After Heparin
Protecting Consumers from the Risks of Substandard and Counterfeit Drugs

Case Study 1

Adulteration of heparin

In late 2007, health authorities at the U.S. Centers for Disease Control and Prevention (CDC) and the FDA began receiving reports of unexpected allergic-type reactions and hypotension in patients undergoing dialysis.³⁷ Reported events sharply increased from December 2007 to January 2008, a clear spike over baseline levels in 2007 and the first eight months of 2008 (figure 2). The events were subsequently linked to heparin, a widely used blood thinner made by Baxter International Inc.³⁸ Additional analysis led to the identification of oversulfated chondroitin sulfate (OSCS), a substance that standard tests were unable to detect³⁹ and whose biological properties can cause the reported reactions.⁴⁰ Although the available data do not permit clear determination of causality for any individual death, the FDA examined a subset of 574 adverse events, including 68 deaths, submitted between January 1, 2008, and March 31, 2008—a period that corresponded with the heaviest reporting.⁴¹ The FDA determined that three deaths were likely caused by OSCS, six were possibly caused by the adulterant, 24 were unlikely and 35 were unassessable.^42,43 Once the products were removed from the market, reports of unusual adverse reactions essentially ceased.⁴⁴ It was later discovered that the adulteration of heparin had occurred during manufacture in China.⁴⁵

Read Full Section: Adulteration of Heparin(PDF)

Case Study 2

Whistle-blower alert: Ranbaxy Laboratories Limited

In 2008, the FDA suspended importation of more than 30 products from Indian generics company Ranbaxy Laboratories Limited after discovering manufacturing quality and safety violations.¹⁶³
Ranbaxy is one of the largest worldwide producers of finished-product generic medicines, as well as of generic active ingredients. Its products filled 52 million U.S. prescriptions in 2007.¹⁶⁴ The FDA conducted an in-depth inspection of two Ranbaxy plants in 2008 that revealed numerous alleged safety and quality issues affecting drugs destined for U.S. patients as well as drugs made for U.S.-sponsored aid programs.¹⁶⁵ Ranbaxy allegedly submitted false testing data to the FDA,¹⁶⁶ improperly conducted stability studies¹⁶⁷ and submitted records to the FDA signed by employees who were not present at the facility at the dates or times of their purported signature.¹⁶⁸ In addition to testing and documentation violations, the FDA warning letters also claim Ranbaxy exposed products to potential cross-contamination with penicillin,¹⁶⁹ had inadequate sterility procedures and failed to adequately investigate sterility failures.¹⁷⁰ According to a Department of Justice subpoena motion, Ranbaxy also used active ingredients made at sites not approved by the FDA, sometimes blending this material with active ingredient from approved plants, and delayed notifying the agency about drugs that did not meet established specifications.¹⁷¹

After notification of potential problems in 2005, the FDA began an investigation, inspecting two Ranbaxy plants in 2006.¹⁷² The FDA found significant GMP violations during these inspections and issued a warning letter to Ranbaxy regarding its Paonta Sahib facility in June 2006.¹⁷³ The FDA then met with Ranbaxy several times but did not take further disciplinary action.¹⁷⁴ In 2008, the agency returned to inspect the Ranbaxy plants and again found significant GMP violations in both loca-tions.¹⁷⁵ The FDA subsequently blocked importation of more than 30 pharmaceuticals from the Ranbaxy plants located in Paonta Sahib and Dewas,¹⁷⁶ including drugs for epilepsy, diabetes and allergies.¹⁷⁷ Drugs from other Ranbaxy plants were not blocked. In 2009, citing ongoing violations, the FDA invoked its application integrity policy and halted reviews of all generic drug applications listing the Paonta Sahib plant as a manufacturing site.¹⁷⁸ In late 2009, the FDA issued another warning letter citing GMP violations, this time to a Ranbaxy facility called Ohm Laboratories in New York State.¹⁷⁹

