Thursday, 5 November, 17:30 – 20:30

SC9: Advanced Techniques for Characterization of Protein Aggregates, Particulates and Contaminants

Co-Instructors:
Matthew Brown, Ph.D. Life Science Specialist, Malvern Instruments
Amber Fradkin, Ph.D, Associate Director, R&D, KBI Biopharma
Stacy Kenyon, Ph.D., Scientist, Bioscience Development Initiative, Malvern Instruments

Overview:
The process of protein aggregation is a complex process driven by many different factors. Understanding this process is a key component for the implementation of QbD approaches during biotherapeutic development or deviation resolution of legacy products. Such in-depth understanding cannot be obtained from standard QC-type analytical methods, but rather relies on the implementation of advanced characterization technologies. As a consequence of these technologies, the biopharmaceutical industry is now offered detailed insights into protein behaviour, allowing evaluation of product stability and process impact. This course will cover some of the latest technologies for advanced characterization of protein therapeutics, together with case studies from industry, on how such approaches can be implemented for product development and understanding.

Detailed Description:
A variety of techniques is available to characterize protein aggregates, which while helpful individually, collectively can offer even more valuable insight into the behaviour of biotherapeutics. A number of widely used technologies are described below.

There is a growing need to be able to quantify aggregates within the sub-micron size range. Some of the latest technology identified in this article now provides the industry with this capability. This ability is becoming more important as companies are required to assess immunogenic risk for parenterals. In addition to detecting and characterizing aggregates, huge importance is now being placed on the identification of particulates and contaminants. Particles detected in a product may not be protein aggregates, but rather contaminants from manufacturing processes and product contact surfaces. New technologies, such as RMM and Morphologically-Directed Raman Spectroscopy (MDRS), are now providing a means by which particulate matter can be distinguished from protein aggregates, thereby greatly facilitating troubleshooting and deviation resolution.

In conclusion, protein aggregation is a consequence, rather than a cause, of degradation. As discussed at the outset, there is a pressing need to understand aggregation pathways, and the risk factors that can induce aggregation, right from the start of the drug development process, in order to devise mitigation strategies and to align manufacturing processes with Quality by Design principles. Given the importance of aggregates and particles to immunogenicity, it is likely that in the future particle quantification and characterisation methods will need to be implemented more readily in GMP compliant environments and in support of QC activities. Indeed particle counting is often far more sensitive than loss of protein monomer, as the protein mass in particles is usually very low. However this understanding must also extend to the manufacturing process and beyond. Not only is it necessary to identify those processing steps most likely to introduce particles and the types of particles involved, but consideration has also to be given to product handling post release, which includes storage and handling in a clinical setting.