DOI: 10.5301/ejo.5000629
`
`ORIGINAL ARTICLE
`
`Ranibizumab prefilled syringes: benefits of reduced
`syringe preparation times and less complex preparation
`procedures
`
`Eric Souied1, Sylvia Nghiem-Buffet2, Claudia Leteneux3, Sascha Bayer4, Audrey Derveloy5, Alexandros Sagkriotis3,
`Guido Becker4, Salomon-Yves Cohen1,2
`
`1 Centre Hospitalier Intercommunal Créteil, Université Paris-Est, Créteil - France
`2 Centre Ophtalmologique d’Imagerie et de Laser, Paris - France
`3 Novartis Pharma AG, Basel - Switzerland
`4 Q_PERIOR AG, Zurich - Switzerland
`5 Novartis Pharma France, Paris - France
`
`ABSTRACT
`Purpose: A recently developed ranibizumab prefilled syringe (PFS) eliminates several preparatory steps versus
`the standard vial-based method, and is expected to reduce syringe preparation time (SPT) and enhance proce-
`dural simplicity for intravitreal injections.
`Methods: Syringe preparation times for the ranibizumab PFS and vial were recorded during standard treatment
`sessions at 2 centers, without randomization. The duration of each step in preparing the syringe was recorded.
`At each center, total SPT (mean total duration of all syringe preparation steps) for each method was compared
`using a 2-tailed t test.
`Results: In total, 97 SPTs were analyzed across both centers. Center 1 SPTs were 46 seconds (PFS) versus 75 sec-
`onds (vial; difference, 29 seconds; p<0.001). Center 2 SPTs were 46 seconds (PFS) versus 63 seconds (vial; differ-
`ence, 17 seconds; p<0.001). This equates to a 27%-39% reduction in SPT when using the PFS rather than the vial,
`resulting mostly from the reduced number of syringe preparation steps associated with the PFS.
`Conclusions: Syringe preparation times for ranibizumab intravitreal injections are significantly shorter with the
`PFS than with the vial. The time saved by using the PFS may benefit physicians and nurses, and the simplicity of
`the injection preparation process with the PFS is advantageous.
`Keywords: Anti-VEGF therapy, Intravitreal injections, Prefilled syringe, Ranibizumab, Syringe preparation time,
`Vial-based syringe preparation
`
`Introduction
`
`In recent years, there has been a significant increase
`in the number of patients who require and are eligible for
`treatment of retinal conditions (1), including visual impair-
`ment due to neovascular age-related macular degeneration
`(AMD), visual impairment due to diabetic macular edema
`(DME), visual impairment due to macular edema following
`retinal vein occlusion (RVO), and visual impairment due to
`
`Accepted: April 27, 2015
`Published online: May 18, 2015
`
`Corresponding author:
`Eric Souied, MD, PhD
`Head of Department of Ophthalmology
`Centre Hospitalier Intercommunal Créteil
`40 Avenue de Verdun
`94000 Créteil, France
`eric.souied@chicreteil.fr
`
`choroidal neovascularization secondary to pathologic myopia
`(myopic CNV). Neovascular AMD and DME are responsible for
`over 50% of patient registrations for severe sight impairment
`worldwide (2-4). This increase has been driven by a combi-
`nation of an aging global population and the introduction of
`new treatment modalities, including anti–vascular endothe-
`lial growth factor (anti-VEGF) therapies such as ranibizumab,
`bevacizumab, and aflibercept (5, 6).
`In patients with myopic CNV, neovascular AMD, and
`DME, ranibizumab treatment results in superior outcomes,
`such as improved visual acuity, relative to earlier interven-
`tions (e.g., photodynamic therapy or laser photocoagulation)
`(7-10). However, anti-VEGF therapies have increased the
`clinical workload, because more patients meet the eligibility
`criteria for these therapies than for the earlier interventions;
`anti-VEGF therapies also require more frequent administra-
`tion and follow-up (5-11). As with most invasive treatments,
`there are safety risks associated with intravitreal injections of
`anti-VEGF agents, such as endophthalmitis (12).
`Many clinicians report that the preparation of ranibizum-
`ab intravitreal injections is time-consuming (data on file); the
`
`EJOISSN 1120-6721
`
`Eur J Ophthalmol 2015; 25 (6): 529-534
`
`© 2015 Wichtig Publishing
`
`Novartis Exhibit 2014.001
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`530
`
`Fig. 1 - Schematic representation of
`treatment centers 1 and 2. HCA =
`health care assistant.
