Journal of Diabetes Science and Technology
`Volume 7, Issue 5, September 2013
`© Diabetes Technology Society
`
`ORIGINAL ARTICLE
`
`Dose Accuracy and Injection Force of Different Insulin Glargine Pens
`
`Arnd Friedrichs, Ph.D.,1 Janine Bohnet, Dipl.-Ing. Biotechnology,2 Volker Korger, Ph.D.,3
`Steffen Adler, Ph.D.,1 Manfred Schubert-Zsilavecz, Ph.D.,2A and Mona Abdel-Tawab, Ph.D.2
`
`Abstract
`
`Background:
`Dose accuracy and injection force, representing key parameters of insulin pens, were determined for three pens
`delivering insulin glargine-based copies, Pen Royale (WR) and DispoPen (WD) for Glaritus® (Wockhardt)
`and GanLee Pen (GL) for Basalin® (Gan & Lee), compared with pens of the originator, ClikSTAR® (CS) and
`SoloSTAR® (SS) for Lantus® (Sanofi).
`
`Methods:
`Using the weighing procedure recommended by DIN EN ISO 11608-1:2000, dose accuracy was evaluated based
`on nonrandomized delivery of low (5 U), mid (30 U), and high (60 U) dosage levels. Injection force was measured
`by dispensing the maximum dose of insulin (60 U for the GL, WR, and WD; 80 U for the SS and CS) at dose
`speeds of 6 and 10 U/s.
`
`Results:
`All tested pens delivered comparable average doses within the DIN EN ISO 11608-1:2000 limits at all dosage
`levels. The GL revealed a higher coefficient of variation (CV) at 5 U, and the WR and WD had higher CVs at all
`dosage levels compared with the CS and SS. Injection force was higher for the WR, WD, and GL compared
`with the CS and SS at both dose speeds. In contrast to the CS and SS with an end-of-content feature, doses
`exceeding the remaining insulin could be dialed with the WR, GL, and WD and, apparently, dispensed with
`the WD.
`
`Conclusions:
`All pens fulfilled the dose accuracy requirements defined by DIN EN ISO 11608-1:2000 standards at all three
`dosage levels, with the WR, WD, and GL showing higher dosage variability and injection force compared with
`the SS and CS. Thus, the devices that deliver insulin glargine copies show different performance characteristics
`compared with the originator.
`
`J Diabetes Sci Technol 2013;7(5):1346-1353
`
`Author Affiliations: 1LWS Risk Management Consult, Brannenburg, Germany; 2Central Laboratory of German Pharmacists, Eschborn, Germany;
`3sanofi-aventis Deutschland GmbH, Frankfurt, Germany; and 4Institute of Pharmaceutical Chemistry, J.W. Goethe-University, Frankfurt, Germany.
`
`Abbreviations: (CS) ClikSTAR, (CV) coefficient of variation, (GL) GanLee Pen, (SD) standard deviation, (SS) SoloSTAR, (WD) DispoPen,
`(WR) Pen Royale
`
`Keywords: dosing accuracy, injection force, insulin pens
`
`Corresponding Author: Arnd Friedrichs, Ph.D., LWS Risk Management Consult, Bahnhofstr. 9, D-83098 Brannenburg, Germany; email address
`arnd .friedrichs@lwsgroup .com
`
`1346
`
`Sanofi Exhibit 2123.001
`Mylan v. Sanofi
`IPR2018-01676
`
`

`

`Dose Accuracy and Injection Force of Different Insulin Glargine Pens
`
`Friedrichs
`
`Introduction
`
`Rr patients with diabetes who self-inject insulin, accurate insulin dosing is a requirement to maintain normal glycemia
`
`levels and minimize the risk of hypoglycemia or hyperglycemia. Compared with vial and syringe, insulin pens offer
`substantial improvements in compliance and flexibility.1,2 Previous studies generally have verified the accurate dosing
`of insulin pens,3- 7 although single doses outside the International Organization for Standardization limits (DIN EN
`ISO 11608-1:2000) have been reported in small-scale studies.3,5,s Injection force is also a key element in the design of
`an insulin pen,9,10 as lower injection forces are associated with simpler operation, more comfortable use,11 and less
`injection-site pain.8
`
`Insulin glargine (Lantus®, Sanofi) copies, Glaritus® (Wockhardt) and Basalin® (Gan & Lee), have been introduced in
`several countries. Copies of biological medicinal products are not directly compared and analyzed against a licensed
`reference biological product according to comprehensive biosimilar regulations.12 In the case of the insulin glargine
`copies, differences have been found in the impurity profiles that result from differences in the production process.12
`Because of these differences in impurities, it has been recommended to investigate their immunological potential to
`ensure patient safety.12 In addition to the insulin glargine copies not being identical with the original, the devices
`used to deliver the copies may also differ from those that deliver the original insulin glargine, resulting in different
`performance characteristics.
