Updated: Dec 7, 2022
We can learn a lot from warning letters. Following FDA enforcement trends is a valuable tool for any savvy marketer, regulatory affairs professional, quality manager, or dietary supplement executive. We can adjust practices before they elevate to warning letters by learning how to read warning letters and act accordingly. This is why I write the weekly Warning Letter Wednesday post on LinkedIn, Twitter, and Facebook. This blog post is an extended version of my Warning Letter Wednesday posts.
This warning letter is a great teaching case. Here are the learning targets.
FDA Inspections Trigger Website Reviews
The company was inspected by FDA in March 2021 and was issued several 483s. The company's website was recently reviewed in February 2022, which led to a letter. Learn about the difference between a 483 and a warning letter here. Usually the FDA investigator reviews a company's website for disease claims before an inspection. That is likely still happening but this is the third recent warning letter where FDA inspections led to a website review at a later date. These website reviews were then elevated to a warning letter. I write these letters here and here. This is a fascinating enforcement trend to watch and a good reminder for companies to clean up their website claims if they have been inspected. This is one of my favorite services Supplement Advisory Group offers.
➡️From warning letter: Although studies (of PS, an ingredient in your product) in humans with Alzheimer’s disease were less dramatic, they still produced significant improvements in cognitive function. In patients with mild dementia, significant cognitive and behavioral enhancing effects were observed.
The company uses a contract manufacturer to make their products. This does not mean the company does not have any GMP responsibilities.
➡️From warning letter: Quality control must approve for release, or reject, any packaged and labeled dietary supplement (including a repackaged or relabeled dietary supplement) for distribution, and you must have documentation of the quality control personnel review and approval for release of any packaged and labeled dietary supplement
👉Asa's commentary: This means a company has to conduct some type of review and release before selling the product. This does not have to be complicated but it has to be written down and followed. If it's not written down it didn't happen is an FDA mantra.
➡️From warning letter: Although a firm may contract out certain dietary supplement manufacturing operations, it cannot contract out its ultimate responsibility to ensure that the dietary supplement it places into commerce (or causes to be placed into commerce) is not adulterated for failure to comply with dietary supplement CGMP requirements.
👉Asa's commentary: This is boilerplate language but a good reminder that although working with a contract manufacturer does mitigate some risks, the basics of quality assurance should be in place. We discuss many of these topics here.
Common GMP Errors
Writing and Following Specifications
➡️From warning letter: You failed to have documentation of the quality control personnel review and approval for release of any packaged and labeled dietary supplement for distribution, as required by 21 CFR 111.140(b)(2) [see also 21 CFR 111.127(h)]. Specifically, your firm distributes the dietary supplements that are contract manufactured for you, but you had no records of a quality control review, approval, or rejection for your finished dietary supplement products. During the inspection, you informed our investigator that you do not review the documentation related to the finished dietary supplement products you receive from contract manufacturers to determine if those finished dietary supplement products have met specifications.
👉Asa's commentary: Not having and following specifications is one of the most common GMP violations. Specifications should be reviewed by a member of Quality and then approved, rejected, or quarantined. This allows problems to be found before products are shipped to the public. I write about this here.
➡️From warning letter: You failed to establish and follow written procedures for holding and distributing operations, to comply with 21 CFR Part 111.453 that include the requirements for holding components, dietary supplements, packaging, and labels,
👉Asa's commentary: Writing and following procedures is an important part of GMPs. Procedures are the "directions" for doing things, commonly referred to as Standard Operating Procedures (SOPs).
➡️From warning letter: You failed to establish and follow written procedures to fulfill the requirements that apply to returned dietary supplements,
➡️From warning letter: You failed to establish written procedures for the requirements to review and investigate a product complaint.
👉Asa's commentary: This is one of the most important parts of being a distributor of dietary supplements. If you are on contact name on the label, you are responsible for reviewing product complaints and informing the FDA of Serious Adverse Event Reports.
Certain Herbs Are Not Allowed
The FDA does not allow the use of certain plants they consider to be dangerous. Pinellia ternata, a TCM ingredient, was called out in this warning letter because it contains ephedrine alkaloids. Learn more about this here. In general, if a plant is not widely used in commerce, it is a red flag of potential danger, or a New Dietary Ingredient (NDI).
