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Physical Stability of 20% Lipid Injectable Emulsions via Simulated Syringe Infusion: Effects of Glass vs Plastic Product Packaging

From the Department of Medicine, Division of Clinical Nutrition and the Nutrition/Infection Laboratory, B. I. Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts

Correspondence: David F. Driscoll, PhD, B. I. Deaconess Medical Center and Harvard Medical School, Baker Building, Suite 605, 185 Pilgrim Road, Boston, MA 02215. Electronic mail may be sent to ddriscol{at}bidmc.harvard.edu.

Background: The United States Pharmacopeia (USP) has proposed large-globule-size limits to ensure the physical stability of lipid injectable emulsions, expressed as the percent fat >5 µm, or PFAT₅, not exceeding 0.05%. Visibly obvious phase separation as free oil has been shown to occur in some samples if PFAT₅ is >0.4%. We recently found that lipids, newly packaged in plastic (P), exceed the proposed USP limits and seem to produce less stable total nutrient admixtures compared with those made from conventional glass (G), which do meet proposed USP standards. We tested the possible stability differences between 20% lipid injectable emulsions in either P or G in a simulated neonatal syringe infusion study. Methods: Eighteen individual syringes were prepared from each 20% lipid injectable emulsion product (n = 36) and attached to a syringe pump set at an infusion rate of 0.5 mL/hour. The starting PFAT₅ levels were measured at time 0 and after 24 hours of infusion, using a laser-based light obscuration technique as described by the USP Chapter <729>. The data were assessed by a 2-way analysis of variance (ANOVA) with Container (G vs P) and Time as the independent variables and PFAT as the dependent variable. Results: At time 0, the starting PFAT₅ level for lipids packaged in G was 0.006% ± 0.001% vs 0.162% ± 0.026% for P, whereas at the end of the infusion they were 0.013% ± 0.003% and 0.328% ± 0.046%, respectively. Significant differences were noted overall between groups for Container, Time, and Container-Time interaction (all p < .001). Bonferroni tests showed significant differences in PFAT₅ levels between Containers at time 0 (T-0; p < .001) and T-0 vs T-24 for P-based lipids (p < .001), whereas no such differences were noted for Time for the G-based lipids. Similar results were noted for PFAT₁₀ levels. Conclusions: We confirm that presently available lipid injectable emulsions packaged in newly introduced plastic containers exceed the proposed USP <729> PFAT₅ limits and subsequently become significantly less stable during a simulated syringe-based infusion. Although modest growth (p = NS) in large-diameter fat globules was observed for the glass-based lipids, they remained within proposed USP globule size limits throughout the study. Glass-based lipids seem to be a more stable dosage form and potentially a safer way to deliver lipids via syringe infusion to critically ill neonates.

Lipid injectable emulsions are complex dosage forms consisting of an internal or dispersed oil phase blended with an external or continuous aqueous phase with the aid of a naturally occurring, egg phospholipids emulsifying agent. To form the core emulsion so that it contains a "fine dispersion" of submicron lipid droplets while minimizing the formation of large-diameter fat globules above 1 µm, the oil-water-emulsifier mixture is homogenized through a small orifice at very high pressures and often repeated in a series of cycles until the desired globule size distribution (GSD) is achieved. The ultimate goal, for example, in a 20% lipid injectable emulsion is the production of a stable emulsion, with a mean droplet size (MDS) of approximately 300 nm or 0.3 µm and a relatively narrow GSD, thereby minimizing the population of large-diameter fat globules. If, for example, the emulsification process is not tightly controlled, the fat globule population found in the large-diameter tail of the distribution will be higher than desired, resulting in a "coarse dispersion."

Destabilization of lipid injectable emulsions manifests as an abnormal GSD, with a right shift in the droplet size distribution, resulting from the fusion of these submicron lipid droplets into large-diameter fat globules via a process known as coalescence. Therefore, analyzing the large-diameter fat globule population of freshly manufactured lipid injectable emulsions should provide an objective assessment of the fineness or coarseness of the finished product. In addition, monitoring this population over time is a stability-indicating process. This information could subsequently be used by the manufacturer when addressing critical decisions to release or withhold a given lot or batch of lipid injectable emulsion for clinical use.

