DIABETES TECHNOLOGY & THERAPEUTICS
`Volume 14, Number 9, 2012
`© Mary Ann Liebert, Inc.
`DOI: 10.1089/dia.2011.0298
`
`ORIGINAL ARTICLE
`
`Diabetes Technology & Therapeutics
`
`Study on the Dosing Accuracy of Commonly Used
`Disposable Insulin Pens
`
`Meike Krzywon, Dipl.-lng. Chemistr/ Thomas van der Burg, B.Sc.,2 Uwe Fuhr, M.D.,3
`Manfred Schubert-Zsilavecz, Mag. pharm., Ph.D.]·4 and Mona Abdel-Tawab, B.Sc., Ph.D)
`
`Abstract
`
`Background: Improved patient comfort and optimal glycemic control have led to the widespread use of insulin pens,
`particularly in Europe. Most of the former studies on the dose accuracy of insulin pens included only a small number of doses
`and pens. In extension to our previous large-scale study testing the dosing accuracy following a randomized dosing sequence
`with each pen, the present study was more directed toward the dose accuracy for one specific dose dispensed repeatedly with
`the same pen. This is the first study providing detailed comparative data on the accuracy of repeated dose delivery with
`prefilled disposable insulin pens at low, middle, and high doses, dispensed over the entire pen volume.
`Materials and Methods: In total, 15 previously unused insulin pens from two lots of each pen type (SoloSTAR® [sanofi(cid:173)
`aventis, Paris, France], FlexPen® [Novo Nordisk A/S, Bagsv<£rd, Denmark], Next Generation FlexPen [Novo Nordisk], and
`KwikPen™ [Eli Lilly, Indianapolis, IN]) were used to deliver 5-unit (low), 30-unit (middle), and 60-unit (high) doses, re(cid:173)
`spectively, dispensed four times from each pen in a nonrandomized manner. Actual doses were determined gravimetrically
`taking the density of the respective insulin into account and were evaluated according to the guidelines (DIN EN ISO 11608-
`1 :2000) of the International Organization for Standardization (ISO).
`Results: All tested insulin pens met the requirements for accuracy with none of the single values being outside the defined
`range of the ISO recommendations (1±1 units, 30±1.5 units, and 60±3 units, respectively).
`Conclusion: The present study demonstrated a consistent and accurate dose delivery at all dosage levels for all tested insulin
`pens, with no clinically relevant differences among the products.
`
`Introduction
`
`SINCE THE FIRST INSULIN PEN was introduced in 1985, in(cid:173)
`
`sulin pens have significantly contributed to improved
`patient comfort and optimal glycemic control.1 They offer
`several advantages over the traditional vial-and-syringe
`method, such as reduced pain during injection, discretion of
`use, easy portability, and fewer claims for hypoglycemic
`events.2-4 Because of these advantages the use of insulin pens
`is widespread, particularly in Europe. 1
`As patients rely heavily upon device accuracy to administer
`the correct amount of insulin, the accuracy of insulin pens is
`an important issue. Insulin pens are available in two types:
`reusable and disposable insulin pens. The most commonly
`used disposable pens include the SoloSTAR® (SR) (sanofi(cid:173)
`aventis, Paris, France), the FlexPen® (FP) and Next Generation
`FlexPen (NGFP) (Novo Nordisk A/S, Bagsv<£rd, Denmark),
`
`and the KwikPen™ (KP) (Eli Lilly, Indianapolis, IN). Several
`studies have been dedicated to comparing the dosing accu(cid:173)
`racy among disposable insulin pens. In general, these studies
`verified the accurate dosing of disposable insulin pens, even
`when compared with the vial and syringe. 5
`13 However, they
`-
`followed different study designs with regard to the number of
`pens and doses tested, yielded partly contradicting results,
`and, with the exception of the study of Krzywon et al., 11 did
`not extend over the whole dosing range but mainly concen(cid:173)
`trated on testing 10-unit and 30-unit doses. Therefore our first
`study was dedicated to comparing the dose accuracy of SR,
`FP, NGFP, and KP over a wide dosing range (1 unit, 10 units,
`30 units, 60 units, and 80 units) dispensed in random order. 11
`The dose regimen of patients with diabetes may require a
`roughly constant daily dose of their basal insulin. For that
`reason the following study was aimed to complement our
`previous study by investigating the dose accuracy of the SR,
`
`1Central Laboratory of German Pharmacists, Eschborn, Germany.
