For a number of years, FDA inspectors have continued to observe dietary supplement firms commit the same egregious violations of manufacturing regulations. Unfortunately, fiscal year 2015 was no different.
Nearly 19 percent of dietary supplement firms that were cited by inspectors for violations of the cGMPs (current good manufacturing practices) allegedly failed to set specifications for the identity, purity, strength and composition of the finished product, INSIDER learned through a Freedom of Information Act (FOIA) request. About 16 percent of firms that were issued a document for violations of cGMPs, or 46 total inspections, failed to verify the identity of a dietary ingredient through an appropriate test or exam, according to the FDA data.
Other common violations of the 9-year-old cGMPs related to batch production records (15.30 percent), written procedures for quality control (QC) operations (13.88 percent) and written master manufacturing records (MMRs, 11.03 percent).
“We’re still seeing observations that are the basics of a GMP system—that is failure to have finished product specs, failure to do identity testing [and failure to have written procedures for quality control]," said Cara Welch, Ph.D., senior advisor to the Office of Dietary Supplement Programs, in a phone interview. “These are serious issues, and the agency is concerned."
FY15 cGMP inspections: 483
Form 483s issued: 281
Total observations: 1,437
Average number of observations: 5.1
Most common observation: failure to establish product specifications
Dietary supplement facilities registered with FDA: 12,964
In the fiscal year that ended on Sept. 30, 2015, FDA issued what’s known as a Form 483 to 58 percent of firms that were inspected, citing “observations" or violations of cGMPs. Of the 281 firms that received the document, companies were cited for an average number of 5.1 observations. The figure is down from an average number of 5.6 observations in the previous year.
FDA adopted the regulations in June 2007—nearly nine years ago—and they have been in effect for even the smallest companies for about six years.
“At some point, they are going to lose the new shine to them," Welch conceded. “I would say the agency is getting frustrated with the overall lack of compliance with the major issues of the GMP system."
Daniel Fabricant, Ph.D., FDA’s former director of the Division of Dietary Supplement Programs, used the “sophomore jinx" analogy, asking whether re-inspected firms are making progress complying with the regulations or continuing to be cited for rudimentary observations such as failure to test ingredients.
“The sophomore year is the most telling in terms of how they improve … because you have a baseline" to compare results, explained Fabricant, executive director and CEO of the Natural Products Association. “Are you seeing from inspection one to inspection two improvement where there were problems? Or are we just looking at, ‘Hey, this is still the end of everyone’s freshman year?’
“The key thing in GMPs is continuous improvement," added Fabricant in a phone interview. “So, if you are not seeing improvement from one to two or from one to three, that doesn’t bode well for anybody."
The question—whether sophomores, or firms that are reinspected, are becoming more compliant with the regulations—isn’t a simple one to answer. Sixty three firms were reinspected in FY15 and cited for an average number of 1.65 observations, according to FDA data INSIDER obtained. That’s down from an average number of 2.22 observations in previous inspections of the 63 firms.
Approximately 16 percent of reinspections—or 10 firms—purportedly failed to verify the identity of a dietary ingredient prior to use through an appropriate exam or test. In the previous inspections, FDA cited 32 percent of the 63 firms for the same violation.
Some of the FDA figures are puzzling—and highlight the limitations of interpreting aggregate data—because one would expect that companies targeted for a reinspection had been cited for numerous cGMP violations in the initial audit, not just an average of 2.22. The FOIA Office noted limitations in the data and referenced its determination through a manual review whether a firm was reinspected.
The reinspection data still reflects continuing areas of concern for the industry. Fifteen dietary supplement reinspections—or nearly one-quarter of all of them—resulted in citations for failure to establish product specifications. Setting product specs, cGMP consultants have noted, is a basic requirement. Around 17 percent of reinspected firms were cited for having inadequate batch production records.
“Largely, it’s the same problem … that systematic issue with GMP compliance," FDA’s Welch said, citing the most common violations in the reinspection data.
“As we’ve seen, the industry knows we need to move much further beyond cGMPs to have a product that consumers can trust," said Pieter Cohen, M.D., an assistant professor of medicine at Harvard Medical School who has researched a number of sports products that are tainted with illegal substances. “So the fact that 60 percent of firms inspected aren’t even making this incredibly low bar of cGMP is frankly embarrassing and poses serious risks to consumers."
Fabricant, the former FDA official, also pointed out some of the limitations in the aggregate data.
“Is it failure to set specification for identity?" he asked, commenting on companies that were cited in FY15 for failure to establish specs. “Is it failure to set a specification for strength, potency [or] purity? I think that those are very different issues."
He also noted distinctions between firms failing to set any specifications at all, and FDA’s interpretation of whether there was an adequate degree of evidence to support the specifications.
