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`
`The Effect on Syringe Performance of Fluid Storage and
`epeated Use: Implications for Syringe Pumps
`avid F. Capes, Dennis Herring, V. Bruce Sunderland, et al.
`
`(cid:160)R
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`(cid:160)D
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`1996
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`50,
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` 40-50
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`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
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`(cid:160)(cid:160)
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`RESEARCH ARTICLE
`
`The Effect on Syringe Performance of Fluid Storage and Repeated Use:
`Implications for Syringe Pumps
`
`DAVID F. CAPES*†, DENNIS HERRING*, V. BRUCE SUNDERLAND*, DALE McMILLAN†and
`CHARLES MCDONALD†
`
`†School of Pharmacy, Curtin University, Bentley and ‡Chemistry Centre of Western Australia, East Perth, Western Australia.
`
`ABSTRACT: Syringe stiction has been reported to cause syringe pump malfunction, hence the effect on syringe
`performance of syringe use and the formulations used in the syringe were investigated. The force required for
`syringe plunger motion (at 2.5 mm min -1), when filled with soybean oil emulsion (SBOE) and with water, and the
`extraction of silicone oil from syringes by these fluids, were measured for Primo®, Talus and Terumo® 10 mL, and
`Terumo 50 mL syringes. The breakloose, average extrusion and maximum force required to maintain plunger
`motion increased after storage ofSBOEfor7days in all syringes tested (p < 0.05). The storage of water increased
`the breakloose force of all syringes, but only increased the maximum force of Talus syringes, and both the average
`extrusion and maximum forces of Terumo 10 mL syringes. The mechanism for this is most likely swelling of the
`elastomer of the piston due to sorption of fluid. The force was found to increase logarithmically with repeated
`syringe use. Electrothermal atomization atomic absorption spectroscopy was used to measure the silicone oil
`content of syringe extractions. Three extractions were performed: repeated flushing, vigorous washing, and storage
`for 7 days with occasional agitation. Up to 69.4% of the silicone oil present in the syringes was extracted with both
`water and SBOE when they were stored or washed. In contrast to water, SBOE also extracted the lubricant when
`the syringe was filled and flushed immediately. If syringes are refilled, stored filled before use, or used over a
`prolonged period, particularly with a SBOE formulation, syringe stiction may occur during infusion with a syringe
`pump.
`
`Introduction
`
`Syringe pumps have become popular for intravenous
`drug infusion in intensive care, coronary care, and
`neonatal units because of the need for accurate infusion
`rates while administering minimal volumes. Drugs com(cid:173)
`monly given by syringe pumps are those for short-term
`and prolonged anesthesia and sedation including hypnot(cid:173)
`ics such as midazolam and propofol, opioid analgesics,
`neuromuscular blocking agents such as atracurium and
`vecuronium, and those for hemodynamic support such
`as dopamine and epinephrine. These drugs are pre(cid:173)
`sented as aqueous solutions except propofol, which, due
`to low solubility in water, is formulated in a 10% soybean
`oil emulsion (1). Diazepam is also available formulated
`in a 15% soybean oil emulsion (2) and may be infused by
`syringe pump. The emulsion may be infused by syringe
`pump for parenteral nutrition of neonates (3,4).
`In medical practice-syringe pumps are used with
`commercially available disposable syringes that have
`been primarily designed for manual use. There have
`been reports of syringe pump malfunction due to so
`
`Received November 11, 1994. Accepted for publication July 21, 1995.
`* Author to whom correspondence should be addressed: School of
`Pharmacy, Curtin University of Technology, GPO BoxU1987, Perth
`6001, Australia.
`This work was supported by Go Medical Industries Pty. Ltd. and in
`part by ICI Australia Hospital Products Pty. Ltd.
`
`called syringe "stiction," sticking of the piston during
`movement down the barrel (5, 6). Stiction occurs when
`the syringe pump fails to overcome the friction between
`the syringe piston and barrel, causing uneven, jerky
`movements and hence fluctuating flow rates. The resul(cid:173)
`tant boluses and periods of no flow have been associated
`with hemodynamic fluctuations during dopamine infu(cid:173)
`sion in neonates (7). Stiction may also activate pump
`occlusion or run-away alarms and was the reason for the
`recent recall of more than a million syringes (8).
