Particle Analysis in Pharmaceutical Applications
Sub-Visible Particle Detection
Sub-visible particles are generally defined as particles in the size range from 2 to 50µm.
For finished products, US Pharmacopeia (USP), European Pharmacopeia (EP) and Japanese Pharmacopeia (JP) specify the protocols, equipment and acceptable limits for sub-visible foreign particulate matter in parenterals, specifically in the ≥10µm and ≥25µm size ranges. The respective web sites are www.usp.org , www.pheur.org and www.sjp.jp These individual methods have recently been harmonized across all three jurisdictions.
Particles bigger than 50µm are detected using visual inspection methods (see Visible Particle Detection)
Existing Measurement Technologies and Limitations
The default technology for performing this analysis is either manual microscopy following filtration or automated particle analysis using light obscuration. Because of the limited statistics and user subjectivity of manual methods, the light obscuration method is normally preferred.
Particle measurements are expressed in Equivalent Circular Diameter or ECD. ECD is a convenient, single unit of measure which can be related to a common reference standard - in this case, NIST-traceable, polystryrene (PS) spheres or beads of known sizes. All size measurements of parenteral particles, regardless of their shape or material, are converted into an ECD measurement for comparison to this standard.
Although light obscuration is widely adopted, it does have some limitations due to the fact that it is an indirect measurement. When a particle transits the measurement zone, the optical beam is obscured with a resulting change in signal strength at the detector. This signal change is then equated to a particle's ECD based on a calibration curve created using PS spheres of known sizes. To the extent that real-world particles in pharmaceutical fluids are composed of materials which differ optically from PS, and are often far from spherical, errors in sizing/counting are inevitable. For some particle types, errors in size and concentration measurements can exceed an order of magnitude. A further limitation is the limited amount of data provided on each particle. The single ECD unit gives no information on the nature of the particle, its origin and whether particles of different types are present in the population.
MFI - Superior Measurement of Sub-Visible Particles
Presently, flow microscopy methods such as MFI are being used in drug research and formulation development. Although MFI is not specified in the respective Pharmacopeia procedures for finished products, it can be used as a substitute technology since it has been shown to be compliant with the respective procedures using NIST-traceable Reference Standards in numerous experiments and laboratories. Results demonstrating MFI's compliance with USP Reference Standards, (Catalog #1500502) are avilable from Brightwell Technologies
