Status – approved; marketed

Organizations involved:

Baxter Hyland Immuno – Manuf.; World mark.

Talecris Biotherapeutics Inc. – Manuf.; USA mark.

NPS Pharmaceuticals Inc – Parent

Bayer Schering AG – Intl. mark.

CSL Bioplasma, Inc. – USA mark.

CSL Bioplasma AG – Manuf.; Intl. mark.; Parent

CSL Ltd. – Parent

Kedrion, S.p.A – Manuf.; Intl. mark.

Grifols Biologicals Inc. – Manuf.; USA mark.

Instituto Grifols, S.A. – Manuf.; Intl. mark.; Parent

Probitas S.A. – Parent

Octapharma USA, Inc. – USA mark.

Octapharma AG – Manuf.; Parent

Biotest AG – Manuf.; EU mark.

Massachusetts Biological Labs. (MBL) – Manuf.

Central Lab. of the Netherlands Red Cross – Former

Harvard University – R&D; Tech.

Bayer Corp. – Former

Cross ref.: See the entry for Plasma (#798), from which this product is derived. See also the entry (#101) for Albumin, rDNA or recombinant human albumin.

Description: Albumin (Human) is a liquid solution containing 96% albumin protein obtained from fractionated pooled human blood Plasma. The source material of Albumin (Human) is Plasma recovered from Whole Blood, Source Plasma, or from placentas from screened healthy donors (mothers having delivered a baby). Albumin produced by different manufacturers is considered therapeutically (generically) equivalent (like many other pooled blood products). Albumin is available in various strengths (concentrations) and sizes (volumes).

Albumin is the most abundant protein in blood plasma. It is generally used in volume expanding plasma solutions for treatment of hypovolemia. Administration of albumin helps maintain water balance and blood pressure.

Albumin (Human) is also used as a stabilizing additive in a number of biopharmaceutical products. It is useful for stabilization and/or dilution of antibodies, enzymes, hormones, and other complex biological molecules to maintain their functional integrity over long periods of time. Albumin also has stabilizing and growth supplement properties and is sometimes used in cell culture media.

Nomenclature: Albumin [BIO]; Albumin (Human) [FDA]; Normal Serum Albumin [FDA former]; Albumin (Human), USP [USP]; human serum albumin [SY]; HSA [SY]

Albumen refers to the thick Albumin-like proteinaceous fluid surrounding fertilized chicken embryos – the white portion of cooked eggs. Chicken ovalbumin protein is the major constituent (about 75%) of albumen.

Companies.: See the Organizations Involved section above for current U.S.-approved manufacturers and marketers.

Biological.: Human serum albumin is a 65 kDa protein consisting of 585 amino acids. Its amino acid sequence contains a total of 17 disulfide bridges, one free thiol (Cys 34), and a single tryptophan (Trp 214). The disulfides are positioned in a repeating series of nine loop-link-loop structures centered around eight sequential Cys-Cys pairs. Albumin is one of the few human plasma proteins that is not a glycoprotein.

Albumin is responsible for 70-80% of the colloid osmotic pressure of normal plasma, making it useful in regulating the volume of circulating blood. Albumin’s role in the maintenance of colloid osmotic or oncotic pressure is essential to keeping fluids in the bloodstream instead of leaking out into the tissues. Albumin is also a transport protein and binds a variety of naturally occurring, therapeutic, and toxic materials in the circulation, including toxins and heavy metals, preventing damage they might otherwise cause. The half-life of albumin is 15 to 20 days, with a turnover of approximately 15 g per day.

Albumin constitutes about 55% of all plasma proteins. Total body albumin is estimated to be 350 g for a 70 kg man, with albumin in blood and distributed throughout the extracellular compartments. Normal levels of albumin in human serum are about 5,000 mg/dL. However, this represents only about 40% of the albumin in the human body, with the remaining 60% in the extravascular (outside the bloodstream) space of tissues where albumin functions as a transport protein and assists in the distribution, metabolism, and regulation of many marginally soluble substances, such as lipids, bilirubin, calcium (Ca+2), tryptophan, various steroid hormones, and many other drugs and small molecules.

Possible causes of a decrease in the level of albumin in the blood include liver or kidney disease or increased loss of albumin from the circulation (e.g., due to excessive bleeding). A diseased liver produces less albumin. In kidney disease, albumin can escape into the urine in large amounts. Severe malnutrition or a very low protein diet can also reduce the albumin level. Providing albumin by intravenous administration provides a volume expander for hypovolemic patients and can improve these problems and correct the low albumin level.

