Identity Testing Under 21 CFR 111.75

If you read FDA inspection reports and warning letters for dietary supplement companies, one citation comes up again and again: the firm did not verify the identity of a dietary ingredient before using it. The requirement is in 21 CFR 111.75, and it is one of the most frequently cited sections of the dietary supplement good manufacturing practice rule.

The rule is short, but it is easy to get wrong. Many companies believe that a supplier's certificate of analysis is enough. For dietary ingredients, it is not. This guide explains what 111.75 requires, which tests count, when you may rely on a certificate of analysis, and how to set up a program that will stand up to an inspection.

What the rule says

Section 111.75 sets out what you must do to determine whether specifications are met. Its first paragraph covers components, and it splits them into two groups.

Dietary ingredients. Before you use a component that is a dietary ingredient, you must conduct at least one appropriate test or examination to verify its identity (111.75(a)(1)(i)). A dietary ingredient is a vitamin, mineral, herb or other botanical, amino acid, dietary substance, or a concentrate, metabolite, constituent, extract or combination of these.

All other components, and the other specifications of dietary ingredients. For components that are not dietary ingredients (for example excipients, capsule shells and flow agents), and for the purity, strength, composition and contaminant specifications of all components, you must confirm that specifications are met. You can do this either by testing, or by relying on a certificate of analysis from a qualified supplier (111.75(a)(2)).

So the identity of every dietary ingredient lot must be verified by you, or by a laboratory working for you. Everything else can be covered by a qualified supplier's certificate.

"Every lot" means every lot

The identity test applies to each lot of each dietary ingredient you receive. Testing the first shipment from a supplier and then skipping later lots is not enough. Neither is testing a "representative" lot each year.

The reason is the history behind the rule. Botanical and other ingredients have been substituted, adulterated or mislabeled in the supply chain, sometimes on purpose and sometimes by mistake. FDA wrote 111.75(a)(1) so that each manufacturer checks the identity of what it actually received before it goes into a product.

The exemption petition

There is one way out of 100 percent identity testing. Under 111.75(a)(1)(ii), you may petition FDA under 21 CFR 10.30 for an exemption. The petition must include a scientific rationale and data showing that a reduced testing frequency, for the specific suppliers named, would not materially reduce the assurance of identity compared with testing every lot. If FDA grants the petition, you test under the terms FDA sets.

In practice very few companies take this route. Building the data takes time, and the exemption applies only to the ingredient and suppliers named. Most companies find that a quick, well-chosen identity test on each lot is simpler.

What counts as an appropriate test

Section 111.75(h) requires that the tests and examinations you use are appropriate, scientifically valid methods, and that they include at least one of the following:

• gross organoleptic analysis (appearance, color, odor, taste);

• macroscopic analysis;

• microscopic analysis;

• chemical analysis;

• other scientifically valid methods.

The key word is appropriate. The test must be able to tell the ingredient you ordered apart from likely substitutes and adulterants. A few practical points:

• Organoleptic examination alone is rarely enough for a powdered extract. Many brown powders look and smell alike.

• Infrared spectroscopy (FTIR or NIR) is fast and useful for single-substance ingredients such as vitamins, minerals and amino acids, provided you compare against a verified reference and set acceptance criteria.

• High-performance thin-layer chromatography (HPTLC) is widely used for botanicals, because it shows a fingerprint of constituents that can separate closely related species and detect common adulterants.

• Microscopy and macroscopy suit whole or cut botanicals, where cell structures and plant parts can be seen.

• HPLC or other assay methods can confirm identity at the same time as strength, when the marker compound is specific to the ingredient.

Compendial methods, such as those in the United States Pharmacopeia or AOAC International, are a good starting point when they exist. Whatever method you use, document why it is suitable for the ingredient: what it can distinguish, the reference material it relies on, and the acceptance criteria.

Relying on a supplier certificate of analysis

For components that are not dietary ingredients, and for specifications other than identity, you may rely on a supplier's certificate of analysis. Section 111.75(a)(2)(ii) lets you do so only if all five conditions are met:

1. You first qualify the supplier by establishing the reliability of its certificate, through confirmation of the results of the supplier's tests or examinations.

