In 2018, probable human carcinogens, NDMA and NDEA, were detected in valsartan and irbesartan manufactured in China and India for global export. These events triggered subsequent cases of nitrosamine detection in other drugs, namely ranitidine and metformin. The presence of nitrosamines in drugs as unintended by-products of production is known, owing to raw materials including sodium nitrite, dimethylformamide, and triethylamine. NDMA and NDEA have been classified into Group 2A (probably carcinogenic to humans) according to the International Agency for Research on Cancer (IARC) carcinogenicity classification. Applying the concept of the ICH M7 guideline to the management of carcinogenic impurities, NDMA and NDEA are classified as Class 1 in ICH M7, and should be managed at or below the permissible levels specific to the compound.
In response to the market need, the FDA provided guidance methods for headspace-GC-MS and direct injection GC-MS for the testing of NDMA and NDEA in sartan drugs. As the list of identified nitrosamines for monitoring has expanded, additional compounds were added to the guidance methods for direct injection GC-MS, per the FDA OTR Combined Direct Injection method.
As investigation has expanded to other non-sartan drugs, the need for liquid chromatography mass spectrometry has become clear, due to potential lability and degradation issues. In 2020 the FDA published guidelines FY20-106-DPA-S (Method 106) and FY20-058-DPA-S (Method 058) for triple quadrupole LC-MS and high-resolution LC-MS, respectively.
Find out more below how Shimadzu can meet your nitrosamines analysis needs, from routine lot and batch release testing to discovery for today and the future.
FDA Combined Direct Injection GC-MS/MS Method
Determination of Nitrosamine Impurities in Sartan Drug Products by GC-MS/MS Method
A direct liquid injection gas chromatograph/ tandem mass spectrometry (GC-MS/MS) method that provides sensitive detection and quantitation of seven nitrosamines in sartan drug products was developed with reference to a GC-MS/MS method published by FDA. Out of the targeted nitrosamines, three are listed by FDA as nitrosamine impurities in sartan drug substances and products. They are N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA) and N-Nitrosodi-n-butylamine (NDBA). The method presented herein fulfilled FDA requirements of system suitability for linearity, S/N and peak area ratio %RSD (n=6). Calibration curves of all three FDA listed nitrosamines displayed R² ≥ 0.999, the S/N of the 5.0 ng/ml linearity standard were ≥ 10 and peak area ratio %RSD (n=6) at 5.0 ng/ml and 10 ng/ml is between 1.74% and 4.37%.
FDA Headspace GC-MS and GC-MS/MS Method
Analysis of N-Nitrosodimethylamine (NDMA) & N-Nitrosodiethylamine (NDEA) in pharmaceutical substance by HSGCMS/MS
N-Nitrosodimethylamine (NDMA) & NNitrosodiethylamine (NDEA) are simplest of Dialkylnitrosamines. They are continued to be released as a by-product and contaminant from various industries and from municipal wastewater treatment plants. Major releases of NDMA, NDEA have been from the manufacture of pesticides, rubber tires, alkyl amines, and dyes. Similarly, these compounds are produced as a byproduct in the manufacturing of Active Pharmaceutical Ingredients (API’s). These compounds are classified as a Group 2A carcinogen (probable human carcinogen) by the World Health Organization. Recently some drug products were discovered to have been contaminated with NDMA & NDEA. It is believed to have been introduced into the finished products as a result of the manufacturing process of the drug substance. This contamination, was far exceeding the regulatory exposure limits specific to drug products. Consequently, medical agencies across Europe as well as the US Food and Drug Administration (USFDA) withdrew all affected drug products from the market. Hence it is very essential to have a sensitive, specific, accurate, reliable & robust method by using suitable analytical technique. In this experiment the In this experiment the pharmaceutical API’s namely Valsartan, Losartan & Olmesartan-Medoximil prone to contamination with NDMA and NDEA are analyzed by using developed HSGCMS/MS method.
Analysis of N-Nitrosodimethylamine (NDMA) & N-Nitrosodiethylamine (NDEA) in pharmaceutical substance by HSGCMS
N-Nitrosodimethylamine (NDMA) & Nnitrosodiethylamine (NDEA) are simplest of Dialkylnitrosamines. These compounds are classified as a Group 2A carcinogen (probable human carcinogen) by the World Health Organization. In this experiment the pharmaceutical API’s namely Valsartan,Losartan & Olmesartan-Medoximil prone to contamination with NDMA and NDEA is analyzed by referring USFDA OTR HS-GCMS method.