`2Medical Devices/Quality, Regulatory & Risk Management, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
`3Clinical Pharmacology Unit, Department of Pharmacology, University of Cologne, Cologne, Germany.
`4Institute of Pharmaceutical Chemistry, J.W. Goethe-University, ZAFES, Frankfurt am Main, Germany.
`The results of the present study have been presented as a poster at the American Diabetes Association's 70th scientific sessions in Orlando,
`Florida, held June 25-29, 2010.
`
`804
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`DOSING ACCURACY OF DISPOSABLE INSULIN PENS
`
`805
`
`FP, NGFP, and KP at the low (5-unit), middle (30-unit), and
`high (60-unit) dosage level when administered repeatedly
`with the same pen.
`
`Materials and Methods
`
`SR and FP were bought from German pharmacies. KP and
`NGFP were bought in pharmacies in the United States and
`France. An overview of the included insulin pens and corre(cid:173)
`sponding needles is given in Table 1. The needles were ap(cid:173)
`plied according to the manufacturers' recommendation.
`In total, 45 previously unused insulin pens from two lots of
`each pen type (15 pens of each pen type for each dosage level,
`respectively) was used for the study. Each of the low (5-unit),
`middle (30-unit), and high (60-unit) doses was dispensed four
`times from each pen in a nonrandomized manner according to
`the dose delivery scheme presented in Figure 1. Between these
`recorded doses intermediate doses were dispensed without
`recording the mass to ensure dose dispensing over the entire
`pen volume.
`The individual insulin pens were operated according to the
`manufacturers' instructions. Prior to starting the sequence of
`measurements, one to two priming doses of 2 units were
`discarded. If still no drops were seen at the top of the needle,
`the priming dose was repeated until this was the case. Fol(cid:173)
`lowing the manufacturers' recommendation the priming do(cid:173)
`ses of the KP were repeated until a visible stream of insulin left
`the needle. All measurements were performed by a single
`investigator to eliminate potential user variability. As per
`manufacturers' instructions the plunger was kept pressed
`down for 10 s, 6 s, and 5 sin the case of SR, both FP and NGFP,
`and KP, respectively, after each dose to ensure that all the
`dialed dose had been expelled. Each dose was deposited in a
`beaker containing a 0.5-1 cm layer of liquid paraffin, whereas
`the pen was held close to the surface of the paraffin layer. In
`case 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. Afterward the dose was weighed immediately
`using an analytical balance (model XP205/M; Mettler Toledo
`AG, Giefsen, Germany), which has an accuracy of 0.00001 g.
`The balance was zeroed before each dose of insulin was de(cid:173)
`posited and weighed. The weights were corrected for the
`specific density of each insulin formulation determined in
`the run-up to the study. For insulin glargine (SR), insulin
`detemir (FP and NGFP), and insulin lispro (KP), the density
`was determined to be 1.0036 g/ cm 3, 1.00798 g/ cm 3, and
`1.00447 g/ cm 3, respectively, using a DMA 4500 density meter
`(Anton Paar GmbH, Bruchkobel, Germany). For each dose
`
`Delivery of the 1st dose of 5U , 30U, and 60U,
`respectively, weighing and recording the mass
`
`Intermediate dose without recording the mass: 60 + 28U for
`the low dose test pens, 55U for the mid dose and 15U for
`the high dose test pens, respectively
`
`Delivery of the 2nd dose of 5U, 30U, and 60U ,
`respectively, weighing and recording the mass
`
`Intermediate dose without recording the mass: 60 + 28U for
`the low dose test pens, 55U for the mid dose and 15U for
`the high dose test pens, respectively
`
`Delivery of the 3rd dose of 5U, 30U, and 60U ,
`respectively, weighing and recording the mass
`
`Intermediate dose without recording the mass: 60 + 28U for
`the low dose test pens, 55U for the mid dose and 15U for
`the high dose test pens, respectively
`
`Delivery of the 4th 5U , 30U, and 60U dose,
`respectively, weighing and recording the mass
`
`FIG. 1. Dose delivery scheme for each pen.
