BPI Interview with Dr. Atanas Koulov of Novartis Pharma AG re. MFI as a Technique to Close the Subvisible Gap in Measuring Aggregation of Protein BioPharmaceuticals
The following interview was published in the BPI EU Conference Bulletin, Issue 4 - April 2010, Formulation Strategies and Analytical Methods
Interview with Dr. Atanas Koulov - Novartis Pharma AG
BPI - What analytical methods are most applicable when studying aggregation?
Koulov: Aggregates are notoriously difficult to study as they span a huge size range and vary in nature. There is a large variety of analytical methods which provide useful information about aggregation, depending on the question asked. We find that the most useful methods on a day-to-day basis are the light scattering techniques (DLS, SEC-MALLS), AF4 and Microflow imaging (MFI).
BPI - What are concerns about particles in the subvisible range?
Koulov: The main concern right now is that protein aggregates may potentially be immunogenic. This concern at the moment is somewhat theoretical as we don't have enough data to make a conclusive statement. We need to still answer a number of questions such as What kind of aggregates are immunogenic if any? What size (or other characteristic) of the subvisible protein particles could lead to higher immunogenicity? More importantly, what is a high concentration in terms of subvisible particles and how the regulatory requirements need to be set? The experimental data that we have on these topics is quite limited.
BPI - The traditional method is light obscuration. What advantages does MFI have over light obscuration?
Koulov: MFI is a far superior over light obscuration, as it provides far more information. In contrast to light obscuration, where the instrument records the number of particles only, MFI provides images of these particles. These images can potentially be used to identify the nature of the particles. For example, it is important to distinguish silicon oil droplets from protein particles in prefilled syringes, which are an increasingly popular delivery method for biopharmaceuticals. Silicon oil particles have a very distinctive appearance and can be readily identified using MFI. MFI is also much more sensitive than light obscuration especially for particles around 1 or 2 micrometers. We have gathered a substantial amount of data that conclusively shows that in these lower size ranges of subvisible particles, MFI is far more sensitive than light obscuration, which provides misleadingly low numbers. All in all, MFI is a much more accurate method. Light obscuration has worked well in the pharmaceutical industry, but now with the emergence of flow microscopy and image analysis methods such as MFI, the industry is quickly embracing them.
Koulov: Dr. Atanas Koulov (head of the analytical R&D laboratory at Novartis Pharma AG in Basel, Switzerland) will present in the Analytical Methods track on "Micro Flow Imaging (MFI) and Dynamic Light Scattering (DLS) As Complementary Techniques to Close the Subvisible Gap in Measuring Aggregation of Protein Biopharmaceuticals" at 2:45 pm on Wednesday, 19 May 2010.
To view complete highlights from this track CLICK HERE
To visit the conference website, go to http://www.bpi-eu.com/
Scientific Publication - PERSPECTIVES, An Industry Perspective on the Monitoring of Subvisible Particles as a Quality Attribute for Protein Therapeutics
AUTHORS
Satish K. Singh *, Nataliya Afonina, Michel Awwad, Karoline Bechtold-Peters, Jeffrey T. Blue, Danny Chou, Mary Cromwell, Hans-Juergen Krause, Hanns-Christian Mahler, Brian K. Meyer, Linda Narhi, Doug P. Nesta, Thomas Spitznagel (2010)
ABSTRACT
Concern around the lack of monitoring of proteinaceous subvisible particulates in the 0.1-10 μm 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 < 10 μm 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 10 μm 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.
Published online in Wiley InterScience. DOI 10.1002/jps.22097
The complete article can be found at:
http://www3.interscience.wiley.com/journal/123327574/abstract