History: Hippocrates first mentioned some of albumin’s physiologic properties. Albumin was not named or studied until the early 1800s. The modern use of human albumin was established during World War II due to demand for plasma substitutes, with development attributed to E.J. Cohn and colleagues at the Plasma Fractionation Lab., Department of Physical Chemistry, Harvard University. The first documented clinical use of human albumin occurred on Dec. 8, 1941 with seven sailors severely burned during the attack at Pearl Harbor. Armour Pharmaceuticals (later Aventis Behring, now CSL Behring) was one of the first commercial companies to manufacture human albumin by using Cohn’s fractionation process.

Companies previously holding licenses for manufacture of Albumin (Human) include: Connaught Labs., Dow Chemical, E.R. Squibb & Sons, KabiVitrum AB, Lederle Labs., Merieux Institute, Ortho Diagnostic Systems (Johnson & Johnson), and Parke-Davis div., Warner-Lambert Co. This does not include companies with descendents still manufacturing the product, e.g., ZLB Bioplasma (now CSL Bioplasma), formed from the merger of Aventis Behring (originally Armour Pharmaceuticals).

Manufacturing: Human albumin is derived from fraction V, the last protein produced in the Cohn-Oncley fractionation process. manufacture of most products includes one or more viral inactivation/removal steps.

Example products, Albumin (Human) 20% and 25%, from Talecris Biotherapeutics Inc. are manufactured by a series of physical separation steps including Cohn-Oncley fractionation (see the Plasma Products entry, #798), depth filtration of the resulting Fraction V, precipitation/acetone suspension, and pasteurization (heat viral inactivation). Total reduction of viruses by the manufacturing process is >17.8 log10 for HIV-1, ≥15.4 for bovine viral diarrhea virus (BVDV; a model for hepatitis C virus), ≥16.2 log for pseudorabies virus (PRV; a model for hepatitis B virus), 12.6 log for reovirus 3 (a model for viruses resistant to physico-chemical agents), and 6.9 log for porcine parvovirus (PPV; a model for human parvovirus B19). Cohn-Oncley fractionation reduces HIV-1 by 3.4 log, BVDV by 3.6 log, PRV by 3.9 log, reovirus 3 by 2.0 log, and PPV by 1.0 log. Depth filtration reduces HIV-1 by 3.4 log, BVDV by <1.0 log, PRV by ≥3.4 log, reovirus 3 by 5.0 log, and PPV by 4.2 log. Precipitation/acetone suspension reduces HIV-1 by ≥5.1 log (evaluated at acetone suspension step), BVDV by 6.5 log, and PRV by ≥4.2 log (each enveloped viruses), with reovirus 3 and PPV not tested. Pasteurization reduces HIV-1 by ≥5.9 log, BVDV by ≥5.2 log, and PRV by ≥4.8 log, reovirus 3 by 5.6 log, and PPV by 1.7 log.

FDA class: Biologic PLA

CBER class: Blood And Blood Derivatives

Approvals: Date = 19410827; first approval for an Albumin (Human) product, granted to the Massachusetts Public Health Biologic Laboratories

Status: In early 1999 (or late 1998), CBER/FDA sent a letter to U.S. physicians indicating that use of Albumin and plasma protein fraction (PPF) outside of rigorous clinical trials “warrants serious consideration” and physicians should “exercise discretion” using these products. The FDA encouraged additional trials with both products and pledged to work with manufacturers to determine whether the approved indications: for each product should be reviewed.

The proper (FDA) name for human albumin was Normal Serum Albumin until a final rule published in the Jan. 29, 1985, Federal Register announced a change to Albumin (Human). As indicated by available FDA letters to manufacturers, the product licenses for Albumin products approved at that time were subsequently revoked and granted (reissued) using the new name.

Albumin (Human) is described in the Code of Federal Regulations, Title 21, Vol. 7, Parts 600-799 (21CFR600-799).

On Oct. 17, 2005, FDA approved Flexbumin [Albumin (Human)] 25% Solution from Baxter. Flexbumin is the first preparation of human albumin to be packaged in a flexible container. Flexbumin has the same indications: and provides the same stability as Albumin in glass bottles, but provides improved convenience for healthcare professionals as its flexible packaging provides less risk of breakage and is more compatible with hospital inventory storage systems. The flexible containers are lighter and require less space, which may ultimately save hospitals money on disposal. Flexbumin uses Baxter’s Galaxy flexible container system, a multi-layer system that helps maintain albumin quality and allows the solution to be stored at room temperature. Galaxy employs barrier technology and a continuous aseptic filling process, and has been used in the U.S. for more than 16 years to package pharmaceutical products.

