Expert Opinion on Drug Delivery
ISSN: 1742-5247 (Print) 1744-7593 (Online) Journal homepage: https://www.tandfonline.com/loi/iedd20
Prefilled syringes for immunoglobulin G (IgG)
replacement therapy: clinical experience from
other disease settings
Ayman R. Kafal, Donald C. Vinh & Mélanie J. Langelier
To cite this article: Ayman R. Kafal, Donald C. Vinh & Mélanie J. Langelier (2018)
Prefilled syringes for immunoglobulin G (IgG) replacement therapy: clinical experience
from other disease settings, Expert Opinion on Drug Delivery, 15:12, 1199-1209, DOI:
10.1080/17425247.2018.1546692
To link to this article: https://doi.org/10.1080/17425247.2018.1546692
© 2018 The Author(s). Published by Informa
UK Limited, trading as Taylor & Francis
Group.
Accepted author version posted online: 13
Nov 2018.
Published online: 07 Dec 2018.
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EXPERT OPINION ON DRUG DELIVERY
2018, VOL. 15, NO. 12, 1199–1209
https://doi.org/10.1080/17425247.2018.1546692
REVIEW
Prefilled syringes for immunoglobulin G (IgG) replacement therapy: clinical
experience from other disease settings
Ayman R. Kafala, Donald C. Vinhb and Mélanie J. Langelierb
a
Medical Affairs, CSL Behring LLC, King of Prussia, PA, USA; bInfectious Disease Susceptibility Program, Research Institute – McGill University Health
Centre, Montreal, Quebec, Canada
ABSTRACT
ARTICLE HISTORY
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.
Received 25 June 2018
Accepted 7 November 2018
1. Introduction
Primary immunodeficiencies (PI) are a group of more than 350
disorders caused by poor or absent function of one or more
components of the immune system [1]. Approximately 70% of
PI patients have primary antibody deficiency [2,3]; the prevalence of clinically significant antibody deficiency has been
estimated at 1:25,000 to 1:111,000 persons [4] and, for these
patients, immunoglobulin G (IgG) replacement therapy (IgRT)
is the standard of care. IgRT is also used in the treatment and
management of some secondary immunodeficiencies and, at
higher doses, for immunomodulation in a variety of inflammatory, autoimmune, and neurological conditions.
IgRT can be administered intravenously or subcutaneously,
and a variety of IgG products are commercially available [5].
Intravenous Ig (IVIG) administration is the traditional
approach, having been successfully used for over five decades
[6]. However, over 25 years of accumulated treatment experience with subcutaneous (SC) Ig (SCIG) [7] has established this
modality as an effective, safe and well-tolerated alternative to
IVIG that offers patients near steady-state IgG levels and the
option to self-administer [5,7]. In addition, SCIG formulations,
in particular those with higher IgG content, allow lower infusion volumes and shorter infusion durations relative to IVIG
[5,7]. Despite the advancements provided by the SCIG route,
further progress in administration logistics will improve its
CONTACT Ayman R. Kafal
PA, USA
Ayman.Kafal@cslbehring.com
KEYWORDS
Acceptability; clinical
experience; convenience;
cost; education; efficacy;
immunodeficiency;
immunoglobulin
G replacement therapy
(IgRT); prefilled syringe;
stability
utility. This is particularly relevant for patients with poor dexterity, coordination issues or visual difficulties, such as the
young and elderly, who may find it difficult or be unable to
self-administer SCIG by the traditional vial and syringe
method. Individualized IgRT regimens can offer improved convenience, flexibility, and quality of life for patients, and
expanding available options through the use of prefilled syringes for SCIG administration is an interesting next step [7,8].
Prefilled syringes are already effectively used for the administration of blood-based products, such as coagulation factors
VII (eptacog alfa) and VIII (moroctocog alfa and efmoroctocog
alfa) for the treatment of bleeding disorders [9–11]. They are
also a promising treatment modality for SC IgRT, particularly
high-concentration SCIG products (i.e. 20% SCIG) as these can
be filled into relatively small syringes that are convenient to
use. They could potentially also be considered as an option for
enzyme-facilitated SCIG products where prefilled syringes
could help simplify the more complex infusion process of
these products. To appraise the practicality of prefilled syringes for SC IgRT, we conducted a pragmatic literature review
to collate the experience from other clinical settings and
indications on the use of prefilled syringes. We present the
findings of our literature review following a brief overview of
the prefilled syringe.
It is important to note that this review includes information
about prefilled syringes from a number of different disease
Medical Affairs, Medical Affairs Department, CSL Behring LLC, 1020 First Avenue, King of Prussia,
© 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
1200
A. R. KAFAL ET AL.
Article highlights
●
●
●
●
●
●
Immunoglobulin G replacement therapy (IgRT) is the standard of care
for patients with primary immunodeficiencies manifesting as antibody deficiencies, and subcutaneous administration is now an established and preferred treatment modality.
Prefilled syringes for drug administration are estimated to account for
over one quarter of all injectables, with their use across a broad
spectrum of clinical indications and settings increasing.
Available evidence demonstrates comparable stability, pharmacokinetics, bioequivalence, efficacy, and safety of drugs delivered by
prefilled syringe relative to conventional vials.
Clinical experience with prefilled syringes shows reductions in preparation time, medication errors, and drug wastage; moreover, prefilled syringes are generally preferred by patients and healthcare
professionals as an acceptable, easy to use, and convenient administration system.
Higher costs associated with prefilled syringes remain a potential
barrier to their introduction in some clinical settings, but cost effectiveness/savings analyses are required to determine their practicality
for defined conditions.
