The Tools of Botanical Quality

Let no herbal supplier or manufacturer undergo poor quality production for lack of quality control tools. There certainly are gaps in available reference materials for certain products, mostly newer ingredients, and the tools might not be in the same convenient shed. However, the market for herbal products is dynamic, with new ingredients popping up every year. In this innovative, competitive segment, the quest for profit and timeliness must be tempered by the current climate of quality assurance—customers and clients at all levels of this market are demanding higher quality, consistent and traceable products.

Quality control is a process involving strict organization, training and testing. There are tools to help manufacturers with each of these control areas. The majority of testing is laboratory based. Despite common constituents, each botanical requires an individualized method of analysis. Getting different manufacturers and suppliers to agree on the proper method for a given herb is not always a simple task.

In 2001, AOAC International, a non-profit scientific association that provides independent volunteer-based assessment of methods, partnered with the National Institutes of Health (NIH), the Office of Dietary Supplements (ODS) and FDA to begin identifying methods for testing dietary supplement ingredients, including numerous botanicals. The goal was to develop 20 official AOAC methods for those dietary supplement ingredients deemed most in need of standard analytical methods.

To date, AOAC’s supplement program has included a number of botanicals on its list of ingredients ranked by need of test methods; bitter orange, black cohosh (triterpine saponins), Siberian ginseng, feverfew, grape seed extract, hawthorn, yohimbe, valerian and boswellia have all made the grade. Botanicals with methods currently under validation or review include: Aloe vera, Asian and American ginseng, cranberry, echinacea, ginkgo, ephedra (FDA mandated), isoflavones (soy/red clover/ kudzu), saw palmetto and St. John’s wort.

Developing a method is only part of the equation. For widespread acceptance as a “standard,” validation of the method is essential. There are two ways to validate a method under AOAC protocol. Single lab validation provides a preview of method performance and offers some measure of its ability to successfully complete a full collaborative study. A full, collaborative validation involves eight to 10 labs and uses a protocol designed in accordance with AOAC Official Methods Program guidelines and approved by the appropriate AOAC methods committee and General Referee. Board and committee members came from the American Herbal Products Association (AHPA), Chromadex, Covance, Triarco and various other stakeholders and government agencies.

Test Time

There are many facets of the QC process for botanical product production, but two big areas of focus are identification of plants and verification of chemical contents. The new GMPs (good manufacturing practices) for dietary supplements mandate 100-percent identity testing, although there is some industry effort to provide a means for exemption from the rule under certain conditions.

“Almost all botanicals will have to be identity tested, unless there is truly no method to do the test,” confirmed Darryl Sullivan, senior manager at Covance Labs, and chair of the AOAC dietary supplement task force committee. “Less than 5 percent of botanicals evade testing; there are thousands [of herbs] that have tests already.” Whatever the final rule, it appears companies will have to ensure the identity of every ingredient they use. For many manufacturers, this could mean hundreds or thousands of botanicals.

Since the emergence of the GMPs, Sullivan said lab work has shifted from a primary focus on finished products to examining raw materials, including efforts to create identity testing and ingredient monographs. He noted the industry is truly in need of identity test methods for thousands of herbs.

Botanical identification can be tricky, and while a particular herb might have been around and in use for centuries, the reference tools to properly identify incoming herbs from the supplier might not exist, might not be accurate and might not be validated. Two different botanicals can have many constituents in common, making it trickier to find the right marker to test for identity. There are other ways to test identity, such as organoleptic methods, but lab testing will be a good portion of the testing protocol.

There are numerous resources available around the globe for most herbs in commerce.

“Our industry has to be diligent in ensuring we’re doing something to evaluate ingredients and make sure what we’re buying is, in fact, accurately identified,” said Michael McGuffin, AHPA’s president. “There are ways to do this; sophisticated and committed companies take the extra steps they need to take for high quality assurance.”

Industry organizations such as AHPA and the American Botanical Council (ABC) have contributed to the reference database for herbs. Mark Blumenthal, founder of ABC, published the German Commission E report, which compiled official German government monographs on more than 300 herbs and herb combinations. There is an update available that covers the 107 most popular herbs in the United States.

AHPA maintains an electronic herbal library, incorporating scientific information and data from many different sources. It also helps keep botanical companies up to date on regulatory affairs. Most recently, AHPA formed a special committee to develop analytical tools for identification and determination of purity of powdered raw materials labeled as Hoodia gordonii stems. As a part of the first phase, AHPA made available two methods that both utilize microscopic and high-performance thin layer chromatographic (HPTLC) techniques. The committee is also developing a high-performance liquid chromatographic method slated for future release.