`
`The objective of the current study was to evaluate the dosing accuracy and injection force of two reusable insulin pens
`[Glaritus Pen Royale (WR; Wockhardt) and GanLee Pen (GL; Gan & Lee)] and one prefilled pen (Glaritus DispoPen
`[WD; Wockhardt]) that have been introduced for injecting Glaritus and Basalin and to compare them with the reusable
`Lantus ClikSTAR® (CS; Sanofi) and the prefilled Lantus SoloSTAR® (SS; Sanofi) pens. Both reusable and disposable
`pens combine an insulin vial and a syringe. However disposable pens are prefilled with an insulin cartridge and
`are discarded when the insulin runs out, whereas reusable pens may be reloaded with insulin cartridges by the user.
`The pens listed above represent all insulin glargine pens commercially available at the time of the study.
`
`Methods
`
`Study Design
`The CS and SS were supplied by the manufacturer
`(Sanofi, Germany). The other pens were purchased by
`Sanofi from official pharmacies: GL in China and WD
`and WR in India. All needles were purchased in Germany
`by Sanofi. For dose accuracy measurements, all pens were
`equipped with BD Micro-Fine + 0.25 mm (31 G) x 8 mm
`needles, and for injection force measurements with BD
`Micro-Fine + 0.25 mm (31G) x 5 mm needles to ensure
`comparability of the data. An overview on the pens
`included in the study is given in Table 1.
`
`Table 1.
`Insulin Pens Included in the Study
`
`Insulin
`pen
`
`cs
`
`WR
`
`Manufacturer
`
`Insulin
`
`Dose
`accuracy
`
`Pen lot
`
`Sanofi
`
`Lantus
`
`C016
`
`Injection force
`
`Pen lot
`
`C0068
`
`Wockhardt
`
`Glaritus
`
`XJ10395
`
`XK11050
`
`GL
`
`Gan & Lee
`
`Basalin
`
`ss
`
`Sanofi
`
`Lantus
`
`101002-09
`018
`
`40 U1428
`40 U1448
`
`XLB01A
`
`coo2a
`
`WD
`
`Wockhardt
`
`Glaritus
`
`DJi0276
`
`DK11997
`
`For determining dose accuracy, each pen type was tested
`at a low (5 U), mid (30 U), and high (60 U) dosage level.
`For the prefilled pens, SS and WD, 15 of each pen type
`were used to deliver each dosage level, totaling 45 pens for each pen type. For the reusable pens, CS, WR, and GL,
`all three dosage levels were delivered from one pen using a new insulin cartridge for each dosage level. In total,
`15 pens of each reusable pen type were included.