Prefilled syringes for IgRT have the potential to offer patients
improved choice and satisfaction, and ultimately impact positively
on patient independence and quality of life.
This box summarizes key points contained in the article.
conditions for which varying infusion paradigms are used. In
several instances, there are important differences between SC
IgRT and other products discussed here e.g., infusion volume
(generally high for SC IgRT and lower for many other products)
and infusion device (generally pump-based infusion for SC
IgRT and pen-type autoinjectors for many other products).
These have been included and discussed as there is a lack of
literature on prefilled syringe products that are directly comparable to SC IgRT in terms of infusion volumes and device
type. Nonetheless, keeping these differences in mind we still
believe many valuable lessons can be learned from the use of
prefilled syringes in other disease areas.
drugs in a closed system, accurate dosing, sterility assurance,
and reduced risk of contamination [13]. Moreover, they offer
patients greater choice, convenience, and ease-of-use, particularly for self-administration. This may lead not only to
improved adherence but greater patient satisfaction, independence, and quality of life. One of the primary disadvantages of
prefilled syringes is the increased unit cost relative to traditional vials, although the price gap is narrowing with increasing demand and production. An overview of prefilled syringe
characteristics relative to conventional methods is shown in
Table 1 [11, 14–63].
The overall design of prefilled syringes is generally consistent, comprising: the plunger, stopper, barrel, Luer lock or slip
tip, and cap [49] (Figure 1). A variety of different manufacturing processes, materials, and drug formulation processes are
used in their production (for a review, see [12,13,49]).
Dependent on purpose (including non-SC use), prefilled syringes are available in a range of sizes [49] and are typically
fabricated from glass or plastic. While most prefilled syringes
in the US, European and global markets are made from glass
[13,49], advances in polymer chemistry have led to an increase
in the use of polymer-based syringes. Needles may be fixed to
the syringe or attached to the barrel via a Luer lock screw cap
mechanism or slip tip, as is typical in non-emergency settings
and for self-administration [12]. As mentioned previously, IgRT
requires higher volumes (and consequently, larger prefilled
syringes) than many other SC injections. Prefilled syringes
that feature a retractable needle to increase safety are also
Table 1. Overview of prefilled syringes compared with conventional methods
(vial/ampoule) for medication deliverya.
Drug/treatment
characteristic
Pharmacokineticsb
Bioequivalenceb
Stability
Efficacy
Safety/tolerability
Treatment/injection
time
Dosing errors
Drug wastage
Patient experience
Cost
2. Prefilled syringes for drug delivery
Since the introduction of a prefilled syringe for heparin over
three decades ago, their use for drug delivery has grown
substantially and now encompasses a broad spectrum of clinical settings and indications. Prefilled syringes are now estimated to account for one quarter of all injectables [12],
a proportion that is expected to grow significantly. The benefits of ready-to-use prefilled syringes include provision of
Figure 1. Design overview of a prefilled syringe.
a
Conventional
vial/ampoule
Comparable
Comparable
Comparable
Comparable
Longer
Prefilled
syringes
Comparable
Demonstrated
Comparable
Comparable
Comparable
Shorter
Yes
Yes
Lower
Low
Fewer
Lower/None
Improved
Comparable/
Higher
References
[11,14–18]
[11,14–18]
[19–27]
[14,28–33]
[14,16,28,29,33–36]
[37–44]
[37,45,46]
[12,47–49]
[16,28,39,50–56]
[38,41,42,56–63]
Information presented represents an overall summary of data from studies included
in this review. Comparison of delivery methods is based on comparing the same
drug/medication when delivered by vial/ampoule or prefilled syringe.
b
Comparison of prefilled syringes with vial/ampoule [11,15] or auto-injector [14,16–18].
EXPERT OPINION ON DRUG DELIVERY
available [49]. The concept of the prefilled syringe has also
been expanded in the form of prefilled pens/autoinjectors that
are activated by a button press or as a result of pressure
applied against the needle end upon administration.
Examples include devices for the administration of insulin
[64,65], and epinephrine [66]. Further developments in prefilled syringe design are paralleled by continuing growth in
their use across the healthcare sector, with marketing predictions estimating sales of prefilled syringes approaching
7 billion units in 2025 (from 2 billion in 2009) [12,67].
3. Prefilled syringes in clinical practice
3.1. Literature search results
Literature published on PubMed was searched to identify
articles reporting on the use of prefilled syringes in clinical
practice. No constraints on the publication type or year of
publication were imposed. The literature search was performed in July 2017. The data presented should not be considered exhaustive, but instead as representative of principal
findings from studies that evaluate clinical use and experience
with prefilled syringes.
The primary search term was ‘(prefilled OR pre-filled) AND
Syringe [MH],’ which identified 229 articles. Using the filters
within PubMed, this list was initially refined to the 69 articles
that were listed as a ‘clinical study’ (n = 37) or ‘comparative
study’ (n = 46) (filtering on ‘clinical study’ also included all
articles listed as a ‘clinical trial’ (n = 35), ‘controlled clinical trial’
(n = 23), or ‘randomized controlled trial’ (n = 21)). The title and
abstract for each of the 69 articles was reviewed and a total of
31 relevant articles were retained. We also screened the titles
of the remaining 160 articles to identify further articles of
interest, and performed additional searches that incorporated
more specific search terms (and derivatives), such as ‘efficacy,’
‘safety,’ ‘convenience,’ ‘preparation,’ and ‘cost.’ This approach
yielded a literature base encompassing a diverse spectrum of
clinical settings, including anesthesiology, hemodialysis, and
emergency medicine, and clinical indications, such as hemophilia, cystic fibrosis, psoriasis, allergy, multiple sclerosis, acromegaly, rheumatoid arthritis, and diabetes.
