Chemical-gas Sterilization of External Surface of Polymer-based Prefilled Syringes and Its Effect on Stability of Model Therapeutic Protein

To reduce the risk of infection during intravitreal injections, the external surface of prefilled syringes (PFSs) must be sterilized. Usually, ethylene oxide (EO) gas or vaporized hydrogen peroxide (VHP) is used for sterilization. More recently, nitrogen dioxide (NO₂) gas sterilization has been developed. It is known that gas permeability is approximately zero into glass-PFSs. However, polymer-PFSs (P-PFSs) have relatively high gas permeability. Therefore, there are concerns about the potential impact of external surface sterilization on drug solutions in P-PFSs. In this study, P-PFSs [filled with water for injection (WFI) or human serum albumin (HSA) solution] were externally sterilized using EO, VHP, and NO₂ gases. For the WFI-filled syringes, the concentration of each gas that ingressed into the WFI was measured. For the HSA solution-filled syringes, the physical and chemical degradation of HSA molecules by each sterilant gas was quantified. For the EO- or VHP-sterilized syringes, the ingressed EO or hydrogen peroxide (H₂O₂) molecules were detected in the filled WFI. Additionally, EO-adducted or oxidized HSA molecules were observed in the HSA-filled syringes. In contrast, the NO₂-sterilized WFI-filled syringes exhibited essentially immeasurable ingressed NO₂, and protein degradation was not detected in HSA-filled syringes.     

Determination of conditions for the production scale sterilization of prefilled syringes

External and internal differences in pressure of prefilled syringes can cause plunger movement during sterilization, which might cause drug product contamination. Consequently the pressure inside the autoclave during sterilization should be controlled carefully to prevent contamination of the drug product by microorganism and particulates. A previously determined theoretical relationship of temperature to pressure in sealed bottles was modified for prefilled syringes to take plunger movement into account. This modification yielded a correction factor that includes a coefficient of linear thermal expansion for the syringe, thermal expansion of the plunger, and friction between the plunger and the syringe wall. To confirm the accuracy of this modified relationship, 100 mL polypropylene prefilled syringes with butyl rubber plungers, some of which carried pressure and temperature sensors, were used to test various sterilization conditions at the experimental scale. The results showed that the major problem in establishing the pressure conditions for production scale sterilization is temperature distribution throughout the load. However, an over pressure sterilization cycle at 121 degrees C and 0.34 MPa showed the best results. Microbial challenge and light-obscuration particle count tests were performed on the syringes from the worst-case location predicted from modified relationship; the results show that these conditions preserved the sterility of the drug product and protected it from particulate contamination.     

Effect of Various Silicone Oil And Tungsten Levels on the Stability of a Monoclonal Antibody in Nine Commercially Available Prefilled Syringes

Prefilled syringes are widely used as a primary container for therapeutic proteins because they are more convenient than glass vials. The stability of biologic molecules can be affected by different syringe materials and techniques, such as silicone oil levels and coating method, amount of tungsten remaining in the glass barrel after using a tungsten pin to create the needle hole, and end of the syringe, which can be Luer locked or pre-staked with a needle. We investigated the impact of these parameters by using a monoclonal antibody to collect the antibody's stability profile and the prefilled syringes’ functionality data. Silicone oil levels had no impact on aggregation levels, and particle counts were lowest for silicone oil–free syringes. Functionality performance was similar and did not change throughout all stability time points for all syringe configurations. The break-loose force for Ompi syringes was initially lower and increased over time to align with those of the other configurations, all of which remained well below 25 N. Tungsten contaminants and agitation stress from shipping studies did not impact quality attributes. This work can help guide the development of similar products in prefilled syringes to ensure selection of the primary container that provides adequate stability for the protein, as well as maintain the desired functionality features over the shelf life of the drug product.     

