Abstract
Glass prefillable syringes are lubricated with silicone oil to ensure functionality and a consistent injection for the end user. If excessive silicone is applied, droplets could potentially result in aggregation of sensitive biopharmaceuticals or clouding of the solution. Therefore, monitoring and optimization of the applied silicone layer is critical for prefilled syringe development. The hydrophobic properties of silicone oil, the potential for assay interference, and the very small quantities applied to prefilled syringes present a challenge for the development of a suitable assay. In this work we present a rapid and simple Fourier transform infrared (FTIR) spectroscopy method for quantitation of total silicone levels applied to prefilled syringes. Level-dependent silicone oil migration occurred over time for empty prefilled syringes stored tip-up. However, migration from all prefilled syringes with between 0.25 and 0.8 mg of initial silicone oil resulted in a stable limiting minimum level of between 0.15 and 0.26 mg of silicone in the syringe reached after 1 to 4 years of empty tip-up storage. The results of the FTIR assay correlated well with non-destructive reflectometry characterization of the syringes. This assay can provide valuable data for selection of a robust initial silicone oil target and quality control of prefilled syringes intended for biopharmaceuticals.
LAY ABSTRACT: Glass prefillable syringes are lubricated with silicone oil to ensure functionality and a consistent injection for the end user. If excessive silicone is applied, droplets could potentially result in aggregation of sensitive biopharmaceuticals or clouding of the solution. Therefore, monitoring and optimization of the applied silicone layer is critical for prefilled syringe development. The hydrophobic properties of silicone oil, the potential for assay interference, and the very small quantities applied to prefilled syringes present a challenge for the development of a suitable assay. In this work we present a rapid and simple Fourier transform infrared (FTIR) spectroscopy method for quantitation of total silicone levels applied to prefilled syringes. Level-dependent silicone oil migration occurred over time for empty prefilled syringes stored tip-up. However, migration from all prefilled syringes with between 0.25 and 0.8 mg of initial silicone oil resulted in a stable limiting minimum level of between 0.15 and 0.26 mg of silicone in the syringe reached after 1 to 4 years of empty tip-up storage. The results of the FTIR assay correlated well with non-destructive reflectometry characterization of the syringes. This assay can provide valuable data for selection of a robust initial silicone oil target and quality control of prefilled syringes intended for biopharmaceuticals.
Introduction
Prefilled syringe (PFS) presentations of biologics intended for both health care provider and self-administration by patients are convenient and therefore desired by drug manufacturers. For glass syringes, silicone oil (polydimethylsiloxane, PDMS) is coated on the internal surface of the barrels to reduce the frictional gliding forces for injection. It is critical that enough silicone is applied during the manufacturing process to ensure functionality because the inability to complete the injection represents an unacceptable failure of a PFS. The uniformity of the silicone oil layer is also a key factor in providing smooth injection functionality (1). On the other hand, excess silicone oil application can lead to droplet detachment into the solution upon storage, which has been associated with cloudy appearance or aggregation of the protein (2⇓⇓⇓–6). Therefore, control and monitoring of the siliconization levels of glass PFSs can be useful for the development of biologics in PFS. A rapid assay to monitor the extent and time dependence of silicone oil migration on tip-up storage for sprayed-on silicone application could help in determination of appropriate controls. The levels of silicone targeted for 1 mL glass PFSs are expected to be within a fairly wide range of about 0.05–1 mg (50 to 1000 μg). Baked-on silicone levels are at the lower end of the range, and sprayed silicone levels at the middle and higher end. Such a small quantity is challenging to consistently and uniformly apply with high accuracy and precision over the entire barrel length. Because of its potentially critical nature, various methods for assaying and characterizing the silicone oil layer applied to the internal barrel of glass syringes can help drug developers and syringe manufacturers to determine appropriate control strategies. In this work we assess various methods and report the performance and implementation of a rapid and simple silicone oil total assay method for quality control of empty spray-siliconized glass PFSs.
