Dataset Information

Principles and procedures for handling out-of-domain and indeterminate results as part of ICH M7 recommended (Q)SAR analyses.

ABSTRACT: The International Council for Harmonization (ICH) M7 guideline describes a hazard assessment process for impurities that have the potential to be present in a drug substance or drug product. In the absence of adequate experimental bacterial mutagenicity data, (Q)SAR analysis may be used as a test to predict impurities' DNA reactive (mutagenic) potential. However, in certain situations, (Q)SAR software is unable to generate a positive or negative prediction either because of conflicting information or because the impurity is outside the applicability domain of the model. Such results present challenges in generating an overall mutagenicity prediction and highlight the importance of performing a thorough expert review. The following paper reviews pharmaceutical and regulatory experiences handling such situations. The paper also presents an analysis of proprietary data to help understand the likelihood of misclassifying a mutagenic impurity as non-mutagenic based on different combinations of (Q)SAR results. This information may be taken into consideration when supporting the (Q)SAR results with an expert review, especially when out-of-domain results are generated during a (Q)SAR evaluation.

SUBMITTER: Amberg A

PROVIDER: S-EPMC7500704 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Principles and procedures for handling out-of-domain and indeterminate results as part of ICH M7 recommended (Q)SAR analyses.

Amberg Alexander A Andaya Roxanne V RV Anger Lennart T LT Barber Chris C Beilke Lisa L Bercu Joel J Bower Dave D Brigo Alessandro A Cammerer Zoryanna Z Cross Kevin P KP Custer Laura L Dobo Krista K Gerets Helga H Gervais Véronique V Glowienke Susanne S Gomez Stephen S Van Gompel Jacky J Harvey James J Hasselgren Catrin C Honma Masamitsu M Johnson Candice C Jolly Robert R Kemper Raymond R Kenyon Michelle M Kruhlak Naomi N Leavitt Penny P Miller Scott S Muster Wolfgang W Naven Russell R Nicolette John J Parenty Alexis A Powley Mark M Quigley Donald P DP Reddy M Vijayaraj MV Sasaki Jennifer C JC Stavitskaya Lidiya L Teasdale Andrew A Trejo-Martin Alejandra A Weiner Sandy S Welch Dennie S DS White Angela A Wichard Joerg J Woolley David D Myatt Glenn J GJ

Regulatory toxicology and pharmacology : RTP 20181215

The International Council for Harmonization (ICH) M7 guideline describes a hazard assessment process for impurities that have the potential to be present in a drug substance or drug product. In the absence of adequate experimental bacterial mutagenicity data, (Q)SAR analysis may be used as a test to predict impurities' DNA reactive (mutagenic) potential. However, in certain situations, (Q)SAR software is unable to generate a positive or negative prediction either because of conflicting informati ...[more]

PMID: 30562600

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Project description:Ebola and cholera treatment centres (ETC and CTC) generate considerable quantities of excreta that can further the transmission of disease amongst patients and health workers. Therefore, approaches for the safe handling, containment and removal of excreta within such settings are needed to minimise the likelihood of onward disease transmission. This study compared the performance and suitability of three chlorine-based approaches (0.5% HTH, NaDCC and NaOCl (domestic bleach)) and three lime-based approaches (10%, 20% and 30% Ca(OH)2). The experiments followed recent recommendations for Ebola Treatment Centres. Three excreta matrices containing either raw municipal wastewater, or raw municipal wastewater plus 10% or 20% (w/v) added faecal sludge, were treated in 14 litre buckets at a ratio of 1:10 (chlorine solutions or lime suspensions: excreta matrix). The effects of mixing versus non-mixing and increasing contact time (10 and 30 mins) were also investigated. Bacterial (faecal coliforms (FC) and intestinal enterococci (IE)) and viral (somatic coliphages (SOMPH), F+specific phages (F+PH) and Bacteroides fragilis phages (GB-124PH)) indicators were used to determine the efficacy of each approach. Lime-based approaches provided greater treatment efficacy than chlorine-based approaches, with lime (30% w/v) demonstrating the greatest efficacy (log reductions values, FC = 4.75, IE = 4.16, SOMPH = 2.85, F+PH = 5.13 and GB124PH = 5.41). There was no statistical difference in efficacy between any of the chlorine-based approaches, and the highest log reduction values were: FC = 2.90, IE = 2.36, SOMPH = 3.01, F+PH = 2.36 and GB124PH = 0.74. No statistical difference was observed with respect to contact time for any of the approaches, and no statistical differences were observed with respect to mixing for the chlorine-based approaches. However, statistically significant increases in the efficacy of some lime-based approaches were observed following mixing. These findings provide evidence and practical advice to inform safe handling and containment of excreta and ensure more effective health protection in future emergency settings.

Dataset Information

Principles and procedures for handling out-of-domain and indeterminate results as part of ICH M7 recommended (Q)SAR analyses.

Publications

Principles and procedures for handling out-of-domain and indeterminate results as part of ICH M7 recommended (Q)SAR analyses.

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