Excipients, the inactive ingredients, and their supply chain

In May 2023, FDA told drug manufacturers to test every container of glycerin, propylene glycol and several other ingredients for two industrial solvents before putting them into medicine, according to the agency's revised guidance on high-risk drug components¹. The instruction followed a run of poisonings from children's cough syrups contaminated with diethylene glycol (DEG) and ethylene glycol (EG). Cases came from at least seven countries, and more than 300 deaths were reported in three of them, mostly among children under 5, the World Health Organization said in January 2023³.

Contamination in those cases came in through the inactive ingredients, the solvents and sweeteners that carry a drug. In October 2022, FDA noted, Indonesian authorities found DEG and EG in a propylene glycol excipient used to make oral liquids. FDA said it had no indication that any of the contaminated products had entered the US supply.

Excipients get far less public attention than active ingredients, and far less public data. This piece explains how FDA oversees them without approving them on their own, the master-file route suppliers use, what the 2023 guidance requires, and what federal records do and do not show about where these materials come from.

What counts as an excipient

Federal drug manufacturing rules define an inactive ingredient as "any component other than an active ingredient," and a component as "any ingredient intended for use in the manufacture of a drug product, including those that may not appear in such drug product," under 21 CFR 210.3⁴. FDA's 2021 notice launching a novel excipient pilot listed examples, among them fillers, diluents, surfactants, solvents, emulsifiers, preservatives, flavors, absorption enhancers, modified-release matrices and coloring agents.

FDA's working catalog is its Inactive Ingredient Database¹⁰, updated each quarter. GxRadar's count of the October 2026 file found 9,076 entries covering 1,795 ingredient names, each tied to a route, a dosage form and an amount. Oral products account for 4,769 of the entries. Our explainer on the Inactive Ingredient Database covers how applicants use those limits, and why your pill changed color explains how different excipients make two versions of the same generic look different.

No separate approval for inactive ingredients

FDA does not issue a stand-alone approval for an excipient. It reviews the ingredient inside each drug application that uses it. For an excipient with no history at the proposed level or route, FDA's 2005 guidance on nonclinical safety studies for excipients¹¹ sets out the testing it expects.

That arrangement has made drug developers wary of new excipients. When FDA announced its Novel Excipient Review Pilot Program¹² in September 2021, it said developers "have been hesitant to use novel excipients" because of uncertainty over whether they would be accepted. The pilot was limited to excipients never used in an approved drug and with no established use in food, and FDA said it expected to accept about four initial proposals over two years.

For generics, the rules on inactive ingredients depend on how the product is used. Injectables and eye drops leave a generic maker the least room to change the recipe, and tablets and capsules the most.

Source: 21 CFR, 2025 edition, via govinfo.gov. Our piece on Q1/Q2 sameness explains how FDA applies the "same ingredients, same amounts" test, and what a generic must share with its brand covers the rest of the comparison.

Compendial standards and Type IV master files

Many excipients, including the solvents named in FDA's 2023 guidance, have a monograph in the USP-NF, the combined United States Pharmacopeia and National Formulary. FDA's 2023 guidance says a drug component "with a name recognized in USP-NF must comply with compendial standards or be deemed adulterated," and that bulk excipients intended for use in a drug are themselves drugs under the Federal Food, Drug, and Cosmetic Act. Our explainer on what USP means on a label describes the standards body.

Suppliers that want to keep their manufacturing details confidential can file a Type IV drug master file (DMF), which covers an "excipient, colorant, flavor, essence, or material used in their preparation," under 21 CFR 314.420⁹. FDA's DMF guidance page¹³ says each additive should be identified by "its method of manufacture, release specifications, and testing methods." FDA neither approves nor disapproves a DMF; it reviews one only when an application refers to it. The user fee and completeness check that apply to ingredient files for generics do not apply to Type IV files. Our explainer on drug master files walks through the process.

Filings have picked up. GxRadar's count of FDA's DMF list¹⁴, current through September 30, 2026, found 3,684 Type IV files in all, 2,346 of them marked active.

Source: GxRadar analysis of FDA's quarterly DMF list (third quarter 2026), by submission date.

Why FDA wants every container tested

DEG has turned up in medicines repeatedly, and FDA's 2023 guidance recounts the history.

Source: FDA guidance, May 2023 (Revision 1)².

FDA said the earlier cases shared a pattern. Drug makers did not run full identity tests on the glycerin, relied on the supplier's certificate of analysis, and often held a copy of that certificate on a distributor's letterhead, so the chain of custody was unknown. It said the 2022 outbreak "resembles previous ones." Our history of DEG contamination in medicines and of the 1937 elixir sulfanilamide deaths tell those stories in full.

Binding requirements sit in 21 CFR 211.84⁵. At least one test must verify the identity of each component, and representative samples of each shipment of each lot must go through identity testing before use. A supplier's report of analysis can stand in for other tests only if the manufacturer runs a specific identity test and validates the supplier's results. The guidance goes further for high-risk components. Because FDA has seen DEG and EG levels vary widely "from container to container," it recommends sampling each container of each lot, and it puts the safety limit for DEG and EG at not more than 0.10 percent, as set in the applicable USP-NF monographs.

What US recall records show

Excipient problems do reach US recalls, though rarely. GxRadar searched FDA's openFDA enforcement records¹⁵ on November 5, 2026, for recall reasons that use the word "excipient" and found 102 records from 2014 through 2026. Fifty of them, all Class II and all from 2022, gave the same reason, that products "were manufactured with contaminated excipient that was recalled from the excipient supplier." Other records describe an excipient contaminated with theophylline in 2021 and one with a high ethylene glycol result in 2023. The GxRadar recall tracker has the full counts by year and class, and our piece on Class II recalls explains that category.

What is known about where excipients are made

Public data on excipient sources are thinner than for active ingredients. FDA's annual quality reports¹⁶ break out ingredient and finished-dose sites by country, as our piece on where FDA's registered drug factories are shows, but they do not publish a comparable count for excipient makers. FDA's DMF list gives holder names without locations, and many excipients never go into a master file at all. GxRadar did not find an HHS or FDA report that measures where US drug excipients are produced.

FDA has flagged the risk in narrower settings. Its fiscal 2024 quality report¹⁷ urged compounders to "know their suppliers" of active ingredients "and excipients," and to know whether those suppliers test what they sell.

FDA's next public data release is routine. FDA updates the Inactive Ingredient Database in January, April, July and October, so the next file is due in January 2027, and under the GDUFA III commitment letter¹⁸ the agency posts quarterly notices showing what changed and what the new entries replaced.