Subvisible (2–100 μm) particle analysis during biotherapeutic drug product development: Part 2, experience with the application of subvisible particle analysis

Abstract

Measurement and characterization of subvisible particles (including proteinaceous and non-proteinaceous particulate matter) is an important aspect of the pharmaceutical development process for biotherapeutics. Health authorities have increased expectations for subvisible particle data beyond criteria specified in the pharmacopeia and covering a wider size range. In addition, subvisible particle data is being requested for samples exposed to various stress conditions and to support process/product changes. Consequently, subvisible particle analysis has expanded beyond routine testing of finished dosage forms using traditional compendial methods. Over the past decade, advances have been made in the detection and understanding of subvisible particle formation. This article presents industry case studies to illustrate the implementation of strategies for subvisible particle analysis as a characterization tool to assess the nature of the particulate matter and applications in drug product development, stability studies and post-marketing changes.

Fcγ Receptor Activation by Human Monoclonal Antibody Aggregates

“…In solutions for injection supplied in containers with a nominal content of less than 100 mL, particles !10 mm and !25 mm are controlled by a light obscuration (LO) method at or below 6000 particles/container and 600 particles/container, respectively. In addition to LO, various methods such as flow imaging, qLD, resonance mass measurement, and nanoparticle tracking analysis are reported to be useful for detection and quantification of subvisible particles of less than 10 mm in size, [34][35][36][37] although it remains unclear what type of subvisible particles should be controlled for and where to set the optimal cutoff for the number of allowable subvisible particles in a product.…”

Application of ER Stress Biomarkers to Predict Formulated Monoclonal Antibody Stability

“…The current specifications require that particles >10 µm and 25 µm in size are reported (United States Pharmacopoeia < 788 >). Particles <10 µm in size are currently not required to be monitored; however, their significance in autoimmune responses and product quality is an area of significant debate . The emergence of technologies such as MFI enables monitoring of particles as small as 1 µm in size, and we therefore report SVPs in the range 1–100 µm in size.…”

Particulate Matter in Injectable Drugs: Evaluation of Risks to Patients

“…A flow cytometer equipped with forward-and side-scattering as well as fluorescent detectors, is able to determine the number of subvisible particles in monoclonal antibody formulations [48]. Moreover, industry case studies have illustrated how strategies for subvisible particle analysis are being developed to assess the nature and amount of particulate matter for better drug product development or stability studies [49].…”