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`
`
`
`EDA
`PDA Journal
`of Pharmaceutical Science and Technology W
`
`
`
`
`Variability in Syringe Components and its Impact on
`Functionality of Delivery Systems
`Nitin Rathore, Pratik Pranay, Bruce Eu, et al.
`
`PDA J Pharm Sci and Tech 2011, 65 468-480
`Access the most recent version at doi:10.5731/pdajpst2011.00785
`
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`
`Variability in Syringe Components and its Impact on
`Functionality of Delivery Systems
`
`NITIN RATHORE“, PRATIK PRANAYZ, BRUCE :U‘, WENCHANG .JI‘, and ED WALLS1
`
`[Drug Product and Device Development, Amgen, Thousand Oaks, CA and 2Department of Chemical Engineering,
`University of WisconsiniMadz'son, Madison. WI ©PDA, Inc. 2011
`
`ABSTRA CT: Prefilled syringes and autoinjectors are becoming increasingly common for parenteral drug administra—
`tion primarily due to the convenience they offer to the patients. Successful commercialization of such delivery
`systems requires thorough characterization of individual components. Complete understanding of various sources of
`variability and their ranking is essential for robust device design. In this work, we studied the impact of variability
`in various primary container and device components on the delivery forces associated with syringe injection. More
`specifically, the effects of barrel size, needle size, autoinjector spring force. and frictional forces have been evaluated.
`An analytical model based on underlying physics is developed that can be used to fully characterize the design space
`for a product delivery system.
`
`KEYWORDS: Break-loose forces, Extrusion force, Device, Autoinjcctor, Prefilled syringe, Delivery forces
`
`LAY ABSTRACT: Use of prefilled syringes (syringes prefilled with active drug) is becoming increasingly common for
`injectable drugs. Compared to vials, prefilled syringes offer higher dose accuracy and ease of use due to fewer steps
`required for dosage. Convenience to end users can be further enhanced through the use of prefilled syringes in
`combination with delivery devices such as autoinjectors. These devices allow patients to self—administer the drug by
`following simple steps such as pressing a button. These autoinjectors are often spring—loaded and are designed to keep
`the needle tip shielded prior to injection. Because the needle is not visible to the user, such autoinjectors are perceived
`to be less invasive than syringes and help the patient overcome the hesitation associated with self—administration.
`In order to successfully develop and market such delivery devices, we need to perform an in—depth analysis of the
`components that come into play during the activation of the device and dose delivery. Typically, an autoinjector is
`activated by the press of a button that releases a compressed spring; the spring relaxes and provides the driving force
`to push the drug out of the syringe and into the site of administration. Complete understanding of the spring force,
`syringe barrel dimensions, needle size. and drug product properties is essential for robust device design.
`it is equally important to estimate the extent of variability that exists in these components and the resulting impact
`it could have on the performance of the device. In this work, we studied the impact of variability in syringe and device
`components on the delivery forces associated with syringe injection. More specifically, the effect of barrel size, needle
`size, autoinjector spring force, and frictional forces has been evaluated. An analytical model based on underlying
`physics is developed that can be used to predict the functionality of the autoinjector.
`
`Introduction
`
`The last decade has witnessed an increase in the pop—
`ularity and sales of prefilled syringes with an annual
`growth rate of 20% in the U.S. market (1). The pri—
`mary factors driving the growth include ease of ad—
`
`
`
`* Corresponding Author: Drug Product and Device
`Development, Amgen, One Amgen Center Dr., MS
`30W—3-A, Thousand Oaks, CA 91320; Phone 805-
`313—6393; E—mail: nrathore@amgen.com
`
`ministration and added convenience for health care
`
`workers and patients (1, 2). Compared to vial config-
`uration, a higher accuracy can be achieved with pre-
`filled syringes and fewer steps are required for dosage.
`An added benefit is the reduced overfill amount due to
`
`significantly lower hold—11p volumes associated with
`syringes. Errors in dosage, and risk of misidentifica—
`tion and contamination, are also minimized. Plastic
`
`prefillable syringes made of cyclic olefins are now
`available as an alternative to glass syringes (3). Con-
`venience to end users and market advantage can fur-
`ther be boosted through the use of delivery devices.