`
`a The data for these pens have been generated in previous
`13
`14
`studies. 7
`·
`·
`
`Each dose of the 5, 30, or 60 U dosage levels was dispensed four times in a nonrandomized manner from each pen/
`cartridge, thus generating 180 values for every pen type (Figure 1).7
`
`J Diabetes Sci Technol Vol 7, Issue 5, September 2013
`
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`IPR2018-01676
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`

`

`Dose Accuracy and Injection Force of Different Insulin Glargine Pens
`
`Friedrichs
`
`The individual insulin pens were operated according to
`the manufacturers' instructions. Prior to starting the
`sequence of measurements, two priming doses of 2 U were
`discarded. If needed, priming was repeated until a drop
`was seen on the tip of the needle. After delivering each
`dose and in accordance with the instruction manual
`for each pen model, the plunger was kept pressed down
`for 5 s with GL and for 10 s with all other pens to
`ensure that the entire dose was expelled. Each dose
`was deposited in a beaker containing a 0.5-1 cm layer
`of liquid paraffin, while the pen was held close to the
`surface of the paraffin layer. If an insulin drop remained
`at the tip of the needle at the end of the relaxation time,
`this drop was stripped off at the paraffin surface, taking
`care that the needle did not strike the paraffin. The dose
`was weighed immediately using an analytical balance
`(XP205/M, Mettler Toledo AG, Giefsen, Germany), which
`has an accuracy of 0.01 mg. The balance was reset to zero
`before each dose of insulin was deposited and weighed.
`The weights were corrected for
`the specific density
`corresponding to 1.005 g/cm3 for Lantus, Glaritus, and
`Basalin, which had been determined in a preliminary
`study using a DMA 4500 densitometer (Anton Paar GmbH,
`Bruchkobel, Germany).
`
`Attachment of new needle and priming with 2-4 U
`
`Delivery of the respective dose, we1gh1ng and recording the mass
`
`Dispensing of 60 + 28 U, 55 U, and 15 U in case of
`5 U, 30 U, and 60 U, respectively, without recording the mass
`
`Attachment of new needle and priming
`
`Delivery of the 2nd dose, we1gh1ng and recording the mass
`
`Dispensing of 60 + 28 U, 55 U, and 15 U in case of
`5 U, 30 U, and 60 U, respectively, without recording the mass
`
`Attachment of new needle and priming
`
`Delivery of the 3rd dose, weighing and recording the mass
`
`Dispensing of 60 + 28 U, 55 U, and 15 U in case of
`5 U, 30 U, and 60 U, respectively, without recording the mass
`
`Attachment of new needle and priming
`
`The injection forces of the WR and GL reusable pens
`and the WD prefilled pen were measured in newtons
`as previously described for CS13 and SS,14 using an
`isometric injection with a Zwick Z0.5 TS testing machine
`(Zwick GmbH & Co. KG, Ulm, Germany). Prior to the tests, the instrument was calibrated by the manufacturer in a
`laboratory environment under standard atmospheric conditions. The results obtained for the WR, GL, and WD were
`compared with previous results generated for the CS13 and SS.14
`
`Figure 1. Dose delivery procedure.
`
`Delivery of the 4th dose, weIghIng and recording the mass
`
`Twenty pens of each type were tested per test series. Each WR, WD, and GL pen was tested once, whereas each
`CS pen was tested twice with the same pen13 and each SS pen three times with the same pen.14 After priming with
`10 U (0.1 ml), the injection force was measured at the maximum dose level for each pen [60 U (0.6 ml) for the WR,
`WD, and GL; 80 U (0.8 ml) for the CS and SS], applying a constant volume flow rate (injection speed) of 6 or 10 U/s.
`The comparison of injection forces at constant volume flow rates has been shown to better represent real-life
`situations.14
`
`Preliminary studies were conducted to determine button speeds (millimeters/second) for specific volume flow rates
`(units/second). The units/second was calculated from the dispensed volume (unit) and the injection time (second).
`The weight of the dispensed dose was measured using an OHaus Discovery DV 215 CD precision and analytical
`balance (capacity 210 g; repeatability 0.1 mg, linearity ± 0.2 mg). The conversion into units was done using the density
`and the concentration (100 U/ml) of the insulin solution. The injection time for complete injection of the dose was
`calculated from the initial movement of the dose button to an injection force exceeding 2 N per 0.025 s.
`
`Calculated regression lines of volume flow rate versus button speed were used to determine the button speed
`required for each pen type to achieve a constant volume flow rate of 6 or 10 U/s. For each pen tested, injection forces
`throughout dose delivery were measured; the maximum injection force was noted and the mean plateau injection
`force calculated.