As the large-diameter population grows, the intravenous (IV) emulsion is becoming less stable, leading to a potential for embolic fat globules, which might affect the safety of the final infusion. The destabilization process is of particular clinical concern when lipid injectable emulsions are administered intravenously to critically ill infants or adults requiring parenteral nutrition (PN) support. Although the internal diameter of human capillaries is between 4 µm and 9 µm for all patient age groups, the vastly reduced surface area and impaired clearance mechanisms for critically ill, premature infants makes lipid injectable emulsion potentially more dangerous in this setting. Consequently, all manufacturers of lipid injectable emulsion products approved for clinical use in the United States must contain a "black box warning" about potentially serious adverse effects related to its use in premature and low-birth-weight infants (see Figure 1^1,2). Black box warnings are mandated by the US Food and Drug Administration (FDA) when it believes there is a significant risk of serious or life-threatening complications associated with the use of a drug.

View larger version (21K): [in this window] [in a new window]   FIGURE 1. Black box warning for lipid injectable emulsions.1,2

The United States Pharmacopeia (USP), which is responsible for setting authoritative drug standards that are enforceable at the discretion of the FDA, has proposed specific globule size limits to ensure the physical stability of lipid injectable emulsions.³ Of the globule size standards identified in USP Chapter <729> entitled "Globule Size Distribution in Lipid Injectable Emulsions," there are 2 separate droplet/globule size populations wherein limits are proposed. The MDS cannot exceed 500 nm, or 0.5 µm, as determined in Method I of <729>, and the large-diameter tail, expressed as the volume-weighted percentage of fat globules >5 µm, or PFAT₅, cannot exceed 0.05%. The original basis for these recommendations came from an assessment of 16 different lipid injectable emulsion products packaged in conventional glass infusion bottles approximately 5 years ago.⁴

On February 26, 2004, an announcement was made to pharmacy directors nationwide of a significant change in the packaging of lipid injectable emulsions from glass to plastic containers, with the "expected months of availability" for the various new products to occur in March or April of 2004.⁵ By June of 2004 at our institution, the supply of conventional glass infusion bottles was exhausted, and replacement with plastic bags commenced. Subsequently, an analysis of the PFAT₅ profile of this new dosage form in accordance with Method II of USP <729> showed significant increases in the large-diameter fat globule population, which now exceeded the proposed globule size limits,⁶ whereas the conventional glass version of this product had previously passed.⁴ This preliminary finding suggested the plastic-based emulsion to be of inferior pharmaceutical quality.⁶ A subsequent investigation of these abnormal fat globule findings with respect to total nutrient admixtures showed the plastic-based lipids produced less stable formulations than identical ones made from glass, which met the proposed pharmacopeial limits.⁷

To explore further the effects of the changes in the PFAT₅ population and the stability of lipid injectable emulsions, we investigated the differences between 20% lipid injectable emulsions packaged in conventional glass (G) vs newly introduced plastic (P) containers, but now extemporaneously prepared in syringes in a simulated neonatal lipid infusion over 24 hours.

	MATERIALS AND METHODS

Top MATERIALS AND METHODS RESULTS DISCUSSION

 
Two 20% lipid injectable emulsion products were used, one in glass (Liposyn III 20%, lot no. 16–327-DE, expiration date October 2005; Abbott Laboratories, North Chicago, IL) and the other in plastic (Intralipid 20%, lot no. 1022373, expiration date March 2006). Eighteen individual syringes per container-type (G vs P), each containing 20 mL of 20% lipid injectable emulsion, were aseptically prepared from freshly opened containers according to the conditions set forth in USP Chapter <797> entitled "Pharmaceutical Compounding: Sterile Preparations."⁸ The infusion protocol for lipid injectable emulsions in our critically ill neonatal population is shown in Table I. The simulated infusions were started using a Harvard Syringe pump (Harvard Apparatus, South Natick, MA) and set at a delivery rate of 0.5 mL per hour for 24 hours. The amount of lipids to be delivered over 24 hours in this simulated infusion experiment was 2.4 g, and this amount would be approximately midrange toward a goal dose at our institution of 3 g/kg/d for patients with an average weight of 1.3 ± 0.6 kg (n = 99), according to recent clinical data collected for a previous compatibility study in neonates.⁹

