VWF Nanofiltration Preserving Multimers at Low Pressure
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Solution Overview
Problem
Current methods for purifying Von Willebrand Factor (VWF) and Factor VIII/VWF complex using nanofiltration through pore sizes less than 35 nm are ineffective, as they fail to retain high molecular weight multimers, leading to non-functional VWF in therapeutic concentrates, which are unsuitable for treating Von Willebrand's Disease and Haemophilia A.
Innovation Solution
Nanofiltration of VWF or FVIII/VWF complex through a sieve with a pore size less than 35 nm, specifically 20 nm, at a maximum pressure of less than 0.5 bar, while maintaining a VWF:RCo/FVIII:C ratio of 0.4 or higher, preserves the high molecular weight multimers and achieves a recovery of over 70% of both VWF and FVIII activities, suitable for treating VWD and Haemophilia A.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If nanofiltration is performed through pore size less than 35 nm to eliminate viruses, then viral elimination efficiency is improved, but high molecular weight multimers of VWF are lost
Solution Approach 1:
The patent applies preliminary action by performing nanofiltration at low pressure (less than 0.5 bar) before final concentration steps. This preliminary low-pressure filtration preserves the high molecular weight multimers while still achieving viral elimination, whereas conventional high-pressure filtration would have caused multimer loss. The low-pressure condition is maintained throughout the nanofiltration process to prevent multimer degradation.
Solution Approach 2:
The patent changes the pressure parameter from conventional high pressure to low pressure (less than 0.5 bar) during nanofiltration. This parameter change allows the filtration membrane to retain viruses while permitting the passage of VWF multimers, even high molecular weight ones, through the membrane. The pressure parameter is carefully controlled to be sufficient for viral elimination but insufficient to force multimer loss.
2Manufacturing precision
If conventional nanofiltration is used to purify VWF concentrates, then purity is improved, but functional activity is reduced
Solution Approach 1:
The patent performs nanofiltration under low pressure as a preliminary purification step before final concentrate formulation. This preliminary action achieves viral elimination and purification while preserving functional activity. The low-pressure condition ensures that the multimer structure remains intact, maintaining VWF:RCo activity throughout the purification process.
Solution Approach 2:
The patent changes the pressure parameter during nanofiltration to less than 0.5 bar, which is significantly lower than conventional nanofiltration pressures. This parameter change allows the process to achieve both high purification quality and preserved functional activity, as the low pressure prevents multimer degradation while still enabling viral particle retention.
3Productivity
If high pressure is applied during nanofiltration to increase flow rate, then productivity is improved, but multimer structure is degraded
Solution Approach 1:
The patent applies low pressure (less than 0.5 bar) as a preliminary condition during nanofiltration to preserve multimer structure. While this reduces instantaneous flow rate compared to high-pressure filtration, the process maintains multimer integrity throughout filtration. The low-pressure preliminary filtration prevents multimer degradation that would occur with high pressure, ensuring structural stability.
Solution Approach 2:
The patent changes the pressure parameter to low pressure (less than 0.5 bar) during nanofiltration, trading off some productivity for multimer structure stability. This parameter change ensures that the multimer structure is not degraded, as high pressure would force multimers through the membrane or cause their breakdown. The low pressure maintains the natural size distribution of multimers.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The process results in a high-purity therapeutic concentrate with preserved multimer structure and enhanced VWF activity, suitable for treating VWD and Haemophilia A, with a VWF:RCo/FVIII ratio of 0.4 or more, maintaining the advantages of VWF-rich concentrates for Haemophilia A treatment.
Implementation Method 1
nanofiltered through a pore size of less than 35 nm
Implementation Method 2
through which viruses with and without an envelope such as, for example, hepatitis A or erythrovirus B19 can be effectively eliminated
Data Source
AI summary
A concentrate of Von Willebrand Factor (VWF) or a complex of Factor VIII/VWF is prepared by creating a solution of VWF or a complex of Factor VIII/VWF containing VWF at a concentration of up to 12 IU VWF:RCo/ml and a VWF/Factor VIII ratio of 0.4 or more; and nanofiltering that starting solution through a filter of pore size of 35 nanometers or smaller. The resulting VWF retains high molecular weight multimers.