"Here it is. 7 pages, so it was short and sweet." And old, but I still hadn't seen it.
"Let me know what you think it means in regard to Teva's current application. "
As I said before in the post Dew stickied a few days ago, I think the problem is reverse engineering the process engineering to get the fragments needed. The same mode of depolymerization can be used, but process variations (temp, pH, depolymerization time) can give rise to different fragments, even if the same sequence is still there. Alkaline beta-elimination, the mode used for enoxaparin, cleaves w/o preference to the presence or absence of a 2-O-sulfo group in the iduronic acid, whereas other depolymerization methods can be more rigid -- but yield different terminal ends. The example given in the response to the CP says that a chain with the sequence ABCEDA can be cleaved into AB and CDEDA with a process that biases cleavage at the C unit, whereas a process that biases cleavage at the D unit will yield ABC, DE, and DA. Sequence is the same but distribution of the short chains making it up are now different. I believe this is the sticking point for Teva and other applicants. Their methods of characterizing these oligosaccharide units are so much slower than MNTA's that it takes them a long time to know if they've got a match or not. Most likely not, so then they have to change a parameter of the process, say the pH, and try again. The stuff at the terminal ends is relatively easy, and Teva has apparently done that long ago, so that's not the issue (i.e. the 1,6 anhydrous ring at the reducing end in about 20% of the mixture).
"Results for polysaccharide chains with molecular mass less than 3,600 Da. indicate that both enoxaparin products show essentially the same variability." (quote from Teva's response)
But showing the same variability in the oligosaccharide chains is not the same as showing the same chains, which is what FDA is asking for in its response to the CP.
"Additional characterization studies are ongoing, and it is Teva’s intention to submit these studies for Agency review as part of our pending ANDA for enoxaparin sodium injection." (quote from Teva's response)
Yeah, yeah. Plod on, boys.
Aside to everyone else. Thanks for being a sounding board for dissecting my various worries on other subjects.
Regards, RockRat
