Some dietary supplement firms will not be ready to comply with good manufacturing practices by the rapidly approaching final deadline, according to a senior FDA advisor on supplement products.

Carl Reynolds, of FDA's Division of Dietary Supplement Programs, says common GMP compliance problems occur in ingredient testing and documentation of procedures. Reynolds worked for FDA for 36 years before leaving in 1999 and working as an industry regulatory consultant, then returning to the agency in October 2009.

"In less than 60 days it all hits the road, folks," he said April 28 at the SupplySide East conference and tradeshow in Secaucus, N.J.

"Quite honestly, some of the smaller firms and some of the medium-sized firms are not there yet. I tried to tell people, 'You need to be ready a year in advance,'" added Reynolds.

Medium-sized firms - 20 to 499 employees - were required to comply with the GMP final rule in June 2009 and firms with 500 and more employees had a June 2008 deadline. The rule published in June 2007 gave small firms, those with fewer than 20 employees, until June 25, 2010 (¹ Also see "FDA Will Rev GMP Inspections Of Medium Supplement Firms, After A Pause" - Pink Sheet, 11 May, 2009.).

"That is not only domestic firms, that is foreign firms as well that export their products to the U.S.," Reynolds said.

Industry stakeholders and FDA officials acknowledge not all firms will be prepared by their compliance deadline, and small firms will be particularly vulnerable to failing because of GMP issues (² Also see "Looming GMPs Could Doom Some Firms Unless Industry, FDA Lend Support" - Pink Sheet, 16 March, 2009.).

Reynolds outlined areas firms should brush up on to comply with GMPs, what FDA is looking for during inspections and violations and problems the agency is finding.

"A GMP inspection, if you have not enjoyed that, is going to be quite an experience for you," he said.

"It will be detailed. It will not take hours. It is going to take days, and maybe weeks. It will be data-intensive. ... They are going to look at your procedures; they are going to look at your records; they are going to look at your facilities."

Reynolds said GMP inspections have not been frequent, with 12 in fiscal 2008 and 28 in 2009. One untitled letter and one warning letter related to GMP inspections have been issued, and FDA has little trending data about GMP violations.

However, inspectors have reported numerous recommendations that FDA is reviewing for possible enforcement action.

Since the supplement GMP rule was published, the Center for Food Safety and Applied Nutrition has had to prioritize other enforcement areas, such as responding to salmonella-tainted peanut products. But the center expects to ramp up its GMP work as all supplement manufacturers become subject to the rule (³ Also see "Research & Development In Brief" - Pink Sheet, 3 May, 2010.).

Representative Samples Are A Must

Reynolds pointed out inadequate quality control often is linked to poor personnel training. "They are not collecting representative samples" and there is "lack of or incomplete identity testing," he said, adding, "That's a biggie."

FDA maintains the GMPs clearly explain representative samples. Collecting a sample from one of 10 containers, for example, is unacceptable. "It has got to be representative of the lot," Reynolds said.

Firms should at least conduct an appropriate identity test for a dietary ingredient, but can rely on a supplier's certificate of analysis for other specifications if a vendor has been qualified.

To qualify suppliers, Reynolds said FDA expects firms to "establish the reliability" of a vendor's CofA through tests, maintain documentation of the qualification process, keep audit records on file and follow up periodically to reconfirm the quality of a supplier.

Procedures "Not Going Far Enough"

Another common problem showing up is documentation of manufacturing procedures, which should explain "exactly what you are going to do," Reynolds said.

For example, if a procedure explains how a piece of equipment is cleaned, it should also include information about the cleaning products.

"Isn't that reasonable?" he said. "But it is not being included."

Firms also are missing the mark in pest control, for which the GMPs require written procedures. Reynolds is aware of facilities with insect and rodent activity in the raw material storage spaces.

Reynolds pointed out FDA is required to provide firms with a form 483 after inspections. The form lists observations that may lead to future enforcement action but do not compel the agency to take any action.

