DK2436700T5 - Afkortet oprensningsfremgangsmåde til fremstilling af streptococcus pneumoniae-kapselpolysaccharider - Google Patents
Afkortet oprensningsfremgangsmåde til fremstilling af streptococcus pneumoniae-kapselpolysaccharider Download PDFInfo
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- DK2436700T5 DK2436700T5 DK11194173.8T DK11194173T DK2436700T5 DK 2436700 T5 DK2436700 T5 DK 2436700T5 DK 11194173 T DK11194173 T DK 11194173T DK 2436700 T5 DK2436700 T5 DK 2436700T5
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- Prior art keywords
- protein
- solution
- retentate
- polysaccharide
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Classifications
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- A61K47/646—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent the entire peptide or protein drug conjugate elicits an immune response, e.g. conjugate vaccines
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- C—CHEMISTRY; METALLURGY
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Claims (21)
1. Fremgangsmåde til fremstilling af oprensede kapselpolysaccharider ud fra et Streptococcus pneumoniae-ce\\e\ysat, hvilken fremgangsmåde omfatter trinnene: (a) at tilvejebringe en fermenteringssuppe omfattende bakterieceller, der producerer en udvalgt Streptococcus pneumoniae-serotype-, (b) at lysere bakteriecellerne fra trin (a) med et lytisk middel, hvorved der fremstilles et cellelysat omfattende celledebris, opløselige proteiner, nukleinsyrer og polysaccharider; (c) at klare cellelysatet fra trin (b) under anvendelse af centrifugering eller filtrering til fjernelse af celledebris, hvorved der fremstilles et klaret cellelysat; (d) at ultrafiltrere og diafiltrere det klarede cellelysat fra trin (c) til fjernelse af urenheder med lav molekylvægt og øgning af polysaccharidkoncentrationen, hvorved der fremstilles et retentat; (e) at sænke pH-værdien af retentatet fra trin (d) til mindre end 4,5 under anvendelse af en organisk syre eller en mineralsyre til udfældning af protein og nukleinsyrer, hvorved der dannes en forsuret retentatopløsning; (f) at fastholde den forsurede retentatopløsning dannet i trin (e) i et tidsrum, der er tilstrækkeligt til at muliggøre, at udfældningsproduktet bundfælder sig, efterfulgt af filtrering eller centrifugering af den forsurede retentatopløsning, hvorved der fremstilles en polysaccharidopløsning; (g) at filtrere den klarede polysaccharidopløsning fra trin (f) gennem et aktiveret kulfilter; (h) at ultrafiltrere og diafiltrere den filtrerede opløsning fremstillet ved trin (g), hvorved der fremstilles en koncentreret oprenset polysaccharidopløsning; og (i) at filtrere den koncentrerede oprensede polysaccharidopløsning fremstillet ved trin (h) under anvendelse af et sterilt filter; hvorved der fremstilles oprensede kapselpolysaccharider i form af en opløsning.
2. Fremgangsmåde ifølge krav 1, hvor den valgte Streptococcus pneumoniae-serotype udvælges fra gruppen bestående af 1,4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19Fog 23F.
3. Fremgangsmåde ifølge krav 1, omfattende trinnene: (a) at tilvejebringe en fermenteringssuppe omfattende bakterieceller, der producerer Streptococcus pneumoniae-serotype 1,4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F eller 23F; (b) at lysere bakteriecellerne fra trin (a) med et lytisk middel, hvorved der fremstilles et cellelysat omfattende celledebris, opløselige proteiner, nukleinsyrer og polysaccharider; (c) at klare cellelysatet fra trin (b) under anvendelse af centrifugering eller filtrering til fjernelse af celledebris, hvorved der fremstilles et klaret cellelysat; (d) at ultrafiltrere og diafiltrere det klarede cellelysat fra trin (c) ved rumtemperatur ved neutral pH i saltfri medier til fjernelse af urenheder med lav molekylvægt og øgning af polysaccharidkoncentrationen, hvorved der fremstilles et saltfrit retentat; (e) at sænke pH-værdien af det saltfri retentat fra trin (d) til mindre end 4,5 under anvendelse af en organisk syre eller en mineralsyre til udfældning af protein og nukleinsyrer, hvorved der dannes en forsuret retentatopløsning; (f) at fastholde den forsurede retentatopløsning dannet i trin (e) i mindst 2 timer ved rumtemperatur til muliggørelse af, at udfældningsproduktet bundfælder sig, efterfulgt af filtrering eller centrifugering af den forsurede retentatopløsning, hvorved der fremstilles en polysaccharidopløsning; (g) at filtrere den klarede polysaccharidopløsning fra trin (f) gennem et aktiveret kulfilter; (h) at ultrafiltrere og diafiltrere den filtrerede opløsning fremstillet ved trin (g), hvorved der fremstilles en koncentreret oprenset polysaccharidopløsning; og (i) at filtrere den koncentrerede oprensede polysaccharidopløsning fremstillet ved trin (h) under anvendelse af et sterilt filter; hvorved der fremstilles oprensede kapselpolysaccharider omfattende serotype 1,4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19F eller 23F i form af en opløsning.
4. Fremgangsmåde ifølge krav 1,2 eller 3, hvor pH-værdien fra trin (e) sænkes til ca. 3,5.
5. Fremgangsmåde ifølge krav 1,2, 3 eller 4, hvor diafiltreringen i trin (h) omfatter en pH-justering til mellem ca. 5,5 til ca. 7,5, fortrinsvis hvor diafiltreringen i trin (h) omfatter en pH-justering til mellem ca. 7,0 til ca. 7,5, endnu mere foretrukket hvor diafiltreringen i trin (h) omfatter en pH-justering til ca. 7,4.
6. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 5, hvor trin (e) fjerner mindst 98 % af protein fra retentatet fra trin (d).
7. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 6, hvor trin (g) fjerner mindst 90 % af proteinet fra den klarede polysaccharidopløsning fra trin (f)·
8. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 7, hvor det aktiverede kulfilter i trin (g) omfatter træbaseret phosphorsyreaktiveret kul.
9. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 8, hvor trin (f) omfatter at fastholde den forsurede retentatopløsning dannet i trin (e) i mindst 2 timer.
10. Fremgangsmåde ifølge krav 1, omfattende trinnene: (a) at tilvejebringe en fermenteringssuppe omfattende bakterieceller, der producerer Streptococcus pneumoniae-serotype 19A; (b) at lysere bakteriecellerne fra trin (a) med et lytisk middel, hvorved der fremstilles et cellelysat omfattende celledebris, opløselige proteiner, nukleinsyrer og polysaccharider; (c) at klare cellelysatet fra trin (b) under anvendelse af centrifugering eller filtrering til fjernelse af celledebris, hvorved der fremstilles et klaret cellelysat; (d) at ultrafiltrere og diafiltrere det klarede cellelysat fra trin (c) ved ca. 4 °C ved en pH-værdi på ca. 6 i natriumphosphatbuffer til fjernelse af urenheder med lav molekylvægt og øgning af polysaccharidkoncentrationen, hvorved der fremstilles et retentat; (e) at sænke pH-værdien af retentatet fra trin (d) til mindre end 4,5 under anvendelse af en organisk syre eller en mineralsyre til udfældning af protein og nukleinsyrer, hvorved der dannes en forsuret retentatopløsning; (f) at fastholde den forsurede retentatopløsning dannet i trin (e) i mindst 2 timer ved ca. 4 °C til muliggørelse af, at udfældningsproduktet bundfælder sig, efterfulgt af filtrering eller centrifugering af den forsurede retentatopløsning, hvorved der fremstilles en polysaccharidopløsning; (g) at justere pH-værdien af den klarede polysaccharidopløsning fra trin (f) til ca. 6, hvorved der fremstilles en pH-justeret klaret polysaccharidopløsning; (h) at filtrere den pH-justerede klarede polysaccharidopløsning fra trin (g) gennem et aktiveret kulfilter; (i) at ultrafiltrere og diafiltrere den filtrerede opløsning fremstillet ved trin (h), hvorved der fremstilles en koncentreret oprenset polysaccharidopløsning; og (j) at filtrere den koncentrerede oprensede polysaccharidopløsning fremstillet ved trin (i) under anvendelse af et sterilt filter; hvorved der fremstilles oprensede kapselpolysaccharider omfattende serotype 19A i form af en opløsning.
11. Fremgangsmåde ifølge krav 10, hvor pH-værdien fra trin (e) sænkestil ca. 3,5.
12. Fremgangsmåde ifølge krav 10 eller 11, hvor diafiltreringen i trin (i) omfatter en pH-justering til mellem ca. 5,5 til ca. 7,5, fortrinsvis hvor diafiltreringen i trin (i) omfatter en pH-justering til mellem ca. 7,0 til ca. 7,5, endnu mere foretrukket hvor diafiltreringen i trin (i) omfatter en pH-justering til ca. 7,4.
13. fremgangsmåde ifølge et hvilket som helst af kravene 10 til 12, hvor trin (e) fjerner mindst 98 % af protein fra retentatet i trin (d).
14. Fremgangsmåde ifølge et hvilket som helst af kravene 10 til 13, hvor trin (h) fjerner mindst 90 % af proteinet fra den pH-justerede klarede polysaccharidopløsning fra trin (g).
15. Fremgangsmåde ifølge et hvilket som helst af kravene 10 til 13, hvor det aktiverede kulfilter i trin (h) omfatter træbaseret phosphorsyreaktiveret kul.
16. Fremgangsmåde ifølge et hvilket som helst af kravene 10 til 15, hvor natri-umphosphatbufferen i trin (d) er 25 mM natriumphosphat.
17. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 16, hvor det lytiske middel i trin (b) er deoxycholatnatrium.
18. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 16, hvor det lytiske middel i trin (b) er et lytisk middel af ikke-animalsk oprindelse, fortrinsvis hvor det lytiske middel af ikke-animalsk oprindelse er udvalgt fra gruppen bestående af: decansulfonsyre, tert-octylphenoxy-poly(oxyethylen)ethanoler, oc-tylphenolethylenoxidkondensater, N-lauryl-sarcosinnatrium (NLS), laurylimi-nodipropionat, natriumdodecylsulfat, chenodeoxycholat, hyodeoxycholat, gly-codeoxycholat, taurodeoxycholat, taurochenodeoxycholat og cholat, endnu mere foretrukket hvor det lytiske middel af ikke-animalsk oprindelse er N-lauryl-sarcosinnatrium.
19. Fremgangsmåde ifølge et hvilket som helst af kravene 1 til 18, hvor mineralsyren er udvalgt fra gruppen bestående af saltsyre, salpetersyre, phosphor-syre og svovlsyre.
20. Fremgangsmåde til fremstilling af en pneumokokvaccine, som omfatter at fremstille oprensede kapselpolysaccharider fra et Streptococcus pneumoniae-cellelysat ved en fremgangsmåde ifølge et hvilket som helst af kravene 1 til 19 og at anvende de oprensede kapselpolysaccharider til fremstilling af en pneumokokvaccine.
21. Fremgangsmåde ifølge krav 20, hvor pneumokokvaccinen indeholder po-lysaccharid konjugeret med en proteinbærer.
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| EP08732592.4A EP2129693B1 (en) | 2007-03-23 | 2008-03-20 | Shortened purification process for the production of capsular streptococcus pneumoniae polysaccharides |
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