Container Closure and Delivery Considerations for Intravitreal Drug Administration · 2021. 5....

AAPS PharmSciTech (2021) 22: 100

Review ArticleTheme: Ocular Drug Delivery and Ophthalmic FormulationsGuest Editors: Qingguo Xu and Iok-Hou Pang

Container Closure and Delivery Considerations for Intravitreal DrugAdministration

Ashwin C. Parenky,1 Saurabh Wadhwa,1 Hunter H. Chen,1,2 Amardeep S. Bhalla,1

Kenneth S. Graham,1 and Mohammed Shameem1

Received 22 October 2020; accepted 30 January 2021

Abstract. Intravitreal (IVT) administration of therapeutics is the standard of care fortreatment of back-of-eye disorders. Although a common procedure performed by retinalspecialists, IVT administration is associated with unique challenges related to drug product,device and the procedure, which may result in adverse events. Container closureconfiguration plays a crucial role in maintaining product stability, safety, and efficacy forthe intended shelf-life. Careful design of primary container configuration is also important toaccurately deliver small volumes (10-100 μL). Over- or under-dosing may lead to undesiredadverse events or lack of efficacy resulting in unpredictable and variable clinical responses.IVT drug products have been traditionally presented in glass vials. However, pre-filledsyringes offer a more convenient administration option by reducing the number of stepsrequired for dose preparation there by potentially reducing the time demand on thehealthcare providers. In addition to primary container selection, product development studiesshould focus on, among other things, primary container component characterization, materialcompatibility with the formulation, formulation stability, fill volume determination, extract-ables/leachables, and terminal sterilization. Ancillary components such as disposable syringesand needles must be carefully selected, and a detailed administration procedure that includesdosing instructions is required to ensure successful administration of the product. Despitesignificant efforts in improving the drug product and administration procedures, ocular safetyconcerns such as endophthalmitis, increased intraocular pressure, and presence of siliconefloaters have been reported. A systematic review of available literature on container closureand devices for IVT administration can help guide successful product development.

KEY WORDS: Ocular; Syringe; Needle; Sterilization; Formulation.

INTRODUCTION

Intravitreal (IVT) administration is currently the stan-dard of care for administration of anti-VEGF agents to treatwet age-related macular degeneration (wet AMD). In addi-tion to wet AMD, IVT injections are also administered totreat ocular conditions such as branched and central veinocclusion, diabetic macular edema (DME), and uveitis. Sincethe 1990s, approval of intravitreal drug products to manageand treat retinal diseases has experienced significant andrapid growth. As of 2020, there are a total of thirteen drug

products approved for IVT administration in the USA. Theseproducts include anti-VEGF agents, a synthetic corticoste-roid, a proteolytic enzyme, and long-acting delivery systems.It is estimated that around 5.9 million intravitreal injectionswere administered in 2016 alone. The rapid growth in IVTadministration of drug products could be attributed to intenseresearch efforts in identifying targets that specifically treatand manage diseases in addition to significant improvementsin delivery systems and devices, administration procedures,relevant materials, and formulations that help preserve thesafety and efficacy of therapeutics (1). Figure 1 isan illustration of an IVT injection and anatomy ofthe human eye (not drawn to scale).

The development of drug products for IVT administra-tion is particularly challenging as ancillary injection compo-nents (such as syringes and needles routinely used for IVTinjections) were not developed specifically for IVT adminis-tration in the eye and even today, there is considerable

Guest Editors: Qingguo Xu and Iok-Hou Pang

1 Formulations Development, Regeneron Pharmaceuticals, Inc., 777Old Saw Mill River Road Tarrytown, New York, 10591, USA.

2 To whom correspondence should be addressed. (e–mail:[email protected])

DOI: 10.1208/s12249-021-01949-4

; published online March11 2021

1530-9932/21/0300-0001/0 # 2021 The Author(s)

http://crossmark.crossref.org/dialog/?doi=10.1208/s12249-021-01949-4&domain=pdf


reliance on devices that are used for delivering non-ophthalmic therapeutics (2). Historically, it was believed thatthe ocular tissue is an “immune privileged” site owing to theblood-retinal barrier, blood-aqueous barrier, and tight junc-tions that restrict entry of cells, proteins, and lipids from thesystemic circulation into ocular tissues. However, significantadvances have been made in understanding the ocularcellular and molecular mechanisms such as the anteriorchamber–associated immune deviation (ACAID). The mech-anism of ACAID suggests that ocular antigen-presenting cellscan transit to the spleen to initiate an antigen specific“regulatory” immune response. Such mechanisms highlightthe presence of cell-mediated immune responses present inthe eye that can lead to a humoral response to the antigeninjected into the eye. Therefore, incidence of ocular inflam-mation, ocular tissue damage, and anti-drug antibody re-sponses (ADA) are clinical responses that are monitoredduring the development of biotherapeutics specifically forocular indications (3). Hence, careful and detailed assessmentof the drug product and device evaluation is critical for thedevelopment of successful IVT therapeutics.

ADMINISTRATION OF IVT INJECTIONS

IVT administration is now commonplace which has madethe administration procedure well established. However,successful IVT injections depend on several importantconsiderations before, during, and after the procedure hasbeen performed. Briefly, considerations such as dose prepa-ration procedure, injection environment, application of localanesthesia to the ocular tissue, use of adequate personalprotective equipment, disinfection of the ocular surface, anduse of topical antibiotics are critical for ensuring patientsafety following IVT administration.

Dose Preparation Procedure

Vials

Single-use vial drug product presentations involve morepreparation steps as compared to a pre-filled syringe.Although detailed instructions are provided in respective

drug product labels, a typical procedure is outlined here. Theplastic cap on the drug product vial is removed and the top ofthe vial is wiped with an alcohol wipe. A filter needle (e.g.,19-gauge × 1½-in., 5-μm) is attached to a syringe and theformulation is drawn aseptically into the syringe from the vial.The plunger rod is pulled back sufficiently to ensure theformulation is in the syringe completely before removing thefilter needle and replacing it with a needle which will be usedfor the IVT injection (e.g., 30-gauge × ½-in.). To ensure thedose to be administered is accurate, the syringe is heldupright and gently tapped to release any air bubbles and theplunger is pushed to expel the drug until the plunger tip alignswith the appropriate dose volume for administration (typi-cally 0.050 mL).

Prefilled Syringe

Pre-filled syringes have a relatively less cumbersomemethod of dose preparation as the product is supplied in thesyringe. In brief, the pre-filled syringe cap is removed fromthe syringe and the injection needle for administration of theproduct to the patient is attached (e.g., 30-gauge × ½-in.). Thesyringe is held upright, checked for air bubbles, and gentlytapped to remove the bubbles which rise to the top. Thebubbles are expelled with the excess drug and dose adjustedby aligning the plunger to the dose mark as mentioned in theproduct label.

