What a supplement maker has to sample, and when

The question people usually ask, and the better one

Did they test the finished product is the usual question about a supplement. It is a reasonable question and an incomplete one.

The dietary supplement manufacturing rules, at 21 CFR part 111, treat finished-product testing as one checkpoint in a chain. Subpart E is where the chain is described.

Its heading is a mouthful with a clear meaning: Requirement to Establish a Production and Process Control System. The word system is doing the work.

Section 111.55 sets the obligation in one sentence. A maker "must implement a system of production and process controls that covers all stages of manufacturing, packaging, labeling, and holding of the dietary supplement."

The system has to be designed, and approved by somebody

Section 111.60 adds two conditions that are easy to skim past.

The system "must be designed to ensure that the dietary supplement is manufactured, packaged, labeled, and held in a manner that will ensure the quality of the dietary supplement." It must also ensure the product is packaged and labeled as the master manufacturing record specifies.

The second condition is a sign-off. The system "must include all requirements of subparts E through L of this part and must be reviewed and approved by quality control personnel."

Section 111.65 adds that quality control operations must be implemented "in your manufacturing, packaging, labeling, and holding operations." The duties of those personnel are set in a separate subpart, covered elsewhere here.

Section 111.73 is one line long and worth quoting because of what it does not say. "You must determine whether the specifications you establish under § 111.70 are met." It sets a duty to find out, and leaves how to a later section.

Five places a sample has to be taken

Section 111.80 is the section that answers what actually gets tested, and it lists five distinct sampling points.

The first is incoming material: representative samples "of each unique lot of components, packaging, and labels that you use." Where these come from a supplier, the requirement extends to "each unique shipment, and of each unique lot within each unique shipment."

The second is mid-process: samples "of in-process materials for each manufactured batch at points, steps, or stages, in the manufacturing process as specified in the master manufacturing record where control is necessary."

The third is the finished batch, and it carries a notable option. Samples of "a subset of finished batches of each dietary supplement that you manufacture, which you identify through a sound statistical sampling plan (or otherwise every finished batch)."

The fourth covers product a company did not make: samples of each unique shipment and lot "of product that you receive for packaging or labeling as a dietary supplement."

The fifth is the label itself: samples "of each lot of packaged and labeled dietary supplements to determine whether the packaging and labeling of the finished packaged and labeled dietary supplements meet specifications."

The word subset is the one to notice

The third sampling point is the one a buyer most often assumes covers everything, and it is written with a documented alternative.

A maker may test a subset of finished batches identified through a sound statistical sampling plan, or, in the parenthetical the regulation supplies, otherwise every finished batch.

That means a compliant operation may not have tested the specific batch in a specific bottle. It may have tested a statistically chosen sample of batches instead.

This is not a loophole so much as a design choice, and it is why the other four sampling points matter. Control is spread across the chain rather than concentrated at the end.

It is also why a certificate of analysis for one lot answers a narrower question than it appears to. What lot, and which sampling point, are the questions that make such a document meaningful.

What happens when a specification is not met

Section 111.77 handles the failure case, and it sorts by which specification failed.

For most categories, quality control personnel "must reject the component, dietary supplement, package or label unless such personnel approve a treatment, an in-process adjustment, or reprocessing." Even then, no finished batch may be released unless it complies with the separate release provision in subpart F.

For component specifications the rule is absolute. Quality control personnel "must reject the component and the component must not be used in manufacturing the dietary supplement."

For received product being packaged or labeled as a supplement, likewise: the product "may not be packaged or labeled for distribution as a dietary supplement."

Section 111.87 names who decides, in one sentence. "Quality control personnel must conduct all required material reviews and make all required disposition decisions."

Rework is allowed, under conditions

Section 111.90 governs treatments, in-process adjustments and reprocessing, and it is written as a pair of prohibitions with exceptions rather than as a permission.

Nothing rejected may be reprocessed or adjusted unless quality control personnel "conduct a material review and make a disposition decision to approve the reprocessing, treatment, or in-process adjustment." The action must also be permitted by section 111.77.

A second paragraph adds a requirement that the approval rest on something. The disposition decision must be "based on a scientifically valid reason."

And a reworked batch does not skip the exit gate. Any batch that is reprocessed, or that contains treated or adjusted components, "must be approved by quality control personnel and comply with § 111.123(b) before releasing for distribution."

The paperwork the subpart leaves behind

Section 111.95 lists what has to exist on paper, and the list is more revealing than a list of records usually is.

Two entries stand out because they require a written justification rather than a result.

One is documentation "of your qualification of a supplier for the purpose of relying on the supplier's certificate of analysis." Relying on somebody else's certificate is permitted, and the reliance itself has to be justified in writing.

The other covers exemptions from finished-batch testing. Where a product specification is verified some other way, the record must include more. It has to hold "documentation that the selected specifications tested or examined under § 111.75 (c)(1) are not able to verify" that the system meets that specification. It must also document that "there is no scientifically valid method for testing or examining such exempted product specification at the finished batch stage."

That is a demanding sentence. Skipping a finished-batch test requires a written case that no valid method exists to run it at that stage.

What this covers, and what it does not

Part 111 is the dietary supplement rulebook. It does not govern a compounded prescription preparation, and it is not the drug manufacturing regulation.

That distinction matters in this market because the same molecule can be sold under different legal frames, and the applicable rulebook changes with the frame rather than with the molecule.

What the subpart gives a reader is a set of better questions. Which sampling point does this test represent. Was the finished batch tested, or a statistically selected subset of batches. If a supplier certificate is being relied on, what qualification stands behind it.

Those are answerable questions, and a company that operates this system has the documents to answer them.

This page describes what the regulation says. It examines no company's records, names no seller, and is not legal advice.

Sources

Each document below is named as it names itself, with the date printed on that document rather than the day it was read.

1. Title 21 Code of Federal Regulations section 111.55, What are the requirements to implement a production and process control system? — Electronic Code of Federal Regulations, Office of the Federal Register, June 2007
2. Title 21 Code of Federal Regulations section 111.60, What are the design requirements for the production and process control system? — Electronic Code of Federal Regulations, Office of the Federal Register, June 2007
3. Title 21 Code of Federal Regulations section 111.73, What is your responsibility for determining whether established specifications are met? — Electronic Code of Federal Regulations, Office of the Federal Register, June 2007
4. Title 21 Code of Federal Regulations section 111.77, What must you do if established specifications are not met? — Electronic Code of Federal Regulations, Office of the Federal Register, June 2007
5. Title 21 Code of Federal Regulations section 111.80, What representative samples must you collect? — Electronic Code of Federal Regulations, Office of the Federal Register, June 2007
6. Title 21 Code of Federal Regulations section 111.87, Who conducts a material review and makes a disposition decision? — Electronic Code of Federal Regulations, Office of the Federal Register, June 2007
7. Title 21 Code of Federal Regulations section 111.90, What requirements apply to treatments, in-process adjustments, and reprocessing — Electronic Code of Federal Regulations, Office of the Federal Register, June 2007
8. Title 21 Code of Federal Regulations section 111.95, Under this subpart E, what records must you make and keep? — Electronic Code of Federal Regulations, Office of the Federal Register, June 2007