Two years after adulterated heparin produced in China killed 81 people in the U.S., Western drug companies, their ingredient suppliers, and regulatory agencies are aligning efforts against unsafe imports. Sources in all quarters agree that the heparin case heightened public awareness of a safety threat and provided a wake-up call to drugmakers, the U.S. Food & Drug Administration, and other regulators. But guarding the global pharmaceutical supply chain against contaminated or unsafe ingredients has proved daunting.
An illustration that the problem continues to plague the industry surfaced earlier this year with the news that the Swiss drug manufacturer Acino recalled batches of the drug clopidogrel. The company took action when an inspection of its active pharmaceutical ingredient (API) supplier in India, Glochem, revealed falsified batch documentation (C&EN, Aug. 23, page 23).
“You can’t imagine how frustrating it is,” says Guy Villax, chief executive officer of Hovione, a Portuguese pharmaceutical chemical company. Villax asserts that European API producers have been aware since long before the heparin incident that the kind of fraudulence alleged at Glochem, and worse, is rife in Asia. “A bunch of us for six years have been waving red flags,” he says, getting little attention prior to 2008. “People said, ‘No, there is no issue.’ Then people died because of heparin.”
Although the tragedy focused the world on the problem, Villax says the general perception is still that tainted heparin and a handful of other criminal contaminations, including diethylene glycol used in Panamanian cough medicines, are isolated incidents. The result is that it’s difficult to build momentum behind policing the supply chain.
“Heparin was a very black situation,” Villax says. “But there are shades of gray. And clopidogrel is clear fraud. It is easy to be profitable through this kind of fraud, and people are not caught. There are no sanctions. What incentive does that leave for those of us who want to play by the rules?”
According to Villax, the concerns of Western API producers have often been dismissed on the assumption that they have a stake in eliminating Asian competition. A bigger problem, however, is getting the public to understand a supply chain in which drug companies outsource the production of APIs to firms in another part of the world that might, in turn, be supplied by other contractors.
“When I meet someone new, it takes me 10 minutes to describe what I do,” Villax says. “And it doesn’t cross people’s minds that FDA is not on top of things.”
Allan Coukell, director of the Pew Charitable Trusts’ Pew Prescription Project, agrees that the public, despite the coverage of heparin, has trouble grasping the issue. A recent Pew survey indicates that the threat from unsafe drugs is perceived as significantly lower than that from unsafe toys, cars, and produce.
The Pew Prescription Project, a drug safety policy and advocacy initiative, has focused on drug supply chain security since the heparin-related deaths, Coukell says. The group is preparing a detailed report due out later this year.
The risk inherent in escalating imports of APIs can be addressed on three fronts, Coukell explains. “First, manufacturers must be held to a higher standard regarding knowledge of their own supply chain,” he says. “Second, FDA clearly needs new authority and the capacity to increase its footprint to cover areas where the drugs are coming from. Third, you ultimately have to be able to rely on foreign regulators to ensure the safety of products coming from their countries.”
FDA has opened liaison offices in India and China, Coukell says. And the Drug Safety & Accountability Act, a bill recently introduced by Sen. Michael Bennet (D-Colo.), would give FDA mandatory recall authority for drugs believed to be contaminated. The bill would lead to more foreign inspections by the agency, Coukell anticipates.
In a speech at China’s Peking University last month, FDA Commissioner Margaret A. Hamburg noted that 80% of APIs consumed in the U.S. are imported. And a growing portion of them are coming from China.
“No regulatory authority has, or will ever have, the resources to inspect every shipment of products from overseas, nor will we have the ability to inspect every foreign manufacturer and facility,” Hamburg said. “So we will work closely with our sister regulatory authorities—especially China’s State Food & Drug Administration—as well as with international and national organizations and with industry. We will find new ways to share information. And we will learn, step by step, to leverage international resources to accomplish our domestic mission.”
The front line in ensuring safety, however, is drawn at the company marketing the drug, according to Richard Friedman, director of manufacturing and product quality at FDA. “Owners of the product must maintain full responsibility for a drug with their name on it,” he says. “It becomes an issue of outsourcing supply management and due diligence.”
For its part, FDA is improving its systems for identifying risk and developing a risk-based method of pinpointing manufacturing facilities around the world that are most important to inspect, Friedman says. FDA has pilot programs with the European Medicines Agency on joint plant inspections and with Australia’s Therapeutic Goods Administration on exchanging inspection data. FDA has been collaborating with overseas regulators since 2000, he notes.
Drugmakers and their suppliers have also identified the need to work cooperatively in vetting overseas suppliers. An industry consortium called Rx-360, formed last year to develop shared audits and act as an information clearinghouse, currently has 45 members. Twenty-two are pharmaceutical companies, and 15 are API suppliers (C&EN, June 22, 2009, page 24).
In addition to facilitating audits and publishing security alerts on its website, Rx-360 will also pool members’ efforts on preventive strategies, says Martin Van Trieste, vice president of quality at Amgen and chairman of the group. Last year, for example, Rx-360 addressed the shortage of the solvent acetonitrile, a situation that suggested the possibility that rogue suppliers might develop a dangerous substitute.
“We brought scientists from member companies together and asked them to think like criminals,” he recalls. “We asked them, ‘What substandard materials would you use if you had less-than-pure intentions and wanted to make a quick buck?’ ” Another group of scientists convened to develop testing methods for these materials, and the information compiled was shared with members.
Trade associations representing pharmaceutical chemical producers in the U.S. and Europe, including the Society of Chemical Manufacturers & Affiliates (SOCMA) and the European Fine Chemicals Group, have been working to focus members and legislators on the problem.
“We have expressed our concerns to Congress and FDA,” says Brant Zell, vice president of quality compliance at Cherokee Pharmaceuticals and chairman of SOCMA’s bulk pharmaceuticals task force. “Unfortunately, it has taken incidents such as the heparin scandal to get the ball rolling.” Progress so far has been slow, he adds.
Although many pharmaceutical chemical producers are frustrated with FDA’s pace, they agree that they need to take ultimate responsibility for vetting their own suppliers. “It still comes down to reputable companies that will follow supply chains all the way through—companies with a social conscience that understand the risk,” Zell says.
That understanding has been enhanced by the recent tragedies, says Steven Wolfgang, a senior policy analyst in FDA’s division of manufacturing and product quality. “When you look at things that went wrong, the number one thing you find is lack of traceability,” he says. “Number two is the willingness to accept the risk of trusting the certificates of analysis without testing.” Incidents such as the heparin and diethylene glycol contaminations put risk in perspective, he adds. Drug companies, Wolfgang says, are realizing that the “buck stops with them.”