3.2. Drug characteristics
A principal consideration for the use of prefilled syringes is their
potential impact on drug characteristics and performance, such
as pharmacokinetics (PK), stability, efficacy, and safety/tolerability. Few studies have directly assessed bioequivalence relative
to medication in the traditional vial and syringe format. Using
a single-dose, randomized, cross-over study design, Shafer et al.
[11] reported comparable PK and bioequivalence (90% CI for
ratio of mean values of Cmax and AUCinf within the bound of
0.8–1.25) of moroctocog alfa for the treatment of hemophilia
A when administered by prefilled syringe compared with traditional vials. Comparable PK and bioavailability have also been
shown for SC administration by prefilled syringe, but relative to
an autoinjector, for drugs such as belimumab [16] and ixekizumab [14] used in the treatment of systemic lupus erythematosus and plaque psoriasis, respectively, the interleukin-6 inhibitor
1201
sirukumab [18] and a pegylated form of recombinant granulocyte colony-stimulating factor, pegfilgrastim [17].
The stability of medications when provided in prefilled syringes
is also important. A variety of different drugs/agents have been
evaluated, including epinephrine [21], insulin [23], penicillin [20],
epoetin alfa [24], netilmicin [26], fluconazole [19], bevacizumab
[22,25], and hepatitis E vaccine [27]. While the clinical indications,
conditions of use, and treatment periods differ for these agents,
the consensus of these studies was of good drug stability in the
prefilled syringe format (Table 2), and confirmed relative to traditional vials in some cases [19,22,24,25]. Furthermore, Garg et al.
showed favorable stability data of penicillin-type antibiotics in
prefilled syringes. Amoxicillin, benzylpenicillin, and flucloxacillin
all showed stability at 2–7 days. This time is substantially longer
than the current shelf-life of 24 hours and supports a change of
clinical practice where these agents can be prepared in advance by
pharmacies, improving safety and workflow [20]. Good drug stability in prefilled syringes has also been reported for U-500 regular
insulin (≥ 28 days when refrigerated) [23], epoetin alfa (up to
6 weeks when refrigerated) [24], netilmicin (300 days at room
temperature) [26], fluconazole (77 days at room temperature)
[19], and bevacizumab (6 months when refrigerated) [22].
Demonstration of a good drug stability profile also led some
investigators to raise additional potential benefits from the use of
prefilled syringes, including cost [19,21,24], convenience/ease-ofuse [19,23], and reduction in drug dosing errors [24]. However, in
the case of bevacizumab, there are contrasting reports on drug
stability/quality in prefilled syringes relative to vials, with one study
[22] reporting no significant differences, and another study [25] an
increase in particle density that was not observed with vials.
Although individual drugs/agents must each be appropriately
evaluated, current experience supports the stability of drugs in
prefilled syringes and their potential application for other
therapeutics.
Our review of the literature did not identify any relevant articles
directly comparing drug efficacy between administration by prefilled syringe and traditional injection methods. However, several
studies have reported efficacy data for treatments administered by
prefilled syringe (compared with a comparator). Although these
studies do not provide a direct comparison with traditional injection methods, they do demonstrate the general viability of use of
prefilled syringes across several disease areas. For instance, in
a phase IV, randomized, double-blind, controlled trial in patients
with rheumatoid arthritis, significantly more patients treated with
SC methotrexate by prefilled syringe than with oral methotrexate
achieved a clinical response according to American College of
Rheumatology (ACR) 20 (78% vs. 70%, p < 0.05) and ACR70 (41%
vs. 33%, p < 0.05) criteria [29]. Similarly, drug efficacy following SC
injection by prefilled syringe has been shown for secukinumab
relative to placebo (~70% vs. 0% showing a clinical response
according to the Psoriasis Area Severity Index [PASI] 75 criterion,
p < 0.0001) [28], for ixekizumab compared with an autoinjector
(mean PASI improvement 89.3% and 86.9%, respectively) [14] in
the treatment of plaque psoriasis, and for belimumab versus placebo in patients with systemic lupus erythematosus (Systemic
Lupus Erythematosus Responder Index clinical response in 61.4%
vs. 48.4%, odds ratio 1.68 [95% CI 1.25–2.25], p < 0.0006) [33].
Studies of patients with neuroendocrine tumors, acromegaly,
and those on dialysis as a result of chronic kidney disease further
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A. R. KAFAL ET AL.
Table 2. Studies evaluating the chemical and/or physical stability of medications supplied in prefilled syringes.
