What the statute asks a buyer to verify

A pharmacy compounding under section 503A is not asked to prove that a bulk drug substance is good. It is asked to satisfy three conditions, two of which fall on the supplier. At 21 U.S.C. 353a(b)(1)(A)(ii) and (iii), the substances must be “manufactured by an establishment that is registered under section 360 of this title,” foreign establishments included, and “accompanied by valid certificates of analysis for each bulk drug substance.”

Those conditions carry weight because of 353a(a), which exempts a qualifying compounded drug from 21 U.S.C. 351(a)(2)(B), 352(f)(1) and 355: current good manufacturing practice, adequate directions for use, and new drug approval. The discipline the statute relies on sits at the establishment that made the substance, which is why the registration check anchors the chain.

One definition decides which establishment to look up. 21 CFR 207.1 makes a bulk drug substance the same thing as an active pharmaceutical ingredient, so search the maker of the API, not the company on the invoice.

• The establishment name, exactly as printed on the manufacturer's certificate.
• The establishment address, which separates two sites under one corporate name.
• The lot number, and the identity and assay methods reported.
• The drug master file number, if the supplier quotes one.

The first lookup: how to verify an API manufacturer is registered with FDA

FDA publishes the Drug Establishments Current Registration Site, “a publication of currently registered establishments which manufacture, prepare, propagate, compound or process drugs that are distributed in the U.S. or marketed for import to the U.S.” It is updated each business day.

The search takes one field: firm name, which causes most failed lookups. Spell the name the way the establishment registered it, taken off the manufacturer's certificate rather than a sales document. A null result is evidence about the string you typed, not about the establishment.

Know what it excludes before reading a blank as a finding. It carries no wholesale distributors and no third-party logistics providers, and no outsourcing facility unless it also registered other operations. A supplier absent from it is very often absent because it is a distributor.

It is a current publication, not a history. Under 21 CFR 207.29 an establishment updates its registration annually, between October 1 and December 31, and one that does not renew drops out. For a foreign establishment, read the United States agent required by 21 CFR 207.69, who may not be “a mailbox, answering machine or service,” and whose duties include “assisting FDA in scheduling inspections.”

Then read the limit. 21 CFR 207.77(a): “Registration of an establishment or listing of a drug does not denote approval of the establishment, the drug, or other drugs of the establishment, nor does it mean that a product may be legally marketed.”

The second lookup: a drug master file number, and what it is worth

21 CFR 314.420 sets out what a drug master file may contain; FDA's naming puts drug substances in Type II: a drug substance, its intermediates, and the materials used in their preparation.

The letter of authorization is narrower than it sounds. Under 314.420(b) an application may incorporate a file by reference only “if the holder authorizes the incorporation in writing.” The letter runs from a holder to a submission. A compounding pharmacy has no submission, so a supplier offering to furnish one has misread who it is for.

Nor is a file number a quality finding, and the agency says so twice. The regulation states that FDA “ordinarily neither independently reviews drug master files nor approves or disapproves submissions,” and FDA's own page states that they “are neither approved nor disapproved.”

What the number is worth is corroboration of a name. FDA publishes the list of files it has received, updated quarterly, carrying the holder name, subject, type, and a status of A for active or I for inactive. Look up the number a supplier quotes and read its holder name in the registration publication. A disagreement between two federal records is the most useful thing you will find.

What each lookup settles, and what it leaves open

Run them in this order. Each narrows the question the next one asks.

The third lookup: who is licensed to ship it to you

Wholesale distribution is licensed by the state, not by FDA. 21 U.S.C. 353(e)(1)(A) provides that no person may engage in wholesale distribution of a prescription drug in any state unless that person “is licensed by the State from which the drug is distributed,” or by the Secretary where that state has set no requirement. Whether the destination state also licenses a distributor shipping in is a question for that state's board of pharmacy.

Federal law makes those licenses visible. Under 353(e)(2)(A)(i) a distributor reports annually “each State by which the person is licensed and the appropriate identification number of each such license,” and under 353(e)(2)(B) FDA maintains a public database of authorized wholesale distributors.