`
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`Dose Accuracy and Injection Force of Different Insulin Glargine Pens
`
`Friedrichs
`
`Statistical Analysis
`The evaluation of dose accuracy was based on the recommendation of the International Organization for Standardization
`(DIN EN ISO 11608-1:2000).15 According to DIN EN ISO 11608-1:2000, the acceptance limit for each individual dose
`should not deviate by more than 1 U for doses < 20 U and not more than 5% for doses >20 U. Hence the acceptance
`limits for the individual doses tested in this study are 5 ± 1 U (4.0-6.0 U), 30 ± 1.5 U (28.5-31.5 U), and 60 ± 3 U
`(57.0-63.0 U). In addition, the statistical tolerance interval (95% confidence level) for the whole injection population at
`each dosage level was calculated according to DIN EN ISO 11608-1:2000, using the formula x ± [k s], where xis the
`average dose for the whole population of each pen at each dosage level, s is the corresponding standard deviation
`(SD), and k is the statistical tolerance limit factor. For n = 60, k = 2.670 at the 95% confidence interval.15 The statistical
`tolerance interval should lie within the upper and lower acceptance limits for each dosage level. The average actual
`dose, SD, and coefficient of variation (CV) were also determined for each dosage level.
`
`An analysis of variance was used to compare the mean injection forces of the WR, WD, and GL. The significance level
`was set to 5% (p = .05). The mean injection force was also compared with the CS and SS using mean injection force
`and SD values for the CS and SS from previously published results.13,14
`
`Results and Discussion
`
`The present study evaluated the dose accuracy and injection force of the insulin pens manufactured by Wockhardt
`(WR and WD) and Gan & Lee (GL) for the delivery of the insulin glargine (Lantus) copies, Glaritus and Basalin, and
`compared them with the reusable CS and prefilled SS pens manufactured by Sanofi to deliver Lantus.
`
`Dose Accuracy
`All tested insulin pens at all dosage levels delivered comparable average doses within the range of the DIN EN ISO
`11608-1:2000 limits (Table 2). The data for the dosing accuracy of the SS have been generated in a previous study using
`two SS batches. However, this had no negative impact based on the good precision of the SS compared with the other
`pens, reflecting one single batch. One of the WR pens, being unable to deliver any of the required doses, was found
`to be faulty and was not included in the evaluation of the dosing accuracy of the WR. At all three dosage levels, the
`average doses delivered by all pens were lower than the target dose, except for the GL at 5 U, where the delivered
`dose was greater than the target dose. The WR and WD pens had higher CVs, reaching 6.4% and 5.4% at the 5 U
`dosage level and ranging between 1.4% and 1.8% at the other dosage levels, respectively. In contrast, both CS and SS
`had CVs of 2.4% and 3.1% at 5 U, respectively, and did not exceed 0.9% at 30 and 60 U. The dosage variability of the
`GL with CVs of 3.5% at 5 U and 0.9% at the other dosage levels was intermediate between the CS/SS and WD/WR
`pens at the 5 and 60 U dosage level and comparable with the SS at the 30 U dosage level.
`
`The distribution of the individual doses according to pen type at the different dosage levels is illustrated in Figure 2.
`The WR and WD pens revealed lower minimum and higher maximum values for the delivered doses at all dosage
`levels, indicating a greater distribution range compared with the GL, CS, and SS pens.
`
`The calculated statistical DIN EN ISO 11608-1:2000 tolerance intervals were within the acceptance range for the GL,
`WR, CS, and SS injector populations at all three tested dosage levels (Table 3). The WD injector population met the
`statistical tolerance limits at 5 and 60 U but failed to meet them for dosing accuracy at the 30 U level, as the statistical
`tolerance interval was less (28.32 U) than the lower acceptance limit at that dosage level (28.5 U). Thus, while the
`individual 30 U doses with the WD were within the acceptance limit (30 ± 1.5 U) according to DIN EN ISO 11608-1:2000,
`the whole population failed to meet the statistical tolerance limit, because the variability of the delivered doses
`was high.
