Interets Et Limites De La Substitution Par Des Seringues Pre-Remplies (S2p) Des Ampoules Et Flacons

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GLEIZE (CC BY-NC-ND 2.0) UNIVERSITE CLAUDE BERNARD – LYON 1 FACULTE DE PHARMACIE INSTITUT DES SCIENCES PHARMACEUTIQUES ET BIOLOGIQES

2016 THESE n°79

T H E S E

pour le DIPLOME D'ETAT DE DOCTEUR EN PHARMACIE

présentée et soutenue publiquement le 21 juillet 2016

par

M. GLEIZE Jean-Cédric

Né le 13 janvier 1989

A Lyon

*****

INTERETS ET LIMITES DE LA SUBSTITUTION PAR DES SERINGUES PRE-REMPLIES (S2P) DES AMPOULES ET FLACONS

ADVANTAGES AND LIMITS OF THE VIAL TO PREFILL (V2P) STRATEGY

*****

JURY

M. HARTMANN Daniel, Professeur

Mme. SCHWARZENBACH Florence, Docteur en pharmacie

Mme. CORNU Catherine, Praticien Hospitalier

GLEIZE (CC BY-NC-ND 2.0)

GLEIZE (CC BY-NC-ND 2.0) REMERCIEMENTS

À la directrice de cette thèse, le Dr. Florence Schwarzenbach, pour m’avoir accueilli dans son équipe et dans la grande entreprise internationale qu’est BD. Merci d’avoir accepté d’encadrer mon travail de thèse d’exercice. Merci pour la confiance que tu m’as accordé et pour tous tes précieux conseils, suggestions et anecdotes professionnelles.

Au Pr. Daniel Hartmann pour m’avoir fait l’honneur de présider le jury de cette thèse.

Merci pour l’intérêt que vous avez porté à mes travaux, pour votre aide et votre confiance.

Au Dr. Catherine Cornu de m’avoir fait l’honneur de faire partie du jury de cette thèse. J’espère que vous serez captivé par ce manuscrit qui marque la fin de mes études de pharmacie ainsi que le prolongement de mon master Eudipharm.

À mes collaborateurs de BD, à Grenoble ou à Franklin Lakes, en particuliers à

Orchidée Filipe Santos, Sophia Li et Steven Ren sans qui ces travaux n’auraient pas aboutis, mais également à tous les membres des Affaires Médicales et des Affaires Réglementaires pour leur bonne humeur et leur gentillesse.

Au Dr Catherine Leger et à Muriel avec qui j’ai travaillé et évolué pendant deux ans de mes études à la Pharmacie Saint-Louis.

Aux membres du CRCL pour leur aide, leurs conseils et leur bonne humeur.

GLEIZE (CC BY-NC-ND 2.0) Aux membres de PLH avec qui j’ai commencé ma vie associative et humanitaire de la plus belle manière.

Aux anciens et aux nouveaux d’XLR Events, fruit de l’amour d’une poignée de futurs pharmaciens pour la musique électronique.

À tous mes camarades de pharmacie, du master Eudipharm et du master GBCP mais

également de médecine et d’odontologie. Je ne pourrais pas tous vous citer tellement j’ai eu la chance de faire tant de belles rencontres pendant ces neufs années d’études ! À tous ceux que j’espère recroiser le plus souvent possible et à ceux que je continuerai à fréquenter, je l’espère, toute ma vie.

J’en place également une spéciale pour mes amis depuis bientôt 15 ans.

À ma famille et en particulier mes parents qui m’ont façonné et qui m’ont permis de devenir l‘homme que je suis aujourd’hui. Merci d’avoir fait en sorte que je ne manque de rien et merci de m’avoir soutenu et poussé pendant toutes ces années et jusqu’à l’achèvement de cette thèse.

À ma sœur qui a finalement fini ses études quelques semaines avant moi… Merci d’avance pour toutes les saveurs que tu me feras découvrir.

Enfin, à Marion. Quel que soit mon futur parcours professionnel, t’avoir rencontré restera la plus belle raison pour moi d’avoir fait des études de pharmacie. Merci pour 7

GLEIZE (CC BY-NC-ND 2.0) l’amour que tu me portes chaque jour ainsi que pour ton soutien sans faille, notamment pendant la rédaction de cette thèse.

GLEIZE (CC BY-NC-ND 2.0)

GLEIZE (CC BY-NC-ND 2.0) TABLE DES MATIERES

REMERCIEMENTS ...... 6

TABLE DES MATIERES ...... 10

LISTE DES FIGURES ...... 12

LISTE DES TABLEAUX ...... 13

LISTE DES ABRÉVIATIONS ...... 14

1. INTRODUCTION ...... 16

2. CLINICAL AND INDUSTRIAL CONTEXT ...... 22

2.1. INDUSTRIAL CONTEXT ...... 22

2.1.1. Expected impacts of V2P ...... 23

2.1.1.1. For BD ...... 23

2.1.1.2. For pharmaceutical laboratories ...... 24

2.1.1.3. For the buyers ...... 26

2.1.1.4. For the users...... 27

2.1.1.5. For the patients ...... 28

2.2. INJECTION ...... 29

2.2.1. The different routes of injection ...... 30

2.2.2. The different injectable formulations...... 34

2.2.3. The different injecting users ...... 36

2.2.4. The different injection devices and packaging ...... 37

GLEIZE (CC BY-NC-ND 2.0) 2.2.5. Regulatory considerations for prefilled syringes ...... 42

3. METHODS ...... 45

4. RESULTS ...... 47

4.1. SELECTED STUDIES ...... 47

4.2. SAFETY ASPECTS ...... 52

4.2.1. Contaminations ...... 52

4.2.1.1. Micro-organisms ...... 52

4.2.1.2. Particles ...... 59

4.2.2. Medical errors ...... 64

4.2.3. Needle-stick injuries ...... 71

4.2.4. Other safety considerations ...... 73

4.3. EFFICACY ...... 74

4.4 WORKFLOW ...... 76

4.5. HEALTH ECONOMICS ...... 78

4.5.1. Costs of medical errors ...... 78

4.5.2. Comprehensive unit price ...... 81

5. DISCUSSION ...... 88

6. CONCLUSION ...... 91

BIBLIOGRAPHIE ...... 95

ANNEXE I: ETUDES INCLUES DANS LA META-ANALYSE ...... 105

GLEIZE (CC BY-NC-ND 2.0) LISTE DES FIGURES

Figure 1: Photo d’une Syrette ...... 18 Figure 2: Photo du Tubex...... 19 Figure 3: The different players of the injection process...... 23 Figure 4: Example of dead space showing in red the remaining fluid after complete depression of the plunger. Bobashev, 2010...... 26 Figure 5: BD Uniject prefillable syringe components ...... 41 Figure 6: Meta-analysis study selection flowchart...... 48 Figure 7: Review study selection flowchart...... 49 Figure 8: Meta-analysis quality assessment summary (Cochrane Collaboration’s tool for assessing risk of bias)...... 51 Figure 9. Identification of glass particles in intravenous infusions by Scanning Electron Microscopy Coupled to Energy Dispersion Spectroscopy, Yorioka 2006...... 60 Figure 10: SEM images of vials and PFS after exposure to PH 11 gutaric acid at 40°C/75% relative humidity for 3 months. Zhao 2014...... 63 Figure 11: Forrest plot comparing dose consistency...... 68 Figure 12: Ishikawa’s diagram illustrating the steps of the medication process with their associated failure modes and the influence of V2P. Adapted from De Giorgi, 2010. . 70 Figure 13: Forrest plot comparing efficacy...... 74 Figure 14: Forest plot comparing procedure time...... 77 Figure 15: The 10 safety tools are laid out in four quadrants, according to yearly costs to gain 1 quali per day and total quali gained per day. De Giorgi, 2010...... 80

GLEIZE (CC BY-NC-ND 2.0) LISTE DES TABLEAUX

Table 1: AANA Position Statement Summary...... 55 Table 2. Mean (Range) of Particles/ml in In-Use Various Intravenous Infusion. Adapted from Yorioka 2006...... 62 Table 3: Number and percentage of syringes labels meeting standard for each criteria ...... 66 Table 4: Comparative frequencies of Needle-stick Injuries from six study hospitals, Llewellyn, 1994...... 72 Table 5: Costs associated with vaccination using multidose vials and prefilled syringes in 2009 in the USA. Pereira 2010...... 84 Table 6: Consumption and costs of the different packaging. Translated from Bellefleur 2009...... 85 Table 7: Consumption and costs of the different packaging. Translated from Cregut- Corbaton 2013...... 86 Table 8: Cost comparison of daily reconstitution with prefilled syringes. Murdoch 2012...... 87