`
`ranibizumab prefilled syringe (PFS) may reduce the injection
`preparation time and improve convenience. Ranibizumab so-
`lution for injection from the PFS was approved in the Europe-
`an Union in 2013 for the treatment of visual impairment due
`to neovascular (wet) AMD, visual impairment due to DME,
`visual impairment due to macular edema secondary to RVO
`(branch RVO or central RVO), and visual impairment due to
`CNV secondary to pathologic myopia. The solutions in the PFS
`and in the vial have the same formulation (0.5 mg given as a
`single intravitreal injection, with an injection volume of 0.05
`mL).
`This study compared syringe preparation time for in-
`jection with the ranibizumab PFS versus the vial, with the
` hypothesis that the PFS would offer significant time savings
`owing to the elimination of several preparation steps. The
`study was conducted in patients with a range of retinal disor-
`ders in a real-world clinical setting. Health care professionals
`also provided their views on what benefits the PFS procedure
`offers, and to whom.
`
`Methods
`
`Study design
`
`A cross-sectional time-and-motion study was conducted
`to collect data on ranibizumab injection preparation times
`in routine clinical practice at 2 treatment centers in France.
`Data were collected in June 2014 at both centers. It was
`planned to include at least 12 sets of preparation data for
`both the PFS and the vial per site, providing a minimum of
`48 syringe preparation time measurements. Data were col-
`lected during standard treatment sessions following the cen-
`ter’s usual procedure.
`All ranibizumab intravitreal injections performed during
`a total of 6 treatment sessions at the 2 treatment centers
`were potentially eligible for time measurement. Injections
`were excluded if the patient objected to having an indepen-
`dent observer present during the treatment. Injections of
`other agents during the sessions were also excluded, as were
`ranibizumab injections that involved disruptions during the
`drug administration process that were due to external fac-
`tors, or if there were other causes of error in measuring the
`preparation time. A signed consent form was not required
`for participation because the study involved only observa-
`tion of clinical practice, and no identifying patient data were
`collected.
`Center 1 was a private retina clinic. It comprised 2 treat-
`ment rooms and a patient preparation room; the treatment
`
`rooms were staffed by a single physician and single nurse
`working across both rooms, and the patient preparation room
`was staffed by a nurse or health care assistant. Center 2 was
`at a public hospital and comprised 2 treatment rooms, with
`2 nurses or a nurse and a health care assistant present in each.
`Injections were administered by a single physician working
`across both rooms. These setups conformed to regulations in
`France, which require intravitreal injections to be performed
`in specially equipped rooms, in contrast to countries such as
`the United States, where injections may be performed in, for
`example, a physician’s office. The setups are illustrated sche-
`matically in Figure 1.
`
`Ranibizumab PFS
`
`The ranibizumab PFS has a Luer lock system to grip the
`needle tightly. The syringe barrel is made of unreactive bo-
`rosilicate glass, which is therefore stable during storage; the
`baked siliconization manufacturing process minimizes the
`risk of transfer of silicone oil into the ranibizumab solution.
`The small syringe barrel (0.5 mL) may reduce the dose vari-
`ability associated with larger barrels. The latex-free plunger
`prevents contact reactions from latex sensitivities or allergies,
`and is nonretractable, preventing nonsterile air from entering
`the barrel.
`
`Data collection
`
`Preparation steps for injections were observed and
`timed by external researchers from Q_PERIOR AG (Zurich,
`Switzerland) who were familiar with the procedures, with
`one observer present in each treatment room. Times were
`directly entered on time-stamped, hard-copy data collec-
`tion sheets. No identifying patient data (such as date of
`birth, name, or sex) were collected. Physicians and nurses
`involved in the study completed a 6-item questionnaire re-
`garding the use of the PFS and their opinions of it, includ-
`ing whether they preferred the PFS or the vial, and reasons
`why, immediately after the last data collection.
`A specific therapy protocol, diagnostic or therapeutic
`procedure, or visit schedule was not required as part of the
`study. Procedures were carried out in accordance with lo-
`cal prescribing information and routine medical practice.
