(In this post, Robert Linhardt, the Ann and John H. Broadbent Jr. ’59 Senior Constellation Professor of Biocatalysis and Metabolic Engineering at Rensselaer, answers questions about a Perspective he co-authored in the June edition of Nature Biotechnology with a team including Janet Woodcock, the Director of the U.S. Food and Drug Administration Center for Drug Evaluation (CEDAR), and Roger Williams, the former head of the United States Pharmacopeial Convention (USP). The Perspective— titled "The US regulatory and pharmacopeia response to the global heparin contamination crisis" —discusses how the FDA, the USP, and international stakeholders have responded to a 2007 crisis in which contaminated heparin – a critical anticoagulant obtained from pig intestines – killed several patients in the United States and caused hundreds of adverse reactions worldwide.)

Q: Briefly, what happened in 2007 that drew attention to this issue?

There was a contamination crisis that led to severe reactions among dialysis patients. People stopped breathing after they were administered heparin, and some of them died. Our immediate concern was to remove the bad drug from the market. The first thing we did was to develop a quick assay to judge whether the drug contained this particular contaminant (which we were able to identify through signature peaks in our analysis) and get it out of circulation. It was an emergency response to minimize the damage. We helped develop two methods, one involving capillary electrophoresis, and one involving NMR, and with that we cleaned up the drug supply. In the subsequent months, we went on to figure out what made the drug bad, and we discovered that an adulterant, abbreviated as OSCS, had been added to the drug. Once we had identified it, it was even easier to detect. And that was the immediate solution.

But then working with the Food and Drug Administration (FDA), and the United States Pharmacopeial Convention (USP), we devised a response that went further, to protect us not just against this single contaminant, but against all contaminants in the future. And that’s more complicated.

Q: The Perspective said the investigation “heralded a dramatic shift in our understanding of the role of identity testing for heparin products,” and describes a long-term response that seems to be a change in our approach to testing. Can you explain that?

There’s a change in regulatory approach in two ways: there is a change with regards to the monograph — which is the regimen of testing required to demonstrate that manufacturers are producing the drug as it was approved by the FDA; and there is a greater acknowledgement of and provision for the global nature of our drug supply.

The monograph of a drug is the description of the analysis that is required to demonstrate that a drug bound for market is the substance, purity, and concentration that has been approved by the FDA. The FDA’s role is to make sure drugs on the market in the U.S. are safe, and the USP’s role is to make sure monographs accurately describe the properties of each drug on the market in the U.S. The problem is that the monograph is generally written when the drug is approved and for some drugs, like heparin, that could be a long time ago. Heparin has been in use since 1935 (and was immediately approved by the FDA when the agency was formed in 1937). Through this process, we’ve realized that we have to be proactive in continuously developing new methods for testing as technology allows, instead of relying on old methods. And to do that, the FDA and USP had to work together in a new way. The USP is now going through the monographs of other complex, older drugs, and updating them, to make sure that they’re monitored better. And the FDA is helping them to identify those drugs.

The other regulatory change acknowledges the global nature of the drug supply. Now that we’re a global world, most of the heparin is being made in China. Yet before this crisis, the Chinese facilities were never inspected by the FDA because the FDA is a U.S. organization. But because the FDA allows imports of the drug, they can require inspections as part of that process. So now the FDA requires inspections of Chinese manufacturing facilities, and they accompany inspectors from the Chinese version of the FDA on inspections to ensure that manufacturers’ are compliant with good, safe manufacturing practices.

Q: What role did your lab play in both the immediate wake of the outbreak, and in the long term?

Our lab is skilled at the analysis of heparin. And one area specifically in which we played a major role is developing an NMR method that is at once highly sophisticated and could be used to routinely evaluate heparin. The pharmaceutical industry had concerns about using NMR to test heparin because it requires a sophisticated analyst— with a graduate-level education —to use it correctly. They needed a method that could be used by a technician, with a high school education, in a remote plant. We helped develop that method – a series of rules or guidelines that made it possible to use easily and consistently evaluate heparin using NMR.

Another role we played was in pushing the idea that we shouldn’t be testing for a single contaminant that showed up in the past, like OSCS, but that we should be testing for the universe of all possible contaminants of adulterants, because we don’t know what the next problem will be. To do that, you really have to understand what should be part of the drug and look for everything that should be there and anything that shouldn’t be there. And, although testing costs money, it all has to be done without changing the price of the drug itself. We advocated for an orthogonal approach, using a series of tests in which each individual test may not reveal an issue, but taken together they form a safety net that always functions. These tests are conducted before the crude material is certified by the USP as the drug heparin.

Q: What are the implications for both the safety of heparin, and for drug safety in general?

Our conclusion is that we as a group feel that the heparin drug supply is safe and, the way the monograph is written, its safety is ensured into the future. We have no expectation that someone could adulterate the drug again, and we cannot foresee a similar contamination crisis in the case of heparin. It now has the most stringent USP monograph of any drug out there. The authors worked for years to devise a method that we think cannot be circumvented.

This kind of proactive approach is going to improve the safety of other drugs. But we’ve had other crises of this kind and when we do, they always sort of come out of left field. I think we may not be able to eliminate all of them, but we want the frequency and severity of these crises to decrease. And our response to these crises each time should decrease the frequency and severity until we have safe drugs.