Determination of Genotoxic Impurity by Chromatographic Method (original) (raw)
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Review on identification and quantification of genotoxic impurities
4043-4065, 2022
Genotoxic impurities can be broadly defined as those impurities that have been demonstrated to cause harmful changes in genetic material regardless of the mechanism. Globally people suffer from various health complications due to genotoxic impurities. Recent recommendations from European and United States (USA) drug regulatory bodies mandate the management of genotoxic and possibly genotoxic contaminants in pharmaceutical ingredients at per million levels. The purpose of this review is to make a critical analysis of the techniques used to comply with the prevailing rules and regulations and very strict limits on genotoxic impurities. Possible strategies to further expand the scope of currently available technologies and regulations are also to be discussed. These strategies include redesigning the synthesis of the drug substance to avoid introducing problematic impurities; modifying relevant process parameters to eliminate or reduce such impurities to negligible levels; Using process understanding to demonstrate that a particular genotoxic impurity cannot be formed or removed efficiently and by conducting toxicity studies to demonstrate that a suspected impurity is not harmful to it at low levels.
A REVIEW ON ANALYTICAL CHALLENGES IN MONITORING AND CONTROLLING GENOTOXIC IMPURITIES
Asian Journal of Pharmaceutical and Clinical Research, 2020
Genotoxic impurities (GIs) are chemical agents that have a DNA-interaction characteristic which can ultimately lead to cancer. Their presence in various drug substances had driven various regulatory authorities to guide monitor, control, and to limit their level in various drug products. The objective of this article is to review the analytical approaches and challenges faced while accessing, monitoring, and controlling GIs in pharmaceuticals and also a brief explanation such as low limits of GIs, matrix interference, non-volatility, and environmental conditions encountered during the analysis of GIs are also discussed in this paper. At present, several modern analytical techniques are being used for the analysis of GIs such as high-performance liquid chromatography, liquid chromatography-mass spectrometry, and gas chromatography-mass spectroscopy that have high selectivity and sensitivity, but at the same time, many researchers have reported several challenges while using these techniques. Impacts of GIs are very important and various international organizations such as the World Health Organization have set out rules for regulating these chemicals. Hence, we can conclude that analytical approaches and their challenges are essential to understand because they play a key role to develop robust analytical methods.
Journal of Pharmaceutical Sciences, 2013
The strategies implemented at Eli Lilly and Company to address European Medicines Agency and US Food and Drug Administration requirements governing the control of genotoxic impurities (GTIs) are presented. These strategies were developed to provide understanding with regard to the risk and potential liabilities that could be associated with developmental and marketed compounds. The strategies systematize the assessment of impurities for genotoxic potential, addressing both actual and potential impurities. Timing of activities is designed to minimize impact to development timelines while building a data package sufficient to either discharge the risk of potential GTI formation or support the implementation of a specification necessary for long-term control. This article presents the background associated with GTI control, the types of impurities that should be assessed, and the actions to be taken when an impurity is found to be genotoxic. A systematic approach to define potential degradation products derived from stress-testing studies is outlined with a proposal to perform a genotoxic risk assessment on these impurities. Finally, an Arrhenius-based strategy is proposed for a rapid assessment of the likelihood of potential degradation impurities to form in the commercial drug product formulation. Importantly, this article makes a proposal for discharging the risk of a potential GTI with supporting data.