`Only time data were collected during this study. Data for
`the ranibizumab vial were collected during 2 half-days at
`center 1 and 1 half-day at center 2. Data for the PFS were
`collected subsequently, for 2 half-days at center 1 and 1
`half-day at center 2. The same medical staff and external
`
`Benefits of ranibizumab prefilled syringes
`
`© 2015 Wichtig Publishing
`
`Novartis Exhibit 2014.002
`Regeneron v. Novartis, IPR2020-01318
`
`

`

` 531
`
`TABLE I - Injection preparation steps when using the ranibizumab prefilled syringe and vial
`
`Step
`number
`
`Step description
`
`Processes involved in ranibizumab vial preparation
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`7
`
`Remove contents
`from box and internal
`packaging
`
`a) Open and empty box
`b)   Open every blister package (injection, filter needle, 
`and syringe) and drop contents onto sterile table
`c) Throw empty box and blister packages into bin
`
`Put gloves on
`
`Open package, take out gloves, and put them on
`
`Attach filter needle
`
`Disinfect vial lid
`
`Draw solution from 
`vial using filter needle
`
`Remove filter needle 
`and attach injection 
`needle
`
`Take syringe, attach filter needle, then replace onto 
`sterile table
`Take off vial cap and disinfect vial with iodine and a 
`compress
`Lance the syringe with the filter needle into vial and 
`draw ranibizumab into syringe, remove syringe (with
`or without filter needle)
`a)   Remove filter needle from syringe, discard into bin
`b)   Take injection needle and attach it to syringe
`
`Adjust dose
`
`Adjust dose to 0.05 mL by depressing plunger
`
`Processes involved in ranibizumab pre-
`filled syringe preparation
`
`a) Open and empty box
`b)   Open sterile plastic package and take out 
`syringe
`c) Throw empty box and blister package into
`bin
`Open package, take out gloves, and put
`them on
`Step not needed
`
`Step not needed
`
`Step not needed
`
`a) Step not needed
`b)   Take syringe, open Luer Lock, and attach 
`injection needle
`Adjust dose to 0.05 mL by depressing
`plunger
`
`observers were present during each session to avoid varia-
`tion in measurements arising from the involvement of dif-
`ferent personnel.
`Seven steps in the preparation of the syringe when using
`the vial and 4 steps when using the PFS were identified during
`pre visits to each center; these steps are described in Table I.
`The 4 steps for the PFS were the same as steps 1, 2, 6(b), and
`7 for the vial; steps 3-5 and 6(a) were not necessary with the
`PFS (Tab. I).
`The timing of each step started at the point when the
`health care professional touched the relevant item (e.g., the
`ranibizumab box in step 1, or the glove package in step 2) and
`ended when the task was completed (e.g., the contents of
`the ranibizumab box were unpacked and the box discarded,
`or the gloves were fully on).
`
`Statistical analysis
`
`It was predicted that there would be 24 evaluable in-
`jection procedures per site, factoring in a dropout rate of
`approximately 20%. A mean difference of 22 seconds (stan-
`dard deviation 15 seconds) in preparation time between
`treatment groups was expected based on data from a labo-
`ratory simulation. Power analysis indicated that the study
`design had least 90% power to demonstrate a statistically
`significant difference in syringe preparation time between
`the PFS and the vial using a 2-sided t test and an α value
`of 5%. Owing to slight differences in setup and processes
`between the 2 centers, treatment comparisons were con-
`ducted within each center. Sample size calculations were
`performed using nQuery Advisor®, 7.0 (Statistical Solutions
`Ltd., Cork, Ireland).
`
`Results
`
`In total, 122 timings of syringe preparation were collected
`across both centers; this was a considerably larger sample
`size than was originally planned, owing to the fact that more
`values could be obtained during the scheduled observation
`periods and there were less exclusions than had been ex-
`pected. Data from 25 injections were excluded owing to an
`inability to determine when the start or end of a step had
`occurred (13 data recordings); a recording point being missed
`while health care professionals were conducting other activi-
`ties (5 recordings); or the external observer being unable to
`determine a timing precisely enough (7 recordings). After
`these exclusions, 97 valid syringe preparation timings were
`collected across both sites (Tab. II). No patients objected to
`being observed for the study.
`At center 1, using the ranibizumab PFS saved a mean of
`29.3 seconds (39%) in syringe preparation time per patient
`versus the vial (PFS 46.0 ± 7.3 seconds [mean ± standard devi-
`
`TABLE II - Sample numbers and breakdown of included and exclud-
`ed data
`
`Center 1
`
`Center 2
`
`Vial
`
`24
`21
`45
`
`PFS
`
`39
`1
`40
`
`Vial
`
`16
`1
`17
`
`PFS
`
`18
`2
`20
`
`Valid
`Excluded
`All samples
`
`PFS = prefilled syringe.