IVT Injection Procedure

Injection site for IVT administration is generally per-formed between the vertical and horizontal rectus muscles atthe pars plana, 3.5–4.0 mm posterior to the limbus as aperpendicular injection (4). Injection procedures requireutmost skill, precision, and experience. A survey of retinaspecialists across the USA revealed that most of thespecialists did not measure the distance from the limbus oninjection while predominantly injecting in the inferior tempo-ral quadrant (5). Further detailed discussion on IVT admin-istration procedure is beyond the scope of this manuscript.

NEEDLES AND SYRINGES AS ANCILLARYCOMPONENTS FOR ADMINISTRATION OF IVTPRODUCTS

Clinical Impact of Needle Gauge Used for IVT Injections

In addition to the administration procedure for IVTinjections, other important considerations when performingIVT injections include the selection of administration compo-nents and devices that will result in safe and effective dosingof the therapeutic. Recommended needle gauges packagedwith IVT drug products approved by the FDA are listed inTables I and II. Vitravene® (fomivirsen sodium) was the firstUS FDA-approved IVT oligonucleotide product used inpatients suffering from cytomegalovirus (CMV) retinitis.Approved in 1998, fomivirsen sodium was administered usinga low-volume syringe (e.g., tuberculin) and a 30G needle atan injection volume of 0.050 mL/dose (6).

Patients experience pain on IVT injections due to thepresence of pressure or sensory receptors on the sclera,

Fig. 1. Illustration of the ocular anatomy and intravitreal injection forthe treatment of ocular diseases

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Table I. List of Approved IVT Implants in the USA

Product name Molecule Owner/company Dose/duration Needle gauge Dimensions References

ILUVIEN® ocularimplant

Fluocinoloneacetonide

Alimera Sciences, Inc. 0.19 mg 25 gauge 3.5 mm × 0.37 mm (7)

OZURDEX® ocularimplant

Dexamethasone Allergan, Inc. 0.7 mg 22 gauge 0.46 mm × 6 mm (8,9)

RETISERT® ocularimplant

Fluocinoloneacetonide

Bausch & Lomb Inc. 0.59 mg/30 months NA (sutured) 3 mm × 2 mm × 5 mm (10)

YUTIQ™ implant Fluocinoloneacetonide

EyePoint PharmaceuticalsUS, Inc.

0.18 mg 25 gauge 3.5 mm × 0.37 mm (11)

VITRASERT® not included as it was discontinued

Table II. Approved IVT Liquid/Suspension Drug Product Formulations

Product name Molecule Manufacturer Formulation/composition Primarycontainerclosure

Needlegauge

Reference

LUCENTIS®

injectionsolution

Ranibizumab Genentech, Inc. 6 mg/mL or 10 mg/mL LUCENTIS®aqueous solution with 10 mM histidineHCl, 10% α, α-trehalose dihydrate,0.01% polysorbate 20, pH 5.5

Vial 30G (12)

LUCENTIS®

pre-filledsyringe

Ranibizumab Genentech, Inc. 6 mg/mL or 10 mg/mL LUCENTIS®(0.5 mg dose prefilled syringe) aqueoussolution with 10 mM histidine HCl,10% α, α-trehalose dihydrate, 0.01%polysorbate 20, pH 5.5

Pre-filledsyringe

30G (12)

EYLEA®

injectionsolution

Aflibercept RegeneronPharmaceuticals, Inc.

40 mg/mL in 10 mM sodium phosphate,40 mM sodium chloride, 0.03%polysorbate 20, and 5% sucrose, pH 6.2

Vial 30G (13)

EYLEA®pre-filledsyringe

Aflibercept RegeneronPharmaceuticals, Inc.

40 mg/mL in 10 mM sodium phosphate,40 mM sodium chloride, 0.03%polysorbate 20, and 5% sucrose, pH 6.2

Pre-filledsyringe

30G (13)

BEOVU®

injectionsolution

Bro luc i zumab-dbll

Novartis AG 6 mg brolucizumab-dbll, polysorbate 80(0.02%), sodium citrate (10 mM), sucrose(5.8%), and Water for Injection, USPand with a pH of approximately 7.2

Vial 30G (14)

MACUGEN®

pre-filledsyringe

Pegaptanibsodium

Gilead Sciences, Inc. 3.47 mg/mL pegaptanib sodium chloride,monobasic sodium phosphatemonohydrate, dibasic sodium phosphate heptahydrate, hydrochloric acid,and/or sodium hydroxide

Pre-filledsyringe

30G (15)

JETREA®

injectionsolution

Ocriplasmin Oxurion NV 0.5 mg ocriplasmin in 0.2 mL citric-buffered solution (2.5 mg/mL)

Vial 30G (16)

TRIESENCE® Triamcinoloneacetonide

Alcon Laboratories,Inc.

40 mg of triamcinolone acetonide, withsodium chloride for isotonicity, 0.5%(w/v) carboxymethylcellulose sodiumand 0.015% polysorbate 80

Vial 27G (17)

TRIVARIS® Triamcinoloneacetonide

Allergan, Inc. 8 mg triamcinolone acetonide in 0.1 mL(8% suspension) in a vehiclecontaining w/w percents of 2.3%sodium hyaluronate; 0.63%sodium chloride; 0.3% sodiumphosphate, dibasic; 0.04% sodiumphosphate, monobasic; and waterfor injection, pH 7.0 to 7.4

Vial 27G (18)

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episclera, conjunctiva, or changes in intraocular pressure(IOP). Factors that may contribute to pain on injectioninclude the drug/solution, rate of injection, volume injected,size/form of the injected product, the needle characteristics(bevel design and gauge), and the injection technique. As of2020, half-inch needles between 27G and 30G have been usedfor IVT injections, except for OZURDEX®, an IVTsustained release implant containing dexamethasone whichutilizes a 22G needle (1). Chaturvedi et al. published onadministration procedure from 281 retinal specialists acrossthe USA that focused on pre-administration, administration,and post-administration IVT procedures. Statistical analysison the injection procedure revealed that about 61% (170/279)of retinal specialists use a 30-gauge needle while 21% (59/279) of retinal specialists chose to use the 31-gauge needle(5). Rodrigues et al. performed studies to determine theimpact of needle gauge on vitreal reflux and pain on injection.It was observed that the force required to penetrate the sclerausing a 27G needle was twice as much compared to a 31Gneedle. Results also demonstrate a significant reduction inpain on injection and vitreal reflux when 29G and 30Gneedles are used in comparison to 26G or 27G needle (19).Vitreal reflux has been identified as a potential complicationfor IVT injection as it may be associated with loss of injecteddrug from the vitreous and adverse events like endophthal-mitis. There have been several clinical studies investigatingthe impact of needle sizes on vitreal reflux and IOP after IVTinjection. Muto and Machida reported similar rates of vitrealreflux with 30G needle and 32G needle in patients receivingaflibercept for the first time (20). However, it was observedthat immediate post-injection IOP was higher when 30Gneedles were used as opposed to 32G needles (20). Inaddition to needle gauge, other important factors such asneedle geometry, syringe size, backpressure at the injectionsite, formulation characteristics, and behavior (Newtonian/non-Newtonian) play a significant role in determining theinjection forces.

