E.C.: USP has been overhauling spectroscopic methods over all the general chapters. Is there any plan to look at some of the older testing methods and any kind of a systematic approach to going through the massive tome – the USP?
B.C.: Well, that’s an ongoing process, as you know. Then, perhaps as you suggest, it’s less systematic than it might be, but there certainly is an activity to go after the methods that we feel are clearly dated, clearly not fulfilling the assessment of quality that we think they should. An example, at the moment, would be that we’re looking carefully at revising the tests we have for metals because that fits into some of the dated categories of suboptimal tests.
And as you know then, as those revisions or those changes to the USP come forward, that they become part of a discussion with members of the pharmaceutical industry because, obviously, they're very much involved and affected with changes in USP. And I think also, as you know, that it’s a bit of a process to bring industry to understand that a change of some sort might be in their own best interest.
E.C.: A lot of work was done in conjunction with the FDA on the heparin case, and they’ve got some pretty good people there because as big as you guys are, your resources are limited. Are you going to be working with them a little more, perhaps?
D.A.: Well, we work with them on many different levels and in many different ways. As you know, unlike pharmacopeias anywhere else in the world, we’re independent of the regulatory agency, and that’s for historical reasons and by statute. At the same time, we have a close working relationship at many levels, and I say that USP welcomes the opportunity to interact with FDA, and we believe that it’s a two-way street.
In the case of recent emergencies, such as the diethylene glycol contaminations of the recent past, and with heparin, the FDA has come to us and worked closely with us to help us move the revision of our standards forward. At the same time, these kinds of issues present a unique problem because when setting specifications for a drug substance or a drug product, one’s setting a specification for what should be there.
When we start talking about the adulterations and contaminations, then that’s saying something shouldn’t be there. To set a general specification to rule out things that shouldn’t be there is a daunting task, and not really exactly what a pharmacopeial specification is. It’s a specification as to the purity of the substance. And so we've had to work with our thinking and our processes to incorporate into specifications the exclusion of materials that clearly should not be there.
Ideally, we’d like to be able to set specifications that would say that this drug substance is very, very pure and that there should be a very small amount of any of these impurities . . . So those are some of the discussions that are going on internally as to how to accommodate the need for really protecting the public from things that might be introduced into a drug substance, and at the same time, write specifications that clearly are outlined in the quality of the drug ingredient itself.
E.C.: The original tests weren’t intended to detect clever fraud, and it was based on trust, and it was just make sure that the manufacturer is cleaning up his product well enough. So it’s kind of hard for you to have a test – it might be any of 5,000 chemicals present. Would you possibly work with some commercial labs for these tests?
D.A.: USP will probably stay away from the forensics piece to focus on the compendial piece and let FDA deal with the regulatory piece. We’ll try to revise monographs to better identify the substance of interest rather than the thousands of things that might’ve been added.
The key issue in the heparin case, in my opinion, is one of supply chain management. That’s a good manufacturing practices issue, and that falls under regulatory purviews. Now, that’s not to say that we’re not very interested in trying to assist – and I think we actually do have a general chapter that relates to general guidelines about supply chain management – but the real issue is that it really is a responsibility of the manufacturer to see that the materials that move through the supply chain move through in a responsible sort of way that protects them from potential adulteration and identifies potential contaminants.
And that’s a real challenge, but to say we, as a pharmaceutical manufacturer, don’t take responsibility for that – we simply want to, at the end of the line, have someone show us that bad things aren’t there – well, that just doesn’t make sense. Certainly, that end-of-the-line evaluation needs to occur, but that’s far from the whole picture.
E.C.: I’m just trying to figure out if Congress can throw some money at this, and perhaps either help you or the FDA or independent labs take a look at it forensically, as you said, to try to figure out what kind of safeguards could be thrown in that wouldn’t bankrupt the pharmaceutical companies, especially the smaller ones. You can't expect them to test for everything.
D.A.: Well, my favorite analogy, really, is with the International Olympic Committee’s drugs group that tries to identify foreign substances that athletes might choose to take. And I think it’s become abundantly clear that even when you're dealing with closely chemically related compounds, such as androgenic substances, that the next one you synthesize can be incredibly hard to detect and hard to figure out.
We could design tests that would guarantee the purity and identity of every material known to man. We could do that. The cost would be prohibitive and everybody would have to have a 900 megahertz NMR and the latest, greatest mass spec and the best density equipment, and it would be…
E.C.: Some of the things I've seen over the years are incredible. I've actually seen people adulterate with materials they know will stick to an HPLC column and not come off, and so then when it comes to us – “Oh, it’s a single peak. It’s pure.”
B.C.: Well, I think the approach we’re taking is to try to write the compendial methods in such a way that unequivocally identifies the material of interest with orthogonal tests – maybe a physical test such as density or hardness or melting point, maybe a chemical test like HPLC or NMR or mass spectrometry. And then in those cases where there’s biological activity, a biological test. And now you have three or more orthogonal methods that zero in on what the characteristics of the material should be.
Any adulterant would likely not pass all three or four orthogonal tests. And if we can keep those tests at a reasonable cost and at a level that doesn’t drive the cost of the drug or the manufacturing up too great an amount that just bankrupts not only the company, but more likely the health care system, that’s the approach, I think, we want to take.
D.A.: With heparin, we have quickly provided an initial method that does do physical and chemical characterization of heparin as well as biological characterization that we believe, as an interim measure, should protect the public from the current contamination issue. And that’s currently official. That is an interim method.
We’re reconvening our advisors to move now toward a much more permanent solution – so to evaluate a broader range of methodologies, to try to meet these requirements that Bill just described. And that would be to really specify the purity of the material in physical terms, in chemical terms, and in biological terms in using methodologies that are effective, accurate, and we hope not prohibitively expensive.
And so we’re trying to achieve two things. One is to come to the very best and sensible specification for heparin going forward. And the second, which we believe is an important part of this, is to come to a specification that is either the same or very similar with that in Europe and, we hope, that in Japan so that we end up with a common specification that will allow the global industry to have as straightforward a process in meeting the specifications as possible.
E.C.: Now, I know that, again, it isn’t said a lot, but the USP is virtually the cornerstone for analysis in over 100 countries, and I don’t think that a large number of those can afford some very expensive equipment. With an eye on that, is there a chance to find ways to get similar results with less trouble or less expense?
D.A.: We can’t consider the possibility of having different qualities of standard for different parts of the world, and there are a whole bunch of social reasons that that’s true.
The World Health Organization is very involved on a global level of thinking of issues that relate much more to developing parts of the world, and they oftentimes will be working with other pharmacopeias in the world, but may come to conclusions that are adaptable to products if they come into places that are very resource-constrained.
The USP’s legal mandate is to protect the public of the United States. And so that doesn’t mean we’re not interested in the protection of the rest of the population of the world, but our first responsibility has to be to protect U.S. citizens, and I think the European pharmacopeia would say the same thing about Europe. So that’s really the thrust and focus of the approach.
