CFSAN Visiting Supplement Companies For Information On Developing GMPs

FDA representatives have visited three dietary supplement manufacturing facilities the last two months and will visit three more the week of Sept. 30 to better understand the manufacturing practices of the supplement industry. The information gathered during the visits will be used as the agency develops its proposed rule for dietary supplement Good Manufacturing Practices.

FDAers making the visits include staffers from the Center for Food Safety & Applied Nutrition Office of Special Nutritionals, Office of Field Operations and Office of Scientific Analysis & Support (Economics Analysis Branch), as well as reps from FDA's Office of the Chief Counsel and various district offices.

The meetings came to fruition this past spring when FDA notified various trade associations, including the Consumer Healthcare Products Association, that it was interested in setting up the visits. Association members willing to host a tour were invited to contact the agency directly.

Each FDA visit is by invitation only, and, according to the agency, has consisted of a general overview of the company's manufacturing process - from receiving raw materials to distributing finished products - as well as a guided tour of the company's facilities.

The first visit occurred on Aug. 10, when the agency toured General Nutrition Products' facility in Greenville, S.C. The next day, FDA toured Perrigo's plant, also in Greenville, followed by a visit to Takeda Vitamin & Food in Wilmington, N.C. Aug. 17.

The visits so far represent a diverse mix: a well-known entity in the mainstream nutritional products' market, a private labeler and a large-scale vitamin manufacturer and distributor.

As GNC's manufacturing facility, General Nutrition Products develops and manufactures a wide range of vitamins, minerals, sports nutrition products and herbal supplements. Perrigo has manufactured numerous mineral products such as zinc, potassium, magnesium, carbonyl iron and chromium picolinate for Wal-Mart's Spring Valley line.

Takeda Vitamin & Food, which manufactures various B and C vitamins, was created in March 1998 as a result of the combination of Takeda USA and Takeda Chemical Products USA (¹ (Also see "Takeda Vitamin & Food USA" - Pink Sheet, 16 Mar, 1998.)). Takeda Chemical Industries was recently implicated in the ongoing vitamin price fixing case (² (Also see "Takeda, Eisai, Daiichi Plead Guilty In Criminal "Vitamin Cartel" Case" - Pink Sheet, 13 Sep, 1999.)).

Speaking at the CHPA symposium on dietary supplements in Arlington, Va. Sept. 13, Office of Special Nutritionals Consumer Safety Officer Karen Strauss said the visits have targeted a wide range of companies thus far, noting "if nothing else, the site visits have demonstrated to us what a diverse industry the dietary supplement industry has become."

"The visits have influenced and reinforced the thinking in developing FDA GMPs for dietary supplements," Strauss continued. "First and foremost, they must be based on sound science...secondly, they must be performance and outcomes based, but allow for flexibility in how the manufacturers meet the requirements." Strauss is authoring the GMPs proposed rule.

Continued future visits are possible, but they will depend on a perceived need from CFSAN as well as the amount of funding the center receives in fiscal 2000, Strauss said. The FDAer did note, however, that all of the agency's visits are scheduled for large companies. "The places that perhaps we would [still] like to visit with are these small businesses," she commented.

The agency held a public meeting on supplement GMPs for small businesses in Las Vegas, Nev. July 12 (³ (Also see "GMP Identity Test Exemption For Small Ingredient Batches Suggested To FDA" - Pink Sheet, 19 Jul, 1999.)). Two additional regional meetings will be held in Salt Lake City, Utah Sept. 28 and Baltimore, Md. Oct. 21.

FDA's next scheduled GMP-oriented site visits will be to Pharmavite's facility in San Fernando, Calif. and Shaklee's plant in Norman, Okla. on Sept. 21. The agency will then tour Long Beach, Calif.-based Botanicals International.

Farouz Ertl, VP-technical & regulatory affairs for Botanicals International, addressed the GMPs at the CHPA symposium, focusing mainly on issues of cleanliness and contamination.

Various practices to be employed in assuring the cleanliness and quality of supplement ingredients are included in the GMP advance notice of proposed rulemaking (⁴ (Also see "Industry dietary supplement GMP proposal published for comments in ANPR." - Pink Sheet, 10 Feb, 1997.)). Ertl, however, stressed the importance of pest control, noting: "We need to have a routine inspection at least once a month."

Botanicals International uses fly traps to catch insects and inspects the traps every two weeks, identifying the captured bugs to see if any came from a country where a bulk ingredient shipment originated.

To control pests, the ANPR states "The use of insecticides or rodenticides is permitted" as long as they do not adulterate, contaminate or affect the quality of the supplements or the equipment being used in the plant.

Ertl, however, noted "pesticides have been one of the top priorities...these days" for dietary supplement marketers, due to their potential for harm and product contamination.

"The fact is, in most cases we do not have tolerances set for pesticides in botanicals, and we really have to set those tolerances," Ertl said. She pointed out that groups such as CHPA are looking into the issue but said "industry has to be proactive...they just can't wait for the trade associations to do this."

CHPA's Quality Protection Working Group, a subset of the Dietary Supplements Strategic Planning Group, has been looking at the topic of pesticides, but anticipates tolerances will eventually be issued by the Environmental Protection Agency instead of being included in FDA's GMPs reg.

EPA sets pesticide tolerances for foods, which FDA subsequently enforces; some botanicals that are additionally used as common spices, such as garlic, already have established tolerances.

Procedures put in place at Botanicals International include gathering information on pesticides through literature searches and discussions with suppliers, establishing educational partnerships with suppliers to minimize pesticide use and paying "a little higher price [to] get botanicals that are pesticide free," Ertl said. Finally, "if you don't have any other choice," a company actually could remove pesticides already in the raw materials, she commented.

Other areas of concern Ertl raised included contamination by heavy metals such as lead, cadmium, mercury and arsenic, as well as contamination by aflatoxins or microorganisms. One such microorganism Ertl is "extremely concerned about" is E. coli.

While the GMP ANPR states procedures should be taken to ensure such contaminants are controlled, specific guidelines are absent. When FDA published the ANPR in February 1997, it requested comments regarding "standards that should be met in certifying that a dietary ingredient or dietary supplement is not contaminated with filth; that it is free of harmful contaminants, pesticide residues, or other impurities; [and] that it is microbiologically safe."