Analysis of inline-filter blockage with trastuzumab formulation using scanning-electron microscopy

The instability of pharmaceutical monoclonal antibodies are affected by physical stimuli including, temperature, denaturant, surfactant, stirring, solid phase adsorption, oxidation, and ultraviolet rays. Clinically, we frequently experience precipitation during preparation of several pharmaceutical monoclonal antibodies for cancer. Although it is possible to remove precipitates in the injection solution during the preparation procedure, potential filter blockade during administration remains a problem with adverse effects on the quality of life of patients. Therefore we sought to investigate factors contributing to this phenomenon. To closely observed the mechanisms involved in blockade of filters during trastuzumab preparation, we prepared samples under the same conditions used in clinical practice and observed them comprehensively. The precipitates that caused filter blockade were observed when the samples were vigorously shaken and left for several hours after dissolving. The precipitates were identified as proteins. The vigorous shaking caused contact between the protein and air, which induced protein precipitation caused by the surfactants derived from the foam formation. We discovered that the external stimulation may cause the instability of monoclonal antibody preparations and, so, it is important for procedures to be as rapid to avoid precipitate formation as much as possible.