How a carcinogen in blood pressure pills changed generic drug testing

In June 2018, pharmacies paid an average of about 9.7 cents for a 160 mg valsartan tablet, according to the federal government's National Average Drug Acquisition Cost survey¹⁰. By December the average was about 37 cents, nearly four times higher. In between, on July 13, 2018, FDA announced a recall of valsartan tablets¹ that might contain N-nitrosodimethylamine (NDMA), an impurity classified as a probable human carcinogen.

That price jump, visible in GxRadar's monthly NADAC series and traced in the valsartan recall and what it did to prices, was the first market signal of a problem that has not gone away. Valsartan was followed by other blood pressure drugs, then the acid reducer ranitidine, then metformin and a string of others. In openFDA's drug enforcement data⁹, GxRadar counted 493 recall records from 2018 through late October 2026 whose stated reason mentions a nitrosamine.

Those records fall into two waves with different chemistry. The first, from 2018 to 2020, involved small, simple nitrosamines such as NDMA that turned up as contaminants. The second, which built through 2024 and 2025, involves nitrosamines formed from the drug molecule itself. FDA's response to each wave produced the system of daily intake limits that now governs how generic makers test their products.

GxRadar analysis of openFDA drug enforcement reports⁹ by report year, matched on the recall reason text. Each record is one product entry, so a single recall covering several strengths can produce several records. Counts for every recall reason are on the GxRadar recalls page.

How NDMA got into blood pressure pills

FDA's laboratory staff wrote at the time that the NDMA was believed to have been introduced¹ into finished valsartan products as a result of the manufacturing process of the drug substance. The agency's later account, on its running page on the ARB recalls², says these impurities may be generated when specific chemicals and reaction conditions are present in the manufacturing process of the active pharmaceutical ingredient (API), and may also result from the reuse of materials such as solvents.

Testing spread across the angiotensin II receptor blocker (ARB) class. Investigators found N-nitrosodiethylamine (NDEA) in valsartan, losartan and irbesartan, and N-nitroso-N-methyl-4-aminobutyric acid (NMBA) in losartan. FDA's page notes that some combination pills pairing valsartan or losartan with amlodipine or hydrochlorothiazide were recalled as well², while products containing only amlodipine or hydrochlorothiazide were not.

One problem became many recalls because of how generic supply chains are built. A single API maker often sells to several finished-dose manufacturers, so one contaminated ingredient surfaced under many different generic labels. GxRadar's piece on where drug ingredients come from covers that structure.

FDA set interim daily limits and developed screening methods, starting with a gas chromatography-mass spectrometry headspace method¹ for NDMA in valsartan.

FDA sets these limits at a daily exposure that approximates a 1 in 100,000 cancer risk after 70 years, according to its 2024 nitrosamine guidance¹¹. Limits can change as data come in; FDA's current table lists NDMA and NDEA unchanged but puts NMBA in a lower-potency category at 1,500 ng/day. FDA scientists also tried to put the actual exposure in context. They estimated² that if 8,000 people took the highest daily valsartan dose (320 mg) containing NDMA for four years, there might be one additional cancer case over their lifetimes.

FDA's broader position, set out on its nitrosamine information page⁴, is that nitrosamines are common in water and foods, including cured and grilled meats, dairy products and vegetables, and that "everyone is exposed to some level." The agency says a person taking a drug at or below its limits every day for 70 years is not expected to have an increased cancer risk.

Ranitidine, a drug that made its own impurity

Ranitidine, sold both by prescription and over the counter, posed a different problem. In the summer of 2019 FDA became aware of independent laboratory testing that found NDMA in the drug, and it warned the public that September³. Further testing showed the impurity in some ranitidine products increased over time and when stored above room temperature.

Because the impurity kept forming after the product left the factory, FDA concluded consumers could be exposed to unacceptable levels. On April 1, 2020, the agency asked manufacturers to withdraw³ all prescription and over-the-counter ranitidine from the US market immediately.