Clinical Experience with Advanced Needle Geometry

Thin-Wall Needles and Micro-tapered Needles

The choice of needles arises from considerations such asallowable injection force, site of administration, and clinicalexperience with certain needle gauges and lengths. In recentyears, manufacturers have the design capability to alter theneedle inner diameter to significantly influence the injectionforce required to administer biologics. International Stan-dards Organization (ISO) 9626:2016, provides needle

dimension details, as mentioned in Table III, to manufac-turers as target dimensions for manufacturing needles. Aclinical trial investigated the impact of extra-thin-wall needles(31G and 32G) on self-administered subcutaneous (SC)injections using three different insulin pens. It was observedthat patients significantly preferred extra-thin-wall needlescompared to thin-wall or regular-wall needles. The studydemonstrated extra-thin-wall needles improved flow charac-teristics and pressure required to inject insulin, whichcorresponds to lower injection force, reduced time to inject,and greater confidence in completing the patient-administered SC injection (21). Therefore, extra-/ultra-thin-wall needles for a given needle gauge may translate toimproved patient experience and injection forces for intravit-real administration as well. Figure 2 demonstrates the variousneedle geometries for any given needle gauge.

Needle geometry and sharpness are important considerationsfor improved patient experience and injection performance duringinjection procedures. Injection performance of various needles wasevaluated in a clinical study examining self-injection ofinsulin subcutaneously, which concluded that even though injectionforces in 28G to 33Gmicro-tapered needles (TerumoCorporation,Tokyo, Japan) were similar to the standard 31G thin-wall (TW)needles (Becton Dickinson), patients concerned about pain oftenpreferredmicro-tapered needle over TWneedles. The 28G to 33Gmicro-tapered needles have an advantage when injecting non-Newtonian fluids as the taper allows for higher shear forces therebyreducing the resistance during injection. Therefore, micro-taperedneedles have the potential to reduce pain and discomfort ofinjections as compared to traditional needles. Krayukhina et al.demonstrated the advantage of using tapered needles as opposedto thin-wall needles concluding that the injection forces required fora 29G tapered needle was consistently lower than a 29G thin-wallneedle when injecting polyethylene glycol 3350, carboxymethylcellulose, etanercept, and omalizumab solutions. Interestingly,injection forces for the 29G tapered needle for glycerin, polyeth-ylene glycol 3350, etanercept, and 70 mg/mL omalizumab solutionwere similar to a 27G thin-wall needle. In the case of non-Newtonian solutions such as 125 mg/mL omalizumab andcarboxymethyl cellulose, injection forces required for the 29Gtapered needle were significantly lower than the 27G thin-wallneedle (22). Figure 2 is an illustration of the various types ofneedles with increasing inner diameters (not drawn to scale).

Needle Bevel Designs

Needle tip geometry and bevel designs such as thenumber of bevels, angularity, and tip facets can impact needleinsertion forces and perceived pain in patients (23). When

Table III. Needle Gauge Dimensions from ISO 9626:2016 Standards (Minimum inner diameters)

Needle gauge Regular-wall inner diameter(mm)

Thin-wall inner diameter(mm)

Extra-thin-wall inner diameter(mm)

Ultra-thin-wall inner diameter(mm)

30 0.133 0.165 0.190 0.24032 0.089 0.105 0.125 0.146

© ISO. This material is reproduced from ISO 9626:2016, with permission of the American National Standards Institute (ANSI) on behalf of theInternational Organization for Standardization. All rights reserved

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31G and 32G needles with a 5-bevel tip design were testedagainst similar needles with 3-bevel tip designs, significantreduction in insertion forces was documented for the 5-beveltip based on patient’s experience when injecting interferonand insulin (24) (23). During in vitro testing on human skinsubstitute, the 5-bevel tip was observed to reduce penetrationforce by 23% on average compared to a 3-bevel needle tip. Ina blinded study performed on diabetic patients comparing the5-bevel design and 3-bevel design, patients overwhelminglyrated the 5-bevel design significantly more comfortable,easier to insert, and preferable than the 3-bevel needle tip(23). These results indicate that investigating bevel designsfor IVT injection needles may result in the selection ofcomponents that improve patient experience (Fig. 3).

Syringes Used for IVT Injections

Intravitreal injections have become increasingly commonand the standard of care for retinal diseases which makessyringes indispensable for the treatment of retinal diseases.For drug products where the primary container is a vial,syringes are an ancillary component used to draw the productfrom the vial and inject into the vitreous, as described inprevious sections. Syringes are generally made of materialssuch as polypropylene, polycarbonate, or glass. Commonlyused syringes for IVT injections are 1-mL luer-lock and slip-luer syringes with 0.5-mL or 0.3-mL syringes being used lessoften. Generally, syringes and needles are two separatecomponents unless the use of staked-in needle syringes isdesired (2). Scott et al. studied the clinical impact of glasssyringes with a slip-luer design and staked needle design onthe presence of silicone oil floaters in the vitreous cavity postIVT injection. Patients who received IVT triamcinolone witha staked needle syringe had significantly higher rates offloaters as compared to patients receiving triamcinolone witha slip-luer syringe (25). Although labels for IVT drug

products packaged in vials may not mention specific syringesfor IVT injections, retinal specialists and drug developmentscientists should consider these observations to minimize anyrisk of unwanted clinical events. With increasingly globaloutreach of therapeutics and inconsistencies in IVT dosepreparation practices, it would be important for drugdevelopment scientists to consider minimizing inconsistenciesand develop drug products that can be utilized with minimalsteps for dose preparation and handling.