Prefilled syringes for immunoglobulin G (IgG) replacement therapy: clinical experience from other disease settings

ABSTRACT

Introduction: Ready-to-use prefilled syringes for drug delivery are increasingly used across a broad spectrum of clinical specialties. For patients with primary immunodeficiencies manifesting as antibody deficiencies, immunoglobulin G (IgG) replacement therapy (IgRT) by subcutaneous administration is an established treatment modality. Expanding IgRT administration options through the introduction of prefilled syringes may further improve its utility.

Areas covered: Here, we collate experience with prefilled syringes from other clinical settings to inform on their practicality and suitability for IgRT. In addition to discussing drug characteristics such as stability, pharmacokinetics, and efficacy, we focus on treatment delivery, physician/patient experience, costs, and the importance of education for the use of prefilled syringes.

Expert opinion: Perceived benefits of prefilled syringes include accurate dosing, sterility, and reduced treatment time, while offering patients greater choice, convenience, and ease-of-use. Our review of clinical experience with prefilled syringes supports this consensus. Relatively few studies directly compare prefilled syringes with conventional administration, and robust studies of cost-effectiveness and health-related quality of life are needed on a drug-by-drug basis. Growth in the availability of prefilled syringes will continue, encouraged by the importance of patient choice and treatment convenience, toward the goal of individualized treatment regimens and improved quality of life.     

Taste and Odour Disturbances in Pediatric Patients Undergoing IV Flush with Normal Saline Administered by Prefilled or Freshly Prepared Syringes: Randomized Single-Blind Study

Background:

Previous studies have reported the occurrence of taste and odour disturbances among patients undergoing IV flush with prefilled syringes of 0.9% sodium chloride (normal saline [NS]). These disturbances have been attributed to the leaching of volatile substances into the NS from the plastic of the syringe. To date, there have been no studies comparing the occurrence of taste and odour disturbances with different NS preparations.

Objective:

To compare the occurrence of taste and odour disturbances in pediatric patients undergoing IV flush with commercially available prefilled NS syringes and NS syringes prepared fresh daily.

Methods:

Patients aged 6 to 18 years who underwent routine flushing of central or peripheral IV tubing were asked to participate in this follow-up randomized single-blind study. Flushing was performed with NS from BD PosiFlush 10-mL sterile prefilled syringes or NS transferred from a polyolefin bag (Baxter AVIVA) to a polypropylene syringe and stored for a maximum of 12 h before use.

Results:

Fifty pediatric patients (mean age ± standard deviation 13.4 ± 3.8 years) who had undergone flushing of IV tubing with NS were interviewed. Taste or odour disturbances were reported by 18 (72%) of the 25 patients who underwent flushing with NS from a prefilled syringe, whereas only 1 (4%) of the 25 who underwent flushing with NS from a freshly prepared syringe experienced such disturbances (p < 0.001).

Conclusions:

There were significant differences in taste and odour disturbances experienced by patients who underwent IV flush with commercial prefilled NS syringes and freshly prepared NS syringes.     

A cost benefit comparison of two antibiotic delivery systems in a children's hospital.

A comparative trial was undertaken in a 301 bed pediatric hospital to determine the feasibility and cost benefit of converting from a minibag intravenous admixture system to one using polypropylene syringes, prefilled with undiluted medication, for the administration of antibiotics. Technical and therapeutic problems unique to a pediatric hospital and the stability of antibiotics in polypropylene syringes were concurrent considerations. The cost of materials and total time involved were measured for each system for a one month period. It was concluded that the prefilled syringe system as a method of dispensing selected parenteral antibiotics, although requiring more time, is more cost effective than the minibag system.     

丙泊酚中/长链脂肪乳预充注射液与注射液的经济性评价

目的:评价丙泊酚中/长链脂肪乳预充注射液与注射液的经济性以及配置药师的满意度.方法:采用现场模拟试验法,由5名配置药师在静脉用药调配中心分别对2种注射液模拟手术室环境进行配置准备.比较2种注射液的配置时间,采用最小成本分析方法评价2种注射液配置的经济性,采用问卷调查方法调查配置药师的满意度,评分1～5分依次表示非常不满...     