`Delivery systems that are preferred by the patients and
`
`468
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`
`perceived to be less invasive than syringes (4) will
`provide commercial advantage to the drug manufae~
`turer. Novel delivery systems for commercial products
`also offer a mechanism to maintain the competitive
`edge in the marketplace (5).
`
`Successful commercialization of prcfillcd syringe eon-
`figurations and autoinjectors requires complete under-
`standing of the mechanism of delivery and the param—
`eters contributing to the delivery forces and injection
`time. The delivery force is attributed to the break-
`loose force (initial force required to set the plunger in
`motion) and the extrusion force needed to sustain the
`plunger movement by overcoming the hydrodynamic
`pressure and the frictional forces. Several factors con—
`tribute to these forces, including but not limited to:
`
`O Barrel siliconization, which primarily affects the
`frictional forces
`
`'
`
`O
`
`'
`
`'
`
`Syringe geometry, including barrel size and needle
`gauge, which primarily affects the force due to
`hydrodynamic pressure drop
`
`Syringe type, such as Siliconized glass or plastic
`
`Stopper type and geometry
`
`including its interaction with
`Product attributes,
`the barrel surface and its rheological properties
`
`' Driving forces, such as the spring for mechanical
`autoinjectors
`
`'
`
`'
`
`Injection volume and time
`
`Subcutaneous resistance
`
`In order to design a robust product presentation, it is
`important
`to understand the role of each of these
`components, estimate their inherent variability, and
`calculate the resulting impact on injection force or
`time. The objective of this study is to characterize and
`measure the effect of variability in components asso-
`ciated with a syringe delivery system, such as syringe
`barrel size, needle size, friction forces, and spring
`characteristics of the autoinjector. The role of product
`properties and its interaction with the syringe surface
`is equally critical and has been evaluated under a
`separate study. Results from that study will be pub-
`lished in a separate article. Subcutaneous resistance is
`also expected to increase the delivery forces; however,
`
`Vol. 65, No. 5, September—October 2011
`
`TABLE I
`
`List of Syringe Types and Lots Used in This
`Study
`
`Number
`
`
`
`
`Syringe
`of Lots
`
`Vendor
`Studied
`Syringe Type
`I"
`I"
`'“i
`
`Vendor l
`3 lots
`Siliconized glass
`Vendor 2
`3 lots
`Siliconized glass
`j
`Vendor 3
`2 lots
`r Siliconized glass
`
`L Vendor4
`l
`lot
`Plastic
`
`4
`
`the impact of interstitial pressure is outside the scope
`of this work. The measurements of extrusion forces
`
`are performed using Instron. a material testing system.
`A predictive model based on the Hagen—Poiseuille
`equation has been developed to understand the flow
`behavior of drug through the delivery systems and to
`help identify malfunctions and failure points associ-
`ated with the delivery system. The mechanistic model
`helps to identify the key process parameters, assess
`their importance, and predict the impact they would have
`on the extrusion force or injection time variability.
`
`Materials and Methods
`
`Siliconized glass syringes and plastic syringes pro—
`cured from different vendors (see Table I) were used
`in this study. Plunger stoppers from two different
`vendors were also evaluated for siliconized glass sy-
`ringes.
`
`Force measurements for syringes were performed us-
`ing Instron, a material testing system. A load cell of
`500 N was used to drive the syringe plunger at a
`constant crosshead speed while measuring the result-
`ing force on the plunger (repeatability of :0.25% of
`reading over a range of 0.4% to 100% of capacity). A
`schematic of the instrument
`is shown in Figure 1.
`Variation in needle size is measured by a syringe flow
`rate fixture which measures the pressure drop for a
`liquid (water) flowing across the syringe barrel and
`needle at a constant flow rate. The set up consists of a
`pump connected to a water reservoir and a pressure
`sensor. The pump discharges water at constant flow
`rate in the capillary, and the sensor measures the
`corresponding pressure drop that is representative of
`the effective internal radius of the needle. Variation in
`
`barrel size of the syringes is measured by the barrel
`bore internal diameter (ID) gauge. it is first calibrated
`using a barrel of known ID. The instrument is then
`
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`
`
`Figure 1
`
`Picture of the lnstron system used for measuring
`extrusion forces.