While Ranbaxy violations were ultimately met with a strong regulatory response, this case calls attention to several weaknesses in existing regulations. The investigations were precipitated by information given to the FDA by a whistle-blower working at Ranbaxy rather than by a routine FDA inspection.^180,181 Clearly, individuals within industry who wish to bring information to the attention of the FDA and other regulatory bodies need to be protected. Moreover, the agency currently lacks the general authority to subpoena witnesses and documents for violations of the Federal Food, Drug, and Cosmetic Act, and may not be able to thoroughly investigate safety issues without outside help such as from the U.S. Department of Justice, which subpoenaed internal company documents in the Ranbaxy case (see section 2.4.1). Increasing the FDA's on-the-ground presence in countries such as India could strengthen its oversight of imported drug products and help it identify issues more readily, according to U.S. Pharmacopeia experts and FDA staff.^182,183

Ranbaxy is not the only large Indian company to be placed on import alert by the FDA. In June 2010, an intravenous antibiotic product manufactured by Claris Lifesciences Limited, in India, was discovered to be nonsterile (which can cause infections) and to contain floating white particles, identified in at least one case as mold.¹⁸⁴ Three intravenous antibiotic products were then recalled by Claris and by three companies that sold the drugs in the United States under their labels through licensing agreements: Pfizer Inc., Sagent Pharmaceuticals and West-Ward Pharmaceuticals.18^5,186 In November 2010, the FDA placed Claris Lifesciences under import alert, preventing its products from entering the United States.¹⁸⁷

Case Study 3

Gentamicin and Flavine International: false labeling conceals unapproved manufacturing plants

In the late 1980s and early 1990s, Flavine International Inc., a broker selling API to U.S. manufacturers, bought low-cost materials from plants in China that were not approved by the FDA and relabeled them as if they were active ingredients from the Long March Pharmaceutical Plant, an FDA-approved facility.²⁰² Flavine sold the falsely labeled APIs, which included bulk shipments of the antibiotic gentamicin to U.S. manufacturers.²⁰³  A few years later, these manufacturers recalled gentamicin products from the market.²⁰⁴

Flavine's labeling deception came to light because the broker was importing more product than Long March's facilities were physically able to produce, leading the FDA to suspect that some of the API came from other unspecified sources.²⁰⁵ In 1994, Long March officials confirmed that materials sold by Flavine had not been made at Long March, even though they were labeled as such.²⁰⁶  In 1997, Flavine International, Inc., was fined, and its owner sentenced to two years in prison.²⁰⁷  A Congressional review of the FDA's Flavine investigation showed that, although the FDA received reports of 1,974 adverse reactions (including 49 deaths) in patients taking gentamicin between 1989 and 1994, the agency's final report did not document any steps taken to alert the two companies that purchased the falsified product from Flavine or to track down suspect material that might remain on the market.²⁰⁸

In 1998, a year after Flavine was fined, the CDC identified 20 adverse patient reactions in California related to gentamicin made by Fujisawa USA (one of the manufacturers purchasing gentamicin from Flavine), including chills, shaking and drops in blood pressure. Thirty-seven similar events were identified in seven other states.²⁰⁹  The CDC report stated that the reactions were probably due to the method of administration, combined with high levels of endotoxin (a toxin produced by bacteria) in Fujisawa's product.²¹⁰

Although the FDA had suspicions about gentamicin packaged under the Long March Pharmaceutical label since the early 1990s, the agency did not recommend detaining gentamicin shipments from the plant until 1999, after an inspection found good manufacturing practice violations at the site.²¹¹

This case and more recent investigations^212,* underscore the importance of purchasing companies scrutinizing their suppliers to verify that all production is actually occurring at the declared sites, and that sufficient quality systems are in place.

