Nitrosamine Impurities in Drug Substances and Drug Products (original) (raw)
Related papers
NAVIGATING NITROSAMINES: ORIGIN, DETECTING, ANALYSING AND REGULATING IMPURITIES IN PHARMACEUTICALS
International Journal of Applied Pharmaceutics, 2024
N-nitrosamines are carcinogenic impurities mostly found in groundwater, treated water, foods, beverages, and consumer products like processed meats, alcoholic beverages, cosmetics, and cigarette smoke. The recent discovery of N-nitrosamines in pharmaceutical products and subsequent recalls pose a significant health risk to patients. Nitrosamine impurities in drug products have appeared as a critical concern in pharmaceuticals prompting extensive scrutiny from regulatory agencies and stakeholders. To avoid carcinogenic and mutagenic effects in patients relying on these medications, authorities have established specific guidelines in risk assessment scenarios and proposed control acceptable limits for nitrosamine impurities in pharmaceuticals. This review provides an information on historical background of Nitrosamine impurities; its carcinogenic effect; the sources and formation of impurities; associated risks of nitrosamines in drug formulations; different analytical techniques for nitrosamine detection. It also gives an understanding of the general Quality Risk management (QRM) process, techniques for measuring nitrosamine impurities with control strategies as directed by the regulatory authorities and how to avoid them in pharmaceutical drug products. A brief review on recalls of drug classes including angiotensin II receptor antagonists, histamine-2 receptor antagonists, antimicrobial agents, and antidiabetic drugs by regulatory bodies due to its potential harm produced by nitrosamine have been discussed. Moreover, the regulatory landscape governing nitrosamine impurities are explored, encompassing recent guidelines from major regulatory bodies such as the United States Food and Drug Administration (USFDA), European Medicines Agency (EMA) and Health Canada (HC) in controlling/eliminating the nitrosamine impurities in pharmaceuticals.
Presence of nitrosamine impurities in medicinal products
Archives of Industrial Hygiene and Toxicology, 2021
In 2018, some sartan medicinal products were reported to be contaminated with nitrosamine compounds, which are potent mutagenic carcinogens. Two nitrosamines received particular attention: N -nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA). These have since been confirmed in different types of medicinal products, including ranitidine and metformin. Consequently, the European Medicines Agency (EMA) started an investigation into the cause of contamination and an assessment of the risk to patients taking contaminated medicinal products. The main source of contamination were changes in production, which involves combinations of amines and nitrogen compounds and the use of specific catalysts and reagents. Withdrawals of medicinal products that took place in Croatia did not lead to a shortage of sartan- or metformin-containing medicines. Moreover, ranitidine had been preventively withdrawn all over the EU, including Croatia, creating shortages at the time, but was subsequentl...
A proficient GC-MS/MSS method was developed for determination of N-Nitrosodimethylamine, N-Nitrosodiethylamine, N-Nitrosodiisopropylamine, N-Nitrosoisopropylethylamine, N-Nitrosodibutylamine impurities in Telmisartan Drug Substance using column Rtx-5 Amine (30m length X 0.32mm diameter) 1.5µm film thickness, Part No.: 12369, Make: Restek. Helium is used as Carrier gas at with Linear velocity of 44.3 cm/sec. The proposed method was validated for System suitability, Specificity, Linearity, LOD and LOQ, Method precision, Intermediate precision and Recovery. All the parameters were found within the acceptable limits. Linearity in the range of LOQ to 150% for each impurity. The established methodology was commercially useful, specific, accurate, precise and suitable for the analysis of Nitrosamines impurities in Telmisartan drug substance Keywords: Gas chromatography with mass spectrometry (GC-MS/MS), Telmisartan drug substance, Nitrosamine impurities, ICH guideline and Method Validation.
