I have heard it said many times, and in many ways, that there is no supplement  “industry” but rather there are supplement  “industries.” Many would rather dissociate from the less than ideal activities that are evidenced by FDA recalls, market withdrawals and safety alerts. While we may argue about how many “industries” there are, there is only one market in which they compete.

Adding Insult to Injury

In a marketplace where high quality products struggle to differentiate from lower quality products, consumers are faced with supplements adulterated with undeclared active pharmaceutical ingredients (APIs). According to federal law, such products are not supplements at all, but unapproved (and therefore adulterated) new drugs. A quick scan of dietary supplement recalls, market withdrawals and safety alerts in the U.S. shows 35 incidents since January 2010. Of those, 30 cite an undeclared drug or API. In fact, FDA served up one heck of a punch on Nov. 23, 2011 by filing a permanent injunction to stop a dietary supplement manufacturer from making and distributing more than 400 products. This action came after the company had already received warning letters dating back to 2004 concerning the use of androstenedione and ephedra alkaloid containing ingredients in dietary supplements. On Dec. 6, 2011, U.S. Marshals seized imported raw materials containing ephedrine alkaloids. The FDA press release stated, “Through this action, FDA removed more than $70,000 worth of these potentially dangerous dietary supplement ingredients from the market.” Finally, federal criminal charges have been filed against a man in an API spiking case in Utah. So while these companies may not fit your personal definition of the “Dietary Supplement Industry” they exist and they are in your marketplace.

FDA Commissioner Margaret Hamburg addressed the issue of adulteration in a keynote address at the Counterfeit Drug Interchange Conference in October of 2010, saying, “It is sad to realize that we live in a world in which some criminals are willing to maximize profits by placing poisons in products like infant formula, toothpaste and medically necessary drugs. But it is a reality we must face. And, more importantly, it is a reality that we must become more proactive in dealing with.”

I don’t know anyone who is more proactive in combating API adulteration in dietary supplements than James Neal-Kababick at Flora Research Laboratories. A leader in analytical methods development who diligently works with manufacturers to ensure their dietary supplement ingredients are not adulterated, he has agreed to provide a rundown on common APIs found in dietary ingredients and how to detect them. 

Detecting Pharmaceutical Adulteration: A Phytoforensic Approach

Certain types of products seem more likely to contain API, so a good place to start is products intended for a target audience. For example, you would check for erectile dysfunction (ED) drugs in men’s virility products; glibenclamide and other anti-diabetic drugs in blood sugar support products; and laxatives, diuretics, anorectics and stimulants in weight loss products. Products to promote relaxation may contain benzodiazepines and psychiatric medicines and bodybuilding and sports performance products may contain aromatase inhibitors and even anabolic steroids.

Now for the stern warning: you cannot assume that only drugs from the expected category are going to show up. I have found PDE-5 inhibitors in sports products and stimulants in men’s virility products. Therefore it is recommended manufacturers implement a check system with as wide a net as possible. While no one analytical approach is the “go to” method for broad API adulteration screening, perhaps nothing is broader in scope than liquid chromatography equipped with a diode array detector (DAD) coupled to an evaporative light scattering detector (ELSD) and mass spectroscopy (MS). 

This combination approach allows for detection of many pharmaceuticals simultaneously and increases the likelihood you won’t miss drugs that don’t respond well in a particular detector. The use of the DAD is very useful for two main reasons: 1) The UV spectrum of a peak can be compared against a spectral database of known APIs for a first screen, and 2) Many novel drug analogues, such as the seemingly endless new PDE-5 inhibitors, have UV spectra matching the parent drugs. However not all compounds absorb in the UV spectrum, so ELSD is valuable for catching those compounds that are invisible to the UV detector. The limitation of ELSD is that it is non-specific and does not provide a way to identify peaks outside of including an external calibration. In this way, the more expensive MS is superior to ELSD in terms of specificity (and often sensitivity). Similar to the DAD where you can acquire a UV spectrum, in MS you can get molecular mass information and a fragmentation pattern that can be matched to an MS database for first pass screening. There are other techniques that can be of great value such as chemical spot tests (think of those field tests police use to see if white powders are illicit drugs). Flash column cleanup followed by high performance thin layer chromatography (HPTLC) and observation through a microscope (where blatant drug crystals in finely powdered herbal material can be observed) are perfectly good first steps. 