Heparin administration using prefilled syringes or ampoules: a comparative cost-effectiveness study

Heparin is commonly administered for prophylaxis of thromboembolism in a dose of 5,000iu in 0.2ml subcutaneously twice or three times daily. The presentation may be as a prefilled syringe or as an ampoule. The effect of the presentation on nursing time and the true costs involved has been studied in two London hospitals. Thirty-eight administrations from prefilled syringes and 27 from ampoules were recorded. The mean times to prepare and administer the dose and dispose of the equipment were 67.6 seconds for a prefilled syringe and 128.5 seconds for an ampoule; the mean time saving per dose (95 per cent confidence intervals) was 60.9 (40.8, 80.9) seconds. The total cost per dose using a prefilled syringe was 104p; using an ampoule it was 113p. A generic cost model was created. The use of prefilled syringes saved approximately one minute of time and 9p (8 per cent) in cost per administration.     

Analysis of hydroxyzine hydrochloride, meperidine hydrochloride and atropine sulfate in glass and plastic syringes.

The apparent stability of combinations of hydroxyzine hydrochloride and meperidine hydrochloride (50 mg/2 ml each) and of these two drugs (50 mg/2.5 ml each) and atropine sulfate (0.4 mg/2.5 ml) in prefilled glass and plastic syringes was studied. Syringes (3 ml) containing the combinations were stored at 25 C and 3 C for 10 days and analyzed at specific time intervals. Absorption spectra, chromatographic characteristics and pH were determined in addition to visual inspection. Results of these qualitative tests indicated that the mixtures apparently were stable for 10 days at room temperature or when refrigerated. No differences were found between solutions stored in glass and those stored in plastic syringes. Degradation of the syringe contents or appearance of additional constituents was not detected in any of the admixtures, and they were considered to be chemically compatible within the limitations of the study. The study suggests that storage of these combinations in syringes is feasible but the results cannot be extrapolated to drug solutions or syringes other than those studied.     

Evaluation of the effect of syringe surfaces on protein formulations

Packaging of drugs in prefillable syringes offers considerable advantages over conventional vials. Almost all major biotech molecules are available on the market today in prefilled syringes, and are safe and efficacious. Newer high-concentration liquid formulations, especially fusion proteins, however, can suffer from instability in prefilled syringes due to syringe components like silicone oil. To assess the effect of siliconized and modified syringe surfaces on protein formulations, the stability of the recombinant protective antigen (rPA) for anthrax, abatacept, a fusion protein formulation with known silicone oil sensitivity, and an antistaphylococcal enterotoxin B (anti-SEB) monoclonal antibody (mAb) was assessed in siliconized, uncoated, and BD-42-coated (a proprietary coating developed by BD Technologies) prefilled syringes under different conditions. Both the soluble protein content and the number of subvisible particles were followed over time. When filled in siliconized syringes, all three protein solutions showed increased number of subvisible particles relative to uncoated or BD-42-coated syringes; the abatacept formulation with known silicone sensitivity also developed visible particles. Although rPA and anti-SEB mAb formulations mainly showed individual droplets, presumably of silicone, the abatacept formulation also showed droplets entangled in a fibrous structure. Uncoated glass and BD-42-coated syringes considerably reduced the formation of both visible and subvisible particles after immediate contact and after agitation. The anti-SEB mAb also adhered as a thin layer to the siliconized surface after agitation, irrespective of storage temperature. The development of visible particles could not be correlated with the loss of soluble protein fraction at protein concentrations above 4 mg/mL. It appears that protein formulations interact differently with different surfaces. The BD-42 coating appears to be a promising solution for packaging silicone-sensitive proteins in prefillable syringes and needs to be investigated further. It is demonstrated that BD-42 provides an inert surface with adequate lubrication while limiting the formation of visible and subvisible particles. It is hypothesized that these particles are formed due to the release of silicone droplets in the solution and result in the formation of silicone-induced visible aggregates.     

