Evaluation of Particle Techniques for the Characterization of Subvisible Particles From Elastomeric Closure Components

Abstract

Evaluating a particle profile for parenteral drug products is a well-known challenge due to inevitable variability of results with limited accuracy to actual particle levels present in the product, especially in the subvisible particulate (SbVP) range. It is important to understand the appropriate SbVP counting/ characterization technology, methodology capability, and the particle source (intrinsic or extrinsic). Elastomeric closures are prevalent in many types of drug product container closure systems and are a known source of particle contribution. These components need to be considered when establishing a drug product particle profile. In this work, we describe available particle extraction methodology and its applicability in the analysis of elastomeric closure components using multiple detection technologies. Optimum sample preparation and analytical techniques were established to evaluate submicron particle and SbVP loads from elastomeric closure components. In addition, the impact of stopper siliconization and polysorbate 80 interaction on the degree of SbVPs in the final drug product was assessed.

Transportation of mAb Dosing Solution in Intravenous Bag: Impact of Manual, Vehicle, and Pneumatic Tube System Transportation Methods on Product Quality

“…Compendial (e.g., USP <788>, European Pharmacopeia 2.9.19, and Japanese Pharmacopeia 6.07) regulations limit the number of particles present in the injectable drug products. 35 Light obscuration is a compendial method used to measure particle counts. For small volume injectables (≤100 mL), the limits applied for particles in the ≥10 and ≥25 μm size ranges are 6,000 and 600 particles per container, respectively.…”

Particles in Biopharmaceutical Formulations, Part 2: An Update on Analytical Techniques and Applications for Therapeutic Proteins, Viruses, Vaccines and Cells

“…119,120,124 A particle species frequently observed and expected in formulations stored in primary packaging systems containing siliconized surfaces (e.g., siliconized vial stoppers, prefilled syringes) are SO droplets. 40,128 Noteworthy, SO droplets are primarily considered a safety concern when serving as a nucleation site for protein aggregation, or in case of intravitreal application; otherwise SO is deemed less critical. 39,122,123,129−133 Accordingly, analysis of SO droplets often focuses on the discrimination of pure SO droplets from other particle types, particularly protein aggregates (or, in addition, mixed SO-protein aggregates).…”

“…53,54,139 Furthermore, RMM and HVM represent interesting options for the analysis of SO droplets in the low micrometer and the submicrometer size range. Whereas in RMM, positively buoyant SO droplets can be discriminated from negatively buoyant particles, such as protein or rubber particles, 35,124,128,140 HVM allows for a direct identification of SO droplets via refractive index determination. 61,62 Chemical identification of SO droplets in aqueous solution can also be performed by Raman microscopy.…”

“…Other packaging-related particles comprise glass particles originating from glass vials and elastomeric particles from rubber stoppers. 99,120,125,126,128,137 Remarkably, glass particles can exhibit comparably large morphological heterogeneity depending on the mechanism of their formation: chips and lamellae resulting from mechanical or chemical stress are of crystalline morphology, whereas silica dissolved from a vial's inner glass surface can form gel-like particles. 144 Approaches to assess glass and rubber particles include visual inspection, light obscuration, optical microscopy, flow imaging microscopy, without necessarily being capable to differentiate glass particles from other types of particles and particle ID techniques.…”

“…144,147 In the subvisible size range, LO was mainly reported as a tool used in extraction or durability studies testing the emergence of glass or rubber particles in the absence of drug product. 128,145 For the actual discrimination of glass lamellae or rubber particles from formulation-related particles (e.g., protein particles), optical microscopy and flow imaging microscopy were shown to be useful techniques. 127,128,137,144,145 These microscopic approaches were reported to allow trained operators to classify particles by morphological appearance down to a minimum particle size of roughly 10 mm 145 or even 5 mm 137 .…”