Saturday, March 01, 2008

Heparin in an Era of Hogwash

Two weeks ago we first posted about an emerging scandal about the production of the drug heparin, a biologic that has been in use for over 70 years. First, we posted about the sudden increase in the frequency and severity of adverse effects due to heparin that carried the Baxter International label. However, its "active ingredient," that is, the heparin itself, was purchased from 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. Furthermore, it turns out that the factory was never inspected by either the US Food and Drug Administration (FDA) or its Chinese counterpart.

Last week, we posted about how the CEOs of Baxter International and Scientific Protein Laboratories did not seem aware of the origin of the heparin for which they were ostensibly responsible. Furthermore, it turns out its origin was not just Changzhou SPL, but a series of small, unregulated Chinese factories.

Since then, the plot has continued to thicken.

A congressional investigation is starting. Per the Wall Street Journal,

congressmen asked whether Baxter had known the Chinese plant hadn't been inspected and suggested the company might therefore be distributing an unapproved drug.

In a separate letter to HHS Secretary Michael O. Leavitt, the lawmakers asked for records relating to the FDA's preapproval inspection policy. They also sought an explanation of the agency's interpretation of the legal status of drugs shipped into 'United States commerce by a drug company that knew or should have known that FDA had not performed a preapproval inspection, as is alleged in the Heparin case.'

Chinese regulators dodged any responsibility. Again, per the Wall Street Journal,

China's drug-safety agency, responding to questions about oversight of an exported blood-thinning compound, said checks of pharmaceutical ingredients made in China are ultimately the responsibility of countries that buy them.

The State Food and Drug Administration said it works with foreign counterparts to monitor drug-ingredient production. But it said that based on international practice, 'safeguarding the legality, quality and safety of active pharmaceutical ingredients' is up to importing countries.

The supply chain of heparin in China appears to be even more difficult to trace than previously reported. An investigative report published in the NY Times, first quoted the CEO of Scientific Protein Laboratories, Mr David Stunce, "we have a collection chain in place, and we stick with that." However,

But interviews with dozens of heparin producers and traders in several Chinese provinces, as well as a visit to a village near here dominated by tiny family workshops that process crude heparin from pig intestines, show the difficulties confronting investigators as they seek to trace the supply chain. The picture that emerges is of a chain more complex, and less orderly, than the one Mr. Strunce laid out.

The Chinese heparin market has become increasingly unsettled over the last year, as pig disease has swept through the country, depleting stocks, leading some farmers to sell sick pigs into the market and forcing heparin producers to scramble for new sources of raw material. Traders and industry experts say even big companies have been turning more often to the small village workshops, which are unregulated and often unsanitary.

One of the wholesalers named by Scientific Protein Laboratories, Ruihua Biochemical in Hangzhou, said it provided a mix of crude heparin that it manufactured and some that it bought 'from small factories nearby in several villages.' The owner, Hua Ruihua, said he never inspected the small factories. 'We are not the government,' he said in a telephone interview. 'We have no right to inspect their pigs or intestines or facilities.'

The owner of one of those workshops, Fan Yinan, said, I sold to Ruihua several times before, but since last September I have had no intestines.' He confirmed that 'no one from Ruihua inspected my pigs or intestines.'

Strunce's response was this non-denial denial, "we have no information to suggest your information is true."

Some heparin is produced in primitive and unsanitary conditions. The Times reporters also visited some small factories, whose operations do not exactly inspire confidence in the safety and purity of their products.

Some experts say as much as 70 percent of China’s crude heparin — for domestic use and for export — comes from small factories in poor villages. One of the biggest areas for these workshops is here in coastal Jiangsu Province, north of Shanghai, where entire villages have become heparin production centers.

In a village called Xinwangzhuang, nearly every house along a narrow street doubles as a tiny heparin operation, where teams of four to eight women wearing aprons and white boots wash, splice, separate and process pig intestines into sausage casings and crude heparin.

The floors had large puddles and drainage channels; the workshops were dilapidated and unheated; and steam from the production process fogged up the windows and soaked the walls. There were large ovens to cook ingredients and halls lined with barrels to store enzymes, resins, intestines and wastewater.

'This is our family-style workshop,' said Zhu Jinlan, the owner of one heparin operation, who stopped sorting pig intestines and invited visitors to a back room, where she lives with her husband and child. 'We’ve been doing this about 10 years.'

Experts say the small, unregulated factories could pose dangers because they do not have the same controls and rules as large slaughterhouses, which also produce crude heparin.

'If you don’t control the incoming source, it’s very hard to get rid of the contaminants,' says Liu Jian, a heparin expert at the University of North Carolina.

Mr. Strunce of S.P.L. says his company never buys directly from the crude-heparin producers, only through its wholesalers, which he called 'consolidators' — Changzhou Techpool, its Chinese joint venture partner, and Ruihua. His company, he said, has records documenting all the transactions.

But here in Rugao, producers of crude heparin tell a somewhat different story. A sales manager for a major supplier, Nantong Koulong, said he sells directly to S.P.L. without going through either of the two wholesalers. 'We provided crude heparin to Changzhou SPL,' said the sales manager, Chen Jianjun. Some of Koulong’s stock comes from the unregulated workshops, he said.