Common Allergen Labeling
➡️From warning letter: ..the finished product label fails to declare the specific species of shellfish allergen sources as required.
👉Asa's commentary: The company disclosed the common allergen (crustaceans) but not the type of crustacean (e.g., Contains: shrimp). This is a common error that can be easily prevented. Here are the specific common allergens that need to be disclosed.
The specific type of nut (e.g., almond, pecans, walnut, coconut).
The specific type of fish (e.g., bass, flounder, Pollack).
The specific type of crustacean shellfish (e.g., lobster, shrimp, crab).
Domestic Street Address or Phone Number
➡️From warning letter: ..the labels fail to bear a domestic address or domestic phone number through which the responsible person (as described in section 761) may receive a report of a serious adverse event with such dietary supplement.
👉Asa's commentary: I review a lot of labels, and it is commonly overlooked. This is how supplement companies track customer complaints and inform the FDA of serious adverse events such as hospitalization
Languages Must Contain The Same Information
➡️From warning letter: ..your product labels contain information in two languages but does not repeat all the required label information (including the nutrition information) in both languages. In accordance with 21 CFR 101.15(c), if a product label contains any representation in a foreign language or foreign characters, all words, statements, and other information required by or under authority of the Act to appear on the label must appear in the foreign language.
👉Asa's commentary: I do not review multi-language labels,, so this is a new one to me. There is so much to learn about GMPs.
Serving Size and Suggested Use
➡️From warning letter: The “Directions” for your Hemorlyn product states to take “2-4 capsules per day with meals,” but the serving size lists “2 Capsules.” The serving size listed should be four capsules.
👉Asa's commentary: The maximum suggested amount consumed at one sitting is a serving size. For example, a serving size that reads take 1-5 capsules daily is a serving size of 5 capsules, which would need to be in the supplement facts panel. This is an amateur error that could have been prevented.
Plant Parts Must Be Disclosed
➡️From warning letter: ..the labels fail to identify in English the part of the plant (e.g., root, leaves) for each of the botanical dietary ingredients in the products, as required by 21 CFR 101.4(h)(1). We note “herb” is not a recognized plant part. Furthermore, we note if an entire or whole plant is used,
👉Asa's commentary: Yes, it really is a rule to list the plant part. Replacing "herb" with "leaf" would be been accurate. This is a great example of what I call a "secondary claim" or a "minor violation" which is something not likely to attract a warning letter on its own/
Correct Plant Listing
➡️From warning letter: ..each product label fails to declare the common or usual name (standardized common name) or Latin binomial of each ingredient used.
👉Asa's commentary: The American Herbal Products Association's (AHPA) Herbs of Commerce is the reference for standardized common names. Thanks AHPA!
Supplement Fact Panel: Line Thickness
➡️From warning letter: The Arthrolyn product’s Supplement Facts label fails to separate the (b)(2)- from the (b)(3)-dietary ingredients with a heavy bar.
👉Asa's commentary: Having the correct line thickness is part of a compliant label. Here is an example of correct line thickness and Supplement Fact Panel layout I made just for you. Label review is one on the many aspects of regulatory compliance my company covers.
Percent Daily Values Label Requirement
➡️From warning letter: The Goldenlife product’s Supplement Facts label bears the following statement: “Percent Daily Values based on a 2,000 calorie diet.” This statement is only permitted when the percent of Daily Value is declared for total fat, saturated fat, total carbohydrate, dietary fiber, or protein as required.
👉Asa's commentary: This is the first time I have seen this in a warning letter, wow.
➡️From warning letter: Any expiration date you place on a product label should be supported by data that demonstrates the product’s shelf life
👉Asa's commentary: A company needs to have stability data in order to substantiate expiration, best, before, or freshness dates.
Many of the items, such as label formatting and layout issues are not likely to lead to a warning letter. Incorrect label formating however is a red flag that the company is not following the basics of GMP-labeling compliance, and this may be a sign of deeper issues.
The quickest way to attract a warning is by making disease claims. This, in combination with serious GMP violations, adds to the risk. The FDA's duty is to protect public safety and not verifying a product's quality may, in some rare circumstances, lead to serious health issues.
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Disclaimer: The educational information provided on this website is for informational purposes only and does not constitute legal or regulatory advice. Contact an attorney for specific legal advice.