According to a number of reports in the Washington Post, New York Times and elsewhere, understaffing and underfunding at the FDA has made them incapable of performing those tasks adequately.
We have heard quite a bit over the last year about toxin-tainted pet foods and children's toys containing high levels of lead coming into the United States from China's unregulated industrial system. Without pollution standards, work safety standards, or quality control standards, China's industries are virtually beyond any form of serious oversight at this point in time. In contrast with stories about tainted pet food and lead-filled children's toys, problems with tainted pharmaceuticals and pharmaceutical ingredients coming out of China have gotten somewhat less attention, in part because most adverse reactions and deaths had occurred outside the US.
That is until a number of heparin-related deaths in the US were reported recently in the Washington Post. The number of deaths in the US due to tainted heparin coming from China is still in question, but the death toll ranges from 19 to over 40 since last Fall. Heparin is a complex carbohydrate containing large amounts of sulfur which has been used for decades to prevent blood clotting during operations, patient dialysis and when collecting blood. Heparin if found at high levels in certain tissues of the body, and pharmaceutical grade heparin is typically extracted from cow lungs and pig intestines.
The story begins in 2006, in Guangdong province on the highly industrialized southeast coast of China. Pig farmers were noticing that their pigs were getting very sick. Pregnant females would deliver sick or dead piglets, and infected young pigs developed a number of respiratory symptoms, and characteristic skin and ear discoloration. The pathogen that caused the outbreak is apparently a virus known to cause “blue-eared pig disease” as farmers call it, and “porcine reproductive and respiratory syndrome” as it is known to scientists. Most Chinese pig farmers call the new illness “high fever disease”. The disease spread rapidly among pig farms along the eastern coast of China throughout 2006 and into 2007. The Chinese government has not released statistics on the magnitude or scope of the outbreak, and initially they resisted all requests for virus samples from scientists around the world.
This particular viral disease was first identified in the United States in 1987, and then in several other countries in 1991 including the Netherlands and Canada. The original virus strains have now spread worldwide, but the those strains isolated in North America and Europe were usually not fatal for infected pigs. Based on genetic analyses, the outbreak of the virus in China appears to involve a much more deadly variant of the virus. Because it affects the pigs reproductive systems and respiratory systems more severely than other organs, the virus is known as PRRS, standing for “porcine reproductive and respiratory syndrome”, as noted above. The newly mutated form of the PRRS virus arose in the same area of China’s highly industrialized southeastern coast (Guangdong province) that saw the rise of the mutated avian flu virus. As a scientist, this makes me wonder if industrial pollution in the food and water fed to livestock may be compromising the animal’s immune systems, and making it easier for viruses to mutate and spread throughout large, crowded herds with diminished immune responses. But I digress from the story.
The story takes a turn in 2007 as pig populations declined precipitously in China. It is not known outside of China how many pigs had to be destroyed in an attempt to prevent the spread of the disease to the entire country. But one estimate reported in the Public Library of Science estimated that over 2 million pigs were infected. Reports of the disease surfacing in nearby countries suggest that any effort to at containing the outbreak were unsuccessful. Pork prices in China skyrocketed and the decline in the size of pig herds led directly to the problems that surfaced in 2007 with tainted heparin produced in China.
Heparin is present in granules in cells of the body called “mast cells”, which are found in pig intestines in large numbers. The process of making heparin in China begins at small farms and larger slaughterhouses where pigs are processed for pork products. The intestines are collected and can be processed by steam or by chemical extraction methods which yield a crude heparin product that must be processed further before use in humans. As pig populations in China plummeted through 2007, a severe shortage of pig intestines threatened the heparin supplies.
As reported in the Wall Street Journal: “Wang Xiangyang, a factory director at the Zhaoyang Intestine & Casing Factory in Shandong, for instance, says his company has been forced to use sheep innards in addition to pig intestines because of a shortage of pig supplies. "We can't get enough pig intestines," Mr. Wang says. "There are a lot of people around who need them."
The company that produced the tainted heparin is “Scientific Protein Laboratories” (SPL), a Wisconsin based company that has supplied heparin to the US for 3 decades. In 1999, SPL partnered with a Chinese firm and set up a processing plant in Changzhou China to collect and process heparin locally. The plant was approved by the FDA to provide heparin to the US in 2004, despite the fact that the plant in Changzhou had not been FDA inspected. The FDA admitted last month that it had violated its own policies by neglecting to inspect SPL’s Chinese plant before approving the drug for sale in the US.
Most of the raw heparin supply comes from small, family-run workshops near slaughterhouses, which send the extracts to larger "consolidators" before they reach refining plants like the one owned by SPL in Changzhou, near Shanghai. It is still unclear where the problem originated, but it most likely began in the family-run workshops that extracted the crude heparin from hog intestines. As the supply of pig intestines declined in 2007 those family workshops more than likely had severe difficulty in meeting supply quotas. They were faced with the choice of informing SPL in Changzhou that they could not meet demands for the crude extract, and lose much-needed income, or they could try to find a cheap heparin substitute to spike the extracts with. This second option would be difficult unless the substitute purified and tested as though it were heparin.
The two graphs here are so-called “mass spectrograms” from the FDA of a tainted heparin sample (top) and an uncontaminated sample (below). In mass spectrometers compounds are ionized, and the ions separated based on their mass. Ions of different mass show up at different positions along the graph. The height of the peaks on the graph are proportional to the number of ions detected.
As you can see from FDA's own analysis of a tainted heparin product there is nearly twice as much of the contaminant (“additional feature”) as there is actual heparin. However, heparin and the contaminant are very near one another in terms of size so they come out very close to one another on the mass spectrograms. The fact that the compound was chemically similar to heparin, and did appear to have blood thinning properties, made it very difficult initially for the FDA to determine what the contaminant was. Obviously, someone along the supply chain figured out a way to make a heparin like substitute which was difficult to differentiate from the real thing.
After much additional work the FDA came to a conclusion about the tainted batches - the “heparin-like contaminant” is a highly sulfated form of chondroitin sulfate, a much less expensive extract of animal cartilage. Chondroitin sulfate is one of the main ingredients in many over-the-counter arthritis relief supplements. It is extracted from the cartilage of animal carcasses. It is chemically similar to heparin except that it lacks the high level of sulfur content. As such, the chondroitin sulfate extracted from cartilage would have to be chemically modified to make it similar to heparin.