EurekaMag.com logo
+ Site Statistics
References:
53,869,633
Abstracts:
29,686,251
+ Search Articles
+ Subscribe to Site Feeds
EurekaMag Most Shared ContentMost Shared
EurekaMag PDF Full Text ContentPDF Full Text
+ PDF Full Text
Request PDF Full TextRequest PDF Full Text
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter
Follow on LinkedInFollow on LinkedIn

+ Translate

The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development



The application of structure-based assessment to support safety and chemistry diligence to manage genotoxic impurities in active pharmaceutical ingredients during drug development



Regulatory Toxicology and Pharmacology 44(3): 282-293



Starting materials and intermediates used to synthesize pharmaceuticals are reactive in nature and may be present as impurities in the active pharmaceutical ingredient (API) used for preclinical safety studies and clinical trials. Furthermore, starting materials and intermediates may be known or suspected mutagens and/or carcinogens. Therefore, during drug development due diligence need be applied from two perspectives (1) to understand potential mutagenic and carcinogenic risks associated with compounds used for synthesis and (2) to understand the capability of synthetic processes to control genotoxic impurities in the API. Recently, a task force comprised of experts from pharmaceutical industry proposed guidance, with recommendations for classification, testing, qualification and assessing risk of genotoxic impurities. In our experience the proposed structure-based classification, has differentiated 75% of starting materials and intermediates as mutagenic and non-mutagenic with high concordance (92%) when compared with Ames results. Structure-based assessment has been used to identify genotoxic hazards, and prompted evaluation of fate of genotoxic impurities in API. These two assessments (safety and chemistry) culminate in identification of genotoxic impurities known or suspected to exceed acceptable levels in API, thereby triggering actions needed to assure appropriate control and measurement methods are in place. Hypothetical case studies are presented demonstrating this multi-disciplinary approach. (c) 2006 Elsevier Inc. All rights reserved.

(PDF emailed within 0-6 h: $19.90)

Accession: 012635515

Download citation: RISBibTeXText

PMID: 16464524

DOI: 10.1016/j.yrtph.2006.01.004



Related references

Control and analysis of hydrazine, hydrazides and hydrazones--genotoxic impurities in active pharmaceutical ingredients (APIs) and drug products. Journal of Pharmaceutical and Biomedical Analysis 54(5): 900-910, 2011

Recent trends in product development and regulatory issues on impurities in active pharmaceutical ingredient (API) and drug products. Part 2: Safety considerations of impurities in pharmaceutical products and surveying the impurity landscape. Aaps Pharmscitech 15(1): 237-251, 2014

Control and analysis of alkyl and benzyl halides and other related reactive organohalides as potential genotoxic impurities in active pharmaceutical ingredients (APIs). Journal of Pharmaceutical and Biomedical Analysis 48(3): 497-507, 2008

Impurities in Drug Products and Active Pharmaceutical Ingredients. Critical Reviews in Analytical Chemistry (): 1-7, 2016

Application of LA-ICP-MS as a rapid tool for analysis of elemental impurities in active pharmaceutical ingredients. Journal of Pharmaceutical and Biomedical Analysis 91: 119-122, 2014

Recent trends in product development and regulatory issues on impurities in active pharmaceutical ingredient (API) and drug products. Part 1: Predicting degradation related impurities and impurity considerations for pharmaceutical dosage forms. Aaps Pharmscitech 15(1): 198-212, 2014

Development and validation of a stability-indicating reverse phase ultra performance liquid chromatographic method for the estimation of nebivolol impurities in active pharmaceutical ingredients and pharmaceutical formulation. Se Pu 33(10): 1051-1058, 2016

Recent developments in the risk assessment of potentially genotoxic impurities in pharmaceutical drug substances. Toxicological Sciences 100(1): 24-28, 2007

Chemometrically assisted development and validation of LC-MS/MS method for the analysis of potential genotoxic impurities in meropenem active pharmaceutical ingredient. Journal of Pharmaceutical and Biomedical Analysis 145: 307-314, 2017

Development and validation of ultra-performance liquid chromatography method for the determination of meloxicam and its impurities in active pharmaceutical ingredients. Annales Pharmaceutiques Francaises, 2018

Development of an LC-MS method for ultra trace-level determination of 2,2,6,6-tetramethylpiperidine-1-oxl (TEMPO), a potential genotoxic impurity within active pharmaceutical ingredients. Journal of Pharmaceutical and Biomedical Analysis 114: 488-492, 2016

Analysis of potential genotoxic impurities in rabeprazole active pharmaceutical ingredient via Liquid Chromatography-tandem Mass Spectrometry, following quality-by-design principles for method development. Journal of Pharmaceutical and Biomedical Analysis 149: 410-418, 2017

Quality Aspects of Oligonucleotide Drug Development Specifications for Active Pharmaceutical Ingredients. Therapeutic Innovation & Regulatory Science 46(5): 611-626, 2012

Overview of genotoxic impurities in pharmaceutical development. International Journal of Toxicology 28(6): 468-478, 2010

Cocrystal and Its Application in the Field of Active Pharmaceutical Ingredients and Food Ingredients. Current Pharmaceutical Design, 2018