Determining silicone oil levels can be challenging. Silicone oil is hydrophobic and soluble in non-polar solvents in all proportions (e.g., hexane, heptane, toluene, and xylene), is insoluble in very polar solvents (e.g., water and alcohols), and is partly soluble (up to 10%) in ethers and ketones (7). Trace analysis of silicones can be difficult because of potential issues with losses (due to affinity of silicone oil to surfaces), contamination (especially inorganic silicon such as glass and dust for non-specific methods), and complexities in sample preparation and analysis (8, 9). For potential routine analysis of silicone oil, an important consideration is the simplicity and throughput of the method, which can become a limiting factor. For instance, graphite-furnace atomic adsorption spectroscopy is a method that can achieve sensitivities of about 10 ng/mL although careful and time-consuming sample preparation in plastic containers and addition of matrix modifiers are needed to avoid contamination by inorganic silicon, formation of silicon carbides in the furnace, or loss of volatile silicone compounds (10). Gas chromatography is specific to silicone oil with sensitivity in the μg/mL range but requires fairly complex and lengthy sample digestion and end-capping procedures (8). Reflectometry is a non-destructive test that can determine the layer thickness on glass barrels and can also provide valuable profile information about the silicone distribution and uniformity that total silicone assays do not provide (11). One potential limitation of reflectometry is that it can be affected by interference in the signal due to the formation of droplets for syringes older than about 1.5 years (11). The signal from droplets is a sum of multiple thickness values that leads to interference and an underestimation of the total silicone oil level (11). Weight-based measurements require careful technique and accurate and precise balances to determine the difference in mass after extraction of silicone oil from syringes. Several studies have shown the feasibility of Fourier transform infrared (FTIR) spectroscopy for assay of silicone oil, but there are no reports documenting both a complete method performance and optimization of throughput for silicone extraction and quantitation from PFSs. For a routine assay of syringe silicone levels, spike recovery and accuracy should be known in addition to other method performance factors. An ideal method would have a high throughput with minimal sample preparation and with a short scan time (for instance, a time-consuming 100 or more scans are often used in FTIR assays). The practicalities of sampling techniques for FTIR analysis of silicone oil have been described (12). FTIR spectroscopy has been used to specifically identify silicones in tissue samples (8, 13). Characterization of coatings, including silanes, applied to glass fibers has also been performed using FTIR (14). Some challenges were reported, such as the glass signal at 1100 cm−1 caused interference when the fibers were ground and pressed into a pellet, low energy transmission was limiting for the direct examination of the fibers, and incomplete recovery of the coatings by solvent extraction with methanol was reported (14). Analysis of silicone oil dissolved in CCl4 was reported to have a detection limit of around 4 μg/mL, but spike recovery, accuracy, precision, and results for actual syringes were not presented (13). Silicone oil emulsions (used in studies of protein adsorption) were analyzed using liquid–liquid solvent extraction followed by FTIR with a reported quantitation limit of 190 μg/mL (15). Linearity for quantitation of silicone oil over the range 0.5 to 10 mg/mL (500 to 10,000 μg/mL) was presented as a poster case study (16). The impact of the requirement for extraction of syringes followed by evaporation and redissolution (for a 100 fold concentration) on method performance (accuracy, spike recovery, intermediate precision, assay throughput, and so on) was not reported in the poster presentation (16). We determined that an FTIR method could be amenable to rapid and routine testing of sprayed-on siliconized PFSs with some optimization to achieve the desired sensitivity and throughput. For our intended application we identified that the ideal sensitivity would allow for direct quantitation of silicone extracted from syringes at levels as low as about 100 to 150 μg/mL and that sample preparation and analysis should take no more than a few minutes.
This report describes the application and detailed performance characteristics (specificity, spike recovery and accuracy, repeatability and intermediate precision, linearity, range, and estimates of reproducibility and quantitation limit) of a rapid silicone oil assay method that uses the FTIR band of silicone oil at 1261 cm−1 (symmetrical (CH3)2-Si deformation band) to quantify the silicone that has been extracted from PFS syringe barrels. In addition to characterizing the performance of the assay according to ICH guidelines, we present results for multiple replicate PFSs from several batches with different initial applied levels. The FTIR assay results were compared to non-destructive reflectometry testing of PFSs. We also used the FTIR assay to demonstrate that excess silicone oil in the barrel of empty PFSs can migrate when stored in a tip-up configuration resulting in a stable, limiting minimum amount of silicone present in the syringe barrel after extended storage.
Experimental
Materials
Glass pre-fillable syringes (Physiolis® and Hypak®) were obtained as custom engineering runs from Becton Dickinson, BD (Franklin Lakes, NJ). The initial silicone oil level targets for syringes were about 0.25, 0.4, and 0.8 mg (250, 400, and 800 μg). The silicone was applied by diving nozzle technology, which applies a uniform layer to the inner barrel. Silicone oil, Dow Corning® 360 Medical Fluid 1000 cSt (Dow Corning, Midland, MI), was used to siliconize the syringes and to prepare calibrator standards and spiking solutions. The solvent used to extract the silicone oil was 95% high-performance liquid chromatography–grade n-hexane.
