By EAS Senior Consultant Tara Lin Couch, Ph.D.
The FDA regulations dictated in 21 CFR 111, Current Good Manufacturing Practice (cGMP) in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements, require that each batch of a finished dietary supplement product must meet quality requirements for identity, purity, strength, composition, and limits of potential contaminants.
Criteria used to establish that these requirements are met are supposed to be provided in a Finished Product Specification developed by the dietary supplement company. FDA issued more than 400 Warning Letter citations for inappropriate specifications in 2013 and 2014. Many of these violations were due to a failure to have Finished Product Specifications at all, but recent Warning Letters have also noted that using solely the input of a dietary ingredient for verifying the strength “By Input” is unacceptable.
The input of a dietary supplement alone is not a scientifically valid analytical test method for determining the strength of a dietary ingredient in a finished product. Chemical testing of the ingredient should be accomplished whenever possible. If that is not possible due to the unavailability of a scientifically valid test method, the testing may be exempted provided dietary ingredient raw material testing, in-process testing, other finished product testing, process controls, and additional information can support that the strength of the dietary ingredient can be verified without testing, as allowed in 21 CFR 111.75(d)(1).
The incoming dietary ingredient raw material must be verified to meet quality requirements for identity, purity, strength, and the lack of potential contaminants. Warehouse controls must then ensure that the material is held in a condition in which its quality is not altered. The material must be formulated at an appropriate amount, with sufficient overage, to meet the label claim while taking into account manufacturing variability. This is dictated in an approved Master Manufacturing Record (MMR). Once executed, the Batch Production Record (BPR) must document that the correct amount of the dietary ingredient was actually dispensed into the product during manufacture. Established in-process examinations and tests are then used to verify that the batch is uniformly mixed and meets the unit dosage weight and weight variation requirements. Variations on weight cannot exceed the overage amount to ensure that even the smallest dosage unit still complies with the label. In-process chemical tests can also be employed to verify the amount of a dietary ingredient. This can be particularly beneficial if the reason a dietary ingredient is exempted from testing is because of matrix interferences or instrumental quantitation limits.
Other finished product testing can also be used to support that an exempted ingredient is present in the product at the correct, labeled amount. Test results from chemically similar ingredients that are determined to be as expected suggest that the exempted ingredient is also present at expected levels because these ingredients will tend to react the same way during manufacture, especially if both ingredients are introduced and processed in the same step. Results obtained from finished product testing of other ingredients whose concentrations are associated with the exempted ingredient may also support that the exempted ingredient is present as expected.
Finally, the number of other finished product ingredient tests that are performed is important. If all other test results are determined to be within specification, it indicates that the product was manufactured according to the MMR and there is no reason to expect anything different from an exempted dietary ingredient.
Dietary supplement companies that are compliant with all parts of 21 CFR 111 will already be performing these activities. A procedure that summarizes the overall process of verifying the addition of a dietary ingredient can then be created and used as the test method reference on the Finished Product Specification. A separate document that describes the details of test exemptions per product should also be generated. The actual result obtained should be acquired from the completed batch production record.
The “By Input” approach is no longer relevant.