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.

Achieving "Zero" Defects for Visible Particles in Injectables.

The reduction of visible particles in injectable products is an important element in the consistent delivery of high-quality parenteral products. An important part of this effort is the control of particles that may emanate from the primary packaging materials. The Parenteral Drug Association (PDA), with the support of the Pharmaceutical Manufacturers Forum (PMF), has undertaken the task of developing test methods to assess the cleanliness of primary packaging components used in the manufacturing of sterile injectable products. Further work is focused on end-to-end analysis of the supply chain to identify additional points where particles may enter the finished product workflow. This includes shipment, receipt, transfer, and fill and finishing operations. This information and appropriate corrective actions and control methods, coupled with appropriate patient risk-based acceptance limits, are intended to provide better and more consistent supply of injectable products that meet current compendial and good manufacturing practice (GMP) expectations. Aligning control limits between supplier and pharmaceutical manufacturers will offer further improvement. This paper describes the formation of a task force to address these needs and current progress to date.LAY ABSTRACT: Visible particles must be controlled in parenteral products. Such particles come from many sources including the primary packaging materials. The Parenteral Drug Association (PDA), with the support of the Pharmaceutical Manufacturers Forum (PMF), has formed a task force to review and improve particle measurement methods and perform an end-to-end analysis of how particles may enter into parenteral products. These activities are intended to lead to more consistent control limits for visible particles and ultimately more consistent supply of high quality injectable products.

Silicone-oil-based subvisible particles: their detection, interactions, and regulation in prefilled container closure systems for biopharmaceuticals.

Recent increased regulatory scrutiny concerning subvisible particulates (SbVPs) in parenteral formulations of biologics has led to the publication of numerous articles about the sources, characteristics, implications, and approaches to monitoring and detecting SbVPs. Despite varying opinions on the level of associated risks and method of regulation, nearly all industry scientists and regulators agree on the need for monitoring and reporting visible and subvisible particles. As prefillable drug delivery systems have become a prominent packaging option, silicone oil, a common primary packaging lubricant, may play a role in the appearance of particles. The goal of this article is to complement the current SbVP knowledge base with new insights into the evolution of silicone-oil-related particulates and their interactions with components in prefillable systems. We propose a "toolbox" for improved silicone-oil-related particulate detection and enumeration, and discuss the benefits and limitations of approaches for lowering and controlling silicone oil release in parenterals. Finally, we present surface cross-linking of silicone as the recommended solution for achieving significant SbVP reduction without negatively affecting functional performance.