Ranitidine accounts for 88 of the nitrosamine recall records in GxRadar's count, the most of any drug. Losartan has 72, valsartan 51 and metformin 46, most of the metformin records from the 2020 extended-release recalls. Smaller clusters in the enforcement data⁹ involve irbesartan (23), varenicline (seven), rifampin (five) and nizatidine, a close relative of ranitidine (three). Each had its own chemistry, and FDA handled them product by product.

Turning case-by-case recalls into a standing rule

FDA's guidance Control of Nitrosamine Impurities in Human Drugs⁵ was first issued in 2020, revised in February 2021 and revised again in September 2024. It asks API and finished-drug manufacturers to assess their processes for nitrosamine risk, test where risk exists, and change processes or specifications when levels exceed the limits.

FDA's investigators were told to look for it as well. In 2022 FDA revised Compliance Program 7356.002⁸, which instructs investigators on drug manufacturing inspections, and added control of nitrosamine impurities to what they evaluate. GxRadar's explainer on CGMP rules describes how that program fits with the rest of manufacturing oversight.

FDA's list of causes⁴ is broad, covering the manufacturing process, the chemical structure of the drug itself, and storage or packaging conditions. Nitrosamines can also form from foods and drugs as they are processed in the body.

When the drug molecule is the source

A different origin explains the second wave in the recall table. Nitrosamine drug substance-related impurities (NDSRIs) are nitrosamines that share structural features with the active ingredient. Many form when the drug molecule reacts with trace nitrites, for example from excipients. Because each one is unique to its parent drug, most lack compound-specific cancer data.

On Aug. 4, 2023, FDA issued Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities⁶. It introduced a Carcinogenic Potency Categorization Approach, which sorts an NDSRI into one of five categories based on structural features and assigns a limit to each.

Once manufacturers started looking, the recall record filled with these compounds. None of the 166 nitrosamine records dated 2024 through October 2026 in openFDA's enforcement data⁹ names NDMA, NDEA or NMBA. They cite compounds such as N-nitroso-duloxetine in duloxetine capsules and N-nitroso desipramine in desipramine tablets, usually described as exceeding FDA's recommended or interim limit. Chlorpromazine, atomoxetine, prazosin and cinacalcet products appear in the same period.

The August 2025 deadline

FDA recommended that manufacturers finish confirmatory testing of at-risk products and submit any needed changes by Aug. 1, 2025. On June 23, 2025, the agency updated that timeline⁷ on its CDER acceptable intake page. Companies that could not finish changes by the date were asked instead to file a progress report by Aug. 1, 2025, as an "NDSRI Update" in the annual report for the application. The report covers what was tested, what was found, the root cause if known, mitigation attempts and an estimated completion date. Makers of products without an approved application, such as OTC monograph drugs, were asked to retain equivalent documentation⁷ so it is available on request.

An NDSRI finding can end in reformulation, tighter specifications, a recall of specific lots, or a temporary gap in supply while a fix is made. FDA's 2024 guidance⁵ includes recommendations for manufacturers that decide to reformulate, which lets a generic change its recipe without starting approval over. Any resulting supply gaps show up on FDA's list, tracked on the GxRadar shortages page, and recalls follow the process described in how drug recalls work.

FDA's message to patients has stayed consistent. "Patients taking prescription medications with potential nitrosamine impurities should not stop taking their medications," the agency says on its information page⁴, and it directs them to talk with their health care professional. For the ARBs specifically, FDA's recall page² tells patients to keep taking their current medicine until a doctor or pharmacist provides a replacement or a different treatment option. A pharmacist can check whether a specific lot was part of a recall.

The intake limits keep moving. FDA maintains its table of recommended limits for individual NDSRIs on the CDER acceptable intake page⁷, and the most recent revision, dated Sept. 24, 2026, added adjustment factors for drugs taken for less than a lifetime.