For 30 years, Jawed Fareed, PhD, and colleagues at Loyola University Medical Center (Maywood, Ill.) have studied heparin and heparin-related drugs, including low molecular weight heparin. Dr. Fareed has been an outspoken critic of how FDA and the scientific community have conducted their research of contaminated heparin, and how little of their findings they’ve shared with the general public.
Pharmaceutical Manufacturing recently spoke to Fareed about these concerns.
PhM: You’re continuing to study the contaminated heparin. Why?
J.F.: Because of our interest in heparin and related drugs. When the contamination issue came, we initially thought that it would go away, but then it became obvious to us that there was more to it, and there were some issues related to the contaminant which require further investigation. Although we were not part of the team which the FDA worked with, we independently continued working on this. . . .On top of that, one of the components of heparin, the contaminant heparin, was used here without any consequences in our dialysis unit, so I got a sizeable amount of that substance, and that led to a major investigation of our institution.
PhM: I get the sense that, when the recent news came out about the contaminated heparin, it wasn’t altogether a surprise to you.
J.F.: Well, the contaminants in heparin have always been there, but those contaminants are carryover contaminants such as dermatan sulfate, heparan sulfate which are found in manufacture. But in this particular case, the contaminant was such that it was suspicious of a deliberate, purposeful contamination, because of the profiling of the patients, and also the material which we analyzed.
So even before the FDA said something, we [knew] that the contaminant could be, not just a real general suspect like dermatan sulfate, but something like a modified derivative of dermatan sulfate. We didn't have the same means as the FDA and the people at other laboratories have, but we had heparinase, we had HPLC. So to make this story short, we did suspect that this was a purposeful, non-heparin derivative contaminant.
PhM: And that heparin would be adulterated for financial gain probably wouldn't come as a surprise?
J.F.: We were the first one to state that. The FDA is saying this now, but we have gone public in our interviews that there was a purposeful intent from the very beginning.
PhM: And are you suggesting that FDA is overlooking this, or just doesn't want to make a conclusion yet?
J.F.: The FDA initially overlooked it, but [FDA commissioner Andrew von] Eschenbach eventually came out and said that they now feel it is a purposeful or intentional adulteration, yes. But initially, the FDA did not acknowledge it. . . . But there has been no attempt made to characterize it in terms of its conditional, structural and biological acuities except for the plant NMR, which shows that this is an adulterated product.
The Nature Biotechnology paper and the paper in the New England Journal of Medicine have superficial information. . . . Different heparin contaminants can be present—the chondroitin sulfates can come from bovine source, porcine source, from fishbones—all kinds of places.
But nobody's addressed the anticoagulant effect of this agent, which is quite interesting. . . . And the pharmacological properties—what it does, what it does to the immune system, what it does to the biochemical system. Since the publication of those papers, nothing has come out from these people.
PhM: Do you think it's just a matter of timing, that it’s taking time to learn more?
J.F.: Well, [FDA] jumped the gun. They wanted to take the credit. I was surprised to see the FDA named in those publications. . . .
PhM: From the manufacturer's perspective, or from a perspective of ensuring clean materials, what have we learned?
J.F.: We have learned that it is easy to contaminate heparin with biological sub-stances—not only with the contaminant which was detected—and adulterate heparin and have it pass the original USP method, which is used primarily to evaluate the potency of heparins. . . .
We have, more importantly, learned that there are sophisticated chemical methods now such as the nuclear magnetic resonance technique, and a special digestion technique with heparinase, which will digest the heparin, but not contaminants such as the oversulfated chondroitin sulfate.
We have also learned that there are other methods, chemical methods which can be used to quantitate oligosaccharides in heparin and compared these in real, 100% heparin versus contaminated heparins. More importantly, the current approaches instituted by FDA requiring NMR and the detection of oversulfated chondroitin sulfate at least assures the integrity of heparin and the absence of oversulfated chondroitin sulfate. So the heparin currently used in the United States is supposedly clear of the main contaminant that is the oversulfated chondroitin sulfate. However, it may not be totally clean from proteins and some other contaminants which can also be present. . . .
PhM: And obviously you know that the USP has revamped its monographs.
J.F.: The USP has worked very deliberately. . . . In the past six months, since February, they have held several very important meetings and have discussed the contaminant quite extensively, expressed concerns over it, expressed remorse over the limitation of the old methods USP has been practicing for the past 40, 50 years, and is in a process of updating methods to properly identify the chemical composition of heparin. And I have to commend the USP in gathering experts to have a dialogue and approach in this fashion.