`
`TABLE 1. INSULIN PENS AND CORRESPONDING NEEDLES INCLUDED IN THE STUDY
`
`Manufacturer
`
`Batch
`
`Insulin
`
`Needles
`
`40Ul42
`40U144
`VH 70047
`VH 70215
`VH 70007
`VH70235
`A 477063
`A 463790C
`
`Glargine
`
`BD Micro-Fine (0.25mm [31 gauge]x8)
`
`Detemir
`
`NovoFine (0.3 mm [30 gauge] x 8)
`
`Detemir
`
`NovoFine (0.3 mm [30 gauge] x 8)
`
`Lispro
`
`BD Micro-Fine (0.25mm [31 gauge]x8)
`
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`Insulin pen
`
`SoloSTAR
`
`FlexPen
`
`sanofi-aventis
`
`Novo Nordisk
`
`Next Generation FlexPen
`
`Novo Nordisk
`
`KwikPen
`
`Eli Lilly
`
`

`

`806
`
`KRZYWON ET AL.
`
`-9-SoloSTAR
`
`- - •- - FlexPen
`
`•••• ,.. ••• NG FlexPen
`
`- t i - KwikPen
`
`5 U dose
`
`0
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`8
`Pen(Number)
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`--e-SoloSTAR
`
`- - • - - FlexPen
`
`···•···· NG FlexPen ~ KwikPen
`
`30 U dose
`
`-
`.
`._ ,,
`• ""• ...... -'..c••···-.-..-=-....__
`............................ -·----------·-·· --............. ..
`
`-'2
`
`~
`QI
`U)
`0
`Cl
`:§
`
`;;i
`U)
`.E
`
`6.5
`
`6
`
`5.5
`
`5
`
`4.5
`
`4
`
`3.5
`
`32
`
`31.5
`
`- 31
`-·c
`
`~ 30.5
`QI
`U)
`0
`Cl
`.!:
`3
`Ill 29.5
`.E
`
`30
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`8
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`Pen(Number)
`
`~ SoloSTAR
`
`- - .- - FlexPen
`
`•···A.···· NG FlexPen
`
`---.!l-
`
`KwikPen
`
`60 U dose
`
`29
`
`28.5
`
`28
`
`0
`
`-·2
`
`~
`QI
`U)
`0
`Cl
`:§
`;;i
`Ill
`.E
`
`64
`
`63
`
`62
`
`61
`
`60
`
`59
`
`58
`
`57
`
`56
`
`0
`
`2
`
`3
`
`4
`
`5
`
`6
`
`8
`7
`Pen(Number)
`
`9
`
`10
`
`11
`
`12
`
`13
`
`14
`
`15
`
`FIG. 2. Distribution of the average actual doses according to pen and dosage level (n = 4). Bold lines represent the Inter(cid:173)
`national Organization for Standardization limits, and the midline represents the target dose. NG, Next Generation.
`
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`DOSING ACCURACY OF DISPOSABLE INSULIN PENS
`
`807
`
`application, a new injection needle was used, which was
`primed in accordance with the manufacturer's recommen(cid:173)
`dation before dose delivery. The whole study was carried out
`under Good Manufacturing Practice conditions and was ad(cid:173)
`ditionally documented by video.
`The evaluation of dose accuracy was based on the guide(cid:173)
`lines (DIN EN ISO 11608-1:2000) of the International Orga(cid:173)
`nization for Standardization (ISO). 14 The statistical tolerance
`interval [x ± (k • s)] (see Results) for each pen should lie within
`the upper and lower acceptance limits for each dosage level.
