As we take aim at questions of quality, we must ask, Where is the target? The label is the first target! In "targeting the question of quality," manufacturers of dietary supplements, both large and small, must hit the quality target. But just where is that target?

Ultimately, each manufacturer (or marketer, in the case of contract manufactured supplements) establishes its own quantitative target - that target is the promise made by the manufacturer on the label of the product. Thus, a product that states that each serving contains 500 mg of valerian root has defined that quantitative weight as its first target, while one that provides a serving of 2 ml of valerian tincture has defined a target that is exactly that quantitative volume. On the other hand, a product that claims to contain 500 mg of valerian root extract standardized to contain 0.8% valerenic acid has a different target (or targets).

The analytical tools needed to reach these targets are also different. On the one hand, a product that only states the weight of each ingredient on the label may be able to hit the quantitative target by weighing the finished product on a scale or balance, so long as all ingredients have been positively identified. However, such products might not hit even this quantitative target unless the manufacturer has established excellent production processes (e.g., to assure that the right quantity of each ingredient went in to the batch, was well blended, and was not deteriorated by processing). The tincture product described here might only need some substantiation of proper identification of the ingredient incorporated into its production record in order to meet a quantitative target.¹ In order to evaluate the tincture qualitatively, however, other questions must be answered: is the ratio of herbal material to volume of extract sufficiently concentrated? Is the chosen solvent appropriate for the extraction of the starting plant material?

On the other hand, an herbal product that claims on the label to be standardized to a marker constituent or constituents will require chemical analysis in at least one, if not several, stages of production.

Before examining the analytical tools that are relevant to this last class of goods, it is important to realize that among the entire range of herbal products, this subclass of products (i.e., those that claim to contain a specified amount of a marker) is most subject to scrutiny. It may be that the failure or perceived failure of these herbal products to meet their label claims has, more than any other product class, led to the general public concern about product quality in the supplement industry.

Without question, members of industry must recognize that a manufacturer bears absolute responsibility to assure that the labeled quantity of a marker compound is present in its product. However, the whole issue of the validity and value of quantifying marker compounds on consumer product labels must be assessed. The American Herbal Product Association's (AHPA) Botanical Extracts Committee recently completed a white paper on the "Use of Marker Compounds in Manufacturing and Labeling Botanically Derived Dietary Supplements."² The document acknowledges that the "beneficial uses of marker compounds include their application for purposes of botanical identification, detection of adulteration, and as indicators of product quality during manufacturing, handling, and storage, ... as shelf life indicators ... [and] as an indicator of pharmacological activity when they themselves are active." However, "pitfalls" of using marker compounds are also described, including "limitations on available testing methods [and] reliance on [markers] as sole identity indicators." The paper goes on to say that "The excessive attention paid to individual compounds has led consumers, retailers, and even extract manufacturers to assume that control of the marker content is equivalent to controlling the physiological effect of the extract," and notes that "these assumptions are not always valid."²

To summarize these background points:

1.

The analytical method needed to assure that a product meets its ingredient claim depends greatly on the nature of the specific ingredient and the ingredient claim.

2. All that can be conclusively shown when a manufacturer verifies label content by a properly chosen analytical method is that a quantitative target has been met. It is important to acknowledge that this certification of "label integrity" may or may not be relevant to a product's quality.

3. The use of marker compounds is not necessary to the production of quality botanical products, and further, even the accurate quantification of a marker compound on the label of an herbal product is not necessarily an implication of quality.

Perfection is preferred. Is it required?

Another question needs to be answered in order to completely understand a manufacturer's responsibility in label compliance: How big is the quantitative target? Is there any tolerance for anything other than perfection, or will only a "bull's eye" do?

One of the specific statutory details of the Dietary Supplement Health and Education Act of 1994 (DSHEA) is the requirement that each of the dietary ingredients in a supplement, or a proprietary blend of these ingredients, be quantified on the product's label. DSHEA reads, "... the listing of dietary ingredients [in a dietary supplement product] shall include the quantity of each such ingredient (or of a proprietary blend of such ingredients) per serving."³

In promulgating the regulations that implemented DSHEA, the U.S. Food and Drug Administration (FDA) determined that its long-standing definitions for Class I and Class II nutrients should serve as the regulatory standards for measuring label conformity for supplement products.⁴ Class I ingredients are "Added nutrients in fortified or fabricated foods," and are required to be present at 100% of the labeled amount. Class II ingredients are those that are "Naturally occurring (indigenous) nutrients," which are not subject to enforcement so long as at least 80% of the claimed amount is delivered. There are regulatory tolerances for both of these classes that recognize that analytical methods are subject to margins of error, sometimes by as much as 5-25%.

