AAPS PharmSciTech, Vol. 12, No. 2, June 2011 ( # 2011)
`DOI: 10.1208/s12249 011 9625 y
`
`Research Article
`Theme: Sterile Products: Advances and Challenges in Formulation, Manufacturing, Devices and Regulatory Aspects
`Guest Editors: Lavinia Lewis, Jim Agalloco, Bill Lambert, Russell Madsen, and Mark Staples
`
`Injectability Evaluation: An Open Issue
`
`Francesco Cilurzo,1,3 Francesca Selmin,1 Paola Minghetti,1 Marco Adami,2 Elisa Bertoni,2
`Sara Lauria,2 and Luisa Montanari1
`
`Received 18 May 2010; accepted 27 April 2011; published online 7 May 2011
`Abstract. The current work aimed to propose a system of scoring to rationalize and support the selection
`of the optimal diameter and length of needles. Four formulations at different viscosity and needles
`ranging from 21 to 26 G and length ranging from 16 to 40 mm were used. Plunger stopper breakloose
`force, maximum force (Fmax), and dynamic glide force were measured by a texture analyzer at the
`crosshead speed of 1 mm/s. Testing was carried out into air or human subcutaneous tissue. The manual
`injectability of the highest viscosity product was assessed by ten evaluators. The comparison of the panel
`test score and the quantitative measurements of the forces permitted to score a given needle syringe
`formulation system keeping also in consideration the pressure created in the subcutaneous space and
`muscles at the injection site. In particular, the following relationship was drawn: at the Fmax up to
`250 mPa, the injection was practically impossible; at Fmax ranging from 160 to 250 mPa, the injection was
`very difficult; at Fmax in the 125 160 mPa range, the injection was feasible, though with some difficulty;
`when the values of Fmax were lower 125 mPa, the injection went smoothly. On the basis of these
`preliminary data, a system of scoring the needle syringe formulation system is proposed to rationalize
`and support the selection of the optimal diameter and length of needles, keeping also in consideration the
`pressure created in the subcutaneous space and muscles at the injection site.
`
`KEY WORDS: injectability; panel test; texture analyzer.
`
`INTRODUCTION
`
`Syringeability and injectability are key product perform
`ance parameters of any parenteral dosage form. The former
`refers to the ability of an injectable therapeutic to pass easily
`through a hypodermic needle on transfer from a vial prior to
`an injection, while the latter refers to the performance of the
`formulation during injection (1). Syringeability includes such
`factors as ease of withdrawal, clogging and foaming tenden
`cies, and accuracy of dose measurements. Injectability
`includes pressure or force required for injection, evenness of
`flow, and freedom from clogging (i.e., no blockage of the
`syringe needle). Syringeability and injectability concepts are
`of particular significance for specialized dosage forms, such as
`injectable emulsions, suspensions, liposomes, microemulsions,
`and microspheres. Over the last 15 20 years, these systems
`have become increasingly important in order to overcome
`issues specifically related to the drug solubility and stability,
`
`1 Department of Pharmaceutical Sciences “Pietro Pratesi”, Università
`degli Studi di Milano, via G. Colombo, 71, 20133 Milan, Italy.
`2 Industrial Development Department, Italfarmaco S.p.A., 20126
`Milan, Italy.
`3 To whom correspondence should be addressed. (e mail: francesco.
`cilurzo@unimi.it)
`
`and achieve the desired rate of release (e.g., prolonged
`release after intramuscular or subcutaneous injection). Vis
`cosity, density, flow are of paramount importance when
`considering such non conventional formulations (2,3).
`Syringeability and injectability can be affected by the
`needle geometry, i.e. inner diameter, length, shape of the
`opening, as well as the surface finish of the syringe (4). This is
`of particular significance for self injection devices, such as
`pens and auto injectors, which are equipped with very thin
`needles. Indeed, patients can use pen injectors which employ
`29 31 G needles. As far as pre filled syringes are concerned,
`common needle configurations for subcutaneous dosing are
`27 G and 25 G (4,5). While reducing the pain of injection, fine
`needles require an increased force to inject the drug.