Extraction of Silicone Oil from Glass PFSs for FTIR Assay
The syringe needles were crimped closed using pliers so that liquid would not leave through the needle. The needle shield was then replaced. Using a positive displacement pipette, 1.0 mL of n-hexane was added to syringes and then the syringes were sealed by one of two methods. A custom-made aluminum plug with a hexane-resistant (e.g., nitrile or perfluoro) o-ring was used to seal the syringes for extraction of silicone oil with n-hexane. Alternatively, the syringe plunger and rod was covered with aluminum foil for sealing the flange end of the syringe barrel. Both sealing methods gave equivalent results. The sealing plug o-ring was seated about 3 mm below the flange. The sealed syringes were vortexed for 1 min such that the hexane formed a vigorous vortex inside the syringe barrel to extract the silicone oil. After extraction the sample was removed for analysis on the FTIR instrument.
FTIR Spectroscopy for Silicone Oil Assay
FTIR spectroscopy of silicone oil in hexane was performed on a PerkinElmer Spectrum 100 instrument (Waltham, MA). Samples were measured in a sealed liquid cell from Perkin Elmer with CaF2 windows and a 0.5 mm path length. A background scan was first performed for hexane from 4000 to 450 cm−1 at 4 cm−1 resolution. The software was set to average four replicate sample scans from 1320 to 1200 cm−1 at 4 cm−1 resolution in absorbance mode resulting in a rapid 30 s scan time per sample. For routine FTIR silicone oil assay readings, a single-point calibration standard was prepared in volumetric flasks targeted to between 400 and 600 μg/mL. The samples were quantitated by comparing their absorbance value at 1261 cm−1 (to at least 4 significant figures) to the standard. Between samples, the cell was washed twice with hexane and dried with a stream of air to remove residue from previous samples. To ensure the cell was clean, the absorbance of hexane solvent was verified to be <0.005 AU.
Reflectometry Measurement of Silicone Oil Layer Thickness
Reflectometry was used to compare the thickness and mass of silicone oil with the measured value determined by FTIR. A Rap.ID Layer Explorer instrument (Particle Systems GmbH, Berlin, Germany) was used to measure the silicone oil thickness of the PFSs, which were then each assayed by FTIR. Eight strips of 50 data points were measured around the PFS barrel and the thickness distribution was used to output the mass of silicone oil. The thickness of the layer was converted to total mass by the software with an adjustment to correct for the unmeasured barrel length (11).
Results and Discussion
Table I shows the performance summary for the FTIR assay of silicone oil extracted from syringe barrels. The performance was assessed based on ICH guidelines (17). Based on the performance factors, the method is suitable for the intended use for extraction and assay of sprayed-on silicone oil from empty glass PFS barrels. The assay developed was very rapid. The overall throughput of the method was less than 5 min per sample including preparation (less than 3 min) and scan time (about 30 s).
Performance Summary of the FTIR Method for Quantitation of Silicone Oil Extracted from Glass PFS Syringes
Specificity of FTIR Silicone Assay
This method uses the infrared absorbance band at 1261 cm−1 specific to the symmetrical (CH3)2-Si deformation band of silicone oil. Hexane was selected as the solvent for the extraction of the glass syringes based on its ability to fully extract the silicone oil and because of the low interference in the FTIR measurements. Methyl isobutyl ketone and chloroform were also assessed but either interfered with the silicone oil quantitation band or had incomplete recoveries with baseline drift, respectively (data not shown). The absorbance spectrum of a silicone oil sample is shown in Figure 1. The inset shows the single-beam raw infrared spectral band for silicone oil dissolved in hexane and the hexane solvent, confirming that the silicone oil peak is adequately resolved from the solvent background. The assay of non-siliconized syringe blanks was below the limit of detection (<LOD), confirming that there were no interfering signals from the syringe itself and that specificity of the method is acceptable (see Table II).
Infrared absorbance spectrum of 800 μg/mL silicone oil in hexane. The inset shows the raw single-beam spectra of the 800 μg/mL silicone oil in hexane (orange line) and the hexane solvent (dashed gray line).