As Class I ingredients in FDA's regulatory policy, a 500 mg vitamin C tablet or rose hips capsule would be expected to contain not less than 500 mg of the identified dietary ingredient. On the other hand, if a 500 mg capsule of ground rose hips stated that it contained 5 mg of "naturally occurring" vitamin C, no enforcement action would be expected so long as the product actually contained a minimum of 4 mg (80% of the claimed total) of vitamin C.

How do these regulations apply to a standardized extract? As stated earlier, it can be argued that it is these products that are most subject to scrutiny by the industry's critics. It has also been argued that, as the marker compound is not actually "added" to a standardized extract, the marker should be treated as a "naturally occurring" constituent, and as such, should be subject to only the 80% rule. For example, valerian root contains valerenic acid in a natural concentration of up to about 0.3% by weight. Valerian root extracts are manufactured to concentrate and control the amount of valerenic acid and a few closely related compounds at, for example, 0.8%. A capsule that is labeled to contain 300 mg of a 0.8% extract would be essentially claiming to contain 2.4 mg of the compounds. What if a validated analysis shows that this product only contains 2.0 mg, or 83% of the claim? What if it were found to contain 50% more than the claimed amount?

FDA has taken the position that no manufacturing shortage will be tolerated for such ingredients. This position is based on the agency's assertion that the Class I definition is relevant not only when a constituent is added to an extract, but also when the level is adjusted, controlled, or manipulated in any manner. It is interesting to contrast this policy with the standards that are currently established in the United States for certain drugs and which allows for specifically defined "potency ranges." An aspirin tablet labeled to weigh 325 mg would not be subject to enforcement even if it actually weighed only 295 mg, and a dose of the heart drug digitalis could be 15% under its label claim and still be considered to be in full compliance with Federal regulations.

Federal regulations are less demanding for a supplement product that contains more than the labeled amount of an ingredient, as a "reasonable excess" is allowed within current good manufacturing practices (GMPs). The United States Pharmacopeia (USP) has established guidance to quantify reasonable excesses for many vitamins and minerals, ranging from just a few percent to up to 200 or 400% of the label claim. No such guidance currently exists for botanical ingredients.

In summary, current Federal regulations require that each of the dietary ingredients in a dietary supplement must be present at not less than 100% of the claimed amount. It is important to be aware that this full measure is expected to be met throughout the shelf life of the product, implying a need for stability testing for any product that quantifies an unstable ingredient. The only exceptions to the 100% rule are the margin of error in analytical methods and an allowance for nutrients or constituents that are naturally occurring and that are not adjusted or manipulated to be treated as Class II nutrients.

Methods Validation

What follows is an update on the current level of accomplishment in the validation of analytical methods for supplements.

First, the definition of the term "validation" is in order. It is generally recognized that the Association of Official Analytical Chemists International (AOAC) represents the "gold standard" in analytical method validation. AOAC utilizes different programs to evaluate analytical methods. Each is designed to confirm by objective examination that an analytical protocol will produce accurate and precise results when applied to a particular class of materials. AOAC offers as one option a "peer-verified method program," in which a method developed by one lab is checked in at least one other independent laboratory.

The highest AOAC standard is the "official methods of analysis (OMA) program." In this program, blinded, identical samples are sent to a minimum of 8 to 10 independent laboratories for analysis using the proposed method. This process leads to publication of the protocol in AOAC's Official Methods of Analysis and may be cited in the Code of Federal Regulations. The program provides a statistical evaluation of the precision and accuracy of the method, as well as data on the analytical variability or margin of error that can be expected. This latter point is very important, because analytical methods that have not undergone this rigorous validation process will have no published, widely accepted data relevant to the method's degree of accuracy. The "100%" rule noted above may actually mean "95-105%" or "85-115%" depending on documented variability of the method.

This author served during 1998 and 1999 on an FDA Working Group on Good Manufacturing Practice for Dietary Supplements. In the final report that the Working Group delivered to FDA's Food Advisory Committee in June of 1999, it was observed that testing for vitamins, minerals and amino acids is usually conducted using methods published by AOAC International or the USP. The report also asserted that "a comprehensive compendium of generally available scientifically validated tests for identification of dietary ingredients has not been compiled," and went on to say, "In particular, valid analytical methodologies are not available for many dietary ingredients, for example, botanicals and biologicals such as blood products, organ tissue, cartilage, and etc."⁵ It is generally assumed, then, that standard analytical methods are available for vitamins, minerals and amino acids.

Considerable resources have been devoted to validating analytical methods for botanicals over the past several years, particularly with regard to chromatographic methods. Most of these efforts have developed objective review processes that are similar to AOAC's "peer-verified method program," that is, a program in which a method is checked by at least one independent expert.

