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.

Introduction

The compendial method for subvisible particle testing, based on USP <788> and <787>, uses light obscuration for monitoring particles having an equivalent circular diameter (ECD) of ≥10 μm and ≥25 μm [1], [2]. As discussed in a previous manuscript [3], health authorities often request testing beyond the limitations of the compendial method and investigation of particles smaller than 10 μm for more complex biotherapeutic parenteral drug products, which may have the propensity to form proteinaceous particulate matter. Consequently, the application of particle analysis across the entire subvisible particle range has become a key consideration during the development of a biotherapeutic drug product [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17]. In this article, we provide examples demonstrating how a variety of subvisible particle analysis techniques can be applied in practice during clinical and commercial development. The term “subvisible” applies to particulate matter of the size range defined as 2–100 μm, which may be proteinaceous or non-proteinaceous.

Subvisible particle analysis requires significant long-term data under actual conditions of drug product storage, with material made at different times and from different facilities, to understand the drug product and method variability. The key to understanding such variability in the particles and amounts seen is to have sufficient data to understand product trends in subvisible particulate matter and the ability to determine if the particulate matter is protein-based or originates from other intrinsic or extrinsic species that are also counted in quantitative subvisible particle assessments [18], [19], [20]. Collection of information on particle morphology and composition may be additional components of particle analysis and trending during development.

The case studies presented are a compilation of the selected experiences of the companies that participated in the preparation of this manuscript, and illustrate ways in which this strategy can be applied. The case studies are organized into two sections: (1) Particle Characterization and (2) Applications of Particle Characterization in Drug Product Development, Stability Studies and Post-Marketing Changes.

While the information presented is illustrative of the types of approaches being taken to evaluate subvisible particles also below 10 μm, the examples are not intended to prescribe strategies or the application of any specific techniques considered necessary to meet requirements in relation to regulatory applications for product development or licensure.