Cetiedil Citrate Injection, Resolve Instability: Case Study - Abstract
Cetiedil Citrate Injection, containing 5 mg/mL cetiedil citrate, sodium chloride, and Water for Injection in Type I glass ampules, having an unadjusted pH of 3.3 to 3.7 was insufficiently stable if stored at controlled room temperature (20º to 25º). Shelf life predictions indicated a 1.66 to 1.8 year expiry period. A solution kinetics study showed maximum stability at pH between 3.5 and 3.8. No advantage was observed in the stabilities when the concentration was increased 10-fold, or one of three buffers (citrate-phosphate, acetate, or succinate) were used. The only alternative was storage at refrigeration or Controlled Cold Storage, 2º to 8º. Arrhenius plots were used to estimate the rate constants at the higher extremes of Controlled Cold (8º) and Controlled Room Temperatures (25º). Eight degrees showed the best promise for satisfactory expiry dating. The experimental and derived temperatures and rate constants were applied to 2 process models that defined all of the steps in the manufacture, testing, release, packaging, transportation and storage, tracking the hypothetical stability in terms of % cetiedil remaining after each step in the process. The models were identical except that one included refrigeration storage and the other did not. The refrigerated solution met stability criteria longer than the non-refrigerated product. However, several processing steps including autoclaving and transportation demanded the application of higher temperatures for a short duration and affected the stability of the product. The data from this study indicate that a 3 year expiry date should be applied.