Some well-known companies supported AHPA’s Hoodia project, showing the ambition for self-regulation in the industry, in terms of quality control. Among the contributors were Alkemists Pharmaceuticals, CAMAG Scientific, Herbal Teas International, Millennium Health, Nature’s Way Products, NOW Foods, Vitality Works and Wulff Africeuticals.

These unified efforts are welcomed, but the majority of previous and ongoing work on testing methods and reference materials is credited to the work of individual companies and contracted labs. The leading companies in a particular botanical segment are usually in the best position to discover the common misidentifications, adulterations and active phtyochemicals.

“We’ve had to develop our own tests,” said Josef Brinckmann, vice president of R&D at Traditional Medicinals. “Even when you take a method from official pharmacopeia, if you do anything unique with y our products—combine them in a different matrix—you have to work with your own lab and/or an independent lab to modify the official method, then validate it to make sure two different labs can get the same results.”

Unfortunately, many herbs hit the market without much in the way of analytical methods, let alone anything validated. “The situation is backwards,” said Frank Jaksch, founder of Chromadex, an independent contract lab that has developed standard testing methods for numerous botanicals, including aloe, horse chestnut, pomegranate, mangosteen, fenugreek and stevia. “Companies often wait until an herb has gained traction in the market, when they really should be developing the standards earlier. You won’t find reference standards and methods until years after their product launch.”

This has been the problem troubling numerous herbs, especially the exotic fruit-based botanical ingredients that have recently become very popular. In the case of hoodia, AHPA and its member companies have produced useful materials to help address the quality issues plaguing that particular herbal market segment. Chromadex has also contributed to the matrix by developing a standard for testing P57 content in hoodia.

Chromadex’s “Hoodia oxypregnane steroidal glycoside reference standard P57” offers a complete characterization of the identity, purity, and moisture content of the P57 standard, which will be independently reviewed. Once verified, the reference standard will be designated as an American Herbal Pharmacopoeia (AHP)-verified reference standard. AHP is one of the top sources for official standards and methods, representing a more specialized version of the U.S. Pharmacopeia (USP).

Pomegranate has taken off much in the way hoodia invaded the American herbal market. Competition to capture this momentum led to wild swings in quality, especially relative to ellagic acid, the focus of pomegranate constituency. According to Cal Bewicke, president of Ethical Naturals, ellagic acid occurs in pomegranate, but only at about 3 percent to 5 percent. “This means to produce an extract containing 40 percent ellagic acid from pomegranate would require a concentration of 80 to 120 times, a very expensive and difficult process,” he noted. “Yet, many of these extracts are very cheap indeed. How is this done?”

This is a case where the problem is not necessarily in the data, but in the interpretation of the data. Upon sharing information, Ethical Naturals and other companies in this market realized pure ellagic acid is very cheap to buy and can be added to a basic extract to elevate the level to 40 percent or higher, while claiming it contains only pomegranate. “Companies should be very careful under these circumstances, because labeling laws require that all ingredients be listed on the label,” Bewicke cautioned. “If ellagic acid has been added, it should be correctly listed.”

Mangosteen and açaí are also under the microscope. In the Journal of Separation Science (2007;30(9):1229-34), researchers published a credible scientific method for testing and measuring xanthones. The study used the HPLC analysis standard (developed by Chromadex for mangosteen xanthones) to define an analytical method that accurately identifies xanthones from the rind of the mangosteen fruit. Edward Walker, Ph.D., Weber State University, lead researcher in the study, said with a xanthone measurement standard now in place, claims concerning xanthone quantity and efficacy can be evaluated through credible research. Chromadex, which had its xanthone method singlevalidated per AOAC protocol, is currently working on açaí standards.

Sometimes it’s not the new, sexy ingredients in desperate need of test methods. Ayurveda is an ancient method of medicine from India. Sami Labs, based in Bangalore, India, has developed reference standards for more than 100 Ayurvedic botanical compounds, from boswellia to yohimbine. The company compiled the references into a database available to the international botanical product and scientific communities. Muhammed Majeed, Ph.D., who founded Sami Labs and Sabinsa Corp., said: “Usually reference standards are supplied by the pharmacopoeia commissions like USP, BP, etc. However, there are a number of products which are still not in any pharmacopoeia and hence the reference standards are not available.” He noted in developing these Ayurvedic herb references, Sami scientists employed various separation techniques including sophisticated column chromatography. They have been characterized by NMR, LC/MS, GC/MS, FT-IR and other techniques such as elemental analysis.

