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Published on: September 25, 2017
Investigation into the genotoxic impurity, 1-methyl-4-nitrosopiperazine, in rifampicin
Ye Tian1, Xiaosha Tao1, Yuanyuan Feng1
1National Institutes for Food and Drug Control, Beijing 102600, China.
Abstract:
This study assessed the presence of the genotoxic impurity 1-methyl-4-nitrosopiperazine (MNP) in 27 batches of rifampicin capsules obtained from 11 manufacturers in China. While they were below the temporary limit of 5 ppm set by the US Food and Drug Administration, the observed levels (0.33-2.36 ppm) exceeded the acceptable threshold of 0.16 ppm. Building upon preliminary findings and degradation experiments, we concluded that MNP is a by-product of the oxidative degradation of rifampicin or is introduced via oxidation or nitrosation during the synthesis process involving 1-methyl-4-aminopiperazine. The pathways of MNP formation were confirmed in this study. Furthermore, we observed that the addition of antioxidants, sealed storage, and selection of dominant crystal forms can aid in controlling MNP levels.
Insights
Genotoxic impurity 1-methyl-4-nitrosopiperazine (MNP) in rifampicin capsules exceeded acceptable levels, despite being below FDA temporary limits. MNP formation pathways were identified, with strategies like antioxidants and sealed storage shown to control levels.
Area of Science:
- Pharmaceutical Chemistry
- Drug Impurity Analysis
- Chemical Process Development
Background:
- Genotoxic impurities in pharmaceuticals pose significant safety risks.
- Rifampicin is a critical antibiotic, and its impurity profile requires stringent control.
- Previous studies suggested potential genotoxic impurities in rifampicin, necessitating further investigation.
Purpose of the Study:
- To quantify 1-methyl-4-nitrosopiperazine (MNP) in rifampicin capsules from Chinese manufacturers.
- To elucidate the formation pathways of MNP during rifampicin synthesis and degradation.
- To identify strategies for controlling MNP levels in rifampicin drug products.
Main Methods:
- Analysis of 27 rifampicin capsule batches from 11 manufacturers using validated analytical techniques.
- Degradation experiments to study MNP formation under various conditions.
- Confirmation of MNP formation pathways through chemical synthesis and analysis.
Main Results:
- MNP was detected in all analyzed rifampicin batches, with levels ranging from 0.33-2.36 ppm.
- Observed MNP levels exceeded the acceptable threshold of 0.16 ppm, although below the FDA's temporary limit of 5 ppm.
- MNP formation was confirmed as a result of rifampicin oxidative degradation or synthesis-related nitrosation/oxidation of 1-methyl-4-aminopiperazine.
Conclusions:
- MNP is a common genotoxic impurity in rifampicin capsules originating from China.
- Understanding MNP formation pathways is crucial for risk assessment and control.
- Implementing antioxidants, sealed storage, and controlling crystal forms can effectively mitigate MNP contamination.
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