EBE Visual Inspection Committee – July 2016
A Biopharmaceutical Industry Perspective on the Control of Visible Particles in Biotechnology-Derived Injectable Drug Products
For the past two years, representatives from eight different pharmaceutical companies which manufacture biotechnological products have been discussing visible particles. 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.
Visible Particle Paper authoring, review, publishing and socializing in conferences
April 3, 2014: 1st EBE Visual Inspection committee meeting F2F in Basel, Switzerland
May 5-7, 2014: Layout/key guiding principles of the paper and case studies socialized during EU CMC Strategy Forum, Sorrento, Italy
Sept 30, 2014: 2ndEBE Visual Inspection committee meeting F2F in Basel, Switzerland
Early 2015 to July 2015: EBE/EFPIA member companies legal/management reviews
September 10-11, 2015:PDA Europe Conference - Particles in InjectablesBerlin, Germany,
Impact of Particles on Quality of Biotherapeutics and Current Approaches for Control, Tapan Das, BMS
October 26-27, 2015PDA Visual Inspection Forum, Berlin, Germany
A Biopharmaceutical Industry Perspective on the Control of Visible Particles in biotechnology derived injectable drug products, Maryam Mazaheri, Medimmune
Oct 27, 2015: Submission of the paper to PDA Journal of Pharmaceutical Science & Technology
May 16, 2016: AAPS NBC Boston, Rountable session Is It Practical to Achieve Zero Visible Particles in Drug Product?Tapan Das, BMS (Moderator) Hanns Christian Mahler Lonza (Speaker)
July 2016: Paper Published in July/August 2016 issue of PDA J
Visible Particle Paper reference
SERGE MATHONET1,*, HANNS-CHRISTIAN MAHLER2, STEFAN T. ESSWEIN3, MARYAM MAZAHERI4, PATRICIA W. CASH4, KLAUS WUCHNER5, GEORG KALLMEYER6, TAPAN K. DAS7, CHRISTOF FINKLER8, and ANDREW LENNARD9
1Global Regulatory Affairs—Biologics CMC, Sanofi R&D, 91385 Chilly-Mazarin, France; 2Drug Product Services,Lonza AG, 4002 Basel, Switzerland; 3NBE Analytical R&D, Abbvie Deutschland GmbH & Co. KG, 67061Ludwigshafen, Germany; 4Analytical Biotechnology, MedImmune, Gaithersburg, MD; 5PDMS Analytical Development, Janssen R&D, 8205 Schaffhausen, Switzerland; 6Quality Combination Products, Roche, 68305 Mannheim, Germany; 7Biologics Development, Bristol Myers Squibb, Hopewell, NJ; 8Analytical Development & Quality Control, Pharma Technical Development Biologics EU, Roche, 4002 Basel, Switzerland; and 9Regional Regulatory Affairs CMC, Amgen Ltd, Uxbridge, UK ©PDA, Inc. 2016
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