- We have posted several times, recently here and here, about the tragic case of suddenly allergenic heparin. Although heparin, an intravenous biologic anti-coagulant, has been in use for over 70 years, serious allergic reactions to it had heretofore been rare. Starting late last year, hundreds of such reactions, and now 21 deaths were reported in the US after intravenous heparin infusions.All the heparin related to these events in the US was made by Baxter International.
- We then learned that although the heparin carried the Baxter label, it was not really made by Baxter. The company had outsourced production of the active ingredient to a long, and ultimately mysterious supply chain. Baxter got the active ingredient from a US company, Scientific Protein Laboratories LLC, which in turn obtained it from a factory in China operated by Changzhou SPL, which in turn was owned by Scientific Protein Laboratories and by Changzhou Techpool Pharmaceutical Co. Changzhou SPL, in turn, got it from several consolidators or wholesalers, who in turn got it from numerous small, unidentified "workshops," which seemed to produce the product in often primitive and unsanitary conditions. None of the stops in the Chinese supply chain had apparently been inspected by the US Food and Drug Administration nor its Chinese counterpart.
- Most recently, we found out that the Baxter International labelled heparin was contaminated with over-sulfated chondroitin sulfate, a substance not found in nature, but which mimics heparin according to the simple laboratory tests used in the Chinese facilities to check incoming heparin. (See post here.) Further testing revealed that the contamination seemed to have taken place in China prior to the provision of the heparin to Changzhou SPL. (See post here.) It is not clear whether Baxter International or Scientific Protein Laboratories had inspected most of the steps in the supply chain, or even knew what went on there.
- The Baxter and Scientific Protein Laboratories CEOs did not seem aware of where they got the heparin on which the Baxter International label was eventually affixed. But one report in the New York Times alleged that Scientific Protein Laboratories would not pay enough for heparin to satisfy any sources other than the small "workshops."
We most recently commented on this case here. There have been some major developments since.
- The US Food and Drug Administration (FDA) inspected the Changzhou SPL plant, finding "significant deviations" from good manufacturing practices.(1) The FDA warning letter asserted "your firm lacked an adequate evaluation of the effectiveness of critical processing steps designed to remove impurities, and critical process parameters were not well defined or controlled." Also, "you received lots of material from an unacceptable workshop vendor that were used in your API [active pharmaceutical ingredient]." In addition, "Your system for evaluating suppliers of crude heparin material is ineffective to ensure that materials are acceptable for use." Finally, "Equipment used to manufacture heparin sodium USP is unsuitable for its intended use."(2)
- Scientific Protein Laboratories (SPL) provided a statement that "the contaminant found in certain lots of finished heparin product was not introduced in the manufacturing process at Changzhou SPL or SPL." Furthermore, "it is now clear that the suspect contaminant was introduced earlier in the supply chain in China and was widespread throughout the unrelated Chinese supply chain of many companies."(1)
- Baxter International claimed it had inspected the Changzhou SPL plant, per the Wall Street Journal, but a senior congressional investigator said, "Baxter conducted one audit of the Chinese plant, in September 2007, and concluded the plant was acceptable."(3) Furthermore, the New York Times reported that "the company sent one person who spent one day in the plant, Mr. Nelson said. Five months later, the F.D.A. discovered myriad problems, he said. 'It really is impossible for a plant to have fallen that far out of compliance in five months,' Mr. Nelson said."(4)
- The FDA seemed to concur that the contamination began in China before the heparin was supplied to Changzhou SPL. Per the Washington Post, "new evidence that links hundreds of serious adverse reactions and scores of deaths among patients given the blood thinner heparin to a man-made contaminant introduced during production in China. Janet Woodcock, director of the agency's Center for Drug Evaluation and Research, said that the contaminant has been traced to 12 different Chinese companies and has been found in heparin batches shipped to 11 nations, all of it from China."(5)
- However, Chinese officials disputed the conclusion that the contamination came from China, and instead suggested it occurred in SPL's plant in the US. Per the Washington Post, "Jin [Shaohong, an official with the Chinese National Institute for the Control of Pharmaceutical and Biological Products] said the Chinese government was conducting its own investigation of the heparin issue, which would include a visit today to Baxter's New Jersey processing plant, where officials hoped to collect additional samples of the tainted drug. He said the allergic reactions could have been created by impurities introduced when the imported raw heparin was refined by Scientific Protein Laboratories (SPL) of Wisconsin and then prepared for distribution in New Jersey."(5)
- Per Forbes, The CEO of Baxter International, Robert Parkinson, "said at a congressional hearing that it wasn't responsible for contaminated batches of Heparin, an anticoagulant used mostly in hospitals, and that it may have been a deliberate contamination." In particular, he said, "we're alarmed that one of our products was used, in what appears to have been a deliberate scheme, to adulterate a life-saving medication, and that people have suffered as a result."(6)
- Per the Chicago Tribune, the CEO of Scientific Protein Laboratories said "Chinese authorities have blocked his company's efforts to inspect suppliers that might have introduced foreign material into the company's heparin.'We started an inspection, but at a certain time the Chinese authorities took over a very significant inspection, and felt we should not be interfering with an inspection by the Chinese authorities,'..."(7)
- Congresspeople blamed the FDA. According to the Wall Street Journal, Rep. John Dingell (Democrat - Michigan) said, "Our citizens can no longer trust their food, drugs, or medical devices are safe when the FDA says they are."(3)
So, everyone is to blame, and practically every organization involved blames another one.
