Where do those little pills come from, anyway?
Written by: Jonathan Toker, Ph.D.
Date: Wed Apr 09 2008
Contract labs specialize in production of supplements, analytical testing, and packaging. These labs can be either cGMP or non-cGMP compliant at this time, and the resulting product could be affected by the way the company treats each batch of product being produced. Until 2010, supplements can be legally produced in non-cGMP facilities. The actual contract lab used by any given supplement company is usually a guarded secret as part of one’s competitive advantage. Therefore, rather than looking to the name on the bottle, one must look at the actual contract lab as the source of the product, and the inherent production risks.
From start to finish at a contract lab
a) Starting Materials
Most contract labs source their raw materials from a wide range of outside suppliers, many of whom specialize in certain classes of materials, such as amino acids, protein powders, minerals, etc. Each supplier provides to the contract lab a certificate of analysis (COA) that is issued for each and every lot (batch) of raw material. Suppliers can be located overseas or domestically with the actual starting material produced anywhere around the world.
When raw materials are received by a contract lab, they should be positively identified. This is usually done easily and quickly by near infrared (NIR) spectroscopy. By matching a characteristic fingerprint spectrum of the raw material with a reference spectrum for the material, identity can be confirmed. Purity (the percent active content of the material) is not usually assayed at this time, depending on the COA of the material for this and any other details. This is the first intersection where impurities that originated in the starting material factory or packaging would enter the contract lab undetected. Note that the NIR identity confirmation is not sensitive to pick up foreign matter in the raw material and is a bulk test only.
An entirely different set of concerns arises with herbal ingredients. Many materials such as St. John’s wort, royal jelly, ginkgo biloba, yucca root, grape seed extract, and many others originate from plant extracts. Currently, there are few standards in place to qualify these raw materials for potency or purity. This means that a bottle containing 100 percent St. John’s wort may actually have 5 percent active while another labeled the same way may have double or triple that amount. The FDA final rule guidance on these materials is still 100 percent identification testing, which is problematic due to current analytical testing limitations of some of these materials. At this time, manufacturers can apply for an exemption to this testing. It is hoped within the herbal industry that further clarity on this situation will arise before the FDA final rule takes effect.
As a result of these regulations, products containing herbal ingredients are generally non-standardized and consumers need to be especially aware of potential issues with these products. As a visual rule-of-thumb, if the “Supplement Facts” panel indicates “Daily value not established” for a given ingredient, it is likely that less than adequate information is known about that particular ingredient. Not only are herbal ingredients of often unreliable content, but their toxicity and benefits have generally not been tested in clinical settings, which further prompts the warning: buyer beware.
b) Processing of ingredients
Once the raw materials are identified upon receipt, the contract lab prepares the formulation according to specifications required by the supplement company. This can include dry mixing, wet mixing, granulation, and other physical handling steps. Containers used for these processes are part of machines that can be manually or automatically operated. Often made of stainless steel parts, these complex mixing bowls are used for a given batch and then cleaned and readied for the next product, one that may be totally distinct from the batch before and after it. cGMP contract labs will follow a set of Standard Operating Procedures (SOPs) that dictate how the machine is to be cleaned, rinsed, and dried. Some facilities conduct a “cleaning verification” whereby some of the rinse wash is tested for the active ingredient from the previous batch. Possible source of contamination #2 arises if a machine is incompletely or incorrectly cleaned leading to carryover from one product to another. In this way, for example, a steroid material from one product batch could be carried over to a protein supplement in the next batch of processed product.
c) Encapsulation/bottling/packaging of the product
The final step within the contract lab takes the mixed product into its final form for the consumer. This can include bulk powder in plastic tubs, pressing powder into pills, or filling capsules with powder. Once again, industry-specific machines are used for this step. Careful cleaning between batches of different product is critical to ensuring no cross-contamination between products. Once the product is in its final packaging, a quality control (QC) unit serves to qualify and inspect the final product. Once again following SOPs, the QC analyst inspects the product against specifications that can include fill weight, color, particle size and other physical characteristics.
