The following case studies illustrate breaches to the pharmaceutical supply chain—the route a drug travels from its raw material origins to the delivery of a finished medicine. These examples, all of which are discussed in Pew Health Group’s report After Heparin: Protecting Consumers from the Risks of Substandard and Counterfeit Drugs, demonstrate the different ways in which contaminated, fake, or otherwise unsafe medicine can reach patients, and underscore the need for reform.
According to estimates by the United States Food and Drug Administration (FDA), 80 percent of the active and bulk chemical ingredients in U.S. drugs now originate overseas.1 The increasingly global and outsourced production of drugs creates vulnerabilities in the pharmaceutical supply system, which, without sufficient oversight by industry and regulators, can put patients’ lives at risk.
Once a finished drug enters distribution, it may pass through many hands before reaching a pharmacy. Stolen and counterfeit medicines have made it onto pharmacy shelves at numerous times over the past decade, yet no comprehensive national system currently exists to track drugs and ensure their authenticity.
An adulterated blood thinner harms patients in the United States.
In early 2008, the U.S. Centers for Disease Control and Prevention began investigating an outbreak of unexpected allergic-type reactions in patients undergoing dialysis.2 Most of these patients had received intravenous heparin, a widely used blood thinner manufactured by Baxter Healthcare.3 Further investigation revealed that an adulterant with toxic effects, oversulfated chondroitin sulfate (OSCS),4 had been introduced during heparin’s manufacture in China.5 OSCS was so similar to real heparin that it fooled standard tests.6
Dozens of Americans suffered adverse reactions, including death.7 Investigations into this tragedy 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 not been identified or penalized.
Manufacturing quality and safety problems at an India-based generics company lead the FDA to ban imports of more than 30 drugs produced there.
Ranbaxy is one of the largest worldwide producers of generic medicines. Its products were used to fill 52 million U.S. prescriptions in 2007.8
The FDA began an investigation of Ranbaxy in 2006. In 2008, in-depth plant inspections revealed numerous alleged safety and quality issues.9 FDA warning letters claim Ranbaxy exposed products to potential cross-contamination with penicillin and failed to adequately investigate the causes of sterility failures during the manufacturing process.10 According to a Department of Justice subpoena motion, Ranbaxy also used active pharmaceutical ingredients made at sites not approved by the FDA.11
The FDA suspended importation of more than 30 Ranbaxy products, including drugs for epilepsy, diabetes, and allergies.12,13 According to the FDA, increasing the agency’s on-the-ground presence in countries such as India could strengthen its oversight of imported drugs.14
A pharmaceutical broker falsely labels medicines importaed into the United States to conceal unapproved manufacturing plants.
In the late 1980s and early 1990s, drug broker Flavine International Inc. bought cheap materials from non-FDA-approved plants in China.15 Flavine falsely labeled the products as having come from Long March Pharmaceutical, an FDA-approved facility.16 They sold the product, including bulk shipments of the antibiotic gentamicin, to U.S. manufacturers,17 who eventually recalled gentamicin products from the market.18 In 1997, Flavine was fined and its owner sentenced to two years in prison.19
This case underscores the importance of manufacturers scrutinizing their brokers and suppliers to verify that all drug production is actually occurring at the declared sites and that sufficient quality control systems are in place.
A major foreign manufacturer of antibiotics for the U.S. market admits it did not follow approved manufacturing standards.
In the 1990s, Italian pharmaceutical manufacturer Biochimica Opos, then a wholly owned subsidiary of French drug company Roussel-Uclaf, deliberately falsified records to conceal its use of undisclosed manufacturing sites in Italy, France, and Romania to produce the antibiotic cefaclor.20 The company ultimately recalled this and other products and withdrew its approved marketing applications.21
In 2001, Roussel-Uclaf’s successor, Aventis Pharma A.G., pleaded guilty to multiple felony charges and was ordered to pay a $23 million criminal fine and forfeit $10 million in proceeds to the U.S. government.22 The case represented the first time a foreign corporation making a drug product entirely outside of the United States received a criminal punishment for providing fraudulent information to the FDA.23 As drug manufacturing becomes increasingly globalized, international collaboration is essential for improving oversight and identifying wrongdoing.
Cough medicine in Panama is mixed with an industrial solvent falsely labeled as sweetener.