Syringeability and Injectability: Impact of Syringe Size andType on Injection Force

Syringeability and injectability for parenteral productsare critical attributes that need to be considered duringdevelopment of a drug product. Syringeability refers to theforce required for an injectable therapeutic to easily passthrough a hypodermic needle of predetermined gauge andlength, at a specified injection rate. Injectability refers to theperformance of the formulation, syringe, and needle duringinjection into target tissues. Factors that are considered whiledetermining the syringeability of a drug product include easeof withdrawal, accuracy of dose measurements, clogging, andfoaming, while injectability includes factors such as pressureor force required for injection, back pressure at the tissue site,and evenness of flow. In case of drug products manufacturedin vials, assessment of both syringeability and injectability isnecessary and both contribute to accurate dosing of patientsin the clinic. For drug products in pre-filled syringes andautoinjectors, significant evaluation is done to assess theperformance according to FDA Guidance for Industry oncontainer closure systems while other guidance documentssuch as ICH Q6A provide guidance on test procedures,injectability, and functionality of the delivery system (26).

For a given formulation (assuming Newtonian behavior),injectability at a predetermined speed is governed by factors

Fig. 2. Illustration of a cross-sectional area of a needle. Wall thickness and inner diameter for varyingneedle types from regular wall, thin wall, extra-thin wall, and ultra-thin wall. (Not drawn to scale)

Fig. 3. Illustration of 3-bevel design (a) and 5-bevel design (b) for needles. This image has been reproducedfrom Hirsch et al. (2012) (#54) with permission from SAGE Publications

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such as needle gauge and surface area of the syringe plunger.Pressure generated within the syringe barrel (P) duringinjection is directly proportional to the force (F) exerted onthe back of the syringe plunger and inversely proportional tosurface area of the syringe plunger (A) (Eq. 1). Therefore, inthe case of certain high-viscosity formulations, one approachto reduce injection forces could entail the use of syringes withreduced barrel diameter which corresponds to lower surfacearea of the syringe plunger.

F ¼ P*A ð1Þ

However, a more detailed equation known as the HagenPoiseuille (Eq. 2) can be derived for estimation of syringeglide force which considers dimensions of the syringe, needle,flow rate, and viscosity of the fluid. In Eq. 2, F is the glideforce (N), δv

δt

� �is the volumetric flow rate, μ is the fluid

viscosity, L is the needle length, Rneedle is the needle innerradius, Rsyringe is the inner syringe barrel radius, and Ffriction isthe frictional force between the plunger and syringe barrel(27,28).

F ¼8

δvδt

� �LR2syringe

R4needle

*μþ F Friction ð2Þ

Product development scientists have an opportunity tooptimize the injection glide force with modulation of formu-lation composition in combination with device selection.Extensive characterization of rheological properties must beperformed during product development. For solutions thatexhibit non-Newtonian behavior, appropriate excipients mustbe screened to maintain acceptable viscosity profiles.Allmendinger et al. performed a detailed investigation toderive equations to predict injection forces for high-concentration protein formulations that exhibit non-Newtonian behavior. Viscosity measurements were per-formed at high shear rates on commercially available proteintherapeutics, and a model was developed to understand thenon-Newtonian behavior of shear-thinning formulations. Theauthors derived an equation based on the transformation ofthe Hagen-Poiseuille law into an equation that accounts forshear rate–dependent viscosity changes that occur when anon-Newtonian fluid travels through the needle (28).

F ¼ 2nþ2 π1−n � L� R2syringe �K � δV=δtð Þn

� Rneedle�� 3nþ1ð Þ � 3nþ 1=2nþ 1ð Þn−1

þ F friction; f δv=δtð Þ ð3Þ

In Eq. 3, F is the syringe glide force, K is the flowconsistency index (Pa sn ), and n is the power law index(dimensionless). K can be derived from the Ostwald-deWaele equation where n < 1 shear thinning behavior, n = 1Newtonian behavior, and n > 1 shear thickening behavior. δV/δt is the volumetric flow, L is the length of needle, Rneedle isthe needle inner radius, Rsyringe is the inner syringe

barrel radius, and Ffriction is the frictional forces between theplunger and syringe barrel.

These equations take into account dimensions of theneedle, syringe, and behavior of the formulation. Non-Newtonian behavior can be observed in high-concentrationprotein formulations and/or polymer formulations, and theseequations can be used for practical applications where drugproducts can be improved for ease of use, safety, and efficacywith adequate understanding of factors that have the highestinfluence on injection force. From Eqs. 2 and 3, the highest-powered factors are radii of the syringe barrel and needle.Therefore, the development of combination drug products fora given administration route should consider using theseequations to recommend a specific needle gauge, syringe, ordevice for evaluation.

Formulation Considerations for Development of InjectableProducts

Drug products developed for intravitreal injections caneither be stored in type I borosilicate glass vials or type Iborosilicate glass pre-filled syringes as listed in Table II. Forpre-filled syringe drug products, liquid formulations come incontact with the syringe barrel (interior), syringe plunger, andneedle. Siliconization of the interior surface of the syringebarrel is performed to provide adequate lubrication betweenthe glass syringe barrel and plunger interface. This helps inadequate functionality of the pre-filled syringe to maintainacceptable break-loose and glide force. However, with thepresence of silicone in the internal surface of the syringebarrel, formulations can interact with the silicone which mayimpact product quality and syringeability. Formulation factorssuch as buffers and surfactants have been shown to signifi-cantly impact the functionality of syringes by changing thesilicone oil coverage in the barrel and lubricity. For example,the type of surfactant used in the formulation can impactglide force for a pre-filled syringe. Wang et al. demonstrated asignificant increase in syringe glide force when pre-filledsyringes containing formulation with polysorbate 80 wereincubated at 40°C. Interestingly, formulations with poloxamer188 when stored at 40°C in pre-filled syringes did not exhibitan increase in glide force. Schlieren imaging of the syringesdetected removal of the silicone oil layer in the polysorbate80 syringes when compared to intact silicone oil layer insyringes containing formulations with poloxamer 188. Theauthors also discuss the correlation of surfactant hydrophilic-lipophilic balance (HLB) values and surface tension valueswith glide force for pre-filled syringe development (29).Similarly, buffers/tonicity agents and formulation pH can alsoimpact the silicone oil lubrication in pre-filled syringes thatmay lead to changes in the syringe functionality duringstorage (30).

