Status: approved; marketed

Organizations involved (historically, a selected few):

Harvard University – R&D; Tech.; Former

Merck & Co., Inc. – R&D; Tech.; Former

Cross ref: See the entries for Plasma Products (#798); Whole Blood (#702); and the entries below for Immune Globulin Intravenous (IGIV) and various immune globulin products. See the Monoclonal Antibody Products entry (#300) for further information about antibodies. See also the animal-derived antivenin and antitoxin (immune globulin-based) entries.

Description: Immune globulin (or immunoglobulin) products are polyclonal antibody-rich fractions obtained from pooled fractionated and purified human blood Plasma (or, animal plasma-derived polyclonal antibodies in the case of antivenins and antitoxins). Immune globulin products contain primarily immune globulin type G (IgG) as the active component. To assure a consistent and broad spectrum of antibodies in the product and economies of scale, immune globulins are generally produced from pooled Plasma from at least 1,000 donors.

Non-specific or regular immune globulin products are derived from pooled plasma from a large number of qualifying donors. Immune globulins derived from selected Plasma from persons with high titers of specific antibodies (from prior antigen exposure) can be used for the manufacture of specialized immunoglobulin preparations enriched with these specific antibodies, sometimes termed hyperimmune globulin. For example, immune globulin prepared from pooled Plasma from donors with high hepatitis B virus surface antigen (HBsAg) antibodies (e.g., from persons immunized with a hepatitis B virus vaccine) can be used to prepare immune globulin with a high level of HBsAg antibodies, i.e., Hepatitis B Immune Globulin (Human).

Immune globulin products are generally used for passive immunization, i.e., humoral or antibody-based immunity can be immediately transferred to a person by injection of immune globulin preparations. Administration of immune globulin boosts the recipient’s level of circulating antibodies, and may be used to treat immunodeficiencies, for treatment of antibody-susceptible infectious diseases, or neutralization of toxins. Human immune globulin is not immunogenic in recipients and is not rejected after administration.

Immune globulin products are generally manufactured for intramuscular or intravenous administration. Intravenous immune globulins are generally more purified and homogenous than those administered intramuscularly. The intramuscular products generally contain more dimers and other polymeric forms of immune globulins and other serum components and immune globulin aggregates. Immune globulins administered intravenously (IVIG) contain purified IgG with much less aggregated immune globulins and extraneous proteins. Most immune globulin products are manufactured for intramuscular administration, with considerable additional effort required for manufacture of intravenous products. However, intramuscular injection of immune globulin considerably reduces its efficacy, because of slow diffusion into the blood stream and local proteolysis of IgG protein. Insufficiently purified immune globulin concentrates are unsafe for intravenous injection, because injection by this route can result in patient shock, particularly hypotensive circulatory failure. Products containing insufficiently homogenous and modified immune globulins must be administered by intramuscular injection.

Intravenous immunoglobulin (IGIV) is an approximately 5% solution of highly refined normal or specific immune globulin (the concentrations of the latter can be even higher) that undergoes additional processing to be administered by the intravenous route. Intramuscular immune globulin (IGIM) usually has a higher, e.g., 16%, concentration of immune globulin. IGIM and IGIV manufactured after 1994 have not transmitted any documented cases of hepatitis C virus (HCV) infection. Some IGIV used before 1994 caused a few cases of HCV infection, but donor screening and viral inactivation processing has been added/upgraded since then.

Each IGIV product is manufactured differently. Most products involve characteristics that may increase risk, including volume load (concentration), osmolality, sodium and sugar content, pH and IgA content. Trade-off are generally made between individual product features and tolerability, efficacy, pathogen safety and convenience.

In Jan. 2006, FDA approved the first subcutaneously administered immune globulin, Vivaglobulin from CSL Behring (see related entry).

Nomenclature: Immune Globulin [BIO]; Immune Globulin (Human) [FDA]; Immune Serum Globulin [FDA former for IGIM, prior to 1/29/1985]; gamma globulin [SY]; immunoglobulin [SY]; Immunoglobulin intramuscular (IGIM) [SY]; Immunoglobulin intravenous (IGIV) [SY]; IGIV [SY]; IGIM [SY]; intramuscular immune globulin [SY]; intravenous immune globulin [SY]

Biological.: Immune globulins (antibodies) originate from B-cells stimulated by exposure to a specific immunogenic epitope (antigen). Antigen-stimulated B-cells, in concert with activated CD4+ T-cells (T lymphocytes or T helper cells), differentiate and mature into plasma cell clones expressing antibodies (immunoglobulins or immune globulins), with each plasma cell clone producing one antibody specific to a single antigen. [Monoclonal antibodies can be obtained from a single immortalized antigen-producing B-cell/plasma cell].

