As drug making goes global, oversight found lacking
The fungal meningitis outbreak has prompted more Americans to ask two questions: Where do my medicines come from, and how do I know they’re safe?
8:31AM EDT October 21. 2012 – NASHVILLE — The medicines you took this morning could have come from anywhere, and everywhere, in the world.
The active ingredient might have been sourced from China. Fillers, binders and other inactive ingredients could have come from India. They all could have been processed in Germany, then sent through Canadian middlemen to the United States for final production and distribution to your local pharmacy.
In short, what’s in your medicine cabinet is the result of a vast, interconnected global web of raw materials suppliers, chemical producers, brokers, re-sellers, drug manufacturers and distributors.
It’s a system that operates largely outside of the public’s consciousness, except when a breakdown puts lives at risk — such as the fungal meningitis outbreak linked to contaminated steroid shots.
The ongoing outbreak has sickened 284 people and killed 23 in 16 states so far. Investigators haven’t said how the steroids became tainted, but they are focusing on a Massachusetts compounding pharmacy that prepared them.
The outbreak has prompted more Americans to ask two questions: Where do my medicines come from, and how do I know they’re safe?
The answers are elusive. The pharmaceutical supply chain’s sheer size and number of players, gaps in regulatory oversight, the government’s inability to order recalls of unsafe drugs and the lack of a tracking system make it difficult for Americans to know exactly what’s in the medicines they take.
‘Supply chain is very vast’
Pharmaceutical imports have more than doubled in the past decade, the U.S. Food and Drug Administration says. It now estimates that 80 percent of ingredients in U.S.-made drugs — and 40 percent of finished medications Americans take — come from abroad.
“The supply chain is very vast,” said Dr. Desmond Hunt of the U.S. Pharmacopeial Convention, which publishes standards for drug products made and sold in the United States. “It’s changed a lot in the last 25 years. It went from being more domestic to being more global in nature.”
U.S. drug companies began turning to foreign sources in the 1980s for a variety of economic, regulatory and logistical reasons, said Molly Bowman, industry research manager for Thomson Reuters. It may be cheaper to get raw ingredients from foreign sources, and easier to develop, test and bring to market new drugs in other countries, she said.
Some foreign pharmaceutical companies have supplied the U.S. market for decades under agreements with American manufacturers. But it wasn’t until the late 1990s that finished medications from India began appearing in the United States, followed by Chinese-made drugs more recently, she said.
“There are lots of (pharmaceutical) products manufactured in India and China that aren’t made in the U.S. anymore,” Bowman said.
Foreign suppliers and manufacturers whose products end up in the United States are supposed to comply with the U.S. Pharmacopeia, which sets standards for the strength, quality and purity of more than 4,500 medicines and their ingredients. It’s written by the pharmacopeial convention, a non-profit scientific organization.
But while it creates the standards, the convention is powerless to enforce them.
That’s the job of the FDA, which requires all manufacturers to comply with the standards for any drug they want to import or market in the United States. State boards of pharmacy, including Tennessee’s, also have incorporated the standards into their own regulations.
Inspections overseas rare
Experts say the regulatory system, as a whole, safely produces, distributes and delivers millions of doses on a daily basis. It’s one that Americans trust, at least when it comes to U.S.-made drugs.
A recent U.S. Government Accountability Office study said the FDA inspects foreign drug manufacturing facilities about once every 11 years. The pace was even slower — once every 14 years — for those in China and India, America’s largest pharmaceutical suppliers.
By comparison, U.S. facilities are inspected every 2.5 years or so, the GAO said.
The FDA says it can’t enter foreign facilities unannounced. In contrast, the FDA can, and often does, conduct surprise inspections of U.S. facilities.
Also, while federal law requires the FDA to inspect U.S. drug facilities every two years, there’s no similar requirement for foreign sites. Up to two-thirds of foreign pharmaceutical sites have never undergone an FDA inspection, the GAO said.
Patient-safety advocates say without the threat of surprise inspections, foreign companies might have less incentive to use good manufacturing practices. One example they cite is tainted heparin that killed more than 80 Americans in 2007 and 2008. It later was traced to a cheaper chemical substitute used in making the drug’s active ingredient in China at a factory that never had been FDA-inspected.
“They might be tempted to cut corners if they know no one’s really watching them,” said Dr. Michael Carome, deputy director of Public Citizen’s health research group.
It’s also a business issue for American companies. The Society of Chemical Manufacturers and Associates, which represents U.S. drug ingredient manufacturers, contends infrequent inspections give foreign companies an unfair competitive advantage. The group has advocated for more foreign inspections.
More regulatory gaps
Carome and other safety advocates also point to other regulatory gaps for foreign pharmaceutical firms.
For example, establishments that don’t directly export to the United States are not required to register with the FDA, even though their products can still reach U.S. consumers through a third party. A manufacturer in Norway who uses ingredients from Vietnam to make a drug that’s sold in the United States would have to register; the Vietnamese supplier would not.
Another issue: FDA regulations for drug ingredients apply only to manufacturing, not to pre-production steps such as collecting and extracting source material.
And excipients — inactive ingredients in drugs such as preservatives, fillers and flavors — are evaluated only as part of the approval process for a new drug.
“From a legal viewpoint, the FDA will say it has authority over all drug components,” said Allan Coukell, health programs director for the Pew Charitable Trusts’ health group. “From a practical point of view, excipients are less likely to come under scrutiny. But they tend to be things that have been used with few problems for many years.”
Despite those efforts, the quality of pharmaceutical ingredients can vary widely:
— Earlier this year, the manufacturer of Makena, a brand-name drug used to prevent premature birth, obtained samples of the drug’s active ingredient from seven unregistered Chinese manufacturers and three U.S.-based repackagers. Eight samples did not meet FDA quality standards, and one of the Chinese samples was not the ingredient at all but glucose instead, the study’s authors said.
— The FDA said a 2006 laboratory analysis of 125 active ingredients obtained from compounding pharmacies found that all met product-quality standards. The FDA study did not say where the pharmacies got those ingredients.
Episodes of tainted pharmaceuticals have prompted several efforts to strengthen security and oversight of the supply chain.
The most recent is the FDA Safety and Innovation Act, which President Barack Obama signed into law in July. Among other things, the law:
— Allows the FDA to collect user fees from generic drug manufacturers, including those who supply active ingredients for generics, with the money earmarked for conducting more foreign inspections. The FDA said it plans to add 16 inspectors in China.
— Requires all ingredient suppliers to register with the FDA if their products are used in drugs made or sold in the United States, not just those who directly export here.
— Mandates that all drug importers register with the FDA.
Despite those efforts, gaps in oversight remain.
The United States does not have a national prescription drug “track and trace” system to prevent counterfeit and substandard drugs from reaching consumers. Advocates say it also would make it easier to recall and trace unsafe drugs.
Another shortcoming: Although the FDA recently was granted authority to order mandatory recalls of contaminated or dangerous food products, it still is limited to seeking voluntary recalls for unsafe drug products.
Those gaps underscore the need to maintain oversight of the medications Americans take, even as episodes such as the meningitis outbreak remain rare, Coukell said.
“On a day-to-day basis we enjoy a very safe system, but there are still risks in the system that we need to address,” he said. “We have to make sure our vigilance keeps up with the risks.”