`Commercial syringes are generally made of polypropyl(cid:173)
`ene with an elastomer piston on the end of the syringe
`plunger. The barrel is lubricated with silicone oil to
`reduce the coefficient of friction of the piston, while
`maintaining a seal to prevent solution leakage past the
`piston (9). Plunger movement is determined principally
`by the type and amount of lubricant, the interference or
`squeeze between the piston and barrel, and the amount
`of compression set (deformation) a constrained piston
`takes during sterilization and subsequent storage (10).
`Water washes have been shown to flush a proportion of
`the silicone lubricant from syringes (11) which may
`contribute to the reported syringe stiction problem, but
`the effect of soybean oil emulsion has not been docu(cid:173)
`mented. Syringe performance may also be influenced by
`the way the syringe is used. Syringes may be used after
`being filled and stored in a refrigerator for periods up to
`seven days (up to a month if frozen) particularly for
`
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`patients at home, depending on drug stability, microbial
`quality assurance, convention and supply practicalities
`at the institution (12, 13). Syringes may also be used
`multiple times. For example, one may be used to draw
`up the solvent, inject it into the vial for reconstitution of
`the powder, draw the drug solution out of the vial once
`dissolved, and then to inject the drug solution into the
`patient or infusion device.
`The aim of this study was to investigate the effect on
`syringe performance of syringe use, and the influence of
`water and of soybean oil emulsion when used in the
`syringe. In order to achieve this, the force required for
`syringe plunger motion and the extraction of silicone oil
`from syringes were evaluated.
`
`Materials and Methods
`
`Syringes
`The following syringe brands and sizes were chosen
`for evaluation: Terumo® 10 mL (Terumo Australia Pty
`Ltd, Melbourne, Australia, B: 2F205), Terumo 50 mL
`(B: 2B626), Talus 10 mL (Livingston, Sydney, Australia,
`B: 23E for extrusion rates and extraction, and B: 18E for
`storage and repeated use) and Primo® 10 mL (Asik,
`Rodby, Denmark, B: 0191019691A18 for syringe plunger
`motion and B: 200289 for silicone oil extraction). Primo
`brand is known as Pharmaplast®, Once®, Steriseal® and
`Ersta® in other countries.
`Primo syringes have a unique plunger piston consist(cid:173)
`ing of a thin ring made of silicone elastomer (Fig. 1)
`designed to minimize contact with the barrel and con(cid:173)
`tents in the syringe. The pistons of Talus, Terumo 10 mL
`and Terumo 50 mL syringes consisted of bromobutyl
`rubber, Santoprene® rubber (Monsanto Polymer Prod-
`
`Figure 1—Photograph of the plunger and piston of a conventional
`syringe (left) and a Primo® brand syringe (right) illustrat(cid:173)
`ing the difference in piston design. The piston of the
`Primo® brand is ring shaped and fits around, rather than
`over the top of the plunger, to reduce the contact area
`with the contents of the syringe.
`
`ucts Co., Akron OH), and an unspecified rubber respec(cid:173)
`tively.
`Approximate quantities of silicone oil (polydimethylsi-
`loxane) claimed to be sprayed into the syringes by the
`manufacturers (personal communication) are Terumo
`50 mL—12 mg, Terumo 10 mL—6 mg, Talus 3.5 mg and
`Primo 2.7 mg. Oil of viscosity 12,500 mm2 s_1 was used
`for the Terumo and Primo brands and 350 mm2 s_1 for
`Talus brand.
`
`Force Required for Syringe Plunger Motion
`
`The force required to initiate and maintain syringe
`plunger motion was measured with an adaptation of the
`methods specified by the Australian Standard (14) and
`Parenteral Drug Association (10). Syringes were tested
`at three speeds using two types of apparatus. The speed
`recommended by the Australian Standard is 50 mm
`min-1 and the others are factors of approximately 20-30
`times slower (as practical according to the equipment
`settings). Nominal speeds were 50, 2.5 and 0.08 mm
`min-1.
