"Exploratory testing can be described as a martial art of the mind. It's how you deal with a product that jumps out from the bushes and challenges you to a duel of testing. Well, you don't become a black belt by reading books. You have to work on it.” —James Bach
With passing consideration, one might think that the process of testing a natural product’s quality is straightforward—a simple matter of confirming that the ingredients that are supposed to be in a product are, in fact, the only substances in the product. This path of thinking might continue to embrace the idea that the really only variable in the equation is how often one does the testing. If it were only that simple.
Ensuring the quality of the products that we consume and recommend to patients is anything but a straightforward task. This is particularly true for naturally derived products, which often contain hundreds of phytochemicals arranged in complex matrixes. The starting material is complex and subject to change under even the most innocuous conditions such as exposure to air, moisture, and light. Natural compounds are rather like moving targets which, nonetheless, require the arrows of analysis to consistently find their mark.
Natural compounds are rather like moving targets which, nonetheless, require the arrows of analysis to consistently find their mark.
This issue of the Natural Medicine Journal we debut a column on quality in which various aspects of quality assurance in the dietary supplement industry will be addressed. It will be a practitioner’s journey into the world of dietary supplement manufacturing. As we travel, we will learn the route, appreciate the landscape, and take some keepsakes back into our clinical practices. In order to start our journey, we need a trail guide.
Our guide is called Final Rule 21 Code of Federal Regulations (CFR), Part III. Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements. 21 CFR Part 111 contains the regulations of the 1994 Dietary Supplement Health and Education Act. These regulations were established by the FDA to set requirements for validated manufacturing and quality processes in order to ensure product safety. The regulations provide explicit requirements regarding all areas of manufacture, including, but not limited to, physical plant hygiene, quality control requirements, record keeping, manufacturing requirements, ingredient and supplier qualifications, and analytical testing requirements. The guidelines are a hybrid of food safety regulations and pharmaceutical regulations and are more similar overall to pharmaceutical regulations. The regulations are, in fact, a very good trail guide when followed to their letter and spirit, and provide an excellent path toward quality dietary supplements.
Integrity of Ingredients
Notwithstanding the soundness of the regulations, this is challenging terrain. Each area governed by 21 CFR Part 111 requires a sophisticated approach to implementing necessary practices in order to be in compliance. Over the next several months, we will explore several of these areas. Just to set the tone for this exploration, let’s start with exploring the identity of the ingredients a dietary supplement. The majority of ingredients in dietary supplement products originate in the natural world, and, in fact, in the food supply. These ingredients are gathered and processed by suppliers and are then sold to dietary supplement manufacturers. Each ingredient comes to the manufacturer with a certificate of analysis (COA). This COA confirms, among other things, the identity of the ingredient. The manufacturer is required to additionally confirm the identity of every received ingredient by conducting their own testing. So far, so good. However, as usual the devil resides in the details.
21 CFR Part 111 requires that the method used to test identity be scientifically sound and that the manufacturer ingredient meet manufacturer pre-set specifications in order to be accepted for manufacturing. One of the challenges with this regulation is that there are many scientifically valid ways to verify identity, but not all of these methods are appropriate for all ingredients. Organoleptic testing, although a scientifically valid form of identity testing and an excellent way to identify certain cut and sifted herbal ingredients, is not appropriate for all materials. Certainly a powdered herbal standardized extract would not be a candidate for organoleptic testing. Even more a sophisticated testing method, such as near infrared spectroscopy (NIR) or Fourier transform near-infrared (FT-NIR), would not necessarily be appropriate for identifying this standardized herbal extract powder. Unless the NIR is accompanied by chemometric analysis, this method may leave a tracing for the powder that is not specific enough and may miss an adulterant. Adulterants are substances that mimic the desired ingredient’s tracing on NIR or FT-NIR, allowing a supplier to cut the ingredient with this other, often inert or unrelated, compound. Even more sophisticated identity testing, say chromatography with high-performance liquid chromatography (HPLC), thin layer chromatography (TLC), or gas chromatography (GC), which are typically quite accurate and sensitive to adulterants, can be inaccurate if the equipment has been properly calibrated, maintained, and controlled. Proper equipment operation speaks to the importance of utilizing qualified laboratories that practice good lab practices (GLP) in order to obtain reliable test results. Assuming that the right test and the right lab are in place, another area of concern is the sampling procedures. If the manufacturer accepts several containers of raw material, what method is used to obtain samples for testing? Are the samples truly representative of the entire shipment of raw material? Sampling is a complex process and one that leaves much leeway. This is quite relevant however, given the fact that many suppliers of raw materials are, in fact, brokers. They obtain the material from a variety of sources and mix all of this material into one lot. A sound sampling process will minimize the chances of missing an inferior or adulterated ingredient in the shipment.
While we have just begun to scratch the surface of the challenges of quality in the dietary supplement industry, it should already be abundantly clear how challenging it is to achieve reliable quality practices even for one component: identity. The willingness on the part of the manufacturer to utilize the best methods in order to address these areas of ambiguity and challenge is a hallmark of those suppliers with a commitment to quality manufacturing. Thankfully, these suppliers exist aplenty, and practitioners’ expectations for this level of quality products will reinforce their commitment to quality.