Process Signature for Lovenox - Patent 2
Prior message was "starting material signature". This one is "structural signature due to process".
This potentially could be blocking for the suppliers of TEVA's or Amphastar's if for example their process uses oxidation conditions and in the end they look for this peak 2.10 ppm to do Quality control check on "shelf life" of the heparin...(??). Apparently the presence of this structural signature will not make the heparin not at risk of coloration. Risk of Coloration can affect Shelf life and the Quality of Lovenox.
I am starting to think the blocking value of these characterization patents has been underestimated by market.Anybody?
if teva/amphastar don't have this Quality control check built in their product, I guess they don't have control on shelf-life of the product and hence maybe their product doesn't measure up to reference standard of Sanofi's Lovenox. If they have it and they test for it, they would be infringing ?
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0002] In one aspect, the disclosure features a method of identifying if a process was used to make a heparin preparation (e.g., an unfractionated heparin preparation or a low molecular weight heparin (LMWH) preparation). The method includes:
determining if a structural signature associated with a peak in the N-acetyl region of a 1H 1D-NMR spectra, e.g., a structural signature associated with the peak at 2.08 ppm of Figure 9 and/or the peak at 2.10 ppm of Figure 1, is absent from or present in a heparin preparation wherein the presence of the structural signature indicates that the heparin preparation was made by a method (e.g., a method that includes oxidation or oxidation followed by treatment with an acid) and the absence of the structural signature indicates that the heparin preparation was not made by the method (e.g., the method did not include oxidation or oxidation followed by treatment with an acid); and
making a decision or step regarding the heparin preparation if the heparin preparation was made by the method (
[0062] In another aspect, the disclosure features a method of determining if a heparin preparation (e.g., an unfractionated heparin preparation or a low molecular weight heparin (LMWH) preparation) is at risk for coloration, comprising:
determining if a structural signature associated with the peak at 2.10 ppm of the <1>H 1D-NMR spectra of Figure 1 is absent from or present in a heparin preparation wherein the presence of the structural signature indicates that the heparin preparation is not at risk for coloration and the absence of the structural signature indicates that that the heparin preparation is at risk for coloration; and
making a decision or step regarding the heparin preparation if the heparin preparation is not at risk for coloration, e.g., the heparin preparation is classified, selected, accepted, released, processed into a drug product, shipped, moved to a new location, formulated, labeled, packaged, released into commerce, sold, or offered for sale, or if the heparin preparation is at risk for coloration, e.g., the heparin preparation is discarded or withheld.
00115] The disclosure is based, at least in part, on the finding that peaks within the N- acetyl region of a 1H 1D-NMR spectra of a heparin preparation are associated with characteristic structural signatures which reflect the process used to make the heparin preparation. For example, the presence of a peak at 2.10 ppm in a <[Chi]>[Eta] 1D-NMR spectra of unfractionated heparin represents a characteristic structural signature that is reflective of an oxidative processing step in the manufacture of unfractionated heparin
[00116] In some embodiments, a method described herein can be used to determine if a heparin preparation (e.g., an unfractionated heparin preparation or a low molecular weight heparin (LMWH) preparation) is at risk for coloration. Some heparin preparations have limited shelf life due, at least in part, to the development of color is the preparation during storage.
00142] These experiments described above show that the peak at 2.10 ppm in the <X>H 1D-NMR spectra of heparin is not OSCS and instead is a characteristic structural signature that is reflective of an oxidative processing step in the manufacture of unfractionated heparin. Based upon the experiments described above, the scheme provided likely results in structures A and B of Figure 16
[00143] In conclusion, it was found that oxidation conditions result in the conversion of N-acetylglucosamine residues at the reducing end of heparin chains to an N- acetylglucosaminic acid which yields a characteristic signal at 2.10 ppm in the iH-NMR spectrum of the heparin. Therefore, this signal does not arise from an impurity or contaminant present within heparin, but rather represents a part of the heparin chain itself.
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