The owner of one such workshop, Ms. Zhu in Xinwangzhuang, said she sold to S.P.L. two years ago. She also sells to Koulong. 'We are really a traditional family-style plant,' she said. 'We have no certificate.'

S.P.L. said it never bought directly or indirectly from Koulong.

The large companies cared more about getting heparin cheap than about where it came from. Again, according to the NY Times,

After an outbreak of blue ear pig disease swept through 25 of China’s 31 provinces and regions last year, prices soared, and many drug suppliers had to look to the small workshops. The epidemic, said Cui Huifei, a heparin expert at the Shandong University School of Medicine, 'made those biotech companies inevitably purchase from the family-style plants, for cheaper prices'

A sales manager for another large slaughterhouse in Shandong Province, north of Jiangsu, said he was approached late last year by a buyer for S.P.L. offering what he described as rock-bottom prices for crude heparin.

'It was impossible,' said the sales manager, Wang Shengfu, who works for Shandong Jinluo Group, a major producer of crude heparin. 'Only small factory-style farms could accept that low price.'

The deal was never consummated.

Wherever it gets its heparin, there were problems in the Changzhou SPL Plant. US Food and Drug Administration (FDA) inspectors finally got to the Changzhou SPL plant, and here is what they found, according to the Wall Street Journal,

Food and Drug Administration inspectors found problems at a Chinese plant that made most of the active ingredient for Baxter International Inc.'s blood thinner heparin, but the agency still hasn't pinpointed a cause for hundreds of bad reactions in people who took the drug.

Among other findings, the FDA said investigators found lapses in the Changzhou, China, manufacturer's quality-control procedures and the way it assessed its own efforts to remove impurities from raw materials.

The FDA also said yesterday it was seeking to examine upstream consolidators and small workshops that supplied raw material to the Changzhou factory. FDA inspectors found in its inspection report that some heparin sold in the U.S. included 'material from an unacceptable workshop vendor.'

Baxter International has recalled nearly all its extant heparin products, as reported in the WSJ article above.

Finally, the toll of serious adverse events linked to heparin has increased to 448, possibly including as many as 21 deaths. (See the same article.)

Health Care Renewal has documented numerous cases of financial mismanagement by leaders of health care organizations. We have discussed misleading marketing by drug, biotechnology and device companies, and by hospitals, academic medical centers, and health insurance companies. We have noted how medical education has been twisted into marketing, and clinical science has been manipulated, aided by pervasive conflicts of interest affecting physicians, academics, and various not-for-profit organizations.

But through all that, even I thought that the purity of the drug supply remained sacrosanct. Even I thought that no US or major multinational pharmaceutical or biotechnology company would sacrifice the purity and quality of the drugs they sold to cut their costs.

I may have thought that over-the-top marketing and shoddy research had inflated the benefit/ harm ratio of many drugs and devices. Up to now, however, I never doubted the purity of an FDA approved drug sold in the US with the logo of a reputable drug or biotechnology company.

In my previous academic life in which I spent a fair chunk of my time as an academic hospitalist, I often oversaw the use of parenteral heparin. I never would have suspected that the raw material in a vial of Baxter heparin came from some primitive, unsanitary, uninspected "family style" workshop in China.

We have reached a new low in US health care. The system is now mired in muck. We need a new generation of muck-rakers to clean it out. We need a total overhaul of the management of US health care organizations. We need managers who once again put patients before profits, and before lining their own pockets. Until things change, more people will die, and we will all eventually drown in the hogwash.


Jenny said...

We have to hope a new administration in Washington will appoint a new FDA management whose mandate is to protect the public, not the drug companies.

It isn't just heparin. Have you noticed all the studies recently finding that various vitamins seem to increase cancer? Did you know that according to the NYTimes almost all vitamins are now all manufactured in China?

And the ingredients for many other pharmaceuticals are also coming from China. As someone dependent on a pharmaceutical (insulin) I find this very troubling.

Anonymous said...

If anyone questions the predatory nature of medicine in the US I offer the following quote from the Feb. 8th WSJ Health Blog on flu:

"Fewer flu patients mean lower profits at hospitals. David Dill, CFO at Lifepoint, told investors at a conference last month put on by financial advisers Stanford Group. “[T]here are cases when you have a strong flu season and the ancillary business is very profitable,” he said, such as when “an elderly person that shows up in the ICU and all of a sudden needs a [tracheostomy tube] to be put in, and that turns into higher acuity business for us. Or on the pediatric side, young kids coming into the hospital, that’s a nice margin for us, as well.”

Steve Lucas

InformaticsMD said...

I believe my continuing saga on how pharma seems to go out of its way to avoid hiring competent Medical Informatics specialists (who probably won't be amenable to data masturbation) is but a small part of a more generalized phenomenon - severe cultural debasement of pharma.

Namely, the pulling away from science and true scientific competence in favor of what might be described as control by "gentleman's C" businesspeople, worsened by the replacement of "men and women of the mind" with incompetents and yes-men and women.

Anonymous said...

that knew or should have known that FDA had not performed a preapproval inspection, as is alleged in the Heparin case.