`It is clear that both the ease of withdrawal of a product from
`a container (syringeability) and its subsequent injection into the
`intended administration site (injectability) must be determined
`for the finished drug product. Both parameters should be
`understood and characterized during product development.
`According to the ICH Q6A Note for Guidance, parenteral
`formulations packaged in pre filled syringes or auto injector
`cartridges should have test procedures and acceptance criteria
`related to the functionality of the delivery system (6). Moreover,
`in the FDA Guidance for Industry on container closure systems
`for packaging human drugs and biologics, the evaluation of
`syringe's performance is required (7). This should be addressed
`by establishing the force to initiate and maintain plunger
`
`1530-9932/11/0200-0604/0 # 2011 American Association of Pharmaceutical Scientists
`
`604
`
`Novartis Exhibit 2218.001
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Injectability Evaluation: An Open Issue
`
`605
`
`Table I. Score of Manual Injectability of Formulation 1. Injectability for a Given Needle syringe Systems Filled with Aliquots of 1 mL of the
`Highest Viscosity Formulation was Considered Acceptable When the Total Score was up to 30, i.e. The Steady Flow of the Tested Formulation
`was Obtained with Moderate Difficulty During its Injection
`
`Needle size
`
`Individual score
`
`Gauge (G)
`
`Length (mm)
`
`#1
`
`#2
`
`#3
`
`#4
`
`#5
`
`#6
`
`#7
`
`#8
`
`#9
`
`#10
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`Total score
`
`22
`23
`
`24
`25
`
`26
`
`40
`16
`30
`25
`16
`25
`12
`
`4
`4
`3
`3
`3
`1
`1
`
`4
`4
`3
`2
`2
`1
`1
`
`4
`4
`1
`1
`1
`1
`1
`
`3
`4
`1
`1
`1
`1
`1
`
`3
`3
`2
`2
`2
`1
`1
`
`4
`4
`4
`2
`1
`1
`1
`
`4
`4
`4
`3
`1
`1
`1
`
`3
`3
`2
`1
`1
`1
`1
`
`3
`4
`3
`3
`3
`1
`1
`
`4
`4
`2
`2
`2
`1
`1
`
`36
`38
`25
`20
`17
`10
`10
`
`movement down the barrel, and the capability of the syringe to
`deliver the labeled amount of drug product.
`In spite of these regulatory requirements, no compendial
`testing procedures are specified in Pharmacopoeias. If difficul
`ties in syringeability can be easily solved varying the needle size
`used in the withdraw procedure, in the meantime issues related
`to injectability can have a big impact on patient's adherence and,
`therefore, such parameter should be investigated.
`In 1979, Ritschel and Suzuki (8) proposed a method to
`determine injectability of parenterals by determining the
`time required to smoothly inject a solution, or suspension,
`into a meat sample under the specified pressure for a given
`syringe needle system. In order to measure the force
`required to inject a liquid through a needle, a dynamom
`eter (9,10) or a micro capillary rheometer connected to a
`dynamometer (11,12) were also used. Eventually,
`the
`instrument developed by Chien et al. (13) was based on a
`constant nitrogen pressure, which moved a metallic punch,
`which was connected to the syringe plunger. These studies
`reported that
`injectability was related to both injection
`speed and product viscosity.
`The current work aimed to propose a system of scoring
`the needle syringe formulation system in order to rationalize
`and support the selection of the optimal diameter and length
`of needles. Since measurement of injection force while the
`needle tip is exposed to air cannot sufficiently indicate the
`formulation's injectability in vivo, the extrusion testing was
`also carried out by inserting the needle directly in a human
`subcutaneous tissue model.
`
`MATERIALS AND METHODS
`
`Materials
`
`In order to evaluate the performances of injectable ther
`apeutics at different viscosity, the following formulations were
`selected: high viscosity lipid based systems (R&D Department of
`Italfarmaco, I, Formulation 1); aqueous suspension (Celestone®
`Cronodose®, Schering Plough S.p.A., I, Formulation 2); W/O
`emulsion (Diprivan®, AstraZeneca, I, Formulation 3) and low
`viscosity lipid based systems (R&D Department of Italfarmaco, I,
`Formulation 4). A Luer Lock glass syringe (BD Hypak, USA),
`0.6 mm inner diameter, was filled with 1 mL tested formulation.
