Much of the activity in herb industry circles over the spring and summer has focused on the proposal by the U.S. Food and Drug Administration (FDA) for current good manufacturing practices (cGMPs) for dietary supplements.1 As discussed in the last issue of HerbalGram,2 the 106-page proposal published on March 13 has been long-awaited and was initially welcomed by industry organizations. They have been pleading with FDA for years to publish new rules for the manufacture of dietary supplements (including herbs), as authorized by Congress in 1994 when it passed the Dietary Supplement Health and Education Act (DSHEA). Congress included this provision in DSHEA to help ensure that dietary supplement products were properly manufactured, and the materials were properly identified and free of potentially harmful contaminants, so that consumers could have confidence in these products.
The biggest issue of concern among industry members is the apparent drug orientation of the cGMPs. Although DSHEA clearly stipulates that new cGMPs should be "modeled" on GMPs that are in effect for the manufacture of conventional foods, the FDA has added numerous testing provisions that are clearly based on pharmaceutical drug GMPs, not food GMPs. The costs involved are estimated to be so significant that the general consensus is that many smaller to medium size firms will not be able to meet the requirements and will be forced out of business. Ironically, this may result in consumers finding a smaller variety of herbal supplements from which to choose in the marketplace, while at the same time there may be a higher level of confidence in the remaining products.
For example, one manufacturer of Chinese herbal formulas, who relies on a third-party contract manufacturer to produce the products, as is the case with many companies, told HerbalGram that the continuous testing required under drug GMPs for pharmaceutical companies might work for so-called "nutraceutical" ingredients (e.g., luteine, lycopene) where there is one plant-derived pure substance (or a group of chemically related compounds) where the manufacturer produces and sells millions of dosage forms of the one product or ingredient. However, he said, his company markets more than 100 products, each containing up to a dozen ingredients. If each ingredient is subjected to quality control testing, and then the finished product is also required to be tested, the costs were simply too high and were not reasonable nor sustainable, he said. He would simply have to go out of business. In an email to the author on June 26, 2003, he wrote:
I had a chance to go over in some more detail the GMP proposal by FDA. The rather extreme testing protocols that had been relayed to me previously do not seem entirely evident from the proposal. For example, [another Chinese herb manufacturer] suggested that every material would have to be tested thoroughly prior to use in manufacturing, and again after manufacturing, including tests of microbiology, pesticides, heavy metals, etc. Such testing, especially double testing, is ruinous to a small organization such as ours where we produce over 150 different formulas, with an average of two batches per year, and 500 different raw materials, with little mark-up to make sure the formulas are affordable. However, it was not [originally] clear that this is the nature of the [FDA's] requirements.
The apparent confusion about how the proposed rules require ingredients and finished products to be tested twice appears to be fairly common within some parts of the herb industry. Annette Dickinson, Ph.D., president of the Council for Responsible Nutrition (CRN), a leading industry trade association, attempted to clarify the situation, explaining that the proposed rule's primary requirement is to test everything in the finished product. If the available testing methodology is not suitable, such testing, as an alternative, may be done on all raw ingredients before manufacturing and again at some point during the manufacturing process. This, in effect, will result in double testing of ingredients to some degree if the finished product does not lend itself to the required testing, and to the extent that the supplier(s) of the ingredient(s) presumably tested each ingredient prior to sending them, and then they are tested again during the processing of the product.
AHPA Holds Regional GMP Meetings
The American Herbal Products Association (AHPA) held a series of five meetings with its members around the country to discuss the cGMP proposal. Each of the meetings (in Los Angeles; Portland, Oregon; San Francisco; Salt Lake City; and New Brunswick, New Jersey) was facilitated by AHPA President Michael McGuffin. A total of 94 individuals from 65 companies (including 50 AHPA members, about 25 percent of the AHPA membership) attended one of these meetings.3
The agenda for each meeting included the following items:
• a general overview of the proposed cGMP rule and of FDA Press Release of March 7, 2003;
• a brief discussion of the impact of the rule on various industry segments (e.g., raw material processors; finished product manufacturers; marketers);
• an in-depth review of the proposed rule (from an AHPA prepared worksheet);
• a brief review of FDA's 1999 survey of the dietary supplement industry;
• discussion of FDA's economic analysis of the projected impact of the proposed cGMPs.
"Visiting our members in their own neighborhoods has been, if somewhat too fast a pace, a very satisfying process," said McGuffin. "I have heard several clear messages from the industry, which clearly support prompt implementation of cGMP for supplement products that will meaningfully address manufacturing issues, but who see real problems with FDA's proposal and especially with that agency's erroneous assumptions about this trade. The input that we have now received from AHPA's members and others has been essential to the initial preparation of our comments." The period for public comment on the cGMPs was extended to August 11. They were originally due June 11, but FDA responded favorably to industry requests for the extension due to the massive amount of material to evaluate in the proposal.
AHPA has now prepared a report that summarizes all of the input from the participants at these five regional meetings. The document can be accessed by AHPA members at the AHPA website, <www.ahpa.org/members/03_0618_Proposed cGMP_Cumulated Input.pdf>. Non-members may request a copy by contacting Natasha Hall via email, <firstname.lastname@example.org>.
CRN Releases In-Depth GMP Comparison
CRN has also held meetings in the process of developing its comments to FDA. According to Dickinson, due to the many details involved in producing comments on so many technical areas, CRN will submit several separate comments to FDA by the August 11 deadline.
