Status: recently approved in U.S.; pending in EU

Organizations involved:

CSL Behring AG – Manuf.; R&D; Tech.; Intl. mark.; Parent

CSL BioPlasma Inc. – USA mark.

CSL Ltd. – Parent

Cross ref: See Immune Globulin Products (#743).

Description: Privigen is a 10% protein aqueous formulation of Immune Globulin Intravenous (Human) using L-proline as stablizer, and with virus inactivation/reduction by three process – incubation at low/acid pH (4), virus (nano)filtration, and a depth filtration step. Unlike other IGIV products, Privigen contains ~250 mmol/L (range: 210 to 290) of L-proline (a nonessential amino acid) as a stabilizer, along with trace amounts of sodium. Privigen contains no carbohydrate stabilizers (e.g., sucrose or maltose) and no antimicrobial preservatives. Privigen is prepared from large pools of human plasma by a combination of cold ethanol (Cohn-Oncley) fractionation, octanoic acid fractionation, and anion exchange chromatography.

The IgG proteins are not subjected to heating or to chemical or enzymatic modification.

Privigen has a purity of >98% IgG, consisting primarily of monomers. The balance consists of IgG dimers (≤12%), small amounts of IgG fragments and polymers, and albumin, with ≤25 mcg/mL IgA. The IgG subclass distribution (approximate mean values) is IgG1, 67.8%; IgG2, 28.7%; IgG3, 2.3%; and IgG4, 1.2%. Privigen has an osmolality of ~320 mOsmol/kg (range: -240-440) and a pH of 4.8 (range: 4.6-5.0). With its unique processing and formulation, the Fc and Fab functions of its immunoglobulin G (IgG) antibodies are retained. Fab functions include antigen binding capacities, and Fc functions include complement activation and Fc-receptor-mediated leukocyte activation (determined with complexed IgG). Privigen does not activate the complement system or prekallikrein in an unspecific manner.

Privigen is packaged in vials containing 50 mL (5 g protein); 100 ml (10 g), and 200 mL (20 g). The dating period is 24 months from the date of manufacture when stored at 2-25C (refrigerated through room temperature), with the date of manufacture being the date of final sterile filtration of the formulated drug product.

Nomenclature: Immune Globulin (IGIV), liquid/CSL [BIO]; Privigen [TR]; Immune Globulin Intravenous (Human), 10% Liquid [FDA]; gamma globulin [SY]; NDC 44206-436-05; NDC 44206-437-10; NDC 44206-438-20 [NDC]

Companies.: Privigen is manufactured by CSL Behring AG (at CBER/FDA est. no. 1766, formerly no. 1598; Berne, Switzerland), a subsidiary of CSL Ltd., formerly the Central Laboratory Blood Transfusion Service, Swiss Red Cross (est. no. 0647). Privigen is marketed in the U.S. by CSL Behring LLC. Presumably, CSL retains fulll worldwide marketing rights (but the product has just received its first approval in the U.S.).

Manufacture: Two dedicated virus clearance steps are used: pH 4 incubation to inactivate enveloped viruses; and virus nanofiltration to remove, by size exclusion, both enveloped and non-enveloped viruses as small as ~20 nanometers. In addition, a depth filtration step contributes to the virus reduction capacity. These steps have been independently validated in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses.

The manufacturing process was also tested for its capacity to decrease the infectivity of an experimental agent of TSE/prion disease, considered a model for CJD and its variant vCJD. Several of the production steps have been shown to decrease TSE infectivity of an experimental model agent. TSE reduction steps include octanoic acid fractionation (≥6.4 log10), depth filtration (2.6 log10), and virus filtration (≥5.8 log10). These studies provide reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, are removed.

FDA class: Biologic BLA

Approvals: Date = 20070726; original BLA

Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling]:

1.1 Treatment of Primary Immunodeficiency: Privigen is indicated for the treatment of patients with primary immunodeficiency (PI) associated with defects in humoral immunity. This includes, but is not limited to, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.

1.2 Treatment of Chronic Immune Thrombocytopenic Purpura: Privigen is indicated for the treatment of patients with chronic immune thrombocytopenic purpura (ITP) to rapidly raise platelet counts to prevent bleeding.

Status: FDA granted full approval on July 26, 2007.

As part of the approval, CSL agreed to conduct various post-approval clinical/surveillance studies. FDA granted CSL a waiver for pediatric studies for the indication of treatment of Primary Immunodeficiency in neonates and infants (up to two years of age), because there are too few subjects with this disease to study. CSL fulfilled the pediatric study requirement for children (older than two years of age) and adolescents. For the indication of treatment of chronic idiopathic thrombocytopenic purpura, FDA granted a waiver for pediatric studies because: the indication is not applicable to neonates; for infants and children, this condition is usually acute and self-limiting, and; chronic Immune Thrombocytopenic Purpura is rare, usually benign, and often does not require specific treatment before remission in pediatric subjects.

CSL Behring plans to launch Privigen in the U.S. in first quarter 2008. A MAA application is currently under review by European Union (EU) regulatory authorities..

Market: The 2007 Average Wholesale Price (AWP) is not available (not in the hard copy Red Book, 2007).

Privigen offers increased convenience and ease-of-use. It is the first and only proline-stabilized liquid IVIG that is always ready for immediate use, requiring no refrigeration or reconstitution.