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How FDA handles this game of cat-and-mouse.
Adulteration of dietary supplements concerns manufacturers and consumers alike. It also affects the credibility of the supplement industry. The extent of intentional adulteration with synthetic pharmaceuticals of products marketed as dietary supplements is significant and on the rise.1 The intentional “spiking” of dietary supplements is done with the intent to impart an effect that cannot be achieved by the dietary ingredients alone.
Use of synthetic pharmaceuticals-drugs and their structurally similar analogs-to adulterate dietary supplements presents a public health threat, more so when structural analogs are used. For, while some of these drugs used by adulterators have been withdrawn from the market by regulatory bodies due to safety concerns, analogs represent largely uncharted territory because their safety was never clinically examined, rendering products containing them unapproved drugs. Illicitly manufactured “designer drugs,” created specifically to evade detection by circumventing testing techniques and exploiting regulatory loopholes, are increasingly prevalent in dietary supplements. Furthermore, it is not uncommon to see concurrent adulteration with multiple agents, in potentially dangerous combinations and in erratic and excessive dosages, since the adulterators are unlikely to employ Good Manufacturing Practices (GMPs). Consequently, the threat to consumers is significant, as adulterated products are used outside the conventional medical practice and may not only contain toxic ingredients but also interact with prescription drugs.
Because the adulterators, driven by quick financial gain, attempt to reach the largest number of people in the least amount of time, adulterated products are sold increasingly through alternative avenues of distribution-in particular, the Internet-making it difficult for regulators to effectively enforce against manufacturers. FDA has alerted consumers to nearly 550 cases of adulterated dietary supplements, to date.2
It really is a game of cat and mouse. In fact, often, by the time FDA investigates and enforces action against a tainted product, the adulterator has either a) removed the drug from the product so that investigators no longer find the adulterant in the formula, or b) adulterators replace the product under investigation with another, different product that contains the same type of adulteration. It takes time for consumers to notice that replacement products may not work the same way that the initially purchased adulterated products did, or for news to spread about an FDA investigation; by that time, the evasive adulterator has already made a lot of money.
The Big Three
Erectile dysfunction, weight loss, and sports performance products continue to lead the way in adulteration.
For over a decade, approved erectile dysfunction (ED) drugs (sildenafil, tadalafil, and vardenafil) and, increasingly, their analogs, have been discovered in products marketed as dietary supplements. More than 120 synthetic analogs have been detected. The current trend is toward rapid propagation of synthetic analogs and addition of multiple concurrent adulterants to the same formulation. There is a need for expanded analytical scope and for non-targeted screening methods to address this challenge.
Adulterated products for weight loss, on the other hand, comprise a larger and diverse category, both functionally and chemically, including stimulants, anorexiants, laxatives, and diuretics. Sibutramine, an anorexiant accounting for the majority of the adulteration in the weight-loss category, was withdrawn from the market in 2010 after FDA review of clinical data indicated increased risk of stroke and myocardial infarction.3
Other common adulterants in weight-loss products marketed as dietary supplements are bumetanide (diuretic; the active pharmaceutical agent, or API, in the drug Bumex), fenfluramine (appetite suppressant; withdrawn), furosemide (diuretic; the API in the drug Lasix), orlistat (lipase inhibitor; the API in drugs Xenical and Alli), phenolphthalein (banned laxative), phentermine (appetite suppressant; the API in Adipex P), phenytoin (anticonvulsant; the API in Dilantin), rimonabant (appetite suppressant; the API in Acomplia), and sertraline (an antidepressant; the API in Zoloft).
Sports performance constitutes the third major category of adulteration. In this category, a massive stream of “designer” anabolic steroids and stimulants-consistently banned by anti-doping agencies-are used. This adulteration category presents the most serious analytical challenge because of the strong product demand, functional and structural diversity and diversification of delivery systems, generally low physiological action levels of hormonal drugs, and the widest possible scope (the World Anti-Doping Agency identifies 10 major prohibited categories).4
Helping to Chase and Corner the Mouse
In an effort to address the issue of tainted products marketed as dietary supplements, the U.S. Pharmacopeial Convention (USP) has convened an Expert Panel (EP) to develop screening methods for synthetic pharmaceuticals as adulterants in products marketed as dietary supplements. USP Expert Panels are volunteer groups of scientists, academics, regulators, and industry members with expertise in a particular topic that aid USP in addressing specific challenges.5
The ultimate goal of the EP is to provide a new United States Pharmacopeia general chapter containing written analytical procedures for the detection of intentional adulteration of dietary supplements with synthetic pharmaceuticals in all three major categories of adulteration (erectile dysfunction, weight loss, and performance enhancement in sports). The methods under consideration by the EP are expected to be a comprehensive combination of chromatographic and spectroscopic techniques, and the analytical strategy will be that of a “toolbox” approach: each laboratory will decide for itself which detection avenues to follow (suitability of use), depending on the available instrumentation, analytical goals, and the types of supplements under scrutiny.
Because there are numerous overlaps between the adulteration categories and new categories of adulteration that only recently came to the forefront (e.g., anti-diabetic, pain relief, and thyroid-support remedies), no one, universal technique may fulfill a “catch-all” promise. Therefore, a combination of orthogonal testing schemes will always contribute to add certainty in the outcome of analysis and detection of adulterants. For confirmatory analysis, however, mass spectrometry is still the most reliable method and should certainly be sought. In some cases (e.g., drugs with hormonal action), the amounts of adulterants that have some physiological effect may be so low that mass spectrometry is probably the only viable analytical option.
The recent USP workshop on “Economically Motivated Adulteration of Food Ingredients and Dietary Supplements” (September 26–27, 2013; USP Headquarters, Rockville, MD) addressed the conventional challenge of adulteration of dietary supplements from substitution or spiking with marker compounds, as well as the emerging concerns over tainted products marketed as dietary supplements and the technologies to detect them.6
The workshop, cosponsored by the Natural Products Association (NPA) and the United Natural Products Alliance (UNPA), recognized the value of a combination of carefully designed documentary quality standards, appropriate reference materials, modern methods of analysis, and spectroscopy and genetic methods to trace and detect adulteration. While fraud is not predictable, and one may only examine the presence or absence of what one tests for, a case was made for standards and reference materials for common adulterants and their analogs, considering repeat offenses in high-value products. The need for scientifically valid test methods, and the use of modern analytical methods, were stressed to ensure that current GMPs are followed in accordance with the regulations. Public standards from USP that are developed with due consideration of method validation parameters (accuracy, precision, specificity, detection and quantitation limit, linearity, range, and robustness) have a role in this regard. The workshop participants stressed the need to pool resources in addressing the challenges from adulteration. USP invites collaboration from organizations and agencies for developing and updating public standards. Monographs and general chapters from USP complement the educational and outreach efforts from these organizations.
USP’s work is currently focused on adulteration of ED supplements, but the other two major categories are also under active development. As underscored by the USP stakeholders on numerous occasions, providing analytical tools and guidance for the industry is invaluable, but equally important is the flexibility to efficiently counteract the adulterators who are continuously working to defy the established norms of pharmaceutical analysis. By building flexibility into analytical strategy, USP is set on leveling the playing field and making it increasingly harder to adulterate dietary supplements with synthetic pharmaceuticals.
Anton Bzhelyansky, MS, is a scientific liaison, and Nandakumara Sarma, PhD, the director of dietary supplements, for the U.S. Pharmacopeial Convention (USP; Rockville, MD), which is responsible for publishing the USP-NF and the Dietary Supplements Compendium (DSC). Other USP staff contributing to this article include Gabriel Giancaspro, PhD, and Claudia Costabile, MA.
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