`
`used to measure the barrel size of different syringes at
`different depths along the syringe axis.
`
`Theory
`
`The system under consideration is fluid flow through a
`prefilled syringe. The syringe consists of a needle of
`length Ln and mean effective internal radius rn at—
`tached to the barrel of mean effective internal radius
`
`rb. The syringes are filled to a specified volume and
`stoppered using an automated stopper placement unit.
`The stopper holds the end of the plunger rod through
`which a force Ftotal is applied in order to drive the fluid
`with a plunger speed \7 (linear speed in length over
`time dimensions).
`
`Break-loose force refers to the maximum force re—
`quired to set the plunger into motion. Extrusion force
`is the total force required to sustain the plunger rod in
`motion While maintaining the desired flow rate of the
`liquid through the needle. This study characterizes the
`
`total extrusion force associated with delivery of a
`product through syringe injection.
`
`Figure 2 shows the schematic of a syringe system. The
`inner surface of the glass barrel
`is lubricated with
`silicone oil as shown in the figure. The force balance
`on the stopper at any time during injection gives
`
`ham 2 Tammi + Thydrmiynamiv
`
`(1)
`
`where Fmta, is the total force needed for driving the
`plunger (also referred to as extrusion force), meon is
`the friction force between the stopper and the syringe
`
`wall, and Fhwmdymmjc is the hydrodynamic force re-
`quired to drive the fluid out of the needle. The details
`of these forces are discussed in the following sections.
`
`A. Friction Force
`
`The friction force arises from the interaction between
`
`the walls of the stopper and the barrel. The inner
`surface of the glass syringe is lubricated (siliconizcd)
`with a thin layer of silicone oil as shown in Figure 2.
`The friction force thus results from the glass~silicone
`oil—stopper interaction. Using the lubrication approxi-
`mation, and assuming a uniform silicone oil layer on
`the inner wall of the barrel, the relation between the
`
`friction force and the injection speed is
`/
`
`__
`Ffiictioti _
`
`zwl’kmlrlilslt)
`.‘
`Oil
`d
`
`\
`
`ppci
`
`'
`
`,
`; __
`V _ 1(1'V
`
`(2)
`
`where no“ is the viscosity of lubricating oil, do” is the
`
`thickness of lubrication layer, ismpper is the length of
`the stopper in contact with glass, and v is the injection
`speed (linear piston speed with dimensions of length
`over time). Equation 2 shows that there is a linear
`dependence of the friction force on the injection speed
`and KC is the constant of proportionality for a given
`
`
`
`
`
`
`
`
`
`Figure 2
`
`stopper
`
`A schematic of the various components and forces associated with the syringe delivery system. The figure also
`shows a schematic of the lubrication of the syringe wall with silicone oil.
`
`470
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`
`dence of the hydrodynamic force on the injection
`speed. Equations 2 and 4 can be combined to give the
`total extrusion force associated with syringe delivery:
`
`I:total _
`
`/21Tp’oilrblstopocr)_
`Cl
`V _
`
`oil
`
`\
`
`(SWMLnr:\)_
`D
`4
`V‘
`1‘
`
`/
`
`(5)
`
`C. Hydrodynamic Force for Non—Newtonian Fluids
`
`The flow of non—Newtonian fluids is more complex
`due to the fact that their viscosity is not constant with
`the shear rate. A power law model is most commonly
`applied to represent the viscosity for such fluids:
`
`7w = KW)”
`
`and
`
`M = Kb)“
`
`(6)
`
`the wall or barrel
`where TW is the shear stress at
`surfaeet y is the shear rate and n is the power law
`index (where n '— 1 represents a Newtonian fluid), K is
`the defined as the flow consistency index, and p. is the
`apparent Viscosity.