Formulation viscosity is directly correlated to injectionforce, increase in formulation viscosity can lead to increasedinjection force for a drug product, and this may also increasethe injection time for a given injection volume. IVT drugproducts are generally restricted to less than 100 microlitersper injection. Therefore, clinical studies that target high IVTdoses of therapeutics may require high-concentration proteinformulations. In general, viscosity for high-protein concentra-tion formulations increase exponentially (>100 mg/mL) and

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therefore, scientists must account for the associated impact oninjection glide force (31). In addition to considerations such asviscosity of the formulations at target concentrations, it isadvisable to understand viscosity profiles of the proteinformulations at the upper specification concentration as permanufacturing capability. Additional optimization in fill-finishoperations may be required for solutions exhibiting non-Newtonian behavior (32). This would provide an overallunderstanding of injection glide force at protein concentrationsrelevant to real-world manufacturing capability for drugproducts (33). Another important consideration for developingIVT drug products is understanding the impact of temperatureon syringeability of the drug product. Since most biologics arestored at 2–8°C, temperature of the drug product can alterviscosity profile of the protein formulation at a specifiedconcentration. Generally, viscosity of a protein formulationincreases with decrease in temperature (34). Therefore, it isimportant to understand the impact of temperature onviscosity of the IVT formulation and consider formulationoptimization that account for incomplete equilibration of thedrug product to room temperature which may influenceviscosity and syringeability. Therefore, formulation factors,such as type of excipients, excipient concentration, buffers,formulation pH, and protein concentration, can play asignificant role in syringeability of pre-filled syringe drugproducts.

Accuracy and Repeatability of Delivered Volume

Accuracy and repeatability of delivered/injected vol-ume are critical to the efficacy and, in some cases, safetyof a given drug. Therefore, it is essential that theproposed administration system/configuration is character-ized for delivered volume during development. Deliveringless than the target volume may lead to under dosingwhich will impact the efficacy and, in the case of somedrugs, may impact the frequency of injection as well.Injection volume is usually based on the intended doseand concentration of a product. IVT injection volumes aretypically between 0.05 and 0.1 mL. However, lowervolumes in the range of 0.01–0.025 mL have been recentlyused to treat retinopathy of prematurity (ROP) in infants(35). Higher injection volumes (> 0.1 mL) may beassociated with a transient increase in the intraocularpressure (IOP). Since many patients receiving IVT injec-tions may already have impaired perfusion, an increase inIOP may further amplify the condition. IOP increase afterIVT injection may also be dependent on factors such asthe intraocular volume, scleral thickness, and scleralrigidity. Kotliar et al. studied the effect of 0.1 mL injectionof triamcinolone on IOP in myopic, emmetropic, andhyperopic eyes (30). IOP increase of 40.6 ± 12.1 mm Hgwas observed after injection compared to pre-operativevalues across different eyes. The increase in IOP wastransient and returned to < 20 mmHg within 2 h. Eyeswith shorter axial length showed a higher increase in IOP.It is also essential to minimize variability in injectedvolume at both lower and higher ends. During develop-ment, selection of delivery components that not onlyaccurately deliver the desired target dose volume but alsominimize variability in the delivered volume in clinical

settings is desirable. The commercially available vialpresentations IVT drug products usually have an overfillto account for volume losses during dose preparation.(36). The administering physician is typically expected todraw a volume larger than the dosing volume into asyringe through a larger gauge needle and expel excessvolume through a narrower gauge injection needle toachieve the intended dose. The situation for DPmanufactured in pre-filled syringes is similar. For example,one ranibizumab pre-filled syringe (PFS) contains 0.165mL of drug to administer a 0.05-mL dose (36). In case ofa pre-filled syringe, the excess volume contained in thesyringe is expelled through the attached administrationneedle. The dose is subsequently set by aligning theplunger with the desired dose mark on the graduatedsyringe or in the case of pre-filled syringes, with a printed/labeled dose mark as illustrated in Fig. 4. Various studieshave emphasized the need for special care in the selectionof delivery component including the plunger, optimizationof dead space or hold up volume, and selecting syringesize that is closer to the dose volume to ensure accuracyand repeatability. A study to determine the accuracy ofIVT volume delivered using three different productsfound that 84% of the injections were greater and 16%of injections were less than the intended 0.05mL volumerespectively (37). Another study showed that the use of alow dead space plunger increased precision while using asmaller size syringe (0.5 mL) resulted in higher accuracycompared to a 1-mL syringe when delivering a 0.05mLdose (38). It is important to note that due to the smallintravitreal space and, therefore, a limited injectionvolume range, higher concentration formulations arenecessary to deliver a higher dose. However, higher

Fig. 4. Illustration of a pre-filled syringe for intravitrealadministration

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protein concentration may be associated with increasedviscosity that may result in reduced accuracy of thedelivered dose. Solutions with viscosity in the range of1–80 cP were evaluated when delivering dose volumes inthe range of 0.03-0.1mLusing various commercially avail-able 1-mL disposable plastic syringes. Dose errors as highas 40% were observed for high-viscosity solutions (45 cP)depending on the type of syringe used (39).

For pre-filled syringes for intravitreal products, glassvials are routinely used for packaging of IVT products andrequire ancillary components such as syringes for administra-tion as described above. However, in recent years, prefilledsyringes (PFS) have become a preferred choice for parenteralbiopharmaceutical products. PFSs have unique advantagessuch as convenience and safe handling (reduced potential forneedle-stick injury) compared to conventional vial drugproducts. Use of PFS reduces the number of steps requiredfor dose preparation and handling since the physician doesnot need to withdraw the product from a vial (36). PFS alsoprovides an opportunity to customize key features such assyringe size and hold-up volume to achieve improvedsyringeability and dose accuracy. Pre-filled syringes areassembled by filling the drug into a syringe barrel followedby sealing of the barrel with a rubber stopper. The stopper isfurther attached to a piston rod that is used to activate thestopper movement during dose preparation and injection.Syringe barrels made of glass are commonly used for IVTdelivery. Developers must understand potential extractablesand leachables from the PFS and characterize their interac-tion with the drug product (40). Although a complete reviewof extractables and leachables is out of scope for thismanuscript, we would like to highlight aspects highly relevantto biologics for IVT administration.

Typically, it is necessary to provide lubrication betweenthe rubber stopper and the glass surface to achieve acceptableforce required to activate the stopper (breaking force) and tomove the stopper along the barrel to deliver the drug (glidingforce). Syringe manufacturers have used the application ofsilicone oil on both syringe barrels and stoppers to achievethe desired lubrication. Several studies have been publishedthat provide an overview and comparison of various barrelsiliconization processes using either medical grade silicone oil,polydimethylsiloxane (PDMS) for spray siliconization orbaked-on siliconization (a process comprised of coating thebarrel with silicone oil-in-water emulsions followed by bakingat 120–350°C and subsequently washing the barrels to removeany non-fixed silicone to provide lubrication (41). Cross-linked siliconization process has also been recently reportedand interestingly has shown to decrease the amount ofleachable silicone oil while maintaining the functionality(42,43).