`
`Souied et al
`
`© 2015 Wichtig Publishing
`
`Novartis Exhibit 2014.003
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`532
`
`Fig. 2 - Breakdown of timing for the
`ranibizumab prefilled syringe (PFS)
`and vial at center 1. The total of the
`means for each step differs slightly
`from the overall preparation time.
`This is because some values for in-
`dividual step timing were excluded
`from the analysis (e.g., owing to
`measurement error); however, the
`total preparation timing would still
`have been eligible for inclusion,
`hence the slight difference.
`
`Fig. 3 - Breakdown of timing for the
`ranibizumab prefilled syringe (PFS)
`and vial at center 2. The total of the
`means for each step differs slightly
`from the overall preparation time.
`This is because some values for in-
`dividual step timing were excluded
`from the analysis (e.g., owing to
`measurement error); however, the
`total preparation timing would still
`have been eligible for inclusion,
`hence the slight difference.
`
`ation; range 34-47 seconds] vs vial, 75.3 ± 14.7 seconds [range
`60-128 seconds]; p<0.001). Step 1 (removal of the contents
`from the box and internal packaging) was reduced by a mean
`of 3.8 seconds for the PFS relative to the vial (11.2 seconds vs
`15.0 seconds, respectively). The mean time for step 2 (putting
`gloves on) was almost identical for both injection preparation
`methods; this was the most time-consuming step (PFS, 17.4
`seconds vs vial, 17.5 seconds). Steps 3-5 (attaching the filter
`needle, disinfecting the vial lid, and drawing ranibizumab
`from the vial) were not performed in the PFS method and
`took a mean of 20.2 seconds in total when using the vial (step
`3, 4.6 seconds; step 4, 5.1 seconds; step 5, 10.5 seconds).
`The mean time for step 6 (removing the filter needle and at-
`taching the injection needle) was longer with the PFS than
`with the vial (7.0 seconds vs 5.0 seconds, respectively),
`while step 7 (dose adjustment) took a mean of 5.5 seconds
`less with the PFS than with the vial (10.7 seconds vs 16.2
`seconds, respectively). Data are shown in Figure 2.
`At center 2, the mean syringe preparation time was 17.0
`seconds (27%) shorter using the PFS than using the vial (PFS
`45.8 ± 9.8 seconds [range 29-64 seconds] vs vial, 62.8 ± 15.6
`seconds [range 21-88 seconds]; p<0.01). Step 1 was a mean of
`8.7 seconds faster with the PFS than with the vial. As at center
`1, there was no significant difference between the PFS and
`the vial in the time taken for step 2. Steps 3 and 5 were not
`carried out in the PFS method and took a mean of 12.2 sec-
`onds when using the vial; step 4 was not performed at center
`2. Step 6 was again slower when using the PFS setting than
`when using the vial (mean of 5.6 seconds vs 3.1 seconds, re-
`
`spectively). Step 7 was a mean of 3.1 seconds faster with the
`PFS than with the vial. Data are shown in Figure 3.
`
`Qualitative results
`
`At center 1, both the physician and the nurse in the treat-
`ment room were satisfied with the PFS because it required
`fewer preparation steps and, in their view, bubbles occurred
`less frequently when using the PFS than when using the vial.
`They thought that anti-VEGF therapy allowed more patients
`to be treated (physician) and older treatments such as photo-
`dynamic therapy and laser photocoagulation were described
`as being not very helpful (nurse). Both the physician and the
`nurse thought that the ranibizumab PFS was better than
`the vial. The primary reasons for this preference were that
`the PFS improved patient safety (potentially reducing the risk
`of ocular adverse events related to the injection procedure)
`and increased dosing accuracy (physician), and improved pa-
`tient safety and increased efficiency owing to reduced injec-
`tion time (nurse). The physician believed that patients would
`experience the greatest benefit from the PFS compared with
`the physician or nurse, while the nurse believed that the phy-
`sician would gain the most benefit. The availability of the PFS
`was not likely to affect the physician’s selection of anti-VEGF
`therapy.