The organizations that have been at the forefront of these efforts here in the United States are the American Herbal Pharmacopoeia (AHP), the Institute for Nutraceutical Advancement (INA), and the USP. For the benefit of some historical context, lest anyone think that the issue of product quality for botanical products is new, the preface to the first edition of the USP, published 180 years ago in1820, stated that the "... evil of irregularity and uncertainty in the preparation of medicines ..." caused physicians to administer medicines "... essentially different than his judgment has prescribed ...." This work, therefore, established specific quantified formulas for the medicines in use at the time, including many botanical formulas. Tincture of Valerian, for example, was to be manufactured with one pound of the root per gallon of solvent, and the solvent was identified as an equal mixture of alcohol and distilled water. An extract so produced represented an early 19th century version of a "standardized" herbal product, known as "Tincture of Valerian, USP."⁶

Over the past few years numerous chromatographic analytical methods for botanicals have been reviewed and published by AHP, INA and USP. Table 1 lists the various herbs for which validated methods have been developed and published by the respective organizations. Table 2 shows the herbs for which methods are currently being developed. The primary emphasis has been on the development of high performance liquid chromatography (HPLC) methods with an occasional development of gas chromatography (GC) or spectrophotometric methods, as appropriate. In addition, both AHP and USP generally include microscopic descriptions for powdered plant material and thin-layer chromatography (TLC) methods, both of which are useful for establishing ingredient identity. Experts in these separate disciplines review each of these different techniques. Some of the work that USP is engaged in sets standards and describes methods that are specific not only to raw materials but also to herbal extracts or products in finished dosage form.

Also of interest in reviewing these tables is the apparent overlap of efforts evident in the choice of ingredients. USP set a specific goal of addressing the 30 or so herbs that enjoy the widest market presence, and INA makes its decisions regarding identification of target herbs by consensus of its 35 sponsoring companies. USP depends upon submissions and input from the nutraceutical industry in developing monographs that establish officially recognized standards of quality. In addition to validating a method, INA often performs a basic R&D function to fine-tune a methodology to improve ruggedness and robustness. INA methods are then submitted to the USP National Formulary for dissemination and public comment. AHP made a decision several years ago to include representative botanicals from several diverse herbal traditions, including Ayurvedic, traditional Chinese, and European and American herbalism. Only a few of AHP's more diverse selection have been duplicated by either of the other organizations. (It should also be noted that the American Botanical Council has developed methods for the analysis of American and Asian ginseng [Panax quinquefolius and P. ginseng, respectively] and eleuthero root [Eleutherococcus senticosus] as part of its Ginseng Evaluation Program. These methods are designed to test raw material as well as finished products.)

The sum of all of these efforts has produced at least one method for each of more than 30 botanicals. Adding those that are now under development by one or another of these organizations will bring the total to about 50 herbs. Additionally, INA will begin to concentrate at least some of its efforts on analytical methods for non-botanical ingredients like chondroitan sulfate and glucosamine.

Where to Go from Here?

So where should the industry go from here in developing analytical methods and industry policies that will provide greater assurance of dietary supplement product quality?

To begin with, every manufacturer should refrain from stating any quantity on a label unless and until they are willing to employ sufficient analytical tools to measure accurately that quantity in the product on which the label will be affixed. This process can certainly include the services offered by contract labs, and is relevant to all classes of dietary ingredients. To the degree that a label claims to deliver a specific quantity of any ingredient, whether a vitamin, mineral, unprocessed herb, or marker compound, a manufacturer must have the tools to confirm that its label claim has been met.

Also, it is essential that the development of validated analytical methods for botanicals be further advanced. In spite of this author's position that a measured quantity of a single compound may not necessarily be synonymous with quality, a significant proportion of the highest volume herbal products now in the market are relatively well controlled as to content. Consumers have therefore come to expect and demand such goods. In order to assure consumers, regulators and others who have taken an interest in supplement products that they are labeled accurately, and that the manufacturers' quantitative targets are being hit, the industry must continue to support these efforts to increase its ability to measure marker compounds precisely.

This developing knowledge, however, only has value if it is used. Many manufacturers have provided financial support for AHP and INA or have applauded USP's active role in standards setting and method development. These same manufacturers need to develop policies, either independently or under the auspices of the trade associations that serve their interests, to take the next step and to agree to use a single analytical method to support their label claims for any particular herb. There have been too many reports of products failing to meet label claim that ultimately had as much to do with use of different analytical methods as with actual failure to meet label claims. The only way that the industry can put an end to such unfortunate reports is to consider uniform adoption of accurate and validated analytical methods.

But at what point in the validation of a method can the industry be expected to reach such conformity? As mentioned earlier, AOAC International represents the "gold standard" in methods validation. If AHP or INA or USP, or even an independent analytical lab, wants a specific method to achieve the highest credibility, so that uniform adoption by manufacturers might actually occur, their methods can and should be submitted to AOAC for validation. (ABC's method for Asian and American ginseng is currently under review by AOAC.)