2. The certificate includes a description of the test or examination method used, the limits of the tests, and the actual results.

3. You keep documentation of how you qualified the supplier.

4. You periodically reconfirm the supplier's certificate of analysis.

5. Your quality control personnel review and approve the documentation that sets out the basis for qualifying the supplier.

In practice, qualification means testing several incoming lots yourself (or at a contract laboratory) for the same specifications the supplier reports, and showing that your results agree with theirs. Periodic reconfirmation means repeating that comparison at a set interval, for example one lot per year per supplier and component, or more often for higher-risk materials. A certificate that shows only "complies" without a method or a result does not meet the rule.

Supplier qualification for certificate reliance is separate from your general supplier approval. A supplier can be approved for purchasing and still not be qualified for certificate reliance on a particular specification.

Packaging, labels and received product

Section 111.75 also covers other materials:

• Packaging (111.75(f)(1)): before use, at least visually identify the containers and closures, and review the supplier's invoice, guarantee or certification.

• Labels (111.75(f)(2)): before use, at least visually examine the label and review the supplier's documentation.

• Product received for packaging or labeling (111.75(e)): visually examine it and have documentation showing it meets your specifications.

• Finished packaged product (111.75(g)): visually examine it to confirm the right packaging and label were used.

Finished batch testing

Identity testing of components does not replace finished product testing. Under 111.75(c), you must verify that finished batches meet product specifications for identity, purity, strength and composition and limits on contaminants, either for every batch or for a statistically sound subset of batches. You select the specifications to test, document why testing them shows the system makes conforming product, and have quality control approve that basis. A specification that truly cannot be tested at the finished stage can be exempted under 111.75(d), but you must document how component and in-process controls make sure it is met.

Common inspection findings

The problems below appear often in FDA observations:

• No identity test on a dietary ingredient; the firm relied on the supplier's certificate of analysis.

• An identity test was performed, but the method could not distinguish the ingredient from a likely substitute (for example, a color check on a botanical extract).

• No written specifications for the component, so there was nothing to test against (111.70).

• Certificates of analysis relied on without any qualification data or periodic reconfirmation.

• Quality control did not review and approve the supplier qualification.

• The component was used before the test results were reviewed and the lot released from quarantine.

Setting up a compliant program

A workable identity testing program has five parts:

1. A specification for each component, stating the identity test method and acceptance criteria for dietary ingredients and the other specifications for all components.

2. A method rationale for each dietary ingredient showing why the test is appropriate.

3. A receiving record for each lot with the identity result, the certificate review and the quality control release decision.

4. A supplier qualification file for each supplier and component where you rely on certificates, with the confirmation results and the reconfirmation schedule.

5. Quarantine until quality control has released the lot.

If a contract manufacturer makes your product, it will usually perform the identity testing. As the brand owner, you should still check that it is done, on every lot, with a suitable method, and that the results are part of the batch documentation you review before release.

How A.P. Lyon can help

The Dietary Supplement cGMP Quality System includes SOP 7-102-DS Component Identity Testing and Supplier Qualification, SOP 7-101-DS Specifications, a Specification Sheet, a Component Identity Test and Certificate of Analysis Review form, and a Supplier Certificate of Analysis Qualification and Periodic Confirmation form, within a complete 112-document 21 CFR Part 111 system.

Own-label brands that use a contract manufacturer can get the same identity testing and specification documents in the Supplement Brand Owner Compliance Pack.

References

• 21 CFR 111.70 and 111.75, Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements (FDA final rule, 72 FR 34752, June 25, 2007; current edition at www.ecfr.gov)

• 21 CFR 10.30, Citizen petition

• FDA, Small Entity Compliance Guide: Current Good Manufacturing Practice in Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements (December 2010)

• United States Pharmacopeia, current official edition (licensed)

Related guides: Brand Owner Duties When a Contract Manufacturer Makes Your Supplements; Serious Adverse Event Reporting for Dietary Supplements; Dietary supplement GMP procedures.

Official sources: 21 CFR 111.75 (eCFR); 21 CFR Part 111 (eCFR).