Analytical Chemistry Comes To The Fore | May 12, 2008 Issue - Vol. 86 Issue 19 | Chemical & Engineering News
Volume 86 Issue 19 | p. 37
Issue Date: May 12, 2008

Analytical Chemistry Comes To The Fore

Testing is critical for preventing and detecting contamination of drugs, food
Department: Science & Technology
Contamination
Samples of heparin were tested in Ram Sasisekharan's lab at Massachusetts Institute of Technology.
Credit: Karthik Viswanathan/MIT
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Contamination
Samples of heparin were tested in Ram Sasisekharan's lab at Massachusetts Institute of Technology.
Credit: Karthik Viswanathan/MIT

IN THE PAST TWO YEARS, several instances of drug or food contamination with a harmful ingredient have made the news: oversulfated chondroitin sulfate (OSCS) in heparin, melamine and cyanuric acid in pet food, and diethylene glycol in cough syrup. All have had lethal consequences. Although the investigations into the sources of contamination are not yet complete, each case might have involved someone deliberately replacing an ingredient with a less expensive material. And not just any cheap alternative, but one known or designed to evade standard analytical tests.

The chemical detective work that uncovered the contaminants in heparin and pet food is chronicled in the following pages. OSCS is a chemically modified version of a cartilage-derived glycosaminoglycan. The altered structure mimics the properties of heparin in regulatory tests, including blood clotting assays. Melamine does an end run around the standard test for protein in animal food—the Kjeldahl test—because the technique really amounts to a test for nitrogen. When melamine is analyzed in the same way, it releases large amounts of nitrogen.

The question increasingly facing drug and food manufacturers and regulatory agencies is how to guard against smart, chemically savvy saboteurs intent on thwarting existing testing protocols. On the subject of the Kjeldahl test as a means to determine protein content, "As long as you're playing by the rules it's a very good test for total nitrogen," says Roger L. Williams, chief executive officer of U.S. Pharmacopeia (USP), the pharmaceutical standards-setting organization in the U.S. Trying to predict what someone would do who's not playing by the rules, however, is "akin to looking for a needle in a haystack when you don't know that you're looking for a needle."

Some of the problems with contamination bypassing quality-control efforts are historical; development of heparin, for example, dates to the 1950s, before the advent of modern chromatographic or spectroscopic techniques. "I like the idea of modernizing tests," Williams says. But to update protocols, USP would need companies to chronicle their internal processes and contribute materials for evaluation.

The case of diethylene glycol is one in which USP is trying to be proactive. Instances of diethylene glycol substitution go back to the 1930s; generally, it was used in place of glycerin, a nontoxic ingredient commonly used in drugs, food, and health care products. Unless someone in the manufacturing process took the step of testing the raw materials, the substitution escaped notice.

In 2006, hundreds of people died in Panama after ingesting cough syrup made with the adulterant, and in June 2007, the Food & Drug Administration initiated recalls of similarly tainted toothpastes imported from China. Diethylene glycol substitution has been an issue frequently enough that USP is updating testing protocols for a number of ingredients, including sorbitol and polyethylene glycol, considered vulnerable to adulteration.

Even if USP were able to modernize all testing protocols, that circumstance would "probably never preclude some really smart people from figuring out the limitations of the tests," notes William F. Koch, who oversees laboratory test development at USP. As a result of the identification of OSCS in heparin, FDA now requires that the drug be tested by nuclear magnetic resonance spectroscopy. The particular flag for OSCS is a peak in the NMR spectrum from an acetyl group. "It wouldn't be too much to imagine that someone would then do something to the contaminant so that it wouldn't have that peak," Koch says. "Then we're back at square one."

But even that is not USP's biggest fear. "I have to say what really worries me is people who don't want to cheat but want to cause harm," Williams tells C&EN. In theory someone could, for example, lace a material with mercury. The mercury might then go undetected because no one expects it to be there, and thus, there is no test for it. Testing all products for all possible contaminants is clearly unrealistic, he notes.

In testimony before the House Energy & Commerce Subcommittee on Oversight & Investigations on April 29, Robert L. Parkinson Jr., CEO of heparin maker Baxter International, said that "resting on old standards—even ones that have worked for decades—is no longer enough." Baxter has convened a group of scientists dedicated to considering "how would-be counterfeiters or saboteurs might threaten our supply chain, much the way that law enforcement or national security agencies have groups dedicated to thinking like potential enemies," he said.

The stakes are high, both in terms of health and safety and in terms of the financial health of companies facing lawsuits over contaminated products. Analytical labs may struggle to adapt to new pressures and processes, but the work they do has never been more important, as evidenced by the following tales of their roles in the heparin and pet food investigations.

 

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