Contamination of the worldwide heparin supply, which resulted in a substantial increase in adverse events and an estimated 81 deaths in the US, appears to have been a deliberate act to increase profits in Chinese workshops.
Speaking at a Congressional hearing on the debacle held on April 29, 2008 [1], David Nelson, an investigator for the Committee on Energy and Commerce, noted that the contaminant, oversulfated chondroitin sulfate, was apparently added to crude heparin in China at some stage in the production process by parties that have yet to be identified. "This contaminant has anticoagulant properties that mimic heparin, but at a much lower production cost–about $20/kg vs $2000/kg to produce crude heparin. Accordingly, there is speculation that the contaminant was added deliberately to increase profits for the workshops and/or consolidators that ship the crude material to Changzhou SPL, SPL Wisconsin, and other heparin [active pharmaceutical ingredient] API producers," he reported.
Nelson said the heparin case "illustrates both the best and the worst of the FDA's performance." He stated that once the increased adverse events were identified, the FDA acted swiftly, but "while the FDA may respond quickly to a crisis when the danger to the public health is known, committee staff found that its routinely poor performance as a regulatory agency . . . invites catastrophe and may have contributed to the tragic use of contaminated heparin on patients in the United States."
FDA Shortcomings
He said shortcomings identified in the FDA included the fact that it failed to inspect the Chinese facility, Changzhou SPL, prior to approving Baxter's application to source its API from that plant; its "woefully inadequate" information technology systems that resulted in identification of the wrong plant for inspection; and its lack of a systematic rationale for ensuring plants had been inspected that allowed that mistake to go uncorrected.
"Intuitively, one would assume that among the most important criteria for prioritizing preapproval inspections would be geography, complexity of the manufacturing process, and sensitivity of the final drug product," Nelson commented. He said that all three of these "commonsense criteria" should have dictated that inspection of the Changzhou plant be given the highest priority. But unfortunately, this was not the case.
Baxter Also to Blame
Nelson also laid some of the blame with Baxter. "What due diligence did Baxter perform to determine that it could safely manufacture heparin API for the US market before using this facility?" he asked, adding that committee staff found several facts that should have alerted Baxter to potential problems but that appear to have been ignored. "Baxter's own records indicate that they were aware that the plant had never been inspected by FDA. It seems very odd that Baxter accepted the risks of using this facility to obtain the API used to manufacture a sterile biologic without an FDA inspection," Nelson reported, adding that when the company did eventually inspect the plant, it did not report any problems. He said this raised "troubling questions" about the FDA relying on third-party inspection or self-inspection as a substitute for its own efforts.
"An FDA Woefully Lacking"
Chair of the Committee on Energy and Commerce, Rep John Dingell (D-MI), said his staff's investigations had revealed "an FDA woefully lacking in the personnel, effective policies, and the will at the highest level to perform the duties entrusted to it by the Congress and the American people." He added: "Our citizens can no longer trust that their food, drugs, or medical devices are safe when the FDA says they are.
"I hope this hearing, as well as the legislation that this committee is now working on, will not only protect the American people but also ensure that those dedicated FDA employees who serve on the front line are able to do their jobs more completely and effectively."
Would Inspection of the Plant Have Made a Difference?
Janet Woodcock (director of the FDA's Center for Drug Evaluation and Research) said there was no justification for the theory that contamination of heparin would have been prevented if the FDA inspection of Changzhou SPL plant had occurred in 2004. "Intentional contamination is difficult to detect during an inspection and, in any case, the contamination appears to have begun long after the inspection would have been completed. Moreover, heparin contamination is not limited to product from Changzhou SPL, so timely inspection of that one firm would probably not have prevented the problem," she stated. She added that process improvements under way will prevent future data-entry errors like the one that led to the wrong plant being inspected.
Woodcock noted: "Unfortunately, there are sometimes factors beyond our control that affect the integrity of a product, such as when someone intentionally contaminates a product. We hope that systems in place would discourage or detect such manipulation, but it would be disingenuous for the FDA to suggest that it would be feasible for the agency to inspect every single production facility and every single product and that such inspection would discover every single problem."
Extra Funding for Foreign Inspections
Under questioning, Woodcock said the FDA will spend $11 million this year on foreign drug plant inspections but that it would cost an additional $250 million each year to inspect every such plant every two years, which it has been suggested should be done. Chair of the Subcommittee on Oversight and Investigations, Rep Bart Stupak (D-MI), said that new proposed legislation would allocate about $300 million to the FDA for foreign inspections.
Committee on Energy and Commerce Subcommittee on Oversight and Investigations. The heparin disaster: Chinese counterfeits and American failures. April 29, 2008. Available at: http://energycommerce.house.gov/cmte_mtgs/110-oi-hrg.042908.Heparin.shtml
Review by Dr. Ramaz Mitaishvili
