Venoglobulin
Immune Globulin Intravenous (Human), Solvent -Detergent Treated - Venoglobulin-S 5% and 10%
Status: approved; marketed
Organizations involved:
Grifols Biological Inc. – Manuf.; R&D; Tech.; USA mark.
Instituto Grifols, S.A. – Intl. mark.
Probitas S.A. – Parent co.
Alpha Therapeutic Corp. – R&D; Tech.; Former
Abbott Laboratories – R&D; Tech.; Former
Green Cross Corp. – Former
Yoshitomi Pharmaceutical Industries, Ltd. – Former
Mitsubishi Chemical Corp. – Former
New York Blood Center, Inc. – Tech.
Cross ref: See Immune Globulin Products (#743).
Description: Immune Globulin Intravenous (Human), Solvent Detergent Treated or Venoglobulin refers to solution (10% or 5%) and lyophilized (freeze-dried) formulations of highly purified monomeric/dimeric immunoglobulin G (IgG) obtained from fractionated pooled human Plasma, with manufacture including solvent detergent and wet heat (pasteurization) treatments for viral inactivation. Alpha introduced the first solvent detergent virus inactivated IGIV in 1991. During manufacture, Plasma is separated and refined by Cohn-Oncley cold ethanol fractionation to obtain immune globulin which is heated for viral inactivation, followed by polyethylene glycol (PEG)/bentonite fractionation, ion exchange chromatography, and viral inactivation by the solvent detergent process (tri-n-butyl phosphate and polysorbate 80; primarily inactivates enveloped viruses). D-Sorbitol is used as a stabilizer during processing and in the final product (1 mg/2 mg protein).
The liquid formulations are available as 5% and 10% solutions. Both concentrations have IgG purity > 99%, as monomeric and dimeric forms (non-polymerized). The 5% solution is packaged in 2.5, 5, and 10 gram vials. The 10% solution is packaged in 5, 10 and 20 gram vials. The product contains no preservatives. Venoglobulin-S, 10% contains: IgG 100 mg/mL; D-sorbitol 50 mg; Albumin (Human) < 2.6 mg/mL; polyethylene glycol < 200 µg/mL; polysorbate 80 < 200 µg/mL; and tri-n-butyl phosphate < 20 µg/mL. For the 5% solution, IgG is present as monomeric and dimeric forms (non-polymerized) over 99%; with 0.2-0.3% as polymers and 0-0.4% as fragments. IgG is present as 65.7-67.2% IgG1, 23.7-25.3% IgG2, 5.7-5.9% IgG3, and 3.0-3.4% IgG4. IgA is present at 15 µg/ml (average). pH is 5.2-5.8 and osmolality is 300 mOsm/L. The 5% solution can be stored at room temperature (less than 86˚F), while the 10% solution should be stored at 2-8˚C (refrigerated). The dating period is 24 months from the date of manufacture (date of the first sterile filtration of the final bulk) when stored below 30˚C.
Nomenclature: Immune Globulin (IGIV)/Venoglobulin [BIO]; Venoglobulin-S [TR]; Venoglobulin-I [TR former upon original approval]; Immune Globulin Intravenous (Human), Solvent Detergent Treated [FDA]; Immune Serum Globulin (Human) [FDA former]; gamma globulin, intravenous [SY]; immune globulin, intravenous [SY]; IVIG [SY]; intravenous immune globulin (IVIG) [SY]; NDC 49669-1622-1; NDC 49669-1623-1; NDC 49669-1624-1 [NDC]
Companies.: Venoglobulin-S is manufactured by Grifols Biological Inc., CBER/FDA est. no. 1694, previously Alpha Therapeutic Corp. (originally independent, later a subsidiary of Green Cross Corp., a subsidiary of Yoshitomi Pharmaceutical Industries, Ltd., later acquired by Mitsubishi Chemical), CBER/FDA lic. no. 0744. Alpha was acquired by Probitas Pharma S.A. in July 2003 and merged into its Instituto Grifols subsidiary. The product is marketed in the U.S. by Grifols Biological Inc., and internationally by Istituto Grifols S.A. and affiliates (previously Alpha Therapeutic Corp. and affiliates, including Green Cross and Yoshitomi). This product was among those acquired by Alpha Therapeutic when it originally purchased Abbott Labs.’ U.S. plasma processing facilities and products in the late 1970s.
Manufacture: All manufacturing takes place at company facilities in Los Angeles, CA. The source plasma used for production of Venoglobulin comes from paid donors (obtained by plasmapheresis). The product is prepared from pooled Plasma by Cohn-Oncley cold-ethanol fractionation (methods 6 and 9), similar to manufacture of intramuscular immune globulin. Fraction II precipitate is fractionated with 4% polyethylene glycol (PEG) and precipitated with bentonite (mineral from clay) at 4˚C. This step is by nature virucidal and provides substantial reduction of viral load. The resulting gamma-globulin I paste is subjected to ion-exchange adsorption purification/chromatography using DEAE-Sephadex media (from Amer-sham Pharmacia Biotech).
For production of the solution formulation, the product from ion-exchange adsorption purification is treated using the solvent detergent process, involving addition of about 1% each of tri(n-butyl)phosphate (TNBP) and polysorbate 80 (Tween 80). This is followed by two successive ion exchange chromatography steps, and diafiltration and concentration. D-sorbitol (5%) is added as stabilizer, and the product is sterile filtered. Product for the solid dosage form is lyophilized (further contributing to viral inactivation). The purification processes have been shown to result in very little change in the physical and chemical properties of the IgG molecules, and the product has an in vivo half-life similar to native IgG. The IgG subclass distribution of the product approximates that of normal human plasma.