`Needles of gauge size ranging from 21 G to 26 G and length
`ranging from 16 to 40 mm (Terumo Europe, B) were attached to
`the syringe tip.
`
`Viscosity Measurement
`
`The rheological properties of the four formulations were
`measured using an Ubbelohde capillary viscometer at a
`temperature of 20±1°C maintained with a thermostatic bath.
`Values were expressed as average of three determinations
`(kinematic viscosity, cSt±standard deviation).
`
`Determination of Injectability
`
`Panel Test
`
`The injectability of the formulation at highest viscosity
`was assessed by 10 subjects who received different needle
`syringe systems (Table I) filled with an aliquot of 1 mL of
`Formulation 1. Before injecting, the participants were appro
`priately trained. The participants were asked to evaluate the
`injectability in terms of
`the ease of
`injection and the
`formulation flow through the needle, using an arbitrary score
`from 1 to 4. In particular, the arbitrary score for both
`parameters was defined as following:
`
`score 1=injection: not possible or very difficult; flow: no
`flow or drop wise;
`score 2=injection: difficult; flow:
`then continuous;
`
`initially drop wise,
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`Fig. 1. Pressure required to expel the fluid (mPa) as a function of
`extruded volume (mL) at the crosshead speed of 1 mm/s. Testing was
`carried out on high viscosity lipid based systems (Formulation 1), an
`aqueous suspension (Formulation 2); W/O emulsion (Formulation 3)
`and low viscosity lipid based systems (Formulation 4) via a 22 G,
`40 mm needle into air
`
`Novartis Exhibit 2218.002
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`606
`
`Cilurzo et al.
`
`Table II. Parameters of Injectability, Plunger stopper Break Loose Force (PBF), Maximum Force (Fmax), and Dynamic Glide force (DGF), for
`Formulation 1 Injected by a Given Needle syringe Systems, as Determined from the Force displacement Plot. The Results are Expressed as the
`mean of Three Determinations±Standard Deviation
`
`Needle
`
`Gauge (G)
`
`Length (mm)
`
`21
`22
`23
`
`40
`40
`30
`
`PBF (mPa)
`
`95.96±2.39
`105.25±16.50
`95.82±4.86
`
`Fmax (mPa)
`
`95.96±2.39
`105.25±16.50
`95.82±4.86
`
`DGF (mPa)
`
`42.86±4.39
`54.14±3.46
`49.71±4.61
`
`score 3=injection: moderate; flow: continuous;
`score 4=injection: easy; flow: continuous.
`
`Injectability for a given needle syringe systems was
`considered acceptable when the total score was up to 30, i.e.
`all volunteers were able to inject the tested formulation with
`moderate difficulty obtaining steady flow. The time required
`to empty the syringe was also measured.
`
`Quantitative Determination
`
`The measurement of the injection force was performed
`in compression mode by using a software controlled texture
`analyzer (Acquati, I). The syringe was positioned in the
`dynamometer holder, downward needle. The plunger end of
`the syringe was placed in contact with a 5 N loading cell.
`Testing was carried out at the crosshead speed of 1 mm/s,
`representative of manual syringe delivery to patient. The
`loading force required to displace the plunger was measured
`(N) as a function of plunger displacement (mm) at a
`frequency of 50 Hz.
`The following parameters were also determined from the
`force displacement plot (4):
`
`plunger stopper breakloose force (or “initial glide
`force”; PBF):
`the force required to initiate the
`movement of the plunger;
`maximum force (Fmax): the highest force measured
`before the plunger finishes its course at the front end
`of the syringe;
`dynamic glide force (DGF): the force required to
`sustain the movement of the plunger to expel the
`content of the syringe.
`
`The registered force values were normalized by dividing
`them for the cross sectional area of the cylindrical plunger
`and therefore expressed in mPa. The experiments were
`performed in triplicate.
`
`In order to evaluate the resistance of subcutaneous tissue
`towards injection, the force required to inject both Formula
`tion 1 and Formulation 4 via 25 G, 16 mm and 24 G, 25 mm
`needles into human subcutaneous tissue was also assessed.
