PFAT5 and the Evolution of Lipid Admixture Stability

Abstract

PFAT5 is defined by United States Pharmacopeia Chapter 729 as follows: the "percentage of fat residing in globules larger than 5 µm (PFAT5) for a given lipid injectable emulsion [is] not to exceed 0.05%." The unstable aggregates are trapped in lungs, liver, and the reticuloendothelial system. Large particles will accumulate in pulmonary capillaries, which are between 4 and 9 µm in diameter. Over the years, there has been an evolution of methods to characterize and define intravenous fat emulsion (IVFE) stability when combined as a total nutrient admixture (TNA). Many studies have claimed IVFE stability measuring mean particle size, zeta potential, and visual checks. Interestingly, none of the studies that claimed the TNA as stable identified an unstable one through testing. This report reviews those parameters and shows they were not a valid measure of lipid stability. The PFAT5 parameter has emerged as the only validated measure of lipid stability. There are clinical consequences of using lipids that exceed the PFAT5 limit. This parameter is applicable to both manufactured and compounded lipid preparations. The clinician should be aware of the limitations of much of the literature concerning the lipid stability assessment. More stability studies are needed using PFAT5 to identify the actual limits of TNA compounding.

Use of Intravenous Lipid Emulsions With Parenteral Nutrition: Practical Handling Aspects

“…Survey data suggest that many organizations in the United States may be compounding small numbers of PN with limited experience or appreciation of the compatibility and stability limitations, potentially placing patients at risk of receiving incompatible or unstable PN admixtures . Contrary to what is often presumed, the incompatible or unstable PN admixture is rarely obvious to the unaided eye, and instead requires a good working knowledge of pharmaceutics …”

“…The US Pharmacopeia chapter 729 provides pharmaceutical specifications for ILE products, describing emulsion stability methods and criteria (intensity‐weighted mean droplet diameter <0.5 µm; volume‐weighted percentage of fat globules >5 µm [PFAT 5 ] <0.05%) also applied to final PN admixtures. Among pharmaceutical criteria, ILE products are most stable at pH ≈7–8, whereas the acidity of the glucose component requires its combination with amino acids for its buffering capacity prior to incorporating ILEs in appropriate proportions for each TNA . However, at a nonacidic pH there are then limits to calcium compatibility, and in turn, electrolytes can destabilize the ILE by reducing the ζ‐potential, which otherwise maintains the homogeneous dispersion of sub‐micron fat droplets in water .…”

“…Among pharmaceutical criteria, ILE products are most stable at pH ≈7–8, whereas the acidity of the glucose component requires its combination with amino acids for its buffering capacity prior to incorporating ILEs in appropriate proportions for each TNA . However, at a nonacidic pH there are then limits to calcium compatibility, and in turn, electrolytes can destabilize the ILE by reducing the ζ‐potential, which otherwise maintains the homogeneous dispersion of sub‐micron fat droplets in water . As the concentration of an ILE is diluted in the course of admixing the TNA, stability is further undermined with a reduction in repulsion forces between lipid droplets, increasing the risk of coalescence .…”

“…Compounding of ILEs with other PN components accelerates the rate of their physicochemical destabilization . Although some physical changes might not be visible initially, these can occur over time, such as aggregation, creaming, and coalescence with fewer lipid globules but of increasing size . This knowledge contributes to the limited duration of stability and the assigned beyond‐use date.…”

“…This knowledge contributes to the limited duration of stability and the assigned beyond‐use date. TNA emulsion stability is particularly compromised by the addition of ingredients that decrease pH or that increase cation load . The qualitative and quantitative limits of numerous combinations of additives for relatively stable admixtures are provided by the manufacturers of specific MCBs, can be found in the literature for selected compounded PN, or must be tested according to accepted pharmacopeial methods.…”