Considerations for Permitted Daily Exposure Calculation for Contaminants in Medicinal Products Manufactured in Shared Facilities

Abstract

The manufacture of different medicinal products in shared facilities creates a risk of cross-contamination. One of the approaches to select the limits for possible contaminants is based on calculating the permitted daily exposure (PDE), i.e. the dose of an active pharmaceutical ingredient or any other substance contaminating a medicinal product that will not be associated with any adverse events in a human in the case of lifetime exposure. The aim of this study was to provide practical guidance on selecting adjustment factors for calculating PDEs to establish limits for potential contaminants in multi-purpose pharmaceutical facilities. The authors analysed the regulatory requirements and literature needed to establish critical effects of contaminants, outlined possible assumptions in the use of quantitative indicators for measuring toxicity, and described the relationship between the PDE and other indicators of the safety of chemical compounds for human health. The article presents an example of PDE calculation for an investigational hypoglycemic medicinal product using a limited amount of open-source literature data. Thus, the article demonstrates the role of information on the primary pharmacodynamic effects of medicinal products in the assessment of their critical effects, which is necessary to implement the most conservative approaches to PDE calculation. The example of PDE calculation presented in the article may be used to assess cross-contamination risks associated with non-dedicated manufacturing facilities.

Keywords

• permitted daily exposure
• pde
• contamination
• interspecies dose extrapolation
• the safety of the use of medicines
• risk control