Some herbs that have been on the U.S. market for a long time have been targets of adulteration, requiring new tests to distinguish between true and false material. In the case of ginseng, which is typically standardized to percent ginsenosides, unscrupulous manufacturers realized ginsenosides are also contained in the ginseng leaf, which is very cheap, compared to the root, which is more expensive but has been the focus of almost all health-related research. To unmask products labeled as ginseng root, but containing ginseng leaf, Ethical Naturals has been working with Chromadex on a method to differentiate between leaf and root extracts. “Much of the technical side of this work is now complete, and the results will be presented to the industry in the very near future,” Bewicke reported. The company has also worked with AHP’s Roy Upton and Jules Skamarack, Eurofins Testing Laboratories, to produce an extensive industry survey and report on the adulteration problem in the ginkgo market. The QC Report was widely disseminated, along with work by AHPA and others, and resulted in a situation where all reputable companies are now able to test for the presence of cheap flavonoid additives in ginkgo extracts.

Bilberry is another example of a problematic category due to adulteration, according to Janksch, who noted UV spectrometry can be manipulated to get to the desired 25 percent anthocyanin standard. There were even reports of companies using mulberry or black bean skins to boost anthocyanin content. 

Indena, a leading bilberry supplier, took the problem head on, developing and validating an HPLC method to identify and quantify the anthocyanins in bilberry plant material and extracts (J AOAC Intl. 2006; 90(4):911-919); separate tests can identify those anthocyanins revealed to be probably not from bilberry. Ed Croom, Ph.D., botanist and scientific and regulatory affairs manager with Indena, said: “Using a peak profile, the peaks and valleys on a bilberry result are unique, and any recurring high peak indicates a possible problem.”

While unique testing methods may improve quality of botanical products and weed out the cheats and fly-by-night companies, it is important for suppliers and manufacturers to share the right information and data with the consistency and detail that defines high quality control. To this end, the industry associations—AHPA, Council for Responsible Nutrition (CRN), Natural Products Association (NPA) and Consumer Healthcare Products Association—have come together to produce a Standardized Information on Dietary Ingredients (SIDI) protocol, a set of voluntary standards for the exchange of relevant and required information between dietary ingredient suppliers and finished product manufacturers. In the style of an MSDS sheet, the SIDI protocol includes three main sections: Product Information Datasheet, the Site Quality Overview and the Site Supply Chain Security Overview.

The developers created a category just for botanicals, which covers nomenclature; production (cultivation details and agricultural specifics, etc.), identification method; GMP compliance details; disclosure of known/potential impurities; physical properties (listing of all ingredients/ excipients, the origin/plant part/binomial, product specs [ash, moisture, pH, organoleptic, microbiology, known impurities, bioassay method]); and compendial grade (USP, AHP, JapanPh, EuroPh, etc.). In addition to the associations, contributions to the SIDI development came from companies such as ADM, Bayer, P.L. Thomas, Nutramax, Pharmavite, Kemin, MB North America and others.

This trend of working together on these QC issues is welcome and long overdue. “For so long the industry lacked a forum for data to come together,” Sullivan said, noting only in the last few years has there been more collaboration towards bringing this scattered information together.

Bewicke agreed, adding: “Over the years, many people and organizations have worked to develop methods and standards for testing botanicals. The result is most of the basic analytical chemistry is well understood, and can be accomplished both by independent labs and companies that have their own well equipped laboratories.”

This doesn’t negate the role of individual companies developing their own tests, but now there will be assessments of such methods. For instance, Verdure Sciences recently redefined the old UV spec test method for total bacosides in Bacopa monnieri, replacing it with an HPLC method to test for glycosides. “Companies can use their own methods, but these will ultimately be measured against any existing validated method,” Sullivan explained. This means validation is the next step.

Even when validated methods exist, Jaksch said it is important for the industry to band together and stop accepting any unsuitable methods. “As long as the industry is moving in the direction of peer-reviewed validated method, then the outlook is good.”

Editor's Note: This is part 2 of a two-part series on botanical quality; part 1, "The Complexities of Botanical Quality", appeared in the Sept. 24, 2007, issue of INSIDER, and can be found online (click here).

The Quality Control section is sponsored by Ethical Naturals; however, the company does not review or approve editorial content.