Glass Leachables as a Nucleation Factor for Free Fatty Acid Particle Formation in Biopharmaceutical Formulations

Industry Perspective on the use and Characterization of Polysorbates for Biopharmaceutical Products Part 1: Survey Report on Current State and Common Practices for Handling and Control of Polysorbates

“…66,72 In another study, it was found that glass leachables (such as NaAlO 2 and CaCl 2 ) may serve as a nucleation factor and induce the formation of FFA particles. 16 It is noteworthy that 25% and 31% of the companies have not seen a correlation of temperature and primary packaging, respectively, for the detectability of insoluble degradation products. In addition, over 30% of the responders did not observe any influence of PS concentration (38%) or pH (31%) on the detectability of insoluble products.…”

“…9 In recent years, there have been reports on PS-related stability issues related to the use of polysorbates in biopharmaceutical products, mainly due to PS degradation induced particle formation by free fatty acids (FFA). [10][11][12][13][14][15][16][17] Due to these challenges and the importance of PS in pharmaceutical products, the scientific interest and focus on PS is steadily increasing, as evidenced by the rising number of biomedical literature referenced in PubMed (www.PubMed.gov) containing both polysorbate and protein as keywords in title or abstract of the publication (Figure 1).…”

Combining Machine Learning and Backgrounded Membrane Imaging: A Case Study in Comparing and Classifying Different Types of Biopharmaceutically Relevant Particles

“… 34 – 36 In contrast, during the generation of the synthetic model FA particles (obtained by spiking into aqueous buffer) the entire mass of FA is instantly released into the formulation resulting in a fast precipitation (hours to days) of poorly soluble FAs. Furthermore, studies by Cao et al (2015) 4 and Almendinger et al (2021) 37 illustrate the potential impact of additional factors like presence of protein or glass leachables (e.g., aluminum ions) on the FA particle formation process. Accordingly, a better adjustment of the composition of synthetic model FA particle samples with respect to, e.g., protein or metal ion content, might improve the morphological resemblance between model and real-life FA particles.…”

“…Interestingly, Almendinger et al 37 propose a two-stage model for the formation of FA particles in the presence of aluminum ions: in the initial phase, nucleation seeds are formed by complexation of aluminum ions and FA, in the second phase, additional FA molecules accumulate at the seeds, which finally results in precipitation of particles. Despite the fact that the authors suggest a change in growth mechanisms before the actual presence of subvisible particles, their hypothesis reinforces that FA particle formation might proceed in successive mechanistic steps.…”

Particles in Biopharmaceutical Formulations, Part 2: An Update on Analytical Techniques and Applications for Therapeutic Proteins, Viruses, Vaccines and Cells

“…110 Additionally, both techniques were also used to identify particles from FFAs in complex with glass leachables. 114 Furthermore, Winters et al described holographic video microscopy as a novel approach for the discrimination of FFA-related particles (oleic acid droplets) from protein particles and silicone oil (SO) droplets in a mixed sample. 61 Nevertheless, the authors also revealed the limitations of the technique when analyzing samples containing particle classes of similar refractive index as in the case of stearic acid particles and protein particles.…”