03 November 2005 11:00 [Source: ICB Americas]
IN THE late 1990s French pharmaceuticals company Roussel Uclaf made a shocking admission. Italian subsidiary Biochimica Opos, it revealed, had been deceiving the US authorities over submissions relating to the antibiotic cefaclor and, it later emerged, over the drugs minocycline and clindamycin. Key intermediates for these three drugs were not being manufactured at the specified facilities approved by the FDA and were instead being made at secret, unapproved sites in Europe. In the US, swift action was taken to shut down production, recall bulk materials and discontinue the distribution and sale of the drugs. Roussel was fined $33 million for conspiracy and defrauding the FDA—the first time a foreign company had been criminally punished over a drug manufactured outside the US and marketed to the American public.
In Europe, however, the repercussions were very different, recalls Guy Villax, chief executive of Portuguese API supplier Hovione. When Opos was prohibited from selling in the US, Villax says, it started “pushing the excess capacity that could no longer be sold in the US, in Europe”—at the same time putting pressure on European competitors such as Hovione, also then in the business of selling monocycline. European regulators were powerless to act. “On the face of European legislation,” Villax was advised, Opos was not doing anything illegal.
This week, new European legislation comes into force to prevent such situations. Under EU directive 2004/27/EC, it will from now on be the responsibility of the holders of drug marketing authorizations or pharmaceutical companies—and specifically of the relevant “qualified person” within these companies—to ensure that their APIs comply to GMP standards.
Europe’s API industry welcomes the new legislation but criticizes the lack of detail about how it will be policed. Without proper enforcement, argue both the European Fine Chemicals Group (EFCG) and the European API association (APIC), the directive will not work. “Now we finally have legislation, now it’s illegal to use APIs that do not meet GMP requirements,” says Villax, a member of the EFCG. “Now come the tricky questions: First, if there are no inspections, how do you find out those that cheat? And secondly, if they are caught, what are the sanctions?”
Over 80 percent of APIs used in European medicines now originate from India and China (see page 26). The number of plants supplying Europe with APIs is unknown, but EFCG puts the figure at up to 10,000, against 1,000 plants supplying the US, where inspections have been mandatory for roughly 50 years. Industry surveys show the differences between a GMP and a non-GMP plant are increased costs of 25 percent, reduced speed to market and a significantly lower degree of flexibility, Villax says. “Since meeting GMP requirements makes your business less flexible and more costly, unless there is an enforced level playing field there will be much more temptation to take shortcuts.”
In a position paper at the end of last year, meanwhile, APIC warned “Unless control over the API supply to the European market is drastically increased, API manufacturers throughout the world who are applying the strict and costly standards of EU regulations and guidelines will have a severe competitive disadvantage against less-ethical companies. ‘Good’ APIs and pharmaceutical firms will be pushed out of business by ‘bad’ APIs and pharmaceutical firms.”
Major health scares concerning API quality are fortunately rare, but they do occur. In Haiti in the mid-1980s, 80 children died after being administered cough medicine in which half the glycerine was adulterated with diethylene glycol, a chemical relative of antifreeze. More recently, in the US, 17 people died as a result of a “substandard” gentamicin API—proof that even the most rigorous enforcement procedures can sometimes fail. In Europe, meanwhile, Villax says it is only a matter of time before there is another scare. “What worries me is that we have better systems to check that the steak on your plate came from the correct cow than we have that your aspirin came from a compliant factory.”
The industry’s “Achilles’ heel,” say insiders, is its over-reliance on brokers. Many smaller European pharma companies have traditionally bought their APIs without ever knowing which firm originally made them. Brokers operate by replacing the API supplier’s original certificate of analysis with their own label to stop the pharma company going direct to the manufacturer. “From that moment on, you have a break in traceability because the pharma company in Europe will never know who made it,” Villax explains.
In the Haiti incident, the adulterated glycerine was made in China and sold to a Hamburg broker, which then sold it to the Dutch broker that eventually sold it to the pharma company in Haiti. No one was ever found to be responsible.
The new directive should make procedures more transparent by encouraging more pharma companies to source their APIs directly from suppliers. In addition, Villax expects many of them will begin requesting written evidence of compliance from manufacturers. Another area where enforcement is being tightened up is during existing, mandatory inspections at pharmaceutical companies. “Today, every producer of medicines is inspected regularly,” Villax says. “So the first step is that inspectors who visit these companies should be given a checklist of about 15 questions they could ask in connection with API suppliers, and that alone should make a huge difference.”
STEp IN THE RIGHT DIRECTION
But while this is a step in the right direction, EFCG insists that only governmental inspections can truly ensure patient safety and a level playing field. At present, says the European Medicines Agency’s head of inspections, Emer Cooke, “There is no routine requirement for competent authorities to inspect the active substance manufacturers, although they may in cases when they suspect serious noncompliance.” EFCG would like to see something much stronger and believes that the new legislation should deter companies tempted not to comply. “My argument is,” Villax says, “they ought to inspect a large enough sample at random, not just in Europe but abroad—frequently enough to cause some concern that ‘I may be caught.’ And then there ought to be stiff sanctions. In the absence of effective deterrence, the directive is not worth the paper it is printed on.”
European API manufacturers are understandably concerned that enforcement should be applied fairly. A recent survey by the Italian Chemical Pharmaceutical Generic Association (CPGA) blames the EU’s lack of policing for increased imports of lower-quality generic APIs mainly from the Far East. Nor is the new directive seen as particularly helpful. “The feeling by EU API manufacturers,” the report continues, “is that after this date the situation will not be much different: Inspections of APIs producing plants located outside the EU are likely to remain ‘rare exceptions’.”
Meanwhile, the potential consequences of poor GMP enforcement “could either be acute or it could be long term—a slumbering risk or ticking time bomb we do not know about,” says APIC vice-president Chris Oldenhof. “It could happen tomorrow or last a decade before something goes wrong.”
The worry is that we may not find out there is a problem until it is too late. Significantly, Villax points out, the Roussel disclosure came at the same time the company was undergoing a merger with Hoechst’s healthcare business, then headed by an American. In the US, unlike in Europe, individuals found guilty of transgressing API legislation are liable to go to jail. “Opos only got found out because it confessed.”-
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