Their are five major structural classes of immune globulin (Ig) – IgG, IgM, IgE, and IgD. Each class varies in its interaction with cell types, complement fixation, and transport across mucosal membranes. IgG comprises 70%-75% of the total serum immune globulins and is the predominant antibody type involved in secondary responses to antigens. IgG has four subclasses – IgG1 (66% of IgG), IgG2 (23%), IgG3 (7%) and IgG4 (4%). All but IgG4 bind complement and are capable of neutralizing antigens substantively similar to the antigens which originally stimulated the B-cells which expressed the molecules. IgM constitutes about 10% of serum immune globulin and is the first antibody to be produced in response to antigenic stimulation. IgM binds complement and has no subclasses. IgA constitutes 15%-20% of serum immune globulins, and is the primary antibody in mucosal secretions, saliva, milk, etc. IgA has two subclasses, IgA1 and IgA2, and does not bind complement. IgD constitutes less than 1% of circulating immunoglobulins, but is found in abundance as B-cell surface receptors. IgD has no subclasses and does not bind complement. IgE is found in immune globulins in trace amounts. IgE is present on the surface of basophils and mast cells and is an important mediator of allergic responses. IgE has no subclasses and does not bind complement. Immune globulin products primarily contain and obtain their functionality from their IgG content.

Non-specific immune globulin products are generally described in terms of total antibody content, not their specific antigen specificities or antibody contents. However, even non-specific immune globulins (IGIV and IGIM) contain sufficient antibodies to be useful for treatment of specific infectious diseases, particularly in persons with low or no antibody titers (e.g., due to immune suppression or lack of prior antigen exposure). Most immune globulin products (intramuscular administration), irrespective of antibody specificity, generally have in vivo half lives of about 21 days. Intravenous immune globulin has been reported to have a mean in vivo half-life of IgG 23-29 days. Immune globulins are generally metabolized, rather than excreted, e.g., in the urine, or eliminated by immune mechanisms. Administration of sufficient immune globulin can be effective, usually increasing protection from infection, lasting up to 2 to 3 months.

After injection of an immune globulin product, its diverse polyclonal antibodies spread throughout the bloodstream and into interstitial fluids where they bind specifically to the their targeted antigens, forming immune complexes that are eliminated via the reticular-endothelium cell system. The antibodies/IgG do not enter cells.

Companies.: Approved manufacturers of Immune Globulin (Human) include Talecris Biotherapeutics Inc. (formerly Bayer Corp.); BioPort Corp., a subsidiary of Emergent Biosolutions; and Massachusetts Biological Labs,

Approved manufacturers of Immune Globulin Intravenous (Human) include: Baxter Hyland Immuno; Talecris Biotherapeutics Inc. (formerly Bayer Corp.); Grifols Biologicals Inc.; Instituto Grifols, S.A.; Octapharma AG; CSL Behring AG; and CSL Behring LLC.

The only approved manufacturer of Immune Globulin Intravenous (Human), 10% Solution and Immune Globulin Intravenous (Human), 10%, Caprylate/Chromatography Purified (IGIV-C) is Talecris Biotherapeutics Inc.

History: Cohn-Oncley fractionation of Plasma was first developed and used for manufacture of immune globulin in the early 1940s. Cohn-Oncley cold-ethanol fractionation involves multiple steps of fractional precipitation, reprecipitation, and washing of Plasma with ethanol at about 4˚C. This results in Fraction II precipitate containing relatively pure IgG but at low yield. In 1944, “Gamma globulin” (IgG) was produced from human serum by Cohn, Oncley, and colleagues at Harvard University, under U.S. Navy contract. See Cohn E.J., et al., “Preparation and properties of serum and plasma proteins IV: A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids,” J. Am. Chem. Soc. 1946; 68: 459–75. The fractionation method was modified/improved in 1954 by Kistler and Nitschmann. The Kistler-Nitschmann method combines cold-ethanol fractionation and extraction, resulting in higher yields with less labor but slightly higher levels of extraneous protein. Affinity chromatography, polyethylene glycol (PEG) frac-tionation, ultrafiltration, and various other more modern methods of protein purification have been adopted for immune globulin products manufacture.

