Particulates in parenteral drug development are a serious issue. In biopharmaceuticals the issue is compounded by reported impacts of protein aggregates and particles on the product’s efficacy, safety, and immunogenicity. As more research is done, characterizing protein aggregates in biologics is becoming an important consideration during forumlaulation.
Characterization of sub-visible particles in parenterals was formally addressed by USP <788> in 1975. At the time of its implementation, USP <788> was primarily concerned with foreign matter, such as rubber stopper pieces, that might not be distributed through the blood system easily. USP <788> states that sub-visible particles above 10 micron and 25 micron must be monitored and reported.
Based on increasing awareness of issues that may arise from particles smaller than what USP <788> currently includes, the FDA is exploring new requirements for characterizing protein therapeutics. They are now requesting that sub-visible particle analysis be done of particles between 2 – 10 microns. This particle size range should be characterized to inform method development and selection, risk assessment, and specification setting. Characterization includes determining the particle's shape, type (i.e. protein, silicone oil, etc), and size distribution. Providing particle images is also suggested. Dynamic imaging particle analysis is uniquely suited to address these new recommendations.
The ability of an imaging particle analysis system to properly identify and count protein aggregates in protein therapeutics is directly dependent on the quality, or sharpness, of the images. Blurry images lead to poor characterization of particles and can effect your particle size distribution.
Blurry images lead to mischaracterization of particles
The better the overall image quality, the easier it is for the instrument’s software to recognize patterns, and in turn characterize particles. Blurry images make it difficult to distinguish protein aggregates from silicone droplets and other contaminants, especially in the 2 - 10 µm range. Poor image quality also makes it difficult for the instrument to discriminate between a single protein amalgamation from several small proteins in close proximity to one another.
Blurry images may lead to unreliable particle size distributions
If particles are not characterized correctly, your size distribution may not be ascertained reliably. Smaller or faint particles (such as those with a low refractive index) may be missed entirely, lowering particle counts. Large particles may be fractionated into smaller particles - reducing the number of large particles while increasing the number of small particles.
Discover how you can improve protein aggregate characterization in parental drug formulations with dynamic imaging particle analysis in our informative eBook, The Ultimate Guide to Dynamic Imaging Particle Analysis.