In Panama in 2006, 78 people died after taking a cough medicine that the government had unknowingly mixed with toxic syrup originating in China.24
The syrup was diethylene glycol (DEG)—an industrial solvent often used in antifreeze formulations—that had been labeled as glycerin (a product commonly used to make medicines into syrups).25 The material passed through brokers in China and Europe, receiving new labels along the way, before finally reaching Panama.26,27 Product testing by these brokers was either insufficient or not performed at all. The Panamanian government ultimately distributed 60,000 units of medicine mixed with DEG to patients.28
False labeling masked the source of the problem from officials; the cause of patient deaths was not identified until more than a month after the adulterated medicine was initially distributed.29
Insulin known to be stolen is discovered on pharmacy shelves
In 2009, thieves stole a truck containing over 120,000 vials of Levemir Insulin® made by Novo Nordisk.30,31 According to an FDA affidavit, the temperature-sensitive medicine was illicitly sold back into distribution through wholesalers, eventually reaching medical centers in Texas, Georgia, and Kentucky.32 Diabetic patients received the stolen goods, with some reporting poor blood sugar control.33 Wholesaler documentation of the insulin’s origins, (what is known as the drug “pedigree”) indicated it was purchased from a national distribution company a day after the medicine was reported stolen.34
State requirements for drug pedigrees and drug wholesaler licensure vary. Most pedigrees are only kept as paper documents and thus easily falsified. A national system to track and authenticate drugs would improve distribution security.
Previously issued drugs, held under unknown conditions, are illegally resold to patients at U.S. pharmacies.
In 2001 and 2002,35 a New Jersey man purchased medicines, including drugs for treating cancer and controlling cholesterol, from Medicaid patients in New York.36 He then sold the drugs to a contact in Florida,37 and together these men made more than $6.8 million by then selling the drugs to a Florida wholesaler. Eventually these diverted drugs reached pharmacies and were given to patients.38 Those who received the drugs were unaware that these medicines already had been dispensed to someone else, held under unknown conditions, and then issued to them as if they were safe and legitimate products.
The criminals were convicted in 2008 for selling diverted Medicaid drugs back into distribution. They received prison sentences of under 10 years each and were ordered to pay a total of $464,446 in forfeitures and fines.39 Though this case resulted in a conviction, it shows how lucrative illicit trade in legal medicines can be, making it increasingly attractive to criminals.
A counterfeit injectable anemia drug is sold into legitimate distribution in the United States, resulting in subtherapeutic dosing and sever side effects for patients.
In 2002, criminals in Florida relabeled up to 110,000 bottles of low-dose anemia drug Epogen® as high-dose versions of both Epogen® and the drug Procrit®.40 The counterfeit drugs passed through several registered and unregistered intermediaries41 before a portion was allegedly sold to a national wholesaler.42 As a result, patients received insufficient levels of life-preserving therapy and suffered painful side effects.43,44
The relabeling of low-dose Epogen® to resemble a stronger product yielded an estimated $46 million in profits.45 The FDA recovered less than 10 percent of the counterfeit medicine;46 more than 90,000 vials may have reached patients. This illustrates the potential for counterfeit drugs from domestic sources to enter the U.S. supply chain.
The Drug Safety Project works to ensure a safe, reliable pharmaceutical manufacturing and distribution system.
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- Date added:
- May 16, 2012
- Joshua Wenderoff, Tel: work202-540-6542
- Drug Safety Project
- Drug Manufacturing and Distribution, Drug Safety
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2 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.
4 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.
5 Usdin, Steve. The Heparin Story. International Journal of Risk & Safety in Medicine. Vol. 21, 99–103. 2009.
6 Parkinson, Robert L., Chief Executive Officer, Baxter International. Testimony before the Subcommittee on Oversight and Investigations, Committee on Energy and Commerce, United States House of Representatives. April 29, 2008.
7 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).
8 Blum, Justin. US Approves Ranbaxy Drugs Despite Questions. Bloomberg. August 13, 2008. http://www.livemint.com/articles/2008/08/13223620/US-approves-Ranbaxy-drugs-desp.html. Accessed May 3, 2010.
9 FDA Media Briefing on Ranbaxy Labs. September 17, 2008. Moderator: Rita Chappelle. http://www.fda.gov/downloads/NewsEvents/Newsroom/MediaTranscripts/ucm121266.pdf. Accessed August 19, 2010.
10 United States Food and Drug Administration. Warning Letter (WL: 320-08-03) to Mr. Malvinder Singh, CEO & Managing Director, Ranbaxy Laboratories Limited. September 16, 2008.
11 United States District Court for the District of Maryland (Southern Division).Motion to Enforce Subpoenas and Points and Authorities. United States of America, petitioner, v. Ranbaxy, Inc., and Parexel Consulting, respondents.
July 3, 2008.
12 United States Food and Drug Administration. FDA Issues Warning Letters to Ranbaxy Laboratories Ltd., and an Import Alert for Drugs from Two Ranbaxy Plants in India. FDA News Release, September 16, 2008. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2008/ucm116949.htm. Accessed February 17, 2010.
