leachables in parenteral drug products and Responses to these from health authorities

摘要

This case presentation will discuss issues regarding extractables and leachables (E&L) observed in parenteral drug products. The presentation will also discuss characteristics of parenterals with respect to E&L's. A number of cases involving common E&L's such as antioxidants and rubber oligomers originating from rubber closures used in parenterals will be given. In addition to the identity, origin and safety of these leachables the responses to these from health authorities will be given and discussed. All questions received from health authorities are relevant and should be addressed as such since the applicant does not know the background of the question and since the applicant is interested to get their product approved. Common container closure systems for parenterals are vials, cartridges, prefilled syringes, pouches, containers, bags etc. in which a number of different rubber closures is used (plungers, stoppers, discs, laminates etc.). Rubber closures are known to be possible leachable donors to pharmaceutical drug products. The use of barrier coatings can reduce the leaching but is costly and will add to the price of the drug product for patients. A large variation in administrated volumes (few μl to several hundred of ml a day) is used within parenteral administration making control strategies as suggested by the PQRI L&E group difficult to follow for large volume parenterals (LVP) due to low resulting analytical detection limits. Keeping a Safety Concern Threshold (SCT) value of 0.15μg/ml as suggested by the PQRI L&E group for Oral Inhaled and Nasal Drug Products (OINDP's) will result in levels similar to the detection limit of typical analytical techniques like HPLC-UV-MS and GC-MS for a drug product with a daily administration of 1 ml.