American Journal of Analytical Chemistry, 2021
Nitrosamine impurities are potentially genotoxic which are considered under cohort of concern as per ICH M7 guidelines and need to be controlled at trace levels during quantification in drug substances and drug products for safe human consumption. Recent regulatory requirements also suggest the need to have highly sensitive analytical methods for the accurate quantification of Nitrosamine impurities. In this paper we have presented simple, rapid and ultra-sensitive LC-MS/MS method for six potential genotoxic nitrosamine impurities: N-Nitroso dimethyl amine (NDMA), N-Nitroso diethyl amine (NDEA), N-Nitroso Ethyl Iso propylamine (NEIPA), N-Nitroso-Nmethyl-4-aminobutyric acid (NMBA) N-Nitroso diisopropylamino (NDIPA) and N-Nitroso dibutyl amine (NDBA) with a LOQ of 0.004 ppm. Chromatographic separation is achieved using Zorbax SB C18 150 × 3.0 mm, 3.5 µ column with 0.1% formic acid in water as mobile phase A and 0.1% formic acid in methanol as mobile phase B at a flow rate of 0.3 ml/min using gradient mode of elution at a total run time of 18 minutes. Six nitrosamine impurities are successfully ionized and quantified in positive mode of atmospheric pressure chemical ionization (APCI) using multiple reaction monitoring (MRM). Method validation is performed as per ICH guidelines evaluating the limit of quantification and detection and found to give good S/N ratios with good linearity range of 0.002-2 ppm with regression coefficient >0.99 for all the six nitrosamine impurities. Method recoveries are established using three-step sample preparation protocol and are found to be satisfactory within 80%-120%. The method can be used routinely applied for the detection of Nitrosamines in Telmisartan at a concentration of 1.5 ng/ml (0.03 ppm with respect to telmisartan concentration of 50 mg/ml).
Innovare Academic Sciences Pvt Ltd, 2020
Objective: A simple and sensitive method development and validation for the simultaneous determination of the N-nitrosamine dimethylamine (NDMA) and N Nitrosamine diethylamine (NDEA) in Olmesartan medoxomil (OLM) API and formulations by a tandem mass spectrometer (GC-MS/MS). Methods: Gas chromatography with a programmed oven temperature controller, Elite Wax (30 m × 0.25 mm × 0.5 µm) column, Helium as carrier gas and hyphenated to the tandem mass spectrometer powered with triple quadrupole mass analyzer, and photomultiplier tube detector. The method was validated as per the United States Food and Drug Administration (USFDA) guidelines. Results: With the selected GC-MS/MS conditions, the NDMA and NDEA 0.08 µg/ml (80 ng/ml) and 0.16 µg/ml (160 ng/ml) injected and Rt. for NDMA 5.634 and NDEA 6.516 min, respectively. A linear/range lies in between 0.024 and 0.120 µg/ml and 0.048 and 0.240 µg/ml for NDMA and NDEA with r2 >0.99. The precision, accuracy, and system suitability are established as per USFDA and ICH guidelines, the sensitivity of NDMA limit of detection and limit of quantification 0.08, 0.024 and NDEA 0.16, 0.048. Conclusion: Other nitrosamine impurities are not involved in the determination of NDMA and NDEA in the OLM using GC-MS/MS and the method is simple, sensitive, rapid, accurate, and precise.
Journal of Applied Pharmaceutical Science
Nitrosamine impurities are potential carcinogens, which are forming from the synthesis of drug substance as byproduct and also forming in presence of NaNO2/HNO3 and secondary amines (e.g., dimethyl amines, diethyl amine etc.,), which should be controlled in the medication of the human beings. Hence, robust and sensitive analytical method is required to control the nitroso amine impurities in drugs. The object of this method is to quantify the N-Nitrosodimethylamine (NDMA) impurity at 0.01 ppm level in ranitidine drug substance (form-1 and form-2) and drug product (tablets and capsules) of different geography. The source of NDMA impurity is also from the dimethyl amine as a key starting material using the ranitidine synthetic process. NDMA is forming when dimethyl amine is reacting with nitrous acid. The optimized LC method conditions were ACE C18-AR 3 µm, 150 × 4.6 mm column, mobile phase A as 0.1% formic acid in water, mobile phase B as 100% methanol, 0.8 ml/minute flow with gradient (time/%mobile phase B): 0/3, 3/3, 15/15, 15.1/100, 17/100, 17.1/3, 22/3, column temperature: 40°C, injection volume 50 µl, and total run time as 22 minutes. The final response achieved with multiple reaction monitoring (MRM) type: MRM [Q1 Mass (Da):75 Q3:58.2 Time (msecond)] in atmospheric chemical ionization positive mode. The optimized method was validated against the International Council for Harmonisation Q2 (R1) and United States of Pharmacopeia general chapter for compendial method validations 1225. This method can detect up to 0.01 ppm and quantify up to 0.03 ppm, the method shows linearity from 0.03 to 20 ppm.
