nitrosamines-main

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.

 

Video - Nitrosamine Recalls and Pharma Quality Control: Current Analytical Trends

FDA Combined Direct Injection GC-MS/MS Method

Determination of Nitrosamine Impurities in Sartan Drug Products by GC-MS/MS Method

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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

Ultra-Sensitive Dynamic Headspace GC-MS/MS Method for Trace Level Quantitation of Nitrosamines in Deferiprone API

Ultra-Sensitive Dynamic Headspace GC-MS/MS Method for Trace Level Quantitation of Nitrosamines in Deferiprone API

The presence of Nitrosamine (NSA) as impurity has been detected recently in several drug substances and drug products. In 2018, N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) were detected in some Valsartan Active Pharmaceutical Ingredients (API) and Finished Dosage Form (FDF). This led to an ongoing investigation to check presence of NSA in pharmaceutical substances and products. One such drug is Metformin; it is used to control high blood sugar observed in patients suffering from type 2 diabetes

Quantitation of 5 NSA in Metformin API as per proposed USP General Chapter <1469> Procedure-4 by GC-MS/MS

Quantitation of 5 NSA in Metformin API as per proposed USP General Chapter <1469> Procedure-4 by GC-MS/MS

Regulatory bodies related to pharmaceutical industry have extensively investigated the presence of genotoxic impurities, called Nitrosamines (NSA), in many drugs. Deferiprone (Fig. 1) is an iron chelator used to treat patients with transfusional iron overload caused by halassemia syndromes. Hence it is imperative to make Deferiprone drug available with safe levels of NSA.

Trace Level Quantitation of 6 Nitrosamines in Metformin API by Dynamic Headspace GC-MS/MS

Trace Level Quantitation of 6 Nitrosamines in Metformin API by Dynamic Headspace GC-MS/MS PDF

Regulatory bodies related to pharmaceutical industry had extensively investigated the presence of genotoxic impurities, called Nitrosamines (NSA), in many drugs. Metformin (Figure 1) is a prescription drug used to control high blood sugar in patients with type 2 diabetes. Patients should continue taking Metformin to keep their diabetes under control and hence it is imperative to make Metformin drug available with safe levels of NSA.

Quantitation of 5 Nitrosamines in Metformin API and Formulation by HS-GCMS/MS

Quantitation of 5 Nitrosamines in Metformin API and Formulation by HS-GCMS/MS PDF

The United States Food and Drug Administration (USFDA) has extensively investigated the presence of genotoxic impurities, called Nitrosamines (NSA) in many Active Pharmaceutical Ingredients (API) & Finished Dosage Formulations (FDF). Several drug products including Angiotensin II Receptor Blockers (ARB) and Ranitidine, have
been found to contain small amounts of NSA such as N-nitrosodimethylamine (NDMA). There has been an ongoing investigation to further check the presence of NSA in other drug products as well, such as Metformin. Metformin is a prescription drug used to control high blood sugar in patients with type 2 diabetes. Patients should
continue taking Metformin to keep their diabetes under control hence, it is imperative to make Metformin drug available with safe levels of NSA.

Qualitative Analysis Using HS-GC-FID/MS when Testing for Residual Solvents in Pharmaceuticals - USP467: Water-Insoluble Samples

Qualitative Analysis Using HS-GC-FID/MS when Testing for Residual Solvents in Pharmaceuticals PDF

The United States Pharmacopeia General Chapter <467> Residual Solvents describes tests for residual solvents in pharmaceuticals that are mainly performed by headspace gas chromatography coupled with flame ionization detection (HS-GC-FID). Residual solvents in pharmaceuticals are strictly controlled based on an evaluation of the risk they pose to human health and classified as Class 1 ,2, or 3 solvents. Testing for these residual solvents in pharmaceuticals requires highly sensitive analytical methods. Qualitative analysis by GC-FID normally requires the use of standard reference solvents, and accurate solvent identification can be difficult when peaks overlap. However, gas chromatography-mass spectrometry (GC-MS) can also provide qualitative information about sample components based on mass spectra. Unknown peaks or peaks that are difficult to distinguish due to their proximity to other analyte peaks can be identified using mass spectrometry, or mass spectrometry can be used to investigate causes of contamination and other issues.

This article presents results from using an HS-20NX headspace sampler and GCMS-QP2020 NX to analyze water-insoluble samples of Class 1 and Class 2 solvents.

Analysis of N-Nitrosodimethylamine (NDMA) & N-Nitrosodiethylamine (NDEA) in pharmaceutical substance by HSGCMS/MS

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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

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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.

LC-MS/MS Method

Simultaneous Analysis of 10 Nitrosamines in an Active Pharmaceutical Ingredient Using a Triple Quadrupole Mass Spectrometer

Simultaneous Analysis of 10 Nitrosamines in an Active Pharmaceutical Ingredient Using a Triple Quadrupole Mass Spectrometer

Nitrosamines can be highly genotoxic, and the nitrosamines NDMA and NDEA are classified as group 2A carcinogens (probably carcinogenic to humans) by the International Agency for Research on Cancer (IARC). ICHM7 provides guidance for the assessment and control of mutagenic impurities in drug products and describes N-nitroso compounds as high-potency carcinogens (cohort of concern) that must be controlled at or below compound-specific acceptable limits. Acceptable intake limits are also being established by regulatory agencies in various countries for an increasing number of nitrosamines, so there is a demand for analysis methods that can quantitate a larger number of nitrosamine compounds.

This article presents a case example in which the LCMS-8060NX triple quadrupole mass spectrometer was used to perform a simultaneous analysis of ten components including nine nitrosamines regulated by the U.S. Food and Drug Association (FDA) and European Medicines Agency (EMA), and N-Nitrosodi-n-propylamine (NDPA) regulated by the European Pharmacopoeia (Ph.Eur.) Commission.