Congress blames the FDA, but congress is responsible for funding the FDA insufficiently for it to inspect all the foreign plants that now supply active pharmaceutical ingredients to the US, and for funding the FDA with "user fees" that may have lead many in the FDA to view the drug companies, rather than the American public, as their clients.
The FDA blames Changzhou SPL and its suppliers, but the FDA is responsible for the safety and purity of US drugs, and therefore has responsibility for the entire supply chain responsible for drugs prescribed in the US.
Baxter International blames nefarious contaminators, but Baxter is responsible for making sure that the drugs it sells are pure and safe.
Scientific Protein Laboratories blames the contaminators, and the Chinese government for blocking attempts to inspect its suppliers, but SPL is responsible for making sure the active pharmaceutical ingredient it sells to pharmaceutical companies are pure and safe.
The Chinese government blames the American companies, but the Chinese government ought to be responsible for products exported from its country.
I could not find any evidence that any leader of any involved organization assumed any responsibility for anything that went wrong during this fiasco. It reminded me of stories that when adolescents are caught by the US police, they often blame their offense on "some dude," otherwise not identified.
This case is an amazing example of global health care dysfunction. Each organization listed above, of course, bears some but not all responsibility. Although the leaders of these organizations are supposedly chosen because of their ability and willingness to take responsibility (and the leaders of the US corporations are paid very handsomely supposedly for taking such responsibility), all they have done so far is try to avoid responsibility, and blame "some dude" for the problems.
And this goes on in an era where physicians are constantly badgered about how they must be responsible, be accountable, and be paid for their "performance."
When we get some adult leadership of health care organizations who are willing to take responsibility and be accountable for their organizations' actions, maybe we will have a more functional health care system. Such leaders might find out that bearing responsibility and being accountable would involve putting patients before profits, or ego. (I also bet adult leaders with more secure egos might be willing to work for less than the millions a year now required by the "imperial CEOs" of US health care corporations.)
Finally, as a reminder of the consequences of the current dysfunction, the death toll for the case of the contaminated heparin is now estimated to be 81.(4)
1. Japsen B. FDA: heparin supplier's Chinese factory 'unsuitable.' Chicago Tribune, April 21, 2008. Link here.
2. FDA. Letter to Dr Yan Wang, General Manager, Changhzhou SPL Company, Ltd. April 21, 2008. Link here.
3. Favole JA, Boles C. Lawmakers seek heparin answers from FDA and Baxter officials. Wall Street Journal, April 29, 2008. Link here.
4. Harris G. Heparin contamination may have been deliberate, F.D.A. says. New York Times, April 30, 2008. Link here.
5. Kaufman M. New data link heparin deaths to Chinese batches, FDA says. Washington Post, April 22, 2008. Link here.
6. LaMotta L. Heparin: the plot thickens. Forbes, April 29, 2008. Link here.
7. Japsen B, Greising D. Baxter CEO tells congress heparin tampering was deliberate. Chicago Tribune, April 29, 2008. Link here.