`With the apparatus used for testing at 50 mm min-1
`the syringe was stationary and the force gauge (Accu-
`force Cadet 0-90 N, resolution 0.1 N, Ametek, Largo FL,
`U.S.A.) was driven down onto the syringe plunger
`button. In contrast, with the apparatus used for the 2.5
`and 0.08 mm min-1 speeds, the force gauge was station(cid:173)
`ary and the syringe plunger button was driven up against
`the force gauge. The net effect of both apparatus was the
`same, the syringe plunger was driven down the barrel at
`a controlled speed with the force required to do so being
`continuously measured and recorded. When checked in
`triplicate with a stopwatch the actual speeds were found
`to be 47.22 (CV ± 1.38%), 2.53 (CV ± 0.01%) and
`0.079 (CV ± 0.04%) mm min-1. The force gauge was
`calibrated regularly with weights and the error was
`found to be ±0.2 N in the range used. However,
`temperature fluctuations during the prolonged runs at
`the slowest speed, caused drift of zero resulting in errors
`up to ±1.0 N with the 0.08 mm min-1 results.
`At least three new syringes were used for each test.
`When the syringe was filled with liquid, the plunger was
`drawn a minimal distance past the graduated capacity
`line, sufficient only to expel the air. With a new, dry
`syringe the plunger was first fully inserted. The piston
`seal was then aligned with the nominal capacity line,
`except for Talus brand which was tested from the
`graduated capacity line of 12 mL. The syringe was
`positioned vertically in the apparatus with the nozzle
`downwards and supported only by the flange. The
`plunger was straightened in the barrel so that the major
`axes of the plunger, barrel and force gauge were parallel
`to prevent lateral forces or rocking of the piston during
`operation. A fluid collection vessel was positioned under
`the syringe when required, so that the fluid height did
`not reach the syringe nozzle during operation.
`Data from the force gauge were available and re(cid:173)
`corded every 0.6 s by an IBM compatible PC on
`specifically written software. A typical data print-out is
`shown in Figure 2. Information derived from these data
`
`Vol. 50, No. 1 / January-February 1996
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`Figure 2—Example of a data printout from a Talus syringe at an extrusion rate of 2.5 mm min- 1, illustrating (A) breakloose force, (B) start of
`average extrusion force, (C) end of average extrusion force, (D) maximum force and (E) piston compressed against end of barrel.
`
`included the breakloose force, average extrusion force,
`and maximum force. The breakloose force is denned as
`the force required to commence movement of the
`plunger, and the extrusion force as that required to
`maintain plunger movement (9, 10). The average extru(cid:173)
`sion force excludes the breakloose force and the sharp
`increase in force at the end when the piston is com(cid:173)
`pressed against the end of the barrel. An average was
`taken of all readings recorded between these exclusions.
`The maximum force is simply the highest force recorded
`during the experiment.
`To establish the effect of extrusion rate, Talus syringes
`were tested at each rate, when used unfilled (i.e., dry),
`and when filled and used immediately with both milli-Q
`water and 10% w/v soybean oil emulsion (Intralipid®,
`KabiVitrum AB, Stockholm, Sweden). All other experi(cid:173)
`ments were subsequently performed at 2.5 mm min-1.
`The linear least-squares regression method was used to
`curve fit the data.
`The force required to maintain plunger motion after
`storage filled with water and with soybean oil emulsion
`was compared with the force when filled and used
`immediately. Talus syringes were tested after storage
`filled for one, seven and 91 days prior to use, but Primo
`and Terumo syringes were tested only after storage for
`seven days. Differences were evaluated by analysis of
`variance, and Fisher's protected least significant differ(cid:173)
`ence test for multiple comparisons was used to ascertain
`the origins of any significant (p < 0.05) differences.
