Abstract
Given the surging interest in developing prefilled syringe and autoinjector combination products, investment in an early compatibility assessment is critical to prevent unwarranted drug/container closure interactions and avoid potential reformulation during late stages of drug development. In addition to the standard evaluation of drug stability, it is important to consider container closure functionality and overall device performance changes over time because of drug–container closure component interaction. This study elucidated the mechanisms that cause changes in syringe glide force over time and the impact on the injection duration. It was an expansion of the previous work, which indicated that drug formulation variables such as formulation excipients and pH affect syringe functionality over time. The current study described an investigative process for troubleshooting prolonged and variable autoinjector injection time caused by an increased syringe glide force variability over time. This increase in glide force variability stems from two root causes, namely plunger dimensional variation and syringe silicone oil change over time. The results demonstrated (a) the underlying factors of silicone oil change in the presence of drug formulation matrices, (b) accelerated stability of syringe glide force as a good indicator of long-term, real-time stability, and (c) that buffer matrix-filled syringes can be used to predict the syringe functionality and stability of drug product-filled syringes. Based on the experimental findings of a variety of orthogonal characterization techniques including contact angle, interfacial tension, and calculation of Hansen solubility parameters, it is proposed that silicone oil change is caused by formulation excipients and a complex set of phenomena summarized as “wet, wash, and delube” processes.
- Prefilled syringe
- Autoinjector
- Glide force
- Injection time
- Hansen solubility parameters
- Interfacial tension
- Contact angle
- Silicone oil
- Drug formulation
Introduction
Subcutaneous delivery has become a viable alternative to intravenous administration of biotherapeutics because of its well-established safety and tolerability profiles, enhanced patient preference and quality of life, and reduced delivery-related health care costs (1, 2). During the past decade, biologics constitute most new injectable drug approvals (3). The delivery of these biologic injectable drugs is often enabled by the prefilled syringes (PFSs) and autoinjectors (AIs) that are most commonly used for subcutaneous delivery of biopharmaceuticals. The advantages of using PFSs and AIs include dosing accuracy, ease of self-administration, and reduced patient involvement in dose preparation (4⇓–6). These drug/device combination products facilitate the shift of the point of care from hospitals to patients’ homes.
Both PFSs and AIs utilize a semifinished syringe prefilled at the manufacturer’s plant with a drug product solution. The functionality of these semifinished syringes throughout their shelf life is critical to the performance of both PFSs and AIs. The interior wall of a syringe is typically coated with silicone oil for lubrication to aid plunger movement during use. Insufficient silicone oil in PFSs may lead to a higher break-loose force and glide force for manual syringes. For AIs, reduced lubrication may lead to longer, more variable injection time and even device stalling. This may result in an unsatisfactory patient experience and even incomplete dosing at times.
As silicone oil is sprayed onto the interior surface of the syringe without chemical bonding, the oil can migrate and change its spatial distribution in empty syringes during storage (7). One study examined the effect of different process parameters of silicone oil coating on PFSs, including curing temperature, applied amount, and viscosity of the silicone oil, on the physical stability and leaching of the silicone coating exposed to the aqueous medium. It reported leaching of silicone into a simple system such as water. Owing to this characteristic, the study emphasized careful consideration of the criteria used during the siliconization of the devices meant to store aqueous biopharmaceuticals (8). Most literature on silicone oil in syringes focusses on the stability of the drug (e.g., monoclonal antibodies) because of undesirable interactions between hydrophobic silicone oil and protein molecules (9⇓–11). Recently, correlations between changes in the lubricity of silicone oil in PFSs and various formulation matrices and the subsequent impact on syringe functionality were demonstrated (12). It was shown that formulation variables such as buffer type and concentration, pH, tonicity agent type and concentration, and surfactant level could impact syringe break-loose and glide force over time.