Dickinson noted that high costs may indeed be a threat to the viability of small companies, but they are also a major issue for large companies. She stated that the CRN comments to FDA will deal with these problems. "FDA's analysis does not come close to accurately predicting the amount of increased testing or the related costs for large companies, and we will be providing data on realistic cost estimates," she wrote in an email to HerbalGram on July 8, 2003. "We will also be suggesting some offsetting health benefits to consumers, to help balance the cost and benefit sides of the equation."
CRN's Regulatory Affairs committee held three full-day meetings since the cGMP proposal was published. Representatives of numerous leading companies helped analyze the proposed rules and their impact in detail. "We are extremely concerned that the rule seems to attempt to test quality into the product, rather than pointing the way to designing well-controlled processes that will effectively assure quality," Dickinson wrote to HerbalGram. She noted that former FDA official Carl Reynolds, who is an expert in cGMPs and has audited many dietary supplement companies enrolled in various third-party cGMP certification programs, "will be assisting CRN's development of its comments to FDA relating to the philosophy and underlying principles of quality assurance."
Dickinson wrote that CRN will also recommend that the cGMP rules include a number of provisions requiring written procedures. "These were included in the industry draft published as the ANPR [Advance Notice of Proposed Rulemaking, published by FDA in 1997 based on a proposal submitted by industry groups4], but FDA omitted them, on the assumption that they merely increase the recordkeeping burden without providing commensurate benefit. Our member companies believe that, on the contrary, written procedures are essential to creating a well-controlled process and to the training and supervision of personnel. Helping companies develop a well-controlled process may be the key to helping small companies (as well as large ones) achieve GMPs."
To help its members understand the details of the proposed cGMPs, CRN posted an 84-page spreadsheet5 that compares the new proposal to one previously submitted to FDA by an industry working group and published in the Federal Register in 1997,4 and to the current GMPs for conventional foods6 and for drugs.7,8 The four-way comparison was produced by Paul Bolar, vice president of regulatory and legal affairs, and his staff at Pharmavite LLC. Bolar is also the chairman of CRN's Regulatory Affairs Committee. The table will be submitted to FDA as part of CRN's public comments and is available on the CRN website, <www.crnusa.org>.
In a speech this past June at the annual convention of the National Nutritional Foods Association (NNFA) in Las Vegas,9 Loren D. Israelsen, director of the Utah Natural Products Alliance, noted that the serious economic challenges posed to the industry by the new cGMP proposal and the prospect that many manufacturers may not be able to meet the requirements would probably put many companies out of business - a point he said was acknowledged by FDA officials. But, he cautioned, any attempts by industry members and their trade associations to publicly criticize this aspect of the cGMPs might be portrayed in the increasingly-hostile media as an "anti-quality" position by the industry critics - regardless of how legitimate and justified the criticisms might be. This puts the industry in a potentially serious no-win situation, he said.
As noted in the previous HerbalGram article on cGMPs, the final regulation will not be forthcoming from FDA until, presumably, some time in 2004. Then it will go into effect in one year for large companies, two years for medium-sized companies, and three years for small companies. Thus, as a practical matter, it will be at least three-and-a-half to four years before all manufacturers of dietary supplements will have to comply with the new cGMPs. This situation creates market opportunities for the various organizations providing third-party certification of GMP and quality control so that companies can show consumers that their products are reliable and contain in the package what is declared on the label.
As noted above, the proposed cGMPs are based on such a pharmaceutical model that the expenses necessary for their full implementation - as they are currently proposed - will significantly affect the way the herb industry operates, and may eliminate some of the small and medium-sized companies. There have been legitimate concerns about the quality of many of the herb and other dietary supplement products manufactured and sold in the U.S. and so it may be understandable why FDA would propose standards that are similar to those required in the conventional drug industry. However, as stated by the Chinese herb formula manufacturer, such requirements may be reasonable for single chemical products like drugs, vitamins, and so-called nutraceuticals, but present a serious analytical challenge to manufactures of herbal products. It will probably take FDA until the beginning of 2004, or possibly later, to sort through the public comments and publish final cGMP regulations. Whether FDA will modify its proposal in response to the public comments is one of the big questions on the minds of many industry leaders; a question whose answer will not be forthcoming for months.
1. Current Good Manufacturing Practice in Manufacturing, Packing or Holding Dietary Ingredients and Dietary Supplements: Proposed Rule. Federal Register Volume 69, No. 49, Docket No. 96N-0417. Washington, DC: Food and Drug Administration. March 13, 2003.
2. Blumenthal M, Watts D. FDA proposes GMPs for dietary supplements. HerbalGram 2003;58:62-64,65,80.
3. CGMP Review Update: Regional Meetings Completed - Additional Input Requested. AHPA Update. Silver Spring, MD: American Herbal Products Assn., Jun 19, 2003.
4. Current Good Manufacturing Practice in Manufacturing, Packing, or Holding Dietary Supplements: Proposed Rule. Federal Register Volume 62, No. 25, Docket No. 5700-9. Washington, DC: Food and Drug Administration. February 6, 1997.
5. GMP Comparison. Washington, D.C.: Council for Responsible Nutrition. Accessed Jun 26, 2003 online at <www.crnusa.org>.
6. Current good manufacturing practice in manufacturing, packing, or holding human food. 21 CFR, part 110.
7. Current good manufacturing practice in manufacturing, processing, packing or holding of drugs: General. 21 CFR, part 210.
8. Current good manufacturing practice for finished pharmaceuticals. 21 CFR, part 211.
9. Israelsen LD. DSHEA Ten Years Later: What Happened? Presentation at National Nutritional Foods Association., Las Vegas, Nevada, June 28, 2003.