Drug/agent
Indication
Epinephrine
Anaphylaxis
Insulin
Diabetes
Benzylpenicillin Skin testing for allergy
Amoxicillin
Flucloxacillin
Epoetin alfa
Anemia
Netilmicin
Bacterial infection
Fluconazole
Candidiasis
Bevacizumab
Age-related macular
degeneration
Bevacizumab
Age-related macular
degeneration and
macular edema
Hepatitis E
Hepatitis
E vaccine
Test temperature/Sample size/
Time pointsa
Room temperature
N = 140
1, 2, 3 months
4°C
N=3
7, 14, 21, 28 days
–20°C, 4°C, and 25°C
N=2
1–7 days
4°C
N=3
3, 6 weeks
7°C, room temperature, 25°C
N=2
Up to 300 days
Room temperature (22–25°C)
N=6
14, 28, 42, 56, 70 days
5°C
N = 3–6
1, 2, 3, 4, 5, 6 months
4°C
N = 2–5
1, 14 days
2–8°C
N = 12
24 months
Outcome
Reference
99.3–101.4% concentration retained (open air; acceptable range
90–110%); pH 3.17–3.23 (acceptable range 2.8–3.6); appearance clear
throughout, no norepinephrine detected
Concentration: ≥ 93.3 ± 2.4% at all time points; differences in %
remaining vs. baseline p = 0.130; no degradation products detected
[21]
> 90% concentration retained at 7 days at 4°C; flucloxacillin stable
≥ 3 days at 25°C; no color change or precipitation detected
[20]
No protein degradation or denaturation detected, with no significant
differences vs. reference vial (p > 0.05)
[24]
Based on > 90% concentration threshold, stability 90 days at 7°C, 30 days
at 25°C, 9 days at room temperature (light); appearance changes and
degradation at room temperature
~100% concentration retained at 70 days (comparable to reference vial);
pH 4.1–4.2 (reference vial 4.2); no changes in appearance observed
[26]
No significant differences (p > 0.05) in concentration or stability
compared to vial; no degradation products detected
[22]
Concentration comparable with reference vial; significant increase
(p < 0.05) in particulate density over time that was not apparent for
the reference vial
No significant changes in immunogenicity, antigenicity, thermal stability,
or morphology
No degradation products detected
[25]
[23]
[19]
[27]
a
The indicated test temperature is the temperature that prefilled syringes were stored at during the study. Sample size is the number of prefilled syringes, number of
batches, or number of samples collected from prefilled syringes that were analyzed at each time point.
show the efficacy of therapeutic agents (e.g. somatostatin analogs
and erythropoiesis-stimulating agents) delivered by SC or IV injection with prefilled syringes [30–32].
In addition to confirming efficacy, regulators require that
comparable safety and tolerability relative to known drug safety
profiles are demonstrated for drugs administered by prefilled
syringe. The study by Braun et al. [29] evaluating SC methotrexate administered by prefilled syringe found similar tolerability
relative to oral methotrexate (adverse events in 66% vs. 62%,
respectively). Reported safety data for prefilled syringe administration of belimumab [16,33], ixekizumab [14], secukinumab
[28] and omalizumab [35], an anti-IgE antibody used to treat
asthma, and a liquid formulation of interferon beta-1a for the
treatment of multiple sclerosis [34], were consistent with the
known safety profiles for these agents. Studies have also examined the immunogenicity of liquid drug formulations delivered
by prefilled syringe. No psoriasis patients treated with secukinumab by prefilled syringe developed treatment-emergent
antidrug antibodies in the work by Blauvelt et al. [28],
a finding that was also reported by Somerville et al. [35] for
patients with allergic asthma treated with SC omalizumab.
The use of prefilled syringes, which have a simplified process and reduced number and associated risk of system vulnerabilities compared with traditional self-filled syringes, has
also been proposed as a measure to improve safety for perioperative anesthesiology medication [36].
3.3. Treatment delivery
Data from studies in different fields highlight that prefilled
syringes can help improve the speed of infusion [37–44] and
the number of dosing errors [37,45,46] when compared with
infusions done using traditional ampoules. It should be noted
that many of these studies were performed in the critical care
field, where reducing infusion time and dosing errors is of key
importance. Moreover, the preparation steps required for
time-critical injections such as those employed in the context
of critical care, make up a larger amount of the total infusion
time when compared with prolonged infusions applicable to
SC IgRT. Although the reduction of administration time may
be less critical for patients on SC IgRT compared with patients
in an acute care setting, employing prefilled syringes to
reduce the number of preparation steps and total time spent
on the infusion could also conceivably reduce dosing errors
and drug waste while improving patients’ satisfaction with
treatment and adherence.
One consideration is the increased packaging used for
prefilled syringes. Relative to packaged vials, packaged prefilled syringes are typically more voluminous and require larger storage space. These issues may be particularly pertinent
in the clinical setting where transportation and storage of
large numbers of prefilled syringes is necessary (with potential
implications on costs).
3.4. Patient experience
Improving patients’ treatment experience is perhaps one of
the single most important goals in the development of new
approaches for drug delivery. Prefilled syringes are recognized
to offer several potential benefits, including improved choice,
convenience, ease-of-use, and satisfaction with treatment. For
many patients, the benefits of prefilled syringes also support
EXPERT OPINION ON DRUG DELIVERY
the transition from hospital-based treatment to home-based
self-administration, which can have a positive impact on quality of life, a foremost concern of patients. Table 3 presents an
overview of findings regarding patient and physician/nurse
experience with prefilled syringes [16,28,50–56].
In an early open-label study of patients with diabetes treated with insulin, patients switching to administration by prefilled syringe (n = 64) almost uniformly reported that the
prefilled syringe was convenient and easy to use (98%),
required little time to use at home (95%) and away from
home (89%), and wished to continue using a prefilled syringe
(91%) [52]. Furthermore, significantly more patients were not
worried about self-injecting after using the prefilled syringe for
4 weeks compared with baseline (87.5 vs. 70.3%, p < 0.05).
Similarly, patient-reported acceptability determined by
a modular self-injection assessment questionnaire was high
at the initiation of self-injecting with prefilled syringes (mean
score 7–8 out of 10) and remained high but with an increasing
trend (mean score 8–9) through 12–48 weeks of treatment in
patients with plaque psoriasis [28,51]. Overall, patients were
confident using prefilled syringes, found them easy to use, and
were satisfied with administration by prefilled syringe [51].
Reported acceptability of the prefilled syringe format was
also high for subjects self-administering belimumab (n = 81),
with device handling acceptable in 98%, the effort required to
use the device acceptable in 90%, and injection time acceptable in 100% of subjects [16]. In the setting of surgical
anesthesia, Webster et al. [56] reported that clinical usability
of a new safety-orientated drug administration system utilizing prefilled syringes was significantly higher relative to conventional administration methods (8.5 [5.9–9.4] vs. 7.5
[3.2–9.8], median [range] on a scale of 0–10; p = 0.027).
