Glowienke, Susanne, Araya, Selene and Lovsin Barle, Ester (2016) Testing strategy for mutagenicity assessment for occupational exposure limit setting of pharmaceutical intermediates. Regul Tox Pharm.

Abstract

Pharmaceutical intermediates (IM) are substances which are used in the synthesis of the active pharmaceutical ingredient. They are not intended for human administration, yet employees may get in contact with them during the manufacturing process. In the context of occupational health, IM are usually considered as substances with no pharmacological activity, however, hazard assessment is necessary to identify potential intrinsic hazards which would cause unwanted adverse effects. In particular, a potential carcinogenic effect influences the protection strategy at the workplace. DNA reactive substances as detected in the Ames test may, even if present at very low levels, lead to mutations and therefore, potentially cause cancer.
The use of in silico methods to predict mutagenicity is increasingly acknowledged and implemented in the recently released ICH M7 guideline for limitation of DNA reactive impurities. In this paper we investigate the possibility to apply (quantitative) structure-activity-relationships ((Q)SARs) during hazard identification to reduce the number of Ames tests needed for hazard assessment of IM while maintaining high standard of protection of the employees. Ames test outcomes for 188 substances used in the pharmaceutical production were compared with their in silico predictions using two different (Q)SAR methodologies (knowledge based and statistical) complemented by expert knowledge. The results of the analysis showed that a negative prediction provides a high confidence that the IM is not mutagenic in the Ames test with the negative predictive value of 97 %. On the other hand the positive predictive value was only 57% and therefore considered too low to reliably consider positive predicted IM to be mutagenic. In order to avoid any unnecessary burden for occupational health purposes caused by falsely positive predicted IM, all positive predicted IM and those with insufficient coverage by the in silico systems are submitted to an Ames test to verify or reject the prediction. It is shown that the described in silico prediction approach ensures appropriate protection strategy of the employees. Resources for performing Ames tests which do not add value to hazard assessment could be reduced.

Item Type:	Article
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/25616