GIAN C. WINKLER*, JENS MIRWALD, KAMILA GROMEK, ESTER LOVSIN BARLE
*Corresponding author
Novartis Pharma AG NIBR, Postfach, CH-4002 Basel, Switzerland

Abstract

In pharmaceutical manufacturing, occupational exposure limits (OELs) and health hazard label elements are achieved via appropriate engineering and industrial hygiene concepts to protect workers from the exposure to chemically reactive intermediates (IMs), compounds with limited or no toxicity information. The testing strategy for hazard identification of IMs has to be optimized for cost efficiency and reduced use of test animals. In addition to worker safety, results of an integrated testing strategy have to be acceptable to regulatory authorities for classification, labelling, packaging and transport of chemicals. This publication describes the presently established Novartis tiered testing strategy and assignment of OEL for IMs. A decision tree provides a step by step guidance. The rationale for the use of each endpoint and the type of data selected are presented.

INTRODUCTION

In pharmaceutical manufacturing occupational exposure limits (OELs) and health hazard label elements are achieved via appropriate engineering and industrial hygiene concepts to protect workers from the exposure to chemically reactive intermediates (IMs) (small molecules < 1000 Da), compounds for which there is limited or no toxicity information. In Novartis, a tiered testing strategy (TTS) is applied for pharmaceutical intermediates. It serves different purposes related to different regulatory settings, e.g. occupational health protection measures as well as labelling according to the Globally Harmonized System (GHS)/or classification, labelling and packaging of substances (CLP) regulations (1, 4). In addition, the acute oral toxicity and  skin irritation studies used in the TTS are in accordance with the United Nations (UN) recommendations on the transport of dangerous goods (2).
In addition to worker safety, results of a practicable integrated testing strategy have to be acceptable by regulatory authorities for classification, labelling and packaging of chemicals. The tests have to be compliant with international regulations a ...