1203
Clinical acceptability also favored the prefilled syringe (8.3
[6.0–9.9], p = 0.001, where a score > 5.0 favored the prefilled
syringe system).
Further data support the positive patient perspective on
the use of prefilled syringes (Table 3). Using a treatment
device scenario design, Cimino et al. [50] conducted a crosssectional study of patients with hemophilia to evaluate patient
preference for five different coagulation factor VIII reconstitution systems: four using a traditional vial and syringe
approach, and one using a single dual-chambered prefilled
syringe. Not only was patient preference for the prefilled
syringe significantly higher than for the other systems/scenarios (71 vs. ≤ 50 for other systems, median preference on
a scale 0–100; p < 0.001), but in practical testing, the prefilled
syringe was preferred over current treatment in terms of ease
of coagulation factor preparation (8.4 [1.6] vs. 6.5 [2.1], mean
[standard deviation (SD)] rating on a scale 0–10, p < 0.001) and
ease of device handling (7.8 [1.8] vs. 7.2 [2.1], mean [SD],
p = 0.007) [50]. Positive responses to the use of prefilled
syringes have also been reported for patients with arthritis,
highlighting the potential value of prefilled syringes in
patients with manual dexterity issues [55], as well as in
patients with high levels of low-density lipoprotein cholesterol
[53]. Furthermore, these and other studies have also examined
the perspectives of healthcare professionals (physicians and
nurses) and carers; overall, responses to the use of prefilled
syringes were positive, in terms of preference, usability,
acceptability, and willingness to self-inject [53–55]. Selfadministration by prefilled syringe was also reported to lead
to a feeling of more independence and improved quality of
life by 89.1% and 83.6% of patients, respectively, in the study
by Striesow and Brandt [55]. The incorporation of prefilled
Table 3. Summary of patient and healthcare professional experience with the use of prefilled syringesa.
Measure
Convenience/
Usability
Time required
Preference
Satisfaction/
Acceptability
Device handling
Independence/
Quality of Life
a
Findings for prefilled syringes
98% of patients considered PFS convenient and easy to use
Median (range) usability score (scale 0–10): 8.5 (5.9–9.4) [vs. 7.5 (3.2–9.8) for conventional methods, p = 0.027]
83–100% of patients/physicians agreed with ease of use/operation
98% of patients reported that the PFS were convenient and easy to use, and 95% reported it took little time to use at
home; 91% wished to continue using PFS
100% of patients considered injection time was acceptable
91% wished to continue using
Median (IQR) preference (scale 0–100): 71 (53) vs. ≤ 50 for non-PFS systems (p < 0.001)
Mean (SD) preference (scale 0–10) to prepare vs. current treatment: 8.4 (1.6) vs. 6.5 (2.1) (p < 0.001)
Mean score (scale 0–10) at baseline vs. 12-weeks use: 7.87 vs. 8.70 feelings about injections, 7.09 vs. 8.23 self-confidence,
6.83 vs. 8.35 satisfaction
Mean score (scale 0–10) at baseline vs. 48 weeks use: ~8.0 vs. ~9.0, feelings about injections, ~7.0 vs. ~8.5 selfconfidence, ~7.0 vs. ~8.5 satisfaction
90% of patients considered effort required to use the PFS was acceptable
Median (range) clinical acceptability (scale 0–10): 8.3 (6.0–9.9) [p < 0.001, where a score > 5.0 favors the PFS over
conventional methods]
87.6% of patients and 92.8% physicians/nurses rated overall assessment ‘very good’ or ‘good’
Physician’s expectations on the benefit of switching to self-administration (by PFS) were met for 92.8% of patients
89% and 93% of patients ‘very willing’ or ‘somewhat willing’ to self-inject, pre- and posttesting PFS
66% of patients confident in self-injecting
Nurses considered satisfaction and preparation ‘very good,’ compared with ‘sufficient’ for non-PFS
98% of patients considered device handling was acceptable
Mean (SD) preference (scale 0–10) vs. current treatment: 7.8 (1.8) vs. 7.2 (2.1) (p = 0.007)
Nurses considered handling ‘very good’, compared with ‘satisfactory’ for non-PFS
89.1% of patients reported that self-administration (by PFS) led to a feeling of more independence, and 83.6% of patients
to improved quality of life
Reference
[52, 53, 56]
[16, 52]
[52, 50]
[16, 28, 51,
53–56]
[16, 50, 54]
[55]
Information presented is a summary of key data reported from studies included in this review, and is not meant to be exhaustive of all data reported by each study.
Abbreviations: IQR, interquartile range; PFS, prefilled syringe; SD, standard deviation.
1204
A. R. KAFAL ET AL.
syringes into advanced delivery devices such as autoinjectors
and autoinjection systems [13,68] offers further improvements
in patient experience, making injections easy, safe, and convenient, while ensuring that the correct dose is always
administered.
3.5. Economic impact
The overall economic impact and cost-effectiveness of introducing prefilled syringes as a replacement for traditional vials
has been evaluated in a variety of clinical settings (Table 4).
Relative to drug administration with a traditional vial and
syringe, prefilled syringes are typically associated with
a higher cost per unit [41,42,56,57,62,63] (Table 4), which
may lead to increased treatment costs. For example, in the
setting of anesthesia, switching from standard ampoules to
commercial ephedrine prefilled syringes was estimated to
increase drug costs by over €50,000 annually in
a retrospective, observational study in 32 operating theaters
[57], and more than double weekly costs (£274.32 vs. £115.72/
week) in a small, retrospective study in the United Kingdom
[62]. The increased unit cost of prefilled syringes represents
a primary barrier to their utilization and widespread provision.
