A total 444 out of 626 inspections for cGMPs (current Good Manufacturing Practices) resulted in the issuance of a "Form 483," according to data Natural Products Insider obtained through a Freedom of Information Act (FOIA) request.
Those firms that received Form 483s from fiscal year 2010 to 2012 were cited for an average of seven "observations," such as failure to keep a facility sanitary, possess the equivalent of a recipe (known as a master manufacturing record [MMR]), or verify the identity of ingredients.
Some firms received as few as two observations, while one company was cited in fiscal year 2012 for 58 violations. A portion of the observations may reflect infractions other than cGMP violations, such as failure to comply with food cGMPs and neglect to report to FDA "serious adverse events" as required under federal law.
In fiscal year 2012the 12-month period ending Sept. 30, 2012253 of the 361 firms FDA inspected received Form 483s. One hundred and eight firms, or roughly 30 percent of the companies inspected, did not receive this document, reflecting the agency's view that they were following the regulations.
One third of cases result in "official action"
FDA expects firms that receive a Form 483 to make the necessary changes in order to comply with the cGMPs. But in fiscal year 2012, FDA classified 116 firms as "official action," initiating such actions as sending them a warning letter, according to a presentation from the agency.
Such an "official action" classification following an inspection "occurs when significant objectionable conditions or practices were found and regulatory action is warranted to address the establishment's lack of compliance with statute(s) or regulation(s)," according to a separate FDA document posted online.
In fiscal year 2012, roughly the same number of dietary supplement firms (116) were classified "voluntary action", making voluntary corrections in response to an FDA inspection. FDA also classified 92 inspections in which it took "no action."
In total, 62 percent of the firms inspected received a classification indicating the companies made the necessary corrections and/or FDA did not consider the observations listed on the Form 483 serious enough to warrant regulatory action. FDA classified roughly one-third of firms as "official action."
"When you look at the numbers of warning letters issued a year and compare it with the numbers of supplements currently on the market, it's safe to conclude that most companies comply with FDA regulations," said Tamara Ward, a spokeswoman with FDA.
Some firms fail basic requirements
While that may be the agency's broad perspective, the observations listed on the Form 483 reflect its more narrow view that most supplement firms it inspects are initially violating at least some cGMPs that a top-ranking FDA official referred to as "minimum" standards.
"Unlike traditional foods, when it's rotten, the consumer will often know by taste or smell, [but] with supplements we're swallowing them based on blind faith in the manufacturer," noted Pieter Cohen, M.D., a general internist at Cambridge Health Alliance and assistant professor of medicine at Harvard Medical School, who has studied supplement safety and reviewed the FDA data. "But FDA inspections appear to reveal a different story: when we take a look behind closed doors, less than a third of companies are doing everything they can to ensure top-notch products."
Drawing broad conclusions from the data is potentially misleading, the leader of a trade organization representing the supplement industry warned.
"Having 10 observations that are insignificant is not as big a deal as one company having one observation where they were failing to do any identity testing," observed Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), the Washington, D.C.-based trade organization representing dietary supplement manufacturers and ingredients suppliers.
"Look at the nature of the 483," he said. "Just looking at the sheer number of 483s that doesn't really tell you what's the impact of the 483 on the quality of the finished product the consumer is actually going to have in his hand."
Marc Ullman, a New York-based supplement lawyer who works with his clients to comply with cGMPs, finds the reported infractions disconcerting.
"We're talking basic failures here," said Ullman, who reviewed the FDA data. "[FDA inspectors] are telling us there are a significant number of players in the industry who are unwilling, unable or don't care what they are required to do to implement the most fundamental operations designed to ensure they are making what they claim they are making because that's what the GMPs are all about."
Shelly Maifarth, principal of the Broomfield, CO-based FDA Compliance Group LLC, which helps companies adhere to FDA requirements, said the cGMPs for dietary supplements reflect a significant change from the former rules. Supplement firms previously were inspected under food cGMPs.
The government inspections are not lackadaisical reviews of a firm's manufacturing operations. FDA shows up at a facility unannounced to conduct an inspection, which usually last several days, said Maifarth, who served as an FDA compliance officer in Denver for 22 years.
"The majority of firms receiving the 483 items have been hit hard by the new requirements," she told Natural Products Insider. "They often do not have the quality personnel in place to implement the requirements, are not prepared for the complexity, and documentation and testing requirements, and have not budgeted for the new expenses of quality and testing. FDA did a large educational campaign, but many firms were not listening."
In a previous analysis of publicly available FDA data, independent consultant Marian Boardley Consulting found the most common cGMP violations in fiscal year 2012 included a lack of identity testing of dietary ingredients, failing to have written procedures for quality control (QC) operations, and an absence of written procedures concerning customer complaints.
"It's baffling to me," Marian Boardley, the principal of the consulting firm, said earlier this year when asked to explain the reasons for the violations she found, "because some of these items are so easy to correct."
A select number of firms were cited for committing dozens of violations. In fiscal year 2012, one company received 58 "observations": Create-A-Pack Foods Inc. of Ixonia, WI, a manufacturer of food and dietary supplements.
In a Sept. 19, 2012, warning letter, an FDA official advised Create-A-Pack Foods owner Glen M. Cochrane that his company was in violation of the Federal Food, Drug and Cosmetic Act and a number of regulations ranging from food-labeling rules to preventative controls for juice to cGMPs for food. The letter didn't specifically mention cGMP violations for supplements, although Create-A-Pack was cited for "misbranding" supplements. Cochrane did not respond to phone messages seeking comment.