In this study, the effect of temperature and time on the performance of syringes in AIs was investigated. Then, Hansen solubility parameters (HSP) distances (13) between the excipients and the contact surface materials of the container closure system were used to assess the physical interactions among them, followed by experimental verifications. Lastly, the holistic mechanisms of silicone oil/formulation matrix interactions were proposed as the “wet, wash, and delube” process.
Materials and Methods
Chemicals
The silicone oil used in the interfacial tension tests was 350 centistokes (cst) Dow Corning 360 Medical Fluid purchased from R.D. Abbot Company, Inc. (Cerritos, CA). This 350 cst silicone oil has the same manufacturer, identical chemical structure of polydimethylsiloxane, and the same density of 0.97 g/cm3 as the 1000 cst silicone oil commonly used in 1 mL long glass syringes. The lower viscosity silicone oil has the advantage of creating fewer air bubbles during the interfacial tension tests. All other excipients were purchased from VWR, Inc. at purity higher than ACS grade. The water was USP grade water for injection (WFI) purchased from J R Scientific, Inc.
Hansen Solubility Parameters Determination
The HSP of water, acetic acid, histidine, citric acid, and polysorbate 80 (PS 80) were taken from the HSPiP Software (version 5.0.04) database (13–14). The HSP of mannitol were measured by Agfa-Gevaert N.V. The HSP of silicone oil and borosilicate glass were taken from the literature (13⇓–15). Silicone oil is unique because it incorporates two HSP sets; one is found in Bittner et al.’s study (1) and the HSPiP Database (14), whereas the other is found in Dounce’s (4) and Rosen et al.’s (17) studies. Both were used to calculate HSP distances between silicone oil and other molecules. Likewise, for PS 80, the hydrophilic, hydrophobic, and combined hydrophilic–hydrophobic value sets were also used. For both silicone oil and PS 80, the shortest HSP distances were used for the results. Unlike other excipients, HSP theory does not apply to sodium chloride (NaCl) after it is dissolved, so a set of “effective” NaCl HSP were calculated using its solubility in organic solvents and HSPiP Software (16). Table I reports these HSP values (13⇓–15).
Hansen Solubility Parameters for Key Excipients, Silicone Oil, Water, and Borosilicate Glassa
Syringe Break-Loose Force and Glide Force Measurement
This testing was performed by dosing syringes (pushing liquid out against the rear of the plunger or push rod) under controlled conditions (typically 290 mm/min) using a Zwick test system, and force measurements were performed with a calibrated load cell. The two force regions of interest were the break-loose force where plunger motion is initiated and the glide force measured through the remaining dosing stroke. The test ended when the plunger reached the end of the syringe barrel and became compressed to the point that the force exceeded a threshold of 50 N. The rapid force rise at the end of the stroke caused by plunger compression against the syringe barrel was excluded from the glide force analysis.
Plunger Dimensional Measurement
A Keyence IM-6020 optical measurement system was used to characterize plunger outer diameter (OD) dimensions. This Keyence system measured components in two dimensions using a telecentric lens and background light. The resulting profile image was analyzed to automatically locate the edges of the component and apply user-programmed geometric dimensional definitions and record the resulting values.
Autoinjector Injection Time Measurement
AI injection process time (IPT) was measured by two different techniques. Method 1 used a video camera to record the entire injection duration and determine the time elapsed between button activation and completion of injection (i.e., needle retraction). Method 2 used a Zwick test system to record the force–time curve and then determine the time elapsed between button activation and needle retraction.
Contact Angle Measurement
An in situ method was developed to measure the static water contact angle (WCA) on the interior wall of intact siliconized glass syringes. The glass syringes were not broken to avoid interferences from broken glass particles. WFI was used to test the WCA. The raw images were captured on Ramé-Hart’s 200-F4 Goniometer using DropImage Standard software and were fit to the syringe cross-section and the water droplet shape in MATLAB (Figure 1). Angles joining the two circles’ tangent lines were extracted as the final WCAs.