`
`Injection Force
`Higher mean plateau and maximum injection forces at 6 and 10 U/s were determined for the GL, WD, and WR at
`60 U compared with the CS and SS at 80 U (Figure 3). At 6 U/s (Figure 3A), the mean plateau injection forces for
`
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`
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`Dose Accuracy and Injection Force of Different Insulin Glargine Pens
`
`Friedrichs
`
`Table 2.
`Average Actual Doses, Standard Deviation, Coefficient of Variation, Average Deviations, Average Relative
`Deviations, Absolute Average Deviations, and Average Absolute Deviation From the Target Dose of the
`Tested Insulin Pens
`
`Pen
`
`Target
`dose (U)
`
`Average
`
`cs
`Glaritus WR
`
`GL
`ssb
`
`Glaritus WD
`cs
`Glaritus WR
`
`GL
`ssb
`
`5
`
`30
`
`4.88
`
`4.92
`
`5.16
`
`4.94
`
`4.81
`
`29.53
`
`29.97
`
`29.83
`
`29.77
`
`29.68
`
`Actual dose (U)
`
`SD
`
`0.12
`
`0.32
`
`0.18
`
`0.15
`
`0.26
`
`0.28
`
`0.54
`
`0.26
`
`0.25
`
`0.50
`
`CV%
`
`Average
`deviation (U)
`
`Average
`relative
`deviation (%)
`
`Average
`Average
`absolute
`absolute
`deviation 8 (U) deviation 8 (%)
`
`2.4
`
`6.4
`
`3.5
`
`3.1
`
`5.4
`
`0.9
`
`1.8
`
`0.9
`
`0.8
`
`1.7
`
`-0.12
`
`-0.08
`
`0.16
`
`-0.06
`
`-0.19
`
`-0.48
`
`-0.04
`
`-0.18
`
`-0.23
`
`-0.33
`
`-0.82
`
`-2.30
`
`-1.62
`
`3.15
`
`-1.14
`
`-3.82
`
`-1.60
`
`-0.13
`
`-0.60
`
`-0.77
`
`-1.10
`
`-1.36
`
`0.13
`
`0.26
`
`0.20
`
`0.13
`
`0.26
`
`0.49
`
`0.42
`
`0.25
`
`0.28
`
`0.51
`
`0.82
`
`2.59
`
`5.28
`
`4.05
`
`2.65
`
`5.28
`
`1.64
`
`1.40
`
`0.83
`
`0.92
`
`1.68
`
`1.36
`
`Glaritus WD
`cs
`Glaritus WR
`
`GL
`ssb
`
`Glaritus WD
`
`60
`
`59.19
`
`59.85
`
`59.68
`
`59.28
`
`59.59
`
`0.35
`
`0.81
`
`0.52
`
`0.36
`
`0.86
`
`0.6
`
`1.4
`
`0.9
`
`0.6
`
`1.4
`
`-0.15
`
`-0.32
`
`-0.72
`
`-0.41
`
`-0.25
`
`0.54
`
`-1.19
`
`-0.68
`
`0.65
`
`0.54
`
`0.72
`
`0.80
`
`1.09
`
`0.90
`
`1.19
`
`1.34
`
`a The absolute average deviation reflects the average of the individual absolute values without considering the algebraic signs in units and
`expressed as percentage of the target dose.
`b Data for these pens have been generated in a previous study.7
`
`Table 3.
