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FDA's long-awaited GMPs for supplements appear as food and drug safety concerns override lingering opposition.
After years of debate and delay, the US Food and Drug Administration finally issued regulations in June that establish current good manufacturing practices (GMPs) for dietary supplements. These rules have been in the works for more than a decade, a period that has witnessed substantial growth in the $20-billion market for vitamins, minerals, herbal products, sports supplements, and other supposedly health-enhancing products. It probably is not just a coincidence that FDA finally received clearance to issue these rules in the wake of mounting concerns over contaminated ingredients from China and other regions of the world increasingly found in foods, animal feeds, and health and beauty products sold to US consumers.
The FDA rules, which were authorized by the Dietary Supplement Health and Education Act (DSHEA) of 1994, apply to all domestic and foreign companies that manufacture, package, and label supplements for sale in the United States. The rules clarify that the final supplement producer is responsible for ensuring that all substances and ingredients in these products meet GMP standards for quality, purity, identity, strength, and composition. The "burden is on the manufacturer" to use the most scientifically defensible method available to determine quality, commented Robert Brackett, director of FDA's Center for Food Safety and Applied Nutrition (CFSAN), in announcing the new regulation.
The lengthy rule (available at www.fda.gov) sets standards for designing and constructing manufacturing facilities to prevent product contamination and adulteration and requires quality-control procedures to ensure a consistent and reliable production process. A key requirement is for manufacturers to test the identity of all ingredients to ensure that supplements meet quality specifications and contain what the manufacturer intends. To avoid redundant testing, however, the final policy permits manufacturers to obtain certificates of analysis from component suppliers that an ingredient meets certain set specifications. This policy allows manufacturers that have established relationships with suppliers to avoid extensive testing for all incoming products, explains Andrew Shao, vice-president of the Council for Responsible Nutrition (CRN). Final manufacturers, though, must qualify those suppliers. The supplement maker also remains responsible for identity testing and is expected to periodically confirm test results by other parties. The GMPs also require detailed recordkeeping and systems for handling and recording consumer complaints. They clarify what information on product quality and appropriate use should be on product labels.
Supplements that fail to meet these requirements would likely be adulterated or misbranded. Minor violations may prompt FDA to require labeling changes or product recalls; more serious infractions could lead to product seizures and even criminal charges.
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While the GMPs set many new requirements for manufacturers, FDA emphasizes that it has taken steps to address industry concerns. The agency intentionally does not specify what kind of testing or procedures companies should follow to ensure product quality, but leaves it to manufacturers to use valid testing procedures able to show that products meet specifications and are not adulterated. And instead of requiring manufacturers to have a "dedicated quality-control unit," the final rule calls for companies to have "quality-control personnel" responsible for this program. This provides leeway for such staffers to perform other functions, an approach important for small companies.
Another accommodation for small firms is to phase in the new policies over three years. While larger companies (those with more than 500 employees) must comply with the regulations by June 2008, smaller firms have another year to meet the new policies, and very small companies (those with fewer than 20 employees) have until June 2010 to comply.
FDA also is proposing a new petition process for companies to seek exemption from the requirement for 100% identity testing for all supplement ingredients. In a companion interim final rule, the agency outlines a system for manufacturers to request exemptions by documenting that the company can still ensure product identity even with less frequent testing. FDA is soliciting comments on this proposal through late September and hopes to move forward quickly to implement a petition process.
Consumer advocates and some members of Congress complained that the new rule does too little to ensure safe and effective supplements. There are no preapproval filing requirements for supplement makers, and the industry and its Congressional backers have long opposed them. DSHEA requires the manufacturer of a new dietary ingredient to notify FDA at least 75 days before it markets a new supplement product, but this requirement applies only to formulations and ingredients developed since 1994 and is fairly vague about what kind of information a company must provide the agency.
Comparing the food versus drug models
Premarket notification, moreover, is far different from prior approval and reflects the main premise of DSHEA: that FDA regulation of dietary supplements follows the model for foods rather than drugs. Supplements are considered safe unless evidence indicates otherwise, and no premarket clinical testing or approval is required. FDA notes, though, that dietary supplements, unlike foods, are packaged into tablets, gelcaps, and capsules, thus requiring process controls to ensure that each tablet contains the ingredient, purity, strength, and composition intended.