`
`The effect of repeated use of syringes was investigated
`by re-using each syringe 12 times when unfilled and also
`immediately after filling. Talus brand was also tested
`after storage filled for 91 days prior to repeated use. The
`linear least-squares regression method was used to curve
`fit the data.
`
`Silicone Oil Extraction from Syringes
`
`Silicone oil extracted from syringes was measured as
`silicon using electrothermal atomization atomic absorp(cid:173)
`tion spectrometry. It was considered the most appropri(cid:173)
`ate method to achieve the low detection limits required
`by this study, with minimal sample handling to avoid
`contamination. Other techniques, notably inductively
`coupled plasma, have silica components that are likely to
`produce relatively high background levels when measur(cid:173)
`ing low concentrations of silicon. The silicone oil concen(cid:173)
`tration was calculated on the basis that silicon is 37.91%
`of the molecular weight of silicone oil of viscosity 12,500
`mm2s"l(9).
`A Varian SpectrAA 40 Zeeman atomic absorption
`spectrometer equipped with an auto sampler and con(cid:173)
`trolled by an Epson PCAX2 computer was used to
`quantify silicon concentrations. Apyrolytic coated graph(cid:173)
`ite tube was used for all measurements. The silicon
`hollow cathode lamp was operated at a current of 10
`mA. Absorbance was measured at 215.6 nm with a slit
`width of 0.2 nm. All absorbances were measured in peak
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`height. The furnace was operated in ten steps at tempera(cid:173)
`ture settings from 85 to 2900°C.
`To avoid potential silicon contamination from the
`environment all syringe manipulations were carried out
`in a class 10 horizontal laminar air flow cabinet. All
`equipment was rinsed thoroughly with milli-Q water and
`allowed to dry under the laminar flow cabinet. Non-
`lubricated plastic equipment was used for water and
`soybean oil emulsion to avoid silicon contamination
`from glassware, but glassware was used with carbon
`tetrachloride solutions. Care was taken to avoid the use
`of glassware to store samples and reagents; plasticware
`was used, and the graphite tube was given a number of
`"tube cleans" to remove contaminating silicon from the
`workings of the furnace and establish a suitable base
`line.
`Calibration curves were produced automatically by
`dilution of a 0.1 mcg mL"1 silicon standard solution to
`15 x 10_6L,with5 x 10-6L of palladium modifier plus 5
`or 10 x 10-6 L of standard solution and 5 or 10 x 10-6 L
`of blank solution. The standard solution was prepared
`from a 1 mg mL-1 silicon bulk solution (Alpha Re(cid:173)
`sources Inc., Stevensville, U.S.A.). The palladium modi(cid:173)
`fier was used to improve sensitivity and also to facilitate
`a high ashing temperature (700°C) for the removal of
`interfering matrix species prior to atomization. The
`modifier was a 500 mg mL-1 palladium solution in 1%
`v/v hydrochloric acid, that was prepared from palladium
`metal (Johnson-Matthey, Royston, England) and
`deionised water was used as the blank. Samples of
`soybean oil emulsion were spiked with the silicon calibra(cid:173)
`tion solution to examine the effect of that matrix on the
`atomization of silicon (compared to the aqueous me(cid:173)
`dium). It was revealed that there was no significant
`enhancement or suppression of silicon atomization by
`the soybean oil emulsion matrix under these conditions.
`The silicon concentration measured in the fluids before
`use with the syringes was 182 meg L_1 (SD ± 10) for the
`soybean oil emulsion and 2 meg L_1 (SD ± 0) for water,
`and the limit of detection was 2 meg L-1. Any drift due
`to degradation of the graphite tube was compensated for
`by recalibration after every ten samples. Containers with
`airtight lids were used, and immediately prior to sam(cid:173)
`pling for analysis the sample container was vigorously
`shaken to disperse the silicone oil.
`Three different extractions were performed (three
`syringes of each brand and size were used) with the
`soybean oil emulsion (B: 77934-51) and water:
`1. Flushing—syringes were filled and emptied repeat(cid:173)
`edly with each successive flush being expelled into
`a separate container. Ten flushes were performed
`but not all were analyzed to rationalize the number
`of measurements required.
