Pooled Plasma, Solvent Detergent Treated – SD Plasma; PLAS+SD; VIPLAS/SD
Status – approved; marketed
Organizations involved:
Talecris Biotherapeutics Inc. – Manuf.; R&D; Tech.
Instituto Grifols, S.A. – Parent
NPS Pharmaceuticals Inc – Former
Precision Pharma Services, Inc. – Former
V.I Technologies, Inc. – R&D; Tech.; Former
Baxter Hyland Immuno – Manuf. other; USA Mark.
American National Red Cross (ARC) – Former
New York Blood Center – Tech.
Cross ref: See the Plasma Products entry (#798).
Description: Pooled Plasma, Solvent/Detergent Treated or PLAS+SD is a liquid formulation of pooled ABO blood group-specific (requires matching with recipient) Plasma (Human), with processing including viral inactivation using the solvent detergent (SD) process. PLAS+SD was the first virally inactivated Plasma or other blood product for transfusion in the U.S. It is prepared from pooled human ABO blood group specific Plasma frozen to preserve its labile coagulation factors and treated with the solvent, tri(n-butyl)phosphate (TNBP), and the detergent Triton X-100 (octoxynol; polyethylene glycol p-isooctylphenyl ether) for inactivation of lipid-enveloped viruses and sterile filtration. The Plasma is derived from blood collected from volunteer donors by the American Red Cross (ARC).
In vitro testing for elimination of viral infectivity by the solvent detergent treatment has shown log10 reductions of vesicular stomatitis virus (VSV) ≥ 5.7 tissue culture infectious dose50 (TCID50); Sindbis virus ≥ 5.7 TCID50; hepatitis B virus (HBV) ≥ 6.0 chimp infectious dose50 (CID50); bovine viral diarrhea virus (BVDV) ≥ 6.1 TCID50; hepatitis C virus (HCV) ≥ 5.0 TCID50; and HIV ≥ 6.0 TCID50.
PLAS+SD is intended for intravenous administration for the same indications: as approved for Fresh Frozen Plasma (FFP), and is an alternative to FFP (which are individual units obtained from a single donor and not pooled and virus inactivated, as is PLAS+SD). PLAS+SD contains both labile and stable coagulation factors in amounts similar to those in FFP, as well as the other proteins present in Plasma. The SD process results in minimal loss of coagulation factor activity and the prothrombin time and partial thromboplastin time remain normal (same as FFP). The product has been shown to be a safe and effective replacement for FFP; results in fewer transfusion reactions than with FFP; and allows long-term, high-dose treatment with no signs of toxicity. In comparison to the variability observed with FFP, SD-treated plasma, as a pooled, sterile-filtered product, delivers consistent volumes, consistent and reproducible levels of coagulation factors, and leukocyte reduction (removal).
PLAS+SD, contains not less than 0.7 units/mL each of Factor V, Factor VII, Factor X, Factor XI and Factor XIII, and not less than 1.8 mg/mL of fibrinogen. The prothrombin time and the partial thromboplastin time are not affected by the product’s processing. PLAS+SD contains no leukocytes and lacks the largest von Willebrand’s Factor (vWF) multimers. PLAS+SD contains no more than 3 pg/mL (ppm) each of tri(n-butyl)-phosphate (TNBP; solvent) and octoxynol (Triton X-100; detergent) as residues from solvent detergent viral inactivation.
PLAS+SD is packaged frozen in plastic bags, each containing 200 mL of SD-treated plasma and labeled with its ABO blood type. PLAS+SD should be stored frozen at -18˚C or colder. Storage stability studies reveal maintenance of product coagulation factors when stored for 12 months at -18˚C.