Testing of the final product for quantitative content of active material is currently not required, but is coming into place with the new regulations by 2010. What this means is that upon QC approval and issuance of a batch-specific certificate of analysis (COA), the product is ready to be released to consumers. What is not positively known at that time is: Was production and mixing even and complete across the batch? Are there any foreign contaminants in the mixture? And most importantly, do the contents of that bottle match the writing on the label? Fortunately, the FDA final rule of June 22, 2007, requires manufacturers to address these questions. For contract labs already following cGMPs, implementation of these rules should be fairly straightforward, although costs to producers are likely to increase due to additional analytical work required. Expect non-cGMP contract labs to get in gear with the rules or face the prospect of shutting down in the coming years.
WADA and the difference between illegal and prohibited substances
At this juncture, it is worth defining the difference between an illegal substance and a prohibited substance. We are all familiar with materials that are regulated by the government that can include cocaine and other opiates, prescription products such as antibiotics, anti-seizure, antidepressants, etc., that are regulated as suitable for certain applications only, under the administration or prescription of a physician. Some of these materials are illegal under any circumstances while others can be used as needed by those to whom permission is granted (usually by a doctor’s prescription).
WADA has defined a list of substances for which their consumption has deemed to be “against the rules” of sport. Athletes who fall within a sport governed by WADA rules are responsible for observing the WADA prohibited substance list. To be clear: WADA-prohibited substances are not necessarily illegal from a regulated standpoint, but are listed because they can provide an athlete with an unfair advantage in sport. The consequence is that some WADA-prohibited substances can legally be produced in the same contract lab as other nutritional supplements. Looking back to the production discussed earlier, one can quickly determine how cross contamination between products can present an otherwise compliant athlete with a tainted product.
Does natural equal safe?
Health food companies and pundits for healthy living often cite that something is “natural”, implying that this automatically equates to “good” or “safe.” It is worth noting here that the most toxic substances in the world are natural (botulism toxin, and other plant and animal toxins such as from the puffer fish and poison dart frog). In the context of nutritional supplements, your body does not know the difference between purified calcium carbonate from the White Cliffs of Dover and purified chalk produced in a laboratory. While allowing for certain unique natural preparations available only in nature, at a chemical level, there is no difference between a substance in “nature” vs. the “lab.” CaCO3 is CaCO3 wherever you find it. With the above under consideration, it is worth keeping an open mind on both synthetic and natural ingredients, and selecting one over the other as needed and on a scientific basis alone.
With the vast majority of athletes competing at the amateur level, one must ask if it matters if a little bit of X gets in my supplement? Focusing specifically on triathlon, age group athletes are not tested currently at any race except the annual ITU World Championship. Therefore the vast majority of triathletes will never see a drug test. Are they willing to pay a little bit more for a supplement that had been prepared in a cGMP contract lab and tested for WADA prohibited substances? The professionals are tested much more frequently and races worldwide. National governing bodies (NGB) such as USA Triathlon inform their athletes that they must comply with the WADA prohibited substance list, informing athletes that it is their own responsibility to do so. However, other than conducting their own testing or avoiding all nutritional supplements altogether, there is no way that a dedicated professional athlete can ensure that neither the food that they eat nor the supplements they consume are clean. Until now…
In part III of this series, I’ll summarize the current testing and certification programs in place in the industry for WADA prohibited substances, and consumer guidelines for buying nutritional supplements. Stay tuned…
This is the third article in our series on nutritional supplements testing and certification programs. The author is Jonathan Toker, an elite-level triathlete and a Ph.D. in organic chemistry. 5.27.08
In a study just released, trace amounts of steroid ingestion can trigger a positive drug test, illustrating the ease by which athletes can end up on the wrong side of anti-drug programs. 6.30.09
Without thinking, some of the athletes taking the outside line put themselves at a disadvantage by running further. Over a common race course with turns, taking the outside line can make quite a difference. 3.16.10
Concerned consumers have been returning certain protein drinks, while affected manufacturers have been working overtime to refute the Consumer Reports study. Let's separate truth from confusion. 7.26.10
Great article series
Reviewed by: gordon withers, Jun 3 2008 9:04PM
Reviewed by: Laurie, Apr 30 2008 1:10PM
Reviewed by: kieth mason, Apr 10 2008 8:11AM