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By Agnes Shanley, Paul Thomas and Michele Vaccarello Wagner with Emil Ciurczak
The detective work required to determine the contaminant was challenging, particularly since there was no developmental data available on the drug, says Moheb Nasr, PhD, director of FDA’s Offce of New Drug Quality Assessment (ONDQA), who led a team that had to, essentially, recreate the QbD data for heparin. “We had to start from scratch, conducting very detailed quality risk assessment of all aspects of the manufacturing process and the product characterization in order to identify what could be the potential cause or causes of this problem,” he says.
Troubleshooting would have been much easier had the right information been on hand. Instead, the team had to redevelop information from the application, with additional information from reviewing the drug master file (DMF), to restructure the type of information needed. Essentially, they had to remap the entire development, manufacturing and product characterization. A systematic, scientific approach was prudent rather than “shooting in the dark” with different analytical methods, Nasr says. Risk assessment was a critical part of the process, Nasr explains. It confirmed that the contamination stemmed from manufacturing quality problems and allowed the team to rule out any impact from the clinical side.
The team used fishbone diagramming to look at every possible impact, whether in raw material, chemical reagents, equipment, manufacturing process or testing methods. “We started doing testing on the biological side and the analytical side, trying to decide what could be an external contaminant that acts like heparin in some ways and has some structural similarities but also has differences, and we focused on that,” he says. Results of the research were published last April in Nature Biotechnology and the New England Journal of Medicine.
The main finding: the source of the contamination was over-sulfated chondroitin sulfate (OSCS), a common dietary supplement, and the adulteration was likely intentional.
As a result of these efforts, FDA contacted the USP and asked it to revise its monographs on heparin; these were published in June. Instead of the ambiguous tests previously required, manufacturers now must subject heparin to testing via electrophoresis and nuclear magnetic resonance (NMR). Rather than broadening efforts to other biologicals, USP has taken a focused approach, restricting monographs to heparin products, striving to balance overly prescriptive measures and potentially expensive analytics with product quality.
“My favorite analogy is with the International Olympic Committee, which tries to identify foreign substances that athletes might choose to take,” says Darrel Abernethy, CSO for USP. “It has 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.”
There will be no silver bullets, he says, or “easy analytical solutions to allow you to look for things when you don’t know what they are yet.” He adds, “We could, in theory, design tests to guarantee the purity and identity of every material known to man, but the costs would be prohibitive, and everyone would have to have a 900-megaherz NMR and the latest, greatest mass spec.”
The goal, he says, is methods that will allow one to unequivocally identify the material of interest with orthogonal tests—physical tests such as hardness, density or melting point, chemical tests such as high-pressure liquid chromatography, nuclear magnetic resonance or mass spectrometry, and a biological test for active materials. “Any adulterant would likely not pass all three or four orthogonal tests,” he continues. USP’s monograph establishes an initial method that does physical and chemical as well as biological characterization, as an interim measure to protect the public from the current contamination, he says, adding that advisory groups are evaluating a broader range of methodology to meet requirements and specify material purity in physical, chemical and biological terms.
Measures by FDA, USP, and heparin suppliers and manufacturers to establish greater control over the product have been “pretty impressive,” according to Jian Liu, PhD, a leading heparin researcher and associate professor at the University of North Carolina School of Pharmacy. Nevertheless, Liu says, the current way of making heparin will always be vulnerable to environmental (e.g., porcine disease) and human (e.g., purposeful adulteration) factors. Three main factors are involved in control of the supply, Liu notes: the global pig supply, the heparin harvesting and purification process, and the analytical control. Like USP’s Abernethy, Liu draws parallels with antidoping procedures for Olympic athletes.
“You have to know what you’re looking for,” he says. But just as athletes find ways to circumvent drug tests, there may always be heparin contaminants that will fall outside of materials inspection parameters. FDA “jumped the gun” in suggesting that it had a handle on the heparin cases and the root of contamination, says Jawed Fareed, PhD, professor of pathology and pharmacology at Loyola University Medical Center (Maywood, Ill.) and whose group has been researching heparin for 30 years. Fareed suspected deliberate contamination the minute the news broke, but also believes that multiple contaminants could be involved beyond OSCS and that FDA and other researchers still know little about the physiologic mechanisms that led to the deaths.
Fareed notes that the Agency attributed just 3 of the 83 reported deaths to heparin containing OSCS, and for those has not provided verifiable supportive data about the deaths. The NEJM article is speculative and over-interpreted, he says. USP deserves credit for its efforts to update its heparin monographs, Fareed says. “They’ve held several important meetings and have discussed the contaminant quite extensively, and expressed remorse over the limitation of the methods USP has been practicing over the past 40 or 50 years,” he says. Fareed and colleagues at Loyola continue to search for answers. “We have learned that it is easy to contaminate heparin with biological substances,” he says. The popularity of low-molecular-weight heparins makes them prime targets for contamination, as are other animal sources, particularly bovine, as porcine stocks decline, Fareed says. “What I’m trying to say is the saga will continue, and people will find other things to contaminate heparin which are not so easy to detect.” USP’s monographs spell out the use of NMR and capillary electrophoresis as tests for heparin specifically.
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