GLEIZE (CC BY-NC-ND 2.0) LISTE DES ABRÉVIATIONS

AANA American Association of Nurse Anesthetist

ABE Accidental Blood Exposure

AUC Area Under Curve

B2B Business to Buisiness

BD Becton Dickinson

BDM-PS Becton Dickinson Medical - Pharmaceutical Systems

CDC Centers for Disease Control and Prevention

CDER Center for Drug Evaluation and Research

CDRH Center for Devices and Radiological Health

CFR Code of Federal Regulations cGMP current Good Manufacturing Practices

FDA Food and Drug Administration

FMECA Failure Modes, Effects and Criticality Analysis

GCP Good Clinical Practice

HBV Hepatitis B Virus

HCV Hepatitis C Virus

HCW Healthcare Worker

HIV Human Immunodeficiency Virus

ICU Intensive Care Unit

IFU Instruction For Use

IM Intramuscular

GLEIZE (CC BY-NC-ND 2.0) ISO International Organization for Standardization

IV Intravenous

MDV Multi-Dose Vial

NSI Needle Stick Injuries

OR Odd Ratio

PFS Prefilled Syringe (see SPR)

PICO Population, Intervention, Comparator, Results (ou Population, Intervention, Comparateur, Résultat)

PMOA Primary Mode Of Action

QS Quality System

RCT Randomized Control Trial

RFD Request for Designation

S2P Substitution par des Seringues Pré-remplies (voir V2P)

SEM Scanning Electron Microscope

SPR Seringue Pré-remplie (voir PFS)

USA United States of America

USP United States Pharmacopeia

V2P Vial to Prefill (see S2P)

WHO World Health Organisation

GLEIZE (CC BY-NC-ND 2.0) 1. INTRODUCTION

Becton Dickinson (BD) est une des principales entreprises mondiales spécialisées

dans les technologies médicales. Elle développe, fabrique et commercialise une large

gamme de dispositifs médicaux, de systèmes d’instruments, de réactifs et de

consommables à usage médical et scientifique, au travers de trois segments : BD Medical,

BD Diagnostic et BD Biosciences.

Les travaux présentés dans cette thèse ont été menés pour le segment BD Medical

qui a pour but d’apporter des solutions innovantes afin d’enrayer la propagation des

infections, développer les modes d’administration de médicaments et améliorer les

traitements. BD Medical est l'un des principaux fournisseurs mondiaux de matériel médical

et un des leaders en termes d'innovation dans le domaine des systèmes d'administration

de médicaments par injection ou perfusion. En particulier, la division BD Medical –

Pharmaceutical Systems (BDM-PS) conçoit, fabrique et commercialise des systèmes

d'administration de médicaments notamment des seringues pré-remplies (SPR), des

systèmes d’auto-injection ainsi que des systèmes de sécurité protégeant les aiguilles après

utilisation.

Salvatore Turco and Robert E. King ont proposé une histoire détaillée des

médicaments parentéraux et de l’utilisation des SPR [1]. Un résumé historique est présenté

ici afin de comprendre les origines de la technologie en question. L’idée même d’injecter

GLEIZE (CC BY-NC-ND 2.0) des médicaments a émergé de l’observation des morsures de serpents et de l’acquisition de connaissances sur la circulation sanguine telle qu’établie par William Harvey au début du XVIIe siècle [1,2]. Lors des 100 premières années, des expérimentations ont été conduites, notamment par Christopher Wren, pour tenter d’administrer des antalgiques à des chiens et des humains en utilisant des outils grossiers, des drogues impures et des solutions non stériles. Bien que certains sujets aient pu survivre à l’expérience, la plupart n’ont surement pas eu cette chance du fait de la méconnaissance des particules et des micro-organismes [1]. Malgré tout, la lutte contre la douleur et la découverte du principe de vaccination ont créé un besoin et une incitation au développement du procédé d’injection. Lors de la Seconde Guerre Mondiale, la nécessité d’avoir un conditionnement facilement transportable sur le champ de bataille et permettant une administration facile et rapide contre la douleur a mené à la création des premiers systèmes pré-remplis dont la

Syrette, l’Ampin et le Tubex [1]. La Syrette (Figure 1) était constituée d’une aiguille fixée à un tube en métal flexible hermétique. L’aiguille était d’abord insérée à travers la peau du patient puis une pression était appliquée sur le tube en métal afin d’injecter le médicament

[1].

GLEIZE (CC BY-NC-ND 2.0)

Figure 1: Photo d’une Syrette

De la même façon, l’Ampin était constitué d’une aiguille fixée à une ampoule en verre. Cette approche permettait au médicament de s’écouler dans les tissus du patient sans application de pression [1]. Enfin, Le Tubex (Figure 2) était constitué d’une aiguille fixée

à une cartouche en verre. La cartouche était insérée dans un réceptacle réutilisable en acier

équipé d’un piston en métal utilisé pour appuyer sur le bouchon de la cartouche et ainsi injecter la solution [1].

Jusqu’aux années 1980, la SPR était vue comme un produit de niche relativement insignifiant [3]. Sanofi et Rhône Poulenc-Rorer ont introduit la SPR pour l’héparine et popularisé cette méthode d'administration [3].

GLEIZE (CC BY-NC-ND 2.0)

Figure 2: Photo du Tubex

L’injection est l’un des gestes médicaux les plus courants. Chaque année, plus de 16 milliards d’injections sont administrées dans le monde [4,5]. Parmi elles, 2 à 2,7 milliards ont été administrées grâce à des SPR en 2009 [6,7], représentant un marché générant 2.5 milliards de dollars de bénéfices en 2009. Plus de 50 médicaments injectables étaient alors disponibles en seringues pré-remplies, représentant plus de 50 milliards de dollars de chiffre d’affaire [8,9]. Des estimations plus récentes suggèrent que le marché global des

GLEIZE (CC BY-NC-ND 2.0) SPR est susceptible d’atteindre 6.9 milliards de dollars de vente en 2018, avec un taux de croissance annuel composé de 13.8% entre 2012 et 2018 [10]. Actuellement le marché de la SPR est dominé par les seringues en verre. Cependant, si les seringues en plastique ne représentaient que 0.5% du marché des SPR en 2012, une hausse de leur part de marché est attendue avec le développement de polymères offrants de meilleurs profils d’extraction et de relargage que les seringues en verre [10]. Il est ainsi estimé que le marché des seringues en plastique va connaitre un taux de croissance annuel composé de 25% entre

2013 et 2019 [11].

L’objet de ces travaux est d’identifier de façon précise et étayée, les avantages et inconvénients de la Substitution par des Seringues Pré-remplies (S2P), des ampoules et flacons, mono- ou multi-doses. L’objectif est tout d’abord d’évaluer les impacts sur la sécurité et la santé des patients et des personnels de santé, ce qui comprend notamment les problèmes de contamination et de conformité des doses. Les impacts économiques seront également évalués depuis l’aspect microscopique du prix unitaire jusqu’aux aspects macroscopiques de l’économie de la santé, en passant par le gain de temps pour chaque injections. Enfin, divers facteurs influençant la faisabilité de cette substitution seront abordés, comme la stabilité et l’interaction contenant-contenu, la facilité d’emploi ou le stockage. Notre étude se fera pour les injections dans un cadre médical, c’est-à-dire par des professionnels de santé ou des volontaires formés pour des campagnes de vaccination.

GLEIZE (CC BY-NC-ND 2.0) Nous excluons ainsi les injections effectuées par le patient lui-même ou par un proche. En effet, l’objectif de ces travaux est de mesurer les impacts de la stratégie de S2P. Or, les ampoules et flacons ne sont déjà plus utilisés dans le cadre de l’auto-injection : ce sont des seringues ou des stylos pré-remplies qui sont prescrits, permettant une utilisation plus simple de la part du patient et ainsi une plus grande sécurité d’injection. A chaque fois les différentes pratiques médicales et les différents systèmes de santé seront pris en compte lorsque cela sera pertinent.

Ces travaux s’inscrivent dans la volonté de BD de développer et promouvoir des solutions répondants aux réalités cliniques et économiques afin de poursuivre sa mission :

«Aider chacun à vivre en bonne santé».

GLEIZE (CC BY-NC-ND 2.0) 2. CLINICAL AND INDUSTRIAL CONTEXT

2.1. INDUSTRIAL CONTEXT

At first, the reader might question what pushes BD, a medical device manufacturer

performing in a business to business (B2B) environment, to look into such a general

question. Why not leave it to public health professionals or to other players of the injection

process. This is explained particularly by the diversity of those players.

