Avoiding the Top 5 Violations of 21 CFR Part 111

Over 10 years ago, the U.S. Food and Drug Administration (FDA) issued 21 CFR Part 111, a set of current good manufacturing practices (CGMPs) for supplement manufacturers. Since then, certain aspects of the ruling have proven difficult for nutraceutical companies to keep up with. Every year the FDA compiles information on CGMP violations. Fortunately, the data from 2017 show that the top five violations of 21 CFR Part 111 all deal in some way with quality, and a new white paper shows how these can be avoided with the right system in place.

#1 Violation: Specify Identity, Purity, Strength and Composition of Dietary Supplement

The most common violation involves 21 CFR 111.70(e), which states that each dietary supplement must have specifications for “the identity, purity, strength, and composition of the finished batch of dietary supplement, and for limits on those types of contamination that may adulterate…the dietary supplement.” The FDA isn’t just concerned with whether or not a company has established these specifications; there also must be scientific rationale behind why these specifications were chosen. It isn’t enough to state what will be tested and how — you must explain why that particular testing established that specifications were met.

Scientific rationale must be provided to show that your sampling and testing methods are adequate. While it should go without saying, there have been times when a company’s specifications are too vague, leading to the FDA issuing warning letters. One example of a vague specification is allowing a large range of a certain vitamin or mineral, which defeats the purpose of establishing specifications in the first place.

#2 Violation: Lack of Written Procedures for Quality Control Operations

Coming in second place is a lack of either establishing or following quality control operations. According to 21 CFR 111.103, “You must establish and follow written procedures for the responsibilities of the quality control operations, including written procedures for conducting a material review and making a disposition decision, and for approving or rejecting any reprocessing.” The main issue here is that a company must be able to show these procedures to the FDA and demonstrate with documentation that it is following them.

All nutraceutical companies must have quality control procedures, including those using contract manufacturers. Sellers must still ensure the quality of the supplements they market through production and process controls, and they must ensure that the supplements are packaged and labeled as specified in the master manufacturing record.

#3 Violation: Lack of Written Procedures for Complaints

The next most common violation is not establishing or following “written procedures for the requirements to review and investigate a product complaint,” which refers to the requirements found in 21 CFR 111.553. These procedures must include how a qualified person will review all complaints, investigate, follow up and determine if corrective action is necessary. The standard operating procedure (SOP) must also include how complaints are documented and demonstrate that the requirements in 21 CFR 111.570 are included.

• Name and description of dietary supplement
• Batch, lot or control number of dietary supplement
• Date complaint was received and name, address or phone number of complainant
• Nature of complaint, including how the product was used, if known
• Reply to the complainant, if any
• Findings of the investigation and follow-up action taken

While most of these criteria are fairly straightforward, the last point requires more specificity. It's vital to realize just how detailed these procedures must be. For example, it isn’t enough to state that a complaint must be verified; the firm must detail how it is to be verified. A specific problem among nutraceutical companies seems to be requiring quality control personnel follow up on the complaints. They must investigate if the complaint arose because something was wrong with the product itself, and they must review and approve follow-up actions.

#4 Violation: Verify That Finished Product Meets Specifications for Identify, Purity, Strength, Composition and Limits on Contaminants

While the number one violation is failing to establish specifications, this violation is failing to ensure that you’ve followed them. According to 21 CFR 111.75(c), a firm must verify that the finished dietary supplement meets the specifications mentioned in 21 CFR 111.70(e). The company must determine what’s going to be tested and how, and document the basis for how that meets specifications. The FDA has identified that “products in the weight loss, sexual enhancement, and body building categories should receive extra attention and scrutiny from their manufacturers and distributors”³ to ensure that these products are not adulterated. Current good manufacturing practices do allow for exceptions to the specifications, but these must be approved by quality control personnel.

If a nutraceutical company uses a contract manufacturer, it must ensure that the finished supplements supplied by the contract manufacturer meet these specifications. Any batch that does not meet specifications must be rejected. The seller is still responsible for establishing and following these specifications.

#5 Violation: No Written Master Manufacturing Record for Each Batch Size

According to 21 CFR 111.205(a), every batch size needs its own master manufacturing record. This is meant to ensure uniformity across batches. The requirements for that master manufacturing record are found in 21 CFR 111.210 and include:

• The supplement’s name and information about its dietary ingredients, including the strength, concentration, weight or measure of those ingredients;
• A complete list of components to be used with an accurate statement of the weight or measure of each;
• The information that will be on the Supplement Facts label and the ingredient list;
• Statement of any intentional overage amount of a dietary ingredient;
• Theoretical yield at each step of the manufacturing process where quality control is needed, and expected yield of final product;
• Information about the packaging and a representative label; and
• Written instructions for manufacturing the supplement.

Companies using a contract manufacturer may assume that they don’t need a master manufacturing record since they don’t do the manufacturing themselves. However, according to the FDA, these nutraceutical companies must still have a master manufacturing record that includes specifications that are applicable to its operations, such as packaging and labeling.

How Automated Systems Help

Passing an FDA inspection is all about show, not tell. Most violations occur not because companies neglect to follow the requirements altogether, but because they can’t show that they’ve followed them. Automated systems, such as an electronic quality management system (QMS), are invaluable in this area. Not only is all the information you need centralized, but whenever an update is made, only the most current version of a document is available and those changes are tracked automatically, leaving behind an audit trail that is FDA ready. This makes it easy to locate the correct SOP when needed.

When action is needed beyond simply modifying a document, such systems can automatically route the document for approval. For example, if a complaint needs to be investigated by quality control personnel, the system can automatically notify the relevant personnel, let them know what action is needed and allow managers to see when a complaint has been resolved. A fully integrated system will also allow users to launch a corrective and preventive action (CAPA) from the complaint itself, if necessary.

Conclusion

The FDA’s regulations for nutraceuticals represent a chance for companies to produce a better product. While being compliant with 21 CFR Part 111 may seem an insurmountable task, automating quality processes with an electronic QMS not only allows companies to achieve compliance, it also gives them further insight into how to improve their processes and deliver a better overall customer experience for consumers.