As Required by the GMPs
Michael Lelah, Ph.D.
Many of you ask about testing of dietary supplements. The rules for testing of dietary supplements are codified in the Food and Drug Administration’s cGMPs (current Good Manufacturing Practices). The relevant section for testing is mostly 21CFR Part 111.75, although other sections do apply. I hope that through this primer you can better understand the complex requirements for testing dietary supplements in the U.S.
First, let’s distinguish between ingredients and supplements as this will help clarify the testing requirements in the GMPs. Ingredients are substances used in the manufacture of a dietary supplement. In a multivitamin for example, all the vitamins, eg Vitamin A, B1, B2, B6, B12, C, D, E, etc, and all the minerals, eg calcium, zinc and magnesium, each represent one ingredient. The supplement is the combination of all these ingredients in the final product formula – a capsule, tablet, or softgel, etc.
For every ingredient in a dietary supplement, the rule says “…you must conduct at least one appropriate test or examination…” to verify its identity. This is a fundamental confirmation that the dietary ingredient is exactly what it is purported to be. With modern analytical equipment available today, in most cases this is possible by chemical analysis, or in the case of some ingredients, by sensory and other physical analysis. Good quality identity testing leads to using good quality ingredients, which lead to good quality products.
Testing for Purity, Strength and Composition
The rule (in this case Section 111.70) requires that the manufacturer set appropriate specifications for identity, purity, strength, and composition. Identity was discussed above. Purity is the opposite of contaminated (by environmental toxins) or adulterated (with added impurities). A pure ingredient or supplement is not contaminated or adulterated. What we call “strength” may be more familiar to you as “potency”, although there is a technical difference. Composition is the formula – it’s the number of milligrams, for example, of each active ingredient, and this appears on the label. The FDA rules require the manufacturer not only to set specifications for these aspects of ingredients and supplements, but also require that the manufacturer “conducts appropriate tests” to ensure that these specifications are met. Testing of ingredients is essential to good quality.
Ensuring Good Process Control
For supplements, tests are required to “ensure that the production and process control system is producing dietary supplements that meet all product specifications”. Thus the purpose of finished product testing is to ensure that everything that was done during the manufacturing process maintains the integrity of the product and that it is not adulterated or contaminated. For example, it is confirming that the mixing, encapsulation, and coating steps of manufacturing produced a good quality product. This is the true purpose of finished product testing. The overall scheme can be expressed as:
Good product = good ingredients (tested for identity, purity, strength, and composition) that are manufactured under good process control that is confirmed by good finished product testing (for identity, purity, strength, and composition).
Special Exemptions for the Testing of Finished Products
Exemptions for testing of finished products is an important consideration, and is discussed in the regulations under section 111.75(d)(1). It is well known, certainly by analytical chemists, that it is sometimes not possible to test all finished products. This could be because there is no standard validated test for a particular ingredient. Or this could be because there is a test which works well for the pure ingredient but fails to work for the same ingredient in a finished supplement. This is also known as the matrix effect, or matrix interference, whereby the other components in the supplement interfere with the test. This could also be because even though a test may be possible, it has to be conducted using extremely expensive research grade equipment, with significant development required, and this is usually not compatible with commercial lab testing.
The FDA recognized this normal limitation in testing and allows for exemptions to the rules discussed above. In the exemption rule, this testing is exempted because there is “no scientifically valid test”. Since there is no valid test, then you can’t test. Even with advances in analytical chemistry, supplement manufacturers are dealing with complex natural products, and testing is difficult to develop and validate.
So what is a manufacturer to do in cases where testing isn’t possible? The FDA says that manufacturers are required to use process checks to ensure correct products. An example might be a ground root. There may be no specific chemical marker for the root, so testing to ensure that the right amount of root is present in the finished product is not simple. In this case, process checks take the place of testing.
This is not the only exemption available. The cGMP rules also allow manufacturers to test a subset of batches. There are specific rules for what is called skip lot testing, but they essentially translate into the concept that manufacturers don’t have to test every batch for everything. The FDA recognizes that not testing every lot may be acceptable in some cases. In this way, manufacturers can, according to the rules, focus their testing on, for example, products that have a higher risk profile, while those with a lower risk profile may utilize skip lot testing for some aspects of product testing. However, all ingredient testing and process controls must follow Good Manufacturing Practices and be properly documented, which assures product quality.
Because the combination of regulations and analytical testing is quite complex, here are a few simple take-aways:
1. All ingredients must be tested for identity.
2. Manufacturers set specifications for ingredient purity, strength, and composition, and test to these specifications.
3. Finished products must also be tested for identity, purity, strength, and composition. The purpose of finished product testing is to ensure good process control as a cross-check.
4. There are exemptions when such testing cannot be done, and there are allowances for skip lot testing, when appropriate, as a means for validating quality controls.
5. When companies follow the testing program as a whole, it is designed to ensure quality.