`
`For non—Newtonian fluids,
`
`the relation between the
`
`pressure drop AP required to drive the fluid at flow
`rate Q in a cylindrical channel of radius r and length L
`can be derived by solving the Navier—Stokes equation
`for a flow in a cylinder (6). Neglecting the pressure
`across the barrel, the hydrodynamic force required to
`drive a non—Newtonian fluid with an injection speed \7
`can be derived as
`
`thdrodynamrc
`
`
`(3n + l\ ” 2*7Klinrfi"+2
`n
`l
`
`3u+l
`
`<1l
`
`_
`
`— KhV"-
`
`(7)
`
`It should be noted that while the hydrodynamic force
`was linear with injection speed for the case of New—
`tonian fluids, it has a non—linear dependence on injec—
`tion speed for non-Newtonian fluids. The total extru-
`sion force can then be estimated by adding the friction
`force to the hydrodynamic component:
`
`thickness of silicone oil. The friction force would
`
`increase with injection speed due to the increase in
`velocity gradient within the lubrication layer. Vari—
`ability in friction force could arise due to non—unifor—
`mity in the thickness of the silicone oil layer on the
`inside surface of the barrel, as well as variations in the
`
`geometry of the barrel and stopper. Protein—barrel
`interactions could further affect the friction force,
`
`B. Hydrodynamic Force for Newtonian FlllldS
`
`The hydrodynamic force results from the pressure
`drop required to drive the fluid out of the syringe. For
`Newtonian fluids, the relationship between the pres—
`sure drop AP and the volumetric flow rate Q (units:
`volume/time) can be obtained using the Hagen—Poi—
`seuille law as
`
`
`8 L
`AP: ”4Q
`171‘
`
`(3)
`
`where it is the viscosity of fluid, r is the radius, and L
`is the length of the cylindrical channel. The equation
`assumes laminar flow (Re < 2300) for an incompress-
`ible liquid though a channel of constant cross section
`diameter of 2r. For a 27 G syringe needle and 1 mL
`syringe barrel used in this study, a plunger speed of
`304.8 mm/min corresponds to a Reynolds number of
`less than lOO. Assuming no interference from the glue
`used in producing a staked needle syringe,
`the total
`hydrodynamic force associated with flow in a syringe
`will depend on the pressure drop across the barrel and
`needle. Equation 3 shows that for constant flow rate Q,
`AP ~ r74. In the syringe system, the radius of the
`barrel is much larger than the radius of the needle
`(rb/rn E 30). As a result, the pressure drop across the
`barrel
`is negligible when compared to the pressure
`drop across the needle (~0(10’6)). There is also an
`entry loss when the fluid enters into a constriction, but
`its magnitude is much smaller than the pressure drop
`across the needle (APIOSS ~ pv2/2 ~ 00077)). Ne—
`glecting the pressure drop across the syringe barrel
`and the entry loss, the hydrodynamic force at a given
`temperature can be estimated from eq 3 as
`
`Fliydtodynamic = (—4. V = KhV
`
`8’rruLnr: _
`1‘H
`
`_
`
`(4)
`
`.
`/
`_ Zfip’oillhlstopoe» __
`Ftotal "7 d—)V
`\
`oil
`
`
`+
`
`(311 'l'
`
`\n
`
`l)“21’rKL“rfi“+2
`
`7
`
`V“~
`
`(8)
`
`
`
`n+1n
`
`r
`
`where Kh is a constant that depends on syringe size
`and fluid properties. Variation in operating tempera-
`ture would affect the solution viscosity and the hydro-
`dynamic force. Equation 4 shows the linear depen—
`
`D. Injection Time Calculation for Autoinjecror
`
`Modeling of an autoinjection device involves a phys—
`ical understanding of the effects of all the components
`
`Vol. 65, No. 5, September—October 2011
`
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`associated with the delivery system. The autoinjector
`system included in this study has an installed spring
`serving as the source of the driving force required to
`inject
`the product from the syringe. The spring is
`installed at a compressed length, which is shorter than
`its free length. At the time of injection, the spring is
`released from its installed length, causing the spring to
`relax while forcing the drug out of the syringe at the
`same time. The driving force from the spring at any
`time when the compressed spring length is “x” is given
`by
`
`Fspring : kiln " X)
`
`(9)
`
`where 10 is the free length of the spring, x is the current
`spring length, and k is the spring constant. A stronger
`spring will provide a higher driving force and a shorter
`injection time. The generalized equation (for both
`Newtonian and non—Newtonian fluids) for the momen—
`tum balance on the stopper can be written as
`
`
`dzx
`dx
`dx\ “
`Kh<
`)
`dt /
`stopper (“:2
`x) det
`
`“k(lo
`
`m
`
`(10)
`
`The terms Kf and Kh correspond to the frictional and
`the hydrodynamic terms, respectively, as described in
`
`the previous section. 1nSmpper is the mass of the stop-
`per, and n is the power law viscosity index of the
`liquid. Equation It) represents a one-dimensional, sec-
`ond—order differential equation capturing the motion
`of the stopper. it is based on the assumption that the
`fluid is always at
`the quasi—steady state where the
`hydrodynamic term corresponds
`to the Poiseuille
`equation.