In many respects, various Albumin products may be considered biogeneric, follow-on biologic or protein, biosimilar, biocomparable, etc. products, particularly in terms of their being approved based on abbreviated applications, including comparative bioequivalence/pharmacokinetic testing, rather than full Phase III-like, placebo-controlled safety and efficacy trials. In “The FDA’s assessment of follow-on protein products: A historical perspective,” Nature Reviews Drug Discovery, published online April 13, 2007, the FDA explains or rationalizes these approvals, noting, “New clinical efficacy data are not ordinarily required for the approval of new therapeutic albumin (natural source) products for existing indications: because the mechanism of action of therapeutic albumin in support of colloidal-oncotic pressure is well understood and albumin products are purified using well-established and consistent manufacturing methods. Albumin also has a well-established safety and efficacy profile because of our extensive clinical experience with the product. approvals of albumin products have been based primarily on conformance to the product and manufacturing standards described in the regulations and performance of the products in small safety trials."

Kedbumin from Kedrion S.p.A. received FDA BLA approval on June 3, 2011. Approval was granted for for treatment of hypovolemic shock, hypoalbuminemia, prevention of central volume depletion after paracentesis due to cirrhotic ascites, Ovarian Hyperstimulation Syndrome (OHSS), Adult Respiratory Distress Syndrome (ARDS), burns, hemodialysis patients undergoing long term dialysis, patients who cannot tolerate substantial volumes of salt solution, and as a priming solution for cardiopulmonary bypass.

Medical: Intravenous administration of albumin increases total blood volume by drawing fluid from extravascular tissues. This is useful for treatment of shock and oncotic deficits. Albumin may be useful for treatment of acute liver failure, severe burns, hypoproteinemia, adult respiratory distress syndrome, cardiopulmonary bypass, neonatal hemolytic disease, renal dialysis, acute nephrosis, erythrocyte (red blood cell) resuspension, acute peritonitis, pancreatitis, mediastinitis and cellulitis.

The minimum plasma level of albumin necessary to prevent or reverse peripheral edema is unknown. Studies indicate that plasma albumin levels should be maintained at approximately 2.5g/dL. This concentration provides a plasma oncotic value of 20 mm Hg.

Albumin may be administered in conjunction with or combined with other intravenously injected products including Whole Blood, Plasma, saline, glucose, and sodium lactate. The addition of four volumes of normal saline or 5% glucose to 1 volume of Albumin (Human) 25% solution gives a solution approximately isotonic and isosmotic with citrated plasma.

Adverse reactions to Albumin (Human) are rare. Nausea, fever, chills or urticaria may occasionally occur, but these symptoms usually disappear when the infusion is slowed or stopped for a short period of time.

Market: The 2005 Average Wholesale Prices (AWPs) for some example Plasma products are Plasmabumin-25 from Talecris, 25% solution, $15.31/20 mL, $30.63/50 mL, and $61.25/100 mL (no changes from 2004); for Plasmabumin-5, 5% solution, $15.31/50 mL and $30.63/250mL (no changes from 2004) (Red Book, 2005). The 2005 Average Wholesale Price (AWP) for Albuminar-25 (25% albumin content) from CSL Behring (now CSL Bioplasma) is $31.25/20 mL vial, $112.50/50 mL vial; and $225/100 mL vial; for Albuminar-5 (5% albumin content) is $40.00/50 mL vial, $112.50/250 mL vial, $225/500 mL vial, and $360.00/1,000 mL vial (Red Book, 2005), with these prices are unchanged from 2004. The 2004 AWP (not in 2005 Red Book) for Albutein 5% albumin content from Grifols Biologicals was $90.00/250 mL vial, and $180.00/500 mL vial; and for Albutein 25% albumin is $36.00/25 mL vial, $90.00/50 mL vial, and $180.00/100 mL vial (Red Book, 2004).

The worldwide market for albumin was about $1.5 billion in 1996 (British Medical Journal, Feb. 26, 2000, p. 533). An estimated 440 metric tons or more of albumin were estimated to be produced worldwide annually from pooled human plasma (source plasma) (according to SG Cowan analysts).

R&D: Various companies are developing recombinant human albumin. For example, in March 2006, Mitsubishi Pharma Corp. was awaiting approval in Japan of, Albrec, containing albumin expressed in Pichia pastoris yeast.