Evaluation and identification of leachables from the container closure system in ophthalmic product
Reape, Derrick (2014) Evaluation and identification of leachables from the container closure system in ophthalmic product. Master of Science thesis, Dublin City University.
Full text available as:
In drug product packaging, migration of components from the container closure system into final formulation can compromise the therapeutic effect of the active pharmaceutical ingredient (API) or pose a health risk to the consumer. In response to this, regulatory expectations have elevated so that pharmaceutical companies show due diligence in the detection, quantitation, identification and monitoring of leachables through the shelf life of product. This work describes methods for the screening, quantification and identification of potential leachables in ophthalmic solutions. Particular focus was given to developing analytical separations using quality by design (QbD) principles.
An ultra performance liquid chromatography (UPLC) method was developed for the analysis of 8 potential leachables in ophthalmic solutions. The method was optimized in the centre of a design space using fractional factorial design of experiments (DOE) ensuring baseline resolution while minimizing analytical run time. Repeatability validation studies were assessed using process capability (CpK) techniques. The test method was geometrically transformed to allow simultaneous analysis on high performance liquid chromatography (HPLC) test systems. Mass spectra were generated for the leachables using an electrospray ionization (ESI) ion trap mass spectrometer.
An extraction and leachable study was executed on an ophthalmic solution under long term stability conditions in Chapter 3. The screening profile and concentration of leachables in the final drug product was monitored with consideration for time, temperature and humidity variables. The structural identity of any detected leachables were unknown and were tracked using their retention time relative to the reference standard. A single leachable was detected and the unidentified leachable was qualified through extraction of the packaging components from the container closure system (Stage I) and comparison to LC profile of the long term stability analysis (Stage II). The identification was confirmed using the LC-MS analytical method developed in Chapter 2. A single leachable, diethyl phthalate, identified using MS, was found to be present due to the adhesive used on the tamper evident seal packaging component. It was quantitated against a qualified reference standard at a maximum level of 8 ppm. The level of 8 ppm is below the allowed 10 ppm threshold level as stipulated by the FDA.
Archive Staff Only: edit this record