Dietary Supplement Enforcement Trends – What is FDA looking for?
The current Good Manufacturing Practice (cGMPs) regulations for dietary supplements in the United States were implemented in 2007, but there is still a great deal of enforcement activity by the FDA. This white paper provides an overview of the regulations, but, more importantly, it highlights some of the most commonly cited issues in FDA Form 483 observations. By understanding the regulations, responsibilities, and common citations, stakeholders can better navigate the regulatory landscape and ensure compliance with these legal requirements.
Regulation Overview
21 CFR Part 111 outlines the cGMP regulations for dietary supplements in the United States (https://www.ecfr.gov/current/title-21/chapter-I/subchapter-B/part-111). It examines the key responsibilities imposed on brand owners, manufacturers, packers, labelers, and holders of dietary supplements. The 16 included subparts (A-P) cover aspects from the beginning of manufacturing throughout distribution and product complaints. The objectives of the cGMPs are to ensure dietary supplements are produced in a quality manner, do not contain contaminants or impurities, and are accurately labeled.
Responsibility for Compliance
Manufacturers of dietary supplements bear primary responsibility for ensuring compliance with 21 CFR Part 111. Their responsibilities include establishing and maintaining quality control systems, employing qualified personnel, maintaining suitable facilities and equipment, and implementing production and process controls to ensure the consistency, identity, purity, strength, and composition of dietary supplements. The manufacturer is also the brand owner in many cases.
Packagers and labelers are responsible for ensuring that dietary supplements are properly packaged and labeled. This includes establishing specifications for packaging materials, performing appropriate testing, and ensuring that the labels accurately reflect the contents of the product.
Holders are individuals or entities responsible for the final release of dietary supplements for distribution. They are responsible for maintaining documentation and records related to manufacturing, packaging, labeling, and distribution. Holders must establish procedures for handling complaints, conducting investigations, and determining the disposition of dietary supplements.
A company may be responsible for multiple facets of the production and distribution and are responsible for all activities conducted within their company. Most importantly, the brand owner is ultimately responsible for ALL activities of the manufacturing and distribution process. This has been noted regularly in FDA warning letters.
483 Citation Trends
The most frequent 483 citations since 2009 have been from 21 CFR 111 Subpart E – Requirement to Establish a Production and Process Control System. Below are the top 5 from Subpart E. (Raw data taken from Marian Boardley Consulting LLC and https://datadashboard.fda.gov/ora/cd/inspections.htm)
111.70 (e): For each dietary supplement that you manufacture you must establish product specifications for the identity, purity, strength, and composition of the finished batch of the dietary supplement, and for limits on those types of contamination that may adulterate, or that may lead to adulteration of, the finished batch of the dietary supplement to ensure the quality of the dietary supplement.
111.75 (a)(1)(i): Before you use a component, you must conduct at least one appropriate test or examination to verify the identity of any component that is a dietary ingredient.
111.75 (c): For a subset of finished dietary supplement batches that you identify through a sound statistical sampling plan (or for every finished batch), you must verify that your finished batch of the dietary supplement meets product specifications for identity, purity, strength, composition, and for limits on those types of contamination that may adulterate or that may lead to adulteration of the finished batch of the dietary supplement.
111.70(b) (1, 2): You must establish component specifications for identity, purity, strength, and composition as necessary and limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch of the dietary supplement to ensure the quality of the dietary supplement.
Recently, the most common citations concern establishing specifications and ensuring these specifications are met. Manufacturers (and brand owners) need to understand the importance of having well-documented specifications and including applicable information such as appropriate methods and acceptance criteria.
Testing and Laboratory Considerations
Scientifically valid methods must be used to determine if specifications are met per 21 CFR 111.75(h)(1). See the example below in this FDA warning letter excerpt:
“You failed to ensure that the tests or examinations that you use to determine whether the specifications are met are appropriate, scientifically valid methods, as required by 21 CFR 111.75(h)(1). Specifically…”
This would apply to all methods being used for identity, purity, strength, composition, and for types of contamination that would adulterate or may lead to adulteration of the finished product. These methods could be simple visual tests to complicated chemical or microbiological tests. Some methods, such as USP microbiological tests, have suitability included in the method itself. This suitability would be used as justification that methods are scientifically valid. Not using scientifically valid methods specifically has also been noted in FDA warning letters:
"However, you are not conducting suitability testing to demonstrate whether these methods are appropriate for testing all of your products."
For other methods, such as chemistry methods for potency, for example, there should be justification readily available to provide FDA to demonstrate that the methods used are scientifically valid.
It is also important to understand that analytical testing, whether performed within the manufacturing facility or outsourced to a third-party laboratory, must follow the appropriate GMP regulations as well. Below is an example from an FDA warning letter citing testing operation violations:
"During the inspection, we observed that your quality control operations did not include reviewing and approving the results of required tests as required by 21 CFR 111.110(c). For example, your laboratory Data Reviewer did not review the electronic audit trail for your analytical testing."
The above examples highlight the importance of using a high-quality laboratory that understands and complies with all of the relevant cGMP regulations. It is also critical that the laboratory can provide support when FDA performs an audit for the brand owner and/or manufacturer.
