Ester Lovsin Barle

Limits for the carry-over of product residues should be based on toxicological evaluation such as described in the Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities. The toxicological evaluation should be performed also for locally administered drugs to ensure patient safety. Currently, there is no guidance on setting PDE for ocular drug substances in particular. The purpose of this investigation was to identify and describe a method for calculating a PDE value for topical ocular drugs (PDEocular). As an alternative method, extrapolation of a PDE for systemically administered drugs to a PDEocular is presented. These methods may be applied in cross-contamination risk assessments for manufacturing of topical ocular drugs. Similarly, the methods apply to systemically administered drugs, if their production precedes manufacturing of a topical ocular drug. We have examined pharmacokinetic (PK) properties of topical ocular drugs and compared them to the PK parameters of systemically administered drugs. Furthermore, we examined possible adverse effects of the carry-over in topical ocular drugs at therapeutic doses.

In the pharmaceutical industry, genotoxic drug substances are developed for life-threatening indications such as cancer. Healthy employees handle these substances during research, development, and manufacturing; therefore, safe handling of genotoxic substances is essential. When an adequate preclinical dataset is available, a risk-based decision related to exposure controls for manufacturing is made following a determination of safe health-based limits, such as an occupational exposure limit (OEL). OELs are calculated for substances based on a threshold dose-response once a threshold is identified. In this review, we present examples of genotoxic mechanisms where thresholds can be demonstrated and OELs can be calculated, including a holistic toxicity assessment. We also propose a novel approach for inhalation Threshold of Toxicological Concern (TTC) limit for genotoxic substances in cases where the database is not adequate to determine a threshold.

In order to assess the occupational health hazard of intermediates (IM), hazard data were traditionally generated through experimental animal testing, which are more and more replaced by alternative methods considering animal welfare and costs. Indeed, there are a number of other ways to assess the health hazards: comparing substances with similar structures, grouping them together into logical categories, doing specialized computer modelling, using weight of evidence approach (WoE) and integrated testing strategy (ITS). We have evaluated the current state of scientific knowledge from the literature and from in silico evaluation tools. We have proposed new ITS for Novartis Pharma own pharmaceutical IM for occupational health purposes which defines the tiered approach in performing in silico, in vitro and in vivo studies which support risk management to prevent workplace diseases that could be triggered by IM and reduces the number of in vivo tests required.

The toxicity of amiodarone Lek formulation (test formulation) was investigated after a single intravenous (i.v.) administration to mice and rats. When compared to the reference item, Cordarone (Cordarone^®; Wyeth Pharmaceuticals Inc., Collegeville, Pennsylvania, USA), median lethal dose (LD₅₀) after i.v. administration in female mice was 294.0 mg/kg body weight (b.w.) for the test formulation and 227.5 mg/kg b.w. for Cordarone. In female rats after i.v. administration, the LD₅₀ value was 269.9 mg/kg b.w. for the test formulation and 192.4 mg/kg b.w. for Cordarone. By altering the particle size of amiodarone in the Lek formulation, we were able to improve the solubility of amiodarone, thereby decreasing the number and quantity of excipients needed for preparation of the i.v. formulation and, consequently, reduced the acute toxic effects observed in the present study.