“If there’s completely absolutely nothing at all [no specification], that’s one thing," Fabricant acknowledged.
Joy Joseph, a cGMP consultant to dietary supplement firms, said many new companies have emerged in the dietary supplement industry. She still encounters firms that aren’t even aware of the FDA regulations in spite of the fact that they were adopted nine years ago.
“We still have a lot of companies that have never been inspected, and still today, most dietary supplement companies don’t have laboratories, and they don’t have qualified people to establish the correct specifications and do the testing," said Joseph, principal consultant with Joy’s Quality Management Systems, in a phone interview.
“And at the end of the day," she added later, “it is the consumer who is being harmed by these products being manufactured by companies who don’t know anything about GMPs."
In FY15, FDA inspected 483 dietary supplement firms for compliance with cGMPs. That’s the same number of inspections as the previous year.
Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), said he would like to see FDA inspect more firms and take a greater number of enforcement actions.
As of March 21, 2015, there were 12,964 dietary supplement facilities registered with FDA. Of that number, 5,046 process or manufacture dietary supplements, according to the agency.
“Not only do they need to do more inspections, but when they find these egregious situations, they need to prosecute enough of them to send a deterrent message to the rest of the industry," Mister said in a phone interview. “Prosecuting two or three companies a year is not … a deterrent."
Cohen, who is a physician at Cambridge Health Alliance in Somerville, Massachusetts, also criticized FDA.
“If someone wants to profit selling supplements, there’s some good news here in these [cGMP] numbers," he said in a phone interview. “The FDA apparently … checks these companies, finds that they are failing inspections, and then doesn’t do anything about it … So, if you are in the business of trying to make money selling supplements, you want to cut corners, you are in the right business today because there appears to be no consequences for not ensuring that what you are selling to consumers is what you think it is or what you think you purchased."
Federal prosecutors bringing actions on behalf of FDA likely disagree. In November 2015, the U.S. Justice Department announced civil and criminal enforcement actions against more than 100 makers and marketers of dietary supplements. The government activity included lawsuits against dietary supplement firms that were allegedly violating cGMPs and making claims that products treat diseases.
Earlier this week, as NPA revealed in a tweet, Sen. Claire McCaskill (D-Missouri) asked the Justice Department for information on cases that it has prosecuted against the industry. The trade association posted a link to the March 29 letter from McCaskill to Attorney General Loretta Lynch.
“The FDA prioritizes enforcement actions based on available resources and the level of safety concern identified," said FDA spokeswoman Marianna Naum in an emailed statement. “The agency faces the challenge of having limited resources to monitor the marketplace for potentially harmful dietary supplements."
Smaller Firms, Dietary Supplement Marketers Still Struggling with cGMPs
Small companies in the dietary supplement industry are continuing to face a harder time than their larger peers complying with the cGMPs, according to industry sources.
"Medium to large companies seem to be doing reasonably well," said Loren Israelsen, president of the United Natural Products Alliance (UNPA), in a phone interview. “It's the small companies that I think many are well intended, but may not have the resource," Israelsen continued, “and therefore [are] still having problems with some of the more difficult, more expensive parts of GMP compliance."
Public records indicate the majority of FDA enforcement actions for cGMP noncompliance, such as civil injunctions, are filed against small, private firms. FDA also has reported that supplement companies with more than 500 employees generally have not been the subject of a so-called official action (OIA) indicated. OIA is an FDA classification associated with significant objectionable conditions of noncompliance.
In reviewing FDA warning letters, Council for Responsible (CRN) president and CEO Steve Mister cited continuing problems of noncompliance that are plaguing marketers of dietary supplements that outsource their manufacturing.
“There continues to be a disconnect with these companies [that] are marketers that they have 100-percent responsibility and stewardship for that product, even though they don’t make it because they put their name on it," Mister said in a phone interview. “The FDA shows up for the inspection and they say, ‘I only market the product. Go talk to my contract manufacturer. He’ll tell you everything that you need to know about the product.’ And FDA keeps saying, ‘That’s not enough.’ The law says if you put your name on it, you need to set the specifications, you need to sit down with the contract manufacturer and ask them, ‘What are the limits on contamination? How do you ensure that it’s a consistent product from lot to lot to lot?’ And a lot of these marketers are not doing it."
Cost is another issue that may be hamstringing smaller firms. "The problem is the vast majority of materials being purchased are powder," Israelsen said. “That requires different equipment, expensive equipment, analytical methods, standards [and] people to run the lab.
“That's the investment part that the small companies are having trouble making," he continued. “Like any other industry, they simply just can't afford the inbound cost of identity, which ... is [a] fundamental starting point. They need to get that right."