A novel approach to the specification of in-vitro dissolution boundaries based on regulatory requirements for bioequivalence.

Although bioequivalence between products has gained considerable importance over the last few years, the concept has not yet been transferred to "within product bioequivalence", i.e. "batch-to-batch bioequivalence". Two different formulations of an active substance are considered bioequivalent if they differ by not more than 20% in rate and extent of absorption. This regulatory requirement should also be satisfied for two different batches of the same formulation ("within product bioequivalence"). Euphylong pellets appear to be the first sustained-release theophylline formulation for which data on the "within product bioequivalence" can be presented. The upper and lower limits of the in-vitro dissolution were specified so that even the most extreme batches within these specifications, which normally do not occur among production batches, are bioequivalent. This novel procedure requires that the in-vitro method used is suitable to detect in-vivo differences. Furthermore, it should be able to predict the in-vivo absorption kinetics on the basis of in-vitro data, at least insofar as a discriminatory ranking is concerned. It has been shown how this approach has lead to the in-vitro specifications of Euphylong pellets and how specially manufactured experimental batches representing the upper and lower specification limits were tested for bioequivalence. Finally, it is shown that a typical production batch conforms well with the specification limits and does not reach the extremes of the experimental batches which were specially manufactured for the purpose of this study.