`
`
`
`Downloaded from on January 3, 2022Downloaded from on January 3, 2022
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Variability in Syringe Components and its Impact on
`Functionality of Delivery Systems
`Nitin Rathore, Pratik Pranay, Bruce Eu, et al.
`
`2011
` PDA J Pharm Sci and Tech
`65,
` 468-480
`
`
`Access the most recent version at doi: 10.5731/pdajpst.2011.00785
`
`
`
`Novartis Exhibit 2229.001
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`
`Downloaded from
`
`on January 3, 2022
`
`Variability in Syringe Components and its Impact on
`Functionality of Delivery Systems
`
`NITIN RATHORE1,*, PRATIK PRANAY2, BRUCE EU1, WENCHANG JI1, and ED WALLS1
`
`1Drug Product and Device Development, Amgen, Thousand Oaks, CA and 2Department of Chemical Engineering,
`University of Wisconsin—Madison, Madison, WI ©PDA, Inc. 2011
`
`ABSTRACT: 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, Autoinjector, 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-up 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
`
`PDA Journal of Pharmaceutical Science and Technology
`
`Novartis Exhibit 2229.002
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Downloaded from on January 3, 2022
`
`[Vendor4[Tie|Phstic|
`
`TABLE I
`
`List of Syringe Types and Lots Used in This
`Study
`
`Syringe
`Vendor
`
`Number
`
`of Lots
`Studied
`
`Syringe Type
`
`Siliconized glass
`Siliconized glass
`Siliconized glass
`
`perceived to be less invasive than syringes (4) will
`provide commercial advantage to the drug manufac-
`turer. Novel delivery systems for commercial products
`also offer a mechanism to maintain the competitive
`edge in the marketplace (5).
`
`Successful commercialization of prefilled syringe con-
`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:
`
`¢ Barrel siliconization, which primarily affects the
`frictional forces
`
`¢
`
`e
`
`¢
`
`e¢
`
`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
`
`e Driving forces, such as the spring for mechanical
`autoinjectors
`
`¢
`
`e
`
`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,
`
`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 instrumentis then
`
`Vol. 65, No. 5, September-October 2011
`
`469
`
`Novartis Exhibit 2229.003
`Regeneron v. Novartis, IPR2021-00816
`
`Novartis Exhibit 2229.003
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Downloaded from
`
`on January 3, 2022
`
`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
`
`Ftotal ⫽ Ffriction ⫹ Fhydrodynamic
`
`(1)
`
`where Ftotal is the total force needed for driving the
`plunger (also referred to as extrusion force), Ffriction is
`the friction force between the stopper and the syringe
`wall, and Fhydrodynamic 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
`
`Figure 1
`
`Picture of the Instron 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 v (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
`
`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 (siliconized)
`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
`
`Ffriction ⫽冉2oilrblstopper
`
`doil
`
`冊v ⫽ Kfv
`
`(2)
`
`where
`oil is the viscosity of lubricating oil, doil is the
`thickness of lubrication layer, lstopper 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 Kf is the constant of proportionality for a given
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 2
`
`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
`
`PDA Journal of Pharmaceutical Science and Technology
`
`Novartis Exhibit 2229.004
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Downloaded from
`
`on January 3, 2022
`
`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 Fluids
`
`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 ⌬P and the volumetric flow rate Q (units:
`volume/time) can be obtained using the Hagen-Poi-
`seuille law as
`
`⌬P ⫽
`
`8LQ
`r4
`
`(3)
`
`where 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 100. 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,
`⌬P ⬃ r⫺4. In the syringe system, the radius of the
`barrel is much larger than the radius of the needle
`⬵ 30). As a result, the pressure drop across the
`(rb/rn
`barrel is negligible when compared to the pressure
`drop across the needle (⬃O(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
`⬃ v2/2 ⬃ O(10⫺7)). Ne-
`across the needle (⌬Ploss
`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
`
`Fhydrodynamic ⫽冉8Lnrb
`
`4
`
`4
`rn
`
`冊v ⫽ Khv
`
`(4)
`
`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:
`
`Ftotal ⫽冉2oilrblstopper
`
`doil
`
`冊v ⫹冉8Lnrb
`
`4
`
`4
`rn
`
`冊v.