Accuracy and Precision (Repeatability) of FTIR Silicone Oil Assay
Linearity, Range, Limit of Detection, and Limit of Quantitation of FTIR Silicone Assay
The FTIR absorbance at 1261 cm−1 for three replicates of seven levels of silicone oil standards (each prepared in triplicate) is shown in Figure 2 (several data points are shown but appear as one due to overlay). The regression statistics demonstrate that the pooled data fit well to a linear correlation over the intended assay range (Table I). The estimated limit of quantitation (LOQ) was calculated as 10 times the standard error of the regression line divided by the slope of the regression line, respectively (Table I) (13). The estimated LOQ of about 61 μg per syringe adequately optimizes sensitivity with throughput for the assay of the levels of silicone oil expected from sprayed-on PFSs. In addition, the measurement is very rapid and simple (fewer than 5 minutes required per sample). It is possible that for future applications there may be a desire to increase the sensitivity (LOQ). A quick estimate based on the square root signal-to-noise ratio dependence on number of scans predicts that increasing from our current 4 to 400 scans would result in a 10 fold increase in sensitivity but would also increase the measurement time from 30 s to about 1 hour. An alternate approach could be to increase sensitivity through pooling of samples followed by concentration through drying and re-dissolution of the sample in a smaller solvent volume, although this would decrease the throughput considerably.
Silicone oil FTIR peak absorbance (AU) at 1261 cm−1 versus level for three standard preparations (several data points and error bars are obscured by their overlay).
Accuracy and Precision (Repeatability) of FTIR Silicone Assay
Spike recovery studies of silicone oil standards (prepared from pure silicone oil by mass) in non-siliconized syringe blanks were used to determine the accuracy and repeatability precision. Non-siliconized syringe blanks were also assayed to confirm specificity. Three replicates at three target levels of silicone oil were spiked into the syringes and then dried (to evaporate the volatile hexane solvent and deposit the silicone oil on the syringes) with a stream of nitrogen. The assay was then performed on these spiked syringes. The measured accuracy of the method was about 90 to 101% (closeness to true spiked value), and the repeatability was about 10% based on the coefficient of variation (CV) for multiple spiked syringe sample measurements (Table II).
Intermediate Precision of FTIR Silicone Assay
A set of ten syringes were analyzed by two analysts on two days each for four total sets of data. These gave an overall average of 235 ± 21 μg (n = 40, CV of 9%). Figure 3 shows a histogram of the complete set of intermediate precision data. The maximum difference of a sub-set average value from the global average value was 8% (255 μg) and the maximum variability within a sub-set was 9%. The variability in these results is a worst-case scenario in that it includes both the assay variability and also the variability in the batch of sample PFSs that were analyzed. These results indicated that the intermediate precision CV of about 9% was acceptable from day-to-day and analyst-to-analyst for the intended assay purpose.
Histogram of the complete set of 40 measurements conducted to assess the intermediate precision of the FTIR assay.
Reproducibility of FTIR Silicone Assay
We compared our FTIR silicone assay results to those reported by Falk et al. as an indirect estimate of inter-laboratory reproducibility (13). They assayed silicone oil in CCl4 (use of this solvent has been limited in recent years) at 1260 cm−1 using a 0.5 mm path length cell obtaining a regression slope of 2.457 × 10−4 AU·mL/μg silicone oil per 0.5 mm cell path length with a standard error of 0.00073 AU. The slopes we obtained in this current work are within 9% of this value (Table I). Differences in the slope are likely due to expected inter-laboratory differences such as the type of solvent (impact on absorbance), the cell (exact path length, cell condition), exact wavelength used, instrument, and so on.
Stability of Calibration Standards for FTIR Silicone Assay
Calibration standards were sealed in containers with a polytetrafluoroethylene (PTFE)-lined hermetic screw cap. After 2 days at room temperature the standard remained within 0.5% of the initial value. Twenty-six measurements of aliquots of a 483 μg/mL standard stored −80 °C for up to 12 months remained stable within 5% of the initial value. We considered the standard stability within 5% as acceptable for the purpose of this assay.
Silicone Oil levels Assayed for Actual Syringe Samples Using the FTIR Assay
Results for several lots of syringes with both 0.25 and 0.4 mg (250 and 400 μg) nominal silicone target levels are given in Table III. All these syringes were assayed at about 3 to 4 months from the initial manufacture date. These PFSs were from custom development engineering runs. The results show that, for these lots, the assay results were within about 75% of the nominal target and that the sample variabilities were also about 15%. The lower measured versus target level for silicone oil is likely due, in part, to migration of excess silicone over time. Aging data in Figure 6 indicates a 10% migration is expected within the first 3 to 6 months. Small deviations in the measured versus target levels can also be due to simple variability in the actual application level as well as the 10% variability in the measurement assay itself.
