Compounding law
The 503A bulk drug substances list: Category 1, 2 and 3.
After reading this you will be able to look up a substance on FDA's 503A bulk drug substances list, say which of Category 1, 2 and 3 it sits in, say what that category permits, and name the four circumstances that must all be true before a Category 1 position stands behind a purchase order.
How to read Category 1, 2 and 3 on the 503A bulk drug substances list
Two documents get called the same thing. The 503A bulks list is a regulation, codified at 21 CFR 216.23. It names six bulk drug substances that can be used in compounding under section 503A(b)(1)(A)(i)(III), and separately names four that FDA evaluated and determined will not be added. Everything else people call the list sits on a second document, FDA's page of nominated substances, and that page is where the three categories live.
The categories are stages of one evaluation, not grades of quality. FDA's January 2025 interim policy guidance defines them. Category 1 substances may be eligible for inclusion, were nominated with sufficient supporting information for FDA to evaluate them, and appear on no other list. Category 2 substances were nominated with sufficient information too, but FDA has identified significant safety risks in their use in compounding pending further evaluation, so the Category 1 position is not extended. Category 3 substances were nominated with too little information for FDA to evaluate them at all.
A category is a fact about a docket, not about a container. It says nothing about the identity, purity or origin of the material in front of you. A third document is often confused with these: 21 CFR 216.24 names drug products that may not be compounded under section 503A or 503B because they were removed from the market for reasons of safety or effectiveness. It applies whatever ground a substance stands on.
01The three categories, and what each one settles.
| Category | What it records | FDA's stated interim position | What it does not settle |
|---|---|---|---|
| Category 1 · Under evaluation | Nominated before January 7, 2025 with enough information for FDA to evaluate, and appearing on no other list | FDA does not intend to act against a compounder, provided four circumstances are all present | Identity, purity or origin of any lot, and whether the substance will ever reach the regulation |
| Category 2 · Significant safety risks | Nominated with enough information to evaluate, and FDA has identified significant safety risks pending further evaluation | The Category 1 position is not extended; FDA publishes a communication describing the risks | Whether the substance may still be placed on the list after evaluation |
| Category 3 · Nominated without adequate support | Nominated with too little information for FDA to evaluate | The Category 1 position is not extended | Anything at all about the substance, because no evaluation has occurred |
| Nominated on or after January 7, 2025 | Received and evaluated on a rolling basis, but not placed in any category | None stated; these substances sit outside the interim policy | Everything the three categories above settle |
The three grounds, read in order
Before a category matters, the ground matters. Section 503A(b)(1)(A)(i) gives three grounds for a bulk drug substance, in a fixed order. The substance must comply with the standards of an applicable United States Pharmacopeia or National Formulary monograph, if a monograph exists, and with the United States Pharmacopeia chapter on pharmacy compounding. If no such monograph exists, it must be a component of a drug approved by the Secretary. If neither is true, it must appear on the list FDA develops by regulation.
The order is doing work. The second and third grounds each open with a condition on the one before, so a substance stands on one ground rather than on whichever reads best. A substance with an applicable monograph never reaches the list, and an entry needing two grounds stacked together has none.
Two conditions travel with every bulk drug substance regardless of ground. It must be manufactured by an establishment registered under section 510, including a foreign establishment registered under section 510(i), and it must be accompanied by a valid certificate of analysis. Those are statutory rather than policy, so they do not soften for a substance in demand.
Category 1 is conditional, and two of its four conditions are about the supply chain
FDA's interim position is narrower than usually quoted. The Agency has said it does not intend to act against a state-licensed pharmacy, a federal facility or a licensed physician compounding with a substance that has no applicable monograph, is not a component of an approved drug and is not on the regulation, only if all four of these circumstances are present at once.
The second is where most purchase files fail, and the guidance closes the obvious escape itself: original manufacturer means the entity that originally produced the bulk drug substance and not a subsequent packer, repacker, labeler, or distributor. A distributor's own registration number does not satisfy it, and neither does a repacker's. The phrase all subsequent manufacturers extends the requirement to everyone who processed the substance afterward.
That is checkable without asking anyone. FDA publishes the Drug Establishments Current Registration Site, a daily publication of currently registered establishments that manufacture, prepare, propagate, compound or process drugs distributed in the United States. It excludes outsourcing facilities, wholesale distributors and third-party logistics providers, so a distributor will not appear there and that absence is evidence about the database rather than about the manufacturer. Look up the establishment named on the source record, not the company on the invoice.
An advisory committee weighs the four criteria at 21 CFR 216.23(c) and makes a recommendation that does not bind the Agency; the document that changes what a pharmacy may lawfully do is the final rule.
- The substance appears in Category 1, was nominated before January 7, 2025 with sufficient supporting information for FDA to evaluate it, and has not been identified as presenting a significant safety risk in compounding.
- The original manufacturer and all subsequent manufacturers of the substance are establishments registered under section 510, including foreign establishments registered under section 510(i).
- The substance is accompanied by a valid certificate of analysis.
- The drug product compounded from it is compounded in compliance with all other conditions of section 503A.
What ended on January 7, 2025
FDA stopped categorizing. The January 2025 guidance states that the Agency does not intend to place substances nominated on or after its publication date into any category, and that products compounded from them fall outside the interim policy. Nominations still arrive through the docket opened in 2015 and are evaluated on a rolling basis.
The categorized set is closed. It can shrink, when a substance is resolved by a final rule or removed for a safety reason, and it cannot grow. A substance carrying no category is not waiting in line for one, because there is no line left to join.