European Chemical Bulletin, 2023
Identifying and quantifying genotoxic impurities (GTIs) in drug substances at trace levels is a difficult task that necessitates using sophisticated, hyphenated analytical techniques. This study provides a complete overview of the current analytical methodologies used for the detection and measurement of GTIs in pharmacological compounds. It focuses on risk assessment and the many analytical approaches used by regulatory agencies and researchers. This review outlines the numerous sources of GTIs while also digging into the industrial processes that lead to their development. A comprehensive range of analytical techniques, including both chromatographic and non-chromatographic approaches, is thoroughly described. Popular analytical techniques such as high-performance liquid chromatography (HPLC), gas chromatography (GC), mass spectrometry single quad LCMS, GCMS, and triple quad approaches have distinct applications, strengths, and limitations. Capillary electrophoresis (CE), LC-MS/MS, GC-MS/MS, LC-HRMS/MS, and Microbial reverse mutation assay (Ames)s for analyzing genotoxic impurities, as well as other hyphenated techniques, were discussed. In addition, The review addresses the issues encountered in GTI analysis, including setting acceptance criteria, defining appropriate reference standards, and validating analytical methodologies. Regulatory rules and requirements established by governing organizations are also investigated. Furthermore, emerging trends and breakthroughs in the field, such as in-silico prediction tools, novel sample preparation processes, and rapid screening approaches, are highlighted. The use of quality-by-design (QbD) principles and automated technologies to improve efficiency is also highlighted. This evaluation is a significant resource for researchers, regulatory bodies, and pharmaceutical companies.
Regulatory Toxicology and Pharmacology, 2006
The synthesis of pharmaceutical products frequently involves the use of reactive reagents and the formation of intermediates and byproducts. Low levels of some of these may be present in the final drug substance and drug product as impurities. Such chemically reactive impurities may have at the same time the potential for unwanted toxicities including genotoxicity and carcinogenicity and hence can have an impact on product risk assessment. This paper outlines a procedure for testing, classification, qualification, toxicological risk assessment, and control of impurities possessing genotoxic potential in pharmaceutical products. Referencing accepted principles of cancer risk assessment, this document proposes a staged threshold of toxicological concern (TTC) approach for the intake of genotoxic impurities over various periods of exposure. This staged TTC is based on knowledge about tumorigenic potency of a wide range of genotoxic carcinogens and can be used for genotoxic compounds, for which cancer data are limited or not available. The delineated acceptable daily intake values of between 1.5lg/dayfor1.5 lg/day for 1.5lg/dayfor lifetime intake and $120 lg/day for 61 month are virtually safe doses. Based on sound scientific reasoning, these virtually safe intake values do not pose an unacceptable risk to either human volunteers or patients at any stage of clinical development and marketing of a pharmaceutical product. The intake levels are estimated to give an excess cancer risk of 1 in 100,000 to 1 in a million over a lifetime, and are extremely conservative given the current lifetime cancer risk in the population of over in 4 (
Genotoxic Impurity in Pharmaceutical Products: A Growing Concern
The term "genotoxic substances" refers to chemical compounds that can cause genetic mutations and contribute to the growth of tumours. Genotoxic impurities in the pharmaceutical industry are a major challenge. The development and regulation of genotoxic sulfonate esters have received a lot of regulatory attention recently. This is to abnormal levels of ethyl-methane-sulfonate (EMS) in pharmaceutical industry. This resulted in an assessment of the impurity in the pharmaceutical industry and to ensure the safety of the people. The impurity is limited to TTC-based limits for all products but other techniques that can evaluate the impurity. In addition, this review article also consists of the different class as per ICH guidelines and the management and future prospective of the impurity.
Scope of Finding Genetoxic Impurities in Pharmaceuticals
2020
Reliable quality is one of the key attributes of drugs nowdays.Patients deserve the highest quality and are expecting to not be put at a risk for health effects especially related to impurities in drug susbstance or drug products.While ICH guidelines for “ordinary” impurities have been available for many years, a harmonized guidelines on how to assess, limits and controls potential health effects of low levels of genotoxic/carcinogenic impurities was lacking and only regional (draft) guidelines exised.With the ICH M7 guidelines entitled “Assessment and control of DNA-reactive (mutagenic) impurities in pharmaceuticals to limits potential carcinogenic risk”,this gap in the internationally harmonized regulatory framework has been filled.This review deals with the history of the guidelines and concepts of risk assessment with a focus on the Threshold of Toxicological Concern (TTC) principle.Furthur, a few example are given on how to deal with potential impurities with mutagenic/carcinog...