Industry News On Fighting Bad Drugs

Of the chemicals he uncovered in various counterfeit malaria pills, Facundo M. Fernandez did not expect to find sildenafil, the active ingredient in the drug Viagra. He also didn’t expect to find the antibiotic erythromycin; one of the building blocks for making the street drug ecstasy; or metamizole, a powerful analgesic that is banned in the U.S. because it is suspected of causing serious bone marrow disorders. Yet the Georgia Institute of Technology chemist, who provides scientific support to international anticounterfeiting operations, has recently found all these chemicals and more in counterfeit malaria pills. “It’s shocking,” he says. “Sick children take these drugs. It’s terrible that they don’t receive the correct treatment. But worse, the chemicals in these counterfeits could make them sicker.”

Putting false active ingredients in fake drugs is just one trend in medicine counterfeiting. Bogus pills used to consist primarily of blanks because counterfeiters focused mostly on making the pills look like the originals. But these days, counterfeiters are increasingly adding all sorts of active ingredients to phony tablets. They slip mild pain relievers such as acetaminophen into pills just to make patients feel like they might be getting better, as was the case in fake Tamiflu seized from U.K. pharmacies in 2007. Sometimes, they add small amounts of the correct active ingredient to dupe testers who may not have equipment to accurately quantitate ingredient levels. More worrisome, some counterfeiters substitute life-threatening chemicals for the real McCoy, such as the antifreeze component diethylene glycol to replace glycerine. The toxic substitute ended up in cough medicines that killed hundreds in Nigeria, Panama, and Bangladesh in recent years.

While international police, pharmaceutical companies, customs officials, scientists, and health and regulatory agencies collaborate more closely to track down fake medicines and those who profit from them, counterfeiters are developing more sophisticated knockoffs and putting them in packaging that possesses anticounterfeiting security features, such as holograms. Science and technology are playing an important role in the anticounterfeiting fight—from the analytical techniques used to quantify fakes to the tracking strategies used to catch perpetrators—but the battle against fake drugs is, by all accounts, far from being won.

Fake pharmaceuticals are incredibly lucrative. In 2010, an estimated $75 billion will find its way into the pockets of those making or distributing counterfeit medicines, an oft-quoted statistic from the Center for Medicines in the Public Interest that many say is probably an underestimation. “Counterfeiters can make more money than hard-drug traffickers, and they have less of a chance to go to prison,” says Aline Plançon, an Interpol policewoman who leads an anticounterfeiting task force associated with the World Health Organization (WHO) initiative called IMPACT (International Medical Products Anti-Counterfeiting Taskforce). For example, the profit margin from counterfeit Viagra is some 10 times higher than for the street drug heroin, notes David Shore, associate director of global security for Europe at Pfizer, the company that produces Viagra. The attractive revenues don’t come with heavy enough consequences, Plançon adds.

In general, hard-drug traffickers are charged under specific hard-drug laws, whereas pharmaceutical counterfeiters typically face a variety of trademark, fraud, or money-laundering legislation, says Thomas T. Kubic, a former Federal Bureau of Investigation agent who now heads the Washington, D.C.-based Pharmaceutical Security Institute, which tracks medicine counterfeiting. “Instead of punching out ecstasy tablets, counterfeiters can reload pill-producing machinery and make Lipitor,” Kubic says. Indeed, those working on the ground are finding an increasing cross-over between hard-drug and pharmaceutical trafficking. For example, at a recent seizure in Istanbul, investigators nabbed 700,000 fake Viagra pills alongside 51 kg of heroin, Shore says.

High profits with comparatively low risks may be a major motivation, but many other factors also enable counterfeiting. Globalization of manufacturing has created more steps between drug production and patient consumption. Counterfeiters have capitalized on “fragmented” supply chains to penetrate markets “with counterfeits that look identical to the original,” says James Thomson, chair of the European Alliance for Fake Medicines. The rise of Internet pharmacies has also permitted anonymous individuals to sell medicines directly to consumers; WHO estimates that half of all drugs sold on the Internet are fakes.

A precise count of just how many fakes currently sit in the world’s medicine cabinets does not exist. The best “guesstimate” is that 1% of drugs in the developed world, including the U.S. and Europe, are counterfeit, says Paul Newton, a doctor at the University of Oxford’s Center for Tropical Medicine, in Laos. In developing nations, between 10 and 50% of drugs are thought to be fake. “But we really have no idea of the full extent of the problem.”

