cGMP violations: How to prevent history from repeating itself

Since FDA began enforcing cGMPs (current good manufacturing practices) for dietary supplements in 2009, the most common violations among inspected facilities have remained largely unchanged—with the list of common deficiencies in fiscal year 2022 (FY22) being no exception.

In fact, data recently disclosed by FDA in response to a Freedom of Information Act request unsurprisingly identified the same list of top 10 cGMP violations for FY22 that we’ve seen for the last 13 years.

How can this be? How can so many within our industry not get it right after all this time? It certainly can’t be due to a lack of trying.

We must consider if these deficiencies are due to a failure to communicate expectations from a regulatory perspective. For example, how can we more effectively clarify potential misunderstandings or training opportunities between industry and FDA investigators during an inspection? How can we increase collaboration to amplify knowledge and understanding of current processes?

Knowledge is power

Warning letters and other regulatory actions issued following an FDA inspection should not be used to shame those receiving them, but rather as signals to determine what can be learned and where improvements might be necessary. The data emerging from FDA cGMP inspections convey a great deal of information to both industry and the agency, as the recorded deficiencies underscore where specific preparations can be implemented prior to inspections and where improvements are needed to meet quality standards.

Additionally, we should look at how current resources can be improved to maximize their value for responsible industry. For example, FDA’s Data Dashboard is a tool responsible industry can leverage to review top deficiencies. However, dietary supplement specifics are not easily found, as they are a subpart of the larger commodity “food” within FDA systems. As such, dietary supplement information is combined with all food inspection statistics and mixed with several other technical foods and inspections, including canned foods, acidified foods, seafood or bakery inspections (aka a general GMP inspection).

Improving deficiencies through existing options

As we jump into the top deficiencies, it is important to set the stage. In FY22, FDA staff and their investigators conducted 517 establishment inspections (EI) for facilities registered as dietary supplement firms, an increase from 275 EIs in FY21. However, the FY22 figures are still below pre-pandemic numbers when FDA reported about 656 EIs in FY17.

The number of inspections compared to the number of registered facilities is still very low, with FDA covering only about 7% of facilities in the dietary supplement industry annually. For comparison, during FY22, the FDA staff in a report (“Justification of Estimates for Appropriations Committee”) indicated they conducted approximately 8,000 food establishment inspections (all subgroups, including dietary supplements) and approximately 3,055 drug establishment inspections. Per another FDA document (“Facts Sheet: FDA at a Glance”), there are 6,799 registered human drug facilities in the U.S., and therefore, using these two values, approximately 45% of registered U.S drug facilities were inspected in one year, compared to approximately 7% of dietary supplement facilities.

FDA has several options when it comes to increasing the number of dietary supplement inspections conducted each year, including using existing systems for other FDA commodity types. One option, for example, includes the agency’s remote regulatory assessment (RRA) authority. FDA utilized this authority during the Covid-19 pandemic to conduct inspections and verify compliance with Foreign Supplier Verification Programs (FSVP). This process was successfully carried out by FDA’s import offices.

It is important to note that if you look at the FDA Data Dashboard for the top 10 citations overall from 2009-2023, failure to implement an FSVP program (21 CFR Part 1.502(a)) ranks number four. When you look at only food-related deficiencies (this includes dietary supplements), and remove medical device, this FSVP deficiency ranks number three overall—a position earned in a very short period of time.

Establishing more frequent use of FDA’s current regulatory authority to conduct voluntary RRAs for dietary supplements could potentially help the agency cover more facilities, prioritize high-risk facilities and products, and improve efficiency. If conducted appropriately, these RRAs could be a significant win for industry, FDA and consumers. In fact, the Consumer Healthcare Products Association (CHPA) has submitted comments to FDA on its draft guidance for RRAs and how to improve inefficiencies to increase visibility into more manufacturing facilities.

Another potential option is creating an FDA program that qualifies third parties to conduct FDA-certified audits to help FDA prioritize its regulatory inspections. While third-party audits may not replace a regulatory inspection, they could help FDA focus its inspection resources on the areas of highest public health risk while having additional third-party audit reports to monitor the industry for compliance. Certified third-party audits are already in the FDA system for the Voluntary Qualified Importers Program (VQIP), a voluntary, fee-based service that allows for expedited entry through the U.S. imports system.

Are FDA and industry speaking the same language?

While dietary supplement quality and regulatory executives have indicated most believe they understand how to write specifications, the FDA data tracked since 2009 suggests there’s room for improvement.

A cornerstone of dietary supplement cGMPs is the requirement to establish specifications for any step in the manufacturing process where control is needed to ensure the quality of the dietary supplement. Failure to comply with this part of the regulation continues to be a top cGMP violation.

Experts in dietary supplement cGMPs have identified challenges in understanding FDA’s expectations for operational product specifications. Typically, a specification written to make a product includes such details as color, moisture, particle size and density. These are important for making a uniform tablet or another finished dosage form.

When it comes to “regulatory” specifications, FDA investigators look for the following, characterized by some experts as the “big five”:

- Identity

- Purity

- Strength

- Composition

- Limits for potential contamination typically include heavy metals (arsenic, cadmium, lead and mercury), pesticides and microbiology. For high-risk products, you may also need to monitor for other known adulterants like pharmaceuticals.

Without these specifications, firms will likely see a citation on an FDA Form 483 at the end of their inspection for a deficiency. Failure to make the appropriate correction could eventually lead to an FDA warning letter.

One potential solution is adding a header to a specification document for each of the “big five,” and to take proper steps to ensure a comprehensive understanding on how FDA uses these terms when it evaluates documents during inspection. And of course, there is the requirement for testing and monitoring to ensure specifications are met using qualified laboratories and appropriate methods.

cGMP complexities

Establishing a dietary ingredient specification for a vitamin or a mineral is technically straightforward. This is because the purity is high, and therefore, the composition is also easily defined. However, dietary supplements contain complex ingredients, including botanical extracts, which are made using different extraction methods. This complicates the definition of purity and composition. Over the last decade, this complexity has been recorded in the list of top 10 cGMP deficiencies.

Finished product specifications create another level of complexity. For example, developing a finished product specification for a botanical blend in a gummy delivery form requires specialized technical and scientific expertise.

Moving forward

After 13 years of documented misunderstanding, it is time for industry stakeholders to ask ourselves whether the dietary supplement cGMP and FDA guidance underestimate the complex nature of some dietary supplement formulas. Are FDA investigators fairly trained for multi-ingredient dietary supplements delivered through innovative form factors?

Undoubtedly, clarification is needed for regulators and industry. This is why CHPA supports increased resources and training for FDA inspectors, as well as continued communication with industry to finally move beyond repeating the same top violations year after year.

Larisa Pavlick is the senior director of product quality and technical affairs at the Consumer Healthcare Products Association (CHPA), where she serves as the leader on quality, technical and manufacturing issues and leads the Product Quality & Manufacturing Controls Committee. Larisa has more than 25 years of industry experience specializing in product development, quality, regulation, and operations, including 12 years in the dietary supplement industry and nearly eight years at U.S. Food and Drug Administration (FDA).