Top 10 Medical Stories of 2008: No. 1

In separate tampering conspiracies, Chinese manufacturers spiked crude heparin and infant formula with artificial contaminants. The respective contaminants, oversulfated chondroitin sulfate (OSCS) and melamine, were most likely known to dissemble the products' key ingredients, heparin and milk protein, respectively, in routine testing. The presumed motive behind the acts is economic, given that both contaminants are cheap additives that reduce the costs of the manufacturing processes. At least 81 Americans died who received the tainted heparin, and the contaminated formula killed at least 4 Chinese infants.

Heparin Scandal

At the end of 2007 and escalating into 2008, an increasing number of allergic-type reactions and deaths in the United States were associated with the intravenous administration (particularly bolus administration) of Baxter's heparin products. Consequently Baxter recalled a number of its heparin products in February, and in April, the FDA reported that a heparin contaminant, OSCS, was the likely cause of 81 American deaths and hundreds of adverse reactions to the suspect product.

With nearly unprecedented speed, 2 international groups of scientists simultaneously published their investigations of the contaminated heparin in the NEJM and Nature Biotechnology in April. It was determined that OSCS, a synthetic product,* which exhibits antithrombin activity in vitro, had triggered hypotension and other adverse reactions by activating the kinin-kallikrein pathway and by generating anaphylactoid complement proteins. Animal studies suggested that some individuals, like those undergoing dialysis, were more vulnerable to the contaminant's hypotensive effects—which may explain the varied reactions to the tainted product.

Baxter's heparin was traced to its Chinese supplier, Scientific Protein Labs, which apparently bought its crude material from a number of Chinese heparin "workshops." In February, the plant was cited by the FDA for several "significant deviations" from good manufacturing processes; however, when and where OSCS was introduced into the heparin remains a mystery. For its part, Baxter got out of the heparin business entirely, and Chinese officials, not surprisingly, have been less than conciliatory in the FDA's investigation.

* Chondroitin sulfate, an essential component of animal cartilage that is marketed as a nutritional supplement for joint pain, was intentionally altered with additional sulfate groups to confer anticoagulant properties to the molecule. The contaminant is structurally identical to Arteparon, an intramuscular drug that was marketed in Europe for the treatment of individuals with degenerative joint disease. Arteparon has been shown to induce an allergic-type response and was withdrawn from the market because of patient deaths, most likely due to thromboembolic complications.

For more on heparin production and the heparin scandal, visit...

• Where Does Heparin Come From?
• WSJ: Product Variations Found in Baxter's Chinese-Made Heparin
• APP: Aiming for a Heparin Monopoly?
• The WSJ Has Gordon Fairclough in China
• APP's Soon-Shiong: No Stranger to Suspect Chinese Suppliers
• More on Heparin Extraction: Zzzzzz
• Heparin Supplier Changzhou SPL: FDA Inspection Form Now Available
• "Contaminant" in Baxter's Recalled Heparin
• Japanese Companies Recall SPL Heparin
• Baxter: No Endotoxins in Recalled Heparin
• NYT: Counterfeit Heparin Likely Altered Chondroitin Sulfate
• More on Faux Heparin Contaminant
• FDA Updates Likely Heparin Death Toll
• Chinese Official: Heparin Contaminant Not Cause of Adverse Reactions
• FDA to China: Prime Suspect Is Heparin Contaminant
• Actions of Heparin Contaminant Revealed
• Heparin Contaminant Not Naturally Produced
• China Is Being, Well, China in the Investigation of Tainted Heparin
• Synthetic Heparin on the Distant Horizon

Also the WSJ provided terrific gross-out pictures of crude heparin production in China, which may or may not have been a part of SPL's pipeline.

Melamine Returns

After melamine was found last year in Chinese-imported wheat gluten, which was used to make domestic pet food, the ersatz protein and renal toxin returned in Chinese-made infant formula. According to news reports, workers at a Chinese baby-formula company, Sanlu, and several milk-collection agencies conspired to spike diluted milk with melamine, which artificially raises the protein level of the product.

WHO reported that Sanlu received related complaints of illness associated with its formula as early as March of this year and was urged in early August by its majority owner, New Zealand's Fonterra Cooperative Group, to initiate a product recall. However, Sanlu (in possible collusion with Chinese government officials) reportedly delayed the recall to avoid a PR scandal during the upcoming Olympic Games in Beijing.

At last count, melamine-tainted baby formula is believed to have sickened more than 53,000 Chinese infants and caused at least 4 infant deaths over the course of this year (see update below). Melamine is known to form poorly soluble crystals in renal tubules, when combined with its byproduct, cyanuric acid.

This year's melamine scandal widened, following concerns that tainted milk was incorporated into other food products like ice cream and chocolate, some of which were exported. In response, the FDA assured consumers that domestically made formula was safe and issued its guidance for acceptable (miniscule) melamine levels in certain products.

According to some reports, eliminating melamine from the Chinese food supply may be next to impossible, because of the difficulty of ensuring the purity of livestock feed in the country. Chinese authorities issued a standard for melamine levels in feed last year; however, melamine was recently discovered in eggs and fish feed in Hong Kong.

For more melamine reading, visit...

• The Return of Melamine
• Cobbled Update of Melamine in Chinese Baby Formula
• Melamine Contamination Expands
• Update on Melamine in Chinese Food Supply

01/01/09 update: Yesterday's NYT reported that the former chairwoman of Sanlu pleaded guilty to selling tainted baby formula. The paper indicates that "consumer complaints about Sanlu’s milk came in as early as December 2007." In court, Sanlu's chairwoman admitted that she knew her company was selling contaminated formula by May 2008 but did not report the problem to local officials until August. Sanlu's formula reportedly sickened nearly 300,000 Chinese children and caused the deaths of 6.

Readers are also referred to "Melamine and the Global Implications of Food Contamination" in the December 25th issue of the NEJM and the FDA's periodically updated web page, "Melamine Contamination in China."