Characterization of Thrombate III®, a pasteurized and nanofiltered therapeutic human antithrombin concentrate

Cai, Kang; Osheroff, Wendy P.; Buczynski, Greg; Hotta, Jun‐ichi; Lang, John M.; Elliott, E. A.; Lee, Douglas C.; Roth, Nathan

doi:10.1016/j.biologicals.2014.01.001

Cited by 12 publications

(5 citation statements)

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“…[20][21][22][23] Over the course of the following years, nanofiltration was introduced also into the manufacturing of cell-derived biologics, including recombinant proteins, derived from mammalian cells or mammalian origin. [24][25][26][27][28][29] Today, nanofiltration is standardly used in the manufacturing processes of PDMPs, such as immunoglobulins (IgG), [30][31][32] coagulation factors such as von Willebrand Factor (vWF), 33 Factor VIII (FVIII), 34,35 Factor IX (FIX), and prothrombin complex, 18,36 and inhibitors such as alpha1-protease inhibitor (A 1 PI), 37,38 antithrombin (ATIII), 39 and C1-esterase inhibitor. [40][41][42] PPTA member companies performed a retrospective data collection and analysis of the virus removal capacity validation data for nanofiltration steps for variety of commercial PDMPs using 15 to 20 nm and 35 to 50 nm nanofiltration platforms.…”

Section: Abstract Plasma Derivativesmentioning

confidence: 99%

“…Over the course of the following years, nanofiltration was introduced also into the manufacturing of cell‐derived biologics, including recombinant proteins, derived from mammalian cells or mammalian origin 24–29 . Today, nanofiltration is standardly used in the manufacturing processes of PDMPs, such as immunoglobulins (IgG), 30–32 coagulation factors such as von Willebrand Factor (vWF), 33 Factor VIII (FVIII), 34,35 Factor IX (FIX), and prothrombin complex, 18,36 and inhibitors such as alpha1‐protease inhibitor (A 1 PI), 37,38 antithrombin (ATIII), 39 and C1‐esterase inhibitor 40–42 …”

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confidence: 99%

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Nanofiltration as a robust method contributing to viral safety of plasma‐derived therapeutics: 20 yearsʼ experience of the plasma protein manufacturers

et al. 2020

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Background: Nanofiltration entails the filtering of protein solutions through membranes with pores of nanometric sizes that have the capability to effectively retain a wide range of viruses. Study Design and Methods: Data were collected from 754 virus validation studies (individual data points) by Plasma Protein Therapeutics Association member companies and analyzed for the capacity of a range of nanofilters to remove viruses with different physicochemical properties and sizes. Different plasma product intermediates were spiked with viruses and filtered through nanofilters with different pore sizes using either tangential or dead-end mode under constant pressure or constant flow. Filtration was performed according to validated scaled-down laboratory conditions reflecting manufacturing processes. Effectiveness of viral removal was assessed using cell culture infectivity assays or polymerase chain reaction (PCR). Results: The nanofiltration process demonstrated a high efficacy and robustness for virus removal. The main factors affecting nanofiltration efficacy are nanofilter pore size and virus size. The capacity of nanofilters to remove smaller, nonenveloped viruses was dependent on filter pore size and whether the nanofiltration process was integrated and designed with the intention to provide effective parvovirus retention. Volume filtered, operating pressure,

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Section: Abstract Plasma Derivativesmentioning

confidence: 99%

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confidence: 99%

Nanofiltration as a robust method contributing to viral safety of plasma‐derived therapeutics: 20 yearsʼ experience of the plasma protein manufacturers

et al. 2020

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“…The presence of prions is also a concern. Attempts to remove prions from plasma-derived products have involved several techniques, including ion-exchange chromatography and nanofiltration [77,78]. Several problems exist with these approaches, in particular the use of exogenous "spikes" derived from prion-infected brain homogenates to measure prion clearance, which may result in an overestimation of the amount of prion removal, and the methods used for the estimation of the reduction in prion load, which ideally should involve bioassay to measure infectivity [79].…”

Section: Purification and Inactivation Techniquesmentioning

confidence: 99%

Current concepts in the prevention of pathogen transmission via blood/plasma-derived products for bleeding disorders

et al. 2016

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The pathogen safety of blood/plasma-derived products has historically been a subject of significant concern to the medical community. Measures such as donor selection and blood screening have contributed to increase the safety of these products, but pathogen transmission does still occur. Reasons for this include lack of sensitivity/specificity of current screening methods, lack of reliable screening tests for some pathogens (e.g. prions) and the fact that many potentially harmful infectious agents are not routinely screened for. Methods for the purification/inactivation of blood/plasma-derived products have been developed in order to further reduce the residual risk, but low concentrations of pathogens do not necessarily imply a low level of risk for the patient and so the overall challenge of minimising risk remains. This review aims to discuss the variable level of pathogenic risk and describes the current screening methods used to prevent/detect the presence of pathogens in blood/plasma-derived products

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“…Virus removal filtration is a robust and effective technology that is commonly employed to ensure the viral safety of biologics and plasma derivatives. [1][2][3] Through a size exclusion mechanism, this step often achieves an effective virus logarithmic reduction value (LRV) of 4 log 10 or greater. [4][5][6][7] Characteristics of certain types of molecules and very high concentration products made possible by recent advances in biologics manufacturing and production can prove challenging for virus filtration steps using a single filter and result in reduced throughput and viral clearance.…”

Section: Introductionmentioning

confidence: 99%

Serial virus filtration: A case study evaluating the product‐dependent impact of control strategies on process efficiency

Kozaili

Shah

Robbins³

et al. 2023

Biotechnology Journal

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The production of biopharmaceutical products carries an inherent risk of contamination by adventitious viruses. Historically, these manufacturing processes have incorporated a dedicated virus filtration step to ensure product safety. However, challenging process conditions can lead to passage of small viruses to the permeate pool and an overall decrease in the desired virus logarithmic reduction value (LRV) for the process. The implementation of serial virus filtration has improved the robustness of such processes, albeit concerns about increased operating times and process complexity have limited its implementation. This work focused on optimizing a serial filtration process and identifying process control strategies to provide maximum efficiency while ensuring proper controls for process complexity. Constant TMP was identified as the optimal control strategy, which combined with the optimal filter ratio, resulted in a robust and faster virus filtration process. To demonstrate this hypothesis, data with two filters connected in series (1:1 filter ratio) are presented for a representative non‐fouling molecule. Similarly, for a fouling product, the optimal setup was a combination of a filter connected in series to two filters operated in parallel (2:1 filter ratio). The optimized filter ratios bring cost‐ and time‐savings benefits to the virus filtration step, thereby offering improved productivity. The results of risk and cost analyses performed as part of this study combined with the control strategy, offer companies a toolbox of strategies to accommodate products with different filterability profiles in their downstream processes. This work demonstrates that the safety advantages of performing filters in series can be achieved with minimal increases in time, cost, and risk.

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Characterization of Thrombate III®, a pasteurized and nanofiltered therapeutic human antithrombin concentrate

Cited by 12 publications

References 10 publications

Nanofiltration as a robust method contributing to viral safety of plasma‐derived therapeutics: 20 yearsʼ experience of the plasma protein manufacturers

Nanofiltration as a robust method contributing to viral safety of plasma‐derived therapeutics: 20 yearsʼ experience of the plasma protein manufacturers

Current concepts in the prevention of pathogen transmission via blood/plasma-derived products for bleeding disorders

Serial virus filtration: A case study evaluating the product‐dependent impact of control strategies on process efficiency

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