`
`For Newtonian solutions (n = l), a reasonably accu—
`rate analytical solution for eq 10 can be obtained by
`using appropriate initial conditions (zero velocity for
`stopper) and applying assumptions including neglect—
`ing the inertia term and considering the system to be in
`a quasi-steady state where the spring force balances
`the hydrodynamic and friction forces. For Newtonian
`fluids, an analytical approximation can then be derived
`HS
`
`x(t) = l0 + (x0 — lo)exp
`
`n+mi
`
`rm
`
`in eq 10), another
`For non—Newtonian fluids (n + l
`assumption regarding the friction force can be made to
`
`derive an analytical solution. As reported later in
`Section D, friction force lies in the range of 1 to 3 N
`for a wide range of injection velocities (injection time
`of 3 to 30 s). For viscous products the hydrodynamic
`force term is significantly larger than the friction term
`and has a stronger dependence on injection speed. If
`the frictional term is assumed to be a constant (C r), an
`analytical solution for non—Newtonian fluids can be
`obtained and is given by
`
`
`
`x(t) =c0 + [—(n *1) k
`
`u/(u’l)
`
`(a~%wwfl
`
`on
`
`where
`
`Co :: lo "‘ Cf/k
`
`Results and Discussion
`
`Based on the theoretical framework presented in the
`previous sections, experiments were conducted to
`measure the parameters contributing to delivery forces
`and injection times, including syringe barrel diameter,
`needle diameter, and autoinjector spring constant. The
`friction forces were also estimated, along with the
`impact of stopper variability and injection speed. Once
`these parameters had been measured, delivery forces
`as estimated by eq 5 were verified with the experi—
`mental data generated using the lnstron. Injection time
`data for test autoinjectors were also compared to the
`calculated injection times as given by eq 11. Once the
`analytical model was confirmed to adequately capture
`the flow behavior inside an injection device, a theo—
`retical stack tolerance analysis was conducted to esti—
`mate the worst—case variability in injection time. The
`following sections describe the results from each of
`these assessments.
`
`A. Characterization of Barrel Internal Diameter
`
`Consistency in barrel size is important in estimating
`the delivery forces as stated in eq 5. The barrel size
`governs the area over which the force is applied to
`push the plunger rod during injection. The force has a
`fourth—power dependence on barrel radius for a given
`plunger speed (second—order dependence for a given
`flow rate). Table II shows the measured values for
`barrel diameters of different syringes. The measure-
`ments were conducted at different sections of syringes
`
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`TABLE II
`
`Vendor 2 (siliconized glass)
`
`
`
`
`
`
`
`
`Measurement of Barrel ID at Different Sections of Syringes
`
`Barrel ID Measurement (mean I standard deviation) mm
`1
`
`Syringe Vendor and Type
`Lot
`—l— Top (flange end) 4
`Middle
`Bottom (needle end)
`
`Vendor 1 (siliconized glass)
`Lot 1
`6.38 I 0.021
`1— 6.39 I 0.018
`6.38 I 0.019
`
`Lot 2
`6.38 : 0.024
`6.39 I 0.023
`[—
`6.38 : 0.025
`
`Lot 3 +_
`6.38 I 0.013
`+ 6.38 I 0.014 +
`6.38 I 0.016
`
`Lot 1
`6.34 I 0.023
`6.35 I 0.023
`6.34 I 0.020
`
`Lot 2
`6.35 I 0023
`L
`6.35 I 0.020
`6.35 I 0.017
`
`Lot 3
`6.35 I 0.018
`6.35 I 0.021
`:—
`6.35 I 0.019
`
`Lot 1+ 6.34 : 0.029
`T 6.34 I 0.027
`6.34 : 0.026
`’1
`Lot 2 f
`6.36 : 0.021
`T
`6.36 : 0.021
`6.36 : 0.021
`_.