Cost of compliance cited for failure rates
Speaking at industry trade shows, FDA officials have expressed concern over the rate of non-compliance. But there has been little improvement, the government data show. In the fiscal year ending Sept. 30, 2012, out of the 361 inspections, FDA issued 253 Form 483s and a total of 1,833 observations. That means 70 percent of facilities that were inspected were cited for an average number of seven infractions each. In fiscal year 2011, the average number of observations, and percentage of firms receiving a Form 483, was about the same.
"cGMPs are the minimum quality standard," observed Daniel Fabricant, Ph.D., director of FDA's Division of Dietary Supplement Programs, in a presentation earlier this month during VIRGO's SupplySide MarketPlace trade show in New York.
So why are so many manufacturing firms falling short of these minimum standards? For starters, the cost of compliance with the cGMPs is expensive, supplement lawyers acknowledged. In addition to the advice of experienced counsel, firms often must retain consultants that are familiar with the nitty-gritty, such as what details to include in an MMR. Third-party auditors also are retained to inspect facilities and certify them as cGMP compliant, although their findings are not binding on FDA.
"I suspect that the majority of firms think the cost of complying with state-of-the-art manufacturing practices is greater than the cost of dealing with a 483," Dr. Cohen opined. "I suspect it's a careful decision, but one that a firm might not want its loyal customers to know about."
FDA also may be taking a tougher stance than it had in the past. Justin Prochnow, a supplement lawyer in Denver, noted the regulations are much more onerous than GMPs for traditional food. He also said FDA has made compliance with cGMPs for supplements a priority.
"I would imagine they are more stringent on compliance with the GMPs than they have been on other areas of the law because they have made it very public and this is their number one area of focus," Prochnow said.
While the rate of cGMP noncompliance has basically remained the same for the past three years, FDA has ramped up the number of inspections from 87 in fiscal year 2010 to 178 in fiscal year 2011 to 361 in fiscal year 2012. FDA officials have attributed the rise in inspections to the regulations taking full effect in 2010 and an increase in the number of field investigators who are available to inspect facilities, according to a report from the U.S. Government Accountability Office (GAO).
Enforcement Key Tool for Regulators
Lawyers who practice supplement law maintain FDA enforcement action is one of the strongest deterrents against cGMP violations. Kabco Pharmaceuticals might know something about that. After it was sued, the contract manufacturer agreed to halt production of dietary supplements until it establishes its facilities are in compliance with cGMPs. [Learn more about how the Kabco case affects the supplement industry in a video interview with attorney Anthony Young].
But it may be years before a firm violating cGMPs is hauled into federal court. A Form 483 does not carry the force of law, and FDA officials often follow up with a letter warning they may take enforcement action if a firm does not get its act together. Kabco, for instance, received a warning letter in 2010 following an inspection of its facilities in Amityville, NY. The U.S. Department of Justice didn't file a lawsuit against Kabco until summer 2012.
Public data and FDA statements indicate the agency is becoming more vigilant in the enforcement of its dietary supplement regulations. During SupplySide Marketplace, Fabricant said FDA issued 42 warning letters to supplement firms through March 2013; and he noted the agency consistently has a three-month backlog of letters signed off and ready for mailing. By comparison, an online FDA database reflects the agency only delivered six warning letters in 2010. Although INSIDER could not confirm with FDA whether that figure was accurate, Ward verified the agency has increased the total number of warning letters that have been sent in recent years.
Still, FDA's dietary supplement team is stretched thin, especially when compared to its overall budget. Citing FDA officials, the GAO revealed the agency's resources for all dietary supplement activities increased from $14.6 million in fiscal year 2009 to a projected $18.9 million in fiscal year 2012. In fiscal year 2012, FDA had an overall budget of roughly $2.5 billion (excluding $1.3 billion in user fees), according to Steven Grossman, deputy executive director of the Alliance for a Stronger FDA.
"For years, FDA has been underfunded and understaffed for its responsibilities in the regulation of dietary supplements," said David Schardt, a senior scientist with the Center for Science in the Public Interest, a Washington, D.C.-based nutrition and health advocacy group.
Fabricant acknowledged the agency's budget crunch at a time when the nation is $17 trillion in debt and grappling with $85 billion in across-the-board cuts under the so-called sequester. He expressed his appreciation to trade groups that have lobbied for more funds.
"We do have limited resources, but we use the tools we have," Ward, the FDA spokeswoman, said. "These include monitoring mandatory reporting of serious adverse events by dietary supplement firms and voluntary adverse event reporting (AER) by consumers and health care professionals. As its resources permit, FDA also reviews product labels and other product information, such as package inserts, accompanying literature and Internet promotion."
The modest increases in FDA's dietary supplement budget don't appear to be commensurate with growth in the natural products industry. According to Nutrition Business Journal, dietary supplements yielded around $30 billion in 2011 sales. That figure is nearly eight times the estimated $4 billion in sales at the time the Dietary Supplement Health and Education Act (DSHEA) of 1994 was passed into law. DSHEA is the law that gives FDA the power to enforce GMPs. Burgeoning demand for dietary supplements is only likely to increase the toll on FDA in its quest to ensure that firms are manufacturing safe, quality products.
Still, Maifarth of FDA Compliance Group maintained cGMPs have been beneficial for Americans, 150 million of whom are said to take supplements.
"The consumer is clearly benefiting from the cGMPs," she said, "as dietary supplements are now more consistent and true products."