GMP Manufacturing Lessons

Manufacturing supplements is not easy. I was a supplement manufacturing & marketing executive for 15 years before starting my regulatory marketing compliance company, and implementing continuous improvement into our Quality Management System required several full-time jobs. Step one in GMP compliance is setting and following specifications, and this Warning Letter Wednesday highlights several GMP lessons, especially the importance of specifications.

Heavy metal specifications. Here, FDA cites the company for not establishing heavy metal specifications for botanical ingredients, which are especially at risk of heavy metal contamination. FDA notes that a lack of ingredient specifications may lead to issues in the finished product. I like this example because it demonstrates that stopping potential problems before they get to the production line is best.

• From warning letter. “The investigator noted that you failed to establish limits on those types of contamination that may adulterate or that may lead to adulteration of the finished batch of the dietary supplement.”

Interestingly, the company did have finished product heavy metals specifications, but it seems FDA pushed back on their arsenic limits, asking for clarification on why they were set so high. This reminds us that specifications must have a scientific rationale. As a good reference point, the American Herbal Products Association (AHPA) is an excellent resource for this.

• From warning letter. We note that the (b)(4) finished product specification for Lead is < (b)(4) ppm and for Arsenic is < (b)(4) ppm. Your batch record for (b)(4) batch (b)(4) reports lead results of (b)(4) ppm. Under 21 CFR 111.70(e), you must establish specifications for limits on those types of contamination that may adulterate, or may lead to adulteration of, the finished batch of dietary supplement to ensure the quality of the dietary supplement. We request that your response address the scientific basis for setting a specification for Lead at < (b)(4) ppm as a level that will not adulterate the dietary supplement.

Testing by input. Over the past two years, FDA has increasingly been citing companies for testing finished products by input rather than using qualified analytical methods. The company’s 483 response seems to show that instead of providing a specification sheet example with valid testing methods, they apparently listed “input” as the test method. This part of the warning letter could have been avoided with a proper 483 response. FDA’s response, “measuring input may be a useful process control, but it is not an appropriate test method for determining the strength specification,” should be an essential mantra written on the wall of every QA/QC department.

• From warning letter. We received and reviewed your December 5, 2023, written response and determined it inadequate. Your finished product specification sheet for your (b)(4) product is lacking adequate strength specifications. The method listed on the finished product specification sheet for determining the strength of (b)(4) and (b)(4) in the finished product is by “input.” While measuring input may be a useful process control, it is not an appropriate test method for determining the strength specification of these ingredients in the finished batch of dietary supplement.

Also, the company was cited for selling a product with a disease claim in the product’s title. This name was redacted in the warning letter, so I reached out to the company that received the letter to ask what the product’s name was, but I have not heard back from them. I’m always intrigued when I see product names cited in warning letters, and I’ve previously written about this here. 

• From warning letter. “Product name, (b)(4): The product name implies the product is intended to cure, mitigate, treat, or prevent migraines.”

Labeling issues are also mentioned in this letter. Check out last week’s post for best practices for labeling dietary supplements. 

Read the full warning letter here. 

DATE ORIGINALLY POSTED: 7/31/24

Disclaimer: The educational information provided here is for informational purposes only. Contact an attorney for specific legal advice. Rule #1 in compliance is to ensure marketing is truthful and not misleading