`Lot 1
`6.21 I 0.024
`6.30 I 0.014
`6.34 I 0.007
`
`Vendor 3 (siliconized glass)
`
`Vendor 4 (plastic)
`
`in order to check the uniformity of the diameter
`
`throughout the syringe length. The “Top” section re—
`
`fers to the flange end and the “Bottom” refers to the
`needle end. Each data point in the table is based on
`measurements performed on a sample size of 20 sy—
`ringes. Data suggest reasonable consistency in barrel
`diameters across the syringe types (within 6.25 to 6.45
`mm). It is also observed that while the cross—sectional
`diameter of glass syringes is uniform along the barrel
`length. plastic (Vendor 4) syringes exhibit a small
`increase in barrel radius at the needle end. Based on
`
`the lots and sample size considered in this evaluation,
`the maximum variation of the barrel diameter in glass
`syringes is estimated to be around 1%, which can
`result in a variation of up to 4% in the hydrodynamic
`component of the extrusion force (eq 4) for a given
`plunger speed.
`
`B. Characterization of Needle Internal Diameter
`
`Needle lD also plays an important role in determining
`the net hydrodynamic force. A small Change in needle
`size can cause a significant change in delivery forces
`or injection time. Equation 5 shows that the force is
`dependent on the fourth power of needle radius.
`In—
`stead of measuring the absolute internal diameter, an
`indirect approach was used to estimate the variability
`in the internal diameter of needles. The method uses a
`
`flow—based set up in which a fluid (water) is pumped at
`constant [low rate through the needle and the pressure
`drop is measured at a steady state. Assuming needle
`lengths are consistent, the variability in the pressure
`drop provides an estimate of the variability in needle
`ED as
`
`Vol. 65, No. 5, September—October 2011
`
`Pressure dropM(
`
`Flow rate‘
`
`r:
`
`/l
`
`Or, variability in pressure drop and extrusion force :
`4 X variability in needle diameter.
`
`in reality, some variation in measured pressure drop
`across needles would be expected due to the variabil—
`ity in the needle lengths as well. This method was used
`to estimate the variability in the needle ID for 27 G
`syringes from different vendors based on a sample size
`of 10 units per data point. Figure 3 shows a box plot
`for measured force (normalized) for different syringe
`
`2
`
`1.8!
`1
`O)
`3 1.65'
`o
`‘14
`‘
`-e 1.4:
`0N)
`'7'; 12:
`L.
`a
`1
`‘o
`: é- é
`
`/
`
`/
`
`t/
`
`+
`
`Outliers
`,/
`a
`\
`.\
`/
`
`
`
`\\
`
`l
`
`.
`m
`Q 1
`I l
`3
`.‘
`Vendor‘s
`;
`
`T
`I
`E
`"'
`
`T
`I
`
`I
`"'
`
`\‘
`
`a
`
`+
`
`Vendor3
`
`Vendor 1
`0'81
`0.6" ' " '
`
`Vendor 2
`
`Figure 3
`
`A plot showing the variability in injection force
`(pressure drop) for multiple lots of different sy-
`ringe types. The force is normalized with the mean
`value of force from Vendor 2 (lot 1) and is reflective
`of needle radius.
`
`473
`
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`

`

`Downloaded from journalpdaorg on May 31, 2012
`
`50*
`
`‘
`
`k = 0.30313 i 8.018291 N/mm(2.2 kgi)
`1;: 0.36032 3% 0.040112 N/mnm kgf)
`k= 0.55612 1 0.037004 N/mm(4.2 kgfl"
`
`systems. The boxes in the plot are drawn from first to
`third quartile with the center line being the median.
