The European Union’s Falsified Medicines Directive (FMD), a law enacted in 2011 to prevent falsified active pharmaceutical ingredients (APIs) from entering Europe’s drug supply chain, went into effect on July 2. The FMD requires that any APIs coming into Europe be accompanied by a written confirmation from a competent authority that the chemicals were manufactured according to current good manufacturing practice (cGMP) standards, the U.S. Food and Drug Administration criterion that has been established as the gold standard for regulatory quality oversight worldwide. The response from Europe’s API suppliers to FMD is: good, but far from good enough.
Characterizing FMD as merely a step in the right direction, Tony Scott, adviser to the European Fine Chemicals Group (EFCG), says the level of trust involved in requiring only a written confirmation on material shipped from China, India and elsewhere is ill advised, given the known instances of falsified documentation and corrupt practices in those countries. He points to the recent, rather glaring example of Ranbaxy, a major Indian generic API supplier that has been embroiled in a data falsification scandal since a plant inspection brought problems to light in 2006.
According to Scott, who was instrumental in forming EFCG and has led the organization since its inception in 2004, the only way to assure the quality of materials entering Europe is to actually inspect the plants manufacturing those materials. In the protracted debate and discussion leading up to the FMD, however, European regulatory authorizes arrived at an estimate of 15,000 to 20,000 facilities supplying APIs to Europe’s drug makers. Inspecting that many plants, it reasonably determined, would be impossible. Scott says EFCG has no idea how regulators arrived at that range. The association insisted during deliberations that fewer than 1,500 sites operated by the top 20 API suppliers from outside the EU are the source of most imported APIs—a number of facilities that could have manageably undergone inspection in time for the law to go into effect, says Scott.
“I think the European authorities have taken a big risk in beginning a process of trust, and I think that is an admirable thing to do,” says Scott. “But where is the enforcement?” The only way to enforce the directive is to physically inspect the plants importing APIs to Europe, he says.
Scott contends that far more powerful lobbyists than the EFCG —including those representing pharmaceutical companies—supported the notion that the number of plants involved would eliminate the possibility of comprehensive inspection, or lead to drug shortages and price increases if an inspection regime were launched.
Enforcement of laws protecting the supply chain has been a thorny issue in Europe for some time, says Scott. He points to a 2001 European Commission directive requiring APIs to meet the cGMP standard. “If that were to have been properly enforced, you wouldn’t need the FMD,” he says. “FMD is really an umbrella over things already in place for regulatory purposes with a view to putting sticking plaster over them and assure that they seem to be working better than they have in the past.”
Scott says the API producers have also expressed a willingness to pay for inspections through a program similar to the Generic Drug User Fee Amendments of 2012 (GDUFA) in the U.S., under which drug makers and API suppliers pay a fee to expedite plant inspections as part of the drug approval process for generic drugs. “We offered, but we were refused by the European Medicines Agency,” says Scott. The agency, Europe’s equivalence to the FDA in the U.S., saw a user free as, “a step too far,” he says. “And very often, dare I say, when the Americans do something and do it well, the European people will just for that reason not do it. And it is really very worrying if this attitude prevails.”
Scott notes that differences between the U.S and European fine chemicals sectors have become a bit problematic elsewhere, as negotiations on pending trade agreements currently find the Europeans, “more advanced in their preparations and thinking than the Americans, who are dragging their feet in all directions.” More on that at Fine Line soon.
FMD, of course, is but one front in the war against falsified, counterfeit, and criminally adulterated drugs which has ramped up considerably since the heparin case in 2008. FMD is also inextricably connected to the competitive landscape in pharmaceutical fine chemicals, where European and U.S. producers have over a long period of time seen much of the business go to lower-cost, and in many cases, lower-quality producers in China and India. While there are many world-class chemical suppliers in these countries, all of which are regularly inspected and glad of it, there are many stories about Chinese companies being inspected, but having the chemicals they supply manufactured by uninspected subcontractors. Scott claims EFCG has presented photographic evidence of this practice to regulators.
And then, there is Ranbaxy, which has truly shaken the Indian API supply sector.
What is lacking, still, is a great public outcry for safer drugs. This is partly a problem of communicating the arcane mechanisms of the drug supply chain. API falsification is a lot harder for the public at large to understand than lead paint on toys. And Scott says regulators throughout the process of developing the FMD, have challenged industry repeatedly for greater evidence of a threat to the public due to falsified drugs.
“They keep saying, ‘show us the body bags,’” says Scott. “We can’t!” And he admits that the issue not resonating with the public is a problem, given the political dimension to making changes in a law that will be perceived as liable to increase the price or interrupt the availability of drugs, and/or raise taxes. It is an uphill climb for EFCG. “Trade associations like ours have a lot of high quality thinkers,” he says. “But only modest resources.”
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