`At center 2, both the physician and nurses were satis-
`fied with the PFS and thought that it was an improvement
`on the vial. This was because the PFS required fewer injec-
`tion preparation steps and, in their view, bubbles occurred
`
`Benefits of ranibizumab prefilled syringes
`
`© 2015 Wichtig Publishing
`
`Novartis Exhibit 2014.004
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`less frequently than with the vial. They also believed that it
`was safer and saved time compared with the vial. The pri-
`mary reason why they preferred the PFS to the vial was that
`it improved efficiency by reducing the injection time (physi-
`cian) and improved patient safety by potentially reducing the
`risk of infection (nurses). The physician believed that nurses
`would experience the greatest benefit from the PFS, followed
`by physicians, while the nurses believed that the physician
`would benefit most. The physician thought that availability of
`the PFS was likely to affect physicians’ selection of anti-VEGF
`therapy. Although nurses do not make decisions on therapy
`selection, they expressed a preference for using the PFS over
`other anti-VEGF therapy options.
`
`Discussion
`
`This study showed a significant reduction in syringe prep-
`aration time with the ranibizumab PFS compared with the
`ranibizumab vial in real-life clinical practice at 2 treatment
`centers in France. At center 1, preparation times were re-
`duced by a mean of 29.3 seconds (39%) using the PFS, while
`at center 2, preparation times were reduced by a mean of
`17.0 seconds (27%). The largest time savings were observed
`across steps 3-5 (attaching the filter needle, disinfecting the
`vial lid, and drawing ranibizumab from the vial, respectively),
`as these were not performed when using the PFS. In addition,
`the physicians and nurses thought there were fewer bubbles
`present when using the PFS, which reduced the time spent
`removing bubbles.
`Health care professionals involved in the study reported
`a high degree of satisfaction with the PFS, citing various ben-
`efits to physicians, nurses, and patients to support this; for
`example, the administering physician was less dependent
`on a nurse being present throughout the preparation of the
`injection, thereby enabling staff reallocation to other duties.
`Fewer syringe preparation steps also reduced the possibility
`of errors. At center 1, it was thought that the risk of infec-
`tion might be reduced for patients because disinfection of the
`vial lid was no longer necessary. Infection risk might also be
`reduced owing to fewer instances of handling components
`of the injection equipment using the PFS than when drawing
`the solution from a vial. PFSs also increase safety versus tradi-
`tional vials, because fewer handling errors occur with the PFS
`(13). Finally, less waste is produced in the PFS procedure than
`with the vial; only 1 needle is required rather than 2, and the
`vial itself is no longer used.
`The benefits in terms of speed of delivery, time-saving,
`reduced complexity of the syringe preparation process, and
`user satisfaction are consistent with earlier studies involving
`insulin and heparin PFSs (14, 15).
`One limitation of the current study is that it focused only
`on the syringe preparation step of ranibizumab administra-
`tion. Time could also be saved during other steps; for exam-
`ple, research on PFSs discussed above has documented time
`savings in steps such as waste disposal. The relatively small
`sample size is a potential limitation; however, the study was
`considerably overpowered given its inclusion of 122 syringe
`preparations versus the planned sample size of 48 prepara-
`tions. In addition, the time-saving benefits of the PFS were
`clearly significant at both centers. A strength of the study is
`
` 533
`
`that it observed standard practice at 2 clinics, 1 private and
`1 public, that are highly experienced in treating retinal dis-
`eases. Although data from the 2 centers could not be pooled
`owing to procedural differences, their results were in agree-
`ment that the PFS resulted in time savings.
`In summary, the PFS improves speed and efficiency of
`ranibizumab administration versus the standard vial. This
`could enable physicians to treat more patients per treatment
`session, to treat the same number of patients in a shorter
`time, or to spend more time in discussion with patients; these
`points were also reflected in the feedback received from phy-
`sicians and nurses.
`
`Acknowledgment
`Medical writing support was provided by Robert Gillies, PhD, Phar-
`maGenesis London, UK. The authors thank the staff and patients at
`the treatment centers for their participation in this study.
`
`Disclosures
`Financial support: Funded by Novartis Pharma AG, Basel, Switzer-
`land.