Development strategy for a glass PFS, lubricated withsilicone oil, for IVT administration of a biologic should, at aminimum, focus on establishing compatibility of drug productwith the container closure, including: characterization of theeffect of silicone oil extractables on the quality and efficacy ofthe drug, characterization of leachable silicone oil over theshelf-life of the product, and contribution of leached siliconeoil to particulate matter in the drug product and wheninjected into the vitreous cavity. Contribution of silicone oilto particle generation and aggregation in protein drug

products has been widely reported (44–46). Proteins mayadsorb to the oil-water interface (47) or silicone oil leachedfrom the barrel into the protein formulation may result inaggregation (44–46). The siliconization method was shown tonot have an impact on particle concentration in the absenceof an air bubble in the filled syringes but may impact thestandards for acceptable particulate matter in ophthalmicinjections which are described in pharmacopoeial guidancesuch as USP <789> or Ph Eur 5.7.1. Due to a stringentcriterion compared to other parenteral injections, the contri-bution of leached silicone oil may be more significant in IVTproducts.

A glass PFS that does not require siliconization has thepotential to not only reduce the particulate matter but alsoreduce the destabilization of biologics sensitive to silicone oil.One such system was described in USPT10,471,212 andUSPT8,722,178. The system comprises of a non-siliconizedglass barrel and a stopper that is coated with a barrier layersuch as PTFE to provide the necessary lubrication. Althoughonly glass PFSs have been commercially available, severalnon-glass PFSs have been proposed in published literatureand patents (22).USPT20170232199 describes a plastic sy-ringe made of cycloolefin polymer or cycloolefin copolymerthat is silicone-free and is suitable for IVT administration.Higher gas permeability of plastic makes development ofnon-glass syringes challenging due to the requirement ofterminal sterilization of ophthalmic products. Correspond-ingly, appropriate risk assessments and studies should beperformed.

Another potential leachable from pre-filled syringes thatwarrants characterization is tungsten. Tungsten pins areroutinely used during syringe forming process, and residualtungsten can potentially leach into the product. Although thesyringe manufacturing process involves washing steps, theymay not eliminate residual tungsten. Small amounts ofresidual tungsten may be sufficient to cause metal-catalyzedprotein oxidation. Residual tungsten may also lead toaggregation and particle formation (48,49).

TERMINAL STERILIZATION OF OPHTHALMICPRODUCTS

Requirements for Terminal Sterilization for IVT PFS DrugProducts

Sterility of ophthalmic products can be achieved byaseptic processing and/or terminal sterilization. Althoughdiscussions on aseptic processing are out of scope for thismanuscript, guidance documents such as ISO 13408-1:2008provide the requirements for aseptic processing of healthcareproducts (50). Terminal sterilization is performed for medicaldevices and pre-filled syringes among other drug productconfigurations for the treatment of several disease indications.Sustained-release ocular drug products administered using amedical device or pre-filled syringe will also require terminalsterilization. Terminal sterilization is defined as a “processwhereby product is sterilized within its sterile barrier system”(51) (ISO/TS 11139:2006). Terminal sterilization is a criticalunit operation and is carried out towards the end of theproduct manufacturing process. Pre-filled syringe drug prod-ucts for IVT are terminally sterilized and packaged to

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maintain sterility and provide a sterility assurance level(SAL) of 10−6 or one non-sterile unit in 1,000,000 unitsthroughout the shelf-life of the product. The SAL is governedby industry guidance for drug products termed “sterile” (52)(ANSI/AAMI ST67:2003).

Effective terminal sterilization requires high degree ofprocess control which ensures product quality and appropri-ate SAL for a given drug product. Therefore, processvalidation of terminal sterilization is critical, and manufac-turers often perform extensive studies and validation cam-paigns to ensure product sterility and impact of terminalsterilization on the drug product. The reader is encouraged torefer to the following references for additional regulatoryrequirements for terminal sterilization of medical devices:

1. International Organization for Standardization 11040-4:2015, Prefilled syringes–Part 4: glass barrels forinjectables and sterilized sub-assembled syringesready for filling

2. International Organization for Standardization 11040-6:2012, Prefilled syringes–Part 6: plastic barrels forinjectables

3. ANSI/AAMI/ISO 11607:2006, Packaging for termi-nally sterilized medical devices

4. USP 27:2004, Sterility, Biocompatibility, BiologicalTests and Assays, Bacterial Endotoxin Test (LAL),Pyrogen Test (USP Rabbit Test), or other applicabletests related to the drug/biological product anddelivery of the drug/biological product

5. AAMI/ANSI/ISO 11737-1:2006, Sterilization of med-ical devices-microbiological methods-Part 1: Determi-nation of the population of microorganisms onproducts

6. USP-NF <1222>, Terminally sterilized PharmaceuticalProducts-Parametric Release

Vapor-Phase Hydrogen Peroxide

Vaporized hydrogen peroxide is a highly effectivesanitizing agent used in aseptic manufacturing facilitiesagainst spores, bacteria, and viruses. Hydrogen peroxide isan oxidizing agent which targets lipids, nucleic acids, andproteins within the microbes. Interestingly, the mechanism ofaction for the liquid form is different from the gaseoushydrogen peroxide. The gaseous form of hydrogen peroxidehas been shown to inactivate pyrons more efficiently thanliquid hydrogen peroxide (53).

Widespread implementation of terminal sterilizationusing vapor-phase hydrogen peroxide (VHP) is still in itsinfancy primarily driven by limitations such as incompatibilitywith cellulosic material, penetration of the sterilant, andvariance in microbial inactivation kinetics. However, addi-tional studies with advanced technologies such as flowcytometry and genetic sequencing on the resistant microbeswould help determine the effectiveness of vaporized hydro-gen peroxide sterilization and enable appropriate processvalidation (54). Although a very effective sanitizing agent, theuse of vaporized hydrogen peroxide is associated with the riskof residual hydrogen peroxide in drug products that may leadto oxidation of biologic drug products. During development,scientists must pay attention to the permeability of selected

container closure components to VHP and characterize for itsingress into the product and any associated qualityimplications.

Ethylene Oxide Sterilization

Ethylene oxide, radiation, and steam sterilization areamong the most common type of sterilization methods in thepharmaceutical/biotech industry. Ethylene oxide is a highlyreactive cyclic ether which is a gas at room temperature and isliquified for use as a sterilant. Ethylene oxide causesalkylation of the amine groups within the microbial DNAwhich leads to microbial death. Although ethylene oxide isextremely effective and widely used in the manufacturingindustry for sterilization of medical devices andpharmaceutical/biotech drug products, ethylene oxide (EO)is a toxic gas with safety implications to the staff, environ-ment, and patients if handled inappropriately (55).

