SATISH K. SINGH,1 NATALIYA AFONINA,2 MICHEL AWWAD,3 KAROLINE BECHTOLD-PETERS,4 JEFFREY T. BLUE,5 DANNY CHOU,6 MARY CROMWELL,7 HANS-JUERGEN KRAUSE,8 HANNS-CHRISTIAN MAHLER,9 BRIAN K. MEYER,5 LINDA NARHI,10 DOUG P. NESTA,11 THOMAS SPITZNAGEL12
1Biotherapeutics Pharmaceutical Sciences, Pfizer Inc., 700 Chesterfield Parkway West, Chesterfield, Missouri 63017
2Biologics Process and Product Development—Analytical Development and Testing, Bristol-Myers Squibb, Hopewell, New Jersey 08534
3Pharmacokinetics, Dynamics and Metabolism, Pfizer Inc, Andover, Massachusetts 01810
4Process Science Department/Biopharmaceuticals, Boehringer Ingelheim Pharma GmbH & Co. KG, D-88397 Biberach, Germany
5Bioprocess Analytical and Formulation Sciences, Merck & Co., West Point, Pennsylvania 19486
6Technology Development, Genzyme, Framingham, Massachusetts 01701
7Analytical R&D, Genentech, South San Francisco, California 94080
8Manufacturing Science and Technology, Abbott GmbH & Co. KG, D-67061 Ludwigshafen, Germany
9Pharmaceutical and Analytical R&D, F. Hoffmann-LaRoche, CH-4070 Basel, Switzerland
10Formulation and Analytical Resources, Amgen, Thousand Oaks, California 93012
11Biopharmaceutical Technology, GlaxoSmithKline, King of Prussia, Pennsylvania 19406
12Biopharmaceutical Development, Human Genome Sciences, Rockville, Maryland 20850
PUBLICATION: Journal of Pharmaceutical Sciences. 99(8): 3302-3321. (2010)
DOI: 10.1002/jps.22097
ABSTRACT: Concern around the lack of monitoring of proteinaceous subvisible particulates in the 0.1–10µm range has been heightened (Carpenter et al., 2009, J Pharm Sci 98: 1202–1205), primarily due to uncertainty around the potential immunogenicity risk from these particles. This article, representing the opinions of a number of industry scientists, aims to further the discussion by developing a common understanding around the technical capabilities, limitations, as well as utility of monitoring this size range; reiterating that the link between aggregation and clinical immunogenicity has not been unequivocally established; and emphasizing that such particles are present in marketed products which remain safe and efficacious despite the lack of monitoring. Measurement of subvisible particulates in the <10µm size range has value as an aid in product development and characterization. Limitations in measurement technologies, variability from container/closure, concentration, viscosity, history, and inherent batch heterogeneity, make these measurements unsuitable as specification for release and stability or for comparability, at the present time. Such particles constitute microgram levels of protein with currently monitored sizes ≥10µm representing the largest fraction. These levels are well below what is detected or reported for other product quality attributes. Subvisible particles remain a product quality attribute that is also qualified in clinical trials. ©2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:3302–3321, 2010
Keywords: biotechnology; particle size; protein aggregation; protein formulation; immunology
LINK TO ARTICLE: http://onlinelibrary.wiley.com/doi/10.1002/jps.22097/abstract