As shown in Figure 3, we can consider the pharmaceutical company which develops

a drug or a vaccine intended for parenteral administration as the first link of the chain. It

then has the choice of the packaging, whether it is only responsible for the integrity of the

drug like a vial or an ampoule, or whether it must also assume the injecting function. It is in

this second case that a company such as BD Medical has a role to play. The next player is

the buyer which will differ depending on the regarded healthcare system. It could be a

hospital or more precisely its pharmacy or a public health insurance or private insurance

company. It could also be a public body such as a state or a local authority, particularly in

the case of vaccination campaigns. Finally, the two last players are the injection provider –

the one who actually performs the injection – and the patient. It may be the same person

in the eventuality of auto-injection but as explained above, this case is out of the scope of

our study.

GLEIZE (CC BY-NC-ND 2.0)

Figure 3: The different players of the injection process.

The effects of V2P for these different players are on the whole expected as PFS have

been commercialized for decades. These effects must nonetheless be verified and

quantified in order to convince each player of the interest of this substitution by presenting

an extensive overview of the matter.

2.1.1. Expected impacts of V2P

2.1.1.1. For BD

The V2P strategy falls for BD within its determination to innovate. This fulfills BD’s

objective: “Advancing the world of health”, through two of the core values of BD. First of all

“We do what is right”, by being committed to the highest standards of excellence and

integrity while keeping in mind the patient’s safety. Secondly “We innovate and improve

continuously” through development, manufacturing and commercialization of products

and services adapted to the current clinical needs and superior to our previous product and

to those of the competition. The purpose of this work, as the purpose of BD values is to 23

GLEIZE (CC BY-NC-ND 2.0) enable a better patient care, because “there is a patient at the end of everything we do”. It

is crucial for BD to promote V2P in order to convince its clients, the pharmaceutical

companies, of the overall benefits of using PFS despite a higher unit price compared to vials

and ampoules.

2.1.1.2. For pharmaceutical laboratories

The pharmaceutical laboratories are the clients of BDM-PS division in the B2B

system. Therefore, the business counterpart is not the patient or the health care worker

but a pharmaceutical company who wishes to sell a ready for use medication packaged in a

PFS. It becomes then a combination product, defined here as at least two distinct products

conditioned together in a same packaging or as a whole and consisting of a drug and a

medical device, a biological product and a medical device or a drug and a biological product

[12]. V2P will enable pharmaceutical companies to offer higher efficacy and higher safety

for drug injections. It will also lead to a unit price rise, however, health agency consider PFS

as a packaging item and therefore do not give value to its advantages. Consequently, the

V2P won’t lead to a reevaluation of the selling price or the reimbursement rate. The

increase of unit cost represents thus a margin decline. This leads at first sight to a

competitive disadvantage and might end up in a limitation of the sales volume. This is why

it is paramount to convince this player of the clinical advantages and also the economic

advantages of PFS so he can make the choice of V2P and in turn convince his own clients.

GLEIZE (CC BY-NC-ND 2.0) This transition towards PFS will however necessitate adaptation on the part of the industrial.

The production lines will have to be modified or even replaced to be compatible with the ready to be filled syringes and therefore will have to be subsequently (re)qualified.

Of note, there is a possibility of vertical integration by the laboratory. This means the pharmaceutical laboratory will develop both the drug and the injection device which enables him to control every elements of the final product. This implies the mastery of technical and regulatory know-how specific to medical devices as the packaging do not only have the function to protect the integrity of the drug anymore but must also carry out a safe and efficient injection. This case mostly occurs when the sales volume is important as for disposable insulin pens developed by Lilly or Novo Nordisk.

All these changes represent considerable investments for the laboratories which emphasize once again the necessity to build a strong case in order to convince them of the value of the process. These investments however, can be offset by direct savings linked to the reduction of overfill. Overfill is the practice consisting in filling the injectable drug container by a volume slightly superior to the volume indicated on the label. This overfill is necessary for every container of device in order to compensate their dead spaces. For conventional syringes as for PFS, the dead space is the volume of liquid remaining in the syringe hub and the needle after complete depression of the plunger as illustrated in Figure

4 [13]. Overfill is also applied for vials and ampoules. Indeed, it is practically impossible to

GLEIZE (CC BY-NC-ND 2.0) draw 100% of the liquid contained in a vial or ampoule and the excess volume must allow

the user to draw and administer the dose indicated on the label [14]. The use of PFS does

not completely eliminate the drug losses linked to overfill but still allows their reduction. It

cancels the losses linked to overfill of vials and ampoules and, to a lesser degree, the losses

linked to the dead space of needles used to prepare injection. This can have a significant

economic impact when the molecule price is high as it is the case for biotechnological drugs

for example.

Figure 4: Example of dead space (circled): the remaining fluid after complete

depression of the plunger. Bobashev, 2010.

2.1.1.3. For the buyers

The buyers represent the most diverse players’ category. Depending on the

considered healthcare system and the healthcare facility, the buyer will either be the 26

GLEIZE (CC BY-NC-ND 2.0) department where the injections are performed, the hospital pharmacy, a state or a local

public body in the context of vaccination campaign, or an insurance organism, private or

public. This diversity leads to a great difference of sensitivity to the multiple arguments of

V2P. The buyers will have in common their great consciousness to any increase of the unit

cost of PFS compared to vials or ampoules. Depending on its proximity to the users (for

example if it is the hospital pharmacy or if it is the department itself) the buyer will be more

or less concerned with the effects of V2P on the users. If the buyer is a larger organism such

as an insurance system or a state, it will be more affected by the public health outcomes

linked to the reduction of medical errors and the related health economics fallout. The

work presented in this thesis is very important to produce precise arguments in order to

convince the players and especially the buyers of the advantages of V2P as they will not be

directly concerned by their effect except the by the increase of the unit price.

2.1.1.4. For the users

The users are the one who will actually use the PFS, i.e. the one who will perform

the injection. In the framework of our study the users are healthcare professionals: nurses,

anesthetists, physicians and midwives but also lay caregivers from the local community, and

trained for specific acts, for example as part of a vaccination campaign in remote districts.

The expected effects of V2P for users mainly stem from the reduction of preparation steps.

This can translate into a time gain for each injection yielding savings in terms of nursing time

GLEIZE (CC BY-NC-ND 2.0) or more efficient vaccination campaigns due to higher injection rate. The elimination of

preparation steps also leads to less syringe manipulation and therefore can lead to less risk

of needle stick injuries (NSI). At first sight, this reduction would only concern NSI happening

before the injection, which means NSI that do not carry the risk of blood-borne pathogen

transmission. V2P could also bring out for the user some problem linked to storage which

may well appear mundane but which could still limit the use of PFS. PFS are packaged in

longer and bigger boxes than vials or ampoules. The storage volume augmentation can

quickly be a problem, especially if the drug necessitates a refrigerated storage. The longer

package can also pose a problem of incompatibility with some medicine trolleys.

2.1.1.5. For the patients

The ultimate player to be impacted by V2P is the patient. It is the patient who must

stay at the center of the pharmaceutical industry members’ focus, and particularly at the

center of the industrial pharmacist’s focus. The expected effects of V2P for the patient are

a greater safety and a better efficacy of injections. The reduction of preparation steps is

supposed to lead to a diminution of the contamination risk. This also alleviates the risk of

preparation errors and therefore diminishes the risk of overdose (toxicity) or underdose

(inefficiency) due to discrepancies between prescribed doses and injected doses.

The aim of this work is to collect reliable data in the literature in order to confirm or

infirm and if possible quantify the expected effects of V2P for each player, while considering

GLEIZE (CC BY-NC-ND 2.0) the specificities of each healthcare systems. The thus highlighted arguments will represent

the basis for the promotion of V2P to each player by allowing a global and solid presentation.

The identification of issues for which the data found in the literature is insufficient will pave

the way for the realization of studies (clinical, economical…) in order to answer those issues.

2.2. INJECTION

The World Health Organization (WHO) thus defines injection: “In medical care, an

injection is the introduction of a drug, vaccine, contraceptive or other therapeutic agent

into the body using a needle and syringe” [15].

Parenteral administrations enable a precise control of doses, bypass the gastro-

intestinal tract which eliminates the influence of the gastric juice and of the first-pass effect,

enable drug administration when oral administration is impossible and allow a strict control

of observance. However, parenteral administrations are associated with pain and carry a

risk of infection: for the patient in case of insufficient disinfection or reuse of the injection

equipment, for the healthcare worker in case of needle-stick injury (NSI) and finally to the

community in case of poor collection and disposal of the used injection equipment.

An injection requires the puncture of the skin to a sufficient depth depending on the

target of the injection. Injections follow a parenteral route of administration, namely a

GLEIZE (CC BY-NC-ND 2.0) route other than through the gastro-intestinal tract. Injections can either be intended to

have a systemic effect or a loco-regional effect.