Instead, isolated snapshot statistics provide a sobering, if incomplete, picture. In 2008, the European Union launched a two-month operation called Medi-fake, which tracked and seized more than 34 million illegal pills. That same year, the pharmaceutical company GlaxoSmithKline reported 289 counterfeit cases of its drugs globally, with the fakes valued at about $11 million. These figures may seem high, but they are actually the company’s lowest in five years.

Other companies are in the same boat. Pfizer’s Shore notes that in the first nine months of 2009, 8.5 million fake Pfizer pills were seized. He adds that counterfeiters have copied 14 of the company’s medicines, which have subsequently infiltrated the legitimate supply chain of at least 36 countries, including the U.S., Canada, and the U.K. Marcy Forman, who leads the U.S. Immigration & Customs Enforcement team responsible for counterfeits, tells C&EN that seizures of suspected fake drugs at the U.S. border occur at least weekly. When U.S. officials caught the fake-drug distributor Kevin Xu in 2007, they found that U.S. citizens had bought $232,568 of his counterfeits over the Internet.

Counterfeiters try to squeeze into European and North American markets, but they have a smoother ride into the markets of many developing nations, which have fewer resources to fight the problem.

One of the few programs that aims to acquire accurate statistics of drug counterfeiting, at least in developing nations, is a Bill & Melinda Gates Foundation-funded project called the ACT consortium. Newton and Fernandez are part of the group, which is currently tracking the malaria drug counterfeiting problem across the African continent.

On an international level, Interpol teamed up with WHO in 2006 to create IMPACT. The task force, led by Plançon, has only a handful of staff who coordinate intelligence received by pharmaceutical companies, local police, national customs officials, and regulatory agencies around the world. Because counterfeiting rings involve nodes in multiple continents, breaking up these rings requires getting all the anticounterfeiting players “ready on time and at the same time” to haul in players simultaneously, Plançon says. This past fall, the team completed an operation called Mamba II that raided 270 buildings in Kenya, Tanzania, and Uganda. They’ve also brought down counterfeiters in Southeast Asia.

In addition to local, national, and international law enforcement, pharmaceutical companies hire former police officers to investigate counterfeiting cases. Pfizer, for example, has former Scotland Yard and FBI agents, and even a former Turkish general, as counterfeit investigators. “When we have built up a case, then we pass the information on to local authorities to follow up on,” Shore says.

The first step to tracking down counterfeiters is figuring out whether a pill is a real or fake. In North America and Europe, myriad labs at regulatory agencies, border control, academia, and pharmaceutical companies use a battery of analytical tools to check suspected pills for authenticity. Wet chemistry, thin-layer chromatography, X-ray fluorescence, high-performance liquid chromatography, and mass spectrometry are all commonly used to find fakes. But the situation is radically different in developing countries. For example, in the entire continent of Africa, only two labs, one in Kenya and one in South Africa, are equipped to check for counterfeits at WHO standards. International labs, such as Fernandez’, provide additional scientific support.

When Michael Green, a chemist at the U.S. Centers for Disease Control & Prevention, travels to Africa to check for fake malaria pills, he opts for basic wet chemistry color tests to verify medicine authenticity. He uses solvents he brings from the U.S., because “you can’t count on the fact that solvents we use regularly at home will be available,” he says. Green has developed simple color tests that can assess whether specific active ingredients can be found in artesunate malaria tablets and Tamiflu influenza medication.

Giving pills a basic physical exam can also highlight fakes. For example, the weight of pills made in current Good Manufacturing Practices-certified labs won’t vary by more than about 1%, whereas fakes can sometimes fluctuate by as much as 10% or even 50%. Calcite (calcium carbonate) is also often used instead of starch as an excipient—the bulk material in tablets. If a pill that normally uses starch as the excipient fizzes when dropped in vinegar—a common reaction with calcite—then “you can be pretty sure it’s a fake,” Green says. Counterfeiters also use talc, dolomite, anhydrite, and gypsum as excipients, says Dallas Mildenhall, a forensic scientist at GNS Science, a government research organization in New Zealand. Some of these materials do not dissolve in water, which every pill should because the contents must be absorbed by the body. If a pill doesn’t dissolve in water at body temperature, then it is likely bogus.

