Viral safety is an important prerequisite for clinical preparations of plasma-derived pharmaceuticals. One potential way to increase the safety of therapeutic biological products is the use of a virus-retentive filter. In order to increase the viral safety of human antihemophilic factor IX, particul...
Viral safety is an important prerequisite for clinical preparations of plasma-derived pharmaceuticals. One potential way to increase the safety of therapeutic biological products is the use of a virus-retentive filter. In order to increase the viral safety of human antihemophilic factor IX, particularly in regard to non-enveloped viruses, a virus removal process using a polyvinylidene fluoride membrane filter (Viresolve NFP) has been optimized. The most critical factor affecting the filtration efficiency was operating pH and the optimum pH was 6 or 7. Flow rate increased with increasing operating pressure and temperature. Recovery yield in the optimized production-scale process was 96%. No substantial changes were observed in the physical and biochemical characteristics of the filtered factor IX in comparison with those before filtration. A 47-mm disk membrane filter was used to simulate the process performance of the production-scale cartridges and to test if it could remove several experimental model viruses for human pathogenic viruses, including human hepatitis A virus (HAV), porcine parvovirus (PPV), murine encephalomyocarditis virus (EMCV), human immunodeficiency virus type 1 (HIV), bovine viral diarrhea virus (BVDV), and bovine herpes virus (BHV). Non-enveloped viruses (HAV, PPV, and EMCV) as well as enveloped viruses (HIV, BVDV, and BHV) were completely removed during filtration. The log reduction factors achieved were $\geq$6.12 for HAV, $\geq$4.28 for PPV, $\geq$5.33 for EMCV, $\geq$5.51 for HIV, $\geq$5.17 for BVDV, and $\geq$5.75 for BHV. These results indicate that the virus filtration process successfully improved the viral safety of factor IX.
Viral safety is an important prerequisite for clinical preparations of plasma-derived pharmaceuticals. One potential way to increase the safety of therapeutic biological products is the use of a virus-retentive filter. In order to increase the viral safety of human antihemophilic factor IX, particularly in regard to non-enveloped viruses, a virus removal process using a polyvinylidene fluoride membrane filter (Viresolve NFP) has been optimized. The most critical factor affecting the filtration efficiency was operating pH and the optimum pH was 6 or 7. Flow rate increased with increasing operating pressure and temperature. Recovery yield in the optimized production-scale process was 96%. No substantial changes were observed in the physical and biochemical characteristics of the filtered factor IX in comparison with those before filtration. A 47-mm disk membrane filter was used to simulate the process performance of the production-scale cartridges and to test if it could remove several experimental model viruses for human pathogenic viruses, including human hepatitis A virus (HAV), porcine parvovirus (PPV), murine encephalomyocarditis virus (EMCV), human immunodeficiency virus type 1 (HIV), bovine viral diarrhea virus (BVDV), and bovine herpes virus (BHV). Non-enveloped viruses (HAV, PPV, and EMCV) as well as enveloped viruses (HIV, BVDV, and BHV) were completely removed during filtration. The log reduction factors achieved were $\geq$6.12 for HAV, $\geq$4.28 for PPV, $\geq$5.33 for EMCV, $\geq$5.51 for HIV, $\geq$5.17 for BVDV, and $\geq$5.75 for BHV. These results indicate that the virus filtration process successfully improved the viral safety of factor IX.
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제안 방법
A validation study was designed to evaluate the efficacy of the Viresolve NFP filter for removal of viruses. A range of virus sizes and non-enveloped or enveloped viruses were employed in order to folly evaluate the filter's performance.
Clotting times were determined on a KC10 coagulometer (Amelung, Lemgo, Germany). Abnonnal toxicity was determined by the abdominal injection of a test sample into mice, with the subsequent monitoring of the toxicity and skin reactivity for up to 7 days post treatment. The presence of pyrogens was detected by administration of the test sample to the ear vein of rabbits, with subsequent monitoring for temperature changes [33].
All the physical and biochemical analyses were performed according to the Standard Operating Procedure (SOP) based on the Korean Pharmacopoeia, European Pharmacopoeia, and US Pharmacopoeia. The factor IX activity was determined using the clotting method with factor IX deficient plasma.
In this study, HAV (strain HM/175/1 오f clone B, ATCC VR-1402), PPV (ATCC VR-742), and EMCV (ATCC VR-129B) were chosen as models of non-envek)ped viruses, and HIV (ⅢB; Advanced BiotechnoLogies, Columbia, MD, U.S.A.), BVDV (ATCC VR-534), and BHV (ATCC VR-188) were selected as examples of enveloped viruses. For the propagation and titration of HAV, PPV, EMCV, HIV, BVDV, and BHV FRhK-4 (ATCC CRL-1688) cells, minipig kidney (MPK) cells (ATCC CCL-166), Vero Cl008 cells (A1CC CRL-1586), C8166 cells (European Collection of Animal Cell Culture), bovine turbinate (BT) cells (ATCC CRL-1390), and Madin-Derby bovine kidney (MDBK) cells (ATCC CRL-22) were used, respectively, as described in previous reports [17-19, 35].
To evaluate the effectiveness and robustness of the Viresolve NFP filtration process in eliminating small, non-enveloped viruses, two different lots of Viresolve NFP disk membranes were challenged withHAV, PPV5 and EMCV (Table 4). No in花ctio니s viruses were detected in the filtrate of any of the two filter lots tested, indicating that these viruses were completely removed to below the detection level.
성능/효과
22ml im membrane was used as a prefilter. The results presented in the present study showed that all the viruses tested were completely removed during the Wesolve NFP filtration process. These results demonstrate that the Mresolve NFP filter is effective for removing smaller size viruses of HAV PPY and EMCV as well as HIV BVDV and BHV from factor IX solution.
The results presented in the present study showed that all the viruses tested were completely removed during the Wesolve NFP filtration process. These results demonstrate that the Mresolve NFP filter is effective for removing smaller size viruses of HAV PPY and EMCV as well as HIV BVDV and BHV from factor IX solution. Considering that parvovirus is one of the smallest viruses found in human fluid, this filter shows potential for increasing the safety of biological products where non-enveloped viruses, including parvovirus and HAV are of concern.
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