Product quality in context: defining quality within the framework of the new dietary supplement GMPs.
When DSHEA became law in 1994, there were an estimated 600 U.S. dietary supplement manufacturers producing about 4000 products. By 2000, however, FDA estimated there were more than 29,000 different dietary supplement products on the market with an average of 1000 new products being added annually.
Growth of the marketplace was fueled by increased consumer demand, often following publicity about the utility and efficacy of a particular herb. For example, in 1996 Linde et al. published a meta-analysis of randomized clinical trials of St. John's Wort (Hypericum perforatum L.) in the prestigious British Medical Journal (BMJ) that concluded the herb was more effective than placebo in treating certain types of mild to moderate depression. A June 27, 1997 broadcast of the popular television news magazine 20/20 highlighted this article, and sales of the herb boomed. Other mainstream media outlets quickly followed with articles on herbal medicine, sending the industry through several years of rapid growth.
Soon, however, mainstream media began to take a closer look at herbs. In 1998, the Los Angeles Times commissioned a survey of St. John's Wort products purchased from retail stores, subsequently reporting that three of 10 tested products contained no more than 50% of the hypericin content declared on the label. A later survey conducted by the Boston Globe (2000), as well as publications in the peer-reviewed scientific literature, reported similar findings.
In 2001, Harkey et al. published an article in the American Journal of Clinical Nutrition, which claimed that in 24 commercial ginseng products tested for ginsenosides content, concentrations of marker compounds differed significantly from the label claims. In 2003, Edwards and Draper published a paper in the Journal of the American Pharmaceutical Association that examined the alkaloid levels in 20 goldenseal (Hydrastis canadensis) products. It revealed that only 10 of 17 root products met USP's proposed alkaloid content standards; five products contained little or no hydrastine, unusual berberine: hydrastine ratios, and unexpected peaks.
Despite the increasing negative media reports, the demand for dietary supplements continues to grow as North Americans discover the potential health benefits, turn to alternative forms of medicine and seek to improve the quality of their lives. In 2006, an article in the Journal of the American Dietetic Association showed more than half (73%) of American adults surveyed report taking some type of non-prescription vitamin, dietary supplement or mineral supplement regularly. Yet despite this widespread use, 48% of Americans surveyed believe supplements are not adequately tested. Similarly, an Ipsos Reid survey conducted in 2005 for Health Canada showed that while upwards of 71% of Canadians consume NHPs (natural health products) either on a daily or seasonal basis, 46% of Canadians believe a lot of claims made by the manufacturers of NHPs are unproven.
Product quality is one of the biggest question marks facing consumers, clinicians, regulators and researchers today. Working definitions of quality within the supplement industry vary. And, as expected, there are some differences between definitions of quality for herbal preparations and for chemically synthesized products. Despite this, fundamental quality parameters are the same for both: identity, purity, content determination (i.e., strength).
The analytical challenges associated with quality assurance range from establishing the identity of the botanical source from which an extract was derived to measuring the amount of one or more desirable or undesirable constituents, such as pesticides, toxic elements, natural toxins or marker compounds. While numerous publications describe procedures for determining constituents of interest, few methods have been evaluated for accuracy, precision or reliability, and often the analysis of finished products is not within the scope of the method.
Embracing Analytical Methods
Analytical methods are intended to generate reliable, accurate data for use by manufacturers or regulators for quality control or enforcement actions, respectively. Reliability, accuracy, precision and specificity are the keys to the utility of a method, but analysts must take steps to prove that any method they use has these features, especially if the method is to be used in a critical setting, such as a quality control lab, a regulatory enforcement action or a clinical laboratory.
Botanical supplement products and their ingredients pose several analytical challenges due to the complexity of the matrix. As a result, methods validation has proven particularly difficult. Raw materials are invariably "irregular" because their chemical composition can depend on extrinsic factors such as geographical origin, weather, and harvesting practices, while finished products frequently contain multiple botanical ingredients.
All of the above challenges are further compounded by the paucity of validated analytical methods and a lack of reliable reference materials, both botanical and chemical.
Fortunately, there are systematic approaches to ensuring that a particular method yields accurate and precise data. The ability of a particular method to fit the specified purpose is one element of validation that is important but often overlooked. When methods are employed outside their scope and applicability they are no longer scientifically valid. Having analytical tools to evaluate dietary supplement identity and purity is not only required under the new GMPs, it is a critical factor for assurance of public safety, developing and maintaining quality assurance standards in manufacturing and, ultimately, for meaningful efficacy testing of these products.
While this industry must bear the burden of its historical failures, it must also react to new quality challenges. Product quality affects market access and growth. This can be an impediment when low-cost, and usually low quality, products confuse and diminish respect and trust by consumers and regulators. The "snake-oil" reputation decreases interest, awareness, acceptance and use of high quality, science-based products. Fraudulent or unsafe products decrease market acceptance and although media coverage of products that do not meet their label claims are more common than unsafe products, the reputation of the overall industry suffers. As a consequence, healthcare providers, researchers and regulators continue to dismiss dietary supplements as potentially significant contributors to healthcare cost reductions.
Implementing the newly published regulations that set out dietary supplement-specific GMPs will challenge manufacturers as well as companies earlier in the supply chain and the laboratories that support the industry. Although industry stakeholders are aware of the quality issues and their growing impact, individual industry members do not necessarily have the required expertise, organizational and financial resources to address them.
Over the coming months, this column will focus on providing insight into some of the unique analytical and quality challenges facing this industry, as well as recommendations for their solution. The goal is to support the dietary supplement industry in developing and implementing credible, cost-effective work plans for quality.
Paula Brown, Program Head of the Natural Health Product Research Group (NRG) at BCIT, directs a multi-disciplinary research facility providing fundamental investigations on product quality, safety and efficacy. In establishing NRG, Ms. Brown has created the capacity to support industry through the entire continuum, from grower to manufacturer, ensuring product integrity is maintained. An active volunteer, she is a founding member of the NHP Research Society of Canada, a non-profit group dedicated to supporting and promoting scientifically rigorous research and education on NHPs. Ms. Brown is also General Referee for the AOAC Dietary Supplements Methods Committee. She can reached BCIT, 3700 Willingdon Avenue, Burnaby, BC, Canada, V5G 3H2, Email: firstname.lastname@example.org
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|Title Annotation:||QUALITY FOCUS|
|Date:||Jan 1, 2008|
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