Nomenclature: Plasma SD/Grifols [BIO]; PLAS+SD [TR; “PLAS+” is reg. to American Red Cross, now Baxter]; Pooled Plasma, Solvent Detergent Treated [FDA]; SD Plasma [SY]; VIPLAS/SD [TR; reg. to V.I. Technologies; no longer used]
Biological.: PLAS+SD has been characterized and shown to be similar biochemically to the starting material, frozen human plasma. There are moderate decreases in Protein S and antiplasmin, and the highest molecular weight multimers of von Willebrand’s Factor (vWF) are absent. The clinical significance of these differences, if any, is unknown. Little or no coagulation factor activation is apparent during the solvent detergent treatment process. Thrombin-antithrombin III complexes and prothrombin split products measured by enzyme immunoassays are not increased. There are no significant perturbations of the normal ratio of plasma proteins and lipids in PLAS+SD, and significant amounts of immune globulins remain in the final product. Thus, the product is substantially identical to pooled Plasma (Human) and plasma from healthy individuals.
Companies.: PLAS+SD was developed and is manufactured by Precision Pharma Services, Inc., FDA CBER est. no. 0386 (formerly V.I. Technologies, Inc./VITEX and Melville Biologics, Inc.), now Talecris Biotherapeutics Inc., then a subsidiary of NPS Pharmaceuticals Inc. In March 2001, VITEX announced a management/staff buyout of its plasma processing operations, forming Precision Pharma Services. Taclecris acquired Precision (and also the plasma products business of Bayer) in April 2005. PLAS+SD was formerly marketed exclusively in the U.S. by the American National Red Cross (ARC; Washington, DC); and in March 2005, Baxter Hyland Immuno assumed the plasma products business of ARC.
The American National Red Cross concluded an agreement with VITEX to distribute PLAS+SD in December 1997. In Dec. 1998, this agreement was extended through Sept. 30, 2000, and included a guarantee by ARC to purchase in excess of $50 million of PLAS+SD over the two-year period of the contract extension. Both companies also agreed to double their sales and marketing resources committed to PLAS+SD, including VITEX adding its own 10-person sales force to concentrate on converting teaching hospitals (where the bulk of transfusion plasma is purchased and used), and ARC more than doubling its investment during the product’s launch phase. ARC also committed to conduct a campaign to highlight the benefits of PLAS+SD to the general public.
In August 2000, VITEX and American National Red Cross (now Baxter) agreed to a six year extension of their agreement for ARC (now Baxter) to have exclusive U.S. marketing rights for PLAS+SD products. This includes PLAS+SD (Universal), currently in Phase III trials, which is expected to eliminate the need for matching plasma donor and recipient blood types (a major advance). The agreement provides for $90 million in SD plasma shipments over six years, including $11 million over the first 12 months, pricing of the Universal product at a premium compared to PLAS+SD, and reduction in PLAS+SD manufacture and inventories in preparation for launch of the Universal product.
In Feb. 2011, Grifols S.A./Instituto Grifols acquired Talecris Biotherapeutics.
Solvent Detergent (SD) Viral Inactivation Process: The Solvent/Detergent (SD) viral inactivation technology, originally licensed by V.I. Technologies from the New York Blood Center (see Tech. transfer section), used with PLAS+SD is similar to that used in the preparation of numerous other plasma products, including various immune globulin and coagulation factor concentrates. Millions of units of PLAS+SD and many other solvent detergent-treated plasma and other products have been transfused without a single documented case of lipid-enveloped virus transmission. For example, using the same process, over one billion International Units of SD-treated Factor VIII have been distributed by the American Red Cross alone with no documented cases of viral transmission. See the Tech. transfer section.
Solvent, e.g., tri-n-butyl phosphate (TNBP) and detergent, e.g., polysorbate 80 (Tween 80) or octoxynol (Triton X-100), in low concentrations disrupt the lipid-rich membranes of enveloped viruses. The SD process does not affect non-lipid enveloped viruses such as hepatitis A virus (HAV) and parvovirus B19. SD treatment has been shown to be capable of significant inactivation of lipid-enveloped viruses, with killing of lipid-enveloped viruses typically observed within the first 15 minutes of usually hours of treatment time. The SD process for virus inactivation has been shown not to alter or inactivate labile coagulation factors, nor to alter or inactivate other plasma proteins such as fibrinogen and immunoglobulins.
