Presence of nitrosamine impurities in medicinal 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.
Nitrosamine Impurities in Drug Substances and Drug Products
Journal of Advances in Pharmacy Practices, 2020
Nitrosamine impurities are known to be mutagenic and carcinogenic, very small exposure of these impurities can lead to cancer. These impurities may be formed and get incorporated into drug substance or drug product through reagent, catalyst, solvent or raw materials used in the process of manufacturing. The various regulatory authority has published the press release or notice regarding the control of these impurities with the interim limit. Nitrosamine impurities can be avoided by taking precaution in the manufacturing of drug substance and drug products. Validated analytical methods are to be used to identify and quantify these impurities hence it needs highly sensitive instrument which can detect these impurities to the trace level at given interim limit. Liquid chromatography or Gas chromatography, along with mass detector is majorly used for their determination.
N-nitrosodimethylamine (NDMA) Contamination of Ranitidine Products: A review of recent findings
Journal of Food and Drug Analysis, 2021
Ranitidine is a medication that has been used to alleviate heartburn and other disorders for over 40 years. Following reports of N-nitrosodimethylamine (NDMA) contamination in ranitidine products, there have been many recalls and registration suspensions. Here, we revise the literature information confirming ranitidine association with NDMA. Then, we highlight the documented mechanisms for NDMA release from ranitidine. In addition, the stability issue for this medicine is discussed. After that, we review and discuss the results of the United States Food and Drug Administration and the Australian Therapeutic Goods Administration laboratory testing of ranitidine products and the detected NDMA levels. Finally, the case of NDMA generation in Angiotensin II Receptor Blockers (ARBs) and ranitidine were compared in an attempt to address the circumstances leading to the current contamination.
N-Nitrosodimethylamine Contamination in the Metformin Finished Products
Molecules, 2020
A GC–MS/MS method with EI ionization was developed and validated to detect and quantify N-nitrosodimethylamine (NDMA) and seven other nitrosamines in 105 samples of metformin tablets from 13 different manufactures. Good linearity for each compound was demonstrated over the calibration range of 0.5–9.5 ng/mL. The assay for all substances was accurate and precise. NDMA was not detected in the acquired active pharmaceutical ingredient (API); however, NDMA was detected in 64 (85.3%) and 22 (91.7%) of the finished product and prolonged finished product samples, respectively. European Medicines Agency recommends the maximum allowed limit of 0.032 ppm in the metformin products. Hence, 28 finished products and 7 pronged dosage products were found to exceed the acceptable limit of daily intake of NDMA contamination. The implications of our findings for the testing of pharmaceutical products are discussed.
Regulatory Toxicology and Pharmacology, 2021
The ICH M7(R1) guideline describes a framework to assess the carcinogenic risk of mutagenic and carcinogenic pharmaceutical impurities following less-than-lifetime (LTL) exposures. This LTL framework is important as many pharmaceuticals are not administered for a patient's lifetime and as clinical trials typically involve LTL exposures. While there has been regulatory caution about applying LTL concepts to cohort of concern (COC) impurities such as Nnitrosamines, ICH M7 does not preclude this and indeed literature data suggests that the LTL framework will be protective of patient safety for N-nitrosamines. The goal was to investigate if applying the LTL framework in ICH M7 would control exposure to an acceptable excess cancer 47 risk in humans. Using N-nitrosodiethylamine as a case study, empirical data correlating 48 exposure duration (as a percentage of lifespan) and cancer incidence in rodent bioassays indicate 49 that the LTL acceptable intake (AI) as derived using the ICH M7 framework would not exceed a 50 negligible additional risk of cancer. Therefore, controlling N-nitrosamines to an LTL AI based 51 on the ICH M7 framework is thus demonstrated to be protective for potential carcinogenic risk to 52 patients over the exposure durations typical of clinical trials and many prescribed medicines. 53 54 Highlights • N-Nitrosamines are part of the ICH M7 cohort of concern (COC) class of impurities • ICH M7 provides a framework for less-than-lifetime (LTL) acceptable intake (AI) derived from a lifetime AI • N-Nitrosodiethylamine (NDEA) exposures at the ICH M7 LTL AIs are of negligible 60 excess cancer risk 61 • The ICH M7 LTL AI guidance should be used to limit exposures to N-nitrosamines
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.
BMJ (Clinical research ed.), 2018
To perform an expedited assessment of cancer risk associated with exposure to N-nitrosodimethylamine (NDMA) through contaminated valsartan products. Nationwide cohort study. Danish health registries on individual level prescription drug use, cancer occurrence, and hospital diagnoses. 5150 Danish patients with no history of cancer, aged 40 years or older, and using valsartan at 1 January 2012 or initiating use between 1 January 2012 and 30 June 2017. Participants were followed from one year after cohort entry (lag time period) until experiencing a cancer outcome, death, migration, or end of study period (30 June 2018). Each participant's exposure to NDMA (ever exposure and predefined categories of cumulative valsartan exposure) was mapped out as a time varying variable while also applying a one year lag. Association between NDMA exposure and a primary composite endpoint comprising all cancers except non-melanoma skin cancer, estimated using Cox regression. In supplementary analys...
Nitrosamines: Economics of the Unknown
Opflow, 2011
This article discusses the effectiveness of using chloramination to comply with the Stage 2 Disinfectants and Disinfection Byproducts Rule (Stage 2 DBPR), if potential nitrosamine formation during and after chloramination might be the result.