Points to Consider: Best Practices to Identify Particle Entry Routes along the Manufacturing Process for Parenteral Formulations.

During the processes involved in pharmaceutical manufacturing, particulate matter may be introduced into a product from a variety of sources and at different points in the manufacturing process. Companies design quality at the beginning of the process to ensure against defects and strive to manufacture products that meet the pharmacopeial standard of being "practically/essentially free" of particles, which can be challenging, though necessary. As particulate matter recalls are predominantly associated with parenteral products, most companies employ a quality risk management program to identify critical parameters or conditions that could affect product quality or patient safety and incorporate systemic and procedural controls to mitigate or reduce the probability of their occurrence. Yet, determining where particulates are most likely to enter the process, what types of materials are most vulnerable, and how the size and number of particles might affect product quality can be very complex. Visual inspection and sampling of the manufactured drug product are designed to control the risk of particulate contamination; building prevention controls will ensure sustainability. This concept paper highlights the necessity of a more thorough understanding of the failure mechanisms that result in particle contamination across a range of products, such as elastomeric components and glass, and processes, such as the formulation and filling of injectables. The goal is to identify process steps within the end-to-end manufacturing process that are most critical to particle generation and entering of visible particles into the final drug product.LAY ABSTRACT: This concept paper highlights the necessity of a more thorough understanding of the failure mechanisms that result in particle contamination across a range of products, such as elastomeric components and glass, and processes, such as the formulation and filling of injectables. The goal is to identify process steps within the end-to-end manufacturing process that are most critical to particle generation and entering of visible particles into the final drug product.

Particulate Generation Mechanisms during Bulk Filling and Mitigation via New Glass Vial.

Contamination with foreign particulate matter continues to be a leading cause of parenteral drug recalls, despite extensive control and inspection during manufacturing. Glass is a significant source of particulate matter contamination; however, the mechanism, source, and quantification have not been extensively analyzed. Quantification of particulate matter generation with lab simulations suggests that glass-to-glass contact on the filling line produces large quantities of glass particles of various sizes. A new strengthened glass vial with a low coefficient of friction surface is proposed to address this root cause of glass particle generation. Lab simulations and two line trials using this new vial demonstrated a substantial reduction of glass particulate generation, of resulting product contamination, as well as of the frequency of required filling line interventions. These results suggest that substantial reductions in particulate matter contamination of all types, glass and non-glass, can be achieved through the use of a new glass vial designed to effectively eliminate a root cause of glass particle generation.LAY ABSTRACT: Contamination with foreign particulate contamination continues to be a leading cause of injectable drug recalls, despite extensive control and inspection during manufacturing. Glass particles are one of the most common types of particulate identified; however, the generation mechanism has not been extensively studied. Lab simulations suggest that routine glass-to-glass contact of vials during the filling process results in large quantities of glass particulate. A new, strengthened glass vial with a low coefficient of friction surface is proposed to address this mechanism. Lab simulations and multiple filling line trials demonstrated a substantial reduction of glass particulate matter generation and product contamination with use of the new vial. These results suggest that this new vial reduces contamination risk by eliminating a root cause of glass particulate generation.