^{*A recent examination of the impurity profiles of 39 samples of bulk gentamicin from the German and U.S. markets found drug substances listed from individual producers with different impurity profiles, suggesting that these producers may have brought in material from other undisclosed sources.}

Case Study 4

Biochimica Opos: Antibiotic ingredients sourced from undisclosed suppliers

In the mid-to late 1990s, an Italian pharmaceutical manufacturer making bulk antibiotics for the U.S. market deliberately falsified records to conceal from the FDA its use of undisclosed manufacturing sites.21^3,214 The manufacturer, Biochimica Opos (Opos), was at the time a wholly owned subsidiary of French drug company Roussel-Uclaf.²¹⁵

The FDA visited Opos' factory in Agrate Brianza, Italy, in May 1996 for a post-approval inspection and became concerned by apparent inconsistencies in information given to them by employees at the plant, including records documenting where the materials used to make one antibiotic—cefaclor—had been manufactured.²¹⁶ In October 1996, Roussel-Uclaf admitted it had not produced cefaclor in accordance with its approved marketing application, and also admitted to similar infractions for antibiotics clindamycin and minocycline for the U.S. market. The company recalled the three products and withdrew its approved marketing applications.²¹⁷

The case was referred to the FDA's Office of Criminal Investigations in 1997²¹⁸ and culminated in multiple felony charges, including conspiracy and distribution of adulterated drugs in interstate commerce with intent to defraud or mislead.²¹⁹ On October 19, 2001, five years after the FDA's initial inspection, Roussel-Uclaf's successor, Aventis Pharma A.G., pleaded guilty to these charges and was ordered to pay a $23,193,600 criminal fine and forfeit $10 million in proceeds to the U.S. government.²²⁰

Roussel-Uclaf had falsified batch production records, raw material logs and work orders to create the appearance that all of its manufacturing occurred at sites designated in its approved U.S. marketing application.²²¹ In reality, the company was outsourcing the manufacture of materials used to make cefaclor to facilities in Italy, France and Romania that were not listed in its application or inspected by the FDA.²²² This put Opos in knowing breach of its approved manufacturing pathway. Further, Opos was found to have used a different, unapproved chemical in place of a required chemical for cefaclor processing.²²³

The Opos case represented the first time a foreign corporation making a drug product entirely outside of the United States received a criminal punishment for defrauding the FDA.²²⁴ One FDA agent reported that the investigation was made difficult by its foreign nature; in particular, some potential witnesses were not subject to U.S. subpoena.²²⁵ However, U.S. investigators did receive assistance from foreign authorities in accessing important documents and witnesses.²²⁶ To support this type of cooperation, the FDA should be allowed to share all information, including trade secret information, in a protected manner with foreign agencies—a general authority that it does not currently have (see section 2.4.3).²²⁷ As drug manufacturing becomes increasingly globalized, international collaboration is essential for improving oversight and identifying wrongdoing.

Case Study 5

Lethal cough syrup in Panama

In Panama in 2006, cough medicine that had been manufactured using a toxic syrup originating in China was unknowingly distributed by the government.²²⁸ The official number of deaths was 78,229 but unofficial reports suggest the possibility of a much larger toll.²³⁰

The Taixing Glycerin Factory in Hengxiang, China labeled barrels of diethylene glycol (DEG), an industrial solvent often used in antifreeze formulations, as glycerin, a common excipient (inactive ingredient) used to make medicines into syrups.^231,232 DEG is chemically similar to glycerin, but it is less expensive to make.²³³ The material passed through brokers in China and Spain, being relabeled at each step, before finally reaching Panama.^234,235 In 2006, the Panamanian government purchased the material and used it to manufacture an estimated 60,000 units of medicines, which were distributed to patients.²³⁶

When patients began to suffer paralysis and die, medical personnel could not determine the cause until more than a month after the adulterated medicine was distributed. Even when the substitution of DEG for glycerin was discovered, relabeling by brokers prevented officials from quickly identifying the source. Each time the fake glycerin changed hands, an international broker created new certificates of analysis indicating identity and purity, presumably without independently testing the product. Obfuscation of records impairs investigations of this sort of deception and shields bad actors from identification and prosecution. As of early 2011, no one in China has been held accountable for the deaths in Panama.