As outlined in Method II of USP <729>,³ samples were analyzed using light obscuration or extinction. The PFAT₅ levels were measured in triplicate for each at the beginning (time 0) and end of study (time 24 hours) using light obscuration or extinction with a single-particle (globule) sensing technique (AccuSizer 780/APS; Particle Sizing Systems, Santa Barbara, CA). All samples required dilution before the analysis due to the high concentration of fat globules present. The measurement range was set at a size threshold of 1.8 µm up to 50 µm, and the details of the analytical procedure were recently described.¹⁰ To ensure that the measurements were performed within the linear region of detection of the instrument, the dilutions necessary for the analysis were optimized for each emulsion beforehand for the time 0 measurements. Subsequently, the number of fat globules sized per sample run did not exceed 60% of the nominal coincidence limit (where >1 particle enters the counting zone producing artifacts) for the laser sensor used in this study (10,000 globules/mL) during any of the measurements (ie, at time 0 or 24 hours).

Results are presented as the mean ± SD and reported for 2 size ranges from the large-diameter tail of the dispersion as (1) USP proposed requirements of PFAT₅, and (2) for very large fat globules (>10 µm), expressed as PFAT₁₀. Statistical significance in the large-diameter fat globule populations between infusion containers was determined using a 2-way repeated-measures analysis of variance (ANOVA) followed by a post hoc test of pairwise comparisons using Bonferroni tests. Differences in the GSD profiles were defined to be statistically significant at p < .05.

	RESULTS

Top MATERIALS AND METHODS RESULTS DISCUSSION

 
To achieve accurate large-diameter globule counts in order to avoid errors related to coincidence limits as previously described, the glass-based (G) lipids required dilutions between 228:1 and 456:1 (water: emulsion sample), whereas the lipids packaged in plastic (P) required dilutions 75–150 times higher to between 17,100:1 and 34,200:1. This fundamental observation confirmed that lipids in plastic are a more coarse, or globule-laden, emulsion compared with those manufactured in glass containers and is consistent with our previous findings.^6,7

Statistical analysis of the population of large-diameter fat globules found between G vs P lipid injectable emulsions showed significant differences by the overall ANOVA for Infusion Container, Time, and the interaction between Infusion Container and Time (all values, p < .001). The PFAT data are shown in Table II. At the outset (time 0), Bonferroni pairwise comparisons showed significant differences (p < .001) in the large-diameter fat globule population expressed as PFAT₅ for G (0.006% ± 0.001%) vs P (0.162% ± 0.026%), as well as for PFAT₁₀ levels (p = .004) for glass (0.003% ± 0.001%) vs plastic (0.018% ± 0.012%). Similarly, when the same large fat globule data were analyzed at the end of study, they were also highly significant (p < .001) at the PFAT₅ level for G (0.013% ± 0.003%) vs P (0.328% ± 0.046%), as well as for PFAT₁₀ levels (p < .001) for G (0.007% ± 0.003%) vs P (0.047% ± 0.021%). The PFAT levels were up to approximately 25 times higher in the P vs G containers. Figure 2 (PFAT₅ vs time) and Figure 3 (Globule number >5 µm/mL vs time) show the changes in the GSD over time for each.

View larger version (9K): [in this window] [in a new window]   FIGURE 2. The PFAT5 profile of glass and plastic at time 0 and 24 hours as syringes.

View larger version (8K): [in this window] [in a new window]   FIGURE 3. The globule number >5 µm/mL profile of glass and plastic at time 0 and 24 hours as syringes.

In comparing the growth of fat globules for each container type, Bonferroni pairwise comparisons showed significant PFAT₅ increases (p < .001) from time 0 to 24 hours for the lipids in P (0.162% ± 0.026% vs 0.328% ± 0.046%, respectively), as well as at the PFAT₁₀ level (0.018% ± 0.012% vs 0.047% ± 0.021%, respectively; p < .001). In contrast, the modest increase in PFAT₅ from time 0 to 24 hours (0.006% ± 0.001% vs 0.013% ± 0.003%, respectively) and PFAT₁₀ levels (0.003% ± 0.001% vs 0.007% ± 0.003%, respectively) was not significant in terms of the growth of large-diameter fat globules for the lipids in G for either size threshold.