Low-level microbial contamination of liquid in syringe hubs leads to an unacceptable risk to the end product

Objectives The aim of this study was to assess the risk associated with microbial contamination in the hub‐fluid in Luer‐lock syringes to the end‐product, and ultimately patients. Methods The hub‐fluid of 48 sterile syringes prefilled with broth was contaminated with a low number of Staphylococcus epidermidis or spores of Bacillus subtilis. After incubation for three weeks, the syringe fills were tested for the presence of bacterial contaminants and some syringes were used to inoculate an end product broth that was then investigated for the presence of microorganisms. Key findings After three weeks of incubation only 20.8% of syringe fills showed turbidity, although following further investigation 70.8% were positive for the presence of viable bacteria, whereas 95.6% of end products became contaminated following injection of the syringe fill. Conclusions These findings add quantitative data that support the current practice of discarding syringes with residue around the cap.     

Stability of multidose, preserved formulation epoetin alfa in syringes for three and six weeks.

The integrity and biological activity of multidose, preserved formulation epoetin alfa stored in syringes at 2-8 degrees C were studied. Three independent 1.0-mL hubless syringes of epoetin alfa 20,000 units/mL were aseptically prepared and refrigerated for three and six weeks (a total of six syringes). Protein integrity was assayed by SDS-polyacrylamide gel electrophoresis (SDS-PAGE), immunoblotting, and glycoprotein detection. Biological activity was determined through a cell-based proliferation assay. The presence or absence of microbial contamination was observed after a one-week culture. A multidose, preserved formulation of epoetin alfa that was opened only at the time of assay served as the reference standard. SDS-PAGE silver-stained gels and immunoblots demonstrated no evidence of erythropoietin degradation after three and six weeks of storage when compared with the reference standard. In addition, SDS-PAGE, immunoblotting, and direct glycoprotein detection found that protein glycosylation was unaffected by the storage. Student's t test detected no significant difference between stored samples and the reference standard in biological activity (p > 0.05). A culture of epoetin alfa in bacterial and eukaryotic cell growth media showed no evidence of contamination. The results suggest that epoetin alfa can be dispensed to patients in prefilled syringes every four to six weeks to coincide with their peritoneal dialysis schedule. The integrity and biological activity of 20,000 units/mL epoetin alfa in prefilled syringes remain intact after three and six weeks when stored at 2-8 degrees C.     

Protein adsorption and excipient effects on kinetic stability of silicone oil emulsions

The effect of silicone oil on the stability of therapeutic protein formulations is of concern in the biopharmaceutical industry as more proteins are stored and delivered in prefilled syringes. Prefilled syringes provide convenience for medical professionals and patients, but prolonged exposure of proteins to silicone oil within prefilled syringes may be problematic. In this study, we characterize systems of silicone oil‐in‐aqueous buffer emulsions and model proteins in formulations containing surfactant, sodium chloride, or sucrose. For each of the formulations studied, silicone oil‐induced loss of soluble protein, likely through protein adsorption onto the silicone oil droplet surface. Excipient addition affected both protein adsorption and emulsion stability. Addition of surfactant stabilized emulsions but decreased protein adsorption to silicone oil microdroplets. In contrast, addition of sodium chloride increased protein adsorption and decreased emulsion stability. Silicone oil droplets with adsorbed lysozyme rapidly agglomerated and creamed out of suspension. This decrease in the kinetic stability of the emulsion is ascribed to surface charge neutralization and a bridging flocculation phenomenon and illustrates the need to investigate not only the effects of silicone oil on protein stability, but also the effects of protein formulation variables on emulsion stability. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1721–1733, 2010     

Taste and/or Odour Disturbances in Pediatric Patients Undergoing IV Flush with Normal Saline Administered by Prefilled Syringe

Background:

At the Children’s Hospital of Eastern Ontario, more than 6000 inpatients per year undergo IV saline flushes by prefilled syringe to assess and maintain patency of IV tubing. In studies involving adults, it has been reported that volatile substances may leach from syringe materials into the saline, leading to taste and/or odour disturbances.

Objective:

To determine the incidence of taste and/or odour disturbances in pediatric patients after flushing of IV tubing with 0.9% sodium chloride (normal saline [NS]) from prefilled syringes.