`
`(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:
`
`w ⫽ K共␥兲n
`
`and ⫽ K共␥兲n⫺1
`
`(6)
`
`where
`the wall or barrel
`w is the shear stress at
`surface, ␥ 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 is the
`apparent viscosity.
`
`For non-Newtonian fluids, the relation between the
`pressure drop ⌬P 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 v
`can be derived as
`
`Fhydrodynamic ⫽冉3n ⫹ 1冊n 2KLnrb
`
`
`
`2n⫹2
`
`n
`
`3n⫹1
`rn
`
`v n
`
`⫽ Khv n.
`
`(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:
`
`冊v
`Ftotal ⫽冉2oilrblstopper
`⫹冉3n ⫹ 1
`冊n2KLnrb
`
`doil
`
`2n⫹2
`
`n
`
`3n⫹1
`rn
`
`v n.
`
`(8)
`
`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 Autoinjector
`
`Modeling of an autoinjection device involves a phys-
`ical understanding of the effects of all the components
`
`Vol. 65, No. 5, September–October 2011
`
`471
`
`Novartis Exhibit 2229.005
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Downloaded from
`
`on January 3, 2022
`
`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 ⫽ k共l0 ⫺ x兲
`
`(9)
`
`where lo 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
`
`mstopper
`
`d2x
`dt2 ⫽ k共l0 ⫺ x兲 ⫺ Kf
`
`dx
`dt
`
`⫺ Kh冉dx
`
`dt
`
`冊n
`
`(10)
`
`The terms Kf and Kh correspond to the frictional and
`the hydrodynamic terms, respectively, as described in
`the previous section. mstopper is the mass of the stop-
`per, and n is the power law viscosity index of the
`liquid. Equation 10 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 ⫽ 1), 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
`as
`
`x共t兲 ⫽ l0 ⫹ 共x0 ⫺ l0兲exp冋冉 ⫺k
`
`Kf ⫹ Kh
`
`冊t册
`
`(11)
`
`For non-Newtonian fluids (n ⫽ 1 in eq 10), another
`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 (Cf), an
`analytical solution for non-Newtonian fluids can be
`obtained and is given by
`
`x共t兲 ⫽ c0 ⫹冋⫺冉n ⫺ 1冊 k
`
`共x0 ⫺ c0兲共n⫺1兲/n册n/共n⫺1兲
`
`t ⫹
`
`n
`
`Kh
`
`(12)
`
`where
`
`c0 ⫽ l0 ⫺ 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 Instron. 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
`
`472
`
`PDA Journal of Pharmaceutical Science and Technology
`
`Novartis Exhibit 2229.006
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Downloaded from on January 3, 2022
`
`TABLEII
`
`Measurementof Barrel ID at Different Sections of Syringes
`
`Syringe Vendor and Type
`
`Top (flange end)
`
`Middle
`
`Bottom (needle end)
`
`Barrel ID Measurement (mean + standard deviation) mm
`
`6.35 + 0.021 Vendor4 (plastic)
`
`Vendor | (siliconized glass)
`
`Vendor2 (siliconized glass)
`
`Vendor3 (siliconized glass)
`
`6.38 + 0.021
`
`6.38 + 0.0243
`6.38 + 0.013
`
`6.34 + 0.023
`6
`35 + 0.023
`6.35 + 0.018
`
`6.34 + 0.029
`
`6.36 + 0.02136 +
`
`6.39 + 0.018
`6.3
`9 + 0.023
`6.38 + 0.014
`
`6.35 + 0.023
`6.35 + 0.020
`
`6.34 + 0.027
`
`6.36 + 0.0213
`
`Lot
`
`1
`
`6.21 + 0.024
`
`6.30 + 0.014
`
`6.38 + 0.019
`6.38 + 0.025
`6.38 + 0.016
`6.34 + 0.020
`6.35 + 0.017
`6.35 + 0.019
`6.34 + 0.026
`6.36 + 0.021
`6.34 + 0.007
`
`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 ID 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-basedset up in whicha fluid (water) is pumped at
`constant flow 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
`ID as
`
`Flow rate
`Pressure dropx Tz
`
`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
`
`©
`Et
`
`Outliers
`
`b
`i
`
`N
`+
`
`\
`
`se:
`
`a
`~~ 14
`@
`= 1.2
`a
`&
`Si SS es °
`a
`=
`=i
`
`T
`T
`t
`Hu=
`
`a
`
`=
`
`Vendor4
`
`Vendor 3
`
`Vendor1
`
`Vendor 2
`
`0.8
`0.6
`
`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) andis reflective
`of needle radius.
