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Sunday, May 01, 2011 12:04:24 PM
lovenox signature & process control
Sorry for those not interested...please ignore
I read briefly the patent
http://worldwide.espacenet.com/publicationDetails/description?CC=US&NR=2009061411A1&KC=A1&FT=D&date=20090305&DB=EPODOC&locale=en_EP
specifically claim 331 which basically is about identifying a structural signature in source material.
in this case p/polysacharide 8(read para [0248]& 0249 )
Of all the 8 structural blocks in lovenox, this patent claims that for the first time p8 was identified. The remaining 7 were structurally identified before
"In addition to the characterization of the seven disaccharides, we also completed structural characterization of unknown p8. Isolation and sequencing of this oligosaccharide using the PEN-MALDI sequencing approach (Venkataraman, et al., Science 286:537-42 (1999)) indicated that p8 is a tetra or penta sulfated, non/mono acetylated tetrasaccharide comprising of one or more of the following: [Delta]U HNAc,6SGHNS,3S,6S; [Delta]U HNS,6SGHNS,3S,6S; [Delta]U HNAc,6SGHNS,3S; or [Delta]U HNS,6SGHNS,3S."
Also this patent claims p8 has a direct correlation to anti-Xa
and anti-IIA activity
(keep in mind, even sanofi could not identify this..which is clear in FDA's cp response ..they were speculating it on 1,6 anhydro ring strcture )
Now in the USP monograph of lovenox it states
"The ratio of the numerical value of the anti-factor Xa activpolymerization
of heparin benzyl ester. The starting ity, in Anti-Factor Xa IU per mg, to the numerical value of the antimaterial,
heparin, is obtained exclusively from porcine factor IIa activity, in Anti-Factor IIa IU per mg, as determined by
intestinal mucosa. •Heparin source material used in the the Assay (anti-factor Xa activity) and the Anti-factor IIa activity, respectively, is not less than 3.3 and not more than 5.3."
Then read para 297 from this patent
"[0297] Further applications of this method include determining the structural signature of the starting material, e.g. porcine intestinal mucosa heparin. This starting material is isolated in slaughter houses and is often unmonitored by standard quality control techniques. Using the methods described above to ensure that the quality of the starting material, e.g., the structural signature and activity, is sufficient to produce acceptable LMWH preparations. Adding this quality control to the beginning of the procedure so that the starting material is consistent helps to decrease batch-batch variability, and thus decrease the number of rejected batches, saving time and money, and resulting in an improved product."
With this understanding , I am not sure how another company (like TEVA) , come up with a new CONTROLLED process for making lovenox.
Seems impossible?????Anybody?
This patent is identifying the "signature"(which is p8) at the source heparin material and saying selecting batches based on "p8" content would yield desired anti-Xa activity as specified in lovenox monograph..
Sorry for those not interested...please ignore
I read briefly the patent
http://worldwide.espacenet.com/publicationDetails/description?CC=US&NR=2009061411A1&KC=A1&FT=D&date=20090305&DB=EPODOC&locale=en_EP
specifically claim 331 which basically is about identifying a structural signature in source material.
in this case p/polysacharide 8(read para [0248]& 0249 )
Of all the 8 structural blocks in lovenox, this patent claims that for the first time p8 was identified. The remaining 7 were structurally identified before
"In addition to the characterization of the seven disaccharides, we also completed structural characterization of unknown p8. Isolation and sequencing of this oligosaccharide using the PEN-MALDI sequencing approach (Venkataraman, et al., Science 286:537-42 (1999)) indicated that p8 is a tetra or penta sulfated, non/mono acetylated tetrasaccharide comprising of one or more of the following: [Delta]U HNAc,6SGHNS,3S,6S; [Delta]U HNS,6SGHNS,3S,6S; [Delta]U HNAc,6SGHNS,3S; or [Delta]U HNS,6SGHNS,3S."
Also this patent claims p8 has a direct correlation to anti-Xa
and anti-IIA activity
(keep in mind, even sanofi could not identify this..which is clear in FDA's cp response ..they were speculating it on 1,6 anhydro ring strcture )
Now in the USP monograph of lovenox it states
"The ratio of the numerical value of the anti-factor Xa activpolymerization
of heparin benzyl ester. The starting ity, in Anti-Factor Xa IU per mg, to the numerical value of the antimaterial,
heparin, is obtained exclusively from porcine factor IIa activity, in Anti-Factor IIa IU per mg, as determined by
intestinal mucosa. •Heparin source material used in the the Assay (anti-factor Xa activity) and the Anti-factor IIa activity, respectively, is not less than 3.3 and not more than 5.3."
Then read para 297 from this patent
"[0297] Further applications of this method include determining the structural signature of the starting material, e.g. porcine intestinal mucosa heparin. This starting material is isolated in slaughter houses and is often unmonitored by standard quality control techniques. Using the methods described above to ensure that the quality of the starting material, e.g., the structural signature and activity, is sufficient to produce acceptable LMWH preparations. Adding this quality control to the beginning of the procedure so that the starting material is consistent helps to decrease batch-batch variability, and thus decrease the number of rejected batches, saving time and money, and resulting in an improved product."
With this understanding , I am not sure how another company (like TEVA) , come up with a new CONTROLLED process for making lovenox.
Seems impossible?????Anybody?
This patent is identifying the "signature"(which is p8) at the source heparin material and saying selecting batches based on "p8" content would yield desired anti-Xa activity as specified in lovenox monograph..