`The abdominal skin was obtained from a donor (Eurasian
`female) who underwent cosmetic surgery. The needle was
`manually inserted 1 in. underneath the skin; afterwards, the
`measurement of
`the injection force was carried out
`in
`compression mode as described above.
`
`Statistical Analysis
`
`Tests for significant differences and multi regression
`analysis were performed by using the software Origin® 8.5
`(Origin Lab., USA). Differences were considered significant
`at the p<0.05 level.
`
`RESULTS AND DISCUSSION
`
`the tested formulations
`The kinematic viscosity of
`increased in the following order: Formulation 2 (1.12±0.00
`cSt)<Formulation 3 (1.64±0.00 cSt)<Formulation 4 (18.66±
`0.02 cSt)<< Formulation 1 (101.23±0.30 cSt).
`
`Qualitative Determination of Injectability
`
`Since it is well recognized that kinematic viscosity deeply
`affects the ejection of a formulation from the syringe via a needle
`to the injection site, the injectability of the highest viscosity
`product, namely Formulation 1, was manually assessed by the
`panel test. As the needle size might influence patient's comfort
`and compliance,
`in this study needles consistent with intra
`muscularly and subcutaneously injections were investigated.
`All subjects were able to inject Formulation 1 into air,
`independently of needle diameter or length (Table I). The
`ease of injection into air was acceptable only for Formulation
`1 via needle 22 G, 40 mm and 23 G, 16 mm (Table I). Since
`
`Table III. Injectability Data, i.e.Plunger stopper Break Loose Force (PBF), Maximum Force (Fmax), and Dynamic Glide Force (DGF), for
`Formulation 2 in air by texture analyser. The Results are Expressed as the Mean of Three Determinations±Standard Deviation
`
`Needle
`
`Gauge (G)
`
`Length (mm)
`
`22
`23
`24
`25
`26
`
`40
`16
`25
`25
`12
`
`PBF (mPa)
`
`107.98±8.34
`104.76±11.89
`101.55±6.98
`110.36±3.62
`111.67±7.88
`
`Fmax (mPa)
`
`107.98±8.34
`104.76±11.89
`101.55±6.98
`110.36±3.62
`111.67±7.88
`
`DGF (mPa)
`
`36.86±6.11
`51.93±3.57
`36.75±6.14
`47.04±9.96
`43.71±5.79
`
`Novartis Exhibit 2218.003
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`Injectability Evaluation: An Open Issue
`
`607
`
`Table IV. Injectability Data, i.e.Plunger stopper Break Loose Force (PBF), Maximum Force (Fmax), and Dynamic Glide Force (DGF), for
`Formulation 3 in air by Texture Analyser. The results are Expressed as the Mean of Three Determinations±Standard Deviation
`
`Needle
`
`Gauge (G)
`
`Length (mm)
`
`22
`
`23
`
`24
`25
`
`26
`
`30
`40
`50
`16
`25
`30
`25
`16
`25
`12
`
`PBF (mPa)
`
`67.14±6.07
`70.36±3.93
`77.14±10.00
`72.50±3.93
`86.43±3.57
`91.07±5.71
`98.57±3.57
`93.93±5.00
`104.29±0.18
`121.07±4.64
`
`Fmax (mPa)
`
`91.07±10.00
`107.14±18.21
`113.57±16.79
`91.79±12.86
`114.64±16.07
`126.79±20.36
`135.00±13.93
`130.36±19.64
`156.07±12.50
`170.71±11.43
`
`DGF (mPa)
`
`71.79±6.07
`83.57±9.64
`93.21±14.64
`72.86±6.43
`90.00±10.36
`100.36±11.07
`113.21±11.43
`106.07±11.07
`127.50±5.00
`142.50±5.36
`
`Formulation 1 was manually extruded by both needles at the
`average rate of approximately 1 mm/s, the measurements of
`injection force were carried out with the same crosshead
`speed.