`The length of the bars (whiskers) is equivalent to 2.7
`times the standard deviation of each data set, and as a
`
`rule of thumb any point lying outside the whiskers is
`considered to be a statistical outlier. The force is
`normalized with the mean value of force for the Ven—
`
`dor 2 syringe (lot 1). The plot shows that Vendors 3
`and 4 syringes have the smallest needle diameter, as
`they have forces 60% higher than other syringes. This
`can cause up to a 60% increase in injection time for an
`autoinjector with these syringes (assuming the hydro-
`dynamic term is dominant). On the other hand,
`sy—
`ringes from Vendors l and 2 have similar forces,
`implying that the needle internal diameters are consistent
`among these syringes. Another important observation
`from the figure is that Vendors l and 2 have outlier
`needles that have up to 30% higher forces. This can
`result in up to a 30% increase in injection time.
`Therefore it is important to evaluate the variability
`in needle ID during the design of an autoinjector
`system. The frequency of such outlier needles could
`be lot-dependent, and its accurate estimation would
`require a larger sample set than that used in this
`study.
`
`C. Spring Force Characterization for Autoinjector
`
`The autoinjector system included in this study has an
`installed spring to serve as a source of the driving
`force required to inject the product from the syringe.
`To efficiently model the autoinjeetor, it is important to
`study the force—extension measurements and estimate
`the corresponding variability. For this purpose, mea—
`surements were performed using springs of different
`stiffness with a sample sine of 10 springs. Figure 4
`shows the plot of force-extension measurements for
`springs of three different spring constants. The shaded
`region indicates the length over which the spring re—
`mains active during injection. The measurements were
`performed using both a static and dynamic test recipe.
`For the dynamic measurement, the spring was gradu—
`ally compressed from its free length and the load was
`recorded as a function of length during compression.
`The plot in Figure 4 shows that the force extension
`profile is within the linear range as expected for
`spring—driven motion. An alternative method (static)
`was also employed in which the Instron compresses
`the spring to the installed length for a few seconds
`prior to force measurement. The spring was then com-
`pressed to the active length, paused. and then the
`
`
`
`70
`
`90
`
`110
`
`7 §.
`130
`150
`
`' ~,,
`170
`
`g 40»
`3—1
`g 30
`
`o m
`
`20»
`
`10»
`
`0,-
`30
`
`.
`
`Figure 4
`
`length (mm)
`
`Plot showing the dynamic force-extension measure-
`ments for springs of different stiffness (indicated
`by different color). The shaded region is the length
`over which the spring remains active during the
`time of injection.
`
`spring load was recorded. As shown in Table III, the
`force values are lower for the static test. This could
`
`potentially be attributed to the fact that static measure-
`ments allow the spring to relax and adjust to compres—
`sion, resulting in lower force relative to the dynamic
`measurement (where the spring is continually com—
`pressed). Either approach can be used to characterize
`the spring strengths, but the worst—case variability should
`be taken into account to design a robust autoinjector.
`
`D. Friction Force
`
`Variability in the inner barrel surface can be estimated
`by measuring the friction forces in empty syringes.
`Friction force can be estimated as the total force
`
`required for moving the plunger inside an empty sy—
`ringe. Measurement of friction force was performed
`using the Instron at an injection velocity ranging from
`3 to 900 mm/min. This velocity range corresponds to
`an injection time of 10 min to 3 s. respectively. for a
`1 mL injection. The wide range of injection times was
`chosen to evaluate very slow plunger movement that
`could potentially occur towards the end of a spring-
`driven autoinjector. Table IV shows the mean, maxi—
`mum, and range of friction force of syringes (includ—
`ing all
`lots) at an injection time of 6 5 (injection
`velocity 304.8 min/min) based on a sample size of 10
`units per syringe lot. The standard deviations listed in
`the table amount to a relatively large percent error and
`
`474
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`PDA Journal of Pharmaceutical Science and Technology
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`
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`
`

`

`Downloaded from journalpdaorg on May 31, 2012
`
`TABLE III
`
`Variability in Spring Load Measurements
`
`Heavy Load (N)—Installed Length
`Light Load (N)—Activated Length
`
`Strength
`Static
`Dynamic
`Static
`4
`Dynamic
`
`A
`21.06 i 0.63
`25.72 i 1.91
`10.67 i 0.26
`11.24 i 0.85
`
`Spring
`
`
`
`
`16.07 i 1.92
`16.32 i 0.30
`32.15 I 5.80
`28.11 i 0.67
`l—
`B
`
`C
`l
`37.02 i 1.27
`45.06 i 3.37
`l8.98 : 0.49
`18.03 i 0.79
`i
`
`are the result of both syringe—to—syringe variability as
`well as the experimental error in measuring forces of
`such low magnitude.