`Overview of the Statistical Tolerance Intervals Determined for Each Insulin Pen at Each Dosage Levela
`cs
`4.58
`
`Units
`
`Actual ISO requirement
`
`5
`
`L
`u
`
`30
`
`60
`
`L
`u
`
`L
`u
`
`4.0
`
`6.0
`
`28.5
`
`31.5
`
`57.0
`
`63.0
`
`Acceptance criteria
`x - (ks)?: L
`x + (ks)~ U
`x - (ks)?: L
`x + (ks)~ U
`x - (ks)?: L
`x + (ks)~ U
`
`WR
`
`4.07
`
`GL
`
`4.68
`
`SSb
`
`4.54
`
`5.19
`
`28.78
`
`30.26
`
`58.24
`
`60.13
`
`5.77
`
`28.51
`
`31.41
`
`57.68
`
`62.01
`
`5.64
`
`29.13
`
`30.51
`
`58.31
`
`61.05
`
`5.35
`
`29.10
`
`30.44
`
`58.34
`
`60.23
`
`WD
`
`4.12
`
`5.50
`
`28.32
`
`31.02
`
`57.30
`
`61.88
`
`a ISO, International Organization for Standardization; L, lower limit; U, upper limit.
`b Data for these pens have been generated in a previous study.7
`
`the GL, WD, and WR were significantly different from one another (p < .05). They were 95%, 68%, and 50% higher
`compared with the CS, respectively (p < .05) and 53%, 33%, and 18% higher compared with the SS, respectively (p < .05).
`In general, the injection force of all pens increased at 10 U/s. At this speed, the mean plateau injection force of GL
`was significantly greater (p < .05) than that of the WD or WR, which were not different from one another. The GL,
`WD, and WR were 76%, 37%, and 29% higher than the CS, respectively, and 50%, 17%, and 10% higher than the SS
`(p < .05, each), respectively.
`
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`

`Dose Accuracy and Injection Force of Different Insulin Glargine Pens
`
`Friedrichs
`
`A
`
`Q)
`
`2
`C) ca
`"' 0
`C
`
`6 ---------------------------------
`
`5 ·······.I····························T······· ···········$ ·················+···············
`
`i:---- - ----:i
`.. ____ 1 ____ _.
`
`. L
`
`0
`
`4 ---------------------------------
`
`cs
`
`WR
`
`GL
`
`ss
`
`WO
`
`B
`31.5
`
`Q)
`
`2
`g> 30.0
`"' 0
`C
`
`'
`'
`'-----,---- -'
`_L
`
`28.5 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`
`cs
`
`WR
`
`GL
`
`ss
`
`WO
`
`C
`
`~ ---------------------------------
`
`57 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -
`
`cs
`
`WR
`
`GL
`
`Reusable pens
`
`ss
`Prefilled pens
`
`WO
`
`■ 6 U/s
`
`□ 1 0 U/s
`
`i§
`
`CS (80 U) WR (60 U)
`
`GL (60 U)
`
`SS (80 U) WD (60 U)
`
`Reusable pens
`
`Prefilled pens
`
`■ 6 U/s
`
`□ 1 0 U/s
`
`i§
`
`A
`
`18
`16
`~ 14
`!!: 12
`:::,
`~ 10
`'!ii
`8
`! 6
`~ 4
`::E
`2
`0
`
`25
`
`B
`~
`!!: 20
`E
`~ 15
`·~
`E 10
`
`('ll
`
`5
`
`0
`
`CS (80 U) WR (60 U)
`
`GL (60 U)
`
`SS (80 U) WD (60 U)
`
`Reusable pens
`
`Prefilled pens
`
`Figure 3. Comparison of mean (± SD) plateau (A) and maximum (B)
`injection force at two injection speeds for each pen and dose tested.
`The CS data comes from Friedrichs and coauthors,13 and the SS data
`comes from Van der Burg.14 *p < .05 versus CS (6 U/s); §p < .05 versus
`SS (6 U/s); p < 0.05 versus CS (10 U/s); §p < .05 versus SS (10 U/s).
`
`The mean maximum injection forces of the GL and
`WD were significantly greater than that of the WD
`(p < .05) at 6 U/s (Figure 3B). The GL, WD, and WR were
`116%, 103%, and 69% higher than the CS, respectively
`(p < .05, each), and 36%, 27%, and 7% higher than the
`SS, respectively (p < .05, each). At 10 U/s, the GL, WD
`and WR were significantly different from one another
`(p < .05) and were 92%, 53%, and 38% higher than the CS,
`respectively. Compared with the SS, a similar average
`maximum force was determined for the WR and 39%
`and 10% higher injection forces for the GL and WD,
`respectively (p < .05, each).