2.2.1. The different routes of injection

As defined by the Center for Drug Evaluation and Research (CDER, part of the Food

and Drug Administration (FDA)), the systemic parenteral routes include [16]:

 Subcutaneous, administration beneath the skin; hypodermic. Synonymous with the term

subdermal (SC).

Subcutaneous administration has a number of advantages compared to the

intravenous route. These include: ease of administration, low incidence of infection, little

pain or discomfort, and minimal medical intervention. Two types of subcutaneous injections

must be distinguished: direct subcutaneous injection and subcutaneous infusion. In the

direct subcutaneous injection, the injected volume is limited (1 to 2ml in general and up to

5ml) [17]. Furthermore, the resorption rate is variable and depends on local factors such as

sclerosis and circulatory state (vasodilatation, vasoconstriction). Among the drugs most

often administered by subcutaneous injection are insulin and heparin. Regarding the

subcutaneous infusion, the rate of administration is generally less than 125ml/hr provided

that the total daily volume does not exceed 2-3 liters in 24 hours [18,19]. The main

indication of subcutaneous infusion is dehydration with administration of isotonic solution

such as 0.9% normal saline or 4% glucose in 0.18% saline. 30

GLEIZE (CC BY-NC-ND 2.0)  Intramuscular, administration within a muscle (IM).

While the rich irrigation of the muscle allows for a quick diffusion of the drug in the

bloodstream, it is more painful. Depending on the injection site, the maximum injection

volume in adult patients is between 2 to 5mL [20]. It is possible to inject aqueous or oily

solutions. There are sustained-release preparations which release the drug progressively

from the point of injection such as the Depo-Provera (Depot medroxyprogesterone acetate)

which is a hormonal contraceptive birth control drug that is injected every twelve weeks.

Intramuscular injection must not be performed in a blood vessel or in contact with a nerve.

It is contra-indicated for patients undergoing an anticoagulant therapy.

 Intravenous, administration within or into a vein or veins (IV).

Intravenous administration can be performed directly (with a syringe) or indirectly

(with an infusion set and a catheter instead of a needle). Infusions are done when the

volume to be injected is high, extending the duration of the procedure. Viscous solutions

cannot be administered using this route. The intravenous route can be superficial, usually

placed in the arm (peripheral venous access) or deep (central venous access), usually placed

in the neck (internal jugular vein), chest (subclavian vein or axillary vein) or groin (femoral

vein). The bioavailability is by definition 100%. However, the rate of administration is crucial:

if the administration is too quick, by direct injection with a syringe for example, there is a

risk of possibly dramatic adverse reactions. It can be the case with propofol which in case 31

GLEIZE (CC BY-NC-ND 2.0) of rapid injection can lead to respiratory depression and apnea [21]. On the other hand, a

too slow infusion can be insufficient to attain an effective therapeutic blood concentration.

 Intra-arterial, administration within an artery or arteries (I-ARTER).

It is seldom used. Examples of intra-arterial administration include vasodilator drugs

for the treatment of arteritis and vasospasm, thrombolytic drugs for the treatment of

embolism or certain chemotherapies for the treatment of localized cancer.

 Intradermal, administration within the dermis (I-DERMAL).

The dermis is a connective tissue constitutive of the skin with the epidermis. It is

composed of protein-type macromolecules (collagen fibrils, elastin and fibronectins),

mucopolysaccharides and diverse type of cells such as fibroblasts (cells participating in the

synthesis of the macromolecules) and cells of the immune system (lymphocytes,

mastocytes and macrophages). The immune system cells are the one of interest for intra-

dermis procedure such as diagnostic tests like the tuberculin skin test, as well as some

preventive vaccines (such as the flu vaccine Intanza®). Therapeutically vaccines (such as

melanoma [22], non-small cell lung cancer [23], hepatocellular carcinoma [24], pancreatic

cancer [25], brain cancer [26], renal cell carcinoma [27], breast cancer [28], ovarian cancer

[29], prostate cancer [30], non-Hodgkins lymphoma [31], B-cell lymphoma [32] and

GLEIZE (CC BY-NC-ND 2.0) tolerance induction (such as gluten tolerance in celiac disease (Nexvax2) or repeated low-

dose allergen [33] are also in development.

The loco-regional parenteral routes are used for the introduction of a diagnostic

drug such as contrast medium or therapeutic drug such as analgesic or antibiotic and

include:

 Intra-articular, administration within a joint (I-ARTIC).

 Intra-cardiac, administration with the heart chambers (I-CARDI).

 Intrathecal, administration within the cerebrospinal fluid at any level of the cerebrospinal

axis, including injection into the cerebral ventricles (IT).

 Intra-peritoneal, administration within the peritoneal cavity (I-PERITON).

 Intra-vesical, administration within the bladder (I-VESIC).

 Intra-ocular, administration within the eye (I-OCUL).

 Intra-corpuscavernosum, administration within the dilatable spaces of the corporus

cavernosa of the penis (I-CORPOR). (Of note: intra-cavernous is also often used but actually

refers to an administration within a pathologic cavity, such as occurs in the lung in

tuberculosis, according to the CDER).

 Intra-medullary, administration within the marrow cavity of a bone (I-MEDUL).

GLEIZE (CC BY-NC-ND 2.0) It is important to note that loco-regional parenteral routes can also have some

limited systemic effects by diffusion through the capillaries or the lymphatic system to the

blood compartment.

2.2.2. The different injectable formulations

In order to be injected, a parenteral preparation must be sterile and minimally

irritating.

Parenteral preparations are sterile preparations intended to be injected, perfused

or implanted in the body. They are prepared with a specific methodology designed to

prevent the introduction of biological or physical contaminants, the presence of pyrogenic

elements and the growth of micro-organisms. They can necessitate the use of specific

excipients to guarantee isotonic properties with the blood, to adjust the pH or to increase

solubility. Injection products can be formulated as dry powders or lyophilized cakes which

must be reconstituted with a suitable diluent before administration. Some parenteral

preparations such as vaccines must be refrigerated until they are administered in order to

maintain stability and to preserve efficacy.

According to the European Pharmacopeia, parenteral preparations are divided in 5

categories:

GLEIZE (CC BY-NC-ND 2.0)  Injections are sterile solutions, emulsions or suspensions. They are prepared by dissolving,

emulsifying or suspending the active substance(s) and any added excipients in water, in a

suitable non-aqueous liquid, or in a mixture of these vehicles. They can be presented in

single-dose or multi-dose containers. Multi-dose preparation will contain antimicrobial

preservatives, as well as aqueous preparations which are prepared using aseptic

precautions and which cannot be terminally sterilized.

 Infusions are sterile, aqueous solutions or emulsions with water as the continuous phase.

They are usually made isotonic with respect to the blood. They are principally intended for

administration in large volume. Infusions do not contain any added antimicrobial

preservative.

 Powders for injections or infusions are solid, sterile substances distributed in their final

containers and which, when shaken with the prescribed volume of a prescribed sterile liquid

rapidly form either clear and practically particle-free solutions or uniform suspensions. After

dissolution or suspension, they comply with the requirements for injections or for infusions.

Freeze-dried products for parenteral use are considered as powders for injections or

infusions.

 Gels for injections are sterile gels with a viscosity suitable to guarantee a modified release

of the active substance(s) at the site of injection.

GLEIZE (CC BY-NC-ND 2.0)  Implants are sterile, solid preparations of a size and shape suitable for parenteral

implantation and release of the active substance(s) over an extended period of time. Each

dose is provided in a sterile container.

2.2.3. The different injecting users

For parenteral administration, the user is the person who performs the injection, by

opposition to the patient who receives it and who is the one affected by the therapeutic

benefits or the adverse reactions. The user can be a healthcare worker (HCW: nurse,

anesthetist, doctor, midwife or pharmacist) or a lay worker who were trained specifically to

perform injections as part of a vaccination campaign in a specific community. The user can

also be the patient himself or a relative who is referred to as a caregiver. Those person

should also be trained but they often rely heavily on the instruction for use provided with

the injection device. Auto-injection (or self-injection) is the term used when the patient

himself performs the injection. This can be done with a regular syringe or with a specific

device such as an auto-injection pen.

In our study we focus on injections performed in a healthcare setting which means

injection performed by a HCW or by a lay worker specifically trained. Auto-injections and

injections performed by a relative are out of our scope. Indeed such injections are already

quite exclusively performed using prefilled devices (syringes, auto-injectors…).

