WASHINGTONFDA inspectors last fiscal year cited a smaller percentage of dietary supplement firms than in the previous 12-month period for alleged violations of cGMPs (current good manufacturing practices), although the average number of "observations" for each business that received a Form 483 remained the same.
In fiscal year 2013 (FY13), 270 dietary supplement firms, or 65 percent of the businesses inspected, received a government document (Form 483) that reflects alleged violations of cGMPs following an FDA inspection, according to data Natural Products INSIDER obtained through a Freedom of Information Act (FOIA) request. FDA inspectors reported 1,913 observations on the Form 483s, or an average of 7.1 alleged infractions of cGMPs for each company. The median number of observations per company was slightly lower: 6.5. One hundred and forty six firms, or roughly 35 percent of the companies inspected, did not receive a Form 483. The data was pulled from FDA's automated Form 483 reporting system and was current as of Feb. 19, 2014.
According to the FOIA data, only 416 firms or 2.8 percent of the total number (14,995) of domestic and foreign dietary supplement firms registered with FDA were inspected last fiscal year, raising a question: Is the inspection data an accurate representation of the broader industry's compliance with cGMPs?
"That data represents what the field sees," said Daniel Fabricant, Ph.D., director of FDA's division of dietary supplement programs, in a phone interview. "That means by observations alone, we got a lot of problems out there. If people have better data, I'm happy to take a look."
He added, "We have more people out of compliance than we have in compliance by virtue of the data."
FDA registration data does not specify the number of registered domestic and foreign dietary supplement firms that are subject to the dietary supplement cGMPs. Fabricant pointed out the data from the food facility registration system reflects significantly broader business types, such as dietary ingredient facilities and other facilities like offices that are likely not covered by the cGMPs.
FDA cannot confirm the number of registered domestic and foreign dietary supplement firms that are subject to the cGMPs, partly because it's unknown how many firms are actually operating. FDA has heard estimates that approximately 4,000 firms are covered under the cGMPs.
Data Consistent with Previous Years
The FY13 FOIA figures showed a slight improvement in cGMP compliance over the previous year. In FY12, 253 businesses, or 70 percent of the dietary supplement firms inspected, received a Form 483, with an average number of 7.2 observations per document, according to data INSIDER obtained from FDA last year.
The FY13 figures are relatively consistent with results in previous years. During the preceding three-year period, 444 out of 626 inspections for cGMPs, or 71 percent of reviews, resulted in a Form 483.
The most recent data indicated many firms are continuing to be cited for elementary violations of the cGMPs. In FY13, the three most common violations of the 7-year-old cGMPs included failure to test ingredients, failure to verify the finished batch met product specifications, and failure to make and keep written procedures for holding and distributing operations.
One hundred and seventeen firms were cited for five or fewer observations, according to an FDA database INSIDER reviewed. Eighty firms received between six and nine observations while 73 firms were cited for at least 10 observations.
The cGMP data for FY13 covers inspections between Oct. 1, 2012, and Sept. 30, 2013. An unspecified portion of the observations reflect infractions for other regulated products, such as conventional food and acified food GMPs. According to industry executives, inspections can last several days or weeks, with FDA meticulously reviewing mountains of records.
The regulations are enforced in an effort to ensure supplementsand the specific ingredients listed on their labelsexclude harmful substances such as heavy metals and are what they claim to be.
"Consumers don't want products that don't meet some level of quality," Fabricant said. "You don't get credit for feeding your kid. You're supposed to feed your kid. It's the same thing here."
In FY13, the most common observation was failure to verify a finished batch of dietary supplements met product specifications such as identity, purity, strength and composition. Sixty two Form 483s, or 23 percent of the total number of Form 483s, cited this observation. A select number of dietary supplement firms were inspected twice during FY13 and cited for the same observation or observations on consecutive Form 483s.
The second most common observation was failure to verify the identity of a dietary ingredient prior to use through at least one appropriate test or examination, with 22.6 percent of Form 483s citing this infraction.
Other common observations included the following:
- failure to make and keep written procedures for holding and distributing operations (52 Form 483s or 19.3 percent);
- failure to qualify the supplier of a component by establishing the reliability of the supplier's certificate of analysis through confirmation of results of their tests or examinations (51 Form 483s or 18.9 percent);
- failure to establish product specifications for identity, purity, strength and composition (or at least one of the latter characteristics) for the finished supplement (49 Form 483s or 18.1 percent);
- failure to establish and/or follow written procedures for quality control (QC) operations (44 Form 483s or 16.3 percent);
- failure to make and keep written procedures to meet requirements that apply to the review and investigation of a product complaint (36 Form 483s or 13.3 percent);
- ·failure to establish component specifications for such things as purity, strength and composition (35 Form 483s or 13 percent);
- failure to establish and/or follow written procedures for holding and distributing operations (34 Form 483s or 12.6 percent); and
- failure to establish an identity specification for each component (27 Form 483s or 10 percent).