Office use is a separate question from the list
Section 503A(a) exempts a compounded drug product only if it is compounded for an identified individual patient based on the receipt of a valid prescription order, or a notation approved by the prescribing practitioner that a compounded product is necessary for the identified patient. A substance's category does not touch that condition.
There are two lawful ways to hold a supply in advance, with different suppliers. Section 503A(a)(2) permits a licensed pharmacist or physician to compound in limited quantities before receiving a valid prescription order, based on a history of receiving such orders within an established relationship. FDA's December 2016 guidance describes the other: hospitals, clinics and practitioners obtain non-patient-specific compounded products from outsourcing facilities registered under section 503B, which may, but need not, obtain patient-specific prescriptions before distributing.
A state board rule sits on top of this rather than instead of it. It governs practice in that state and does not alter the federal exemption; a state permitting what federal law does not exempt has created none. Ask for the board rule and the federal ground as two separate answers.
The research legend is a description, not a permission
21 CFR 201.125 is cited far more often than it is read. It provides that a drug subject to 21 CFR 201.100 or 201.105 is exempt from section 502(f)(1) of the act if it is shipped or sold to, or in the possession of, persons regularly and lawfully engaged in instruction in pharmacy, chemistry or medicine not involving clinical use, or engaged in law enforcement, or in research not involving clinical use, or in chemical analysis or physical testing, and is to be used only for such instruction, law enforcement, research, analysis or testing. That sentence, scope clause included, is the whole section.
Read what it does not do. It prescribes no wording, so no label text is required by it and none invokes it. It is keyed to who holds the material and what they do with it, so the exemption travels with the recipient and the use, not the container. And it reaches section 502(f)(1) alone, adequate directions for use, so it says nothing about section 505 or section 503A.
The legend people quote comes from a different regulation, for a different class of product. 21 CFR 809.10(c)(2)(i) requires a specific statement, prominently placed, on an in vitro diagnostic product in the laboratory research phase of development that is not represented as effective. A sterile injectable material is not an in vitro diagnostic product, and borrowing that wording does not import that exemption. A supplier who relies on that exemption relies on it for a particular recipient and a particular use, not for a particular container, and the printed line does not carry it. Ask what channel the material is supplied on, who is verified to receive it, and where the material ships.
What this means for a buyer
Work in the statute's order rather than the list's. Settle the ground first: is there an applicable monograph, is the substance a component of an approved drug, or does it appear in the regulation. Only when all three fail does a category become the operative question, and only Category 1 carries a stated position.
Then ask for the four things that make that position stand up. Two are documents a supplier either holds or does not, which makes them fast to test. The third is a public fact you can read for yourself on FDA's list. The fourth is not the supplier's at all: compounding in compliance with all other conditions of section 503A is the pharmacy's own obligation, and no supplier document discharges it. The answers belong on the lot record rather than in a conversation. Every entry on the GradeBio register prints the basis it is supplied on, with the authority named, on the entry itself.
02Four questions, and what a complete answer looks like.
| Ask | Why it is asked | A complete answer |
|---|---|---|
| Which of the three grounds under 503A(b)(1)(A)(i) does this entry stand on | The grounds are read in order and exactly one applies, so an entry needing two stacked together has none | One named ground, with the monograph, the approved drug, or the citation to 21 CFR 216.23(a) |
| Who originally produced the substance, and what is that establishment's section 510 registration | The interim position requires the original manufacturer and every subsequent manufacturer to be registered, and a distributor's registration is not the manufacturer's | The establishment named, and checkable by you in FDA's daily registration publication |
| Where is the certificate of analysis for this lot | Section 503A(b)(1)(A)(iii) requires a valid certificate for each bulk drug substance on every ground, not only for Category 1 substances | A certificate issued against the lot number on the container, kept with that lot |
| What is the current category, and what does its update note say | The column carries only where the substance sits; the note carries why it moved and when | The category, the date of the last change to it, and the reason FDA gave for the change |
Sources
- Federal Food, Drug, and Cosmetic Act section 503A, 21 U.S.C. 353a 21 U.S.C. 353a(a), (a)(2), (b)(1)(A)(i)(I)-(III), (b)(1)(A)(ii), (b)(1)(A)(iii)
- 21 CFR 216.23, Bulk drug substances that can be used to compound drug products in accordance with section 503A 21 CFR 216.23(a), (b), (c); 84 FR 4710, Feb. 19 2019
- 21 CFR 216.24, drug products removed from the market for reasons of safety or effectiveness 21 CFR 216.24
- FDA guidance for industry, Interim Policy on Compounding Using Bulk Drug Substances Under Section 503A of the Federal Food, Drug, and Cosmetic Act (January 2025, final) Sections II and III; the four circumstances in section III; the definition of original manufacturer
- FDA guidance for industry, Prescription Requirement Under Section 503A of the Federal Food, Drug, and Cosmetic Act (December 2016, final) Section III.D, Compounding Office Stock/ Compounding for Office Use; section 503B(d)(4)(C)
- 21 CFR 201.125, Drugs for use in teaching, law enforcement, research, and analysis 21 CFR 201.125
- 21 CFR 809.10(c)(2)(i), labeling for in vitro diagnostic products 21 CFR 809.10(c)(2)(i)
- FDA, Drug Establishments Current Registration Site (DECRS) DECRS database description and scope
Request access.
Accounts are opened for licensed practice and verified research institutions, after a person has read the request.