A Biopharmaceutical Industry Perspective on the Control of Visible Particles in Biotechnology Derived Injectable Drug Products

The EP and Unite States Pharmacopeial (USP) monographs for Parenteral Preparations require drug products for parenteral administration to be "practically free" or "essentially free" of visible particles, respectively. Both terms can be considered and have been used interchangeably. These definitions acknowledge the probabilistic nature of visual particle inspection. The EP monograph 2031, Monoclonal Antibodies for Human Use9, as revised in 2011 set the following expectations and requirements for visible particles in monoclonal antibody drug products, as noted below in excerpts from different sections in the monograph: Definition: Examined under suitable conditions of visibility, they are practically free from particles. Production: As part of the in-process control each container (vial, syringe or ampoule) is inspected after filling to eliminate containers that contain visible particles. During development of the product it must be demonstrated that either the process will not generate visible proteinaceous particles in the final lot or such particles are reduced to a low level as justified and authorised. Tests-Appearance: They are without visible particles, unless otherwise justified and authorised. The question remains unresolved for a clear meaning of the term "without visible particles" that may lead to differences in understanding between industry and agencies. Is this term intended to mean "zero particles" or is there any intention to distinguish between particle type such as: 9zero extraneous visible particles9 or 9zero proteinaceous particles9? Furthermore, how can 9zero9 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 particles after production? PHARMEUROPA Vol. 23, No. 3, July 2011 provided explanatory notes and summary of changes to the monograph 2031 to be published in Supplement 7.3. The merit of the 2011 monoclonal antibody monograph revision was that EP 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". It was stated in the explanatory notes that: - Without Visible particles was intentionally kept to give clear guidance that the presence of visible particles is unwanted and the appropriate formulation studies should be performed during development to find an optimal formulation. - practically free could not be a pass/fail criteria in a test and that - visual inspection is not a quality control test, even though performed at the end of the production. As a result of the probabilistic nature of detecting particles by visual inspection method, without (zero) visible particles is an unrealistic requirement for QC release/shelf life testing of any parenteral product and especially those of biotechnological origin. Even with significant formulation and container development, supported by long term stability studies and stress stability studies (e.g. agitation) the probability of a visible particle being present cannot be completely eliminated. Interestingly, a requirement of without (zero) visible particles is not aligned with the small molecule parenterals which states "essentially/practically free" of visible particles. In our view, "ractically free from particles" should be considered a suitable acceptance criterion for injectable biotech and small-molecule products, as long as appropriately defined. Furthermore, we argue that visual inspection is a suitable QC release test and that "practically free from particles" is a suitable specification when adequately described. The purpose of this position paper is to review best practices in the industry in terms of visual inspection process 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. This position paper applies to biotechnology derived drug products including monoclonal antibodies in late phase development to licensed products.