Medium-sized dietary supplement firms should not be fooled if FDA gets off to a slow start inspecting for good manufacturing practices compliance, but should expect a marked uptick in the agency's volume of inspections.

Medium-sized firms - firms with 20 to 499 employees - have a June 25 deadline to comply with FDA's GMP final rule.

Brad Williams, special assistant to the director at FDA's Division of Dietary Supplement Programs, says inspectors are not likely to come knocking too soon after June 25 because the companies will have only just begun keeping GMP records, leaving limited data to review.

However, inspections will start "within a number of months and then I would expect a fair number," he told industry stakeholders April 30 at the annual SupplySide East tradeshow in Secaucus, N.J.

Williams said the agency's relatively slow pace of GMP inspections during the first year of compliance for large firms, which began June 25, 2008, is no predictor for the coming year (¹ Also see "Supplement GMPs Stress Responsibility, Put Firms In Driver’s Seat For Testing" - Pink Sheet, 25 June, 2007., p. 3).

Daniel Fabricant, VP of scientific and regulatory affairs with the Natural Products Association, agrees.

"I think folks will be surprised" by the pace as mid-sized firm GMP inspections get under way, Fabricant said in an interview. "I think they will be conducting a lot of inspections."

Fabricant predicts the agency will inspect between 200 and 300 medium-sized supplement firms - a figure he estimates as half the total - within a year after the deadline.

FDA is unclear on the number of supplement firms in the three size brackets, but estimates the total number of U.S. supplement firms at about 1,500.

Fabricant puts the number of mid-sized firms "upwards of 500." If FDA gets to half of the medium firms in a year, he says, "that is fantastic."

Even if medium-sized firms will not face GMP inspections right away, Fabricant says, "I would be ready as of June 26. That's the law."

Small firms, those with fewer than 20 employees, will be expected to be GMP ready by June 25, 2010.

Phase One Progress

Williams said FDA has conducted as many as 13 GMP inspections of large firms - firms with more than 500 employees - since that first phase of GMPs went into effect.

While FDA does not know how many large supplement firms there are, industry estimates suggest 13 inspections would represent roughly half of large firms. Experts estimate the total is probably somewhere in the mid-twenties.

Williams attributed the number partly to the fact FDA found some firms were "not as large as they thought," and therefore were not yet subject to supplement GMPs under the regulation. In those cases, the agency conducted food GMP inspections instead, and the numbers were not counted toward the supplement GMP inspection total.

An FDA spokesman said identifying large firms has been challenging because the agency is "unable to accurately estimate the number of employees a particular firm has."

"Therefore, when trying to plan for inspections under the first compliance date, FDA decided to use annual volume of sales in dollars to estimate firm size, but we found that some micro firms had 'macro' earnings," and were not large firms, he said in an e-mail.

Boots On The Ground

Williams also said understaffing at FDA has meant fewer inspectors are available, a problem that cannot be fixed overnight. This would presumably continue to present a challenge for the agency as it works to inspect medium-sized firms.

While "the government is making an attempt to straighten things out and bring people on board," adequate staffing will trail adequate funding, he said.

Williams said FDA will hire more inspectors in accordance with anticipated appropriations funding but noted properly training inspectors can take three years from hiring to "boots on the ground."

"You can't just take someone and say, 'Start doing dietary supplement inspections.' You need to train them," he said.

Williams may not see much of an increase in supplement-dedicated inspectors, however.

The Obama administration budget request for fiscal 2010 released May 7 includes only $11 million and 58 full-time equivalents related to dietary supplement programs within FDA, a "minimal" increase over current levels, according to an agency spokesperson.

The Stick

Williams said FDA will be ready to "start shaking a stick" at any noncompliant firms.

"What we need to do is get your attention and get you into compliance," he said. "We stop when we hit compliance. That's what we want."

Williams also said FDA would take seriously a report that a firm is not in compliance. "If somebody brings a problem firm to our attention, we will look into it," he said.

Williams said it is important that firms not lie about how many employees they have.

"When an investigator comes to the door and says, 'How many employees do you have?,' I'd rather you say, 'I won't tell you' than lie. Lying sends you to jail."

Williams added, "If we ever find out that you are keeping off-the-record books, we'll be able to do something about that."

The Inspection

Williams said while there is not currently an official checklist for inspections, eventually the agency will implement a computerized establishment inspection report system similar to those used with GMPs for other types of products.

Referred to at the agency as "turbo EIR," the system provides FDA inspectors a protocol to take them through the inspection process and help produce a form 483 report, which is a list of "inspectional observations."

Fabricant said once the EIR system for supplements is available, it will allow industry "to better understand all the aspects and structures in which field personnel are carrying out inspections."

Williams said on that day, firms can expect to see trained FDA investigators who have been working "for a number of years."

Two areas "key" for GMP compliance are having established written procedures and set specifications, he said.

Andrew Shao, the Council for Responsible Nutrition's VP of scientific and regulatory affairs, said documentation will be critical.

Companies need to document not only what specifications they use in manufacturing, but also the "scientific basis for how and why specifications have been established," Shao said.

Records showing suppliers have been qualified are particularly important, said Shao. Mid-size firms must have records ready showing their suppliers are qualified because FDA will ask for them without a doubt, he said.

"Know your supplier," Shao said, echoing a frequent refrain of GMP experts (see ² Also see "For Ingredient Suppliers, GMP Compliance Means Surviving And Thriving" - Pink Sheet, 11 May, 2009.).

"This is FDA's biggest concern when it comes to GMPs, because if suppliers and their ingredients are not properly sourced and qualified (resulting in sourcing of poor quality ingredients), then the rest of the GMP process is moot," he said in an e-mail.

Inspectors will also look for outdated standard operating procedures, so firms should make sure they have up-to-date SOPs, Shao said.

"Change control" documents will also be crucial, he said. "If documents, procedures or processes are changed, this must be accompanied by change control" records, he said. "FDA inspectors will look to examine when, how and why changes were implemented, and without change control, they will not be able to assess these."

Fabricant said firms also must be able to follow their "master manufacturing records," to verify they have followed through on intended actions.

- Katie Stevenson (k.stevenson@elsevier.com)

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