`
`Determination of Injectability by Texture Analyzer
`
`The force applied to a syringe plunger during the
`injection of a formulation via a needle is dissipated in three
`ways: (a) overcoming the resistance force of the syringe
`plunger; (b) imparting kinetic energy to the liquid; and (c)
`forcing the liquid through the needle (12). Additional force is
`also required to overcome the pressure resistance when the
`vehicle is administered to subcutaneous tissue. The preva
`lence of one or more events determines the profile of loading
`force versus plunger displacement graph. The patterns
`obtained by extruding four formulations through the needle
`22 G, 40 mm of length are exemplified in Fig. 1.
`In the force vs. displacement plot of
`low viscosity
`formulations, three different portions can be identified: the
`former is related to the force required to displace the plunger,
`namely plunger stopper breakloose force (PBF). This max
`imum value is followed by a plateau (second portion)
`indicating the streamline of the formulation through the
`needle occurs with a constant force. In this portion the
`average load required to sustain the movement of the plunger
`
`to expel the content of the syringe is calculated and reported
`as dynamic glide force (DGF). During the third portion, the
`force rapidly increases because of the compression of syringe
`plunger against the end of syringe body. This trend was
`recorded in the case of Formulation 2 and Formulation 3
`(Fig. 1). For both formulations (Table II and Table III), PBF
`overlapped the maximum force (Fmax) independently of the
`needle size, suggesting that the highest value of force was
`required to promote the plunger motion; afterwards, the
`formulation could freely flow through the needle. Also the
`force required to inject both formulations ranged from
`95 mPa to 110 mPa independently of the needle diameter or
`length.
`To get a continuous flow of Formulation 4, the maximum
`force was higher than PBF and DGF (Table IV). Moreover, it
`can be noticed in Fig. 1 that DGF increased linearly during
`the plunger displacement.
`The lipid based formulation at highest viscosity, namely
`Formulation 1, evidenced a different pattern (Fig. 1). Once
`Formulation 1 started to flow through the needle, the force
`remained almost constant in the second portion of the plot
`until the compression of plunger to the syringe's body was
`measured. Thus, PBF could not be determined (Table V). It
`can be assumed that the limit factor to get a steady streamline
`is the passage through the needle due to the viscosity of the
`formulation. Generally speaking, the kinematic viscosity (ν)
`
`Table V. Injectability Data, i.e. Plunger stopper Break Loose Force (PBF), Maximum Force (Fmax), and Dynamic Glide Force (DGF), for
`Formulation 4 in air by Texture Analyzer. The results are Expressed as the Mean of Three Determinations±Standard Deviation
`
`Needle size
`
`Gauge (G)
`
`Length (mm)
`
`22
`
`23
`
`24
`25
`
`26
`
`* not detectable
`
`30
`40
`50
`16
`25
`30
`25
`16
`25
`12
`
`PBF (mPa)
`
`*
`*
`*
`78.21±19.64
`*
`*
`*
`*
`*
`*
`
`Fmax (mPa)
`
`126.43±8.93
`128.21±6.07
`250.36±28.21
`139.29±18.93
`161.79±6.43
`172.14±3.57
`275.36±16.07
`231.79±5.00
`302.14±9.29
`373.57±18.57
`
`DGF (mPa)
`
`115.00±10.00
`122.86±7.14
`237.50±16.43
`129.29±13.93
`156.79±6.43
`166.79±5.36
`227.50±8.93
`221.07±2.86
`294.29±10.00
`365.71±18.93
`
`Novartis Exhibit 2218.004
`Regeneron v. Novartis, IPR2021-00816
`
`

`

`608
`
`Cilurzo et al.
`
`the formulation and DGF required to extrude the
`of
`formulation through the needle were related by a semi
`logarithmic power law: using the 22 G, 40 mm needle the
`following relationship was found: DGF=39 log (ν)+39 (F=
`23.07; R2=0.9079).