Unlike the higher direct cost per unit versus vials, prefilled
syringes may provide cost savings to the healthcare provider
due to a number of factors. First, with prefilled syringes there
is an expected cost saving due to the elimination of ancillary
equipment required for drug preparation with vial-based
injections, although this was not specifically assessed in the
articles identified in our literature search, so more data are
needed to assess contribution of ancillary supplies to the
budget impact of prefilled syringes. Second, several studies
have shown that prefilled syringes may result in less drug
waste. Wazny et al. [63] conducted a retrospective analysis of
epoetin alfa drug costs for patients in Manitoba, Canada, after
a province-wide switch from multidose vials to administration
using prefilled syringes. Despite a higher unit cost ($15.68 vs.
$14.73/1000 units), the average weekly drug cost per patient
was 6.4% lower with prefilled syringes ($183.23 vs. $195.71).
When extrapolated to the total study population, the annual
cost saving was estimated to be over $500,000, which was
attributed to lower drug wastage with prefilled syringes [63].
Lower costs relative to vials, through a reduction in drug
wastage, were also reported for the use of thiopental prefilled
syringes in one UK hospital (£780 vs. £2036/year) [61], and for
ephedrine prefilled syringes for obstetrical anesthesia (€2.6 vs.
€3.1/patient, over a two week period) [58]. Similarly, a budget
impact analysis by Benhamou et al. [59] revealed that use of
more costly atropine prefilled syringes in French operating
theaters resulted in a potential annual budget saving of over
€5 million (approx. €9 million vs. €14.3 million), which was
attributed in part to a reduction in drug wastage [59]. Third,
the use of prefilled syringes may result in cost savings due to
less nursing time being required. For example, in a French
observational study [60], the use of ephedrine prefilled syringes in a single operating theater reduced overall annual
costs by approximately €2800 and was associated with saved
nursing time, as well as improved safety. Savings in nursing
time were also cited as a main contributor to the 50–70%
reduction in costs reported with the use of heparin prefilled
syringes for the treatment of deep vein thrombosis relative to
traditional IV infusion (£4.80 vs. £9.52–16.81/day) [38], and in
Table 4. Cost of administration by prefilled syringe compared with conventional methods (vial/ampoule).
Cost
Drug/agent
Cost saving
Epoetin alfa
Thiopental
Ephedrine
Ephedrine
Atropine
Heparin
Indication
Hemodialysis
MDV: $14.73
PFS: $15.68
(per 1000 units)
Obstetric anesthesia V&S: £4.79
PFS: £9.00
Obstetric anesthesia Ampoule: €1.1
PFS: €3.4
Emergency
Ampoule: €1.65
medicine
PFS: €3.57
Operating theaters Ampoule:
€0.18–0.28
PFS: €5.50
Deep vein
IV: £9.52–16.81
thrombosis
PFS: £4.80
(per day)
Cost incurring
Anesthesia
Cardiac surgery
a
Unit cost
Ephedrine
Anesthesia
Ephedrine
Anesthesia
Influenza
vaccine
Influenza
vaccine
Influenza
Influenza
Vial: n.r.
PFS: n.r.
Ampoulea: €0.74
PFS: €3.62
Ampoulea: £1.85
PFS: £3.00
MDV: $1.88
PFS: $3.97
MDV: n.r.
PFS n.r.
Conventional treatment/
vial
Prefilled
syringe
Difference
Reference
PFS: $12.48 saving;
$518,519/year
[63]
PFS: £1256
saving/year
PFS: €0.5 saving/patient
[61]
PFS: €0.32–1.22 per patient; ~€2800/
year
PFS: €5,255,304 saving/year
[60]
PFS: £26.21–62.66 saving/patient
[38]
€178
(per anesthetic)
n.r.
PFS: €23 more costly/anesthetic
[56]
PFS: €51,567 more costly/year (32 sites)
[57]
£274.32
(per week)
$4714.20–4931.46
(per 1000 doses)
$8920.21
(per 1000 doses)
PFS: £158.60 more costly/week
[62]
PFS: $708.92–926.18 more costly/1000
doses
PFS: $324.21 more costly/1000 doses
[42]
$195.71
(per patient,
per week)
£2036
(per year)
€3.1
(per patient)
€0.78–1.69
(per patient)
€14,278,648
(per year; including
medication errors)
£50.21–86.66
(per 5-day treatment)
$183.23
(per patient,
per week)
£780
(per year)
€2.6
(per patient)
€0.46–0.47
(per patient)
$9,023,344
(per year; including
medication errors)
£24.00
(per 5-day
treatment)
€155
(per anesthetic)
n.r.
£115.72
(per week)
$4005.28
(per 1000 doses)
$8596.00
(per 1000 doses)
Includes cost of drug, plus diluent, syringe, needle, and/or gauze, as appropriate.
Abbreviations: IV, intravenous; MDV, multi-dose vial; n.r., not reported; PFS, prefilled syringe; V&S, vial and syringe.
[58]
[59]
[41]
EXPERT OPINION ON DRUG DELIVERY
large-scale vaccination programs (25–75% reduction in nursing cost) [41,42]. Finally, prefilled syringes may be associated
with a reduction in medication errors and their associated
costs. This was a key contributing factor to the significant
cost savings (€9 million per year) reported by Benhamou
et al. [59] in their budget impact analysis of atropine prefilled
syringes. Also, a small, prospective study by Webster et al. [56]
discussed that while drug costs for surgical anesthesia delivered using a prefilled syringe-based system were greater than
with conventional methods (€178 [102–428] vs. €155
[111–390], median [range], p = 0.041), the higher cost may
be offset by the expected reduction in number of medication
errors [56].
