FDA and industry have long wrestled with appropriate dissolution methodology for injectable suspension products. Investigations into the relevance of the dissolution methods utilized has shown wide variation in in vivo results despite consistent in vitro performance. As FDA notes in a recent article (here) on the new potential improved method developed to address “gaps between in vitro and clinical data, CDER researchers have investigated triamcinolone acetonide injectable suspensions as a model to develop improved methodologies to assess injectable suspension performance. Triamcinolone acetonide injectable suspensions exhibit significant clinical variability; for example, measurements of time to maximum concentration in vivo (Tmax) can vary from 1 to 216 hours” using standard dissolution testing methods.” The Agency attributes this variability to the potential for flocculation of the suspension in vivo.
FDA also suggests that a method that more closely mimics the product’s performance may be related to the fact that injectable suspensions are injected intramuscularly and thus the flow of bodily fluids around the injection site is minimal, unlike an intravenous solution’s entry into the circulation, where fluid availability and fast flow are found.
The FDA believes that the high shear nature of the current dissolution apparatus may contribute significantly to the difference between the results seen on in vitro dissolution and the significant difference in in vivo observation of pharmacokinetic behavior. The article describes FDA’s observations and research in its effort to more closely relate in vitro dissolution to in vivo performance of injectable long-acting suspension products.