Issue Date: June 18, 2007
Trusting Medicine From China
CHINA IS AN INCREASINGLY competitive supplier of drug ingredients to the U.S. But in the wake of recent scandals involving Chinese food and drug ingredients, critics are asking for more controls on imports from that country.
Last month, the Synthetic Organic Chemical Manufacturers Association (SOCMA), a U.S.-based group of fine chemicals makers, reiterated its call for the Food & Drug Administration to step up visits to overseas pharmaceutical plants. The association claims that foreign-made active pharmaceutical ingredients (APIs) are often produced in plants that have never been inspected by FDA.
SOCMA's statement was prompted by media reports that a cough syrup formulated with counterfeit Chinese glycerin had killed dozens of people in Panama last November. Glycerin is an edible substance that is routinely used in making medicinal liquids. Unscrupulous businesspeople have from time to time substituted diethylene glycol for glycerin to cut costs. This practice prompted FDA to issue a recommendation last month that all manufacturers of pharmaceuticals test any glycerin they plan to use for diethylene glycol contamination.
An official investigation in China found that the counterfeit glycerin supplied to Panama was made by Jiangsu-based Taixing Glycerin. The report said the Chinese company had been selling diethylene glycol under the name "TD glycerin." The investigators also found that Taixing had been diligent in telling its buyers what the product actually was. But the Panamanian importer of Taixing's product had falsified the content labels, the Chinese report said.
Executives at Chinese pharmaceutical companies claim to be shocked by what happened in Panama and dismayed at the damage it has inflicted on their industry's image. Yan Zhou, general secretary of the China Pharmaceutical Industry Association (CPIA), says she is infuriated that a Chinese company was involved. She acknowledges that counterfeiting is a widespread problem in China, but she argues that the practice is in no way representative of the country's top drug exporters. "Would it be possible for China to keep exporting more and more drug ingredients if our products were consistently substandard?" she asks.
Xiao Dong Li, deputy director of the technical operations department at Shanghai Pharmaceutical, one of China's largest drug companies, says he never wants counterfeit Chinese drug ingredients to harm anyone again. Li says he welcomes more frequent FDA inspections of plants in China. However, he adds that foreign importers of Chinese products also "bear big responsibilities."
Most Chinese pharmaceutical companies, Li says, will supply products to foreign customers on the basis of required specifications. If buyers ask for specifications that do not meet their own market's requirements, the Chinese supplier is not the only one to blame.
As for the U.S., Li adds, "all APIs made by Shanghai Pharmaceutical and exported to the U.S. or Europe have been inspected and approved by the U.S. FDA or its European equivalent." He says it's extremely difficult to falsify the labels of such products, which are, in any case, tested again by the U.S. or European buyers upon receipt. CPPA's Zhou says she is not aware of APIs being exported to the U.S. from plants that haven't been inspected by FDA. "Sometimes SOCMA or other associations urge quality controls as a trade barrier to protect the interests of their members," Li says.
THE ASSERTIONS of these executives contradict SOCMA's argument that many plants making APIs for the U.S. market are never inspected. Sources tell C&EN that SOCMA's claim is questionable if the association is referring to regulated pharmaceuticals that are sold by prescription. The group is mostly correct, though, if it's referring to over-the-counter (OTC) medications and nutraceuticals, because plants making ingredients for these products are routinely exempted from inspection.
Guy Villax, chief executive officer of the Portuguese API manufacturer Hovione and chairman of the pharmaceuticals business committee of the European Fine Chemical Group, says he has been lobbying for years for more inspections of pharmaceutical plants abroad.
Villax, a former member of C&EN's advisory board, says it's unlikely that a plant exporting APIs to the U.S. could do so without a visit by FDA inspectors, particularly when the ingredients are used in regulated drugs. But he argues that, because of deficiencies in other aspects of the inspection regime, patients in both Europe and the U.S. are not sufficiently protected against shoddy pharmaceutical ingredients.
European government inspectors do visit some plants outside the continent that make pharmaceutical ingredients for both OTC and prescription medicines, Villax says. Still, many such plants remain unvisited by European inspectors.
FDA INSPECTORS visit all plants anywhere in the world that make pharmaceutical ingredients for the U.S. market, but only if these ingredients go into prescription medicines. When it comes to OTC products or nutraceuticals, FDA inspects only the formulation facilities that make pills, syrups, or ointments out of ingredients sourced from various places, Villax says.
For OTC pharmaceuticals, FDA checks whether the formulators have systems in place for ensuring the integrity of the ingredients they are sourcing. He says formulators usually recognize shoddy ingredients for what they are. "If there's a seller who's cheating in order to be able to supply a drug ingredient at a lower price," Villax says, "there's also an idiot who knows for sure that the price he's paying is way too low."
Because a crime as heinous as intentionally supplying harmful drugs or drug ingredients seemed unlikely until recently, legal penalties are light in most countries, Villax points out. He says stricter regulations are nearing implementation in Europe. "The clamping down is going to be very tough," he says.
Dave McCleary, senior vice president of sales at Chemwerth, the largest U.S.-based importer of APIs from China, says his company does not get involved with OTC ingredients or nutraceuticals. Competition in those businesses is intense and the profit margins are low, he says. Chemwerth buys regulated pharmaceutical ingredients from China made in plants where Chemwerth has been allowed to set up its own quality control systems.
McCleary confirms that it's unlikely that counterfeit ingredients could make their way into medicine prescribed to patients in the U.S. When a medicine requires a prescription, he says, the degree of scrutiny is high. For injectable substances, bad quality could easily be deadly, but the number of mandatory analysis reports required before the substance can be used is also particularly high, he says. The bottom line is that "for regulated APIs, if there are problems, they will be picked up," he says.
On its website, FDA explains that since 2002 it has followed a "risk-based" method for deciding which plants it needs to inspect frequently. In 2004, the agency clarified that plants making prescription pharmaceuticals require a higher degree of regulatory oversight than those involved in making OTC treatments. The agency says its model helps it to best allocate its oversight resources.
Peter Saxon, a New Jersey-based consultant who advises drug companies in China on FDA compliance issues, expects Chinese API makers to increase their exports to the U.S. He even sees Chinese companies exporting finished formulations in the near future. With a degree of disdain for SOCMA's call for more FDA inspections of plants abroad, Saxon comments that "SOCMA may want to put China out of the API business, but it just will not happen in our lifetime."
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