Handheld analytical devices based on Raman and near-infrared spectroscopy are ideal for field situations because they are noninvasive: Pill pouches don’t even need to be opened to be assessed for authenticity. These tools are not without challenges, however. Identifying chemical components in samples requires comparing the acquired spectra with reference spectra from a database. However, reference spectra of the same drug from different, legitimate manufacturers may vary. One solution researchers are pursuing is to use sophisticated statistical algorithms for comparing spectra.

If a comprehensive ingredient list of a tablet is required, then the tool of choice is mass spectrometry, Fernandez says. Checking pill authenticity of a large batch of pills using mass spec would take hours, and sometimes days, because of the extensive sample prep required—grinding up pills, for example. Fernandez has spearheaded the use of new mass spectrometry techniques that can take mass spectra directly from the surface of a pill. That strategy has sped up analysis by a factor of 60, Fernandez says.

As counterfeiters put increasingly good fakes on the market, some companies are investigating the possibility of putting special chemical tags in the coating of pills that could distinguish the originals. The U.S. Food & Drug Administration has given a preliminary go-ahead to try out this strategy, but European regulators have kiboshed the idea of allowing “anything in tablets unless it needs to be,” Pfizer’s Shore says.

Aside from exploring the idea of adding security features to a pill, companies around the world have primarily considered adding authenticity features to pill boxes and packaging. Yet any new security features for packaging last only about 18 months before counterfeiters can produce mimics, Shore says. Holograms were one of the first security features pharmaceutical companies added to packaging. But counterfeiters have been able to hire reputable hologram-making companies who don’t even realize they are supplying to counterfeiters, Shore notes. He says drug counterfeiters have purchased from a company that also supplied holograms for Euro bank notes. In fact, counterfeiters’ ability to add holograms to packaging is so common that “one pharmaceutical company reported a counterfeit product that had a hologram on the packaging, but in their genuine product, they had never actually put one,” Kubic says.

Another security feature that has come and gone are so-called color-shift logos, which change color as the label twists in the light, Shore says. Only three companies in the world could make the ink for these logos, he says. “Then we found a pack in Hong Kong earlier this year that was such good quality it was almost impossible for the laboratory to tell whether it was a real product or not.” Pfizer has stopped using this technology, Shore says. He did not divulge what the company is now using as security feature, but he says that Pfizer maintains a queue of new technologies to replace whatever counterfeiters can adeptly mimic.

Those wanting to prevent counterfeiting are trying out bar codes or RFID tags on packaging so that pharmacists can check the pedigree of a package before dispensing the drug. If the package has been dispensed elsewhere, then it’s a likely sign that a counterfeiter has reused security tags for fakes. Yet as much as holograms, color-shift logos, bar codes, or RFIDs might be appropriate security measures in industrialized societies, “in tropical Asia, Africa, and South America, it’s going to be very difficult for them to be used,” because they require sophisticated detection technology, Newton says.

Despite the challenges of identifying counterfeits, finding the counterfeiters can be even more difficult. Those involved are increasingly using forensic science to track down perpetrators. One strategy is to take a closer look at the isotopes of elements that form the pill’s excipient. These isotopes can give geographical clues about where the pill was manufactured. For example, isotope analysis of a calcite excipient found in a counterfeit malaria drug called artesunate helped GNS Science’s Mildenhall figure out that the fake pills were probably made at the border between China and Vietnam. In particular, the unusual isotope ratios of calcium, hydrogen, and oxygen suggested that the calcite had not come from the typical ocean source but instead from a hydrothermal mine. Because there is only one hydrothermal mine in the world—in southern China—the calcite helped narrow down where the manufacturing was being done.

The calcite data supported other evidence Mildenhall had that pointed to the region. He had also been scrutinizing pollen found in the fakes. Pollen “is found in all pills—real or fake,” he says. But the pollen found on the counterfeit malaria drugs also came from plants native to the China-Vietnam border.

Mildenhall’s pollen and calcite analyses, in combination with analyses from Fernandez, Green, and Newton, eventually allowed the IMPACT team to orchestrate the arrest of a Xu Qiang, a counterfeit trader in southern China. The team published a rare article about the case (PLOS, DOI: 10.1371/journal.pmed.0050032). Details of many other cases in the fight against counterfeits have not been released.

Even though “we are seeing some successes, fighting counterfeits has a long road ahead,” Thomson says. “The fact is, these people can make fakes look perfect and they can get them into the distribution system. Is it possible to stop medicines counterfeiting altogether? I doubt very much whether it is. All we can do is to try our best to secure the supply chain.”

