cGMPs / QRM Process

A Skeptic Remains

Loyola University’s Dr. Jawed Fareed believes further heparin studies need to be done lest the past repeat itself

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.

PhM: You're saying that even though they have revised the monographs, they still have a ways to go?

J.F.: USP has not totally revised the monographs as yet, but USP is in the steps to revise the monograph for heparin and low molecular weight heparin.

PhM: And what about similar occurrences? Could this kind of thing happen in other areas?

J.F.: Well, we have the low molecular weight heparin—enoxaparin and dalteparin and so on. Fortunately, the material used in the making of enoxaparin is free of oversulfated chondroitin sulfate at the present time.  But it's important to continue checking on this thing.
 
In Europe, they have released some batches of enoxaparin which contained five percent of oversulfated chondroitin sulfate, assuming that it will not have any consequences.  And I'm not sure whether it was wise or not. . . . Any product coming out of heparins—low molecular weight heparins and heparin-derived products—can be affected by this contaminant.

PhM: Obviously, everybody's going to be more on the alert.  Would you say that this is going to scare off people who might be trying to adulterate the product?

J.F.: The supply and demand is what determines the balance of these products. The low molecular weight heparins are so popular now, and the sales of these materials will reach over $5 billion soon.  So everybody wants to make a low molecular weight heparin.  So a lot of unfractionated heparin is diverted to manufacture low molecular weight heparin. So the people can pay premium prices for the materials to make low molecular weight heparin. That leaves the unfractionated heparin in limbo, and people have to start paying the price for it, too. 

So to precisely answer this question, eventually they're going to run out of the hogs' mucosal heparin, and the next thing which we will find is heparin from other tissues that's not chondroitin sulfate and other animals, such as sheep, goats, and even cows, can be contaminated. So that will be the next step. Hopefully, the FDA will institute PCR [polymerase chain reaction testing] to make sure that that is not there. . . . What I’m trying to say is that this saga will continue on, and people will find other things to contaminate heparin, which are not so easy to detect.

PhM: And are some of the companies that are receiving these materials, are they equipped to handle the testing?

J.F.: No. If you differentiate between the bovine and porcine mucosal heparin . . . not until you do PCR can you define the differences. So I think that we should also be proactive and make sure that we do PCR technique to see that there is no contamination, or allow people to mix the porcine mucosal heparin with the goat heparin or the sheep heparin after proper regulatory compliance and control.

PhM: And what would that do, exactly, if they're allowed to mix?

J.F.: Well, a lot of time you can get away with it.  [Laughs.]  And chances are, nothing. I mean, the goat and sheep, I don't think [there] will be any implication. . . . What I'm trying to simply say is that the next level of adulteration is to use real heparin, which is indistinguishable, unless you use sophisticated techniques, between the pork heparin and sheep or goat heparin, or bovine heparin.

PhM: Where do you see this, say, six months or a year from now?

J.F.: I think we will see an increase in the price of unfractionated heparin.  We will have guidelines from European community and from U.S. FDA and USP to quality-assure heparin. We will have a development of newer drugs to be used in the case of a shortage of heparin. I think the heparins, including low molecular weight heparin and unfractionated heparin, will survive. The cost may be increased.

And there will be a thrust from manufacturers to go, maybe, from porcine to bovine heparin, and try to see if they can provide data that there will be no mad cow disease, foot-and-mouth disease, and other viral factors. We have at least five times more bovine heparin than porcine, and just simply because there is mad cow disease. I mean, everybody's eating steak and bovine meat every day.  So this is not a big issue. . . . People are going to say, "Okay, if I have the bovine material, I can purify it, I can clean it, I can show that there is no viral contaminants and so forth. I'd like to use bovine material."  So that could be an approach.

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