`2. Storage with occasional agitation—syringes were
`filled, stored for seven days, inverted 180° three
`times for five out of the seven days, and then
`emptied. For both of the above, the syringes were
`filled to the nominal volume mark (care was taken
`not to draw back past this mark to avoid extracting
`
`"extra" silicone lubricant from beyond the mark)
`and inverted 180° three times.
`3. Washing—syringes were washed by shaking vigor(cid:173)
`ously (piston aligned with nominal volume mark)
`with five separate quantities of 1 mL, and the
`washings were pooled for analysis.
`
`In an effort to extract all the silicone oil present, an
`adaptation of a method for extraction from elastomeric
`closures was used (6). Because of the higher concentra(cid:173)
`tions, flame atomic absorption spectrometry was used to
`determine the silicone oil concentration. Three syringes
`of each brand and size were washed five times with 1 mL
`of carbon tetrachloride (AnalaR, BDH Chemicals Ltd,
`Poole, England) and the washings pooled. The carbon
`tetrachloride was evaporated and the residue dissolved
`in methyl iso butyl ketone (MIBK, AR Ajax Chemicals,
`Auburn, Australia). A Varian 475 flame atomic absorp(cid:173)
`tion spectrometer with a nitrous oxide/acetylene flame
`was used. The silicon hollow cathode lamp was operated
`at a current of 10 mA with a slit width of 0.2 nm. A stock
`solution of silicone oil 20 mg mL-1 (12,500 mm2 s_1 Dow
`Corning 200 Silicone Fluid, Dow Corning, Midland MI,
`U.S.A.) in MIBK was used to prepare calibration
`solutions of 0, 5 and 10 mg mL-1. The efficiency of
`silicone oil extraction with carbon tetrachloride wash(cid:173)
`ings was validated by washing 3 syringes to which 3.5 mg
`of silicone oil had been added. Two mL of a 1.75 mg
`mL-1 solution in hexane (AR Ajax Chemicals, Auburn,
`Australia) were instilled and the hexane evaporated
`using a vacuum rotary evaporator with a stream of hot
`air applied to the syringe.
`
`Results and Discussion
`
`The effect of extrusion rate upon the force required to
`maintain the plunger motion of Talus syringes, when
`used unfilled, and filled and used immediately with
`soybean oil emulsion and with water, is shown in Figure
`3. The logarithmic and linear curves of best fit to the
`mean data gave similar results, but the logarithmic curve
`is shown for clarity of data presentation. The average
`extrusion force increased as the extrusion rate de(cid:173)
`creased with soybean oil emulsion (r2 0.898), as did the
`maximum force with water (r2 0.593), but both forces
`decreased as the extrusion rate decreased when used
`unfilled (r2 0.948 and 0.643). The coefficient of determi(cid:173)
`nation was less than 0.2 for the average extrusion force
`with water and the maximum force with soybean oil
`emulsion. Since there was no clear relationship with
`extrusion rate, 2.5 mm min-1 was chosen for all subse(cid:173)
`quent experiments because it provided a manageable
`and convenient time interval (20 minutes compared with
`10.4 hours for the 10 mL size at 0.08 mm min-1).
`The effect of the duration of fluid storage in Talus
`brand syringes prior to use is shown in Figure 4. With
`water, the average extrusion force was significantly
`greater after storage filled for one, seven and 91 days
`when compared to filled and used immediately (0 days),
`but there was no difference between the storage periods
`(i.e., one and seven days, one and 91 days, seven and 91
`
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`Figure 3—The effect of extrusion rate on the (A) average extrusion
`force and (B) maximum force (mean ± SD) of Talus sy(cid:173)
`ringes (B: 23E) when used unfilled, and immediately after
`filling with water and with soybean oil emulsion. The
`regression line is not shown if r2 < 0.2, i.e., for the
`average extrusion force with water and maximum force
`with soybean oil emulsion, n = three or four, except for
`unfilled at 2.5 mm min- 1, where n = 12. Nominal extru(cid:173)
`sion rates were 50, 2.5 and 0.08 mm min- 1.