Because supplements often contain ingredients found in drugs and make claims about improving or affecting health, many policymakers believe that these products should adhere to some drug standards. At the same time, DSHEA won support from the supplement industry and policymakers who believe that these products are safe, can make a real contribution to public health, and should not be hamstrung by excessive and unnecessary regulation.
The 1994 act does provide FDA with a process for documenting that a supplement is harmful or contaminated and should be removed from the market. But the process is long and complex, and FDA has attempted to use it only with ephedra-containing supplements, with limited success.
The food–drug dispute has colored the debate over GMPs for the past decade. Dietary-supplement manufacturers generally agreed that setting GMPs was a reasonable approach for ensuring product safety and quality. CRN, a trade group representing larger supplement makers, has backed product-quality standards as one way to establish a level playing field for the many companies testing their products voluntarily through third-party organizations such as NSF International, ConsumerLab.com, and the US Pharmacopeia (see sidebar, "USP assesses supplements"). Many small companies complained, however, that GMPs would establish ingredient-testing requirements too similar to standards for drugs and much too expensive for many small manufacturers.
The US Pharmacopeia assesses supplements
Consequently, it took years for FDA to craft GMP regulations acceptable to industry and their allies on Capitol Hill and in several administrations. Following extensive discussions with manufacturers, FDA issued an Advance Notice of Proposed Rulemaking in 1997 that posed several questions for public comment. It took another six years for the agency to publish just the proposed rule.
During this period, evidence emerged about serious health risks associated with supplements containing steroids and stimulants. In January 2000, FDA launched a broad crackdown on supplements making unsubstantiated health claims. The agency seized products that promised to prevent cancer and cure autism. FDA laboratories identified numerous products that lacked key ingredients, had excessive amounts of lead, were contaminated with bacteria, or had ingredients not listed on the label. Then-FDA commissioner Mark McClellan announced further initiatives to improve consumer information on supplements and sent out a wave of Warning Letters. The Federal Trade Commission also filed complaints against supplement firms for allegedly unsubstantiated or false advertising claims.
Support for stronger supplement regulation came in April 2001 from the Health and Human Services Office of the Inspector General. It issued a report recommending the registration of supplement manufacturers with FDA and mandatory adverse-event reporting to strengthen federal oversight of the supplement industry. Soon after, Senate investigators reported thousands of adverse reactions to weight-loss dietary supplements containing ephedra. FDA moved to ban the substance from over-the-counter drugs, but could only begin the convoluted legal process for pulling ephedra supplements off the market.
These problems culminated in 2003 with the death of a major-league baseball player, which prompted more Congressional hearings on supplement regulation and new legislative proposals. Even Senator Orrin Hatch (R-UT), the prime advocate for limited federal oversight of dietary supplements, backed legislation adding supplements with anabolic steroids to the controlled substances list.
As the evidence mounted about risky supplements, FDA unveiled its GMP proposed rule in March 2003. Despite public concerns about supplement quality, several manufacturers maintained that DSHEA did not require FDA to issue GMPs at all, and that industry self-regulation was perfectly adequate to ensure product quality and safety.
To address such contentions, FDA asked the Institute of Medicine (IOM) to assess supplement risks and propose appropriate regulatory action. The resulting report, which was issued in April 2004, urged Congress to strengthen quality controls on supplements, ensure the accuracy of product labels, and take stronger enforcement action against misleading claims. The report stopped short of recommending premarket approval for supplements, but called for mandatory adverse-event reporting and supported more research into the clinical effectiveness of these products. While consumer groups praised the study, manufacturers objected that FDA already had sufficient authority to remove harmful products from the market and that new legislation was not needed.