Examples of FTIR Silicone Assay Data Obtained for Multiple Lots of Syringes with Ages of Less than 4 Months with 0.25 and 0.4 mg Nominal Initial Silicone Oil Targets
Comparison of Reflectometry Measurements with FTIR Assay Results for Empty PFSs
Results for individual empty syringes measured by reflectometry and then assayed by FTIR are shown in Figure 4. Two lots were compared: Lot G (target silicone = 0.25 mg, age = 7.6 months); and Lot H (target silicone = 0.4 mg, age = 5.2 months). These results show that the reflectometry and FTIR assay correlated very well within the errors and variability of both methods. The results for Lot G were 218 ± 17 μg by FTIR compared with 207 ± 23 by reflectometry. The results for Lot H were 304 ± 26 μg by FTIR compared with 308 ± 26 μg by reflectometry. See the section on silicone oil migration for a discussion about the measured level and the age of the PFSs. Figure 5 shows the reflectometry results for ten replicates of the silicone oil distribution over the length of the PFSs for lot H (target silicone = 0.4 mg, age = 5.2 months). The distribution and uniformity of the silicone oil layer has been shown to be critical for functionality (1). The ability of the reflectometry method to provide thickness and distribution profile information about the layer is one major advantage it has over the total silicone assay by FTIR. The data for each profile is the average of eight radial strips around the circumference of the PFS. The profile results show a good coverage of silicone oil over the entire length of the barrel, which can be attributed to the diving-nozzle siliconization technology. The profiles also indicate the uniformity of the siliconization is quite good for the ten replicates.
Correlation of the average silicone oil mass determined by reflectometry with the total silicone oil assayed by FTIR for 10 syringes from two different lots: open circles, Lot G (target silicone = 0.25 mg, age = 7.6 months); filled diamonds, Lot H (target silicone = 0.4 mg, age = 5.2 months). The dashed line indicates the theoretical prediction for a 1:1 correlation between the two methods.
Ten replicates of the silicone oil distribution over the length of the PFS for Lot H (target silicone = 0.4 mg, age = 5.2 months) measured by reflectometry. The data for each profile is the average of eight radial strips around the circumference of each PFS.
Silicone Oil Migration over Time from Empty PFSs Stored Tip-Up in Tubs
We assayed multiple lots of empty syringes, at multiple repeated time points, with initial targets of 0.8, 0.4, and 0.25 mg of silicone oil. The PFSs were stored as received in sterile-wrapped tubs of 160. Overall trending analyses of the compiled data are presented in Figure 6. The results show greater migration of silicone oil from the empty PFS with a higher initial target level. The data for the 0.8 mg target PFS indicated there was a significant loss due to migration over the first year of storage. The silicone level of the 0.8 mg PFS stabilized to a limiting minimum of about 0.23 mg after about three years. Migration loss for the initial 0.4 mg PFSs stabilized at a minimum of about 0.17 to 0.26 mg after between 1 and 3 years. The 0.25 mg initial target level PFSs had a lower migration that stabilized at a minimum of about 0.15 to 0.19 mg after between 1 and 4 years of empty storage. The results are consistent with a level-dependent migration and redistribution of silicone oil in the barrel. The migration over time resulted in a fairly stable limiting minimum level of between about 0.15 and 0.26 mg of silicone after between 1 year and 4 years of storage for all PFSs with a wide range of 0.8 to 0.25 mg of initially applied silicone target levels. A poster case study had reported a high and unexplained variability in the silicone oil levels for multiple lots of PFSs (16). Based on our current findings it is possible that reported variability in silicone levels on PFSs could have been due to differences in the silicone application technology (e.g., whether a diving nozzle was used or not) or due to differences in the age of the assayed PFSs.
Silicone oil assay results versus tip-up storage age. The data is aggregated together from multiple measurements of several lots at multiple time points for overall trending assessment. The results are the average assayed value with error bars representing the standard deviation of multiple (≥10) measurements. Results are for three initial target silicone oil levels: 0.8 mg, red triangles; 0.4 mg, green squares; 0.25 mg, blue circles. An exponential line was fitted to the data to highlight the overall trends over time: 0.8 mg target data (red dash-dot line, R2 = 0.99), 0.4 mg target data (green line, R2 = 0.70), and the 0.25 mg target data (dashed blue line, R2 = 0.85).