GLEIZE (CC BY-NC-ND 2.0) 2.2.4. The different injection devices and packaging

The injection device purpose is to enable a safe and effective injection or infusion of

the correct amount of drug at the right location (within a blood vessel, at the correct skin

depth, within the right compartment). The location of the injection will determine the

choice of the appropriate needle, considering its length and gauge. The bevel can also vary

and will affect the pain perceived at injection. The packaging purpose is to protect the drug

from its manufacture until its injection by guaranteeing its sterility and stability. For

conventional presentations, the packaging (ampoules, vials) is different from the injection

device (syringes, needles). On the other hand, the PFS acts both as a packaging and an

injection device. All products prepared for parenteral administration must be designed to

enable the user to visually inspect the drug prior to the injection. This is stressed in the case

of powders in order to check their complete dissolution or suspension. However, it is a

requirement for every parenteral drug, notably because it is possible for particulate matter

to be present in the final product, often from the rubber bung of the vial shedding material

when punctured by a needle.

GLEIZE (CC BY-NC-ND 2.0) There is a great variety of equipment for injected drugs which fulfill, as we saw,

different missions:

 Packaging o Ampoule: a mono-dose sealed glass capsule. The tip of the capsule must be broken off to

open the ampoule. o Vial: a glass container with a metal-enclosed rubber seal. The liquid is drawn with a needle

through the rubber seal. It can either be mono or multi-dose. o infusion bag: plastic bag with a port protected by a cap to connect the infusion line.

Frequently, a second port with a rubber seal is present to allow injection of additives in the

bag.

 Injection Devices o Syringe: A syringe is a simple pump consisting of a plunger that fits tightly in a tube. It is

either made of glass or plastic. The tip is designed to form a leak-free connection with a

needle or an infusion line, usually through a standard Luer taper. There are two varieties

of Luer taper: Luer-lock where both parts are locked in position by screwing them and Luer-

slip where both parts are simply pressed together and held by friction. o Hypodermic needle: hollow needle with a defined length, gauge and bevel depending on

the site of injection.

GLEIZE (CC BY-NC-ND 2.0) o Catheter: usually a cannula-over-needle device, with a flexible plastic cannula comes

mounted over a metal trocar. The trocar is used to insert the cannula into the vein and is

then withdrawn and discarded. The catheter possesses a connecting hub for a syringe or an

infusion line. o Infusion line: plastic tube connecting an infusion bag with a catheter or a needle, often fitted

with a drip chamber which prevents air from entering the blood stream (air embolism), and

allows an estimation of flow rate.

The first way to perform an injection is to use a syringe and needle(s) to draw the

drug and potentially the diluent from a vial, ampoule or infusion bag before connecting the

syringe to an appropriate injection system (needle, catheter, infusion line) depending on

the targeted route.

There is a second way involving equipment acting both as a packaging and an

injection device, namely a PFS: a plastic or glass syringe filled in advance with a defined dose

of drug and sold ready to use. The PFS can be fitted with a fixed needle or with a Luer taper

to be connected with an appropriate injection system, which is often sold in the same

packaging.

GLEIZE (CC BY-NC-ND 2.0) Of note, another way was explored: the Jet injector. It is a device that uses a high-pressure narrow jet of the injection liquid instead of a hypodermic needle to penetrate the epidermis.

It is powered by compressed air or gas or by a spring. Jet injectors are especially interesting for use in mass-vaccination because they are supposed to be used safely and efficiently for multiple patients. However, because the jet injector breaks the skin barrier, there is a potential of biological material being transferred from one patient to the next therefore, the WHO no longer recommends jet injectors for vaccination due to risks of disease transmission [34].

The devices in our scope will be on one hand the syringe and needle used with vials and ampoules which can be referred as the conventional systems, and on the other hand the prefilled syringe as well as UnijectTM (Figure 5: BD Uniject prefillable syringe components ) which, notwithstanding the design, can be considered as a PFS with regards to its intended use.

GLEIZE (CC BY-NC-ND 2.0)

Figure 5: BD Uniject prefillable syringe components

Pens and patch injectors, while being combination products both protecting and injecting the drug are not considered in our study as they are intended for auto-injection.

Infusion bags are also out of our scope because their indication is different than that of syringes or PFS. Finally, jet injectors were not considered as they carry a risk of spreading pathogens between patients and their use is as such not recommended by the WHO anymore [34].

GLEIZE (CC BY-NC-ND 2.0) 2.2.5. Regulatory considerations for prefilled syringes

Prefilled syringes can be considered as a combination product, associating a drug

and a medical device in a single packaging unit. This is defined in the United States of

America (USA) by the Code of Federal Regulations (CFR), precisely in 21 CFR 3.2(e) |12]. The

term combination product includes: “A product comprised of two or more regulated

components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that

are physically, chemically, or otherwise combined or mixed and produced as a single entity”

which includes PFS. Of note, combination products also include separate products packaged

together in a single package or products packaged separately but intended for use only with

one another. To determine which FDA center has jurisdiction on the product, the Primary

Mode Of Action (PMOA) must be determined. The PMOA is the therapeutic action that is

expected to make the greatest contribution to the overall intended therapeutic effect of

the combination product. In the case of prefilled syringes, the POMA is the injection drug,

which means the Center for Drug Evaluation and Research (CDER) should have the lead on

PFS regulation, rather than the Center for Devices and Radiological Health (CDRH).

According to 21 CFR 3.7, the company has to ask for the classification of his product through

a Request for Designation (RFD) submitted to the Office of Combination Products. The RFD

is based on the PMOA, the similarity to other regulated products and the Center with most

experience or expertise.

GLEIZE (CC BY-NC-ND 2.0) The PMOA of PFS usually result in a CDER lead which means the company has to apply for a New Drug Application or Biologic License Application and not a Pre Market

Approval or a 510K premarket notification required for medical devices.

In the French Code de la Santé Publique, there is no definition for combination product yet. However, Art. R. 5211-2 clarifies the subject: “Medical devices intended for the administration of a drug are regulated by the medical devices section. However, when a medical device form with a drug an integrated product intended exclusively to be used within the given association and not reusable, this product is regulated by the clauses applicable to drugs. The device is compliant with the essential requirements of security and performance for medical devices.”

The integrated product mentioned above falls into the USA’s CFR definition of a combination product although it is not defined here as a specific category. The French Code de la Santé Publique only stipulates that such products must follow both medical device regulations and drug regulations.

In the USA, combination products are defined and regulated by the law but there are currently no specific current Good Manufacturing Practices or Quality System regulations (cGMPs/QS) for combination products. Both sets of cGMP/QS regulations apply: part 820 as the combination product includes a device constituent part and parts 210 and

GLEIZE (CC BY-NC-ND 2.0) 211 when a drug constituent part is included or parts 600 through 680 when a biological product constituent part is included [35].

Concerning the Vial to Prefill strategy (V2P) as such, the USA’s Food and Drug

Administration (FDA) requires that any change in the manufacture of a drug product, whether major or minor, be put into place only after the license holder assesses the effect of the change on the identity, strength, quality, purity, and potency of the molecule, because these factors will influence the safety and effectiveness of the pharmaceutical [36].

In addition, FDA has stringent requirements for changes that may affect parenteral drug product. These requirements pertain to moving a therapeutic to a prefilled syringe from another container, and changes in the size or shape of a container that holds a sterile drug product [37]. Any such change is considered to be “major” by FDA and must be documented in a prior approval supplement. Stability and clinical testing for parenteral drugs depend on a multitude of factors, including the formulation, indication, mode of administration, size and functionality of packaging, and the introduction of new materials. Any potential need for clinical or stability data must be noted and planned for at the outset, and included in the stability protocol [38].

GLEIZE (CC BY-NC-ND 2.0) 3. METHODS

In 2009, a review on the same subject was undertaken on behalf of BDM-PS. As our

study is both an update and an original work, the search strategy was initially based on the

one used in 2009, focusing only on the documents published since then. However, this

strategy, based on different independent strings of key words used in PubMed Medline as

well as targeted journals was not considered exhaustive enough, especially as it did not

include interesting references found in other PFS studies. A new search strategy was

therefore created. This strategy was based on the PICO process (Population, Intervention,

Comparator, Results), using Medical Subject Headings (MeSH) terms: the population was

left out because the disease or age group was not relevant, the intervention was PFS, the

comparators was syringes and injections in general and the outcomes were medication

errors, economics, time and safety. This new search was performed in PubMed Medline as

well as EbscoHost databases (most notably Academic Search Complete and Health

Economic Evaluations Database). The limitation to studies published since 2009 was hold to

keep relevant articles only – the injection practices tend to evolve quite quickly – and to

keep the number of studies manageable. However, when relevant, older references cited

in the extracted literature or in previous BD work were also included. The review was

designed to include a wide range of document types (randomized control trials, reviews,

time and motion studies, case-control studies, WHO and competent authorities’ statement)

to capture as much evidence as possible. In order to generate more robust and statistically 45

GLEIZE (CC BY-NC-ND 2.0) significant results, a meta-analysis was undertaken with a search strategy derived from the review’s strategy by limiting the results to Randomized Controlled Trials (RCTs) only as per the Cochrane Handbook recommendations.

