FDA scientists found a nitrosamine rising in ketamine vials after light exposure

Authors at FDA’s Office of Pharmaceutical Quality reported on October 28 that N-nitroso-ketamine, a nitrosamine impurity of the anesthetic, increased in ketamine injection after the product was exposed to light and then stored in the dark. In the abstract’s words, levels rose from about 5 ng/mL to 100 ng/mL “in some cases” within eight weeks. The paper, in the International Journal of Pharmaceutics, calls the impurity a potential carcinogen.

It is not an FDA position. Every author works in the office and FDA funded the work, but the paper states that it “reflects the views of the authors and should not be construed to represent FDA’s views or policies.” No ketamine recall in FDA’s enforcement database mentions a nitrosamine (searched October 30), and searches found no FDA safety communication or labeling request on the subject.

The study measured an impurity in vials. What that means for a patient depends on a benchmark built for a different use of the drug.

Light first, then weeks in the dark

The authors exposed ketamine injection to light in two ways, ambient and intense, the intense arm including the international photostability standard (ICH Q1B) of at least 1.2 million lux hours. They then stored the vials in the dark and kept measuring. They describe the design as reflecting “clinical reality where multi-use injectable ketamine experiences multiple intermittent light exposures during use.”

The paper’s introduction describes this two-stage design as applied to a commercially available 10 mg/mL product and an in-house formulation, with other vendors’ products measured only before exposure. The products are not named, and the abstract does not say which one reached 100 ng/mL. The study covers ketamine injection; esketamine nasal spray was not studied.

The result surprised the authors. Light exposure first lowered N-nitroso-ketamine. Then, in the dark, it climbed: from a baseline near 5 ng/mL past 14 ng/mL, reaching 100 ng/mL in some cases within eight weeks. Light-protected control vials rose by at most 4.7 ng/mL. The authors attempted kinetic modeling and experiments to explain the mechanism, and the abstract does not claim an answer. A companion paper in July, on manufacture of the drug substance, found that an unidentified nitrosating agent appeared to matter more than activated carbon or solvent choice.

Where 14 ng/mL comes from

FDA’s recommended acceptable intake for N-nitroso-ketamine is 1,500 ng per day. The figure comes from FDA’s 2023 guidance on nitrosamine drug substance-related impurities, which used the compound as a hypothetical worked example (potency category 5), and it remains in the drug center’s current limits table, which says that if a listed nitrosamine forms, the listed limit applies. FDA defines such a limit as the daily intake that approximates one additional cancer case per 100,000 people, assuming exposure every day for 70 years. The guidance is nonbinding, and the table notes that a listing does not confirm the impurity is present in any product.

To turn a daily intake into a concentration, FDA divides it by a product’s maximum daily dose from its labeling. The authors used “the highest maximum daily dose (MDD) for any ketamine product,” 1,074 mg a day, which gives about 1.4 parts per million, or roughly 14 ng/mL in a 10 mg/mL product. The Ketalar label lists per-kilogram anesthesia doses (intramuscular induction of 6.5 to 13 mg/kg) rather than a daily total, so the 1,074 mg figure is the paper’s. The authors add: “Ketamine products with a lower recommended dose will have a higher acceptable concentration for NNKet.”

So 14 ng/mL stacks two worst-case assumptions: the largest daily dose the authors identify for any ketamine product, taken every day for a lifetime.

FDA’s September update on shorter treatment courses

On September 24, FDA’s drug center said that adjustment factors for less-than-lifetime treatment “may now be scientifically supported” for nitrosamine impurities, changing a position it had held until then. For a course of a month or less, a recommended limit may be multiplied by 80; for more than a month up to a year, by 13.3; for more than a year up to 10 years, by 6.67; beyond 10 years there is no adjustment. Applicants must propose the adjustment and FDA evaluates each case. Where a label covers both short-term and long-term use, FDA says it generally considers long-term use. The update does not mention ketamine.

The ketamine paper was received by the journal on April 20 and accepted on October 10, and it uses the unadjusted lifetime figure.

The same arithmetic at a depression dose

Ketamine’s labeled use is anesthesia; treating depression is off-label. A widely studied depression regimen is 0.5 mg/kg intravenously over 40 minutes, as in the ELEKT-D trial (twice weekly for three weeks, New England Journal of Medicine, 2023) and several registered trials. For a 70 kg adult that is 35 mg, or 3.5 mL of a 10 mg/mL product.

Behavioral Wire’s arithmetic, using the paper’s 1,500 ng per day figure without the September adjustment: the concentration that would deliver 1,500 ng in a 35 mg dose is about 429 ng/mL, roughly 30 times the 14 ng/mL benchmark. A 3.5 mL draw from a 100 ng/mL vial would contain about 350 ng, or 23 percent of that figure. Reaching 1,500 ng would take 15 mL, or 150 mg.

That is a dose-based comparison, not a measure of patient risk. The study did not measure patient exposure, 100 ng/mL was reached only in some cases, and the sources reviewed here do not say how often a vial in clinical use meets the light and storage conditions that produced it. As a product-quality matter, 14 ng/mL stays tied to the labeled dosing.

What labels and packaging say

The authors suggest that container-closure systems that limit light, “such as amber glass vials, may help mitigate nitrosamine formation risks.” The controls in the experiment were light-protected vials, and the abstract reports no head-to-head test of amber against clear glass.

All 15 human-use ketamine injection labels listed on DailyMed on October 30, one of them a 2012 repackager label, tell the user to protect the product from light. None specifies the color of the glass. The 10 mg/mL presentations among them are mostly 20 mL multiple-dose vials holding 200 mg; one is a 10 mL single-dose prefilled syringe. The authors write that parenteral ketamine is “commonly packaged in multi-use clear glass vials for all approved Abbreviated/New Drug Applications,” which the labels neither confirm nor contradict.

Because the rise appeared after the light was removed, an instruction to protect a vial from light does not by itself address exposure that has already happened. That is an inference from the study design, not a result the paper reports. A patent application published May 15 by Fresenius Kabi USA (priority date November 2024) claims a ketamine injection containing a nitrite scavenger, ascorbic acid, to hold N-nitrosoketamine down during storage. It is a filing, not product data, and reports tests of the applicant’s own compositions.

What the study leaves open

The authors call their finding “a post-market safety concern for ketamine drug products stored in clear glass vials,” a statement about product quality under the conditions they tested. The paper does not assess risk to patients at anesthetic or depression doses. The open questions are the ones the chemistry left behind: which nitrosating agent is responsible, whether amber glass prevents the rise, which of the tested products reached 100 ng/mL, and whether FDA will apply its September adjustment to a drug whose use in depression is brief, intermittent and off-label.