The probability of seeing a particle in a drug product container varies according to the size and nature of the particles as well as container and inspection conditions. There is not a clear definition of the size at which a particle becomes visible, due to the probabilistic nature of detecting particles. Regulatory monographs in Europe and the United States require drug products for parenteral administration to be “practically free” or “essentially free” of visible particles.
In the case of biotechnological products, the problem is complicated by the fact that all protein solutions contain particles and these may or may not be visible. The EP monograph 2031, Monoclonal Antibodies for Human Use, as revised in 2011 requires monoclonal antibody drug products be ”without visible particles, unless otherwise justified and authorised”. The term "without visible particles" can be highly misleading in the context of what is practically achievable and may lead to differences in understanding between industry and agencies. Is the term “free from visible particles” intended to mean "zero particles" or is there any intention to distinguish between particle type such as: “zero extraneous visible particles” or “zero proteinaceous particles”? Furthermore, how can “zero” particles as a criterion for release testing be reconciled with “practically free from particles” and a low, justified level of proteinaceous particles after production?
This position paper reviews best practices in the industry in terms of visual inspection processes and associated operator training, QC sampling, testing and setting acceptance criteria corresponding to “practically free of visible particles” and providing considerations when visible proteinaceous particles are deemed unavoidable. It also provides a brief overview of visible particle characterization, and perspectives on patient safety. The current industry position is to consider “practically free from visible particles unless otherwise justified and authorised” as a standard requirement for QC release of biotechnology derived drug products including monoclonal antibodies subject to compliance with the European Pharmacopoeia. The paper provides guidance on how the presence of proteinaceous particles, when a quality attribute of the molecule, may be justified.
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Visible Particle Paper abstract
EBE Visual Inspection Committee – Linkedin