The first immune globulin (IGIV) product for intravenous use, Gammagee-V, from Merck Sharp & Dohme (now Merck & Co.) was approved in 1963 but was never launched in the U.S. as an IGIV product. Gammagee-V was packaged with an early measles virus vaccine and used to reduce reacto-genicity to the vaccine (see the Measles Virus Vaccine entry #491), with injection of IGIV immediately following injection of the vaccine reducing the vaccine’s reactogenicity adverse effects. Manufacturing included chemical reduction and alkylation of proteins (IgG) to control and prevent fragmentation, aggregation, and eliminate anti-complement activity when administered by intravenous injection. Gamimune, the first marketed IGIV, from Cutter Labs. (later Miles and Bayer, now Talecris Biotherapeutics Inc.) was launched in the U.S. in 1981. Manufacturing included alkylation with iodoacetamide and reduction with dithiothreitol (DTT) to reduce/eliminate fragmentation, aggregation, and anti-complement activity. The manufacturing process was changed in 1986 to provide unmodified IgG. Sandoglobulin from Sandoz Corp., now Carimune from Novartis Corp., was the first chemically-unmodified IGIV approved by FDA in 1984. Alpha introduced the first solvent detergent virus inactivated IGIV in 1991.

Two IGIV products, Gammagard from Baxter Hyland and Polygam from the American Red Cross, now Baxter Hyland (both manufactured by Baxter Hyland), were associated with over 100 cases of infection with hepatitis C virus (non-A, non-B hepatitis) and were recalled in 1994. Their manufacturing processes were subsequently changed to include a solvent detergent (S/D) virus inactivation step and the products were reintroduced as Gamma-gard S/D and Polygam S/D.

Manufacture: The Code of Federal Regulations, Title 21, Chapter 1, Part 640, Subpart J – Immune Globulin (Human) [21CFR640.102] describes standards and methods for manufacture of intravenous immune globulin (IGIV). All currently marketed products are manufactured using the Cohn-Oncley cold ethanol fractionation process except for Sandoglobulin/Carimune which is manufactured using the Kistler-Nitschmann variation of this process. Specifically, most manufacturers of Immune Globulin for intramuscular administration use Method 6 (Cohn) and Method 8 (Oncley) for Plasma fractionation. The immune globulin is usually further isolated (and virus removed as a result) by processes including filtration (e.g., Sando-glo-bulin), diafiltration and ultrafiltration (e.g., Gamimune N), ultrafiltration and ion exchange chromatography (e.g., Poly-gam S/D and Gammagard S/D), and polyethylene glycol (PEG) fractionation and ion exchange chromatography (e.g., Veno-globulin S). Albumin (Human) is used as a stabilizer in some products, e.g., Gammar-P.I.V., Polygam S/D, Gam-magard S/D and Venoglobulin S. Sandoglobulin/Carimune contains sucrose and Gamimune N contains maltose as stabilizers. Gammar-P.I.V. and Venoglobulin S contain the highest levels of IgA content, 25 mg/mL and 15-50 mg/mL, respectively. Polygam S/D and Gammagard S/D contain less than 3.7 mg/mL (in 5% solution) of IgA, and only traces are detectable in Sandoglobulin and Gamimune N. Two products are packaged as liquid solutions, Venoglobulin S and Gamimune N, and the others are packaged as lyophilized (freeze-dried) powder.

Various methods have been used to reduce anticomplement activity (attributed to formation of IgG aggregates during manufacture and storage) including pepsin or plasmin digestion of the concentrates, beta-propriolactone (BPL) treatment, fractionation using polyethylene glycol (PEG) as a precipitating agent, and other techniques. Some methods use additive hydrocolloids, glycerol, xylitol, mannitol, sorbitol, glycine, albumin, and nonionic surfactants to stabilize gamma globulin against aggregate formation.

Approvals: Date = 19430908; first approval of an Immune Globulin (Human) or IGIM product, granted to Massachusetts Public Health Biologic Labs.

Status: See Code of Federal Regulations (CFR), Title 21, Chapter I, Part 640, Subpart J, Sec. 640.100, “Immune Globulin (Human).”

The Code of Federal Regulation (CFR) Section 640.103(b) originally described the protein composition of Immune Globulin (Human) in terms of absolute electrophoretic mobility, computed from measurements made by moving boundary electrophoresis. However, moving boundary electrophoresis equipment is currently not commercially available, and all U.S. manufacturers of Immune Globulin (Human) have calibrated more modern electrophoresis methods against the older boundary electrophoresis method and amended their product license applications. Subsequently, section 640.103(b) was amended to read, “At least 96 percent of the total protein shall be immunoglobulin G (IgG)...[truncated]”

A final rule published in the January 29, 1985 Federal Register changed the proper (FDA) name from Immune Serum Globulin to Immune Globulin (Human). As indicated by several FDA letters, the approvals for all products approved at that time were subsequently revoked and granted (reissued) using the new name.

