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Primerjava virusne filtracije monoklonskih protiteles v laboratorijskem in proizvodnem obsegu.
Škrinjar, Patrick (Author), Narat, Mojca (Mentor) More about this mentor... This link opens in a new window, Vašl, Jožica (Co-mentor)

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Abstract
Monoklonska protitelesa predstavljajo v farmacevtski industriji znaten delež bioloških zdravil. Protitelesa ali imunoglobulini (Ig) so kompleksne molekule, velike približno 150 kDa, katerih pridobivanje poteka s pomočjo sesalskih celic v za to namenjenih bioreaktorjih. Ker se lahko med procesom proizvodnje produkt okuži z virusi, je v zaključnih procesih potrebno zagotoviti njihovo odstranitev. Tako se virusi odstranijo s kromatografskimi tehnikami ter postopki inaktivacije virusov in filtracije virusov. Slednjo lahko izvedemo na 2 načina, kot direktno (DFF) ali kot tangencialno filtracijo (TFF). V našem primeru je bila izvedena direktna filtracija, s čimer smo želeli primerjati koraka filtracije virusov v proizvodnem in laboratorijskem merilu. Poskus v laboratoriju je bil izveden pri enakih pogojih kot v proizvodnem merilu, uporabljeni so bili filtri enakega tipa in proizvajalca. Za poskus smo uporabili tlačno posodo in jo z digitalnim manometrom uravnavali pri stalnem tlaku. Filtrat smo zbirali v čaši, njegovo masa pa spremljali s tehtnico. Vzorcem smo pomerili pH, prevodnost, koncentracijo, vsebnost agregiranih mAb, vsebnost kislih in bazičnih različic mAb, odstotek čistosti, vsebnost ostalih različic mAb in izračunali izkoristke filtracij. Podatke smo primerjali s t-testom in primerjali povprečja rezultatov laboratorijskega merila z 3SD intervali rezultatov proizvodnega merila. Dokazali smo, da je proces filtracije virusov v laboratorijskem merilu primerljiv s procesom v proizvodnem merilu za parametre pH, prevodnost, vsebnost agregatov, odstotek čistosti, vsebnost kislih in bazičnih različic mAb in vsebnost različic mAb 2. Pri parametrih koncentracija, donos, vsebnost različic mAb 1 in različic mAb 3 smo ugotovili statistično signifikantno razliko med podatki pridobljenimi v laboratorijskem in proizvodnem merilu.

Language:Slovenian
Keywords:Monoklonska protitelesa, zaključni procesi, kromatografija, filtracija virusov, laboratorijsko merilo, proizvodno merilo
Work type:Master's thesis/paper (mb22)
Tipology:2.09 - Master's Thesis
Organization:BF - Biotechnical Faculty
Year:2020
Publisher:[P. Škrinjar]
UDC:606:61:577.27:602.44:616-097.3(043.2)
COBISS.SI-ID:30332419 This link opens in a new window
Views:214
Downloads:4
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Secondary language

Language:English
Title:Comparison of virus filtration steps for monoclonal antibodies at laboratory and production scale
Abstract:
Monoclonal antibodies represent a significant proportion of biologics in the pharmaceutical industry. Antibodies or immunoglobulins (Ig) are complex molecules about 150 kDa in size that are produced by mammalian cells in dedicated bioreactors. As the product can become infected with viruses during the production process, it is necessary to ensure their removal in the downstream processes. Thus, viruses are removed by chromatography steps, virus inactivation and virus filtration procedures. The latter can be performed in 2 ways, as direct (DFF) or as tangential filtration (TFF). In our case, direct filtration was performed, with which we wanted to compare the virus filtration steps on a production and laboratory scale. The laboratory test was performed under the same conditions as on production scale, using filters of the same type and manufacturer. A pressure vessel was used for the experiment and it was adjusted at constant pressure with a digital manometer. The filtrate was collected in a beaker and its mass was monitored using a balance. The samples were measured for pH, conductivity, concentration, content of aggregated mAbs, content of acidic and basic variants of mAbs, percentage of purity of mAbs, content of other variants of mAbs and calculated step yields. The data was compared using a t-test and the averages of the laboratory scale results were compared with the 3SD intervals of the production scale results. We proved that the process of virus filtration on a laboratory scale is comparable to the process on a production scale for parameters pH, conductivity, aggregate content, percentage of purity, acid and basic mAb variants and mAb 2 variants content. For parameters concentration, step yields, mAb 1 variants and mAb 3 variants content, a statistically significant difference between the data obtained in the laboratory and production scale was found.

Keywords:Monoclonal antibodies, downstream processing, chromatography, virus filtration, laboratory scale, production scale

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