Water contact angles for a well-lubricated, fully siliconized glass syringe (empty, as received by the manufacturer) were around 108.6° ± 2.7°.
Interfacial Tension
The interfacial tension (IFT) between the silicone oil and the aqueous samples was measured using Ramé-Hart’s 200-F4 Goniometer with DropImage Advanced software. The initial beta value ranged from 0.02 to 0.08, testing time spanned over 20 h, and the raw data files were fit to the Hua–Rosen theory (17) using MATLAB. Hua–Rosen theory states that the IFT changes with time and that the relationship between them is
(1)where t is time, γt is the IFT measured at t, γm is the IFT at mesoequilibrium (t = ∞), γ0 is the initial IFT in pure solvent (t = 0), t* is the time at the transition to equilibrium, and n is the hydrophobicity of the surfactant. The values of γm, γ0, t*, and n were computed by fitting eq 1 against IFT vs. time charts in MATLAB (Figure 2). Then, the IFT at 90 days was extrapolated and the prolonged storage effects estimated along Hua–Rosen theory.
Evolution of interfacial tension for 0.06 wt.% PS 80/350 cst silicone oil over time.
Silicone Interferometry
The syringe silicone layer was quantified using Unchained Lab’s Bouncer silicone thickness and distribution analyzer. The running conditions were six lines along the axis and 200 points per line with 45 mm total scanned syringe length per specimen. Layer thicknesses and masses were averaged for two specimens per sample.
Results and Discussion
Prior work by Shi et al. demonstrated the impact of formulation matrices on syringe glide force upon accelerated stability (12). The current study aims to address three related aspects of the reported findings: (a) if the accelerated stability of syringe glide force is predictive of shelf life stability at the storage temperature; (b) if the data from buffer matrices are consistent with results from drug products; and (c) how the syringe glide force change would impact AI performance.
Figure 3a shows the chronological evolution of a 1 mL AI product’s injection time for 13 different batches. Although the mean injection time for each batch was always below the specification limit for batch release (10 s [s]), large variability of injection time in multiple samples across two lots exceeded the 10 s specification limit, essentially failing the batch release test. The resulting investigation revealed that the long and variable injection time for this AI product was mainly caused by variable syringe glide force profiles, as shown in Figure 3b. In conjunction with a drive spring having a relative low spring constant, this AI product demonstrated longer and more variable injection time when a higher force was needed to push the plunger down the syringe barrel to expel the liquid.
(a) Autoinjector injection time (mean ± 3σ) for 13 separate device batches (x axis), with 10 s being the upper specification limit. (b) Representative glide force profiles for a single batch of syringes yielding long and variable injection time for autoinjectors.
An extensive investigation (Figure 4) showed two root causes of the variable syringe glide force: (a) plunger dimensional variation associated with specific trim dies; and (b) silicone oil properties that are dependent on drug product formulation, storage time, and temperature. Small batches of custom-made plungers were obtained to investigate the impact of plunger dimensional variation. The trim edge OD was measured individually for each plunger and tested for glide force. A weak correlation was observed between the plunger trim edge OD and the syringe glide force, as shown in Figure 5. As expected, a larger trim edge OD led to a higher glide force because a higher radial force was applied with a wider trim edge because of plunger compression onto the syringe barrel. This led to higher friction between the plunger and the barrel. Nonetheless, it is worthy of disclosure as such a correlation has not been reported before.
Investigation road map on root causes of variable syringe glide force.
Syringe glide force (N) vs plunger trim edge outer diameter (OD, mm).
The second, and less appreciated, cause of glide force variability was change to the syringe’s silicone oil layer. Figure 6 presents syringe glide force data generated during a head-to-head comparison of two products with different formulation matrices. Even though both products used identical component lots for both the barrels and the plungers, they showed distinct stability profiles for syringe glide force. Product X, which failed the AI injection time specification limit as mentioned previously, showed a steady increase in the level and variability of syringe glide force over 6 months upon 25°C storage. On the other hand, Product Y with excellent AI injection time performance exhibited very good stability of syringe glide force. The data suggested the dominant cause of the different glide force profiles was differences in drug formulation (either drug molecule and/or buffer matrices).
