Heparin: A Wake-Up Call on Risks to the U.S. Drug Supply

Why is the Heparin Case Study Important?

The adulteration of heparin, a widely used blood thinner, is a tragic example of the risks resulting from an increasingly globalized and complex pharmaceutical manufacturing system. The U.S. Food and Drug Administration (FDA) estimates that 40 percent of the finished drugs used by U.S. patients, and 80 percent of their active ingredients, are manufactured abroad.^1–3 While the vast majority of drugs in American pharmacies and medicine cabinets are safe, globalization and reliance on outsourced manufacturing creates new risks, including deliberate tampering with ingredients and inadequate quality controls in plants that operate largely outside the scrutiny of the FDA.

As a result of the heparin adulteration, dozens of patients in the United States suffered adverse events,⁴ and several lost their lives.⁵ Investigations into this occurrence have revealed a number of systemic failures, including inadequate oversight and supply chain management. Ultimately, heparin's complex production chain was vulnerable to abuse by perpetrators who have yet to be identified or penalized.

What Happened?

In early 2008, the U.S. Centers for Disease Control and Prevention (CDC) began investigating an outbreak of unexpected allergic-type reactions dating from November 2007 in patients undergoing dialysis.⁶ Most of these patients had received intravenous heparin manufactured by Baxter Healthcare.⁷ Further investigation revealed that a synthetic adulterant with toxic effects, oversulfated chondroitin sulfate (OSCS),⁸ had been introduced during heparin's manufacture in China.⁹ OSCS costs nearly 100 times less to produce than heparin¹⁰ and is so similar to the actual drug that it was undetected by standard tests.¹¹

Dozens of Americans suffered adverse reactions, including death.¹² Baxter Healthcare, the major U.S. manufacturer of heparin, along with 14 other U.S. companies recalled at least 11 drug products and 72 medical devices containing heparin.¹³ According to local health agencies and news reports, heparin products were also recalled in Australia, Denmark, France, Germany, Italy, Japan, Sweden, and Switzerland.^14-17

In response to the adulteration, the U.S. Pharmacopeial Convention, a nongovernmental standards-setting authority for medicines in the United States, has updated its testing standards for heparin.¹⁸ Baxter reports that it has instituted a number of initiatives to secure its supply chain against future adulteration—from reviewing relationships with high-risk suppliers to conducting more intensive audits.¹⁹

How is Heparin Made?

Heparin is derived from animal mucosal tissues, almost exclusively from pigs. China, due to its large swine herds, is essential to the market for heparin.²⁰ The supply chain for the drug begins at slaughterhouses, followed by small workshops that harvest basic heparin material (known as “heparin crude”) by extracting the mucous membranes from pig intestines. Heparin crude is then sold, sometimes through consolidators, to other plants that then further refine the material into an active pharmaceutical ingredient (API).^21,22 Finally, this API is combined with inactive ingredients (often a sterile solution) to create a finished heparin product such as a vial of injectable medicine.

At What Point Was the Heparin Supply Chain Breached?

Both Baxter and the FDA remain unable to pinpoint the exact source or sources of the heparin adulteration, but evidence suggests OSCS was likely introduced by entities upstream of the Chinese API production site, Scientific Protein Laboratories–Changzhou (SPL-CZ). Baxter's heparin API had been manufactured using crude material from China since 1996;²³ SPL-CZ became part of Baxter's heparin supply chain in 2004.^24,25

During investigations following the adulteration, OSCS was identified in both the finished heparin API made by SPL-CZ and in the crude material provided to the factory from Chinese consolidators.²⁶

Why Was the Deparin Adulterated?

The FDA believes that the adulteration was an economically motivated act.^27,28 OSCS entered the supply chain at a time when a widespread swine virus outbreak had greatly diminished Chinese pig herds.²⁹ The price of pigs increased in 2007,³⁰ and the cost of heparin grew more than 100 percent between May and November 2007.³¹

One industry insider estimates that one to three tons of OSCS must have been produced and used to dilute the heparin, which would have generated $1 million to $3 million in profit for those who sold it.³²

What Other Problems Were Exposed by the Tragedy?