`
`Vol. 65, No. 5, September—October 2011
`
`473
`
`Novartis Exhibit 2229.007
`Regeneron v. Novartis, IPR2021-00816
`
`Novartis Exhibit 2229.007
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Downloaded from
`
`on January 3, 2022
`
`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 1 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 1 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 autoinjector, 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 size 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
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 4
`
`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 s (injection
`velocity 304.8 mm/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
`
`PDA Journal of Pharmaceutical Science and Technology
`
`Novartis Exhibit 2229.008
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`Downloaded from on January 3, 2022
`
`TABLEIII
`
`Variability in Spring Load Measurements
`
`Spring
`Strength
`
`Heavy Load (N)—Installed Length
`Dynamic
`Static
`Static
`Dynamic
`*0.
`67
`T+.
`11.24 + 0.85
`10.67 + 0.26
`21.06 + 0.63
`25.72 + 1.91
`
`|Bo|28.11 + 0.67 32.15 + 5.80 16.32 + 0.30 16.07 + 1.92
`
`
`45.06 + 3.37
`18.98 + 0.49
`18.03 + 0.79
`
`Light Load (N)—Activated Length
`
`37.02 + 1.27 .
`
`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
`displacementfor 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 (meanofthe profile) is more
`representative of average lubrication of the syringe
`barrel. The maximum value can be used inthe esti-
`mation of worst-case scenarios as well as in the de-
`
`tection of failure points.
`
`Figure 5(b) shows the dependenceoffriction 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 (S00 N) used for Instron measure-
`ments. This could as a result contribute to large rela-
`tive error in measuredfriction 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 oninjection 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 snapshotof 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 mm/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 | to 3 N forall
`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 |
`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 wetted sy-
`ringe (product-filled syringe) and will be discussed in
`a separate article.
`
`Calculated Mean, Maximum, and Rangeof the Friction Force at an Injection Time of 6 s
`
`Syringe
`Source/Type
`Vendor |
`
`Injection Time: 6 s
`
`Std (N)
`
`Std (N)
`
`
`
`|Vendor3_|96T8220|299
`
`Vol. 65, No. 5, September—October 2011
`
`475
`
`Novartis Exhibit 2229.009
`Regeneron v. Novartis, IPR2021-00816
`
`Novartis Exhibit 2229.009
`Regeneron v. Novartis, IPR2021-00816
`
`
`
`
`
`on January 3, 2022Downloaded from
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Figure 6
`
`Plot showing the effect of different stoppers on
`glide friction force at an injection time of 9 s (205
`mm/min).
`
`E. Impact of Stopper Variability
`
`The stoppers used in glass syringes are also lubricated
`using silicone oil. Different stoppers could have dif-
`ferent levels of lubrication, different materials of com-
`position, and some geometrical variations that could
`affect friction forces. In this study, stoppers from two
`different vendors are used and the impact on friction
`force is evaluated. The stoppers are expected to be
`similar except for the am