The regulatory requirements in 21 CFR 111, Current Good Manufacturing Practice (cGMP) in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements, that dictate the need to establish specifications to ensure finished product quality in regards to identity, purity, strength, composition and limits of potential contaminants per 21 CFR 111.70; and then determine whether these specifications are met via testing in 21 CFR 111.75 have been the most heavily scrutinized and enforced cGMP area by FDA since 2010.

Initially the issue was a lack of raw material (dietary ingredients and components), in-process material, packaging component, labeling, and finished product specifications altogether. This then transitioned into specifications that didn’t address all of the necessary categories; and the fact that testing to determine if the specifications had been met wasn’t performed or was only performed on some materials and product batches. Now the focus from FDA inspectors is unquestionably the establishment of finished product specifications and testing for strength in finished dietary supplement products that contain herbs or botanical ingredients—with an enforcement environment that has become quite confusing and controversial. Why?

As defined by the Dietary Supplement Health and Education Act of 1994 (DSHEA), a dietary ingredient may include a variety of different compounds or substances. The specifications that must be established for the strength of the dietary ingredients formulated into the finished product depend on the claims made in the Supplement Facts panel (SFP) of the dietary supplement label. For herbs and other botanical ingredients, label claims in the SFP are frequently based on the total amount of the plant, or plant part. The use of a “proprietary blend” claim in the SFP is also common when multiple herbs and other botanicals are formulated into a product. However, if the intentional formula addition of an herb or botanical is to achieve a particular amount of a chemical constituent—as may be the case in order to support a product structure/function claim—then that constituent may also be claimed on the SFP. Total curcuminoids in turmeric (Curcuma longa) is an example of the latter. Whatever the SFP claim is, will be the strength specification on the finished product.

Testing must then be conducted to determine if the established specifications have been met. A caveat to this required testing is that the test method used must be appropriate and scientifically valid per 21 CFR 111.75(h)(1) and 111.320(b). There is no definition of a scientifically valid test method, but in the Preamble to the Final Rule, FDA described a scientifically valid test method as one that is specific, accurate, precise, and consistently does what it is intended to do (referred to as intermediate precision or “rugged” in the laboratory).

Modern chemistry techniques and methodologies coupled with sophisticated analytical instrumentation allows for the quantitation of most chemical constituents at very low concentration levels (strength), even in complex matrices, so when a finished dietary supplement product label claim of a particular chemical constituent within an herb or botanical ingredient is made, a scientifically valid test method is usually available. In contrast, test methods that are specific, accurate, precise and rugged for an entire plant or plant part, or proprietary blend of multiple herbs and/or other botanicals, are likely not available.

When a scientifically valid test method is not available, other testing, controls and information must then be used to ensure the dietary supplement meets its established specification for strength without this finished product testing. And, in fact, the dietary supplement cGMP requirements dictated in 21 CFR 111 were designed to accommodate for this. The so-called “exemption clause” of 21 CFR 111.75(d)(1) states:

“You may exempt one or more product specifications from verification requirements… if you determine and document that the specifications… are not able to verify that the production process control system is producing a dietary supplement that meets the exempted product specification and there is no scientifically valid method for testing or examining such exempted product specification at the finished batch stage.”

Of course, in a cGMP environment, if it’s not documented in a thorough and detailed manner and hasn’t been reviewed and approved by the quality unit (QU), it didn’t happen. A standard operating procedure (SOP) regarding the use of the testing exemption must, therefore, be developed and implemented. This SOP must describe all other testing, controls and information that will be used for the verification of strength without finished product testing, including:

- Warehouse controls

- Raw Material specifications

- Master Formula

- Master Manufacturing Record (MMR)

- Batch Production Record (BPR)

- In-Process testing

- In-Process controls

- Other Finished Product testing

A scientific assessment and exemption strategy for each finished dietary supplement product, and each particular strength specification that will be exempted, must also be prepared, documented and reviewed, and approved by the QU.

Compliance with the extensive responsibilities of the QU dictated in 21 CFR 111 is now the next-most scrutinized and enforced cGMP area by FDA, behind specifications and testing!

Tara Lin Couch, Ph.D., owner of TLC Regulatory and Laboratory Consulting, is an analytical/organic chemist who also obtained a bachelor’s degree in mathematics. She has more than 35 years of diverse laboratory and regulatory experience in academic, field, contract and manufacturing environments. Couch is a sought-after expert on issues pertaining to quality control in pharmaceutical, dietary supplement, tobacco manufacturing and the cannabis industries. As a consultant, she assists with the development, improvement and implementation of quality systems that are scientifically sound, efficient, practical and compliant with FDA regulations.