The heparin incident revealed a number of supply chain management and oversight failures:

• Baxter began receiving heparin API made at SPL-CZ in 2004, but it did not conduct its own audit of the plant until 2007, relying instead on an earlier assessment by a different company.³³
• The FDA approved SPL-CZ as a supplier for Baxter without conducting a pre-approval inspection, in part because the agency confused SPL-CZ with another site in the agency's database.³⁴
• The inspection conducted after the adulteration by the FDA of SPL-CZ found a number of manufacturing quality issues, including insufficient quality control systems for incoming raw materials.³⁵
• When Baxter sent investigators to retroactively evaluate its supply chain in 2008, they were denied access to upstream workshops and consolidators.³⁶ The FDA was also denied access to two upstream consolidators of heparin.³⁷
• SPL-CZ was classified within China as a chemical plant and therefore was not registered with the Chinese State Food and Drug Administration.³⁸ As a result, it likely did not receive any oversight from the Chinese authorities.

What Can Be Done to Protect Patients?

To prevent another event like the heparin adulteration, Congress must enact legislative reforms to better safeguard the U.S. pharmaceutical supply. The legislation must:

• Ensure meaningful control of globalized pharmaceutical manufacturing by requiring modernized systems for supply chain management and quality.
• Increase FDA oversight of high-risk plants overseas through adequate resources and improving the agency's infrastructure and tracking systems.
• Eliminate barriers to FDA's drug supply safety work by providing it with the regulatory authority needed to fulfill its mission.

The Drug Safety Project works to ensure a safe, reliable pharmaceutical manufacturing and distribution system.

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References

1 U.S. Government Accountability Office (September 2010) Drug Safety: FDA Has Conducted More Foreign Inspections and Begun to Improve Its Information on Foreign Establishments, but More Progress is Needed. Appendix 1: Comments from the Department of Health and Human Services. (Publication No. GAO-10-961).

2 Hamburg, Margaret. Commissioner, United States Food and Drug Administration. Testimony before the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, United States House of Representatives. April 13, 2011. http://republicans.energycommerce.house.gov/Media/file/Hearings/Oversight/041311/Hamburg.pdf.  Accessed April 27, 2011.

3 U.S. Government Accountability Office (March 1998) “Food and Drug Administration: Improvements Needed in the Foreign Drug Inspection Program” (Publication No. GAO/HEHS-98-21).

4 U.S. Government Accountability Office (October 2010). Food and Drug Administration: Response to Heparin Contamination Helped Protect Public Health; Controls That Were Needed for Working With External Entities Were Recently Added. (Publication No. GAO-11-95).

5 Ibid.

6 United States Centers for Disease Control and Prevention. Acute Allergic-Type Reactions Among Patients Undergoing Hemodialysis—Multiple States, 2007–2008. Morbidity and Mortality Weekly Report, February 1, 2008 / 57 (Early Release); 1–2. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm57e201a1.htm.  Accessed May 3, 2011.

7 Ibid.

8 Kishimoto, Takashi Kei, Viswanathan, Karthik, et al. Contaminated Heparin Associated with Adverse Clinical Events and Activation of the Contact System. New England Journal of Medicine, June 5, 2008 358: 2457–67.

9 Usdin, Steve. The Heparin Story. International Journal of Risk & Safety in Medicine. Vol. 21, 99–103. 2009.

10 Ibid.

11 Parkinson, Robert L., Chief Executive Officer, Baxter International. Before the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, United States House of Representatives. April 29, 2008.

12 U.S. Government Accountability Office (October 2010). Food and Drug Administration: Response to Heparin Contamination Helped Protect Public Health; Controls That Were Needed for Working With External Entities Were Recently Added. (Publication No. GAO-11-95).

