RESUMEN
Regulatory monographs in Europe and the United States require drug products for parenteral administration to be "practically free" or "essentially free" of visible particles, respectively. Both terms have been used interchangeably and acknowledge the probabilistic nature of visual particle inspection. 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. Therefore, the term "without visible particles" can be highly misleading in the context of what is practically achievable. This may lead to differences in understanding between industry practitioners and regulatory agencies. Is this term 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" as stated in the definition and a low, justified level of proteinaceous particles after production?The purpose of this position paper is to review best practices in the industry in terms of visual inspection process and associated operator training, quality control 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 gives perspectives on patient safety. This position paper applies to biotechnology-derived drug products including monoclonal antibodies in late-phase development to licensed products. LAY ABSTRACT: In the 2011 monoclonal antibody monograph revision, European Pharmacopoeia experts acknowledged that protein products may also contain proteinaceous particles at release or that protein particles may form during storage. Indeed, industry experience has demonstrated that therapeutic proteins such as monoclonal antibodies can exhibit a propensity for self-association leading to the formation of aggregates that range in size from nanometres (oligomers) to microns (subvisible and visible particles). As a result, the requirement for drug product appearance for monoclonal antibodies was changed from "without visible particles" to "without visible particles unless otherwise authorised or justified". In our view, "practically free from particles" should be considered a suitable acceptance criterion for injectable biotechnology and small-molecule products, as long as appropriately defined. Furthermore, we argue that visual inspection is a suitable quality control release test and that "practically free from particles" is a suitable specification when adequately described.
