Analysis of Particulate Matter in Liquid-Finished Dosage Forms.

Pharmacopeias recognize particulate matter as a common phenomenon. The current regulatory requirements relating to particulate matter in parenterals state that solutions for injections or infusions are clear and "practically" (or "essentially") free from ("readily detectable") particles when examined under defined conditions of illumination. Pharmaceutical companies are required to know their processes and have them under control. In order to control and reduce the potential influx of particulate matter, Novartis Technical Operations in Unterach developed a particle life-cycle program that involved an establishment of a dedicated particle laboratory operating under clean room conditions. The analytical capabilities of this particle laboratory were crucial for the characterization of particles and supported identification of potential sources of particulate matter. After implementing this program and respective actions, product and process understanding significantly improved. This resulted in a decrease of reject rates, AQL (Acceptable Quality Limit) failures, and corresponding batch rejections, thereby increasing the availability of Novartis products from Unterach for the patients. The main objective of this article is to show the detailed particle characterization approach including Quality by Design (QbD), methods, and equipment. Examples from projects and particulate matter investigations are presented. Parenteral formulations should not contain particulate matter. However, as external contamination as well as formation of particles during manufacturing cannot be entirely excluded, pharmaceutical companies use visual inspection and AQLs to monitor occurrence of particles. To ensure patient safety, Novartis Technical Operation in Unterach established a particle-free analytical laboratory with a focus on particle characterization and root cause analysis of particle formation. The ultimate goal is to reduce occurrence of particles in formulations altogether, and increase process understanding. The approach toward particle characterization adopted at Novartis Technical Operations in Unterach is presented in the article.