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Evaluation of nitorosamine impurities
As for nitrosamine impurities in APIs and drug products, we will provide overall support from assessment of contamination risks and establishment of analytical methods to actual testing.
In June of 2018 in Spain, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) which are carcinogens were detected in sartan type drugs. Also, in September of 2019, NDMA was detected in ranitidine type drugs in the USA.
The Ministry of Health, Labour and Welfare has directed the manufacturing and sales entities to analyze the API and its formulation using a method with adequate detection level and if the analysis result cannot deny the possibility of exceeding the provisional standard, then the information must be shared with medical institutions etc. and recall action must be taken.
Shionogi Pharma, being a CDMO, can conduct a very thorough analyses covering starting materials, intermediates, API and drug products and their respective processes.
| Ingredient | Maximum Daily Value （mg） |
NDMA Limit Value (in API) （ppm） |
NDEA Limit Value (in API) （ppm） |
|---|---|---|---|
| Valsartan | 160 | 0.599 | 0.166 |
| Irbesartan | 200 | 0.479 | 0.133 |
| Olmesartan | 40 | 2.39 | 0.663 |
| Losartan | 100 | 0.959 | 0.265 |
| Ranitidine | 300 | 0.32 | ― |
| Nizatidine | 300 | 0.32 | ― |
Risk Evaluation
Our process chemist who has specialized knowledge conduct a comprehensive evaluation of the nitrosamine contamination risks, including starting materials and solvents impurity information and bi-production risk during manufacturing processes.
Nitrosamine synthesis
risks during API processes
Contamination risks to
products and raw material
Contamination risks from
other products
UHPLC
Dissolution Tester
Hi-sensitivity analysis of API and pharmaceuticals
In order to test individual pharmaceuticals, method validation is required for each. We also undertake appropriate method validation in consideration of the characteristics of the target pharmaceutical.
Proposal for control strategy
Identify and establish threshold values for nitrosamines
Decide control strategy and determine measurement points
Establish test method and conduct experiments and measurements
Evaluate and provide action plans for control strategy
Develop high-sensitivity analysis method following the ICH guidelines and take measurements
Besides nitrosamines, we can develop high-sensitivity test methods for other impurities such as elemental impurities and mutagenic impurities following the ICH guidelines. Based on a wealth of technology and experience cultivated through CMC development research, we handle all through analysis method investigation, method validation, and acquisition of actual values.
