Identity Out of Focus

Meeting the new GMP requirements for identity testing.

By Paula Brown

As the calendar ticks away toward the first of the GMP compliance deadlines, regulatory imperatives begin to join market-based motivators in the drive to define and implement quality. Statements of concern over product quality have been uttered by companies, regulators and scientists since the infamous LA Times Wall Street Journal story of a decade ago. Product quality is stated as a high priority issue that even affects government funded research (see NCCAM’s product quality statement at www.nccam.nih.gov/research/policies/bioactive.htm), and yet the most fundamental quality issue of all, establishing identity, is still a challenge.

While there is widespread agreement on the importance of product quality, operational definitions of the term re­main divergent. The working definitions of quality and the quality parameters employed by individual companies within the supplement industry range from simple to complex. For example, some companies may ascertain quality by determining that material was grown organically, the correct plant species and plant part (or extracts thereof) are present, and the product has been manufactured in a sanitary fashion. Along with identity criteria, other companies may set explicit specifications for microbial load, adventitious agents and content of desirable constituents.

In promulgating the Final Rule on GMPs for Dietary Supplements, FDA built in considerable flexibility by allowing individual companies to design their own specifications. However, FDA also laid down an underlying definition of the quality concept in the glossary to the final rule, which reads: “Quality means that the dietary supplement consistently meets the established specifications for identity, purity, strength, and composition, and limits on contaminants, and has been manufactured, packaged, labeled, and held under conditions to prevent adulteration.”

Of all the GMP measures, the requirement for 100% identity testing of dietary ingredients has arguably caused the greatest consternation among industry members. Driven by FDA’s experience in the plantain/digitalis case (as noted in the preamble of the GMP regulation), the agency has come to the conclusion that misidentification of dietary ingredients poses a public health threat. Furthermore, FDA believes this threat is great enough to justify requiring a higher degree of quality assurance for dietary ingredients in supplements, as compared with other dietary components.

For well-characterized, single chemical entities (i.e., folic acid, glucosamine hydrochloride, etc.), specifications for identity have been established and corresponding validated analytical methods published by recognized authorities, such as pharmacopoeias. This is generally not the case for the more complex botanical, biological and multi-ingredient products, yet the GMP regulation requires that identity specifications be set for each component and the finished product. Furthermore, the tests and methods used to determine whether specifications are met must be both appropriate and scientifically valid.

How Hard Can It Be?

Creating a specification for a botanical dietary supplement ingredient may appear simple on the surface—all you have to do is state the analytical technique, diagnostic features, method, and tolerances. It should be easy, and if people traded dietary ingredients like they trade fresh fruit, it would be easy. Not only can most people tell apples from oranges, but many can also spot the differences between Red Delicious and Granny Smith varieties. Alas, that’s not the way most dietary ingredients occur in commerce in this day and age.

For botanicals, the primary objective of identity testing is to ensure the component is derived from the correct plant part and species. Whether due to accidental contamination or outright economic adulteration, the number of control points for these risks are rapidly growing as the supply chain becomes increasingly global in nature. The challenges in ensuring botanical identity are further compounded by the relative “fuzziness” of plant species boundaries; the inherent intra-species variability in plants (think of coffee, tea, and wine); the constraints of classic taxonomic identification; and for chemical identification testing, our ignorance of the complete phytochemistry of most species in commerce.

Classification by morphological examination is based largely on floral morphology, but even when traded as the botanical and not an extract, most supplement ingredients do not include the floral parts and therefore a classic taxonomic approach may provide little, if any, assistance in determining identity.

However, the collection and preservation of voucher specimens endures as an essential requirement for ensuring botanical identity. The collection and retention of a properly identified physical specimen that is representative of the raw material is the most highly reliable means for ensuring and documenting identity.

“A Standard Operating Procedure for Plant Vouchers” was recently published by Hildreth et al. in Analytical and Bioanalytical Chemistry. The article differentiates between the terms “voucher specimen,” “retention samples,” and “reference materials.” According to the authors, a botanical reference material is a preserved specimen of confirmed identity, whereas a voucher specimen is a reference material associated with a specific lot or batch of plant material, and as such serves to authenticate the identity of that lot or batch. They clearly state that a retained sample alone cannot authenticate identity without substantial supporting research and validation.

A perfectly acceptable technique for identification is physical comparison of a newly acquired material against a reference material whose identity has been definitively established. Of course this method only works if the new material and the reference are in a form that allows diagnostic differences and similarities to be observed. In this respect, the more highly processed a material, the less likely it is that a simple physical examination will be able to definitively establish identity. Even if you can definitively differentiate Actaea pachypoda from racemosa, this may not be sufficient if your master manufacturing record specifies isopropanolic extract of Actaea racemosa spray dried onto maltodextrin. FDA will require you to take it one step further and ensure you can differentiate your product from an ethanolic Actaea racemosa extract spray dried onto rice powder.

How Much Testing is Enough?

A useful guide for the type and number of identification tools that need to be applied to a dietary ingredient is provided in the 1999 FDA Food Safety Advisory Committee report. Through this report, available at www.cfsan.fda.gov/~dms/ facgmp.html, the committee addressed the difficulties likely to be encountered in identifying processed botanical ingredients and suggested a hierarchy of testing protocols based on the form in commerce of the target ingredient.

Identity may be evaluated using or­ganoleptic/macroscopic, microscopic, chemical, and/or genetic techniques. The form of the botanical (i.e. whole, cut and sift, powder, extract) is the principle determinant of which analytical technique(s) need be employed. In the hands of an experienced practitioner, an organoleptic (sensory) assessment or a microscopic examination may be sufficient to ensure the identity of raw botanicals (whole, cut and sift, or powder). In the case of highly processed material, such as extracts, chemical analyses are typically required. In either case, comparison to a material with an impeccable pedigree adds credibility to the process.

The industry trend toward an increasing reliance on chemical chromatographic techniques to determine identity is fraught with serious perils. The equipment is expensive to purchase and complicated to operate, and there is a paucity of validated test methods. Section 111.75 of the GMP regulation states that the tests used must be appropriate, scientifically valid methods, and Section 111.320 reinforces that you must verify that the testing methodologies are appropriate for their intended use. In other words, the method must be validated to ensure that it is fit for purpose (determining identity) and suitably rugged. In order for a method to be fit for the purpose of ensuring identity it must be proven to discriminate related species and common adulterants.

Chemists entering the identity field have begun to wrestle with the concept of validating qualitative chemical methods for identity verification. In 2003 Koll et al. published in Journal of the AOAC a first attempt at defining a systematic ap­proach to assuring the utility of modern thin-layer chromatography to identity determination. The technical jargon and statistical analyses can be intimidating, but the underlying rationale is simple: To ensure methods reproducibly provide the true answer.

The Bottom Line

While on the surface the 100% identity testing requirement may appear excessive and onerous, it may not be as hard as it seems. In practical terms, most manufacturers will deal in a finite set of dietary ingredients and will not be constrained to treat each incoming raw material as though it were a complete unknown. The question that should be asked by the QC (quality control) team is not “what is this?” but “is this ingredient X?” In such cases, a simple test that lets you say “this is not X” may be more valuable than the exotic and expensive tests required to answer the question “what is this?”. Furthermore, if the answer is, “no it isn’t X,” the material should be rejected.

As noted in the 1999 FDA committee report mentioned previously, the technique that you use to make the comparison may vary from material to material based on the form in which the material is received, but in the end, they are just tools. The underlying process remains the same. The most important parts of the botanical identity process and the keys to success hinge on a library of reference ingredients, solid specifications and test methods, processes for rejecting material and trained personnel.NW