The New General Rules of Pharmacopoeia for Nitrosamines USP <1469> will be officially implemented on December 1st

The United States Pharmacopoeia General Chapter <1469> NITROSAMINE IMPURITIES (hereinafter referred to as the General Chapter) was formally implemented on December 1, 2021

a) Establish control limits for nitrosamines to ensure the reduction or elimination of such impurities;

b) Provides analytical methods and method validation requirements for monitoring nitrosamine levels

Nitrosamine impurities belong to highly toxic genotoxic impurities, which can be introduced into pharmaceutical products or produced as impurities in a variety of ways

The general rules apply to the evaluation of seven nitrosamines, including: N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), N -Nitrosoethylisopropylamine (NEIPA), N-nitrosodibutylamine (NDBA), N-nitrosomethylaniline (NMPA) and N-nitrosomethylaminobutyric acid (NMBA)

Based on experience or literature reports, the general rules summarize the main sources of nitrosamines:

Under certain conditions and in the presence of certain reagents, solvents, raw materials and processing aids, the processing of bulk drugs is carried out

The drug itself may degrade under certain conditions to form nitrosamines (such as ranitidine)

Degradation of solvents that cause the formation of dialkylamines (such as dimethylformamide [DMF])

Impurities in raw materials, solvents (including recovery solvents), reagents or catalysts

Impurities in materials and intermediates, reagents and solvents used to prepare starting materials or intermediates

Impurities in water, auxiliary materials or processing aids used in the production of finished products

Under certain reaction conditions and in the presence of the necessary precursors required to form nitrosamines, in the pharmaceutical manufacturing process

The impurities in the closed system of the finished drug container may include impurities that can form nitrosamines, especially those related to amine-containing materials and potential sources of nitrosating agents (such as nitrite, nitrocellulose)

Consistent with the FDA and other officials’ control thinking on nitrosamine impurities, the general rules require a risk assessment of potential nitrosamine impurities, and full consideration of all potential sources of nitrosamine introduction, including APIs, excipients, water, and solvents , Manufacturing process, packaging composition and formulation stability

The general rule states that the seven known nitrosamine impurities have potential and established toxicity and no therapeutic value

If multiple nitrosamine impurities are detected in a preparation or drug substance at the same time, and the total nitrosamine level calculated by the maximum daily dose (MDD) exceeds 26.

As the daily allowable exposure of nitrosamine impurities is very low, only nanograms, it is required to use particularly sensitive analytical methods for the detection of nitrosamines

Proper sample preparation is critical in the analysis of trace impurities
.
Improper sample preparation procedures may artificially cause the generation or loss of nitrosamine impurities
.
For nitrosamine impurities analytical method verification requirements, if it is a quantitative analysis method, the verification recommendations include scope, accuracy, repeatability, intermediate precision and limit of quantification
.
If it is a limit test, it should include specificity, recovery rate, detectability and solution stability
.

In order to help suppliers better detect nitrosamine impurities, the General Rules proposes four quantitative analysis methods (see 8.
1 Quantitative Procedures)
.
For these four quantitative analysis methods, only pharmacopoeial methods need to be confirmed
.

For limit testing, this general rule does not provide a method, only a sample preparation procedure (see 8.
2 Limit Test Procedures)
.
For more details, see USP <1469> NITROSAMINE IMPURITIES
.