On Nov. 13, 1998, FDA sent a warning letter to U.S. physicians alerting them to the potential risk of acute renal failure (ARF) associated with the administration of Immune Globulin Intravenous (Human) (IGIV) products. Since IGIVs were first introduced in 1981, the FDA had received over 114 worldwide (approximately 83 U.S.) adverse event reports of renal dysfunction and/or acute renal failure associated with IGIV administration, including 17 deaths. Preliminary evidence suggested that IGIV products containing sucrose may present a greater risk for this complication. Hyperosmolality of certain reconstituted products, as well as differences in stabilizer sugar choice and content between IGIVs, may be among the factors that have contributed to different reported rates for renal dysfunction among the various IGIV products. Most cases (about 88% of U.S. reports) were associated with the sucrose-containing products (Sandoglobulin (now Carimune); Panglobulin; Gammar-P I.V. and Gammar-I.V.). Revised package inserts for these products include a boxed warning concerning the risk of ARF, new precautions, and new dosage and administration recommendations.

Tech. transfer: 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 (#799) for further information about solvent detergent viral inactivation, used primarily for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).

Medical: After injection of immune globulin, the injected antibodies are present in the bloodstream and in interstitial fluids where they bind specifically to their targeted antigens to form immune complexes that are then eliminated via the reticular--endothelial cell system. Onset of increased antibody-based immunity is very rapid, with IgG/antibody dissolved in the bloodstream upon intravenous administration. With IGIV, essentially 100% of the administered dose is functionally available. With IGIM, some immune globulin may pool and be broken down by proteolytic enzymes in muscle tissue. The peak serum levels of IgG then generally fall rapidly in the first week after administration as the IgG diffuses into tissues other than the blood.

Immune globulin can provide protection (protective antibody levels) against certain infections for up to 2 to 3 months. IGIV is often used to quickly attain high levels of circulating IgG/antibodies where intramuscular immune globulin (IGIM) is contraindicated. A commonly accepted goal for maintenance of immune globulin (IgG) to provide adequate protection from microbial infection is about 200 mg/100 mL of Plasma. The efficacy of IGIV products for reduction of incidence of infectious disease generally varies from about 50% up to 100%.

IGIM/IGIV dosages are generally determined by disease state (indication), the level of deficiency, the titers of desired antibodies in the product, and other factors that may vary depending on the patient and disease. For example, 100-400 mg/kg may be administered at an initial dose for immune globulin replacement therapy (e.g., for primary immune deficiency), doses administered monthly, and doses adjusted upward if serum IgG levels remain low. After primary administration, doses may need to be administered every 3-4 weeks to maintain IgG levels. Doses of up to 2,000 mg/kg (2 g/kg) and more frequent administration may sometimes be required for some Indications:, e.g., immune thrombocytopenic purpura (ITP).

Disease: Primary immune deficiencies are the disease(s)/indication(s) most often treated with non-specific immune globulin products. Primary immunodeficiencies are generally caused by genetic defects in B or T cells, complement, or phagocytic cells – the main components of the immune system involved in defense against infectious organisms. More than 50 types of primary immunodeficiencies are recognized. In the U.S., agamma-globulinemia (lack of IgG) occurs in about 1/50,000 persons; and severe combined immunodeficiency (SCID) occurs in about 1/100,000 to 500,000 persons. Persons with primary immunodeficiency usually have low concentration or an absence of individual immunoglobulin types or IgG subclasses; or the immunoglobulin levels may be normal or even elevated but the molecules do not function properly (e.g., have structural defects). Primary immunodeficiencies occur more frequently in infants and children than in adults, and more frequently in males than females. In adults, more women than men develop primary immunodeficiencies. Immune deficiency can also be acquired, e.g., Acquired Immune Deficiency (AIDS) due to infection with Human Immunodeficiency Virus (HIV; LAV; HTLV-III)

Primary immunodeficiencies are associated with a high morbidity and mortality from recurring and opportunistic infections and malignancies, i.e., the patients have deficient defenses against infectious disease and malignant cells. B-cell immunodeficiencies are often associated with infections by encapsulated bacteria, e.g., Staphylococcus, Streptococcus, and Pneumococcus. T-cell immunodeficiencies, including AIDS, are associated with increased susceptibility to viral, protozoal, and fungal infections, particularly those associated with intracellular pathogens, e.g., Candida albicans, Pneumocystis carinii, cytomegalovirus (CMV), and mycobacteria. Children with primary immunodeficiency who regularly receive intravenous immune globulin can maintain normal growth and infection rates.