Independently for the review and the meta-analysis, the duplicates were searched for and the studies were then screened based on their title and abstract before being analyzed in full text in a second phase. The reasons for exclusion were population (e.g. injection drug users), intervention (e.g. auto-injection) and outcome (e.g. prescription errors or molecule related adverse drug reactions). For the review, the study design was not a reason for exclusion in the title/abstract part. The case-report studies were however rarely used in the final analysis as they are not necessarily representative of the whole population. The case-report studies were still kept in the database and may be used in the future to illustrate typical errors and help identify the therapeutic classes presenting major risks. For the meta-analysis, the study design was a reason for exclusion as it is focused on

RCTs.

A quality assessment was done in both cases. For the review it was adapted from the Quality Assessment Tool for Quantitative Studies of the Effective Public Health Practice

Project to comprehend study designs other than RCTs. For the meta-analysis, the Risk of

Bias Assessment Tool of the Cochrane Collaboration was used.

GLEIZE (CC BY-NC-ND 2.0) 4. RESULTS

4.1. SELECTED STUDIES

For the meta-analysis, 291 studies were extracted from the databases, 222 were

screened based on title and abstract, 16 were analyzed in full text and 8 studies were finally

included. This is summarized by Figure 6: Meta-analysis study selection flowchart. The

studies included in the meta-analysis are referenced in annex I. For the review, 965 studies

were extracted from the databases and the selected journals, 725 were screened based on

title and abstract, 273 were analyzed in full text and 40 were finally included. Nine other

studies published before 2009 but still essential were included from a previous work done

by BD. This is summarized by Figure 7.

GLEIZE (CC BY-NC-ND 2.0)

Figure 6: Meta-analysis study selection flowchart.

GLEIZE (CC BY-NC-ND 2.0)

Figure 7: Review study selection flowchart.

GLEIZE (CC BY-NC-ND 2.0) The quality assessment for the meta-analysis is shown in Figure 8. For one article

(Llewellyn et al.) [39], the randomization method was not disclosed resulting in an unclear risk. The blinding of participants was not possible as standard and prefilled syringes do not look exactly the same, especially for nurses which were, for most endpoints, the actual study subjects. However, one article (Sundy et al.) [40] was actually a sub-group analysis of a placebo-controlled RCT performed to evaluate efficacy in subgroups using standard and prefilled syringes. As the original objective of the study was not focused on the injection method but on the molecule, the nurses were not influenced in a way or another, reducing the risk of bias, hence the unclear risk instead of high risk. Two other studies (Adapa et al. and Moreira et al.) [41,42] were simulated studies in which the participants did not know the objectives and therefore should not have been influenced either. The blinding of outcome assessment was also complicated due to the nature of the comparison. However, for biologic (Area Under Curve, AUC) or chemical (concentration) endpoints the assessment was done by a blinded operator for three studies (Sundy et al. Adapa et al. and Talbot et al.)

[40, 41, 43] resulting in a low risk.

GLEIZE (CC BY-NC-ND 2.0)

Figure 8: Meta-analysis quality assessment summary (Cochrane Collaboration’s tool for assessing risk of bias). 51

GLEIZE (CC BY-NC-ND 2.0) 4.2. SAFETY ASPECTS

The security aspects regroup elements threatening the health integrity of the

patient or of the HCW. This includes contaminations of the drug or the medical device and

medical errors in general which impacts the patient, as well as NSIs which is a threat for

HCWs.

4.2.1. Contaminations

4.2.1.1. Micro-organisms

Microbial contamination can occur during the preparation steps, originating from

the HCW and/or the environment, or at the administration steps, associated to cross-

contaminations between patients and usually due to unsafe practices.

A literature review performed in 2000 yielded a rate of microbiologic contamination

of injectable preparations ranging from 6.3% to 31.6% in French hospitals [44]. Propofol

was especially pointed out: as it lacks conservatives, the ampoules were contaminated

near-systematically upon opening by the nurse. Two studies, one in France, one in United

Kingdom, demonstrated that 8% of 0.9% sodium chloride syringes, manually prepared by

nurses in the wards, were contaminated [45, 46]. The source of contamination appeared to

be from hand contact with the filling equipment in the uncontrolled ward environment [45]

or from failure to disinfect the external surface of the saline ampoules prior to opening [46].

GLEIZE (CC BY-NC-ND 2.0) The combined influence of the environment and manipulations by the HCW was exposed in Stucki et al. study [47]. By collecting and testing unused syringes containing compounded sterile preparations in their operating rooms they observed a 0.5% rate of contamination which suggested that two syringes prepared in their hospital could be contaminated every day. This observation led to an investigation of the sources and probability of potential contamination by simulating syringe-filling operations in three common hospital environments. Five milliliters of sterile trypticase soy broth were withdrawn from 100mL vials in a 10mL syringe. Five milliliters of filtered air were aseptically added to support potential aerobic growth and the syringes were incubated for 14 days according to United States Pharmacopeia (USP) recommendations. Syringes were prepared in three different environments: an International Organization for Standardization (ISO) class 5 horizontal laminar-airflow hood in an ISO class 6 cleanroom, an ISO class 7 drug preparation area of an operating room, and an uncontrolled decentralized pharmacy in a ward. For each environment, syringes were prepared employing four common high-risk manipulations (air introduced into syringe, syringe without cap, syringe tip in contact with fingers and syringe tip in contact with object) as well as a simple control filling. Of the 1500 syringes prepared in three different environments, none produced within the cleanroom contained microorganisms, 6% were contaminated in the operating room, and 16% were contaminated in the ward (p < 0.0001). This study shows that contamination of parenteral preparations is a significant risk which is influenced by manipulation errors and the 53

GLEIZE (CC BY-NC-ND 2.0) environment. As shown in the results, the use of prefilled syringes may be useful for preventing bacterial contamination of parenteral preparation during preparation steps.

Regarding specifically the preparation steps, Ninomiya et al. evaluated the aseptic efficacy of prefilled syringes compared with ampoules in a polluted environment similar to a disaster site [48]. Consistent with a disaster setting, the authors tested epinephrine, atropine sulfate, lidocaine hydrochloride, sodium bicarbonate and glucose solutions. Each of these solutions in 10 PFS and 10 ampoules were placed in a box of contaminated soil

(dust created by collapsed buildings and smoke from fire) along with needles and empty syringes for the ampoules. Each of them was prepared in the box, by connecting the needle and the syringe and by filling the syringe when using ampoules. All syringes were then checked for bacterial contamination. No bacterium were found in any of the PFS while in the case of ampoules, 6 of the 10 samples containing epinephrine, 9 of the 10 containing atropine sulfate and all of the samples for the other drugs tested positive for bacteria. A statistically significant difference was observed between the PFS and ampoule for each tested drug which indicates that, in environments with airborne contaminants, the use of prefilled syringes may be useful for preventing bacterial contamination of parenteral preparation.

GLEIZE (CC BY-NC-ND 2.0) Another source of microbial contamination is the reuse of injection equipment.

Contrary to medical errors, these unsafe practices represent a clear violation of the best clinical practices. Reuse of injection equipment was responsible in 2000 of 21 million hepatitis B virus (HBV) infections (32% of new HBV infections), 2 million hepatitis C virus

(HCV) infections (40% of new HCV infections) and 260 000 human immunodeficiency virus

(HIV) infections (5% of new HIV infections) [49]. The American Association of Nurse

Anesthetist (AANA) issued a list of rules addressing this problem in their position statement number 2.13 (Table 1) [50].

Table 1: AANA Position Statement Summary

• Never administer medications from the same syringe to multiple patients • Never reuse a needle even if on the same patient • Never refill a syringe once it has been used, even for the same patient • Never use infusion or IV administration sets on more than one patient • Never reuse a syringe or needle to withdraw medication for a multi-dose vial • Never re-enter a single use medication vial

According to the WHO, the major cause of widespread unsterile injection practices is an insufficient supply of syringes and needles, which is why these practices are more often found in developing countries. Directly or indirectly, the community is also at risk of these transmissible infections as, in many instances, the used equipment is reused, sold, or

GLEIZE (CC BY-NC-ND 2.0) recycled because of its commercial value as well as being subject to unsafe health care waste management.