Changes In Motion 

Food and Drug Administration Amendments Act of 2007

On September 27, 2007, the Food and Drug Administration Amendments Act of 2007 (FDAAA) (Public Law 110-85) was signed into law. Section 913 of this legislation created section 505D of the Federal Food, Drug, and Cosmetic Act (the act), which requires the Secretary of Health and Human Services (the Secretary) to develop standards and identify and validate effective technologies for the purpose of securing the drug supply chain against counterfeit, diverted, subpotent, substandard, adulterated, misbranded, or expired drugs. Section 505D directs the Secretary to consult with specific entities to prioritize and develop standards for identification, validation, authentication, and tracking and tracing of prescription drugs. No later than 30 months after the date of enactment of FDAAA, the statute also directs the Secretary to develop an SNI to be applied to a prescription drug at the point of manufacturing and repackaging at the package or pallet level, sufficient to facilitate the identification, validation, authentication, and tracking and tracing of the prescription drug. An SNI applied at the point of repackaging is to be linked to the SNI applied at the point of manufacturing, and to the extent practicable, the SNI should be harmonized with international consensus standards for such an identifier. (See Section 505D(b)(2).) The provisions in section 505D(b) of the act complement and build on FDA’s longstanding efforts to further secure the U.S. drug supply.

FDA sought public comment on specific questions related to development of an SNI by opening a docket to receive information. 73 FR14988 (March 20, 2008). We also shared this request with State governments, other Federal agencies, and with foreign governments. We received 59 comments from a range of stakeholders, including manufacturers, wholesalers, pharmacies, trade and health professional organizations, technology vendors, health professionals, consumers, and state governments. The standards included in this guidance are based on information received in response to our request for comment and the agency's familiarity with identification standards already in use for certain prescription biologics. 

Scope of this Guidance 

This guidance addresses only package-level SNI. For this purpose, FDA considers the package to be the smallest saleable unit placed into interstate commerce by the manufacturer or the repackager for sale to the pharmacy or other dispenser of the drug product. Standards for prescription drug SNI for the pallet level or other intermediate levels, such as cases, are not included in this guidance. Linking of a repackager SNI to a manufacturer SNI is also not addressed in this guidance. Additionally, standards for track and trace, authentication, and validation are not included in this guidance. This guidance is intended to be the first of several guidance's and regulations that FDA may issue to implement section 505D of the act; issuance of this guidance is intended to assist with the development of standards and systems for identification, authentication, and tracking and tracing of prescription drugs.

New Tricks

Buying drugs on the Internet just got a little scarier.  The U.S. Food and Drug Administration is warning the public about criminals posing as FDA special agents and other law enforcement personnel as part of an international extortion scam.

The criminals call the victims — who in most cases previously purchased drugs over the Internet or via “telepharmacies” — and identify themselves as FDA special agents or other law enforcement officials. The criminals inform the victims that purchasing drugs over the Internet or the telephone is illegal, and that law enforcement action will be pursued unless a fine or fee ranging from $100 to $250,000 is paid. Victims often also have fraudulent transactions placed against their credit cards.

The criminals always request the money be sent by wire transfer to a designated location, usually in the Dominican Republic. If victims refuse to send money, they are often threatened with a search of their property, arrest, deportation, physical harm, or incarceration.

“Impersonating an FDA official is a violation of federal law,” said Michael Chappell, the FDA’s acting associate commissioner for regulatory affairs. “The public should note that no FDA official will ever contact a consumer by phone demanding money or any other form of payment.”

FDA special agents and other law enforcement officials are not authorized to impose or collect criminal fines. Only a court can take such action, with fines payable to the U.S. Treasury.

Anyone receiving a telephone call from a person purporting to be an FDA or other law enforcement official who is seeking money to settle a law enforcement action for the illegal purchase of drugs over the Internet should refuse the demand and call the FDA’s Office of Criminal Investigations Metro Washington Field Office at (800) 521-5783 to report the crime.

In addition to posing as FDA officials, criminals have posed as special agents of the DEA, FBI, U.S. Secret Service and U.S. Customs Service as well as U.S. and Dominican prosecutors and judges. In response, the FDA, in conjunction with various federal, state, and local agencies, is actively pursing criminal charges.

The FDA also reminds consumers to use caution when purchasing prescription drugs over the telephone or the Internet. In addition to the increased risk of purchasing unsafe and ineffective drugs from Web sites operating outside the law, there is the danger that personal data can be compromised