This work is limited in focus to the assay of total silicone oil levels in empty PFSs. A limitation of all total silicone assays, including the FTIR assay described in this work, is that they cannot assess the distribution or uniformity of the applied silicone oil layer over the entire barrel length. It is known that the distribution of silicone oil and ultimately the retention of functionality are critical to monitor for PFS development and that total silicone level is only part of the data needed in PFS development studies. Complementary methods such as reflectometry are suitable for confirming the distribution of oil on empty PFSs. Another limitation of the FTIR method is that for each time point we had to perform destructive extraction and analysis of the silicone oil, meaning that changes for any one individual PFS could not be monitored over time. The data we presented is therefore based on sampling statistics. In contrast, given that the exact same PFS could potentially be monitored over time by reflectometry, then reflectometry can provide additional insight into silicone distribution changes on empty storage of PFS that might correlate with functionality. Also, as an instrumental method that does not require use of solvents, reflectometry may also be more suitable for use at a parenteral fill–finish facility. In this work, the FTIR assay was able to successfully track and monitor migration of total silicone oil over time, which is an important aspect to consider for storage of empty PFSs. The data for the migration rates as a function of applied level, and the final limiting minimum values, are useful in PFS design space development and quality control and storage strategies.
Tracking the Balance of Silicone Oil due to Migration from Empty PFSs Stored Tip-Up in Tubs
The balance of silicone oil lost from the inner barrel of syringes due to migration over time when stored in a tip-up orientation in sterile-wrapped tubs was investigated. We assessed a tub 0.4 mg PFSs aged 26 months, which assayed at 252 μg per syringe. The first measurement of these PFSs, performed after 5 months of tip-up storage, gave 329 μg of silicone oil per barrel. We cut a portion of the Tyvek® insert sheet from an aged tub of 160 PFSs, extracted it with hexane, and assayed the extract for silicone oil. We measured that an average of about 43 μg of silicone oil per PFS had migrated (dripped out) and collected onto the insert sheet inside the sterile tub packaging. Also, because the sealing plug o-ring sits about 3 mm inside the barrel during extraction, we wiped this area on the extreme flange end and assayed for recovered silicone oil. We determined that about 69 μg of silicone was accumulated at the extreme bottom of the flange end for these aged PFSs. These data are consistent with the migration of silicone down the syringe and accumulation at the extreme flared end of the barrel flange with some dripping onto the insert sheet inside the sterile tub over long storage times. The average mass recovered from the insert sheet (43 μg), the extreme end of the flange wipe (69 μg), and each PFS itself (252 μg) sum to 364 μg per syringe compared to the first measured barrel value of 329 μg after 5 months. Consistent with Figure 6, this indicates that the silicone oil had migrated from the main inner barrel on empty storage and partly accumulated at the end of the flange and partly dripped out onto the tub insert sheet over time. The total silicone assay by FTIR has additional value for measurements, such the migration onto the insert sheets, because of its ability to extract and specifically assay for silicone oil from surfaces other than PFS barrels. Another advantage of the FTIR assay approach is that it is also possible (with further development and confirmation of performance) that the total silicone oil assay could be adapted to assay silicone oil on non-glass materials such as polymeric syringes or stoppers.
Summary and Conclusions
A rapid and simple FTIR-based method for measuring the concentrations of silicone oil sprayed in PFS syringe barrels in less than 5 minutes was developed and evaluated. The data indicated that the method is suitable for the intended use of measuring the sprayed silicone oil levels for the characterization of PFS syringes. Measurement of several lots of syringes at multiple time points demonstrated that migration occurred on empty tip-up storage. Migration was level-dependent, with higher initially applied levels experiencing a greater rate and overall loss upon initial storage. The silicone oil levels reached a stable limiting minimum value of between 0.15 and 0.26 mg of silicone after between 1 and 4 years of storage for all PFSs with between 0.25 and 0.8 mg of initially applied silicone. We demonstrated that some migrated oil had accumulated on the extreme edge of the flange and some had dripped onto the tub insert sheets. These results provide valuable design information for achieving balance between applying enough silicone oil lubricant to ensure functionality while avoiding excess application that can potentially lead to particle formation or aggregation of sensitive protein solutions. This assay can be used to generate data to inform the quality control of empty glass PFSs. The trending data can be used as a guide for the behavior of silicone oil migration from empty storage of PFSs to aid, in combination with other assessments, in the selection of initial target silicone oil target levels for PFSs intended for biopharmaceuticals.
Conflict of Interest Declaration
The authors declare that they have no competing interests.
- © PDA, Inc. 2014
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