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2nd Progress and Challenges in Protein Particles and Immunogenicity of Biotherapeutics 2015: Filling in the Gaps in Risk Evaluation and Mitigation
Date: 12-13 November, 2015
Venue: US Pharmacopeia Conference Cente, Rockville, Maryland
Co-sponsored by: IABS and Health Canada
Scope and objective:
The efficacy of therapeutic proteins can be compromised by patients' immune response to the proteins, resulting in antibody-mediated alteration of the proteins' activity or bioavailability. It is well established that highly repetitive motifs, such as those that would occur in large protein aggregates in therapeutic protein products, can enhance immunogenicity and can be produced during the pharmaceutical manufacturing process. While particles greater than 10 µm in size are monitored by light obstruction test in combination with the visible appearance test, the presence of sub visible particles (0.1-10 µm), large assemblies containing thousands to millions of protein molecules, in therapeutic protein products is not routinely monitored or controlled.
In 2009, IABS and FDA cosponsored a conference which focused on
a) The mechanism of protein folding
b) The characteristics of sub visible and visible protein particles that may influence immunogenicity including the size, type (reversible, protein class), composition, amount, and conformational status);
c) The risks associated with the propensity to generate immune responses including the route of administration, dose, and frequency, duration of administration and indication;
d) The factors that influence the formation of large protein aggregates and methods to reduce protein aggregation (approaches in formulation, and protein design) including case studies of occurrence of these particulates in manufacturing;
e) Analytical methods that are useful in quantifying these particles and approaches to the design of suitable control strategies that mitigate the risk to product quality.
One key outcome of that meeting was the realization that further study was required to improve our knowledge of how sub visible protein particles form, how they are accurately quantitated and characterized, and how they evolve over the shelf life of the drug product. There was consensus that standardization of quantitation technology was needed. While there was evidence that some types of particles might relate to immunogenicity, there were also clear gaps in understanding how this happened and whether this applied to all types of protein particles in all biotherapeutics. It was also unclear how this information related to developing a control strategy for each product during development.
It is now better understood that virtually all protein drug products possess some level of sub visible particles. IABS will cosponsor another meeting on 12-13November 2015 at the USP, Rockville, Maryland, USA to revisit these topics in light of what has been learned in the past 6 years. Progress in understanding the science of protein particle formation, the evolution of the analytical technologies for characterization and measurement of sub-visible protein particles, the advances in standardization of protein particle measurements, and their possible relationship of protein particle attributes to safety and efficacy of biotherapeutics will be highlighted. The goal of the meeting is to assess the progress of the past half-decade, and its implications for risk management during biotherapeutic product development.