`According to the ISO guidelines the calculated statistical tol(cid:173)
`erance limit should not deviate from the target dose by more
`than 1 unit for the delivery of 5 units and not by more than 5%
`for the delivery of 30 units and 60 units. For the individual
`doses tested in this study the acceptance limits are 5 ± 1 units
`(4.0-6.0 units), 30 ± 1.5 units (28.5-31.5 units), and 60 ± 3 units
`(57-63 units). In addition, the arithmetic average of the actual
`doses, the SD, the coefficient of variation, and the average
`deviation in units and percentage from the target dose were
`calculated.
`
`Results
`
`According to the delivery scheme 60 doses were gravi(cid:173)
`metrically measured at each dosage level for each pen type,
`and the actual dose was calculated on the basis of the deliv(cid:173)
`ered masses and the density of the insulin solution. In general,
`the 5-unit doses were equally distributed around the target
`dose, whereas most of the 30-unit and almost all of the 60-unit
`doses were found to be below the target dose (Fig. 2). How(cid:173)
`ever, none of the tested insulin pens showed any trend toward
`increasing or decreasing doses with repetitive dosing.
`Despite the high number of doses measured (720 in total,
`180 per pen model) the study demonstrated a consistent and
`accurate dose delivery at all dosage levels for all tested insulin
`pens with none of the single values outside the specified limits
`recommended by ISO.
`The arithmetic average of the actual doses, the SD, and the
`coefficient of variation, as well as the average deviation in
`units and the average relative percentage deviation from the
`target dose, are summarized in Table 2.
`
`The average values determined for each pen at each dosage
`level were found to lie close to each other and to the target
`dose. For all tested insulin pens the average deviation of the
`actual dose from the target dose was below 2% at all tested
`dosage levels. The average deviations from the target dose
`ranged between -1.14% and -0.06% at 5 units, between
`- 1.01% and -0.11% at 30 units, and between -1.32% and
`- 0.55% at 60 units. Moreover, only marginal differences be-
`tween the tested insulin pens in the reproducibility of dose
`delivery were detected. The highest variation was observed at
`the lowest dosage level of 5 units with values ranging between
`3.1 % and 4.1 %, whereas at the higher dosage levels (30 units
`and 60 units) the coefficient of variation ranged between 0.5%
`and 0.9%.
`The statistical tolerance intervals determined for each pen
`at each dosage level are presented in Figure 3. All calculated
`tolerance intervals [x ± (k • s)] were found to lie within the
`acceptance range for each dosage level for each pen, where xis
`the average value of the actual doses for each pen at each
`dosage level, s = SD, and k is the tolerance limit factor, which
`was found to be 2.670 on the basis of the 95% confidence
`interval for n = 60.14
`
`Discussion
`
`Six studies examined the comparable dosing accuracy of
`disposable insulin pens.5
`11 In general, dosing accuracy was
`-
`found to be good in all studies. Two studies comparing the SR
`with the FP reported few doses outside the ISO limits for both
`pens.5
`6 However, the number of pens included in these
`'
`studies was very small (eight pens and three pens, respec(cid:173)
`tively, of each type) and did not meet the ISO recommenda(cid:173)
`tions. Therefore these data may not be considered robust. In
`fact, repeating the study of Asakura et al. 6 on a 10-fold higher
`number of pens (30 pens each) revealed comparable accuracy
`of the SR and the FP with no single value of the 2,280 doses
