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By Agnes Shanley, Paul Thomas and Michele Vaccarello Wagner with Emil Ciurczak
A Heparin Timeline
Heparin is an anticoagulant that has been used for more than a half-century to prevent unwanted clotting in post-surgical patients and those on dialysis. In January of this year, Baxter International, which produces roughly half of the U.S. heparin supply, recalled nine lots of product after news broke of a spike in deaths in patients taking heparin. The cause: hypotensive/allergic reactions to the medication. A few weeks later, Baxter recalled all remaining lots.
In March, FDA attributed the source of the contamination as over-sulfated chondroitin sulfate, a common dietary supplement. The degree of contamination ranged from 2% to 50% in the samples FDA tested. As the over-sulfated version was not known to occur naturally and was significantly cheaper than raw heparin, deliberate manipulation of the product was suspected.
The contamination source proved to be a plant in Changzhou, China, owned by Wisconsin-based Baxter supplier Scientific Protein Laboratories (SPL). SPL subsequently passed the blame onto its vast network of suppliers. FDA admitted that it had failed to inspect the Changzhou plant, as it should have before the drug was approved for sale in 2004.
Though no official source of the contamination has been found, FDA has worked to clear up several issues. It has announced that it is opening an office in China (as well as India), will be dedicating more inspectors to the country, and has received funding from congress to do so. It has also coauthored published research—namely a New England Journal of Medicine article in April—that outlines the scientific rationale behind the OSCS deaths.
In June, the U.S. Pharmacopeia (USP) released revised monographs for heparin sodium and heparin calcium, accompanied by two new and two updated official USP Reference Standards, giving industry (and FDA) improved guidelines for assurance testing heparin sodium and calcium drug substances.
For now, the Agency says, the heparin supply is under control and sufficient testing methods are in place to keep it that way. “The heparin supply in the US is being tested and is free of this contaminant,” Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research (CDER), has said.
“We now have a mechanistic link, and we are confident that this contaminant does trigger the adverse events seen, so we feel the adverse reactions will now cease.”
This year, the world was riveted by coverage of the recall of several lots of the blood thinner, heparin. Not only were patient deaths connected to tainted heparin, but the case became the subject of Congressional hearings, triggering severe criticism of the FDA and the drug industry. At a time when the U.S. is outsourcing more drug development and manufacturing offshore, the recall and its aftermath made more people doubt the safety of APIs and other raw materials made in China. The events of the heparin saga are well known (Box, right).
Rather than rehash the story, this article considers the practical lessons—in cGMP, vendor auditing and Quality by Design (QbD)—that the pharmaceutical industry might draw from this case. They’re lessons that must be learned fast, because, as pharmaceutical supply chains become more global, complex and opaque, heparin may be just the tip of the iceberg. A survey by Pharmaceutical Manufacturing and Marsh Consulting Group suggests that supplier auditing and supply chain safety are nowhere near where they need to be. And experts say the climate is such that another crisis is within reason. “It’s going to get worse before it gets better,” predicts Warren Perry, compliance advisor for Qumas Consulting (San Francisco). Research into the root causes of heparin contamination suggests intentional tampering, and in a way that differs somewhat from earlier cases of tainted drugs.
For one thing, several lots of contaminated product still passed basic analytical and compendial quality tests, suggesting that whoever contaminated the compound had a sophisticated understanding of the limits of both. The heparin case also occurred at a time when the boundaries separating counterfeit from substandard drugs are blurring. “The level of sophistication of counterfeit drugs has gone up,” says Patrick Lukulay, director of the U.S. Pharmacopeia’s (USP’s) Drug Quality and Information Program, designed to strengthen pharmaceutical QC and QA in developing countries. “Previously, in Africa and in Asia, counterfeit products were comprised of either nothing in the capsule or starch or some inferior raw material. Now counterfeiters are putting the right stuff in there, but inferior quality material that doesn’t meet the pharmacopeial standards that you’d expect for that product.”
Recreating the Wheel
Heparin provides justification for the need for Quality by Design practices within the industry. When news of the heparin deaths first broke, FDA, USP and academic scientists were called upon to help determine what the heparin contaminant was and how it got there, and whether analytical and compendial tests were sufficient to protect the public (Box, below).
Sleuths on the Case
The analytical sleuthing to determine the nature and source of the heparin contaminant was impressive. Ram Sasisekharan, PhD, from MIT, at the behest of the FDA (in the person of Moheb Nasr), spearheaded a joint effort to discover what, if anything, was wrong with a number of lots of heparin, distributed by Baxter Healthcare. Work was already started by Dr. Nasr’s group at CDER, who had already used capillary electrophoresis (CE) and heparinases; they demonstrated that something was in the samples that did not qualify as heparin. He asked Sasisekharan to qualify exactly what the adulterant(s) was. One problem, of course, is that heparin is derived from pigs, and natural products are never exactly the same.
Heparin is mostly a polymer of disaccharides (two-ring sugars) with each unit containing uronic acid and glucosamide. When the various stereoisomers, sugars and sulfation patterns are combined, there are potentially 32 disaccharide units to be included in what is labeled “heparin.” The size of the task suggested two more research groups be
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