`In the case of lipid based formulations, it can be noticed
`that the thinner the needle diameter, the higher the DGF and
`Fmax values. As an example, when the needle length was kept
`constant at 25 mm, linear relationships between the needle
`inner diameter expressed in mm (di) and the DGF as well as
`the Fmax were found:
`
`Formulation 1 DGF ¼ 1375:0 di þ 982:4 ðR2 ¼ 0:9995
`
`Fmax ¼ 1403:6 di þ 1006:5 ðR2 ¼ 0:9921
`
`Formulation 4 DGF ¼ 372:5 di þ 315:1 ðR2 ¼ 0:9648
`
`Fmax ¼ 416:4 di þ 364:3 ðR2 ¼ 0:9999
`Formulation 1, having higher viscosity than Formulation
`4 also demonstrated higher slope value.
`A linear trend was also observed keeping constant the
`needle inner diameter. As an example when the needle inner
`diameter was set at 22 G or 23 G, the DGF proportionally
`increased with respect to the needle length for Formulation 4
`(R2>0.9984). Even if such correlations cannot have a general
`relevance,
`they allowed us to qualitatively highline the
`dependence of the injectability on kinematic differences of
`formulations. A full evaluation of the dependence of Fmax on
`the needle gauge and length and the formulation viscosity was
`also carried out by a multivariate regression analysis
`combining all 28 performed measurements. A poor sound of
`correlation was found:
`
`
`238:9di þ 1:8l R2 ¼ 0:6665
`Fmax ¼ 93:8 þ 2:0n
`where l is the needle length. Moreover, the only significant
`parameter influencing the extrusion of formulation through a
`given needle syringe systems appeared to be the nominal
`inner diameter of the needle (p<0.02).
`Measurements of injection force while the needle tip is
`exposed to air cannot indicate the formulation's injectability
`in vivo since subcutaneous tissues have limited physiological
`space and provide resistance toward injection. Hence, further
`experiments were carried out by using a subcutaneous human
`tissue model to determine injectability. For ethical concerns,
`the use of subcutaneous tissue was limited to investigate the
`performances of Formulation 1 and Formulation 4 via
`needles 24 G, 25 mm and 25 G, 26 mm. The measured
`texture profiles overlapped those recorded when injected
`towards air (data not shown) and the quantitative values are
`summarized in Fig. 2. As expected, the values of Fmax and
`DGF were higher because of the resistance opposed by the
`subcutaneous tissues.
`In all cases, the ratios between the force values obtained
`in the different experimental set ups were almost constant to
`1.1. Being independent of needle size, these ratios were
`mainly related to the increase of force required to overcome
`the tissue resistance. Hence,
`the force values obtained
`injecting formulations towards air should be rectified by this
`ratio in order to obtain more comprehensive information
`supporting the selection of the needle/syringe system.
`The comparison of the manual injections (Table I) and
`the in vitro normalized values for the highest viscosity
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`Fig. 2. Injectability paramenters (PBF: plunger stopper break loose
`force, Fmax: maximum force, DGF: dynamic glide force) for For
`mulation 1 and Formulation 4 injected in subcutaneous tissue by
`texture analyzer. The results are expressed as the mean of three
`determinations±standard deviation
`
`formulation (Table II) led us to draw a relationship between
`the arbitrary score and the values of force measured by
`texture test, namely:
`
`the Fmax up to 250 mPa,
`at
`the injection was
`practically impossible and it corresponds to the total
`score from 0 to 15;
`at Fmax ranging from 160 to 250 mPa, the injection
`was very difficult, corresponding to the total score
`from 16 to 25;
`at Fmax in the 125 160 mPa range, the injection was
`feasible, though with some difficulty, corresponding
`to the total score to the total score from 26 to 35;
`when the Fmax were lower 125 mPa, the injection went
`smoothly and it corresponds to total score from 36 to 40.
`
`CONCLUSION
`
`At high viscosity value, the flow of the product through
`the needle was the most critical step, rather than the initial
`plunger displacement. To select the needle syringe systems,
`the back pressure created in the subcutaneous space at the
`injection site should be always carefully taken in consider
`ation because it might influence the force required to displace
`the plunger.
`The preliminary results reported in this study allowed
`us to establish a scoring system to rationalize and support
`the selection of the optimal the needle syringe formulation
`system.
`
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`Regeneron v. Novartis, IPR2021-00816
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`Regeneron v. Novartis, IPR2021-00816
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`