13 United States Food and Drug Administration. List of Drugs Manufactured at the Dewas and Paonta Sahib Facilities of Ranbaxy Laboratories, Ltd. http://www.fda.gov/DrugsGuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/ucm118441.htm. Accessed February 17, 2010.
14 United States. Food and Drug Administration Consumer Health Information. “FDA Beyond Our Borders.” http://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/ucm103044.pdf Accessed June 18, 2010.
15 Henkel, John. Probe Proves effective Against Antibiotic Smuggling Scheme. FDA Consumer. January-February 1998. http://permanent.access.gpo.gov/lps1609/www.fda.gov/fdac/departs/1998/198_irs.html Accessed February 21, 2010.
17 Thompson, Cheryl A. FDA Admits to Lacking Control Over Counterfeit drug Imports. Health-System Pharmacists News, American Society of Health-System Pharmacists. June 9, 2000. Accessed February 21, 2010: http://www.ashp.org/import/news/HealthSystemPharmacyNews/newsarticle.aspx?id=135.
19 United States Department of Justice “New Jersey drug firm and owner sentenced and fined in illegal pharmaceutical and money laundering scheme.” Press release. Thursday, April 10, 1997.
20 Lewis, Carol. FDA Investigators’ Reports--January-February 2002. FDA Consumer Magazine. January 4, 2002.
22 United States Food and Drug Administration. The Enforcement Story, Fiscal Year 2001. Chapter 6: Office of Criminal Investigation. http://www.fda.gov/ICECI/EnforcementActions/EnforcementStory/EnforcementStoryArchive/ucm106657.htm. Accessed August 22, 2010.
24 Rentz, E.D., L. Lewis, et al. Outbreak of Acute Renal Failure in Panama in 2006: a Case-Control Study. Bulletin of the World Health Organization 2008; 86:749–756.
26 Schier JG, Rubin CS, Miller D, Barr D, McGeehin MA. Medication-associated diethylene glycol mass poisoning: A review and discussion on the origin of contamination. Journal of Public Health Policy. 2009. Vol. 30, No. 2.
27 Rentz, E.D., L. Lewis, et al. Outbreak of Acute Renal Failure in Panama in 2006: a Case-Control Study. Bulletin of the World Health Organization 2008; 86:749–756.
30 United States Food and Drug Administration. Update to FDA Alert about Stolen Insulin. August 26, 2009. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm180320.htm. Accessed November 12, 2010.
31 Ciolek, Michelle M, Special Agent, Office of Criminal Investigations, U.S. Food and Drug Administration. Affidavit in Support of Search Warrant. USA v. Altec Medical Inc and RX Healthcare Inc. Document number: 8:09-cr-00814-WMC. July 21, 2009.
33 United States Food and Drug Administration. Update to FDA Alert about Stolen Insulin. August 26, 2009. http://www.fda.gov/ForConsumers/ConsumerUpdates/ucm180320.htm. Accessed November 12, 2010.
34 Ciolek, Michelle M, Special Agent, Office of Criminal Investigations, U.S. Food and Drug Administration. Affidavit in Support of Search Warrant USA v. Altec Medical Inc and RX Healthcare Inc. Document number: 8:09-cr-00814-WMC. July 21, 2009.
35 United States Attorney’s Office. “Boca Raton man and New Jersey man sentenced in $7 million human growth hormone and tax scheme.” Press release, July 31, 2008. http://www.justice.gov/usao/fls/PressReleases/080731-01.html. Accessed January 1, 2009.
40 Thompson, Cheryl A. Counterfeit drugs arise from various sources; wholesalers blamed for promoting drug diversion. Am J Health-Syst Pharm. Vol. 60 August 1, 2003.
41 Eban, Katherine. Testimony before the Committee on Criminal Justice, Drug Policy, and Human Resources, United States House of Representatives. Hearing on “Sick Crime: Counterfeit Drugs in the United States,” November 1, 2005.
42 Young, Donna. Counterfeit Drug Lawsuit Points Finger at Wholesaler, Pharmacy. Am J Health-Syst Pharm, Vol. 61, October 1, 2004.
43 Fagan, Kevin. Testimony before the Committee on Criminal Justice, Drug Policy, and Human Resources, United States House of Representatives. Hearing on “Sick Crime: Counterfeit Drugs in the United States” November 1, 2005.
44 Young, Donna. Counterfeit Drug Lawsuit Points Finger at Wholesaler, Pharmacy. Am J Health-Syst Pharm, Vol. 61, October 1, 2004.
45 Thompson, Cheryl A. Counterfeit drugs arise from various sources; wholesalers blamed for promoting drug diversion. Am J Health-Syst Pharm. Vol. 60 August 1, 2003.
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