In 1990, a study was conducted in to evaluate whether vials used several times were containing at least traces of blood [51]. They sampled vials used in anesthesia with multiple uses, and the comparative group was made of single-use vials. The authors identified that

11/492 (2.24%) multiple-use vials tested were positive for blood, as opposed to 1/369 (0.3%) for single dose vials. Therefore, they concluded by recommending to change not only the needle but also the syringe between each patient and this is now part of the good clinical practice (GCP).

The non-compliance to the GCP for injection procedures is a major source of cross- contamination between patients, in developing countries as well as in developed countries.

In developing countries, the shortage in the supply of disposable syringes and needle is often mentioned [52] and the lack of education is also responsible. In India, a study showed that only 22.5% of injections were administered with a sterile syringe and needle.

The authors pointed that while the level of knowledge about HIV and HBV transmission by unsafe injections was satisfactory amongst prescribers and community it was inadequate amongst providers (i.e. the people actually performing the injections) [53]. A self- administered questionnaire in five China provinces showed that among 180 vaccinators

(ranging from chief doctors to lay workers), 1.1 to 6.7% in each province were reusing a 56

GLEIZE (CC BY-NC-ND 2.0) disposable syringe and 0 to 1.7% were reusing a disposable needle [54]. Regarding reusable syringes and needle, 0.6 to 4.4% of users were using an insufficient sterilization method such as soaking them in hot water or wiping them with alcohol-soaked cotton [54].

In developed countries, shortage of supplies is hardly a problem, yet outbreaks of infection are still linked to unsafe injection practices. In January 2008, 8 persons were contaminated with HCV following endoscopy procedure in the same clinic [55]. Two source patients were identified. Of 49 HCV-susceptible persons whose procedures followed that of the first source patient, 1 (2%) was HCV infected. Among 38 HCV-susceptible persons whose procedures followed that of the second source patient, 7 (18%) were HCV infected. Reuse of syringes on single patients in conjunction with use of single-use propofol vials for multiple patients was observed during normal clinic operations. The resulting public health notification of ∼50,000 persons was the largest of its kind in United States (USA) health care

[55]. Between 2001 and 2011, 35 patient notification events were related to unsafe injection practices in the USA, resulting in an estimated total of 130,198 patients notified.

Among the identified notification events, 74% occurred since 2007, including the 4 largest events (> 5000 patients per event). The primary reason identified (≥16 events; 44%) was syringe reuse to access shared medications (eg, single-dose or multidose vials). Twenty-two

(63%) notifications stemmed from the identification of viral hepatitis transmission, whereas

13 (37%) were prompted by the discovery of unsafe injection practices, without evidence

GLEIZE (CC BY-NC-ND 2.0) of bloodborne pathogen transmission [56]. Medications that were commonly implicated

included anesthesia medications, such as propofol (7 notification events) and fentanyl

(mainly in the context of narcotics diversion), saline flush solutions, and various infusion

therapies containing vitamins or chelating agents [56]. HCV is not the only micro-organism

which can be transmitted this way: in 2012, two outbreaks of Staphylococcus aureus

infection were identified in American outpatient clinics involving hospitalization of 10

patients and one death, where single-dose preservative-free vials were used for multiple

patients [57].

To alleviate the problem of unsafe practices, education of HCWs is paramount.

However, it has not yielded complete and acceptable results yet as shown in an American

Nurses Association study of 2013 in which 325 nurses demonstrated suboptimal adherence

to clinical best practices [58]:

 4% administered medication from same syringe to multiple patients

 18% had reused a needle on the same patient

 82% had refilled used syringes

 49% had re-entered a single-use vial to prepare doses for multiple patients.

The use of PFS could efficiently avoid such cross-contaminations due to reuse of

contaminated injection material. PFS are more and more recognized as a solution to this

public health problem such as S. Paparella has written in the Journal of Emergency Nursing: 58

GLEIZE (CC BY-NC-ND 2.0) “Ideally, prefilled syringes should be used whenever possible for flushing intravenous sites

and ports to avoid the risk of using a contaminated flush bag or vial.” [59] However, PFS are

often not fitted with auto-disable features. This leaves the possibility for someone to reuse

the PFS as a normal syringe to draw and inject another drug. As this is counter-intuitive, it

would have to be in a context of poor education and/or injection device shortage: i.e.

developing countries. Fitting PFS with auto-disable features for such countries should

therefore be considered, especially if the V2P strategy lead to the replacement of auto-

disable conventional syringes.

4.2.1.2. Particles

Parenteral drugs might be contaminated by glass particles, originating from the

breakage of the ampoule’s neck or from a delamination of the inner surface of the glass

vessel. Despite their small size (a few µm as illustrated in Figure 9. Identification of glass

particles in intravenous infusions by Scanning Electron Microscopy Coupled to Energy

Dispersion Spectroscopy, Yorioka 2006.Figure 9Error! Reference source not found.), glass

particles injected by IV route can cause phlebitis and give damage to the lungs, brain, kidney,

liver and spleen, and injected by IM route can cause pain, bleeding or hematoma formation,

acute inflammatory induration and transient nodules [60, 61]. Glass particles are

especially an issue in case of intrathecal/epidural administration [62].

GLEIZE (CC BY-NC-ND 2.0)

Figure 9. Identification of glass particles in intravenous infusions by Scanning

Electron Microscopy Coupled to Energy Dispersion Spectroscopy, Yorioka 2006.

Yorioka et al. [60] evaluated the particulate contamination in 6 types of peripheral infusions (electrolyte solutions admixed with potassium chloride from a glass ampoule or a

PFS, electrolyte solutions admixed with sodium chloride from a glass ampoule or a PFS, electrolyte solution admixed with dobutamine hydrochloride from 3 ampoules and diluted

GLEIZE (CC BY-NC-ND 2.0) dobutamine hydrochloride in a PFS) for a total of 300 samples. As controls, particulate contamination of these electrolyte solutions was also examined. The size and number of particles were measured using a light blockage particle counter. The number of particles was compared according to the particle size (≥1.3µm, ≥5µm, ≥10µm, ≥50µm).

As shown in Table 2, the number of particles ≥1.3mm in diameter was significantly higher in fluids admixed with potassium chloride in a glass ampoule than those admixed with this drug in a PFS (p<0.0001). The number of particles ≥1.3mm in diameter was significantly higher in fluids admixed with sodium chloride in a glass ampoule than those admixed with this drug in a PFS (p<0.0001). The number of particles ≥1.3mm in diameter was estimated to be higher in fluids admixed with dobutamine hydrochloride in glass ampoules than in those admixed with this drug in pre-filled syringes. Since dobutamine hydrochloride in PFS is administered using a syringe pump, the recovery of residual solutions of administration was judged difficult, and sealed products were examined instead, explaining the absence of statistical comparison between dobutamine hydrochloride preparations.

GLEIZE (CC BY-NC-ND 2.0) Table 2. Mean (Range) of Particles/ml in In-Use Various Intravenous Infusion.

Adapted from Yorioka 2006.

Another source of glass particles in parenteral formulations is glass delamination, which is the release of glass flakes or lamellae from the surface of the glass container. This is a problem known to be found in vials which was shown to increase with terminal sterilization and increased pH and sulfate treatment vials [63]. Moreover, glass delamination is known to take place at the heel section, bottom, and shoulder area of vials where the high temperatures during the formation process may leave residual internal stresses [64]. Zhao et al. [65] compared vials and PFS performance by inspecting the inner surface topography using a scanning electron microscope, before and after storage of pH

7.5 NaCl-phosphate buffer at 40°C for 1 month or after a 3 month exposure to pH 11 glutaric acid solution at 40°C. Glutaric acid solution at high pH has previously been shown to delaminate glass vials under similar conditions [66]. Defects were observed on the vials surface before exposition to glutaric acid while PFS showed a much smoother surface. After

GLEIZE (CC BY-NC-ND 2.0) exposure to glutaric acid (Figure 10), vials from Vendor A displayed the largest pits. Vials from Vendor B showed much smaller pits, though the number of pits was larger. A smooth surface was observed for PFS by scanning electron microscope (SEM).

Figure 10: SEM images of vials and PFS after exposure to pH 11 gutaric acid at

40°C/75% relative humidity for 3 months. Zhao 2014.

In conclusion, for glass particles contamination which occurs on opening single-dose glass ampoules, the use of PFS can avoid this issue altogether. As shown above, PFS are also less prone to glass delamination. In the end, the V2P leads to less glass particle contamination and therefore present a specific interest for drugs administrated intrathecally.

