What began as an urgent, industry-wide safety review of nitrosamine impurities has settled into a permanent feature of pharmaceutical quality management. The call-for-review deadlines have passed — the obligation has not.
Following the detection of nitrosamine impurities in several medicines, the EMA reviewed the issue under Article 5(3) of Regulation (EC) No 726/2004, setting a framework that applies to all marketing authorisation holders, for both chemical and biological products.
The three steps
The framework asked every holder to work through three steps:
- Step 1 — risk evaluation: identify which products are at risk.
- Step 2 — confirmatory testing: test where a risk is identified.
- Step 3 — submit changes: vary the marketing authorisation as needed.
The principal deadlines, after several extensions, have now passed — but the underlying duty to control nitrosamine risk continues for the life of every product.
New methods for setting limits
A significant scientific update introduced refined ways of setting acceptable intakes, including a carcinogenic-potency categorisation approach and an enhanced Ames test protocol. Where a new or updated acceptable intake is established, holders are generally expected to implement corrective and preventive actions within three years.
The current focus: NDSRIs
Attention has shifted from the original referral to routine lifecycle control — and, increasingly, to nitrosamine drug-substance-related impurities (NDSRIs), a more complex class formed from the active substance itself. Guidance from the EMA and partners continues to be updated, so a one-time assessment is not enough.
How PQRA helps
PQRA supports nitrosamine risk assessments, limit-setting strategy, confirmatory testing and the resulting variations.
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