Quantitation of 8 Nitrosamines in 12 different solvents by LC-MS/MS system

Quantitation of 8 Nitrosamines in 12 different solvents by LC-MS/MS system PDF

In June 2018, the American Food and Drug Administration (FDA) was informed of the presence of an impurity identified as N-nitrosodimethylamine (NDMA) in the ARB valsartan. Through investigation, the Agency determined that numerous valsartan and a few other ARB drug products from different manufacturers contained unacceptable levels of nitrosamines. The drug product manufacturers voluntarily recalled the affected batches of these drug products, which led to a drug shortage in some of the affected products. In addition, the FDA evaluated processes that use common amines in API synthesis and learned that common synthetic pathways could also introduce other types of nitrosamine impurities besides NDMA.

Quantitation of 6 Nitrosamines in 5 Sartans by LC-MS/MS system as per the proposed USP General Chapter <1469>

Quantitation of 6 Nitrosamines in 5 Sartans by LC-MS/MS system as per the proposed USP General Chapter <1469> PDF

The Drug Regulatory Authorities first noticed the presence of the nitrosamine (NSA) impurity, NNitrosodimethylamine (NDMA) in products containing valsartan in July 2018. Valsartan is an Angiotensin II Receptor Blocker (ARB) and belongs to a family of analogue compounds commonly referred to as the Sartans. Further, a few other nitrosamines were subsequently detected in other drug substances belonging to the Sartan family, other Active Pharmaceutical Ingredients (API’s), and Finished Pharmaceutical Products (FPP). These included N-nitroso-dimethylamine (NDMA), N-nitroso-N-methyl-4-aminobutyric acid (NMBA), N-nitrosodiethylamine (NDEA), N-ethyl-N-nitroso-isopropylamine (NEIPA), N-nitroso-diisopropylamine (NDIPA) and Nnitroso- di-n-butylamine (NDBA).

Quantitation of NDMA, NMBA, NDEA, NEIPA, NDPA, NDIPA, NMPA and NDBA in 12 different solvents by LC-MS/MS system

Quantitation of NDMA, NMBA, NDEA, NEIPA, NDPA, NDIPA, NMPA and NDBA in 12 different solvents by LC-MS/MS system

Nitrosamines, refer to any molecule containing the nitroso functional group. These molecules are of concern because nitrosamine impurities are probable human carcinogens. Although they are also present in some foods and drinking water supplies, their presence in medicines is nonetheless considered unacceptable. Recovered materials such as solvents, reagents, and catalysts may pose a risk of nitrosamine impurities due to the presence of residual amines (such as trimethylamine or diisopropylethylamine). If the recovery process involves a quenching step (i.e., nitrous acid used to decompose residual azide), nitrosamines could form during solvent recovery. These nitrosamines may be entrained if they have boiling points or solubility properties similar to the recovered materials, depending on how recovery and subsequent purification takes place (e.g., aqueous washes or distillation). This further increases the risk of contamination in material recovery. For these reasons, some drug products using APIs manufactured by certain “low” risk processes were found to be contaminated .

Traditionally the GCMS is a preferred and simple technique to determine the nitrosamines in solvents. However, NMBA can only be detected by the LCMS technique. In this poster, an LCMS method has been developed for the simultaneous determination of 8 nitrosamines in 12 different solvents.

Quantitation of 6 Nitrosamines in Losartan API by LC-MS/MS system as per the proposed USP General Chapter <1469>

Quantitation of 6 Nitrosamines in Losartan API by LC-MS/MS system as per the proposed USP General Chapter <1469>

Chemicals such as methanesulfonic acid (mesylate), benzenesulfonic acid (besilate), and p-toluenesulfonic acid (tosylate) are used in the process of synthesizing active pharmaceutical ingredients. These compounds are likely to generate sulfonic acid ester as a reaction byproduct. These compounds are known as potential genotoxic impurities (PGI) and are a significant cause for concern among pharmaceutical manufacturers. This article introduces the analysis of sulfonic acid esters utilizing the GCMS-QP2010 Ultra.

Detection and Quantitation of Nitrosamine Impurities in Drug Substances by LC-HRMS on LCMS-9030

Detection and Quantitation of Nitrosamine Impurities in Drug Substances by LC-HRMS on LCMS-9030

Most concerned nitrosamines (see Table 1) are small and polar compounds, which may be interfered by co-eluting species present in the testing samples in LC-MS/MS and LC-HRMS analysis. High-resolution MS methods are capable of distinguishing co-eluting interferences. An example was reported by Yang et al [4] recently, which revealed that the presence of N,N-dimethylformamide (DMF) may affect the quantitation results of NDMA in metformin products if the mass accuracy and mass resolution are not sufficient. To date, both dedicated methods for NDMA only and simultaneous analysis method for more NSA are reported and used. In this application note, an orthogonal method for detection and quantitation of up to eight nitrosamines as listed in Table 1 by LC-HRMS on LCMS-9030 is described

Got DMF? Chromatographic separation and identification of NDMA and DMF using LCMS-9030

Got DMF? Chromatographic separation and identification of NDMA and DMF using LCMS-9030 pdf

Chromatographic separation and identification of dimethylformamide (DMF) and N-nitroso-dimethylamine (NDMA) was performed to prevent overestimation of NDMA when DMF interference is present. This method can easily be implemented for the impurity evaluation of active pharmaceutical ingredients (API), intermediates, and final drug products irrespective of triple quadrupole or high-resolution mass spectrometers.

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