Since ethylene oxide is widely used for external surfacesterilization in manufacturing, the FDA requires submissionof significant manufacturing control data and documentationto demonstrate sterility and acceptable quality of the drugproduct for commercial products. Briefly, the filled/finishedproduct is loaded on to pellets and exposed to a validatedcombination of humidity, ethylene oxide gas, temperature,and time. Deep vacuum cycles aid in driving humidity andethylene oxide into palletized product. Following the expo-sure of EO to the pelletized product, a validated in-chambervacuum purge process or a post-sterilization aeration processis applied to achieve EO levels below permissible exposurelimits (56).

One important quality attribute is the residual ethyleneoxide present during manufacturing of biologics that can alterdrug product quality during storage of commercial products.Therefore, the FDA also requires quantitative data thatdemonstrates acceptable residual levels of ethylene oxidethat does not alter the quality attributes of the drug product.

In all cases where terminal sterilization is being evalu-ated with ethylene oxide, it is essential to determine thecontainer-closure integrity; as for liquid products, ingress ofethylene oxide into the aqueous environment would lead toformation of ethylene glycol in the drug product. Anothercommon impurity is the presence of ethylene chlorohydrinwhich may form when ethylene oxide comes in contact withfree chloride ions present in glass and plastic (57).

Nitrogen Dioxide Sterilization

Nitrogen dioxide sterilization of external surfaces hasemerged as an alternative to the ethylene oxide sterilizationprocess due to its ease of handling and a sterility assurancelevel similar to ethylene oxide. Nitric oxide is a reddish-browngas with a boiling point of 21°C at sea level which can beintroduced rapidly into packages in the sterilizing chamberwith little to no vacuum. A potential advantage of no vacuumis the reduction in risk of stopper movement in pre-filledsyringes under vacuum. Sterilization and aeration processescan be carried out at room temperature or lower; this is anadvantage as compared to ethylene oxide and hydrogenperoxide sterilization processes. Furthermore, the concentra-tions of gas required to achieve terminal sterilization are

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relatively low (1–2%). Another significant advantage ascompared to ethylene oxide and hydrogen peroxide steriliza-tion is the time required to run a typical sterilization cyclewhich ranges from 2 to 3 h as compared to days for ethyleneoxide sterilization cycles (58,59). Nitrogen dioxide inactivatesall forms of microorganisms, including bacteria, bacterialspores, fungi, fungal spores, and viruses. The mechanism ofmicrobial kill is primarily through single-stranded breaks inthe DNA which increase with increasing nitrogen dioxideconcentration (60). Materials that are compatable/non-compatible for sterilization using Nitrogen dioxide are listedin Table IV.

A head-to-head sterilization study was conducted onsyringe tubs prior to filling operation where biologicalindicators (BI) are placed at various locations on the syringetub and Tyvek bags. The nitrogen dioxide sterilization processwas carried out for 15 min as opposed to the vaporizedhydrogen peroxide process carried out for 43 min. Resultsdemonstrated that the nitrogen dioxide cycle was consistentand lethal to all BI across several syringe tubs placed atdifferent locations in the sterilizing chamber. However, theVH sterilization cycle was not very effective in its lethalityagainst the BI across several syringe tubs (61). Another studydemonstrated the ability of the nitrogen dioxide gas to beused as a surface sterilant for pre-filled syringes. The studydescribed 1-mL glass syringes that were filled with water forinjection and exposed to the nitrogen dioxide sterilizationcycle. The authors demonstrate no ingress of nitrogen dioxide(assay limit < 0.024 ppm) through the syringes. Since NO2

converts to NO3-, the detection of NO3

- can be performed bycolorimetric assay as a release test (62).

Although several studies have demonstrated the advan-tages of using nitrogen dioxide, it is a relatively newertechnology which would benefit from additional studies andwhite papers/publications in collaboration with industry andacademia.

Challenges with Terminal Sterilization Using OxidizingAgents

Impact of Residual Sterilizing Oxidant on Container ClosureSystems

Studies have demonstrated the impact of vaporizedhydrogen peroxide sanitization within isolators on platinumcured silicone tubing, glass vials, syringes, and stoppers. It isimportant to understand the interaction of container closuresystems and commonly used components in the

manufacturing process with the sterilizing agent to ensurethe sterilizing agents do not have a detrimental effect onproduct quality. For example, silicone tubing had decreasedpropensity to adsorb vaporized hydrogen peroxide ascompared to gamma irradiated silicone tubing. Glass vialsof various sizes when exposed to varying levels of VHP (50to 500 ppb) demonstrated a correlation between VHPconcentration in the isolator and adsorbed VHP within thevial albeit with high variability among replicate vials. Thevariability was not attributed to isolator air flow but ratherthe varying rate of VHP diffusion into the vials. Stoppersused in drug products are generally coated with hydropho-bic fluoro-polymer to minimize drug-stopper interaction;exposure of these coated stoppers to VHP was observed tohave negligible levels of VHP adsorption. Empty 1-mLsyringes were exposed to 500 ppb VHP for 24 h and wereobserved to have negligible amount of hydrogen peroxideadsorption in the inner surfaces of the syringe. Innersurfaces of prefilled syringes are coated with silicone oilfor ease of injection which makes the inner surfaceshydrophobic thereby reducing the amount of hydrogenperoxide adsorbed on the surface. In general, it wasobserved that there was a correlation between surfacehydrophilicity and the amount of hydrogen peroxideadsorbed. Therefore, unit operations that reduce thehydrophilicity of surfaces (reduced water) would lead toreduced hydrogen peroxide uptake (63).

Impact of Ingress of Sterilizing Oxidant on Drug ProductQuality

Undesired ingress of oxidizing sterilizing agent into thedrug product during terminal sterilization can have signifi-cant safety and efficacy concerns for biologics. Severalamino acid residues such as methionine, cysteine, histidine,and tryptophan have been identified as “hot spots” foroxidation events following exposure to hydrogen peroxide(64). To assess the impact of VHP ingress, hydrogenperoxide spiking studies are commonly performed duringdrug product development to determine the rate and extentof protein degradation. Residual hydrogen peroxide impactsnot only liquid protein formulations but also drug productsthat undergo lyophilization. Cheng et al. demonstrated thatwhen protein formulations are spiked with 5 ppm ofhydrogen peroxide prior to lyophilization, an average of94.1% of the spiked hydrogen peroxide was removed duringlyophilization (56). Oxidation occurred during lyophlizationand even when the formulation is frozen. Furthermore,

Table IV. Material Compatibility for Nitrogen Dioxide Sterilization Process

Compatible Not compatible

Stainless steel, polyethylene, polyetherimide,anodized aluminum, polypropylene, polycarbonate,gold (plating), PET/PETG, cyclic olefins, glass/ceramic, polystyrene, PVCa, fluoropolymers,polysulfones, siliconea, Viton (gaskets), Hypalon

