Dr. Patricia W. Cash, an expert in visible particle identification & control and a former senior director in analytical biochemistry at MedImmune, recently spoke with Cambridge Healthtech Institute about the importance of visible and subvisible particles for biopharmaceuticals. Dr. Cash also discussed some of the technology progress in characterisation of these particles, as well as the regulations on particle control and risk-based mitigation strategies. Dr. Cash will be presenting a Training Seminar on Characterisation and Control of Particulates, From Aggregates to Visible Particles, which will take place from 15-16 November, 2017 in Lisbon, Portugal, as part of the 9th Annual PEGS Europe Summit.
Dr. Patricia W. Cash is a senior leader with over 25 years’ experience in all aspects of analytical development, specification setting, quality control testing and preparing and defending regulatory filings. She has served as senior director in the Analytical Biochemistry Department at MedImmune, where her group was responsible for developing and implementing analytical methods used for characterization, lot release, and in-process testing of all protein projects at various stages of development. She was also a director of analytical development at Sanofi Pasteur and worked as a scientist at BMS. She is currently an independent consultant, working with multiple biotechnology companies. She is an expert in visible particle identification and control, particularly in protein-based products (as confirmed by winning of the 2016 Fred Simon award for a paper on visible particle analysis).
CHARACTERIZATION AND CONTROL OF PARTICULATES, FROM AGGREGATES TO VISIBLE PARTICLES
As a veteran of the industry, how has the industry changed or matured in terms of understanding the causes of aggregate formation and mechanisms of action?
The pharmaceutical industry has changed over the last 20 years with the advent of biopharmaceuticals. Aggregation, which can lead to larger sub-visible and visible particle formation is a "particular" concern for biologicals. Inherent particles are common in biopharmaceiticals and it is thought that they form from an aggregation of aggregates, starting small and getting bigger. There are multiple methods of aggregation that have been identified, so a root cause cannot usually be assigned. It is incumbent on the manufacturer to examine aggregation and understand the mechanisms of formation likely for each particular product.
Why are visible and subvisible particles especially important for biopharmaceuticals?
The problem is that all biopharmaceutical solutions contain aggregates that vary in size and amount. Thus, a truly particle-free formulation for a biological is not obtainable. As an industry it is up to us to monitor and control the amount and size of particles in our solutions. There are industry standard methods for small aggregates and sub-visible particles. There are no methods nor standards commonly used for sub-micron particles or visible particles. The industry needs to address this gap. Furthermore, there is not an agreed upon size that distinguishes between subvisible and visible particles. The size particle an individual can "see" is variable depending on the analyst as well as the conditions of observation.
What is some of the latest technology progress in characterization of visible, sub-visible and submicron particles?
For submicron particles, newer instruments such as nanosight are available, but they are not routinely used. They are most useful in product development, enabling companies to understand the mechanism of particle formation. For sub-visible particles, companies are concerned about 2-10 micron particles, which are now required to be tracked by many regulatory agencies. Most companies simply use the HIAC method for these smaller particles. There are flow through type instruments available which allow visualization of the particles. The future seems to be new instruments that allow identification of the particle (through FTIR for instance) as proteinaceous or foreign.
What are the latest regulations on particle control and risk-based approaches to mitigation strategies?
EP Monograph 2031 is being revised to require that solutions be particle-free. This is not a realistic expectation for biopharmaceuticals. There is an EBE effort underway to develop a position statement to be socialized with EMA Biologics Working Party. Some of the other hot topics in particle control are the use of automation visual inspection stations, particle analysis for lyophilized products and other products where the visible appearance test is destructive to the product, the effect of polysorbates on particle formation, particle requirements for drug substance and the size parameters of visible particles.
To learn more about Dr. Patricia Cash’s training seminar and the PEGS Europe Summit, visit PEGSummitEurope.com/PEGS-Europe-Particle-Formation