2. CDMO Services
  3. Evaluation of nitorosamine impurities

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.

Structural formula of NDMA Structural formula of NDEA
Ingredient Maximum Daily Value
NDMA Limit Value
(in API)
NDEA Limit Value
(in API)
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

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



Dissolution Tester

Dissolution Tester

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.

High-sensitivity analysis of drug substances and pharmaceuticals

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.

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