This was not the first DEG poisoning. Indeed, the use of DEG to manufacture Elixir Sulfanilamide (a liquid antibiotic) in the United States in 1937 caused more than 100 deaths and led directly to the enactment of the Federal Food, Drug, and Cosmetic Act.²³⁷ Between 1937 and 2008, there were more than 750 documented deaths in 10 countries associated with exposure to drugs contaminated with DEG.²³⁸ The largest loss involved the deaths of 236 children in Bangladesh between 1990 and 1992.²³⁹ According to an investigation by the New York Times, 50 tons of fake glycerin shipped to the United States in 1995 were fortunately identified.²⁴⁰ But in 1997, at least 88 children in Haiti were reportedly killed by this adulterant,²⁴¹ which was also traced back to a Chinese manufacturer and involved one or more brokers.²⁴² In 1998, DEG poisoning was implicated in the deaths of 33 children in Guragon, India.²⁴³ After the disaster in Panama, the U.S. Food and Drug Administration issued guidance that all glycerin used in drug manufacturing, including glycerin imported into the United States, be tested for DEG.²⁴⁴  The U.S. Pharmacopeia released a more stringent monograph for glycerin with revised testing methods in 2009.²⁴⁵

Case Study 6

Medicaid drugs purchased on the streets and resold into distribution

Two men were convicted in 2008 for selling diverted Medicaid drugs back into distribution, where the drugs ultimately reached pharmacies and unsuspecting patients.⁴⁶⁸ According to the U.S. Attorney's Office in the Southern District of Florida, a man named Michael Manno purchased the drugs—including medicines for treating cancer and controlling cholesterol, as well as human growth hormone—from Medicaid patients in New York.4⁶⁹ Manno, based in New Jersey, sold the drugs to Patrick Bronder in Boca Raton, Florida.⁴⁷⁰

Manno and Bronder made more than $6.8 million by selling the drugs to a Florida wholesaler, who eventually sold the diverted drugs to pharmacies that dispensed them to patients.⁴⁷¹ Patients receiving the drugs were unaware that these medicines already had been dispensed to someone else, held under potentially unsafe conditions, and then issued to them as if they were a safe and legitimate product.⁴⁷²

This example of diversion of prescription drugs from the street, which took place in 2001 and 2002,473 is not unique. In 2010, three men were indicted for distributing prescription drugs without a license.⁴⁷⁴ Between 2002 and 2005, the defendants allegedly purchased drugs from the street and from other unlicensed sources.⁴⁷⁵ The men allegedly used these drugs to fill orders they solicited from pharmacies. By shipping the diverted medicine through a licensed wholesaler in Texas, they grossed more than $13 million.⁴⁷⁶

Case Study 7

A counterfeit injectable drug eludes tracking

Epogen® is a high-cost injectable drug used to treat anemia. A counterfeit version was sold into legitimate distribution in 2002, resulting in subtherapeutic dosing and, reportedly, severe, painful side effects. Criminals in Florida relabeled up to 110,000 bottles of low-dose Epogen® (2,000 units/mL) to create a counterfeit high-dose (40,000 units/mL) Epogen® and a similar drug, Procrit®.⁴⁹² They acquired at least some of the low-dose Epogen® from a Florida pharmacy that falsified records to indicate that local patients had purchased the drugs.⁴⁹³ By one calculation, the relabeling of low-dose Epogen® to resemble a stronger product yielded the criminals a $46 million profit.⁴⁹⁴

The counterfeit high-dose drugs passed through several registered and unregistered intermediaries⁴⁹⁵ before a portion was allegedly sold to a national wholesaler.⁴⁹⁶ Although federal statute requires smaller wholesalers to track the drugs they buy and sell, those listed as authorized distributors by manufacturers, most often the larger distributors, are exempt from the requirement (see section 3.3.2).⁴⁹⁷ Thus, the provenance of products entering an exempted wholesaler's warehouses would not be passed on to subsequent purchasers. The counterfeit drugs were eventually sold to patients by a major chain drugstore.⁴⁹⁸

Recovering from a liver transplant, 19-year old Tim Fagan of New York⁴⁹⁹ received counterfeit Epogen,® and cancer patient Maxine Blount⁵⁰⁰ received counterfeit Procrit®. These patients and others received lower levels of life-preserving therapy than they needed, and they suffered painful side effects. According to his father's testimony, Tim Fagan endured excruciating side effects every time he injected the counterfeit medication.⁵⁰¹

FDA investigators were able to recover less than 10 percent of the counterfeit medicine;⁵⁰² more than 90,000 vials may have reached patients.