FDA and cGMP experts have said the most common observations above, such as failure to test ingredients and establish product specifications, relate to very basic, but crucial cGMPs, increasing the chances that the final supplement will be tainted with harmful substances and fail to match the ingredient information listed on the product label.
"We need to know that the information on the [dietary supplement] label is not misleading, and the FDA needs more information to take action when necessary," said Sen. Dick Durbin (D-IL) on July 30, 2013 while announcing plans to reintroduce legislation that would require more information on labels.
Justin Prochnow, a lawyer with Greenberg Traurig in Denver, said the cGMP data underscores that FDA is making cGMPs one of its biggest priorities. The burgeoning number of cGMP inspections supports his premise. FDA inspections have soared from 87 in FY10 to 361 in FY12 to 416 last year.
The regulations were issued in 2007 and took effect for the largest companies the following year. The smallest firms had until June 2010 to comply.
FDA couldn't specify the percentage of dietary supplement firms subject to the cGMPs that have been inspected since the regulations took effect. Federal law requires that firms register with FDA if they are manufacturing, processing, packing or holding dietary supplements for consumption in the United States. But "the universe of supplements and companies is unknown," according to a 2012 report from the Department of Health and Human Services' Office of Inspector General.
FDA said there are 7,106 U.S. companies registered with the agency as dietary supplement firms. In addition, 7,889 foreign businesses are registered as dietary supplement companies, authorizing them to import dietary supplements into the United States, the agency said. FDA does not have data on the number of domestic or foreign firms that are actually selling dietary supplements in the United States.
"This is such a big industry, and there's still a lot of companies out there that have not gotten their arms around all the compliance requirements," said Dean Cirotta, president and COO of EAS Consulting Group, which specializes in FDA regulated matters.
Prochnow, the Greenberg Traurig lawyer, indicated it's not surprising that dietary supplement firms receive at least a few observations given the breadth of the GMPs.
"It's a little bit like a roadside sobriety test," Prochnow said. "To some extent, it depends on how adamant the officer or inspector is about coming up with something. I think you are doing pretty good [if a dietary supplement firm only receives one or two observations]. If you are coming away with double digits, obviously you have a lot of work to do."
Steve Mister, president and CEO of the Council for Responsible Nutrition (CRN), cautioned that the numbers are potentially misleading. For instance, he questioned whether FDA inspectors are targeting companies that are more likely to be violating cGMPs.
Inspections are "primarily random, but we do follow up with firms," Fabricant said when asked about the criteria the agency uses to determine which firms to inspect. He also said the Center for Food Safety and Applied Nutrition (CFSAN) and Office of Regulatory Affairs give inspectors assignments.
Mister and others noted that observations on a Form 483 vary widely, from failure to test ingredientsa major infractionto leaving a can of soda in a prohibited area or failure to effectively don hair restraints.
"I'm not surprised at the numbers because of the complexity of the dietary supplement cGMPs and the thoroughness of FDA's inspections," said Anthony Young, a lawyer with Kleinfeld, Kaplan & Becker in Washington, who also serves as general counsel for the American Herbal Products Association (AHPA).
INSIDER shared with Young and other sources for this article cGMP data showing that 72 percent of firms received a Form 483 in FY13, but the FOIA office revised the data revealing that only 65 percent of companies inspected were cited for observations.
Supplement advocates added it can take an industry years to come into compliance with new regulations. For instance, Mister pointed out that the seafood industry struggled to comply with HACCP regulations for years. "You did not have overnight compliance with those" seafood regulations, he said. "Five or six years into it, FDA was happy that half the industry was compliant."
Trade associations including CRN and the Natural Products Association (NPA) asserted that their members have demonstrated a strong commitment to cGMPs. For instance, NPA CEO John Shaw said a number of members reported that FDA inspected their business for the second time during the last year without issuing a Form 483.
Still, Shaw cited "GMP violations and adulterated ingredients" as "the biggest sources of FDA enforcement action, and subsequently, bad press in the industry today."