13 Ibid.

14 Bogdanich, Walt. Japan: Heparin Recalled as Precaution. New York Times. March 11, 2008. http://query.nytimes.com/gst/fullpage.html?res=9B02E1DD1F3AF932A25750C0A96E9C8B63. Accessed August 20, 2010.

15 Schwartzkopff, Frances. Sweden Pulls Contaminated Sanofi Heparin Batches (Update3). Bloomberg. April 24, 2008. http://www.bloomberg.com/apps/news?pid=newsarchive&sid=aj.u8ersCaQc&refer=europe. Accessed August 20, 2010.

16 Swissmedic recalls Heparin products in Switzerland. Swissmedic. March 20, 2008.  Accessed August 20, 2010.

17 Australian Government Department of Health and Ageing Therapeutic Goods Administration. Heparin products—safety alerts & advisory statements. Accessed February 21, 2011.

18 Usdin, Steve. The Heparin Story. International Journal of Risk & Safety in Medicine. Vol.21, 99–103. 2009.

19 Gardner, Erin. Director, Corporate Communications, Baxter International Inc. Direct communication, February 19, 2010.20 Usdin, Steve. The Heparin Story. International Journal of Risk & Safety in Medicine. Vol. 21, 99–103. 2009.

21 Strunce, David G. President and Chief Executive Officer, Scientific Protein Laboratories LLC. Testimony before the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, United States House of Representatives. April 29, 2008.

22 Usdin, Steve. The Heparin Story. International Journal of Risk & Safety in Medicine. Vol. 21, 99–103. 2009.

23 Parkinson, Robert L. Chief Executive Officer, Baxter International. Testimony before the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, Unite States House of Representatives. April 29, 2008.

24 Usdin, Steve. The Heparin Story. International Journal of Risk & Safety in Medicine. Vol. 21, 99–103. 2009.

25 Parkinson, Robert L. Chief Executive Officer, Baxter International. Testimony before the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, Unite States House of Representatives. April 29, 2008.

26 Ibid.27 U.S. Government Accountability Office (October 2010). Food and Drug Administration: Response to Heparin Contamination Helped Protect Public Health; Controls That Were Needed for Working With External Entities Were Recently Added. (Publication No. GAO-11-95).28 Usdin, Steve. The Heparin Story. International Journal of Risk & Safety in Medicine. Vol. 21, 99–103. 2009.29 Ibid.

30 Gardner, Erin. Director, Corporate Communications, Baxter International Inc. Direct Communication, February 19, 2010.

31 Wu, Huifang. Orientbit Technology Co., Ltd. Direct communication, August 24, 2010.

32 Villax, Guy, Member of the Board and Head of Globalization Task-Force, European Fine Chemicals Group. “Business of Counterfeit Heparin and its Implications.” Presentation at the 3rd EFCG Pharma Business Conference. May 29, 2008. Lisbon, Portugal.

33 Parkinson, Robert L. Chief Executive Officer, Baxter International. Testimony before the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, Unite States House of Representatives. April 29, 2008.

34 Woodcock, Janet, M.D. Director, Center for Drug Evaluation and Research, United States Food and Drug Administration. Testimony before the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, United States House of Representatives. April 29, 2008.

35 United States Food and Drug Administration. Warning Letter WL 320-08-01, to Dr. Yan Wang, Ph.D., General Manager, Changzhou SPL Company, Ltd (a/k/a “Kaipu”). April 21, 2008.

36 Gardner, Erin. Director, Corporate Communications, Baxter International Inc. Direct communication, February 25, 2011.

37 U.S. Government Accountability Office (October 2010). Food and Drug Administration: Response to Heparin Contamination Helped Protect Public Health; Controls That Were Needed for Working With External Entities Were Recently Added. (Publication No. GAO-11-95).38 Hepeng, Jia. Regulators scramble to tighten loopholes after heparin debacle. Nature Biotechnology. Vol. 26, No. 5. May 2008.