Nitrosamine Impurities: Why This Became Everyone's Problem

In 2018 valsartan products were recalled after NDMA was found in the drug substance. The contamination came from a route change made years earlier, and nobody had been looking for it because nothing required them to.

What followed applies to every marketing authorisation holder, not only the sartans.

Why they are treated separately

Nitrosamines sit in the cohort of concern under ICH M7: compounds so potent that the usual threshold of toxicological concern does not apply and compound-specific limits are required instead.

An acceptable intake for a nitrosamine is measured in nanograms per day, orders of magnitude below an ordinary mutagenic impurity limit. Detecting them requires methods sensitive enough to find that, which is a large part of why the industry was not finding them before.

The three steps FDA asks for

Step 1: risk assessment. Every product. Look at the synthetic route, the recovered solvents and catalysts, the raw materials and their suppliers, the manufacturing equipment, and the formulation and packaging. The classic sources are a secondary or tertiary amine meeting a nitrosating agent, recovered solvents carrying contamination between campaigns, and nitrite in excipients.

Step 2: confirmatory testing. Where the assessment identifies a risk, test with a validated method sensitive to the limit.

Step 3: report and act. Where a nitrosamine is found above the acceptable intake, submit changes to the application and take action on distributed product, which can include a field alert and a recall.

The step people skip is the first. A documented risk assessment concluding there is no risk is the deliverable, and its absence is the finding.

NDSRIs are the harder version

Nitrosamine drug substance-related impurities form when the drug substance molecule itself is nitrosated. The nitrosamine is therefore unique to your product, which means no established acceptable intake exists and no method is sitting on a shelf.

FDA's approach uses a carcinogenic potency categorisation to assign a recommended acceptable intake based on structural features, so that a sponsor is not required to run a carcinogenicity study for every NDSRI.

Any drug substance with a secondary or tertiary amine is a candidate, which is a large fraction of small molecules.

The part that keeps recurring

This is not a one-off exercise. A risk assessment reflects the route, the suppliers and the excipients at the time you did it. Change any of them and the assessment is stale, which makes nitrosamines a standing input to change control rather than a project that finished in 2021.