Another IOM report in early 2005 addressed the need for more research into the efficacy and safety of "complementary and alternative medicines," which include dietary supplements. The report found that manufacturers have little incentive to finance such studies and that the National Institutes of Health and other researchers would have to provide support. The report noted that a general lack of quality control for supplement manufacture made it difficult for researchers to obtain consistent samples needed for clinical trials, and that manufacturing-process standards were critical for such research to go forward.
Meanwhile, FDA's draft rule on GMPs generated some 400 comments from industry, healthcare professionals, consumer groups, and government officials and agencies. There were questions about the lack of validated tests for ingredient purity and composition and concerns about added record keeping requirements. Although it took months for agency staffers to review and process all the comments, by 2005, FDA was promising that a final rule would be issued "soon." But complaints from small companies that new testing requirements would force them out of business delayed approval by the Office of Management and Budget, which gives the final sign-off on major new federal regulations.
Addressing oversight difficulties
The GMPs escaped from regulatory limbo this year, partly because Democratic leaders in Congress cast a sharp eye on dietary-supplement oversight. In addition, the discovery of toxic substances in pet foods, toothpaste, and other imported Chinese products raised concerns that similar risks may apply to the growing volume of raw materials from Asia used in the production of pharmaceuticals and dietary supplements. It was hard to argue against standards for ensuring the quality of related products.
This latest scandal involving poorly regulated ingredients from China is not without precedent. Patients in Haiti and other countries have been poisoned on several occasions by cough syrup and other liquid medicines containing toxic diethylene glycol (DEG) instead of pure glycerin. In June, Chinese regulatory authorities announced a five-year plan for increasing inspections and surveillance of food and drug ingredients and closed down some manufacturers, but this appeared to be part of an effort to avoid more curbs on US imports of Chinese food products, additives, and other ingredients.
Continued evidence of DEG in health products, however, prompted FDA to issue a guidance in May 2007, recommending that manufacturers perform appropriate tests to ensure that any glycerin used in preparing liquid drugs is not contaminated. The document refers to limit and identity tests listed in the USP glycerin monograph and a thin-layer chromatography test method. FDA also advises manufacturers to identify reliable suppliers for glycerin and other ingredients associated with contamination problems.
Persistent evidence of contaminated imports reflect FDA's difficulties in monitoring and identifying noncompliant food and drug ingredients from overseas. In announcing the new GMP rule, FDA officials said they would adopt a risk-based approach to ensuring manufacturer compliance with quality standards. That translates into relatively few direct inspections of manufacturers, particularly those overseas, unless evidence of contamination or rule violations surfaces. FDA's reliance on supplement manufacturers and packagers to ensure ingredient quality is a symptom of the limits on agency enforcement and oversight capabilities. While FDA conducts more than 1000 drug GMP inspections in the US every year, it visits only a few hundred foreign manufacturers, despite the growing portion of drug ingredients and generic drugs now coming from India, China, and other countries.
Whether FDA's GMP rule will ensure high-quality and safe dietary supplements will be examined further by Congress. The House Energy and Commerce Committee recently asked the Government Accountability Office to examine dietary-supplement concerns, including overly vague health claims in product labels, FDA's ability to detect safety problems, and the status of adverse-event reporting.
One result of the IOM report of 2004 was to spur Congress to enact the Dietary Supplements and Nonprescription Drug Consumer Protection Act in December 2006. The law replaces voluntary adverse-event reporting for supplements with a required system that goes into effect in December 2007. Manufacturers are working with FDA to clarify reporting policies as the implementation deadline draws near. Key issues include what information should be placed on product labels to advise retailers and consumers how to report adverse events, what qualifies as a "life-threatening" adverse event, and where certain information should be written on FDA's MedWatch form.
When DSHEA was enacted in 1994, it applied to about 4000 products sold in the US. Today, the supplement market includes some 30,000 products. Yet, FDA funds for overseeing supplements have declined. While the new GMP regulations may help improve the quality of these diverse products, FDA will need more resources to establish a level playing field for producing and marketing dietary supplements.
Jill Wechsler is Pharmaceutical Technology's Washington editor, 7715 Rocton Ave., Chevy Chase, MD 20815, tel. 301.656.4634, firstname.lastname@example.org.
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