Areas of involvement

Chemical drugs/Biological drugs

Cycle

Conventional methods require 20 working days for development and validation, while process route evaluation and software‑based prediction cycles are assessed on an as‑needed basis.

Instrument

Liquid chromatography–mass spectrometry (LC-MS/MS, LC-MS)
High-resolution mass spectrometry (Q-TOF)
Gas chromatography–mass spectrometry (GC-MS/MS, GC-MS)

Regulations or guidelines

ICH M7, USP <1225>, FDA “Control of Nitrosamine Impurities in Human Drugs,” Chinese Pharmacopoeia Volume IV Guideline 9101, Chinese Pharmacopoeia Volume IV General Rule 0431, and others.

1

18

The recommended AI limit of 18 ng/day corresponds to the category-specific TTC for N‑nitrosamine impurities. N‑nitrosamines classified as Category 1 are expected to exhibit high carcinogenic potency; however, the category-specific TTC for N‑nitrosamine impurities is considered to provide adequate protection for patients.

2

100

The recommended AI limit of 100 ng/day is based on two well‑characterized, rigorously tested N‑nitrosamines—N‑nitrosodimethylamine (NDMA) and 4‑(methylnitrosamino)-1‑(3‑pyridyl)-1‑(butanone) (NNK)—for which the corresponding AI limits are 96 ng/day and 100 ng/day, respectively. The carcinogenic potency of N‑nitrosamines classified as Group 2 is expected to be no greater than that of NDMA and NNK.

3

400

Compared with Category 2, N-nitrosamines in this category exhibit lower carcinogenic potency, owing, for example, to the presence of weakly deactivating structural features. The proposed AI limit is set at a fourfold reduction in carcinogenic potency.

4

1500

N-Nitrosamines belonging to Category 4 may be metabolically activated via the α-hydroxylation pathway, but their carcinogenic potency is expected to be low—either because this pathway is sterically or electronically disfavored, or because alternative detoxification pathways are favored. According to ICH M7, the recommended acceptable intake (AI) limit is 1,500 ng/day, set at the threshold of toxicological concern (TTC).

5

1500

Due to steric hindrance or the absence of an α‑hydrogen, N‑nitrosamines belonging to Category 5 are expected not to undergo metabolic activation via α‑hydroxylation, or to form unstable metabolites that do not react with DNA. The recommended acceptable intake (AI) limit is 1,500 ng/day, as established under the Threshold of Toxicological Concern (TTC) framework in ICH M7.