Total elimination of viruses by the manufacturing process (primarily cold ethanol fractionation, PEG/bentonite fractionation, and solvent detergent treatment) is >23 log for HIV-1, >6.0 log for HIV-2, >9.7 log for Sindbis virus, >9.4 log for vesicular stomatitis virus (VSV), 7.0 log for vaccinia virus, ≥8.5 log for encephalomyocarditis virus (EMV), ≥6.4 log for porcine parvovirus (PPV) and 7.0 log for hepatitis C virus (HCV).
The final product is routinely tested for sterility, pyrogenicity, safety, antibody potency (measles, diphtheria, poliovirus, and hepatitis B virus), hepatitis B virus surface antigen (HBsAg), protein composition, anticomplementary activity, prekallikrein activator, solubility, moisture, heat stability, pH, molecular size distribution, intradermal skin test in humans, and content of albumin, IgG, polyethylene glycol, mannitol, and total protein.
FDA class: Biologic PLA
CBER class: Blood And Blood Derivatives
Approvals: Date = 19710430; PLA, first approval, granted to Abbott Labs.
Date = 19780815; first approval, according to the CBER/FDA database; However, an FDA approval letter on this date reports that the product license was withdrawn and granted (reissued) to Alpha Therapeutic Corp., new owner.
Date = 19881013; PLA/ELA no. 85-0468 and 88-0241; Indication = first approval for Immune Globulin Intravenous (Human), trade name Venoglobulin-I, a lyophilized powder formulation
Date = 19911113; PLA supplement; Indication = solvent detergent viral inactivation processing added to manufacturing process, and new solution formulations approved
Indications: [full text of "INDICATIONS AND USAGE” section from a recent product insert/labeling]:
Immunodeficiency: Venoglobulin-S, 10% is indicated for the maintenance treatment of patients with primary immunodeficiency syndromes, such as congenital agammaglobulinemia, common variable immunodeficiency, X-linked gammaglobu-lin-emia, severe combined immunodeficiency, and Wiskott-Aldrich syndrome.
Venoglobulin-S, 10% is especially useful in treating patients who require an immediate and substantial increase in intravascular immunoglobulin levels, and in patients with limited muscle mass, or with bleeding tendencies for whom intramuscular injections are contraindicated.
Idiopathic Thrombocytopenic Purpura (ITP): Veno-globulin-S, 10% is indicated for use in the treatment of acute and chronic ITP in clinical situations which require a rapid rise in platelet count, for example prior to surgery, in control of excessive bleeding or as a measure to defer splenectomy. Venoglobulin-S, 10% is also indicated in cases of chronic (greater than 6 months duration) ITP to maintain platelet counts above 30,000/mm3 in children and above 20,000/mm3 in adults. It is currently not possible to predict which patients with ITP will respond to therapy, although the increase in platelet count in children seems to be better than that of adults.
Kawasaki Disease: Venoglobulin-S, 10% in conjunction with high dose aspirin (100 mg/kg/day) is indicated for the treatment of Kawasaki disease. Treatment with a single dose of 2 g/kg of Venoglobulin-S resulted in a significantly lower (p = 0.007) incidence of coronary artery abnormalities when compared to the historical control group.
Tech. transfer: U.S. 6,162,904, “Manufacturing Method for Intravenously Administrable Immune Globulin and Resultant Product,” Dec. 19, 2000, assigned to Alpha Therapeutic Corp., appears to describe Veno-glo-bulin manufacture. A process is disclosed for integral, continuous manufacture of intravenously-administrable immune globulin (IGIV) involving heating purified immune globulin for viral inactivation, PEG/bentonite fractionation, followed by solvent detergent viral inactivation. The continuous process is carried out in solution without the need to precipitate the desired gamma globulin (no handling of solid intermediates). See Example 3, “Manufacturing Method for Intravenous Immune Globulin and Resultant Product.”
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: The 2007 Average Wholesale Price (AWP) for Venoglobulin-S 10% is $575.00/50 mL vial; $1,150.00/100 mL; and $2,300.00/200 mL Red Book, 2007). The AWP for Venoglobulin-S 5% is $287.50/50 mL vial; $575.00/100 mL; and $1,150/200 mL.
Companies involvement:
Full monograph
767 Immune Globulin (IGIV)/
Nomenclature:
Immune Globulin (IGIV)/Venoglobulin [BIO]
Venoglobulin-I [TR former upon original approval]
Venoglobulin-S [TR]
Immune Globulin Intravenous (Human), Solvent Detergent Treated [FDA]
Immune Serum Globulin (Human) [FDA former]
gamma globulin, intravenous [SY]
immune globulin, intravenous [SY]
intravenous immune globulin (IVIG) [SY]
IVIG [SY]
NDC 49669-1622-1; NDC 49669-1623-1; NDC 49669-1624-1 [NDC]
FDA Class: Biologic PLA
Year of approval (FDA) = 1971
Date of 1st FDA approval = 19710430
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
blood products
human materials used<!-- humansource -->
immune globulins, human <!-- immunoglobulins -->
Albumin (Human)
aspirin
bentonite
ethanol
Fraction II
gamma-globulin I paste
glucose
glycine
heat treatment (pasteurization)
lyophilized (freeze-dried)
mannitol
Plasma (Human)
polyethylene glycol (PEG)
polysorbate 80 (Tween 80)
Sephadex
sodium chloride
sorbitol
tri-n-butyl phosphate (TNBP)
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)
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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