`
`Figure 2. Distribution of actual doses categorized by pen type at the
`(A) 5, (B) 30, and (C) 60 U dosage levels.7 The dotted lines represent
`the International Organization for Standardization limits. The line
`near the middle of the box represents the median (50th percentile),
`the lower and upper ends of the box represent the 25th and 75th
`percentiles, and the small square is the mean. The ends of the
`whiskers represent the minimum and maximum values, respectively.
`Data for the SS pens have been generated in a previous study.7
`
`In general, the results of the injection force study show
`that the Lantus pens, CS and SS, require a significantly
`lower injection force compared with the reusable or
`prefilled insulin pens containing the insulin glargine
`copies. The lower injection force may be of great benefit for diabetes patients with reduced finger joint mobility
`or limited hand strength.16- 19 Therefore, future clinical studies are warranted that determine the impact of a lower
`injection force on the ease of operation and handling comfort of insulin pens by patients with impaired motor skills
`in daily practice.
`
`J Diabetes Sci Technol Vol 7, Issue 5, September 2013
`
`1351
`
`wwwJdst.org
`
`Sanofi Exhibit 2123.006
`Mylan v. Sanofi
`IPR2018-01676
`
`

`

`Dose Accuracy and Injection Force of Different Insulin Glargine Pens
`
`Friedrichs
`
`General Observations
`When the cartridge is close to empty, the GL, WD, and WR are designed to allow the user to dial a dose higher than
`the remaining dose in the cartridge. Where the plunger of the WR pen could not be depressed, the plunger of the
`WD pen could be depressed completely, suggesting to the patient that the higher dose was actually delivered. In the
`case of the GL pen, the plunger stopped after the remaining amount of insulin was dispensed, indicating that the
`entire insulin dose had not been delivered. The ability of the new insulin pens to dial a dose that is higher than that
`remaining in the pen could pose a potential safety issue because patients are unaware that the actual dose injected is
`less than what was desired. In contrast, the CS and SS pens have an end-of-content feature that prevents dialing more
`than the remaining dose.
`
`In conclusion, all pens fulfilled the requirements of dosing accuracy defined by DIN EN ISO 11608-1:2000 at all three
`dosage levels, with the WR, WD, and GL showing greater dosage variability compared with the CS and SS. Only the
`injector population of WD at the 30 U dosage level failed to meet DIN EN ISO 11608-1:2000 criteria. Lower injection
`forces were observed with the Lantus CS and SS pens compared with the new reusable and disposable pens, WD, WR,
`and GL, for the insulin glargine copies, Glaritus and Basalin. Thus, the devices used to deliver the insulin glargine
`copies have different performance characteristics.
`
`Funding:
`
`This study was funded by Sanofi.
`
`Disclosures:
`
`Volker Karger is an employee of sanofi-aventis Deutschland GmbH. Arnd Friedrichs and Steffen Adler are employees of LWS Risk Management
`Consult GmbH, a paid consultant to sanofi-aventis Deutschland GmbH.
`
`Acknowledgments:
`
`Editorial support was provided by Tom Claus, Ph.D., of PPSI (a PAREXEL Company) and funded by Sanofi.
`
`References:
`
`1. Lee WC, Balu S, Cobden D, Joshi AV, Pashas CL. Medication adherence and the associated health-economic impact among patients with type 2
`diabetes mellitus converting to insulin pen therapy: an analysis of third-party managed care claims data. Clin Ther. 2006;28(10):1712-25.
`
`2. Summers KH, Szeinbach SL, Lenox SM. Preference for insulin delivery systems among current insulin users and nonusers. Clin Ther.
`2004;26(9):1498-505.
`
`3. Asakura T, Seino H, Kageyama M, Yohkoh N. Dosing accuracy of two insulin pre-filled pens. Curr Med Res Opin. 2008;24(5):1429-34.
`
`4. Clarke A, Spollett G. Dose accuracy and injection force dynamics of a novel disposable insulin pen. Expert Opin Drug Deliv. 2007;4(2):165-74.