Polyurethane, thermoplastic elastomers (TPE),nylon, polyester, polyolefin, Delrin (polyacetal), PSU, PEI,cellulose-based (some paper), polyester or styrenelabel stock

aDepending on the material gradeNot an exhaustive list

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oxidized proteins were prone to aggregation during thelyophilization process (64). Similar to vaporized hydrogenperoxide, detrimental effects of ethylene oxide have beenreported in the literature; significant degradation of humanserum albumin and pegylated granulocyte-colony stimulat-ing factor have been reported (66). Therefore, undesiredingress of ethylene oxide into the drug product has beendemonstrated to be detrimental to the drug productdepending on protein oxidation potential, formulationcharacteristics, and primary container material, all of whichhave the potential to for unwanted clinical consequences(67). Eisner et al. demonstrated the importance of samplehandling while performing analysis for hydrogen peroxidein drug product. Degradation of hydrogen peroxide wasobserved to be faster at − 20°C when compared to 2–8 °Cwhen antibody formulations were spiked with hydrogenperoxide, while hydrogen peroxide was most stable inantibody formulation when stored at − 70°C (65)

London et al. demonstrated that external surface termi-nal sterilization with ethylene oxide on ranibizumab pre-filledsyringes did not have any negative impact on ranibizumabpotency, concentration, and stability when incubated at 2–8°Cfor ≤ 3 years (68).

Funatsu et al. demonstrated the presence of residualethylene oxide on empty cycloolefin polymer barrels whichwere sterilized using ethylene oxide (ISO 11135:2014 stan-dards) prior to filling of the formulation (58). In the study, theauthors demonstrate significant degradation of human serumalbumin at cysteine and methionine residues with ethyleneoxide concentrations as low as 34 μg/syringe. It is importantto note that residual ethylene oxide levels for EO-sterilizedmedical device based on the ISO 10993-724 standard is 4000mg/syringe (67). Therefore, it must be noted that althoughregulatory requirements may be met for residual levels, thelevels required for maintaining drug product quality may bemore stringent.

These considerations for biologic drug products are notunique to a specific administration route, and biologicsintended for IVT administration also need to be carefullymonitored for protein degradation events to ensure productsafety and efficacy.

IVT PRODUCTS THAT EXTEND DURATION OF IVTINJECTIONS IN THE CLINIC

Reducing dosing frequency of IVT injections would be asignificant improvement in the patient’s quality-of-life suffer-ing from chronic indications such as wet age-related maculardegeneration and diabetic retinopathy where frequent IVTinjections are administered.

Intraocular delivery devices have been established andapproved by the FDA for small-molecule therapeutics;however, there are no approved devices delivering biologics.Several companies are focused on developing novel devicesand delivery systems for IVT sustained release of biologicswhich reduce frequency of injection for biologics.

There are several considerations for the development forsustained release devices which include factors such asselection of biodegradable or non-biodegradable polymer,polymer back bone chemistry, immunogenicity of the polymersystem, stability of the molecule, size of the device, site ofimplantation, implantation procedure, repeat dosing and/ordevice refill procedure, and time interval between repeatdosing (69).

Several academic and industry publications have focusedon biodegradable polymers such as poly(lactic-co-glycolicacid), polycaprolactone, and proprietary polymer blends thatdegrade at specific rates for release of active ingredient in thevitreous. However, only a handful of approaches are inclinical development as therapies for reducing dosing fre-quency while maintaining therapeutic efficacy (Table V).

CONCLUSION

IVT injections are standard of care for treating variousintraocular diseases. The clinical procedure for successfullyinjecting drugs in the intravitreal space has been studiedand reported on extensively by retina specialists, academi-cians, and industry scientists. The procedure also requirescareful selection of administration components such assyringes and needles. In recent years, there has been aspecialized focus on improving intravitreal injection devicesand products. Examples include improvements in needledesigns that enhance injectability and reduce complicationssuch as vitreal reflux for chronic diseases such as diabeticmacular edema and wet-AMD. Improvements in syringedesigns such as the development of silicone-free syringesand needle bevel designs can further improve existing drug

Table V. Clinical Investigation of Therapeutics for Reduced IVT Dosing Frequency

Technology Sponsor Mechanism of action Latest phase

Bioresorbable hydrogel containing tyrosine kinase inhibitor Ocular Therapeutix Tyrosine kinaseinhibitor

Phase I

Anti-VEGF mAb conjugated to a phosphorylcholine-basedbiopolymer

Kodiak Sciences Anti-VEGF Phase III

Bispecific antibody angiopoietin-2/VEGF-A (Faricimab) Roche Anti-VEGF Anti-Ang-2 Phase IIISunitinib malate microparticle depot Graybug Vision Anti-VEGF Phase IIa/Phase IIbADVM-022 IVT gene therapy Adverum Biotechnologies Anti-VEGF Phase IIFusion protein aflibercept—high dose Regeneron Pharmaceuticals Anti-VEGF Phase II/IIIPort delivery system Roche Anti-VEGF Phase III

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products specific for intravitreal administration. Maintainingaccuracy and precision while injecting small volumes ischallenging, and it is important to understand the capabilityof the administration components during drug productdevelopment.

In addition to intravitreal injections, other injectionroutes such as suprachoroidal and sub-retinal injections havedemonstrated promise in delivering therapeutics to theintended site of action within the ocular tissues. Microneedlesare one such devices that can enable injection of therapeuticsinto ocular tissues while being minimally invasive as com-pared to intravitreal injections.

Furthermore, the latest generation of therapeutics whichinclude cell and gene therapies may bring a new paradigm forophthalmic drug product development. Depending on theintended site of action, development of specialized devices,materials, formulations, and manufacturing processes may bewarranted which meet the criteria for safety and efficacy asper regulatory guidelines.

ACKNOWLEDGEMENTS

The authors would like to thank James Sutherland andMichele Leone for providing editorial support for themanuscript and Gera Karafin for the help with illustrationof a pre-filled syringe.

Open Access This article is licensed under a CreativeCommons Attribution 4.0 International License, which per-mits use, sharing, adaptation, distribution and reproduction inany medium or format, as long as you give appropriate creditto the original author(s) and the source, provide a link to theCreative Commons licence, and indicate if changes weremade. The images or other third party material in this articleare included in the article's Creative Commons licence, unlessindicated otherwise in a credit line to the material. If materialis not included in the article's Creative Commons licence andyour intended use is not permitted by statutory regulation orexceeds the permitted use, you will need to obtain permissiondirectly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/.

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