An additional reported cost associated with prefilled syringes is the increased packaging relative to packaged vials
(approximately 20 times the volume), which necessitates
substantially greater storage capacity and impacts directly
on cost, especially where refrigeration is required [42].
Relative to vials, increased costs associated with prefilled
syringes, which include those contingent on bulkier packaging, have been reported in the setting of large-scale vaccination programs. This is illustrated by findings from
a controlled, comparative study of influenza vaccination in
two Canadian clinics that reported prefilled syringes
increased overall costs by $709–$926, including $260 for
refrigerated storage, per 1000 individuals immunized [42].
Also, a time-motion study in the United States reported
a $324 higher cost (of which $11.4 was attributed to storage) per 1000 immunizations with the use of prefilled
syringes [41]. However, the authors of both studies point
out that the increased costs would be offset by significant
economic savings in a pandemic situation.
Overall, the increased unit cost of prefilled syringes should
not alone be a deterrent to their introduction as an alternative
drug delivery option. Cost effectiveness and cost savings can
be achieved. Several factors may influence this, including the
clinical setting, scale of need, and expected benefits from the
introduction of prefilled syringes. Importantly, the reduced risk
of human dosing errors and drug contamination relative to
reconstitution from vials may provide considerable benefit,
both in terms of cost and patient well-being.
1205
using a tip-to-tip connector) in case prefilled syringes do not
match infusion pump requirements. Instructions highlighting
the differences between the two methods could be valuable for
patients switching to prefilled syringes from vial-based administration. Patients should work with their physicians to determine
the best way to make dose adjustments using prefilled syringes
(e.g. combining multiple syringes).
In most cases, fewer steps will be required for administration with prefilled syringes, which could simplify teaching and
increase ease of use for patients [71–73], factors that are likely
to have a positive impact on adherence and patient satisfaction with treatment. With a simpler infusion option for
patients and a decreased number of follow-ups, this is likely
to impact less on nurses’ time, allowing nurses to assist in
other areas of their place of work.
5. Considerations for use of prefilled syringes for
IgG replacement therapy
Medications provided in traditional vials require manual handling to prepare the drug for injection using a separate syringe.
In the setting of SCIG self-administration, patients may be
required to pool multiple vials or draw up IgG into a larger
syringe prior to use with a pump. These tasks require confidence and dexterity and may be difficult for some patients,
especially the young and elderly. Furthermore, IgRT is indicated in patients with secondary immunodeficiency diseases
and other conditions, such as the autoimmune neuropathy
chronic inflammatory demyelinating polyneuropathy, the
manifestations of which may compromise dexterity. Prefilled
syringes, in contrast, are easier to hold and eliminate the
manual handling associated with drug preparation, simplifying
the administration process, and requiring fewer supplies. As
such, training patients in self-administration by prefilled syringe is also simplified. These factors are important considerations when a significant number of patients requiring IgRT will
opt for home-based self-administration. A large number of
patients indeed appear to opt for this form of administration,
with data from the United Kingdom and Sweden showing
approximately 80% of newly diagnosed patients opting for
home-based IgRT [7].
6. Conclusion
4. Role of education and training
While the studies discussed above present data on different
aspects of drug administration using prefilled syringes, no
studies were identified that specifically investigated the role
of patient education and training in this area. In general,
however, there is good evidence in the literature to support
the overall importance of patient education, particularly in the
context of treatment adherence [69,70].
The training required for administration using prefilled syringes will likely show similarities to existing training for vial-based
products, as several steps required to perform the infusion (e.g.
identifying and cleaning a suitable infusion site) will be identical.
Specific differences would include the omission of steps such as
transferring fluid from vials to syringes and the inclusion of
instructions for performing syringe-to-syringe transfers (e.g.,
Administration of medications by prefilled syringe is an established and important treatment option that can offer significant advantages over the more traditional treatment
administration methods (Table 1). Recently, there has been
significant growth in the availability and use of prefilled syringes across a broad spectrum of clinical settings. This growth
is predicted to continue and accelerate. While the literature
describing direct clinical comparisons with traditional vial and
syringe is not extensive, evidence from studies investigating
a variety of drugs indicate that drug stability, efficacy, and
safety are maintained when administered by prefilled syringe.
Also, and despite potential cost implications in some settings,
prefilled syringes require less drug preparation and nursing
time, and may reduce drug-dosing errors. Moreover, clinical
experience with prefilled syringes indicates they are preferred
1206
A. R. KAFAL ET AL.
by patients, physicians, and nurses as an acceptable, convenient, easy to use administration system. Ultimately, this has the
potential to improve patient satisfaction, independence, and
quality of life. We anticipate that the benefits of prefilled
syringes will also apply for patients who require IgRT.
7. Expert opinion
The perceived benefits of prefilled syringes compared with
conventional administration methods are generally well established. In addition to device characteristics such as accurate
dosing, sterility, and reduced contamination risk, prefilled syringes reduce treatment time and offer patients greater choice,
convenience, and ease-of-use. Our review of the available
evidence encompasses a variety of therapeutic indications
describing clinical experience with prefilled syringes and supports this consensus. It was noteworthy, however, that despite
their widespread clinical use we found a limited number of
clinical studies in the literature reporting direct comparisons of
prefilled syringes with more conventional administration
approaches (e.g. vial and syringe).
For patients requiring IgRT, SC administration has improved
available treatment options (Figure 2). SCIG is a safe and welltolerated alternative to IVIG with comparable efficacy.
