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.

Threshold Values for Impurities (Allowable Maximum Value)

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 -

(Source) Ministry of Health, Labour and Welfare

CASE1Risk 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

CASE2Hi-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.

Hi-sensitivity analysis of API and pharmaceuticals

CASE3Proposal 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.