC 0078-0122-95; NDC 0078-0124-96; NDC 0078-01244-93 [NDC]
Sandoglobulin was renamed as Carimune by ZLB Behring (now CSL Behring) in August 2002.
Companies.: Carimune is manufactured by CSL Bioplasma AG, a subsidiary of CSL Ltd. The product (originally Sando-globulin) was developed and formerly manufactured by the Central Laboratory Blood Transfusion Service, Swiss Red Cross (est. no. 0647). The product was previously marketed in the U.S. and internationally as Sandoglobulin by Sandoz Inc./AG, which became Novartis. It is now exclusively marketed in the U.S. by CSL Bioplasma Inc. and internationally by its parent, CSL Behring AG, both subsidiaries of CSL Ltd.
The source Plasma used is obtained from unpaid volunteer U.S. donors, indicating it is collected by the American National Red Cross (ARC), and previously further processed by the American National Red Cross, now by Baxter which assumed this from ARC in March 2005.
Manufacture: Carimune is manufactured from pooled Plasma by the Kistler-Nitschmann cold ethanol fractionation method, similar to Cohn-Oncley fractionation. Parts of the fractionation may be performed by other companies (i.e., plasma and intermediate fractions may be from other companies). Fraction II is reacted with trace amounts of immobilized porcine (pig) pepsin enzyme at a pH of 4 (Kistler-Nitschmann modification). This contributes significantly to virus inactivation, particularly enveloped viruses. The product is formulated with sucrose and lyophilized. manufacture does not include specific IgA depletion steps, so Carimune contains traces of IgG4, which has electrophoretic mobility similar to IgA. Cari-mune manufactured since June 2, 2003 has been nano-filtered.
Carimune manufacture includes several filtration steps which are carried out in the presence of filter aids, including the separation of the cold ethanol precipitates. Four of these filtration steps have been validated for virus inactivation. The associated manufacturing log10 reduction factor (LRF; viral load reduction) is 15.5 log for HIV; 16.0 log for pseudorabies (PRV); 9.3 log for Semliki Forest virus (SFV); 12.4 log for Sindbis virus; and 14.1 log for bovine enterovirus (BEV). The acid-pepsin step has been shown to have LRFs of ≥ 6.1 log for HIV; ≥ 5.3 log for PRV; ≥ 4.4 log for bovine viral diarrhea virus (BVDV); and ≥ 6.8 log for SFV. The PRV and the two model viruses for hepatitis C virus (HCV), BVDV and SFV, were all inactivated within one-tenth and HIV within one-half of the total incubation time used during actual manufacture. Cumulative (overall total) viral clearance (LRF) by elimi-nation (removal) and inactivation during the manufacturing process has been shown to be ≥ 21 log for HIV; ≥ 19 log for PRV; ≥ 15 log for SFV; and ≥ 14 log for BEV.
FDA class: Biologic PLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19840607; first approval, PLA; granted to Sandoz Corp.; Indication = for primary immune deficiencies (PID) and idiopathic thrombocytopenic purpura (ITP); [Supplemental approvals for other indications: not available]
Date = 20030300; launch (not approval date) for Carimune NF; Indication = added nanofiltration to manufacturing
Indications: See other IGIV products for exemplary "INDICATIONS AND USAGE” information. Carimune NF is approved for primary immunodeficiency, and immune thrombocytopenic purpura (ITP), acute and chronic.
Status: ZLB Bioplasma (after merger of Aventis Behring and ZLB Bioplasma; now CSL Bioplasma) filed a BLA supplement for approval of a liquid chromatographically-purified IGIV formulation (presumably comparable to Carimune NF). The application was accepted in Oct. 2002, but FDA later requested additional clinical data. ZLB’s/CSL’s liquid IGIV has received approval in Switzerland, and expansion of registrations to other European countries was anticipated in the second half of 2004.
Carimune NF, i.e., product manufactured with an additional nanofiltration step for virus removal, was launched in the U.S. in March 2003, with Carimune then being the first/only nanofiltered IGIV.
In June 2005, ZLB Behring announced enhancements to the packaging of Carimune NF, including a new RSS (Reduced Space Symbology) bar code; peel-off labels with lot number and expiration date, e.g., that can be appended to patients’ charts/records; a tamper-evident seal applied to cartons; and bold, new graphics, making the packages more distinctive and recognizable.
Market: The 2007 Average Wholesale Price (AWP) is $115.00/1 g; $303.00/3 g; $606.00/6 g; and $1.212.00/12 g (Red Book, 2007).
Companies involvement:
Full monograph
770 Immune Globulin (IGIV)/Carimune
Nomenclature:
Immune Globulin (IGIV)/Carimune [BIO]
Carimune [TR]
Sandoglobulin [TR Sandoz/Novartis]
Immune Globulin Intravenous (Human) [FDA]
gamma globulin [SY]
IGIV [SY]
immune globulin, intravenous [SY]
intravenous immune globulin (IVIG) [SY]
NDC 0078-0120-94; NDC 0078-0122-95; NDC 0078-0124-96; NDC 0078-01244-93 [NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1984
Date of 1st FDA approval = 19840607
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
blood products
human materials used<!-- humansource -->
immune globulins, human <!-- immunoglobulins -->
porcine source materials
acid conditions (low pH)
ethanol
Fraction II
immune globulin G4 (IgG4)
Kistler-Nitschmann fractionation
lyophilized (freeze-dried)
maltose
Namalva cells
pepsin digestion
Plasma (Human)
porcine pepsin
sodium chloride
sucrose
viral (nano)filtration
viral inactivation, acid (low pH)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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