`
`The profiles of the friction force as a function of
`displacement for siliconized glass syringes (Vendor 2)
`are shown in Figure 5(a) using an injection speed of
`304.8 mm/min (injection time of 6 s). The profiles
`correspond to a sample size of 20 data points for two
`syringe lots. The profile has an initial peak in the force
`that corresponds to the break—loose force. The profiles
`of friction force show that there could be significant
`variation in the lubrication in the glass syringes. it
`should be noted that for analysis purposes the mean
`value of the friction force (mean of the profile) is more
`representative of average lubrication of the syringe
`barrel. The maximum value can be used in the esti—
`mation of worst—case scenarios as well as in the de-
`
`tection of failure points.
`
`Figure 5(b) shows the dependence of friction force on
`injection velocities for different syringes. Friction
`force increases linearly with injection velocity, which
`is in agreement with the theory (eq 2). it should be
`noted that friction forces in syringes are less than 1%
`of the load cell (500 N) used for lnstron measure—
`ments. This could as a result contribute to large rela—
`tive error in measured friction forces, especially at low
`
`TABLE IV
`
`velocities. The friction force is slightly higher for
`plastic syringes, especially at low speeds, and shows a
`weaker dependence on injection speed. This is due to
`the fact that there is no lubrication in plastic syringes
`and thus the frictional force follows solid—solid cohe—
`
`sive behavior. Figure 5(c) shows the snapshot of vari-
`ability in friction force of different lots of syringes at
`an injection time of 6 s (which corresponds to an
`injection velocity of 304.8 min/min). The figure shows
`that
`the variability in friction force is comparable
`within each lot of syringes. The practical range of
`injection time is 30 to 3 s, and the friction force for
`this range of injection time varies from 1 to 3 N for all
`the syringes under consideration. Such variability in
`friction forces may not have a significant impact on
`injection times for high-viscosity products, where the
`hydrodynamic component of eq 1 is dominant. How—
`ever, for low-viscosity products, the frictional forces
`could be the key determinant of injection time and
`hence the syringe barrels and stoppers should be thor—
`oughly characterized to estimate the worst~case fric—
`tion force. It should also be noted that once the sy-
`ringes are filled with product,
`friction force may
`change due to the interaction between product and
`barrel surface. Such product—specific interactions re-
`quire measurement of friction force in a wettcd sy—
`ringe (product~filled syringe) and will be discussed in
`a separate article.
`
`Calculated Mean. Maximum, and Range of the Friction Force at an Injection Time of 6 s
`
`"T
`Injection Time: 6 s
`
`
`yringe
`m...—
`S
`.
`lV'ean
`Max
`Range
`
`Source/Type
`f (N)
`Std (N)
`f (N)
`l
`Std (N)
`min (N)
`max (N)
`Vendor 1
`1.79
`0.39
`208
`l
`0.44
`1.02
`3.20
`lT
`—1
`
`Vendor 2
`1.93
`0.40
`2.34
`0.47
`0.97
`3.40
`
`
`
`
`
`
`Vendor 3
`Vendor 4
`
`1.96
`2.34
`
`L
`
`0.38
`0.25
`
`l"
`
`2.20
`3.12
`
`0.48
`0.42
`
`]
`
`1.23
`1.55
`
`1'
`
`2.99
`3.83
`
`Vol. 65, No. 5, September—October 2011
`
`475
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`

`Downloaded from journalpdaorg on May 31, 2012
`
`E Stopper Vendor A
`Stopper Vendor B
`
`2.5
`
`2
`
`1 5
`
`l
`
`0.5
`
`A a
`
`Ci
`.9
`
`.E
`LHLl—t
`
`0
`
`
`,
`fl
`1'
`'.‘
`*
`Syringe Vendor l
`Syringe Vendor 2
`
`Figure