`
`Figure 4—The effect of the duration of storage of water, and of
`soybean oil emulsion on the (A) average extrusion force
`and (B) maximum force of Talus syringes (B: 18E) at an
`extrusion rate of 2.5 mm min-1 (mean ± SD, n =12).
`
`days). However, with soybean oil emulsion it increased
`significantly after storage filled for one day, further after
`seven days, and further again after 91 days. The maxi(cid:173)
`mum force increased four-fold after storage filled with
`water or soybean oil emulsion for one day, and by
`approximately a further 50% when stored for seven
`
`days. There was a further significant increase with water
`between seven and 91 days, but there was not significant
`difference with soybean oil emulsion. Since storage filled
`for seven days was sufficient to achieve near maximum
`effect for both the average extrusion and maximum
`forces, and pharmacy dispensed prefilled syringes are
`
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`often stored for this period, it was the time interval
`chosen for investigation of the other brands.
`Storage of soybean oil emulsion for seven days signifi(cid:173)
`cantly increased the average extrusion, maximum and
`breakloose forces of all syringe brands tested (Table I).
`Storage of water significantly increased the breakloose
`force of all syringe brands tested, but only had a
`significant effect on the maximum force of Talus syringes
`and both the average extrusion and maximum forces of
`Terumo 10 mL syringes. The average extrusion and
`maximum forces of Primo brand (which has a silicone
`elastomer piston) was not affected by water storage.
`Repeated use of the syringes increased both the
`average extrusion force and the maximum force, the
`exceptions being Primo when unfilled, and Terumo 10
`mL maximum force with soybean oil emulsion and with
`water (Fig. 5). The increase in force when the syringes
`were not filled is undoubtedly due to mechanical sweep(cid:173)
`ing of the silicone oil lubricant from the barrel as a result
`of piston movement (9,11). If this were the mechanism,
`then both forces would be expected to plateau in a
`logarithmic fashion, as progressively less silicone lubri(cid:173)
`cant was removed with each sweep. The coefficient of
`determination for the curve of best fit to the logarithmic
`mean data supports this hypothesis in most cases (Table
`II). Although the regression line with the Terumo 50 mL
`syringe had a positive gradient and a reasonable coeffi(cid:173)
`cient of determination (except with soybean oil emul(cid:173)
`sion), the forces seemed to peak during repeated use.
`Primo brand had the lowest gradients, showing it was the
`least affected by repeated use. The decrease in force
`with repeated use of Primo when unfilled and Terumo
`10 mL with soybean oil emulsion may have been due to
`spreading of the silicone oil. The latter may also have
`been due to a lubricating effect from the emulsion.
`When Talus brand was stored filled for 13 weeks (91
`days) the maximum force on the initial use was equal to
`
`the breakloose force, and was much greater than on
`subsequent uses (Fig. 6). Except after storage, the
`maximum force usually occurred at some point other
`than at initiation of plunger motion (Table I). It is
`unlikely to be caused by the nature of the fluid since
`both water and soybean oil emulsion gave the same
`result. When the syringes were first removed from their
`package the plunger piston had been in a fixed position
`for some considerable time since manufacture, and
`when moved, an impression of the piston remained on
`the barrel wall. This is probably due to sorption of
`silicone oil from the barrel wall by the elastomer of the
`piston, which is known to occur (9), and seems to explain
`the elevated maximum force, and correspondence with
`the breakloose force, on initial use after storage. Sweep(cid:173)
`ing of silicone oil over the impression would explain why
`the maximum force was not increased with subsequent
`use. The breakloose force of Terumo and Primo syringes
`was also significantly increased after storage of both
`fluids for seven days (Table I), suggesting that the
`elastomers of these brands also sorb silicone oil from the
`barrel wall. An impression of the piston was obvious on
`the barrel of new Terumo syringes after the piston had
`been moved, but not on the Primo syringe.
`The data in Figures 3 and 5 were compared to
`evaluate for differences between the forces when sy(cid:173)
`ringes were used unfilled or filled and used immediately.