In addition, to illustrate the corresponding number of globules per mL for all PFAT time points, these data are also shown in Table III. Here, it is noted that the number of fat globules per mL between lipids packaged in G vs P showed an approximate 50-fold increase for the lipids in P.

	DISCUSSION

Top MATERIALS AND METHODS RESULTS DISCUSSION

 
In the neonatal population, lipid injectable emulsions are required due to the extremely limited fat stores of the neonate, particularly premature infants, and therefore are usually begun within the first couple of days of life. Docosahexanoic acid, or DHA (22:63), and arachidonic acid, or AA (20:46), are required in preterm infants for growth and development and are formed by the provision of the essential fatty acids linoleic (18:26) and linolenic acid (18:33), as found in soybean oil lipid injectable emulsions.^11,12 The efficiency of the conversion of linolenic acid to DHA is poor compared with linoleic to AA,¹³ and supplementation specifically with DHA in feeding formulas has been shown to be beneficial when enteral nutrition is possible.¹⁴

View larger version (8K): [in this window] [in a new window]   FIGURE 4. Large-diameter profile of U.S.-based lipids (10%, 20%, and 30%) packaged in conventional glass bottles16 before introduction of plastic containers.

The GSD data clearly show that lipid injectable emulsions available in the United States as plastic infusion containers are coarse dispersions compared with the fine emulsions routinely produced in conventional glass bottles, including when compared with the former glass version of the current plastic product. Figure 4 depicts the profile of Liposyn III and Intralipid as log PFAT₅ vs lipid concentration when both were available in glass containers¹⁶ (ie, before March/April 2004), and Figure 5 shows the differences between them for 20% lipid injectable emulsions after the latter plastic product replaced the glass container in the United States.⁶ Clearly, the plastic-based lipid injectable emulsion currently available in the United States cannot meet the proposed globule size limit as stated in Method II of USP <729> of PFAT₅ <0.05% necessary to meet pharmacopeial specifications. The obvious question is whether the coarseness of the GSD that has been recently identified as unique to the plastic-based lipid formulations is clinically significant.

View larger version (8K): [in this window] [in a new window]   FIGURE 5. Large-diameter profile of U.S.-based 20% lipids packaged in plastic containers vs conventional glass bottles6 after introduction of plastic containers.

From the outset (time 0), the significantly higher proportion (2 logs) of fat globules >5 µm in the P-based lipids (2.56 x 10⁶/mL) compared with G-based lipids (4.96 x 10⁴/mL) as shown in Table IV is concerning because it may invoke greater participation of the immature reticuloendothelial system (RES) of the premature infant in the clearance of lipids from the plasma. In animals, the RES clearance of sizeable numbers of large-diameter fat globules from unstable total nutrient admixtures has produced evidence of oxidative stress in the tissues of the lung and liver,^17,18 with additional supporting data (elevated aspartate aminotransferase [AST] levels) indicating hepatic damage.¹⁸

In all cases during the simulated syringe-based infusion, the large-diameter tail of lipid injectable emulsions grew from the samples measured at the outset (time 0) to the final samples at 24 hours. The growth observed in the G-based lipid infusions was not significant and all measurements had PFAT₅ <0.05%, with the highest level recorded at a PFAT₅ = 0.023%. In contrast, the growth in the large-diameter tail from the P-based lipid infusion was statistically significant from time 0 to 24 hours, and all samples measured exceeded PFAT₅ <0.05%. Of the 48 measurements conducted on the P-based lipids at the 24 hour interval, 4 samples exceeded 0.40%, with the highest PFAT₅ value at 0.439%.

The coarseness of the P-based lipids found in this study corroborates previous findings^6,7 and most likely reflects an intrinsic change in the manufacturing process(es) of the new product rather than the plastic container because similar lipid injectable emulsions from another manufacturer in the same plastic bag have been shown to meet the proposed USP <729> globule size limits.¹⁹ In the neonatal intensive care unit, the intravascular exposure of very high concentrations of large-diameter fat globules upon IV infusion that exceed proposed USP limits, coupled with the lipid doses up to 6 times that routinely used in adults (3 g vs 0.5 g/kg/d), heightens the clinical safety concerns associated with newly introduced lipid injectable emulsions packaged in plastic containers.

