The dietary supplement good manufacturing practices final rule provides "a very flexible framework for required testing," said Vasilios H. Frankos, director of the dietary supplement programs division for FDA's Center for Food Safety and Applied Nutrition.

The long-anticipated ¹ regulation was posted for advanced display on the Federal Register June 22, thirteen years after the Dietary Supplement Health and Regulation Act authorized its creation.

Under the final rule, supplement manufacturers will be required to "evaluate the identity, purity, strength, and composition of their dietary supplements," the agency says.

According to Frankos, one major change between the final GMPs rule and the proposed version is a reduction in testing requirements.

"Other than a mandatory 100 percent ingredient identity test for incoming dietary ingredients, we have prescribed no specific testing program," he said during a press briefing.

"Rather, we leave it to the firm to have a scientifically valid testing system where a mix of in-process testing and finished product testing will ensure that the dietary supplements meet specifications and are not adulterated," Frankos stated.

"We're not requiring specific methodologies that are in monographs or something like that. If the method can be validated and is well-controlled, than that can be accepted," he said.

The agency also added flexibility to the final rule's 100 percent identity testing requirement by simultaneously issuing an ² interim final rule designed to allow firms to petition for exemptions from the requirement.

"This petition would be accompanied by evidence that the supplier has adequate process controls in place to consistently produce the dietary ingredient over a period of time and that the reduced testing is statistically sound," Frankos explained.

However, the agency has "no preconceived notions of what such a petition would contain, so we are asking for comment on what would be considered adequate evidence to support a reduced testing requirement for incoming dietary ingredient," he said.

The GMP final rule relaxed finished product testing requirements included in the proposed rule that several industry trade groups described as "overly burdensome" and "exhaustive" (³ Also see "Supplement GMPs Focus On Process Controls Urged By CHPA, NNFA" - Pink Sheet, 11 August, 2003., p. 3 and ⁴ Also see "Supplement GMP Testing Requirement Alternatives Urged By AHPA Members" - Pink Sheet, 30 June, 2003., p. 8).

According to the proposed rule, FDA "would require that you test each finished batch of the dietary ingredient or dietary supplement produced before releasing for distribution to confirm that specifications are met" (⁵ Also see "Dietary Supplement “Flexible” Testing Requirements Proposed In GMPs" - Pink Sheet, 10 March, 2003., p. 3).

The final rule gives firms the options of testing "a subset of finished batches of dietary supplements based on a sound statistical sampling" or testing all finished batches of supplements.

"We think the final regulation is strong, but more reasonable than the proposed version," Natural Products Association Executive Director and CEO David Seckman said. However, "at 800-plus pages we'll need to take a longer, more careful look at this document to fully determine its impact on the industry and consumers."

Another major change from the proposed to final rule is that the final rule does not apply to dietary ingredient manufacturers or suppliers, "but only to persons who manufacture, package or hold dietary supplements," Frankos said.

"The manufacturer is thus responsible for ensuring that the ingredients used in the production of a dietary supplement are such that they produce a product consistently meeting cGMPs."

Exclusion Of Dietary Ingredient Firms

"It's important to note that excluding raw dietary ingredient producers and suppliers from cGMPs does not weaken the rule," Frankos said.

Rather, it "shifts the burden for insuring the quality of the dietary ingredients used in the dietary supplement to the manufacturer of the dietary supplement," he said.

"The decision was made that the best way to manufacture a quality dietary supplement is to have the party that is responsible for making the dietary supplement confirm that every ingredient that goes into that product meets specification," Frankos explained.

"It was felt that putting the onus on the manufacturer was a more efficient and defensible way in which to require quality be met," he continued.

According to Council for Responsible Nutrition President and CEO Steve Mister, the decision was appropriate. "That's exactly where the responsibility should be," he said. The finished product manufacturer has the relationship with the consumer because it is the firm's on the label, Mister explained, and a consumer wants to know the manufacturer is "standing behind that product."

Therefore, "I think it's entirely appropriate that FDA puts the onus on that finished product maker," he said.

Furthermore, "It would be naive to think that everybody else now doesn't have any responsibility because we know that the marketplace will impose" a responsibility on ingredient firms, Mister added.

