Physical stress testing of insulin suspensions and solutions.

Insulin pen-cartridge devices have evolved in order to increase patient compliance and convenience of use in a portable, multiple dosage device. With the advent of a portable insulin containing device, stability considerations have evolved from standard chemical indicators to include the effects of temperature and agitation on physical characteristics. To address these issues, two automated physical stress tests were developed based on market research data and input from regulatory authorities to understand the effect of thermomechanical stress on the product. First, the temperature cycling and resuspension test (TCRT) includes temperature cycling (25-37 degreesC) combined with agitation. The high temperature and extreme agitation test (HTEAT) includes continuous high temperature (37 degreesC) exposure combined with 4 h daily agitation. The total stress exposure is a function of the temperature, agitation, and time. The tests range from moderate stress (TCRT) to considerable stress (HTEAT) determined from the number of cartridge inversions and average daily temperature. Physical stress testing of both insulin suspensions and solution formulations in cartridges were performed and interpreted with respect to multiple endpoints. For suspensions, prolonged exposure to extreme stress caused the protein to form agglomerates, either in the suspension or adhered to the cartridge walls. In contrast, protein solutions subjected to the same extreme stress conditions did not exhibit any visually detectable change. Visual changes in the product under physical stress conditions can increase dose-potency result variability as well as exhibit acid-insoluble aggregates.