Accelerated stability of syringe glide force for Products X and Y upon 25°C storage for up to 6 months.
To determine if a silicone oil change was caused by antibody molecule or formulation excipients, a study was conducted to investigate the buffer matrix/silicone oil interactions. This study showed how buffer (type and concentration), pH, tonicity agent (type and concentration), and surfactant can affect syringe glide force over accelerated stability (12). Schlieren imaging of PFS upon accelerated stability (images shown in Reference 12) revealed a significant change over time in silicone oil morphology on the interior wall of acetate/PS 80-filled syringe barrel on 25°C storage. This corresponded well to a dramatic increase in syringe glide force (12). The acetate/PS 80-filled syringes had lower WCAs (70° ± 16°) compared to those of the original empty syringes (∼109° ± 3°). The lower angles indicated a significantly modified silicone layer inside the syringe. The citrate-filled syringe containing no PS 80 showed minimal change in silicone oil morphology or glide force upon accelerated stability. Such syringes, however, have normal WCAs (111 ± 2°), indicating a more stable silicone oil layer inside the syringes (12).
According to Shi et al., no difference in glide force between the initial conditions and the 6 months real-time stability data at 5°C storage was observed, even though changes at 25°C were apparent (12). Syringe functionality was monitored from the samples stored at 5°C for up to 29 months. This was done to determine the relationship between accelerated and real-time stability performance for syringe glide force. Figure 7 shows a correlation between syringe glide force of 5°C/29 months and 25°C/3 months conditions for a wide variety of samples covering different buffer (acetate, histidine, and citrate) and pH conditions (ranging from 4.5 to 6.5). It indicates the practical relevance of monitoring accelerated stability for syringe glide force, which can be used to predict long-term, shelf life performance of syringe functionality. Although this sounds intuitive, there was no prior report that demonstrated the use of accelerated stability of syringe glide force to predict its shelf life performance. This is because accelerated stability at 25°C or above had been considered too harsh to model silicone oil stability on syringe per conventional wisdom.
Accelerated stability of syringe glide force (GF) at 25°C/3 months for acetate, histidine, and citrate buffers of various pH conditions, in comparison with their 5°C/29 months performances.
The data set shown prior was from placebo solutions without any active pharmaceutical ingredient (e.g., monoclonal antibodies). It is important to determine if the drug formulations containing monoclonal antibodies at various concentrations would behave similarly in glide force stability. Figure 8 shows that a specific monoclonal antibody formulation exhibited a good correlation in glide force stability between 25°C/3 months and 5°C/36 months. The data also suggested a lack of impact of drug product concentration for this drug molecule, as 2 and 40 mg/mL concentrations do not show a significant difference in glide force changes. The observation of a much larger change in glide force for mannitol-containing drug formulations compared to NaCl-containing formulations was consistent with the buffer only experiments that contained no drug. This was indicative of the dominance of the buffer matrix in affecting syringe functionality.
Comparison of prefilled syringe glide force between 5°C/36 months and 25°C/3 months for a drug product at 2 and 40 mg/mL concentrations.
The preceding results demonstrated that plunger dimensional variability and alterations to the silicone oil layer caused by the formulation matrix can, in isolation, result in changes in glide force. Although the plunger friction inside the barrel is a complex process, as governed by the Stribeck curve (18), the syringe plunger friction in this context can be simplified into the static friction equation,
(2)
The normal load, N is tied to plunger dimensions, specifically the ODs of the sealing ribs and the trim edge. Figure 5 shows the relationship between the individual plunger’s trim edge OD and the glide force. It was found that the wider the trim edge, the higher the glide force. This is because of the larger OD of the plunger trim edge compressing harder against the interior barrel wall, increasing the normal load N, hence increasing friction F. On the other hand, per Stribeck’s curve, the friction coefficient µ can increase significantly from the hydrodynamic friction regime when there is a full film of lubricant. Mixed or boundary friction regimes are attained when the lubricant becomes deficient or modified (19).