"If I have to comply with these things, I'm going to put requirements on my suppliers so that I can assure a quality product at the end of the day," he pointed out.

American Herbal Products Association President Michael McGuffin agreed: "I guess you could say that it's a decreased burden on suppliers, but I think in a sense it's a recognition that the marketplace will place the burden on the supplier."

Additionally, McGuffin stressed, "I don't see this as an increased burden on manufacturers."

"It says they have to do what they had to do before. ... Yes, it's a big deal because it's one of the bigger changes from the proposed rule to the final rule, but I don't see it as an increased burden on manufacturers," he said.

United Natural Products Alliance Executive Director Loren Israelsen, however, is "disappointed" dietary ingredient manufacturers are not "within the scope of the rule."

While FDA agrees "ingredient manufacturers are both central and indispensable to quality management ... they made the choice to place the burden of confirming quality of raw material ingredients on the finished product manufacturer," he said.

"Because of the global nature of our supply chain, and in view of recent events, the message that I'd hoped would be communicated to the global industry is quality begins literally in the field and at the raw material level," Israelsen explained.

"The manufacturer of ingredients into finished forms clearly has a responsibility to confirm identity of what they're purchasing, but the principal responsibility should be on the company selling the raw material," he said.

In response to a question during the press briefing about how the GMPs address "imported ingredient problems," Frankos said, "I think the GMPs are very thorough in addressing the issue of 'what is the product that you're putting in there and is it what you say it is.'"

"Now, we will never be able to avoid products that have been intentionally contaminated. I just want to make sure you understand that," he said.

Certificates Of Analyses

"The rule acknowledges that a manufacturer can use a certificate of analysis as an indication of the identity and quality of the incoming raw materials," Frankos said.

Additionally, the rule acknowledges a manufacturer can use certificates of analyses to confirm the identity of non-dietary ingredient materials used in the supplement, he said.

However, "the rule also recognizes there are different qualities of certificates of analyses and that there is an onus on the manufacturer to periodically confirm the identity and the accuracy of the certificate of analysis through independent testing," Frankos said.

According to the rule, "a firm may rely upon a certificate of analysis from its supplier of a component, provided that certain criteria are met."

The rule lists five criteria. Perhaps most notably, the CofA must include "a description of the test or examination method[s] used, limits of the test or examinations, and actual results of the tests or examinations."

"Well, that's fairly significant," McGuffin said. "My longstanding quip is, 'apparently, the only piece of analytical equipment that you need to create a CofA is a typewriter,'" he said. "The way I read this rule, it wouldn't tolerate that."

Other criteria include: "the firm qualifies the supplier by establishing the reliability of the supplier's certificate of analysis through confirmation of the supplier's tests and examinations" and "the firm periodically reconfirms the supplier's certificate of analysis."

The variable quality of CofAs and the need for an established standard for such documents was a concern Frankos raised at a June 19 stakeholder forum held by the United States Pharmacopeia.

"If you haven't looked at the range of CofAs that are coming into the dietary supplement [industry], you'll be shocked at the variety," he said.

The CofA discussion initiated by Frankos led USP to make developing a guiding "statement on a certificate of analysis" an action item for the standards setting body. It was decided the Dietary Supplement General Chapters Expert Committee should take up the issue.

Timeline And Enforcement

The rule goes into effect Aug. 24, but there is a three-year phase-in period for companies to comply to "limit any disruption for dietary supplements produced by small businesses," FDA says.

Companies employing 500 or more full time equivalent employees must be in compliance with the rule by June 2008, companies with fewer than 500 FTEs have until June 2009 and companies with fewer than 20 FTEs have until June 2010, according to the agency.

FDA will be developing an enforcement strategy for the supplement GMPs "in the upcoming months as the rule is implemented," CFSAN Director Dr. Robert Brackett stated.

"I was concerned to hear that FDA apparently has no specific plans to beef up inspection or enforcement for the time being with respect to the GMP reg." Israelsen said. However, "They may have more news to share with the industry and the public on that in the coming months," he added.

- Katia Fowler (k.fowler@elsevier.com) and Jessica Lake (j.lake@elsevier.com)

Supplement GMPs Stress Responsibility, Put Firms In Driver’s Seat For Testing

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