Imagine that you run a government agency responsible for ensuring complicated products are made safely and, in particular, the manufacturing processes for key ingredients are kosher. Not an easy task, in the best of circumstances. But how should you react if a company gives one of your inspectors a hard time? Let's say, for instance, that your inspector arrives at a plant and, instead of being provided the necessary paperwork and access to the production area, the inspector is directed to an entirely different office and given only a limited set of documentation to review.
In some circles, this is called getting the bum's rush. But that's exactly what happened last August, when an FDA inspector visited a Synbiotics facility in Vadodara, India, which makes active pharmaceutical ingredients. The inspector was denied access to the plant and never got to review the operations. Instead, the inspector was escorted to a business office at another location and had to rely on answers to questions and a review of paperwork to complete a review. Even then, the inspector was able to determine that the unseen facility was committing significant deviations from Current Good Manufacturing Practice, although that conclusion was hardly surprising, given the treatment.
Certainly, a warning letter was in order, but the episode also raises a larger question - should the FDA have been a little tougher on the company? Before we try to answer this, let's consider some context. For the past few years, theagency has been under considerable pressure to do a better job of monitoring foreign plants. This can be traced to the infamous scandal in which contaminated heparin made in China was linked to 81 deaths and numerous injuries back in 2007 and 2008.
Since then, the U.S. General Accountability Office issued a scathing report about FDA oversight. Several House Republicans followed up by chastising the agency for failing to fully probe the heparin episode and, more recently, the House Committee on Oversight & Government Reform has become particularly interested in activities in Puerto Rico, thanks to manufacturing fraud at a GlaxoSmithKline facility and production problems at a Johnson & Johnson plant involved in countless product recalls.
This is not to say the FDA has failed to tackle problems when they become apparent. Two years ago, for instance, the agency determined that Ranbaxy Laboratories sold misbranded or adulterated drugs in the U.S., the generic drug maker's largest market. The FDA reacted by halting approvals at two plants in India, after previously banning imports of more than 30 generic medications. There is still no resolution and, clearly, the FDA has attempted to use this transgression as an example of what may occur when a company fails to follow good manufacturing practices and remain responsive.
Given the heparin scandal and the general uneasiness about manufacturing standards overseas - where a fair amount of active pharmaceutical ingredients are made - it may be worth asking whether the FDA should get tougher on some API manufacturers. This is not to say that each mistake is worthy of regulatory banishment and that a company should not be permitted to resolve problems. But refusing to allow an FDA inspector on the premises should not be tolerated.
The December letter to Synbiotics, by the way, was not the only one issued at the time. The agency actually issued warning letters to four different API manufacturers and slammed them for a host of significant deviations from cGMPs. These included failures to establish a stability program to monitor APIs, maintain adequate laboratory controls and maintain adequate records, or demonstrate that analytical tests can detect and quantify impurities or degradants in an API.
To some, these may be considered run-of-the-mill problems - serious, sure, but not so highly unusual as to set off alarms and close them down. But then . . . just read one of the letters to get a better idea of what occurred at one company. The December missive sent to Macco Organiques in Quebec, Canada, notes that the deviations found and written up on a 483 form were the same type as those contained in a 483 filed in June 2001 � nearly a decade earlier. Perhaps Macco had its act together in the interim and only recently lapsed back into bad practices. Or maybe not. Maybe Macco required more adult supervision over the years, but that simply wasn't possible. Just the same, the FDA wrote that it "takes repeat deviations very seriously."
Good to know. But then it's hard to take the FDA seriously when all it does is issue warning letters. We asked theFDA about its decisions in these situations and a spokesman wrote back that it would be worth taking a look at chapters4 and 9 of the Regulatory Procedures Manual. These contain a host of carefully crafted regulations that speak to why,how and when the FDA should consider various enforcement actions, from issuing warning letters to strategies for dealing with problem importers. And yes, the manual is worth aclose read.
In the agency's defense, it is also worth remembering that the FDA did post the letters on a prominent spot on its web site, which helped to generate some publicity and awareness of the problems. Yet this begs a question: If these violations were so serious and there is so much concern about the safety of foreign suppliers these days, why did the FDA exercise some discretion and not go further to prevent these companies from shipping allowing their products into the U.S.? Certainly, the FDA should be expected to follow the procedures detailed in the manual and, of course, there are good reasons - including legal reasons - for an agency to take measured steps.
Yet the FDA might also want to use one of these instances to set an example. This is not a new concept, after all - parents try this tactic with their children all the time. So if an API supplier is a problem child, perhaps the FDA should try sterner measures. Synbiotics might make a good example. The company essentially humiliated the agency by refusing to allow an inspector on the premises. This is the sort of scenario U.S. policy makers and legislators fear will happen, particularly in China, where enforcement provisions are still taking hold as the FDA attempts to create a meaningful with China's State Food and Drug Administration.
Setting a tone, especially at this point in time, may have some value. Consider that the FDA is now getting ready to outsource inspection functions, suggesting the possibility that oversight could become more inconsistent. Why? For one reason, the move could reduce the number of inspections that plants would reportedly undergo each year. Remember that the U.S. GAO last year issued a report that noted the agency already inspects foreign plants once every nine years, compared with once every 30 months for plants in the U.S.
Meanwhile, though, more manufacturing will be done overseas, so how is the FDA to keep up otherwise? "Werecognize that third-party inspection programs need to bea bigger part of the discussion, because we can't do allthe work ourselves," John Taylor, the FDA's acting principal deputy commissioner, told an industry conference, according to Bloomberg News. "We're looking at anything, anythingand everything that will allow us to leverage our Resources better."
Presumably, outsourcing would make it possible to inspect more plants more often, which is a good thing. But what happens when a supplier gives the bum's rush to a third-party inspector? The ensuing bureaucracy just might make it more difficult to bring the supplier to heel. Sure, the FDA will work with regulators in other countries to adopt uniform procedures for all sorts of scenarios, but the agency should consider that setting a tone today can go a long way toward making clear what is - and isn't - acceptable tomorrow. The next time a supplier refuses an inspector to enter the premises, the FDA should scour its manuals and come down hard. Warning letters may be a desirable and necessary step in a difficult process, but the agency should not allow itself to be humiliated again.
Ed Silverman is a prize-winning journalist who has covered the pharmaceutical industry for The Star-Ledger of New Jersey, one of the nation's largest daily newspapers, for more than 12 years. Prior tojoining The Star-Ledger, Ed spent six years at New York Newsday
and previously worked at Investor's Business Daily. Ed blogs about the drug industry at Pharmalot, at www.pharmalot.com. He can be reached at email@example.com.