Validation of the pellet coating process used for a new sustained-release theophylline formulation.

Within the scope of the validation process described in this report, the influence of the process parameters on the factors determining the quality of Euphylong pellets during the spraying process is examined. The process is challenged within the meaning of the validation guidelines. Investigations within the scope of product-independent validation of the automated fluid bed coating apparatus (Wurster setup) used here provide the basis for installation qualification and operational qualification as defined by the PIC convention and the GMP guidelines. Within the scope of a classification of risks, potential operating and system errors are examined, giving consideration to the worst case conditions, and the relevance of the "blue book" to the process is discussed. Three critical process parameters (spraying temperature, air velocity and relative humidity) are investigated with respect to their influence on the goal parameter "in-vitro release of the active ingredient after 1 h". Product-related validation of the process is accomplished by means of statistical experimental design (factorial design). Statistical analysis is done using the methods described by Box-Wilson and Yates and by response surface research and grid-search methods via contour plots and isometric graphs. This yields the acceptable range of process parameters with respect to product quality. Finally the differences between validation and optimization are discussed.

Validation of the in-vitro dissolution method used for a new sustained-release theophylline pellet formulation.

The in-vitro release method used within the scope of the galenical development of Euphylong pellets and subsequently employed on a routine basis is described. The suitability of the method is demonstrated by means of the validation procedure. The release system used is based on the standard USP XXI apparatus (paddle method) and consists of three essential components: a) dissolution apparatus (paddle model). b) measuring unit (spectrophotometer), c) data acquisition and analysis system. It is demonstrated that in-vitro release rates of theophylline from Euphylong pellets can be accurately investigated with other models as well, since the course of release is not affected by pH value, buffer capacity, surface tension, turbulence of the dissolution medium or agitation by the apparatus. The accuracy of the method as well as its precision and ruggedness are investigated and described. The influences arising from the withdrawal of specimens from the bulk product and of sampling from the release vessel are discussed. The accuracy of the analytical records generated by the computer system is shown and the ruggedness of the analytical program investigated under "worst case conditions". The documentation of the results obtained is described and examined with respect to reliability in the face of system and operating errors. All pertinent guidelines (GAP, FIP guidelines for dissolution testing, etc.) are taken into consideration and their relevance to the above investigation assessed.

Feasibility of in-vitro/in-vivo correlation in the case of a new sustained-release theophylline pellet formulation.

This contribution attempts to relate the in-vitro drug release properties of theophylline from Euphylong pellets to serum theophylline concentration/time curves. Comparisons are made according to methods presented in recent publications (e.g. using mean residence time) and by juxtaposition of analogous values. For this, the mutual relationship of equal release times (absorption) and % amounts released or absorbed at fixed times are evaluated. The in-vitro data required for the computational evaluations were obtained using a paddle apparatus (according to USP XXI) at 100 rpm, buffer pH 7.4. The feasibility of converting the in-vitro to the in-vivo curve by means of a chronological transformation is examined, as well as in-vitro/in-vivo dependence on numerically fitted model parameters. Finally, in an attempt to imitate the in-vivo curve profile, the apparatus parameters for the in-vitro tests were subjected to extreme variation. The effect of the presence or absence of sink conditions is discussed and evaluated. In the concluding overview, the feasibility of predicting the in vivo behaviour of Euphylong pellets on the basis of current so-called "in-vitro/in-vivo correlation" procedures is assessed.