The PFAT₅ limit of Method II of USP <729> is viewed as a stability-indicating parameter for lipid injectable emulsions.¹⁶ The reasons for this are obvious given the mechanism of instability inherent to all lipid injectable emulsions. Instability manifests as a growing population of large-diameter fat globules as a result of the fusion or coalescence of submicron lipid droplets. Thus, the acceptable starting point to monitor for changes in stability would be to apply methods of analysis that can accurately measure the large-diameter population in the tail of the GSD. Although there are several techniques capable of individually counting this population of large-diameter fat globules (ie, microscopy, electrical zone sensing or via the Coulter Counter, optical zone sensing or light obscuration/extinction) to accomplish this task,²⁰ Method II of the USP has determined light obscuration/extinction to be the reference method, as it has been for approximately 20 years for aqueous injectables as per Chapter 788 of the USP entitled "Particulate Matter in Injections."²¹ In fact, our first published work applying light obscuration/extinction in analyzing the stability of 90 different TNAs set out to "provide evidence to support its application to IV fat emulsions and TNA formulations."²² We found that when the PFAT₅ level exceeded 0.4% (or approximately 1 log higher than the measured baseline (0.020% ± 0.010%, n = 360 samples), the emulsions showed visible evidence of instability (ie, phase separation and free oil). In this same study, which also applied dynamic light scattering (DLS) to determine MDS as currently proposed in Method I of USP <729>, the MDS results gave no indication of the stability of the formulations, until the DLS data were subsequently stratified according to the light obscuration/extinction findings. Hence, Method I of USP <729> is primarily indicated as a qualitative measure of the homogenization process and is not stability-indicating, as is the case in Method II.

This study shows that plastic-based lipid injectable emulsions have very different large-diameter profiles compared with lipids packaged in conventional glass bottles, and a profile that appears to be further along the path toward instability. Increases in this population above proposed USP limits (ie, PFAT₅ <0.05%) indicate the product is less stable and occurs in a patient population that is uniquely susceptible to serious adverse effects associated with the administration of lipid injectable emulsions, as per the FDA-mandated black box warning regarding its use in infants. The normal metabolic fate of stable, submicron lipid injectable emulsions on infusion is principally by the actions of lipoprotein lipase found along the walls of the vascular endothelium. In contrast, large fat globules (>1 µm) seem to be more rapidly cleared and by a different mechanism, and although their binding sites and their destinations are not known, their metabolic fate is most likely by phagocytosis via macrophages of the RES.²³

Finally, although there appears to be some clinical disagreement about the proper "hang time" of lipid injectable emulsions with respect to infectious risks (ie, 18–24 hours²⁴ vs 12 hours²⁵), the present GSD data make another case for shorter infusion times on the grounds of stability. In fact, the mandate from USP <797> for "lipid-based emulsions where administration must be completed within 12 hours" should be strictly applied.⁸

In conclusion, the lipid injectable emulsions now available in P are unique compared with other nutrition emulsions made in G in that they do not meet the proposed specifications of USP <729>. During a simulated infusion, growth of large-diameter fat globules found in the tail of the droplet size distribution was significant over 24 hours. At present, this finding is most concerning in critically ill premature infants and neonates. Whether this translates to an unsafe product will require further clinical investigation, but nonetheless, these results indicate that a significant change in the quality of lipid injectable emulsions, coincident with its introduction in P, has occurred.

Top MATERIALS AND METHODS RESULTS DISCUSSION

 
Dr Driscoll is a consultant or researcher in the area of lipids for AstraZeneca, B. Braun, Biolink, and Hospira companies. Presented in part as a scientific paper (036) at the Clinical Nutrition Week in Dallas, TX, February 14, 2006.

Received for publication June 30, 2006. Accepted for publication September 13, 2006.

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Journal of Parenteral and Enteral Nutrition, Vol. 31, No. 2, 148-153 (2007)
DOI: 10.1177/0148607107031002148


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