Modified NAP test: A simple and Responsive Nitrosating Methodology for Risk Evaluation of NDSRIs
Journal of pharmaceutical sciences , 2023
N-Nitroso compounds have been listed as one of the cohorts of concern as per ICH M7. In recent years, the regulatory focus has shifted from common nitrosamines to nitroso-impurities of drug products. Thus, the detection and quantification of unacceptable levels of nitrosamine drug substance-related impurities are of great concern for analytical scientists during drug development. Moreover, risk assessment of nitrosamines is also an essential part of the regulatory filling. For risk assessment, the Nitrosation Assay Procedure suggested by WHO expert group in 1978 is being followed. However, it could not be adopted by the pharmaceutical industries due to the limitation of drug solubility and artefact formation in the test conditions. In this work, we have optimized an alternative nitrosation test to investigate the likelihood of direct nitrosation. The technique is simple, where the drug solubilized in an organic solvent is incubated at 37°C with a nitrosating agent named tertiary butyl nitrite in a 1:10 molar ratio. LC-UV/MS-based chromatographic method was developed to separate drug substances and respective nitrosamine impurities using the C18 analytical column. The methodology was successfully tested on five drugs with varying structural chemistry. The procedure is straightforward, effective, and quick for the nitrosation of secondary amines. This modified nitrosation test and WHO prescribed nitrosation test have been compared and found that the modified methodology is more effective and time-saving.
Determination of N-nitrosamine precursors in DW by UFLC-MSMS
a b s t r a c t N-Nitrosamines are potent mutagenic and carcinogenic emerging water disinfection by-products (DBPs). The most effective strategy to control the formation of these DBPs is minimizing their precursors from source water. Secondary and tertiary amines are dominating precursors of N-nitrosamines formation during drinking water disinfection process. Therefore, the screening and removal of these amines in source water are very essential for preventing the formation of N-nitrosamines. A rapid, simple, and sensitive ultrafast liquid chromatography-tandem mass spectrometry (UFLC-MS/MS) method has been developed in this study to determine seven amines, including dimethylamine, ethylmethylamine, diethylamine, dipropylamine, trimethylamine, 3-(dimethylaminomethyl)indole, and 4-dimethylaminoantipyrine, as major precursors of N-nitrosamines in drinking water system. No sample preparation process is needed except a simple filtration. Separation and detection can be achieved in 11 min per sample. The method detection limits of selected amines are ranging from 0.02 μg/L to 1 μg/L except EMA (5 μg/L), and good calibration linearity was achieved. The developed method was applied to determine the selected precursors in source water and drinking water samples collected from Midwest area of the United States. In most of water samples, the concentrations of selected precursors of N-nitrosamines were below their method detection limits. Dimethylamine was detected in some of water samples at the concentration up to 25.4 μg/L.
Biological & Pharmaceutical Bulletin, 2019
Valsartan products, commonly used to treat high blood pressure and heart failure, have been recalled in many countries due to the presence of an impurity, N-nitrosodimethylamine (NDMA), in the recalled products. We present and evaluate a GC-MS-based analytical method for the determination of NDMA levels and attempt an investigation of NDMA concentrations in valsartan drug substances and associated products. The limit of detection and limit of quantification for the method were estimated to be 0.1 and 0.5 µg/g, respectively, when testing a 0.5-g sample. A good trueness (99%) with a small relative standard deviation (1.9%) was obtained for a valsartan product spiked with NDMA at a concentration of 1.0 µg/g. Additionally, a valsartan drug substance and the associated product, which were previously determined to have NDMA contamination, were analyzed by the method. The NDMA content by our method was very close to previously determined values. Finally, six samples, including valsartan drug substances and associated, commercially available products in Japan, all of which were derived from the company implicated in the NDMA contamination, were analyzed by our method, revealing that none of these samples contained detectable concentrations of NDMA. Overall, the data indicate that the present method is reliable and useful for determination of NDMA in valsartan drug substances and associated products.