Manufacture: PLAS+SD is prepared from ABO blood group type-specific units of human plasma (Fresh Frozen Plasma) collected from volunteer donors, and provided to VITEX/Precision/Talecris by the American Red Cross (unpaid volunteer donors; now Baxter). Plasma frozen within 15 hours of collection is debagged, pooled, and thawed at a temperature below 35˚C. An upper limit of 2,500 individual units may be pooled (mixed) to form a single manufacturing lot of the product. Calcium chloride (CaC12) is added, the product undergoes filtration, and is transferred to a process tank. The adjusted pooled plasma is virus-inactivated by the addition of solvent, 1% tri(n-butyl)phosphate (TNBP), and detergent, 1% Triton X-100 (octoxynol; polyethylene glycol p-isooctylphenyl ether). The mixture is incubated at 31 ± 2˚C for four hours to inactivate lipid-enveloped viruses. The solvent and detergent levels are reduced by extraction with 5% soybean oil at 18 ± 4˚C for 15 minutes, followed by clarification by sedimentation and filtration. Residual solvent and detergent are further removed by reverse phase column chromatography on C-18 Gel at 20-25˚C. The product is filtered (1.0, 0.45 and 0.22 µm filters), and the protein concentration is adjusted by ultrafiltration. The product is sterile filtered (0.22 µm; to remove leukocytes, bacteria and other cells) and aseptically filled into sterile bags which are then sealed, inspected, labeled, and frozen.
PLAS+SD contains no more than 3 µg/mL (ppm) each of residual TNBP and Triton X-100. Results when residual reagent concentrations were measured in 13 consecutive lots: TNBP: 0 to 1.78 ppm (x≤1) and Triton X-100: 0 to 1.03 ppm (x≤1). Final container testing includes: visual inspection; protein composition by cellulose acetate electrophoresis; identity test by immunoprecipitation; coagulation factor assays for the following factors: Factor V, Factor VII, Factor X, Factor XI, Factor XIII and fibrinogen; protein content by the Kjeldahl method; assays for sodium, potassium and hydrogen ion concentrations, TNBP and Triton X-100 content; ethyl alcohol content; isoag-glutinnin titers; antibodies to HIV (l/2) and hepatitis B virus (HBsAg); endotoxin by limulus amoebocyte lysate (LAL) test; sterility; and a general safety test in mice (from 21 CFR 610.11).
All lots of PLAS+SD are polymerase chain reaction (PCR; nucleic acid testing; NAT) “negative for HAV nucleic acid” prior to release. A negative result means that the product has been tested and shown to have not more than an average of 9.4 GE (genome equivalents) of HAV genomic material per mL.
FDA class: Biologic BLA
CBER class: Blood and Blood Derivatives
Approvals: Date = 19980506; first approval; BLA, ref. no. 93-0253 and 97-0141
Date = 19990629; BLA supplement; Indication = addition of claim for final product testing for hepatitis A virus using a sensitive PCR (NAT) technique
Date = 20020500; BLA supplement; Indication = added Black Box warning to labeling/insert regarding contraindication in patients undergoing liver transplants and patients with severe liver disease and known coagulopathies, and advise that patients receiving large amounts be monitored for thrombosis, excessive bleeding and DIC
Indications: [full text of thee "INDICATIONS AND USAGE” section from recent product insert/labeling]:
The indications: for use of PLAS+SD, Pooled Plasma, Solvent/Detergent Treated, are limited and include: treatment of patients with documented deficiencies of coagulation factors for which there are no concentrate preparations available, including congenital single-factor deficiencies of Factors I, V, VII, X, XI and XIII, and acquired multiple coagulation factor deficiencies; reversal of warfarin effect; and treatment of patients with thrombotic thrombocytopenic purpura (TTP).
PLAS+SD is not indicated when coagulopathy can be corrected more effectively with specific therapy, such as vitamin K, antihemophilic factor (Factor VIII) concentrates or other coagulation factor concentrates.
PLAS+SD is not indicated as a volume expander when blood volume can be safely and adequately replaced with other volume expanders.
Status: Precision Pharma Services, Inc. (formerly V.I. Technologies/VITEX and Melville Biologics), now Talecris Biotherapeutics, has been approved for manufacture of Plasma since June 1973.
In 1998, the U.S. Justice Department began an investigation of potential antitrust violations involving the American National Red Cross obtaining exclusive marketing rights for PLAS+SD. No publicly disclosed actions resulted from this.