Quantity != Quality

(or, More is Not Always Better)

Almost all that has been discussed thus far has been related to a product's quantitative targets established by the label of the products. But does the simple assurance that the labeled amount of an ingredient is actually in the bottle also assure the quality of a product?

The quantitative presence of a single chemical marker in a botanical extract does not, in and of itself, assure that the extract is qualitatively superior to the raw herb or an extract that is not "standardized" in this manner. The quantitative presence of a single chemical marker, in fact, is often not even sufficient to assure the identity of the botanical.

The fact is that some of the finest quality herbal products in the marketplace DO rely on "standardizing" to one or more marker compounds - and that others of the finest quality herbal products in the marketplace reject the use of marker quantification in their marketing, and even in their manufacturing.

... but What is "Quality?"

What is the quality target? How can a manufacturer be certain that it is always delivering products of high quality? How is the quality of an herbal product assessed when the label does not quantify a marker? How can consumers be assured that low quality products are either removed from the market or conspicuously identified as inferior?

Ultimately, the question of quality comes down to this: did the product completely deliver everything that the customer expected? Why does a young, active man purchase a ginseng product? Why does a household's caretaker provide echinacea supplements to his or her family during the cold season? What kind of relief does a middle-aged man expect when he takes his saw palmetto extract each morning?

And almost certainly, the quality of a botanical product starts with the quality of the raw material. Dedicated cooks understand that the quality of the meal they prepare is directly related to the quality of the ingredients they start with. A pretty good broth results from a pale bunch of celery, a couple of limp carrots, an onion with a soft spot on each end, a sprig of yellowing parsley, and a dash of pre-ground pepper. With a little more effort, however, a quite delicious stock will result if they harvest the celery and carrots and parsley from the garden while the water is starting to boil, chop the center portion out of a couple of leeks and bother to crack a few peppercorns with a mortar and pestle.

And if the garden is not so bountiful? Still, dedication to producing a high-quality meal has taught certain subjective skills to differentiate the highest quality ingredients that are so necessary to the finished product. These skills are primarily of an organoleptic nature, skills that rely on observable characteristics, such as color and smell, firmness or taste.

What does this cooking analogy have to do with targeting the question of quality in botanical dietary supplements? As noted above, the quality of a botanical product starts with the quality of the raw material. While objective criteria may be useful, and in some cases even necessary when measuring certain quantitative markers, there is no substitute for subjective experience when measuring many of the quality characteristics that are essential to production of the highest quality finished products. To make the best quality herbal product, the expertise of an herbalist or botanist, or someone with the experience to recognize the quality features of raw material ingredients is essential. To ignore this experience and expertise is to assume that a gourmet meal can be made with poor ingredients.

But even the best of raw materials and a wealth of herbal expertise cannot guarantee a high-quality product if the manufacturing process is not properly designed and monitored to produce a product that fully delivers the consumer's expectation. The amount and form of each ingredient must be relevant to the intended use of the finished product. A manufacturer must develop excellent production processes to assure that the right quantity of each ingredient goes in to each batch, is well blended, and is not deteriorated by processing.

Although this list is not complete, the elements listed here are necessary tools for hitting the quality target for an herbal product:

*

high quality herbs

* knowledgeable & experienced staff

* proper formulation

* excellent manufacturing processes

* adequate finished product testing throughout the intended shelf life

Any attempt to measure quality is bound to fail if it relies solely on quantitative tools; this is tantamount to what Ed Steele, a noted regulatory consultant, has said: "You can't test quality into a product." The route to true quality assurance is even more difficult that it might at first seem. Hopefully some of the suggestions made in this paper might further advance quality in the herbal dietary supplements market.

Michael McGuffin is president of the American Herbal Products Association. He has over 20 years experience in the herb industry and is co-editor of AHPA's Botanical Safety Handbook and most recently, the managing editor of Herbs of Commerce, Second Edition.

References

1.

Eisner S, managing editor. Guidance for Manufacture and Sale of Bulk Botanical Extracts. 2001: Botanical Extracts Committee, American Herbal Products Association.

2. Eisner S, managing editor. Use of Marker Compounds in Manufacturing and Labeling Botanically Derived Dietary Supplements. 2001: Botanical Extracts Committee, American Herbal Products Association.

3. Dietary Supplements Health and Education Act of 1994 (DSHEA), Title 21, United States Code, Part 343(q)(5)(F)(ii).

4. Title 21, Code of Federal Regulations, Parts 101.9(g)(3)(i) and (ii).

5. FDA Food Advisory Committee, GMP Working Group. Draft Report of the Food Advisory Committee, Dietary Supplement Working Group On Ingredient Identity Testing, Records, and Retention. June 25, 1999.

6. Spalding L. Hewson T. et al. The Pharmacopoeia of the United States of America. Boston: C. Ewer. 1820.