Use of the permitted daily exposure (PDE) concept for contaminants of intravitreal (IVT) drugs in multipurpose manufacturing facilities.

A toxicological evaluation to determine the product specific permitted daily exposure (PDE) value is an accepted method to determine a safe limit for the carry-over of product residues in multipurpose manufacturing facilities. The PDE calculation for intravitreal (IVT) injection of small and large molecular weight (MW) drugs follows the guiding principles set for systemic administration. However, there are specific differences with respect to the volume administered with IVT administration, pharmacokinetic and pharmacodynamics (PK-PD) parameters and potential for toxicity. In this publication, we have proposed a method to derive PDEIVT in the presence of IVT dose. In the absence of an IVT dose we have a proposed default extrapolationof the systemic PDE for intravenous (IV) administration to the PDEIVT dose by applying a factor of 500 based on comparison of the volume of vitreous humour with the plasma volume, as well as provided examples for PK-PD and toxicity considerations.