SD-treated plasma manufactured by Octapharma has been approved in Germany since 1991; is in routine use in other countries including Austria, Germany, France, and the Netherlands; and has completely replaced Fresh Frozen Plasma use in Norway and Belgium.
Tech. transfer: The solvent detergent viral inactivation technology was originally developed by and licensed from the New York Blood Center (New York, NY). For example, see U.S. patent 4,820,805.
VITEX/Precision Pharma holds exclusive marketing rights (see the Tech. transfer section) for solvent detergent viral inactivation of transfusion plasma products in North America licensed from the New York Blood Center, while OctaPharma AG has European rights to solvent detergent inactivation for transfusion plasma. Otherwise, solvent detergent viral inactivation has been nonexclusively licensed to many companies.
Medical: Various safety-related factors affect the choice of either PLAS+SD or Fresh Frozen Plasma (FFP) when Plasma is required for transfusion. PLAS+SD is a pooled product containing standardized levels of plasma proteins, is sterile filtered to remove bacteria and intact leukocytes, and is manufactured with a viral inactivation step that virtually eliminates risk of infection with HIV, hepatitis B, hepatitis C, and other lipid enveloped viruses. However, the SD process does not remove risk of infection with non-lipid enveloped viruses or unknown pathogens that may go undetected through donor screening. SD inactivated (and fresh frozen plasma products) may contain non-lipid enveloped viruses, such as hepatitis A virus and parvovirus B19, and prion agents such as Creutzfeldt-Jakob disease (CJD) that may get past the screening process.
Although the risk of infectious disease transmission through FFP is considered low by historical measures, blood/plasma donations made during the “window period” of viral infection remain problematic. The window period is that period of time between infection and possible virus detection using currently available tests. For example, HIV screening tests rely on detection of HIV antibodies, and infection (as determined by antibody response) may be undetectable for weeks. PLAS+SD eliminates the risk of window period infection for all lipid enveloped viruses including HIV, hepatitis B, hepatitis C and others yet-to-be detected. In contrast, Fresh Frozen Plasma is obtained from a single donor, rather than pooled plasma from several thousand donors. This substantially decreases the likelihood of viral contamination (including non-enveloped viruses not affected by the SD process) to that in a single donor’s blood. The plasma is not subjected to a viral inactivation process, and HIV, hepatitis B and other enveloped viruses in the plasma not identified through donor screening may be present.
The National Hemophilia Foundation (NHF) in Dec. 1998 issued a recommendation that PLAS+SD be used instead of untreated fresh frozen plasma for transfusion, except in emergencies when it is not available. Other organizations have issued similar recommendations.
Market: Average Wholesale Price (AWP) not available (product not in the Red Book).
R&D: Universal PLAS+SD, now from Talecris Biotherapeutics, entered Phase III pivotal trials in April 2000. Universal, the next generation of PLAS+SD, would eliminate the need for matching the blood (red blood cell type) compatibility of donor and recipient. Technology for this product (e.g., application EP97113466.3) has been licensed from the product’s original developer, Octapharma AG, which first launched its own version in Europe in 2000.
Companies involvement:
Full monograph
799 Plasma SD/Griflols
Nomenclature:
Plasma SD/Grifols [BIO]
PLAS+SD [TR; "PLAS+" is the reg. trade mark; held by American Red Cross; primary trade name]
Pooled Plasma, Solvent Detergent Treated [FDA]
SD Plasma [SY]
VIPLAS/SD [TR held by V.I. Technologies; not used]
FDA Class: Biologic BLA
Year of approval (FDA) = 1998
Date of 1st FDA approval = 19980506
(in format YYYYMMDD)
Index Terms:
biopharmaceutical products
blood products
human materials used<!-- humansource -->
Factor V
Factor VII
Factor X
Factor XI
Factor XIII
fibrinogen
polysorbate 100 (Tween 100)
prothrombin, human
thromboplastin
tri-n-butyl phosphate (TNBP)
vegetable oil extraction
viral inactivation, solvent detergent
Whole Blood
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
Copyright© 2020, Biotechnology Information Institute