Understand, Set And Meet Specifications

Reynolds said setting and meeting specifications is "absolutely critical" for compliance. "The issue of specifications is a big deal. There are 754 mentions of specifications in the rule - 754."

He observed that more stakeholders need to read and understand the GMPs, saying he is "astonished" by the lack of knowledge in the industry regarding the definition of "specification."

"Unfortunately, many in the industry do not seem to have a firm grasp on what this regulation speaks of when it speaks of specifications. Please look at the definitions and what they mean, so that you really can focus more on some of the intent of the regulation."

Firms must set numerous specifications, such as for incoming materials, labels, packaging materials and finished products.

"If you do not set specifications, if you do not monitor the setting and the compliance with those specifications, you are going to have a long inspection," Reynolds said.

Firms also need a process for monitoring and meeting specifications, including covering corrective action when deviations occur.

But corrective action plans are "not very well understood in the industry," Reynolds said.

"This regulation requires that if you have a specification that you have set in a master manufacturing record that you have to monitor for compliance to that specification."

Firms should have a process to change procedures as needed because they are "not static," Reynolds said.

"It is not wrong to make changes as long as you go through a documented procedure and it is approved" by a quality-control unit.

Check The Manual

Reynolds advised stakeholders to obtain the Compliance Program Guidance ⁴ Manual for dietary supplements FDA recently published to provide field investigators with inspection goals.

It includes manufacturing areas CFSAN wants the investigators to focus on, including methods to use, samples to collect and how they should be analyzed. The manual also covers making regulatory or administrative recommendations based on findings from inspections.

Further, the manual addresses inspecting testing documentation, manufacturing specification documents and master manufacturing records, and evaluating quality-control procedure documents and pest control plans.

FDA wants investigators to trace the history of at least two products, Reynolds said. As a consultant conducting an audit he would do the same, including tracing all the information back to batch records.

"I would want to go through and see all the documentation related to the incoming materials related to that product. I would want to see how you do identity testing, what you have done about qualifying" a certificate of analysis, he said.

Recordkeeping Is Crucial

Reynolds said he often finds incomplete records, specifically batch and master manufacturing records.

"If they even exist, they don't contain the information that's required," he said, adding that without documentation, in FDA's eyes a procedure doesn't exist.

Firms should be meticulous about keeping records, which must be available to inspectors. Providing copies upon inspectors' requests also is required.

Adverse event reporting is not required under GMPs, but inspectors will look at that information. They "will be looking in detail at how you handle your adverse event reporting," Reynolds said.

Expiration dating on supplement labels is not required, but FDA will ask for supporting data if a firm includes a date.

Make Corrective Actions During Inspections

Firms should make corrections if possible during an inspection.

"If you have to revise a standard operating procedure, try to revise that before the inspection is finished," Reynolds said.

While changing an SOP will require future training for a firm's staff, FDA accepts interim responses.

"You can say, 'Such and such made an inspection, and during the inspection, they listed these things. During the course of the inspection, we corrected these things. Since the inspection, we have corrected these things, and we anticipate being able to correct these things,'" Reynolds said.

When firms change an SOP, they should provide FDA a copy of documented changes.

Reynolds said FDA's "quite active" outreach efforts have given guidance to industry on GMP regulations. The agency also has trained its staff.

Additionally, FDA plans to publish a small business entity guide for dietary supplement firms. The guide's release was delayed by a lawsuit filed by frequent agency critic Jonathan Emord, claiming the supplement GMPs violate the Dietary Supplement Health and Education Act and FDA has not provided thorough guidance for compliance (⁵ Also see "FDA's Frankos Grades GMP Complaint Recordkeeping "Needs Improvement"" - Pink Sheet, 23 November, 2009.).

- Katie Stevenson ( ⁶ k.stevenson@elsevier.com )

FDA's Reynolds Marks Top GMP Trouble Spots As Deadline Looms

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