Idiopathic thrombocytopenic purpura (ITP), also known as primary idiopathic or autoimmune thrombogenic purpura, is defined as thrombocytopenia (e.g., platelets below 20,000/µL) without other causes or associated with other diseases, e.g., HIV--infection, systemic lupus erythematosis, or nonimmune thrombocytopenia. The disease is characterized by destruction of self or autoantibody-coated platelets and phagocytes in the spleen, liver, and bone marrow. Low platelet counts (thrombo-cytopenia) can lead to serious complications, e.g., intracranial hemorrhage and other serious bruising and bleeding upon injury. See also the Platelets entry (#802). In children, the disease can be acute or chronic. Over 80% of cases are the acute form, with about 60% recovering in 4-6 weeks and over 90% recovering within 3-6 months after onset, even without any treatment. Acute ITP progresses to chronic ITP in about 15%-20% of affected children. About one-third of children with chronic ITP who are not treated enter remission within months or years of diagnosis. Treatment for ITP generally consists of corticosteroids or intravenous immune globulin therapy. The American Society for Hematology issues recommendations for treatment of pediatric ITP.

Market: About 20 companies worldwide produce IGIV. Annual worldwide sales have been estimated to be in excess of 50 metric tons with a value in excess of $1.5 billion

As reported in a Biotest presentation, the Review of Australia's Plasma Fractionation Arrangements, 2007, estimated world immune globulin demand to be about 87 tons in 2008, 77 tons in 2006, 68 tons in 2004; and projected demand of about 92 tons in 2010, 104 tons in 2012, and 118 tons in 2014. Demand has been rather steadily increasing. The U.S. represents one third of global immunoglobulin demand.

The worldwide market for IVIG was reported to be $1.62 billion in 2002, with this expected to grow to $2.5 billion in 2010. Generally, the U.S. accounts for about one-half of a pharmaceutical product’s worldwide sales.

In Jan. 2005, the Centers for Medicare and Medicaid Services (CMS) issued an interim interim increase in its allowable Medicare payment limit (reimbursement rate) for IVIG. The new rate of $56.72/g (J1563) replaces the originally published rate of $40.02 per gram. Among the ~50,000 Americans with primary immunodeficiency, 7,000 receive treatment through Medicare.

In Feb. 2005, CMS implemented a new add-on billing code to compensate for the administration of immune globulin. This new code became active Jan. 1, 2006, and affects both HOPPS and physician practices. CMS implemented a temporary add-on payment to cover the additional preadministration-related services required to locate and acquire adequate IGIV product and prepare for an infusion of IGIV during this current period of market instability. The new add-on code is G0332, with a payment rate of $75 for the hospital outpatient setting and $69 for the physician office setting. These rates are only for calendar year 2006. CMS had determined that the pricing for IVIG is accurate, and that there was no overall product shortage. However, CMS acknowledged that in the face of such factors as increasing IGIV demand and manufacturer allocation of many formulations (shortages), physician office staff have to expend extra resources on locating and obtaining IGIV products and scheduling patient infusions.

Periodic/sporadic shortages of immune globulin products continue to occur, often due to the complexity of their manufacture and the relatively few manufacturers often encountering difficulties in manufacturing, including cGMP violations, consent orders, etc. Factors contributing to short supplies include the discarding of Plasma and manufactured lots due to Creutzfeldt-Jacob disease or virus contamination, and increased demand for the products for both their approved and off-label uses.

There are an estimated 50,000 immune suppressed persons in the U.S. requiring IGIV. A typical adult dose is reported to be 35 grams/month or 420 grams/year. At a rate of $39/gram, this comes to about $16,400/patient annually.

In its March 30, 2004 price list, FFF Enterprises, a major biologics distributor, reported a 2 mL vial of IGIM (no company source specified) as costing $23.52.

In Aug. 2005, CSL Ltd., the owner of CSL Behring, reported, “The current price of IVIG in the US - CSL’s major market - is around $US39 per gram and this could rise by one or two dollars in the next year.”

As reported by CSL, in Dec. 2003, “Global IVIG [IGIV] volumes are forecast to grow at 3-6% per annum over the next five years, reflecting an increase in the number of therapeutic applications for IVIG.”