`Conflict of interest: Eric Souied has received payment for consultan-
`cy, travel, and review activities from Allergan, Bayer, and Novartis;
`has been a board member and consultant for Théa; and has received
`payment for lectures and travel from Heidelberg. Salomon-Yves
`Cohen is a consultant for Bayer and Novartis. Claudia Leteneux and
`Alexandros Sagkriotis are employees of Novartis Pharma AG. Audrey
`Derveloy is an employee of Novartis Pharma France. Sascha Bayer
`and Guido Becker are employees of Q_PERIOR AG, which has re-
`ceived funding from Novartis to conduct this study. Sylvia Nghiem-
`Buffet has been a consultant for Novartis Pharma AG, Bayer AG, and
`Allergan.
`Meeting presentation: A poster of this study was presented at the
`14th European School for Advanced Studies in Ophthalmology (ESA-
`SO) Retina Academy meeting, Istanbul, Turkey, November 13, 2014.
`
`3.
`
`4.
`
`References
`1.
`Framme C, Wolf-Schnurrbusch UE, Lobsiger H, Bayer S, Wolf S.
`[Adapted and standardised patient management in the treat-
`ment of neovascular AMD in the outpatient setting of a uni-
`versity eye hospital.] Klin Monatsbl Augenheilkd. 2012;229:
`812-21.
`2. Owen CG, Fletcher AE, Donoghue M, Rudnicka AR. How big is
`the burden of visual loss caused by age related macular de-
`generation in the United Kingdom? Br J Ophthalmol. 2003;87:
`312-7.
`Bunce C, Wormald R. Leading causes of certification for blind-
`ness and partial sight in England & Wales. BMC Public Health.
`2006;6:58.
`Congdon N, O’Colmain B, Klaver CC, et al; Eye Diseases Preva-
`lence Research Group. Causes and prevalence of visual impair-
`ment among adults in the United States. Arch Ophthalmol.
`2004;122:477-85.
`5. Menon G, Walters G. New paradigms in the treatment of wet
`AMD: the impact of anti-VEGF therapy. Eye. 2009;23(Suppl 1):
`S1-7.
`Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth
`factor in ocular fluid of patients with diabetic retinopathy and
`other retinal disorders. N Engl J Med. 1994;331:1480-7.
`Brown DM, Kaiser PK, Michels M, et al; ANCHOR Study Group.
`Ranibizumab versus verteporfin for neovascular age-related
`macular degeneration. N Engl J Med. 2006;355:1432-44.
`
`6.
`
`7.
`
`Souied et al
`
`© 2015 Wichtig Publishing
`
`Novartis Exhibit 2014.005
`Regeneron v. Novartis, IPR2020-01318
`
`

`

`534
`
`8.
`
`Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev
`T. Ranibizumab versus verteporfin photodynamic therapy for
`neovascular age-related macular degeneration: two-year re-
`sults of the ANCHOR study. Ophthalmology. 2009;116:57-65.
`9. Wolf S, Balciuniene VJ, Laganovska G, et al. RADIANCE: a ran-
`domized controlled study of ranibizumab in patients with
`choroidal neovascularization secondary to pathologic myopia.
`Ophthalmology. 2014;121:682-92.
`10. Mitchell P, Bandello F, Schmidt-Erfurth U, et al; RESTORE study
`group. The RESTORE study: ranibizumab monotherapy or com-
`bined with laser versus laser monotherapy for diabetic macu-
`lar edema. Ophthalmology. 2011;118:615-25.
`11. Han DP. Age-related macular degeneration, anti-VEGF ther-
`apy, and ophthalmic imaging: is there a best practice? JAMA
`Ophthalmol. 2013;131:1124-6.
`
`12. McCannel CA. Meta-analysis of endophthalmitis after intravit-
`real injection of anti-vascular endothelial growth factor agents:
`causative organisms and possible prevention strategies. Retina.
`2011;31:654-61.
`13. Kasi GS, Prabhu SV, Sanjay S, Chitkara A, Mitra M. Prefilled
`syringes versus vials: impact on vaccination efficiency and pa-
`tient safety in Indian private market. Pediatr Infect Dis. 2013;
`5:181-6.
`14. Plevin S, Sadur C. Use of a prefilled insulin syringe (Novo-
`lin Prefilled) by patients with diabetes. Clin Ther. 1993;15:
`423-31.
`15. Barber ND. Heparin administration using prefilled syringes or
`ampoules: a comparative cost-effectiveness study. Int J Pharm
`Pract. 1993;2:15-7.
`
`Benefits of ranibizumab prefilled syringes
`
`© 2015 Wichtig Publishing
`
`Novartis Exhibit 2014.006
`Regeneron v. Novartis, IPR2020-01318
`
`