`There would seem to be little difference because the
`only statistically significant difference was in the average
`extrusion force data of Talus in Figure 3, when filled and
`used immediately with water.
`The implication of elevated forces required for sy(cid:173)
`ringe function is that the possibility of the piston sticking
`in the barrel is increased. Sticking of the piston in the
`barrel can affect syringe pump function by causing
`fluctuating flow rates, pump alarm activation, and delay
`in the commencement of infusion. Fluctuations in flow
`
`TABLE 1
`Effect of the Storage of Water and of Soybean Oil Emulsion (SBOE) on Syringe Average Extrusion,
`Maximum and Breakloose Forces (N)"
`
`Syringe
`
`FUP-
`
`7 Days
`
`FUI
`
`7 Days
`
`Water
`
`SBOE
`
`(N)
`
`3.1(1.1)
`1.0 (0.4)
`18.2 (4.6)
`15.1 (2.5)
`
`4.8 (1.0)
`1.9 (0.7)
`26.0 (6.0)
`29.6 (8.3)
`
`Average Extrusion Force
`Primo
`Talus
`Terumo 10 mL
`Terumo 50 mL
`Maximum Force (N)
`Primo
`Talus
`Terumo 10 mL
`Terumo 50 mL
`Breakloose Force (N)
`5.5 (0.3)*
`4.3 (1.0)
`Primo
`6.3 (0.5)*
`2.2 (1.0)
`11.5(2.4)*
`1.2 (0.4)
`Talus
`11.1 (2.3)*
`1.6(1.1)
`5.6 (1.8)
`20.5 (3.4)*
`3,2 (1.7)
`Terumo 10 mL
`19.3 (2.6)*
`14.2 (4.6)
`30.9 (0.6)*
`11.7(4.3)
`Terumo 50 mL
`32.4 (4.0)*
`0 Force is presented as the mean and SD (in parenthesis), n = Primo: 4-7, Talus: 12, Terumo 10 mL: 3-7, and Terumo 50 mL: 3.
`b FUI = filled and used immediately.
`c Force beyond gauge capacity (90 N) during operation, for all but one syringe.
`* 7 days different to FUI, p < 0.05.
`
`4.4 (1.1)
`1.6 (0.8)
`26.1 (1.6)*
`14.2(1.1)
`
`5.6 (0.4)
`11.5(2.3)*
`34.3 (2.8)*
`28.1 (0.9)
`
`2.7(1.1)
`1.4 (0.9)
`21.8 (3.2)
`15.5 (3.1)
`
`3.6(1.1)
`2.5 (1.5)
`30.6 (4.5)
`28.6 (8.1)
`
`5.3 (1.8)*
`6.4 (1.0)*
`32.9 (3.7)*
`41.8C
`
`6.3 (0.6)*
`12.5 (2.5)*
`42.5 (4.4)*
`>90c
`
`Vol. 50, No. 1 / January-February 1996
`
`45
`
`Fresenius Ex. 2005
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`

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`
` on December 3, 2015
`
`A : Average Extrusion Force
`
`B: Maximum Force
`
`Trial Number (log scale)
`Figure 5—The effect of repeated use upon the mean (A) average extrusion force and (B) maximum force. Syringes were used 12 times at an
`extrusion rate of 2.5 mm min-1 when unfilled, or filled and used immediately with water or with soybean oil emulsion, n = three,
`except for Talus with water and soybean oil emulsion where n = 12. The regression line is not shown if r2 < 0.2.
`
`rate can have important consequences when potent
`vasoactive drugs with a short duration of action are
`being infused (7). If the occlusion pressure alarm senses
`force from the drive mechanism, rather than pressure
`from the infusion line, then activation of the alarm is
`dependent on the force applied to the syringe plunger.
