Updated to address incidents of adulteration
istockphoto.com The U.S. Pharmacopeia (USP) announced last month that it has updated its standards for the blood thinner heparin sodium and the sweetener glycerin, signaling a desire to better regulate drugs produced overseas.
The revisions were made to address instances of adulteration that have resulted in hundreds of deaths, said Roger Williams, MD, chief executive officer of USP. These include a series of international incidents in which glycerin was adulterated with diethylene glycol over several decades and heparin was adulterated with oversulfated chondroitin sulfate (OSCS) in 2007 and 2008.
"In much of the world today, safety nets are flawed. … The problem is that we are now receiving medicines from overseas in dramatically increasing ways that challenge our own safety nets," Dr. Williams said at a Feb. 4 news conference. An estimated 60% to 80% of pharmaceutical ingredients, as well as an increasing percentage of finished drug products, now come from China and India, Dr. Williams noted.
The updated monograph now includes improved analytical methods for measurement of heparin activity and detection of OSCS, the contaminant implicated in more than 200 deaths last year, said Darrell Abernethy, MD, PhD, the USP’s chief science officer. The new standard for heparin will take effect in August after a comment period, and the standard for glycerin will take effect in May. Associated reference standards for other potential contaminants are also in development.
Dr. Abernethy said the contamination of both glycerin and heparin were apparently cases of economically motivated intentional adulteration by substituting a cheaper ingredient for the nominal active ingredient.
"For financial gain, there have been foreign materials put into drugs," Dr. Abernethy said, "and it’s turned out that those foreign materials are toxic. In both of these cases, they had the potential to kill people."
The FDA requested revisions to the USP monographs for the two substances, he said. In the case of glycerin, the request was to set a limit for the level of diethylene glycol, while in the case of heparin, it was to detect the presence of OSCS.
Dr. Abernethy called the use of OSCS as a substitute for heparin "very clever criminal activity done by very sophisticated chemists" who knew that the sheep plasma clotting assay, the existing standard test for heparin, would not detect the inexpensive contaminant. Chondroitin sulfate is a dietary supplement that is extracted from the cartilaginous tissue of cows, pigs, and sharks; heparin is extracted from pig intestines.
Dr. Abernethy said an epidemic of swine virus in 2006 in China—the source of most of the world’s heparin active pharmaceutical ingredient—"set the stage for the current catastrophe." The drop in the pig population caused materials for heparin to become "many-fold more expensive," he said, and the search for cheaper materials to use in heparin production apparently led to the use of OSCS. When the toxicity of the adulterated heparin was detected in 2008, officials realized that the entire worldwide supply of the essential blood thinner was at risk, leading to the call for the heparin monograph update.
He noted that this presented a challenge, because heparin is a complex substance. "When one is trying to identify a chemical that shouldn’t be in there, you’re looking among a large number of potential molecules," Dr. Abernethy added.
A Proactive Stance
Image courtesy of the U.S. Pharmacopeia
The chemical structure of oversulfated chondroitin sulfate, a substance used in China to adulterate heparin. Moheb Nasr, PhD, director of the Office of New Drug Quality Assessment at the FDA’s Center for Drug Evaluation and Research, praised the international collaborative effort of the USP, which worked with industry as well as standards organizations in Europe and Japan in revising the standards.
"It’s a global problem that demands global leadership and a global solution," Dr. Nasr said. He said that in the future, the FDA and USP must take a more proactive stance to assure the purity and quality of the drug supply, rather than just reacting to cases of adulteration.
USP officials agreed, noting that one way to do that is by establishing a spectral library for pharmaceutical ingredients, a project that is currently in the pilot stage.
"It’s an arms race, finding the next contaminant, and it’s a needle in a haystack," said William Koch, MS, PhD, the USP’s chief metrology officer. "We have to find a better way of identifying what a material is rather than what it isn’t. The thought behind the spectral library is to develop the signatures, or the fingerprints, or the groups of spectral information that uniquely define a given molecule or a given product."
He said the USP is currently undertaking a pilot library project using Raman spectroscopy, which may be expanded to other wavelengths in the electromagnetic spectrum in the future. —Tim Donald