Figure 9 summarizes the additive effect of the syringe silicone oil level and plunger trim edge OD on the syringe glide force. It illustrates the dynamic interactions of these two variables on plunger friction inside the syringe. The top row indicates when there is a normal state of silicone oil on the barrel surface. For example, when the syringes are just filled with drug product solution, the variation of plunger trim edge OD only has a minor impact on syringe glide force, ranging from good to excellent. However, when the silicone oil properties are modified via PFS aging with the presence of drug product solution, as shown at the bottom row, the plunger dimensional effect is exacerbated. This leads to poor or fair glide force profiles with substantial variability. The bottom right quadrant is exactly what happened to Product X in Figure 6; it shows significant variability in syringe glide force, whereas the top left quadrant describes its control, Product Y, which has a consistent glide force profile. In summary, while the plunger trim edge OD affects the normal load N in the static friction equation of F = N × µ; the interactions of drug formulation excipients with the siliconized glass barrels can strongly impact the µ value (coefficient of friction) via either reduction in the silicone oil layer or modification of its properties.
Syringe glide force profiles under different combinations of silicone oil level and plunger trim edge outer diameter (OD).
To elucidate the excipient effects on PFS glide force, HSP were used to probe the mechanisms of formulation excipients’ interactions with silicone oil. The cohesive energy of a solvent or polymer can be broken into three components mathematically expressed by
(3)where δt is the total solubility parameter, δd is the nonpolar component, δp is the polar component, and δh is the H-bonding component (13). The HSP three-dimensional coordinate is constructed by setting δd, δp, and δh as axes. Furthermore, solvent-polymer HSP coordinate distances (referenced herein as “distance” or “HSP distance”) are inversely related to solvent–polymer compatibility expressed as
(4)where (δd1, δp1, δh1) and (δd2, δp2, δh2) are the HSP coordinates for solvent and polymer, respectively (13). A weight factor of four was retained in eq 4 to compensate for the nonpolar/nonpolar physical interaction’s nondirectionality (13).
In prefilled siliconized glass syringes, solution and primary packaging material interactions consist of (a) glass–silicone; (b) silicone–solvent; (c) silicone–excipients; (d) glass–excipients; (e) glass–solvent; and (f) excipient–excipient systems. In Table II, HSP distances, as calculated using eq 4 and the coordinates listed in Table I, were used to estimate their relative intensities. However, the HSP concept applies more to molecules than to ions, so only acetic acid, histidine, and citric acid in buffer solutions were considered. Also, accepted practices dictate an 8 MPa1/2 HSP distance as a threshold for optimal solvent compatibility with typical polymers (16). Thus, these interactions can be categorized into three levels: strong for distances less than 8 MPa1/2 (red), medium for distances from 8 to 15 MPa1/2 (blue), and weak for distances greater than 15 MPa1/2 (black).