Methods:

Inpatients aged 5–18 years who had undergone routine flushing of central or peripheral IV tubing with commercially available prefilled NS syringes were interviewed. Children aged 5–10 years used a visual hedonic scale to rate taste and odour sensations, and those aged 11–18 years used a numeric rating scale.

Results:

During the study period (April to July 2011), a total of 104 pediatric inpatients (21 aged 5–10 years and 83 aged 11–18 years) underwent NS flushing of central (10 patients [10%]) or peripheral (94 patients [90%]) tubing. For 100 of these patients, BD Posiflush NaCl 0.9% 10-mL sterile prefilled syringes were used, and for 4 patients BD Saline XS NaCl 0.9% 10-mL sterile prefilled syringes were used. Taste and/or odour disturbances were reported by 76 (73%) of the patients. Twelve patients described more than one taste or odour sensation. Taste and odour disturbances were detected by children in both age groups.

Conclusions:

Flushing of IV tubing with prefilled NS syringes resulted in taste and/or odour disturbances in a pediatric population.     

Stability of U-500 regular insulin in prefilled syringes

ObjectiveTo evaluate the stability of U-500 regular insulin in prefilled syringes stored under refrigeration for up to 28 days.MethodsU-500 regular insulin was drawn up in 1 mL insulin syringes in a clean, nonsterile environment to emulate conditions of a patient's home. Samples were assayed using a stability-indicating reverse-phase high-performance liquid chromatography method immediately after preparation (day 0) and after 7, 14, 21, and 28 days under refrigeration. Before evaluation, all samples were diluted to a concentration of 40 units/mL in the starting mobile phase. Stability was determined by evaluating the percentage of the initial concentration remaining at each time point.ResultsAt least 93.3% of the initial U-500 insulin concentration remained throughout the 28-day study period, with no statistically significant changes in the amount remaining. The percent of initial concentration remained above 97% for the first 21 days of the study.ConclusionA prefilled syringe with U-500 regular insulin is stable for at least 28 days when stored under refrigeration. These data are similar to those reported for U-100 regular insulin, indicating that prefilling syringes with U-500 insulin is a safe and effective practice for patients who are unable to accurately draw up their own point-of-care doses.     

预灌封注射器密封系统完整性研究

目的:通过微生物侵入挑战性试验,确认采用预灌封注射器包装的小容量注射剂产品的密封完整性.方法:按无菌生产要求在预灌封注射器内灌装胰胨大豆肉汤培养基,培养14 d后,置于大肠埃希菌菌悬液中浸泡4 h.浸泡后样品继续培养7 d,观察细菌侵入情况.结果:培养7 d后,注射器内培养基均无细菌生长.结论:预灌封注射器密封系统能满足密封完好性的要求,可保证产品不受细菌侵入.     

Sweeping of Adsorbed Therapeutic Protein on Prefillable Syringes Promotes Micron Aggregate Generation

This study evaluated how differences in the surface properties of prefillable syringe barrels and in-solution sampling methods affect micron aggregates and protein adsorption levels. Three syringe types (glass barrel with silicone oil coating [GLS/SO+], glass barrel without silicone oil coating [GLS/SO?], and cyclo-olefin polymer [COP] barrel syringes) were tested with 3 therapeutic proteins (adalimumab, etanercept, and infliximab) using 2 sampling methods (aspiration or ejection). After quiescent incubation, solutions sampled by aspiration exhibited no significant change in micron aggregate concentration in any syringes, whereas those sampled by ejection exhibited increased micron aggregates in both GLS syringe types. Micron aggregate concentration in ejected solutions generally increased with increasing density of adsorbed proteins. Notably, COP syringes contained the lowest micron aggregate concentrations, which were independent of the sampling method. Correspondingly, the adsorbed protein density on COP syringes was the lowest at 1-2 mg/m², which was much less compared with that on GLS syringes and was calculated to be equivalent to only 1–2 protein layers, as visually confirmed by high-speed atomic force microscopy. These data indicate that low-adsorption prefillable syringes should be used for therapeutic proteins because protein aggregate concentration in the ejected solution is elevated by increased protein adsorption to the syringe surface.     

