Safety Considerations in Supplement Formulation

Identifying food standards have been around a long time. In fact, something can only be named as something if it meets a certain standard (Code of Federal Regulations (21CFR), section 130). It is clear and simple; neither innovation nor permutations cannot change the basic threshold. This level playing field ensures for bread to be bread it must meet the bread standards of identity, and cannot mutate into a mango-floured, anthocyanin-colored, açaí-flavored, cloned-bovine proteinized, selenized-yeast loaf that still competes for consumer attention as B-R-E-A-D. Standards of identity were originally promulgated to provide a measuring stick (and club) for egregious and malicious adulteration and misbranding. Original standards of identity resembled recipes for home-made counterparts, describing the composition of foods in exquisite detail. FDAs thinking in providing such detailed mandatory composition was to preclude modifications of basic, staple, food formulas that would allow consumer deception to occur, and address a concern that the burgeoning synthetic food additives of questionable safety would insidiously find their way into foods prematurely.

Standards of identity or at least standards of expectations should also be relevant to consumers of dietary supplements and natural products. Most of us take multivitamin/mineral supplements that usually contain about a dozen basic vitamins and about the same number of minerals. That is the concept behind taking one multivitaminto get the most needed nutrients at the right levels at about the right frequency.

However, the market of late has become more bizarre, with multis including an ever-escalating breadth of micronutrients (many of dubious necessity) and permutations. Boron, tin, nickel and vanadium have become new regulars, while aluminum, germanium, gold and platinum are touted as micro-micronutrients. Some supplements are so laden with overt toxic moieties, such as arsenic, lead and mercury or rare earths, such as strontium, uranium and thallium, that it is small wonder the entire periodic table is not listed as the complete list of all the required nutrients.

Formulations are being fine-tuned to meet specific demographics and niche users, such as adolescents, seniors, men, women, children, athletes, etc. In the past, formulators combined ingredients and the products were marketed as joint formula, menopause formula or gastrointestinal formula. The newest angle is tailoring specific nutritional combinations to specific, ethical, pharmaceutical medications. For example, one manufacturer supplies a proprietary mixture of vitamin B6, B12 and D, plus folic acid and calcium to use with heartburn and acid reflux medications such as Nexium®, Prevacid® and Prilosec®. This firm also offers a combination of vitamins B6, B12, folic acid and coenzyme Q10 (CoQ10) for use with cholesterol medications, including Lipitor®, Zocor® and Prevachol®. Has nutrigenomics been supplanted with supplementomics?

Then there are botanicals and herbs. Does Echinacea or ginseng mean the same thing to all manufacturers, consumers, researchers, clinicians and regulators? And, the combination of so many diverse botanicals in a product ... is it necessary, is it safe? Is there data on the combination of Lonicera, Forsythia, Schizonepeta, ginger, Chinese Vitex, Isatis root and Echinacea? Or the combination of Rehmannia root, common yam, wolfberry fruit, Chinese dodder seed, Eucommia bark, deer antler, Asiatic cornus fruit, Chinese angelica root, cinnamon bark, Lindera root, Alpinia fruit, preying mantis egg case and Chinese leek seed?

Is safety really being considered? Do we understand the nature of these newly incorporated minerals into daily preparations? Valence state is critical for some of the known toxicants, such as chromium (Cr) VI versus Cr III. Valence and solubility are factors in absorption and distribution, and systemically target organs or sensitive tissues. Should arsenic or mercury be added or allowed, while at the same time be limited or avoided? What about additivity or synergy among similar moieties or elements? Copper, silver and gold are all IB transition metals, but are they all needed, and what are the effects if all are present? How many of these ingredients are strictly for marketing purposes (the cachet of platinum or horny goat weed for its subliminal visual)?

A baseline for safety should look at ingredients monographs, which have been scientifically developed via an independent, rigorous and transparent process. Valid monographs, such as those developed by the U.S. Pharmacopoeia (USP), contain relevant and specific information related to identity, analytical testing methodologies, acceptance criteria, impurities, active constituents, packaging and labeling information. Physical reference standards, i.e., purified and analyzed chemical compounds are used as a chemical yardstick to ensure each batch of product coming off of the assembly line is the same and as pure as the previous batch.

The monographs found in USPs National Formulary (USP-NF) are not static. There are changes in format, inclusion criteria, specifications, analyses, and a myriad of innovative products and processes. Volunteer experts, many of them internationally-based, convene in person and electronically to deliberate on the elements of a particular industry-submitted ingredient monograph. When an ingredient is deemed safe, or safe enough to be used at a specified exposure, then the expert committee swings into action. Of primary importance is identity: it must be characterized so a consistent and unambiguous material is tied to specifications, analytical tests for purity and impurities, acceptance criteria and limits on unwanted/unavoidable elements, etc. New ingredients are continually being presented for systematic review, coming not just from current research and development activities among American dietary supplement entrepreneurs, but also from the collections of traditional medicines in China, India and elsewhere.

Creativity and innovation are not suspect and should not be treated unfairly. They are the leading edge of global safety determinations, clinical evaluations, agricultural practices to standardize and consistently provide a cognizant genus/species, and provide consumers with products and ingredients that may ameliorate many human problems. However, safety must be the first and most differentiating threshold for evaluation and incorporationnot the post-mortem when increasing adverse-event reports spotlight a problem.

James C. Griffiths is the vice president of food and dietary supplement standards and Darrell R. Abernethy is chief science officer at the U.S. Pharmacopeia ( USP.org ).

Editor's Note: Looking to learn more about USP's Dietary Supplements Compendium? Join USP's Gabriel Giancaspro, Ph.D., on Tuesday, April 29, at 10 a.m. at SupplySide East for a compare/contrast session. Get registered and learn more online at SupplySideShow.com.