Hansen Solubility Parameter Distances (MPa1/2) between Key Excipients, Silicone Oil, Water, and Borosilicate Glass Demonstrating Strong (red), Medium (blue), and Weak (black) Interactions
PS 80 was the only excipient to have a strong interaction with silicone, as shown in Table II. Therefore, it is very likely that PS 80 could “contaminate” the silicone layer by adsorbing onto silicone or by penetrating the polymeric siloxane chains. As a surfactant, PS 80 could further emulsify the silicone layer into droplets and remove silicone from glass surfaces. Besides silicone oil, PS 80 also had strong interactions with acetic acid and medium interactions with glass, water, histidine, and mannitol. Thus, functioning as a “bridge”, PS 80 could connect silicone oil with otherwise less compatible components. Additionally, Table II illustrates increasing HSP distances between silicone oil and the three buffering agents in the order of acetic acid, histidine, and citric acid. This suggests that acetic acid has stronger interactions with silicone oil compared to histidine or citric acid, which is consistent with the trend of observed syringe glide force impact: acetate > histidine > citrate. Moreover, HSP distances between the excipients and glass are in the following order: acetic acid < PS 80 < silicone oil < histidine < water < citric acid. Both acetic acid and PS 80, with shorter HSP distances, could compete with silicone oil over the glass surface and affect glide force by reducing its contact area. In contrast, histidine and citric acid, with longer HSP distances, present lower risks to interact with glass or silicone oil.
Therefore, three intertwining mechanisms of glide force increase can be proposed based on calculations of HSP distances and verified using multitechnique experimentation. As illustrated in Figure 10, the glass and excipients compete for silicone oil interactions via a “wash” mechanism, the excipients and silicone oil compete for glass coverage via a “wet” mechanism, and the silicone oil and solvent compete for excipient interactions via a “delube” mechanism.
Possible mechanisms for glass syringe silicone layer modification by excipients.
IFT was used to verify the “delube” and “wash” mechanisms. As expected of a surfactant and shown in Table III, PS 80 was the only excipient that significantly reduced silicone/water IFT at equilibrium. This is consistent with PS 80 having the shortest HSP distance to silicone oil (<8 MPa1/2). As well accepted in colloid chemistry, an IFT reduction suggests PS 80 could emulsify silicone oil into the water phase. This “emulsification” could occur first by adsorbing onto the silicone layer surface (“delube” mechanism, Figure 10) then by surrounding isolated silicone droplets and pulling them away from the layer (“wash” mechanism, Figure 10). Additionally, the results in Table III suggest neither mannitol nor NaCl alone significantly impacted silicone oil IFT at equilibrium, which is consistent with their long HSP distances from silicone oil, indicating weak physical interactions. Furthermore, among the three buffers, none alone significantly reduced the IFT for silicone oil in water at equilibrium. This is consistent with their HSP distance calculations predicting none would have strong physical interactions with silicone oil.
Interfacial Tension (IFT) of Water and Select Excipients against Silicone Oil at Equilibrium
Along with individual excipients, the combined effects of excipients against silicone oil were also investigated. As the multifaceted silicone oil/matrix interactions at 90 days and room-temperature (23 °C) were similar to those at 2–3 years and 5°C, per fitting IFT data to Hua–Rosen theory (17), the IFT between the solution and silicone oil in typical long-term, refrigerated conditions can be estimated using these values (Table IV). These results indicated that (a) PS 80 can significantly reduce the IFT for all buffers and (b) PS 80 can lower the IFT more when combined with mannitol than with NaCl. This explains the “tonicity agent effect” on glide force for NaCl vs. mannitol as described previously (12). In sum, these IFT results showed that PS 80, with or without assistance of other excipients, can promote “emulsification” of silicone (the lubricant) into the water phase and consequently lead to a glide force increase through a “delube” and/or “wash” mechanism as illustrated in Figure 10.
Calculated Interfacial Tension Values between Excipients and Silicone Oil at 90 days and 23°C As Fitted to Hua–Rosen Theory
The HSP distances predicted that there would be a strong interaction between acetic acid and glass, which could affect glide force through the proposed “wet” mechanism (Figure 10). Thus, the effect of acetate buffer (without PS 80) on the glide force of siliconized glass syringes was investigated. Syringes filled with 40 mM acetate buffer at pH 4.5 and 5.5 were tested, while water-filled syringes were used as the control. As demonstrated in Figure 11, there were insignificant changes in glide force after 2 and 4 weeks, but after 12 weeks, the syringe glide force increased notably for all samples. The water-filled samples had the smallest increase in glide force, only increasing from ∼1 N to ∼1.5 N on average, whereas larger increases were observed for acetate buffer-filled syringes, with the mean glide force being 1.9 N at pH 5.5 and 3.2 N at pH 4.5. The results indicated that acetate buffer at low pH (e.g., pH 4.5) can still cause a significant increase in syringe glide force, even without PS 80.