Risk Mitigation of Plunger-Stopper Displacement Under Low Atmospheric Pressure by Establishing Design Space for Filling-Stoppering Process of Prefilled Syringes: A Design of Experiment (DoE) Approach

There is a concern that low atmospheric pressure typically encountered during shipment could result in plunger-stopper displacement in prefilled syringes impacting sterility and container closure integrity (CCI) of drug product.¹ In this work, following DoE principles we first investigated the impact of filling and stoppering operating parameters on creation of bubble height as performance parameters among others in nominal 1 mL and 2.25 mL Type I glass prefilled syringes (PFSs) with staked needle and rigid needle shield (RNS). Bubble height ranging from <2.0 mm to >15.0 mm were produced in syringes by filling water and vacuum stoppering at operating vacuum pressure ranging from 400 mbar to 950 mbar using a pilot scale filling-stoppering machine. We found that for a particular nominal fill volume in prefilled syringe, as the stoppering vacuum pressure increased, bubble height decreased resulting in plunger-stopper placed closer to the fill level. Subsequently, syringes with varying bubble size were exposed to reduced atmospheric pressure ranging from 628 Torr to 293 Torr bracketing the low pressure recommended by ASTM D4169 standard to qualify shipping containers for transportation of drug products. We found inverse linear correlation between bubble height and plunger-stopper displacement under low atmospheric pressure. However, plunger-stopper displacement increased exponentially as atmospheric pressure decreased. The results suggest that air bubble size in filled glass syringes should be minimized in order to mitigate sterility and container closure integrity (CCI) risk to drug product in prefilled syringes.     

Sources of injecting equipment for drug users in Moscow, Russia

Syringe exchange programmes (SEPs) were approved in Moscow in 2002 and studies to evaluate access to sterile syringes are now needed. Clients of a non-governmental organisation (NGO) providing outreach to IDUs were interviewed concerning behaviours within the previous 30 days. Of 232 IDUs, 64% were male, mean age was 25 and mean duration of injection drug use was 5.8 years. Twelve percent reported injecting with used syringes and using prefilled syringes; 6% passed syringes to others and 91% shared paraphernalia. Seventy nine per cent admitted that they had never had a sterile syringe every time they needed it. Among women, 45% used pharmacies as their only source of injecting equipment. Out of 10 potential syringe sources, pharmacies were the major source, especially for women. The other two major sources were other drug users and drug dealers. NGOs offering syringe exchange were mentioned by 9%, whereas medical institutions were reported as the least popular source. Almost all (99%) reported that syringes are not expensive and their procurement is not difficult, but 83% mentioned that buying syringes at pharmacies often involves a risk of being examined by law enforcement staff. These results indicate that significant barriers for procurement and use of sterile syringes exist in Moscow.     

Extended stability of iobenguane under simulated clinical conditions.

PURPOSE: The stability of iobenguane sulfate stored at 4-7 degrees C over 91 days was studied. METHODS: An iobenguane sulfate solution at a concentration of 2.2 mg/mL was prepared in a top-fill i.v. bag using 143 mg of iobenguane sulfate and 65 mL of Sterile Water for Injection, USP. The solution was poured through a 0.22- microm filter assembly for sterilization into 60 1-mL polycarbonate plastic syringes. Each syringe was filled with 0.9 mL of the iobenguane sulfate solution and stored in amber plastic bags at 4-7 degrees C. The stability of iobenguane sulfate was analyzed using high-performance liquid chromatography immediately after solution preparation and on days 7, 14, 28, 42, 56, 70, and 91. Samples were inspected for chemical purity by observing for particulate formation and color change. RESULTS: The mean concentration of ioben-guane exceeded 93% of the initial concentration in all samples throughout the 91-day study period. No changes in color or turbidity were observed. CONCLUSION: Iobenguane sulfate 2.2 mg/mL was stable for 91 days when stored in polycarbonate syringes at 4-7 degrees C.