`measured being outside the ISO limits.8 Similar good results
`within the ISO limits were obtained for the NGFP, when
`comparing it with the FP.9 Comparing the SR with the NGFP
`revealed good performance of both pens but reported few
`doses outside the ISO limits for both pens. 10 All the above-
`
`TABLE 2. OVERVIEW ON THE AVERAGE OF THE ACTUAL DOSES, THE STANDARD DEVIATION, THE COEFFICIENT
`OF VARIATION, THE AVERAGE DEVIATION IN UNITS, AND THE AVERAGE RELATIVE PERCENTAGE DEVIATION
`FROM THE TARGET DosE FOR ALL PENS AT EACH DOSAGE LEVEL
`
`Target
`dose (units)
`
`Actual dose
`
`Average dose (units)
`
`SD (units)
`
`CV%
`
`Average
`deviation (units)
`
`Average relative
`deviation (%)
`
`5
`
`30
`
`60
`
`4.943
`4.972
`4.969
`4.997
`29.769
`29.698
`29.729
`29.968
`59.283
`59.247
`59.206
`59.667
`
`0.153
`0.202
`0.188
`0.160
`0.253
`0.275
`0.210
`0.215
`0.357
`0.324
`0.503
`0.517
`
`3.1
`4.1
`3.8
`3.2
`0.8
`0.9
`0.7
`0.7
`0.6
`0.5
`0.9
`0.9
`
`-0.057
`-0.028
`-0.031
`-0.003
`-0.231
`-0.302
`-0.271
`-0.032
`-0.717
`-0.753
`-0.794
`-0.333
`
`-1.14
`-0.57
`-0.62
`-0.06
`-0.77
`-1.01
`-0.90
`-0.11
`-1.19
`-1.26
`-1.32
`-0.55
`
`Pen
`
`SR
`FP
`NGFP
`KP
`SR
`FP
`NGFP
`KP
`SR
`FP
`NGFP
`KP
`
`CV, coefficient of variation; FP, FlexPen; KP, KwikPen; NGFP, Next Generation FlexPen; SR, SoloSTAR.
`
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`808
`
`6
`
`-C 5
`
`::J
`
`4
`
`31.5
`
`-§30.0
`
`5 U dose
`
`5.51
`
`5.47
`
`5.42
`
`4.44
`
`4.47
`
`4.57
`
`-SR -
`
`FP -
`
`NGFP
`
`KP
`
`30 U dose
`
`30.44
`
`30.43
`
`30.54
`
`30.28
`
`29.40
`
`28.97
`28.5 ~ - - - - - - - - - - - - - - - - - - - -
`NGFP
`KP
`-SR-
`FP
`
`29.17
`
`60 U dose
`6 3 - . - - - - - - - - - - - - - - - - - - - - - -
`
`-§ 60
`
`61.04
`
`60.54
`
`58.34
`
`58.39
`
`58.30
`
`57.87
`57~ - - - - - - - - - - - - - - - - - - - -
`
`FIG. 3. Tolerance intervals for each pen at each dosage le(cid:173)
`vel. Bold lines represent the International Organization for
`Standardization limits, and the midline represents the target
`dose. FP, FlexPen; KP, KwikPen; NGFP, Next Generation
`FlexPen; SR, SoloSTAR.
`
`mentioned studies included only a small number of doses and
`pens. In terms of an overall assessment of the dosing accuracy
`we conducted the first comparable study on a large scale in(cid:173)
`cluding the most common insulin pens, SR, FP, NGFP, and
`KP, covering the low (1 unit), the middle (30 and 40 units), and
`the high (60 units) dosage levels for all pens in addition to the
`80-unit dosage level for the SR in line with ISO guidelines. 11
`
`KRZYWON ET AL.
`
`The 10-unit dose was also included because this dose was part
`of other comparative studies. This largest comparative study
`carried out so far revealed an excellent dosing accuracy for all
`tested insulin pens, with none of the single values (1,260 in
`total) at all dose levels being outside the defined range of the
`ISO recommendation. Previously reported dosing outside the
`6
`ISO limits5
`10 could not be verified in this study. 11
`'
`'
`Following the ISO recommendation, the 1-unit dosage level
`should have been chosen for the low dosage level for all pens
`and the 40-unit and 80-unit dose as middle and high doses,
`respectively, for SR. Our current study assessed the dosing
`accuracy at the 5-unit (low), 30-unit (middle), and 60-unit
`(high) dosage levels for all pens, to enable comparability with
`previously published studies and because of the greater
`clinical relevance of the 5-unit dose compared with the 1-unit
`dose. The results obtained represent the dosing accuracy in
`the hands of a professional and do not take into account
`variabilities that may be introduced by users with diabetes in
`daily practice.