`The occlusion alarm pressure of syringe pumps surveyed
`
`TABLE II
`Gradient and Coefficient of Determination of the Curve of
`Best Fit to the Logarithmic Mean Force Data for Repeated
`Syringe Use Presented in Figure 5
`
`Syringe Contents Gradient
`
`Gradient
`
`in 1987 (15) ranged from 390 to 1450 mmHg. Many
`pumps now have the option of setting a low occlusion
`alarm pressure, such as 100 mmHg, in an attempt to
`minimize infiltration and ensure rapid response (16).
`When using a 50-mL Terumo syringe, a force of approxi(cid:173)
`mately 9.0 N would be interpreted by the pump to be a
`pressure of 100 mmHg, and could activate the alarm.
`Similarly, a force of approximately 2.6 N with a 10- mL
`syringe would be interpreted as a pressure of 100 mmHg.
`The data in Table I indicate that if the syringes tested
`were used in pumps with occlusion alarms set at 100
`mmHg (and sensing from the drive mechanism), false
`alarms would occur because the syringe forces measured
`exceeded these alarm limits. The occlusion alarm pres(cid:173)
`sure settings necessary to prevent false alarms would be
`563 and 585 mmHg for the Talus and Primo 10-mL
`syringes, respectively (calculated from 15 N), and 1365
`and 385 mmHg for the Terumo 10- and 50-mL syringes,
`respectively (calculated from 35 N). More than a million
`Becton Dickinson brand syringes were recalled recently
`because their high breakloose force was causing false
`alarms with syringe pumps (8). A high breakloose force
`may also delay the commencement of infusion, particu(cid:173)
`larly at low flow rates. To prevent an elevated break-
`loose force causing these problems after storage of
`syringes prefilled, it may be necessary to move the
`syringe plunger prior to putting it into a syringe pump.
`
`PDA Journal of Pharmaceutical Science & Technology
`
`Unfilled
`Water
`SBOE
`Unfilled
`Water
`SBOE
`
`Unfilled
`Water
`SBOE
`
`Unfilled
`Water
`SBOE
`
`Primo
`
`Talus
`
`Terumo
`10 mL
`
`Terumo
`50 mL
`
`46
`
`Average
`Extrusion Force Maximum Force
`r2
`r2
`0.799
`0.341
`0.934
`0.901
`0.926
`0.934
`
`-0.488
`1.540
`0.672
`4.817
`3.978
`3.033
`
`0.428
`0.952
`0.923
`0.915
`0.907
`0.902
`
`-1.274
`0.522
`3.872
`7.285
`6.177
`3.872
`
`6.640
`1.866
`2.585
`
`19.299
`24.501
`19.440
`
`0.742
`0.175
`0.366
`
`0.844
`0.901
`0.482
`
`9.440
`-0.034
`-2.835
`
`24.388
`32.922
`13.656
`
`0.657
`0
`0.415
`
`0.578
`0.761
`0.101
`
`Fresenius Ex. 2005
`Bass et al. v. Fresenius Kabi USA, IPR2016-00254
`
`

`
`Downloaded from
`
`journal.pda.org
`
` on December 3, 2015
`
`the 50 mL size is greater than 30 N when stored for seven
`days filled with water or soybean oil emulsion.
`The extraction methods were designed to simulate
`conditions encountered in clinical practice. The flushing
`method subjects the syringe to the same agitation
`conditions encountered during routine use, for example
`syringes are flushed twice during recontitution. Ten
`flushes is unlikely to occur in clinical practice but it was
`extended to this number to establish trends. The storage
`method is analogous to conditions that would be encoun(cid:173)
`tered when a patient is dispensed seven days supply at
`once. The three 180° inversions were only gentle agita(cid:173)
`tion, of the type that could be expected during transport
`home, and taking them out of the refrigerator, and
`replacing them, several times during the week. The
`washing method would not be encountered clinically,
`but was performed to establish the level of extraction
`achievable. The quantity of silicone oil recovered by
`carbon tetrachloride washing is compared with the
`quantity claimed to be sprayed into the syringes by the
`manufacturers in Table III. The efficiency of recovery of
`the silicone oil by carbon tetrachloride washing was
`found to be 99.4% (SD ± 45.8).
`Silicone oil was detected in only three of the 20 water
`flushes, and the proportions extract