Improved virus safety and purity of a chromatographically produced Factor IX concentrate by nanofiltration

Hoffer, Lutz; Schwinn, Horst; Biesert, Lothar; Josić, Dj.

doi:10.1016/0378-4347(95)00107-t

Cited by 32 publications

(18 citation statements)

References 10 publications

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“…Over the last 10 years, the so‐called prothrombin complex concentrates (PCCs) have almost completely been replaced in the treatment of this disease [2,7]. PCCs contain other vitamin K‐dependent clotting factors and inhibitors together with FIX, but in the highly purified concentrates such proteins are removed to below the level of detection [3–6].…”

Section: Introductionmentioning

confidence: 99%

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Vitronectin in clotting factor IX concentrates

Josić

Kannicht²,

Löster³

et al. 2001

Haemophilia

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Highly purified, plasma-derived factor IX (FIX) concentrates are produced in large part by a combination of anion exchange and heparin affinity chromatography. However, the concentrates still contain some accompanying proteins. The main impurity has turned out to be the adhesive glycoprotein, vitronectin. It occurs in concentrates exclusively in its multimeric form, in contrast to the situation in plasma. The multimeric vitronectin can be removed either by nanofiltration with a crossflow system or by size-exclusion chromatography. When these FIX concentrates are used as therapeutic agents, the fact has to be taken into account that considerable amounts of multimeric vitronectin are given to the patient. The physiological consequences of the dosage of this protein have not yet been investigated. Although no thrombogenicity has been reported in connection with the above-mentioned FIX concentrates, we recommend that the impurity should be removed from the preparation with the methods described here.

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Section: Introductionmentioning

confidence: 99%

“…in the case of surgery [2,7]. A large number of these highly purified FIX preparations are produced from PCCs by further purification [3–5]. This suggests that the component(s) responsible for increased thrombogenicity in former preparations with lower specific activity are removed in subsequent purification steps.…”

Section: Introductionmentioning

confidence: 99%

Vitronectin in clotting factor IX concentrates

Josić

Kannicht²,

Löster³

et al. 2001

Haemophilia

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“…As shown in Figure 3, the production of F IX from cryopoor plasma is a relatively straightforward process containing two anion-exchange chromatographic steps and one affinity step with Heparin Sepharose FF. In addition to the solvent detergent treatment for inactivation of lipid-enveloped viruses, the virus filtration was added as a second step for virus removal [20]. It was later proved that this is also a very efficient way to remove vitronectin.…”

Section: Discussionmentioning

confidence: 99%

“…The S/D reagents were then removed and a final chromatographic step is performed on Heparin Sepharose Fast-Flow (FF, GE Healthcare). The eluate of the heparin affinity column undergoes virus filtration [6, 8, 20]. The nanofiltration technology is based on a PVDF membrane, rendered especially hydrophilic by a patented method (Viresolve, Millipore, Billerica, MA, U.S.A.).…”

Section: Methodsmentioning

confidence: 99%

Use of proteomics for validation of the isolation process of clotting factor IX from human plasma

Clifton

Huang

Gašo-Sokač

et al. 2010

Journal of Proteomics

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The use of proteomic techniques in the monitoring of different production steps of plasma-derived clotting factor IX (pd F IX) was demonstrated. The first step, solid-phase extraction with a weak anion-exchange resin, fractionates the bulk of human serum albumin (HSA), immunoglobulin G, and other non-binding proteins from F IX. The proteins that strongly bind to the anion-exchange resin are eluted by higher salt concentrations. In the second step, anion-exchange chromatography, residual HSA, some proteases and other contaminating proteins are separated. In the last chromatographic step, affinity chromatography with immobilized heparin, the majority of the residual impurities are removed. However, some contaminating proteins still remain in the eluate from the affinity column. The next step in the production process, virus filtration, is also an efficient step for the removal of residual impurities, mainly high molecular weight proteins, such as vitronectin and inter-alpha inhibitor proteins. In each production step, the active component, pd F IX and contaminating proteins are monitored by biochemical and immunochemical methods and by LC-MS/MS and their removal documentedOur methodology is very helpful for further process optimization, rapid identification of target proteins with relatively low abundance, and for the design of subsequent steps for their removal or purification.

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“…Typically, complete removal is obtained for viruses with a size larger than the mean pore size of the membrane. Another filtration system using Viresolve Ò 70 tangential flow procedure was found to retain high MW proteins from an Austrian FIX product [39]. A high-purity FIX concentrate purified by metal chelate chromatography and virally inactivated by SD is nanofiltered on Planova Ò 15 nm [38].…”

Section: Coagulation Factorsmentioning

confidence: 99%

Nanofiltration of plasma‐derived biopharmaceutical products

Burnouf¹,

Radosevich²

2003

Haemophilia

191

140

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This review presents the current status on the use and benefits of viral removal filtration systems--known as nanofiltration--in the manufacture of plasma-derived coagulation factor concentrates and other biopharmaceutical products from human blood origin. Nanofiltration of plasma products has been implemented at a production scale in the early 1990s to improve margin of viral safety, as a complement to the viral reduction treatments, such as solvent-detergent and heat treatments, already applied for the inactivation of human immunodeficiency virus, hepatitis B and hepatitis C virus. The main reason for the introduction of nanofiltration was the need to improve product safety against non-enveloped viruses and to provide a possible safeguard against new infectious agents potentially entering the human plasma pool. Nanofiltration has gained quick acceptance as it is a relatively simple manufacturing step that consists in filtering protein solution through membranes of a very small pore size (typically 15-40 nm) under conditions that retain viruses by a mechanism largely based on size exclusion. Recent large-scale experience throughout the world has now established that nanofiltration is a robust and reliable viral reduction technique that can be applied to essentially all plasma products. Many of the licensed plasma products are currently nanofiltered. The technology has major advantages as it is flexible and it may combine efficient and largely predictable removal of more than 4 to 6 logs of a wide range of viruses, with an absence of denaturing effect on plasma proteins. Compared with other viral reduction means, nanofiltration may be the only method to date permitting efficient removal of enveloped and non-enveloped viruses under conditions where 90-95% of protein activity is recovered. New data indicate that nanofiltration may also remove prions, opening new perspectives in the development and interest of this technique. Nanofiltration is increasingly becoming a routine step in the manufacture of biopharmaceutical products.

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Improved virus safety and purity of a chromatographically produced Factor IX concentrate by nanofiltration

Cited by 32 publications

References 10 publications

Vitronectin in clotting factor IX concentrates

Vitronectin in clotting factor IX concentrates

Use of proteomics for validation of the isolation process of clotting factor IX from human plasma

Nanofiltration of plasma‐derived biopharmaceutical products

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