`All tested insulin pens revealed an excellent repetitive
`dosing accuracy in the low, middle, and high dosage levels,
`thus assuring dose accuracy over the whole insulin pen. The
`tolerance limits defined by the ISO standards were met by all
`pens at all dosage levels. No single dose from SR, FP, NGFP,
`and KP at any dosage level was delivered outside the pre(cid:173)
`specified limits of the ISO guidelines. Again, previously
`published data that reported individual doses below the ISO
`limit for the SR, FP, 5
`6 and NGFP10 could not be verified. For
`'
`all pens at all dosage levels only minor deviations from the
`target dose not exceeding 1.32% were observed. Being well
`within the defined ISO limits, these deviations may be re(cid:173)
`garded negligible in daily practice.
`The comparable dosing accuracy of all insulin pens revealed
`in this study confirms the results of our earlier study using a
`randomized dosing sequence11 and the results of Penfomis and
`Horvat, 8 demonstrating comparable dosing accuracy of SR and
`FP at the 5-unit and 30-unit dosage level. The outcome of this
`study is also in line with a clinical study carried out by Frie(cid:173)
`drichs 15 demonstrating comparable dosing accuracy for both
`SR and FP when used by device-naive subjects.
`
`Conclusions
`
`The present study reveals similar repetitive dosing accu(cid:173)
`racy for the tested insulin pens SR, FP, NGFP, and KP. None of
`the four insulin pens delivered at the low, middle, and high
`dosage level doses outside the prespecified limits of the ISO
`guidelines. Existing marginal differences among the pens in
`the deviation of the actual doses from the target dose are
`negligible in daily practice.
`
`Acknowledgments
`
`The authors thank Stefan Kamlot for the fruitful discus(cid:173)
`sions and his valuable contribution to the manuscript. This
`study was sponsored by sanofi-aventis.
`
`Author Disclosure Statement
`
`T.v.d.B. is an employee of sanofi-aventis. M.K., M.S.-Z.,
`M.A.-T., and U.F. declare no competing financial interests.
`T.v.d.B. was involved in the design of the present study. M.K.,
`M.S.-Z., and M.A.-T. were responsible for the realization/
`
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`

`DOSING ACCURACY OF DISPOSABLE INSULIN PENS
`
`809
`
`evaluation of the study, and U.F. was responsible for its sta(cid:173)
`tistical evaluation.
`
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`
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`faction using insulin pens. Expert Opin Drug Deliv Diabetes
`Educ 2009;35:799-809.
`3. Robertson KE, Glazer NB, Campbell RK: The latest devel(cid:173)
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`in
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`5. Haenel H, Weise A, Sun W, Pfi.itzner JW, Thome N, Pfi.itzner
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`betes Sci Technol 2008;2:478-481.
`6. Asakura T, Seino H, Kageyama M, Yohkoh N: Dosing ac(cid:173)
`curacy of two insulin pre-filled pens. Curr Med Res Opin
`2008;24:1429-1434.
`7. Pfuetzner A, Asakura T, Sommavilla B, Lee W: Insulin de(cid:173)
`livery with FlexPen: dose accuracy, patient preference and
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`8. Penfornis A, Horvat K: Dose accuracy comparison between
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`Technol Ther 2008;10:359-362.
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`
`Address correspondence to:
`Mona Abdel-Tawab, B.Sc., Ph.D.
`Central Laboratory of German Pharmacists
`Carl-Mannich-Strafie 20
`65760 Eschborn, Germany
`
`E-mail: M.Tawab@zentrallabor.com
`
`Sanofi Exhibit 2132.006
`Mylan v. Sanofi
`IPR2018-01676
`
`