Read FDA's caution before treating a hit as an answer: “Reporting by a wholesale drug distributor or third-party logistics provider does not mean the facility is licensed or approved by FDA or the facility is in compliance with applicable state and federal regulations.” The database records that a report was filed; the issuing board records the license. Use it to learn which boards to ask, then confirm the number in the board's own search.

What a registration record cannot tell you

None of the three answers whether anyone has been inside the building. FDA's inspection classification database publishes a closed inspection's final classification as no action indicated, voluntary action indicated, or official action indicated, the last meaning “a facility is in an unacceptable state of compliance.”

Two limits produce confident wrong readings. FDA states it “does not represent a comprehensive listing of all conducted inspections,” and it excludes state-conducted and pre-approval inspections. A final classification is usually sent to the firm within 45 to 90 days from the close of an inspection. An establishment with no entry has no published classification, which is not the same as a clean one.

The check that runs the other way is faster. Import Alert 66-40, “Detention Without Physical Examination of Drugs From Firms Which Have Not Met Drug GMPs,” lists foreign establishments whose drugs may be held at the border. Presence is a finding. Absence is not.

Which leaves the question that outruns all five sources. 21 CFR 211.84(d)(1) requires that “at least one test shall be conducted to verify the identity of each component of a drug product.” Paragraph (d)(2) lets a supplier's report of analysis stand in for the rest, but only if the manufacturer runs at least one specific identity test itself and “establishes the reliability of the supplier's analyses through appropriate validation.”

A drug compounded under section 503A is exempt from 21 U.S.C. 351(a)(2)(B), the provision that part 211 implements, which is why the sentence is useful here: it is not a rule binding the compounder, it is the standard to hold a supplier to, in the regulator's own words. Ask whether the supplier runs its own identity test on the container it received, or releases on the manufacturer's certificate. Those are two operations and they leave two records.

What this means for a buyer

The order is the method. Name and address off the certificate, registration by firm name, the quoted file number against its holder name, the distributor's license with the issuing board. The classification and the import alert come last, because neither means anything until the establishment is named.

What you hold at the end is narrower than it sounds. You will know that a named establishment is registered and current, that a submission exists under a matching holder, that a distributor reported a license the state confirms, and whether any published classification or alert bears on that establishment. You will not know that the container on your bench holds what the label says. That is settled by an identity test on it, run by a party who answers for the result. A supplier that names the establishment of origin on the lot record makes all five lookups possible; one that names only itself makes them impossible.

Sources

1. Federal Food, Drug, and Cosmetic Act sec. 503A 21 U.S.C. 353a(a), (b)(1)(A)(i)-(iii)
2. Federal Food, Drug, and Cosmetic Act sec. 501(a)(2)(B) 21 U.S.C. 351(a)(2)(B)
3. Federal Food, Drug, and Cosmetic Act sec. 502(f)(1) 21 U.S.C. 352(f)(1)
4. Federal Food, Drug, and Cosmetic Act sec. 503(e) 21 U.S.C. 353(e)(1)(A), (e)(2)(A)(i), (e)(2)(B)
5. FDA, Code of Federal Regulations 21 CFR 207.1
6. FDA, Code of Federal Regulations 21 CFR 207.29
7. FDA, Code of Federal Regulations 21 CFR 207.69
8. FDA, Code of Federal Regulations 21 CFR 207.77(a), (b)
9. FDA, Code of Federal Regulations 21 CFR 211.84(d)(1), (d)(2)
10. FDA, Code of Federal Regulations 21 CFR 314.420(a), (b)
11. FDA, Drug Establishments Current Registration Site DECRS, Center for Drug Evaluation and Research
12. FDA, Drug Establishment Registration search Center for Drug Evaluation and Research, registration search
13. FDA, Drug Master Files Center for Drug Evaluation and Research
14. FDA, Types of Drug Master Files Center for Drug Evaluation and Research
15. FDA, List of Drug Master Files Center for Drug Evaluation and Research
16. FDA, Annual Licensure Reporting by Wholesale Drug Distributors and Third-Party Logistics Providers Drug Supply Chain Security Act
17. FDA, Inspection Classification Database Office of Regulatory Affairs
18. FDA, Import Alert 66-40 Detention Without Physical Examination of Drugs From Firms Which Have Not Met Drug GMPs