title: Determination and application of the permitted daily exposure (PDE) for topical ocular drugs in multipurpose manufacturing facilities.
abstract: 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 PDEocularis 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.
authors.affiliation: a Novartis Pharma AG, Postfach , Basel , Switzerland.
authors.forename: Ester
authors.initials: E
authors.lastname: Lovsin Barle
authors.affiliation: b Novartis Pharma AG NIBR, Postfach , Basel , Switzerland.
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Bizec
authors.affiliation: a Novartis Pharma AG, Postfach , Basel , Switzerland.
authors.forename: Milica
authors.initials: M
authors.lastname: Glogovac
authors.affiliation: a Novartis Pharma AG, Postfach , Basel , Switzerland.
authors.forename: Kamila
authors.initials: K
authors.lastname: Gromek
authors.affiliation: b Novartis Pharma AG NIBR, Postfach , Basel , Switzerland.
authors.forename: Gian Christian
authors.initials: GC
authors.lastname: Winkler
mesh_terms: D004305:Dose-Response Relationship, Drug; D004340:Drug Contamination / Q000517:prevention & control*; D004345:Drug Industry / Q000592:standards*; D005123:Eye / Q000187:drug effects; D006801:Humans; D000072499:Manufacturing and Industrial Facilities / Q000592:standards*; D009883:Ophthalmic Solutions / Q000009:adverse effects* / Q000592:standards*; D018570:Risk Assessment
chemical_list: D009883:Ophthalmic Solutions
keywords: Ocular drug; cleaning validation; multipurpose manufacturing facility; permitted daily exposure; risk assessment