"It's time for industry to step up and do what is needed to develop a culture of compliance, starting with upper management on down," Shaw said.
Reasons for Noncompliance
Consultants and lawyers have suggested some firms may have not lived up to cGMP standards because compliance is expensive.
Cirotta cited a "lack of financial and personnel resources" as common reasons for noncompliance with cGMPs.
"It is not an inexpensive regulation to comply with," Mister acknowledged. "It has its costs, but the tradeoff is by having GMPs, we are producing products consistently that consumers know they have what they are supposed to have."
Shaw cited a number of reasons for firms receiving a Form 483, including the complexity of regulations that feature "many nuances," differences of opinion between the inspector and the company, and relatively minor violations.
"More disconcerting however, is the number of inspections and Form 483s that result in warning letters or other official enforcement actions," he said.
FDA Enforcement Action
According to data FDA ran on Sept. 5, 2013 and presented by Fabricant at a U.S. Pharmacopeial Convention in September 2013, 117 of 350 inspections that were expressly designated under an FDA code as falling under dietary supplement cGMPs, or 33 percent, were classified by the FDA district office overseeing the inspection as official action indicated (OIA). The classification doesn't necessarily mean FDA will take an enforcement action against a company, such as issuing a warning letter or seeking an injunction in court, Fabricant explained, but it reflects the agency's opinion that enforcement action is justified.
"The plan is to get back to firms when you find violations in a quick manner," Fabricant said. "Does it always happen? No, generally because of [limited] resources and priorities."
In FY13, FDA sent approximately 70 warning letters to dietary supplement firms for violations of regulations, including cGMPs, according to the agency. The figure excludes warning letters sent to firms that allegedly made claims rendering their products drugs.
One hundred and forty three inspections explicitly falling under the cGMPs, or 41 percent, were classified as voluntary action (VAI). The classification means observations were cited, and FDA is giving a company an opportunity to come into compliance, Fabricant said. The classification does not necessarily mean FDA has reinspected a firm and found no existing problems.
"It's not a compliant inspection, not by any means," Fabricant said, commenting on the VAI classification.
Dietary supplement firms have 15 days from receipt of a Form 483 to respond to FDA. The agency could not provide figures on the number of dietary supplements that responded to a Form 483 in FY13. According to FDA, that information is not captured in its data systems.
Young, the lawyer from Kleinfeld, Kaplan & Becker, said FDA generally doesn't let a firm know whether it considers a response to a Form 483 adequate. He said FDA usually conducts a follow-up inspection the following year or later to confirm a company addressed observations that were identified during the previous visit.
However, Young said some FDA districts provide a supplement firm what is known as an "establishment inspection report," typically signaling the agency does not intend to take further enforcement action.
"The districts are different with regard to whether they routinely send out establishment inspection reports," he said. "Some of them do rather routinely and others of them just don't."
Roughly 26 percent of inspections in FY13 that were expressly designated as falling under the cGMPs were classified as no action indicated (NAI), according to Fabricant. Firms that were not issued a Form 483 or that were cited with only a few, relatively minor observations are likely to fall into this category.
The numbers presented by Fabricant at the USP convention encompass OAI, VAI and NAI classifications for several months of FY13.
Some industry sources have argued the number of firms adequately responding to a Form 483 is a more accurate gauge of the industry's compliance with cGMPs. But FDA reminded industry that even a timely and full response to a Form 483 doesn't mean FDA would find in a subsequent inspection that the company is in full compliance with cGMPs.
If a company lacks specifications, what good is a response to a Form 483, Fabricant asked.
According to an FDA compliance manual, the agency will submit close-out letters to firms following the issuance of a warning letter if it confirms the violations have been adequately addressed and other conditions have been satisfied. FDA typically confirms that observations have been corrected by conducting a follow-up inspection, the manual states. FDA issued two close-out letters to dietary supplement firms in FY13, according to the agency.
"I think everyone likes to get what they paid for," Fabricant said, commenting on consumers' expectations and the role of the cGMPs. "I would hope people get the message that we are taking things seriously."
Some industry executives, including a former FDA official who oversaw drafting of the cGMPs, said the message is clear.
"The FDA is certainly not taking its foot off the gas as far as inspecting and really continuing to make GMP compliance if not the number one priority, certainly at the top of things it's concerned about," said Bill Frankos, Herbalife Ltd.'s senior vice president of global product science, safety and compliance.
To access resources on cGMPs, check out INSIDER's Dietary Supplement GMP Quality and Compliance Center.