Historically, protein aggregates and particles in drug products have been classified as visible particles if they were seen during a visual inspection. However, they are subvisible if they are not detected with a high probability during visual inspection (in the micrometers size range, with focus on >2 um, >5um, >10 um and >25 um) and high molecular weight species (dimers and other oligomeric species—nanometers in size).
Several studies have suggested that protein aggregates and subvisible particles may contribute to tolerance reversal and promote an immune response against protein biotherapeutics. Nonetheless, it is important to note that even if a biotherapeutic contains some aggregates, such as subvisible particles or visible particles, it can still be considered safe and effective. Immunogenicity is influenced by various factors, including the patient, therapy, product and dosing, making it challenging to isolate the specific impact of aggregation and particle formation.
Particles in parenteral preparations are considered an obligatory critical quality attribute, and major pharmacopoeias (e.g., European Pharmacopoeia, United States Pharmacopoeia, Japanese Pharmacopoeia) provide guidelines for limits on subvisible and visible particles. The generic limits for subvisible particles were established based on industry experience and were not directly linked to clinical safety risks. Recently, health authorities have requested the inclusion of submicron particles in the particle control strategy, establishing product-specific limits for subvisible particles based on clinical experience. Additionally, the visual inspection process has gained significant attention during health authority audits. This includes implementing a holistic control strategy, providing adequate training and qualification for visual inspectors using well-designed challenge test sets, and ensuring efficient investigational procedures for issue remediation.
Atanas Koulov, CSO, Clear Solutions Laboratories said, “In recent audits by global health authorities, we have experienced increased focus and scrutiny on the subvisible and visible particle control strategies. Establishing product specific limits for subvisible particles and a compliant visual inspection practice require depth of knowledge in the subject matter, holistic product and process understanding, as well as a well thought-through qualification strategy.”
Atana’s statement is why we are excited to announce the upcoming free 2023 PDA Particle Control in Biopharmaceuticals webinar. Moreover, Atanas Koulov has more than 15 years of experience in BioPharma development from Roche/Genentech, Novartis and Lonza. His focus areas are particle contamination and control, forensic chemistry, analytical development and quality control. He has authored more than 50 publications. Atana will also speak at the 2023 Particle Control in Biopharmaceuticals webinar, and the topic of his talk is called Control of Visible and Subvisible Particles - Are We Doing the Best We Can? An Industry Perspective.
Other speakers at the webinar includes the following:
Ewa Marszal (U.S. FDA) joined the FDA in 1999 and is a CMC reviewer in the FDA CBER division. She is the FDA liaison for the protein expert committee for USP <788>.
Ewa will give “A perspective on the history of the pharmacopeial limits for subvisible particulate matter.”
John Carpenter (Carpenter Biopharma Consulting LLC) is Professor Emeritus at the University of Colorado, author of more than 300 peer review publications, editor of the Journal of Pharmaceutical Sciences and organizer of the Colorado Protein Stability Conference.
John’s topic will be on the following: Adverse Immunogenicity of Protein Drugs: Roles for Aggregates/Particles and Inadequate Analytical Methods.
The Webinar will take place on July 12 at 17:30 CET / 11:30 EDT / 8:30 PDT. We encourage all readers to register for this insightful event and take advantage of the Q&A session to share knowledge and expertise with industry experts.
Other great upcoming PDA events on related topics are:
- PDA Training Course: How to Handle Test Sets in Visual Inspection, 4-5 Oct 2023, Markt-Schwaben, Germany
- PDA Training Course: An Introduction to Visual Inspection: A Hands-on Course, 15-16 November 2023, Berlin
- 2023 PDA Visual Inspection Workshop, 14 November 2023, Berlin
- 2024 PDA Visual Inspection Forum, 2024