However, improvements can be made. Advances are needed
to widen the accessibility of SCIG as a treatment option in
patients who may find SC administration by traditional vial
and syringe challenging. Supported by their widespread use in
other clinical settings, the introduction of prefilled syringes
represents an attractive alternative to the vial-based packaging for SCIG therapy. This is an important step toward the
goal of individualized IgRT treatment regimens that can be
tailored according to individual patient circumstances, with
the goal of enhancing quality of life.
Of significance, reductions in medication errors and drug
wastage were reported with prefilled syringes. This is important
for patients and healthcare providers alike. For the latter, these
reductions have implications for overall costs and on the decision-making process for the provision of treatment in the prefilled syringe format. In our opinion, the higher unit cost of
prefilled syringes (relative to vials) is mostly responsible for the
widely held belief that treatments administered via prefilled
syringes are more expensive than conventional approaches.
While cost is a key consideration and may be a barrier to
more widespread introduction of prefilled syringes, unit cost
of prefilled syringes continues to fall with increasing demand.
Moreover, evidence from various clinical settings outlined here
demonstrates that the introduction of prefilled syringes cannot
only be cost effective, but cost saving. However, this is not the
case for all clinical settings examined and serves to illustrate the
need for robust cost-effectiveness studies on a case-by-case
level to convince healthcare providers and payers of the
added value provided by prefilled syringes, such as SC IgRT.
Studies identified in this review show that drugs delivered
by prefilled syringe are comparable with those delivered by
conventional administration methods for parameters such as
stability, pharmacokinetics, efficacy, and safety. Indeed, this is
mandated by regulatory agencies before approval of alternative devices for drug delivery/administration. One of the key
factors supporting the use of prefilled syringes for treatment
administration is the perceived impact on the drug delivery
process. We found evidence from a variety of clinical settings
confirming the anticipated reductions in drug preparation/
treatment time with prefilled syringes. Notably, this included
significant savings in nursing time, and associated cost benefits. Studies evaluating SCIG will be needed to confirm that
such savings can be achieved in IgRT. From the stability data
for monoclonal antibodies [19,22,25], the use of prefilled syringes was not detrimental to the shelf life of these products.
Similarly, current data suggest prefilled SCIG syringes have the
same shelf-life as the vial-based product (e.g. IgPro20 has
a shelf life of 30 months at 20–25°C in both vials and prefilled
syringes) [74]. The similar stability and increased convenience
of prefilled syringes represents a significant advantage for Ig
therapy, allowing patients increased convenience regarding
their therapy.
The lack of studies investigating the impact of prefilled syringes specifically on health-related quality of life was unexpected. Rather, the studies we identified in our search were
concerned more with patient/physician experience with prefilled
syringes. Health-related quality of life has previously been investigated in the context of IVIG and SCIG therapy for IgRT; improvements in several important aspects have been observed for
home-based SCIG, relative to hospital-based IVIG. This supports
steps, for example the introduction of prefilled syringes that can
help make SCIG more widely accessible. A simpler IgRT infusion
method could benefit patients with low dexterity and help
patients administer this at home, reducing time spent at hospital.
This could also result in fewer patient follow-ups with nurses,
leading to reduced healthcare costs. There is a need, therefore,
Figure 2. An example of a dosing regimen for PI switching from IVIG to SCIG based on a 1:1 dose conversion ratio.
A 60 kg patient currently on 24 g IVIG (0.4 g/kg) every four weeks equating to an infusion volume of 240 mL. A conversion rate of 1.37 should be applied when converting from IVIG to SCIG
in the United States.*SCIG dose can be adjusted based on clinical response and serum IgG trough levels.†Volumes should be rounded to the nearest available syringe size or combination of
syringes.
Abbreviations: IVIG: intravenous immunoglobulin; PI: primary immunodeficiency; SCIG: subcutaneous immunoglobulin.
EXPERT OPINION ON DRUG DELIVERY
for robust studies evaluating health-related quality of life relating
to the use of prefilled syringes in SCIG. The outcomes of such
studies, and further developments in the area of SC administration, will be of significant interest.
Moving forward, we envisage continued and significant growth
in the availability of prefilled syringes for an increasing number of
treatments and therapeutic areas. The past few years alone has
seen the introduction of many new entrants in the prefilled syringe
market. In part, this will be driven by the growing demand for, and
importance placed on, patient choice that is evident across the
whole healthcare sector. Convenience, in particular, is also becoming a key attribute of treatments; this is what patients are asking for
and can help to improve independence, satisfaction and quality of
life. Such improvements are also likely to foster a positive impact
on patient adherence.
Funding
The authors were supported by CSL Behring LLC. DC Vinh was supported
by a salary award as Clinician-scientist research scholar from the Fonds de
recherche du Québec–Santé (FRQS). Editorial assistance was provided by
Meridian HealthComms Ltd., funded by CSL Behring.
Declaration of interest
AR Kafal is an employee of CSL Behring LLC. DC Vinh has served as an
advisory board member for CSL Behring Canada, Astellas Canada, and
Shire Canada; has received research support from CSL Behring Canada;
and has received clinical trial support from CSL Behring Canada, Shire, and
Cidara. MJ Langelier has served as an advisory board member for CSL
Behring Canada. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in
or financial conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.
Reviewer disclosures
A reviewer on this manuscript has disclosed that they are a consultant for
evolve, Korean Green Cross, Shire; an investigator for evolve, Korean Green
Cross, Shire, Prometic, Octapharma, CSL Behring. Another reviewer on this
manuscript has disclosed that they received an investigation grant from
Grifols and a travel grant from CSL, LFB, biotest.
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