`
`J Diabetes Sci Technol Vol 7, Issue 5, September 2013
`
`1352
`
`wwwJdst.org
`
`Sanofi Exhibit 2123.007
`Mylan v. Sanofi
`IPR2018-01676
`
`

`

`Dose Accuracy and Injection Force of Different Insulin Glargine Pens
`
`Friedrichs
`
`5. Hanel H, Weise A, Sun W, Pfotzner JW, Thome N, Pfotzner A. Differences m the dose accuracy of insulin pens. J Diabetes Sci Technol.
`2008;2(3):478-81.
`
`6. Krzywon M, Abdel-Tawab M, van der Burg T, Fuhr U, Schubert-Zsilavecz M. Dosing accuracy of commonly used disposable insulin pens.
`Curr Med Res Opin. 2010;26(4):901-5.
`
`7. Krzywon M, van der Burg T, Fuhr U, Schubert-Zsilavecz M, Abdel-Tawab M. Study on the dosing accuracy of commonly used disposable
`insulin pens. Diabetes Technol Ther. 2012;14(9):804-9.
`
`8. Pfutzner A, Asakura T, Sommavilla B, Lee W. Insulin delivery with FlexPen: dose accuracy, patient preference and adherence. Expert Opin
`Drug Deliv. 2008;5(8):915-25.
`
`9. Bode A. Development of the SoloSTAR insulin pen device: design verification and validation. Expert Opin Drug Deliv. 2009;6(1):103-12.
`
`10. Perfetti R. Reusable and disposable insulin pens for the treatment of diabetes: understanding the global differences in user preference and an
`evaluation of inpatient insulin pen use. Diabetes Technol Ther. 2010;12 Suppl l:S79-85.
`
`11. Martin JM, Llewelyn JA, Ristic S, Bates PC. Acceptability and safety of a new 3.0 ml re-usable insulin pen (HumaPen) in clinical use. Diabetes
`Nutr Metab. 1999;12(5):306-9.
`
`12. Owens DR, Landgraf W, Schmidt A, Bretzel RG, Kuhlmann MK. The emergence of biosimilar insulin preparations--a cause for concern?
`Diabetes Technol Ther. 2012;14(11):989-96.
`
`13. Friedrichs A, Karger V, Adler S. Injection force of reusable insulin pens: Novopen 4, Lilly Luxura, Berlipen, and ClikSTAR. J Diabetes Sci Technol.
`2011;5(5):1185-90.
`
`14. Van der Burg T. Injection force of SoloSTAR® compared with other disposable insulin pen devices at constant volume flow rates. J Diabetes
`Sci Technol. 2011;5(1):150-5.
`
`15. International Organization for Standardization. ISO 11608-1:2000 pen-injectors for medical use -- part 1: pen injectors -- requirements and test
`methods. http:Uwww .iso.org/isolcatalogue detail.htm?csnumber=19545. Accessed May 14, 2010.
`
`16. Papanas N, Maltezos E. The diabetic hand: a forgotten complication? J Diabetes Complications. 2010;24(3):154-62.
`
`17. Redmond CL, Bain GI, Laslett LL, McNeil JD. Hand syndromes associated with diabetes: impairments and obesity predict disability.
`J Rheumatol. 2009;36(12):2766-71.
`
`18. Rosenbloom AL. Limitation of finger joint mobility in diabetes mellitus. J Diabet Complications. 1989;3(2):77-87.
`
`19. Savas S, Koroglu BK, Koyuncuoglu HR, Uzar E, Celik H, Tamer NM. The effects of the diabetes related soft tissue hand lesions and the
`reduced hand strength on functional disability of hand in type 2 diabetic patients. Diabetes Res Clin Pract. 2007;77(1):77-83.
`
`J Diabetes Sci Technol Vol 7, Issue 5, September 2013
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`1353
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`wwwJdst.org
`
`Sanofi Exhibit 2123.008
`Mylan v. Sanofi
`IPR2018-01676
`
`