Average glide force for siliconized glass syringes filled with pH 4.5 or pH 5.5 acetic acetate (AA) buffer or water and then stored at 40°C for 2, 4, and 12 weeks.
As shown in Table V, for the three excipient solutions after 12 weeks and 40°C storage, there were no significant differences in layer thickness and total weight (as measured by interferometry) for retained silicone on the glass syringes. It is thus unlikely that the acetate buffer simply “stripped” the silicone away from the glass. Moreover, the WCAs on the syringe for each solution were above 90°, indicating the interior surface remained hydrophobic. It is plausible that acetic acid infiltrated the silicone oil layer and further migrated to the silicone/glass interface where it competed with the silicone oil for glass surface coverage and reduced its contact area (“wet” mechanism in Figure 10).
Silicone Oil Layer Thickness, Total Weight, and Water Contact Angle for Syringes Exposed to Different Buffer Solutions and Water at 40°C for 12 Weeks
Based on the HSP calculations and experimental findings, a holistic view is emerging to account for the complex mechanisms of PFS glide force change upon stability (Figure 12). The increase in syringe friction was attributed to two factors. The first one was reduced silicone oil coverage as it becomes unstable on glass surfaces caused by either (a) surfactant, acetic acid, or histidine competing with silicone oil for glass contact; or (b) silicone oil being pulled away from the glass by surfactant, mannitol, and histidine. The other factor was reduced silicone lubricity owing to contamination of the silicone oil by PS 80 and other excipients. The change in silicone oil cohesion and its adhesion to glass because of the excipient induced “wet, wash, and delube” effects resulted in an increase in plunger friction inside the syringe barrel over time. The complexity of this “wet, wash, and delube” process can cause variation in plunger friction sometimes in an erratic fashion.
Schematics for mechanistic understanding of syringe glide force change over time upon stability in a “wet, wash, and delube” process.
Conclusions
This was a case study of AI injection time and PFS glide force being impacted by silicone oil change over time and elucidation of the mechanisms behind the interactions of drug formulation excipients and silicone oil.
This study demonstrated that the syringe glide force could increase over time because of silicone oil changes, which may lead to longer and variable AI injection time. This can have a negative impact on patient experience, dosing accuracy, and device batch releases. The data showed that accelerated stability of syringe glide force was a good indicator of real-time stability, and that the buffer matrix-filled syringe was a good surrogate for drug product-filled syringe in syringe functionality stability studies. Syringe glide force increase was caused by dynamic interactions between formulation excipients and silicone oil, water, and glass, based on HSP calculation and experimental confirmation. Such complex interactions affect surface wetting and silicone oil coverage and lubricity, leading to three intertwined mechanisms (wet, wash, and delube) for glide force changes.
It is important to assess the risk of formulation/silicone oil compatibility during early formulation development for biopharmaceuticals. The goal is to select suitable excipients and pH conditions to avoid potential negative impact on device performance stability. Tools such as HSP theory, IFT testing, contact angle, and Schlieren imaging can be used to evaluate syringe glide force stability and AI injection time performance throughout the shelf life.
Conflict of Interest Declaration
The authors declare that they have no competing interests related to this article.
Acknowledgments
The authors would like to acknowledge Ross A. Allen, Jonathan G. Parker, Lei Li, Karthik Vaideeswaran, Andrew Ratz, Le Ho, Nandhini Verma, and Megha Maheshwari for their contributions to the study. The authors would like to thank David S. Collins, Ronald G. Iacocca, and Arup Roy for their thorough review of the manuscript.
- © PDA, Inc. 2020
