Status: approvals withdrawn

Organizations involved:

Baxter AG – Manuf.; Former inv.

Oesterreichisches Institut fur Haemoderivate GmbH (OIH) – R&D; Tech.; Former

Cross ref: See the entry for Anistreplase (Eminase) (#606), of which this product is a component. See the Fibrinolytic and Thrombolytic Enzymes entry (#613).

Description: Lys-Plasminogen (For Further Manufacturing Use) is a lyophilized (freeze-dried) concentrate of lys-plasminogen purified from pooled, cold ethanol fractionated, human blood Plasma (Fraction II+III). Lys-plasminogen is human plasminogen enzyme with a terminal lysine group. The product is ≥ 95% pure Lys-plasminogen. Viral inactivation during manufacture involves a lyophilization/vapor-heat treatment process (60˚C for 10 hours at about 1,200 mbar in nitrogen atmosphere).

Lys-Plasminogen (For Further Manufacturing Use) was used exclusively for the manufacture of Anistreplase (Emi-nase) by Wülfing Pharma GmbH. Lys-Plasminogen has in vitro and in vivo assay fibrinolytic activity identical to Anistrep-lase (Emi-nase). [After reconstitution, each mL of Anistreplase (Eminase) solution contains 10 mg +/- 2 mg of Lys-Plasminogen].

Nomenclature: Lys-Plasminogen, conc. [BIO]; Lys-Plasminogen (For Further Manufacturing Use) [FDA]; plasminogen (For Further Manufacturing Use) [SY]

Companies.: Lys-Plasminogen (For Further Manufacturing Use) was developed and manufactured by Oesterreichisches Institut fur Haemoderivate GmbH (Vienna, Austria), CBER/FDA est. no. 0258, which later became Immuno AG, now Baxter AG. The product was purchased exclusively by Wülfing Pharma GmbH for manufacture of Anistreplase (Eminase), marketed by Shire Richwood Inc., formerly Roberts Pharmaceuticals.

Manufacture: Lys-Plasminogen is purified from cold ethanol fractionated (Fraction II+III) pooled human blood Plasma. Fraction II+III paste is purified by 12% ethanol precipitation and Lysine-Biogel affinity chromatography. A viral inactivation step involves lyophilization/vapor-heat treatment (60˚C for 10 hours at about 1,200 mbar nitrogen). The overall process has been shown to reduce HIV-1 in spiked plasma samples by at least 21 log (1021). See the Tech. transfer section for further manufacturing information.

FDA class: Biologic PLA

Approvals: Date = 19891127; first approval, PLA; granted to Oesterreichisches Institut fur Haemoderivate GmbH

Date = 20000207; license revoked

Indications: “approved only for further manufacture of Anistrep-lase under a shared manufacturing agreement with Wülfing Pharma GmbH”

Status: The product may still be manufactured for use in European and/or other foreign countries.

Tech. transfer: U.S. 5,556,766, “Method of Producing Lys-Plasminogen,” Feb. 6, 1994 (and earlier 5,371,007; also EP 0353218), assigned to Immuno AG (formerly OIH, now Baxter AG), describes methods for preparing high purity lys-plasminogen from plasma. Cohn fraction III is obtained by phosphate precipitation from plasma; crude plasminogen is precipitated from non-plasma proteins with ethanol; absorbed onto an immobilized lysine affinity chromatography column; and bound plasminogen is eluted. Bulk purified plasminogen is converted to lys-plasminogen by enzymatic reaction with plasmin (obtained from plasma) with dialysis at 1-20˚C for 6-60 hours. The conversion is halted by addition of aprotinin. The resulting lys-plasminogen is lyophilized.