Due to newly introduced EU GMP (Good Manufacturing Practice) guideline for Medicinal Products for Human and Veterinary use, product specific permitted daily exposure (PDE) for toxicological evaluation in multi-purpose facilities are required within a documented process for risk assessment. European Medicines Agency (EMA) guidance on setting PDE limits so far focused on systemic administration routes such as intravenous (IV), oral or inhalation. This article provides guidance on setting PDE values for risk management purposes in multi-purpose facilities for active pharmaceutical ingredients (APIs) applied as topical otic drugs to the outer ear canal. The therewith determined PDE otic, is used for the calculation of maximum safe carry-over (MSC) in manufacturing scenarios where a topical otic product is manufactured followed by another topical otic product.
Contract Development and Manufacturing Organizations (CDMOs) that manufacture large, diverse portfolio of chemical and pharmaceutical substances require pragmatic risk-based decisions with respect to the safe carry-over between different chemical entities, as well as for worker protection. Additionally, CDMOs may not have access to primary study data, or data are generally lacking for a specific substance. While pharmaceuticals require the establishment of health-based exposure limits (HBELs) (e.g., occupational exposure limits [OELs] and permitted daily exposure [PDE] limits), the limits for nonhazardous substances could be set in a protective and pragmatic way by using default values, when internally required. Because there is no aligned definition provided by authorities, nor agreed default values for nonhazardous substances, we provide a decision tree in order to help qualified experts (such as qualified toxicologists) to identify the group of nonhazardous substances and to assign default HBEL values for specific routes of exposure. The nonhazardous substances discussed within this publication are part of the following subgroups: (I) inactive pharmaceutical ingredients, (II) pharmaceutical excipients or cosmetic ingredients, (III) substances Generally Recognized as Safe (GRAS), and (IV) food ingredients, additives, and contact materials. The proposed default limit values are 1 mg/m 3 for the OEL and 50 mg/day for the PDE oral and intravenous (IV) route.
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