If you want to take the investigative approach often employed by FDA, then your goal is to identify every peak you see in the separation. That is going to require some phytoforensic techniques because you need to know some phytochemistry to anticipate what constituents the botanical ingredient will likely contain and where those phytochemicals appear in the separation. For a chromatogram with only a single peak obtained from a raw material whose label lists 20 herbs, common sense suggests the peak is almost certainly a drug; this is the easiest form of API adulteration to spot. Then there are the “herbal” samples that are bright yellow (like sulfur) or pure white crystals. These are clues that you might have a pharmaceutical drug and not an herbal extract—keeping in mind there are many single chemical ingredients such as amino acids and excipients that are also white powders. Once you’ve done some chromatography, examination of the chromatogram for peaks that don’t make sense given the phytochemicals you’d expect from the ingredient label, you should dig deeper. Leave no stone unturned. This is very serious work that requires expertise in phytoforensics and some pretty expensive equipment; those are the breaks if you want to sell products in certain categories. 

Anabolic steroids. To screen for known common anabolic steroids, either liquid or gas chromatography with MS can be employed. Unfortunately, there is a constant stream of novel anabolic steroids being developed in clandestine labs around the world. Examining MS fragmentation patterns can give you hints about the parent drug category and functional group substitution on the steroid rings, but may not allow a definitive identification. Good sample preparation techniques are therefore critical and I cannot stress enough that procedures designed for urine cleanup, as used in drug testing labs, are not appropriate as they often miss a lot of compounds. 

5-PDE inhibitors. If you don’t know what a 5-PDE inhibitor is, sildenafil (Viagra) is an example. This is one of the most challenging categories as novel analogues of ED drugs are constantly appearing in supplements. As if finding a new ED drug every month isn’t alarming enough, the recent trend is to mix several of these APIs together. So remember when screening for ED drugs not to stop once you find one; there could very well be more. Using the phytoforensic approach of accounting for every peak, we have found other compounds like phentolamine and dapoxetine in combination with PDE-5 inhibitors. Careful screening and evaluation of UV spectra and MS fragmentation patterns led us to possible drug candidates, which were then followed by confirmation against a chemical standard. When the compound is a novel analogue, we can tentatively confirm the class, but must isolate and characterize in order to confirm the identity of the API. Recent work suggests a new generation of 5-PDE inhibitor is being used that is more difficult to detect in a screen because the core structure is different than the known parent drugs. 

Weight loss drugs. Probably the most common API is the banned anorectic drug sibutramine, for which there are currently at least two analogues and an active metabolite. It is reasonable to anticipate additional derivatives will appear in future screens. There has been an increase in sibutramine adulteration recently, despite the widespread knowledge of the problem, possibly because existing stores of this now-banned drug are being “dumped” into the supplement ingredient stream. Other compounds to consider targeting include undeclared laxatives, diuretics and so-called “legacy” drugs that have been banned due to safety issues or those that are simply no longer in use, having been replaced by more modern drugs. API adulteration in this category of supplements has included stimulants like theophylline and methylhexaneamine (sorry, it is not in geranium folks), sympathomimetic amines (such as amphetamine, phentermine and ephedrine) and even benzodiazepines and other anti-anxiety drugs. So this is a very complicated class to screen due to the diversity of the potential APIs and would in fact require multiple screens across a wide variety of drug classes.

FDA’s Good Manufacturing Practice (GMP) regulations do not mention APIs, but the preamble, section 111.70 (a) states: “You must establish a specification for any point, step, or stage in the manufacturing process where control is necessary to ensure the quality of the dietary supplement and that the dietary supplement is packaged and labeled as specified in the master manufacturing record.” I’d say that if you know your product category has a history of adulteration with APIs, this provision pretty much tells you that a control point is needed. So if you have products in the aforementioned categories, it would be reasonable to implement a screening protocol for potential APIs for incoming raw materials.

The trade organizations and FDA have agreed to work together to help stamp out the API spiking problem and the American Herbal Products Association (AHPA) has created a website to keep the dietary supplement industry informed on issues related to illegal tainted products being sold as dietary supplements (www.keepsupplementsclean.org). To assist manufacturers in ensuring the integrity of their products, AHPA has worked to provide industry tools under its Botanical Authentication Program. Although not specific to API adulteration this is an excellent resource (www.ahpa.org/Default.aspx?tabid=242). In November 2011, The American Botanical Council, in collaboration with the American Herbal Pharmacopoeia and University of Mississippi’s National Center for Natural Product Research, announced an initiative to educate members on supplement adulteration problems, challenges and solutions.

It is my hope that through this article and other resources, manufacturers will be able to mitigate the risk associated with dietary supplement ingredients adulterated with APIs and will seek support in selecting the most appropriate methods to integrate into their quality control programs. Companies work hard to build a quality brand and it just isn’t worth the risk of damaging your brand by having FDA post a warning letter on the Internet saying you are selling drugs as dietary supplements.