Module 3 - Strategic case studies in practice

Water solubility

N- Nitrosamine Abbreviation

Structure

CAS

Log K ow

N- nitrosodi- phenylamine

86-30-6

3.13

0.000177 mol/L

NDPh

N- nitrosodi- ethanolamine

1116-54-7

-1.29*

7.45 mol/L

NDELA

N- nitrosopyrrolidine

NPYR

930-55-2

-0.19

9.99 mol/L

N- nitrosopiperidine

NPIP

100-75-4

0.36

0.67 mol/L

N- nitrosomorpholine

NMOR

59-89-2

-0.44

8.61 mol/L

N- nitrosomethyl- nitroguanidine

NMNG / MNNG

70-25-7

-0.809*

1.29 mol/L*

2.3.3. Potential causes of erroneous analytical results

Depending on the sample matrix, artificial formation of N- nitrosamines during extraction and clean-up is possible when N- nitrosamine precursors (secondary amines and nitrites) are present in relevant quantities in the sample, in particular if acidic solutions are used. Activated carbon materials (used for SPE) should be treated with caution as they may lead to the formation of N- nitrosamines during the processing if sufficient precursors are present in the matrix [Boyd et al. (2011)]. Several inhibitors were used for workup procedures described in the literature, including sulfamic acid, ascorbic acid, and tocopherol [Perera (2006)]. Workup using sodium hydroxide is known to reduce artificial formation of N- nitrosamines, too [Huang et al. (2013)]. Artificial formation of N- nitrosamines should be taken into consideration during analytical validation to exclude any significant impact on the results. However, considering the typically low levels of N- nitrosamines in pharmaceuticals, recovery rates in the range of 80 – 120 % are deemed acceptable. Based on the available information so far, as per the current Questions and Answers document 8 , interference in analytical methods can also be caused by: • presence of trace amounts of nitrosamines in testing materials utilised (e.g. water, airborne sources, plastics products, rubber/elastomeric products)); • in situ formation of nitrosamines (as seen e.g. with ranitidine at high temperature conditions).);

• identification of the specific peak of a certain nitrosamine (e.g. DMF co-eluting with NDMA).

8 https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-information- nitrosamines-marketing-authorisation_en.pdf

EMA/369136/2020

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