GLEIZE (CC BY-NC-ND 2.0) 4.2.2. Medical errors

The awareness of medical errors’ major role in adverse events occurrence abruptly

appeared following the publication of the American study “To err is human” in 2000, which

brought to light both the very high amount of these errors as well as the importance of the

consequences in terms of public health [67]. A very recent study claims that medical error

is the third leading cause of death in the USA, after heart disease and cancer [68]. By

analyzing medical death rate data from studies between 2000 and 2008, the authors have

extrapolated that over 250,000 deaths per year stemmed from a medical error, which

represents 9.5% of all deaths annually in the USA. While it is difficult to estimate the exact

burden of medical errors, let alone the fraction which can be attributed to errors linked to

injections, these numbers go to show the importance of fighting medical errors.

Medical errors can be seen as deviation from the 5 rights of medication

administration (right patient, drug, dose, route, and time) and can have consequences

ranging from delayed or less efficient treatment to serious toxic effects and death [69].

Concerning the time of administration, the use of PFS has no influence on the

adherence to the prescribed posology. It can however lead to a quicker administration as

shown in the Workflow results section but this is out of the scope of medical errors and will

be discussed below.

GLEIZE (CC BY-NC-ND 2.0) Concerning the exactness of patient, drug and route, the use of PFS may lead to a better labeling and therefore can help avoiding these errors. A study on 149 syringes containing midazolam, insulin, norepinephrine, dopamine, potassium or magnesium prepared in a critical care unit showed that only a minority, 40.9% (61/149), were labeled entirely correctly according to the criteria listed in Table 3: Number and percentage of syringes labels meeting standard for each criteria . Out of the 11 errors listed by the authors,

9 could be prevented by the use of PFS. The drug name, amount of drug, concentration, identity of diluent and date and time of production has to be stated on the PFS with an acceptable level of legibility as stated in the cGMP [70]. The preparer’s initials and the countersignature is no longer needed for PFS. The information related to the patient (name and location) may still be necessary to add on the PFS. This means in this study, 178 labeling errors out of the 182 recorded (97.8%) could be prevented by the use of PFS.

GLEIZE (CC BY-NC-ND 2.0) Table 3: Number and percentage of syringes labels meeting standard for each criteria

The Joint Commission Medication Manufacturing Standards, as part of its third goal that aims to improve the safety of using medications, states that only oral unit-dose products, PFSs, or premixed infusion bags should be used when available [71]. Similarly, the

Institute for Safe Medication Practices offers recommendations toward prevention of error related to suboptimal syringe labeling and recommends the use of commercially available,

PFSs already labeled used when possible [72]. Additional authors and government bodies recommend supplying anesthetic drugs for intravenous use in PFSs rather than ampules [73,

74]. Anesthesia is the only area where medications are typically prescribed, prepared, administered, and recorded by a single individual (an anesthesiologist or anesthetist)

GLEIZE (CC BY-NC-ND 2.0) without any other health professional to check or monitor the process. This fact increases the risk to patients of an error [73].

The last type of medical error is dose error. The meta-analysis points out two randomized controlled studies [41, 42] addressing dosing errors. The nurses were presented with an emergency situation in a simulated clinical environment with an adult mannequin (Adapa et al.) [41] or a child or infant mannequin depending on the scenario

(Moreira et al.) [42]. The nurses were required to prepare and inject a norepinephrine injection followed by an epinephrine injection (Adapa et al.) [41] or were given an emergency scenario with a variety of drugs to choose from: Atropine, Epinephrine,

Midazolam, Fentanyl, Succinylcholine, Ketamine, Lidocaine, Rocuronium and Etomidate

(Moreira et al.) [42]. After the exercise, the syringes and PFS were collected and the concentration of the remaining drugs was determined. The dose consistency was expressed as the percentage of syringes meeting USP standards (i.e. +/- 10% of variation). As shown in Figure 11, the use of PFS clearly leads to a better dose consistency (Odds Ratio (OR) 9.13

[4.30, 19.38]) with a low heterogeneity (I²=0%). This is especially true when looking a PFS versus syringes prepared at the bedside. Adapa et al. also measured the dose concentration of syringes prepared in advance by a physician in the ward, or prepared by the hospital pharmacy. In these cases, while PFS seem to achieve better dose consistency, the difference is not statistically significant [41].

GLEIZE (CC BY-NC-ND 2.0)

Figure 11: Forrest plot comparing dose consistency.

The use of PFS suppresses the preparation steps which are particularly prone to errors. A cross-sectional study was carried out in the United Kingdom in which validated numerical and drug calculation tests were given to 229 second year nursing students and

44 registered nurses [75]. The objective was to assess drug calculation ability of nursing students and registered nurses. The study found that the numeracy test was failed (<60% score) by 55% of the students (median score 57%) and 45% of the registered nurses (median score 63%), while 92% of students (median score 35%) and 89% of registered nurses

(median score 40%) failed the drug calculation test. The results were even worse when only looking the drug calculation test subpart “drug percentages and infusion rates”, in which

97% of the students (median score 0%) and 95% of registered nurses (median score 6%) failed. Such calculation errors can lead to dramatic accidents as in a 2004 infamous French

GLEIZE (CC BY-NC-ND 2.0) case where confusion between the mentions “1% 1ml” and “10mg/ml” ended in a fatal dose error (100 times the prescribed dose) for the young patient [76].

Medical errors are the fruit of a complex process involving multiple steps, some of which may be influenced by the V2P. Figure 12 summarize the steps of the medication process for injectable drugs and their associated failure mode. In green are the failure modes which are prevented by the use of PFS. The hatched green boxes represent failure modes which may be prevented by PFS in some case, due to a better and more legible labeling of PFS. In orange are the failure modes which represent a higher risk with PFS. This is the case for “wrong volume injected”. The number of PFS with different dosage for one given drug is limited. Therefore a physician might prescribe an intermediate dose which necessitates the injection of only a fraction of a PFS. If the nurse forgets to empty partially the PFS before injection, there will be a risk of overdose. The hatched orange boxes represent failure modes which may represent a higher risk. The introduction of air is not a problem only for PFS. However, as PFS are viewed as “ready-to-use” the nurse might forget to purge the syringe before injection. Air bubble of PFS was reported as a potential issue in patients with foramen ovale [77]. It is reported that up to 35% of patients have undiagnosed foramen ovale, making systemic emboli a distinct possibility, particularly in unstable cardiovascular conditions. However, the volume of air required for significant cerebral or

GLEIZE (CC BY-NC-ND 2.0) coronary emboli is not known, and no report of gas embolism due to a lack of purge of an air bubble was identified in the literature review performed.

Figure 12: Ishikawa’s diagram illustrating the steps of the medication process with their associated failure modes and the influence of V2P. Adapted from De Giorgi, 2010.

GLEIZE (CC BY-NC-ND 2.0) 4.2.3. Needle-stick injuries

All safety aspects of injection do not concern the patients. Needle-stick injuries (NSI)

carry serious risks of accidental blood exposure (ABE) for HCW. The WHO reports that of

the 35 million health-care workers worldwide, 2 million experience percutaneous exposure

to infectious diseases each year [78]. It further notes that 37.6% of Hepatitis B, 39% of

Hepatitis C and 4.4% of HIV in Health-Care Workers around the world are due to NSI.

The possible outcome for a HCW of a NSI will be different whether it happens before

or after the injection. In pre-injection NSI, the HCW will only suffer a minor wound caused

by a sterile instrument or an exposure to a negligible quantity of drug. However, in case of

post-injection NSI, the HCW will risk an ABE. The post-infection NSI are therefore the most

critical ones. The use of PFS should definitely alleviate the risk of pre-injection NSI as there

will be no preparation required anymore. However, the post-injection NSI should not be

reduce, except if the PFS is equipped with a safety needle shielding feature. As such features

can also be associated to detached needles, this is not a differentiating factor.

A study [39] compared the frequency of NSIs in 6 hospitals over a 6-month period

between Carpuject® and conventional systems. Carpuject® is a cartridge-needle unit which

must be loaded in a holder equipped with a plunger before injection. While Carpuject® is

not a PFS strictly speaking, its mode of operation is very similar and it eliminates most of

the preparation steps as a PFS would. As shown in Table 4Error! Reference source not

GLEIZE (CC BY-NC-ND 2.0) found., the frequency of injuries was over 30% higher for the conventional delivery system compared to the cartridge-needle units (1 needle-stick per 16,149 injections versus 1 per

9,053 for conventional systems).

Table 4: Comparative frequencies of Needle-stick Injuries from six study hospitals,

Llewellyn, 1994.

When looking at the details in Table 4, we see the reduction of NSIs is not only due to a reduction of pre-injection NSIs (0 with PFS vs 3 with vials) but of a reduction of NSIs at every step of the procedure. Therefore, this study suggests a reduction of ABE risks with

PFS. While this is promising for PFS, it was not expected and might be due to the specific design of the Carpuject® device, although it is not fitted with a needle shielding safety

GLEIZE (CC BY-NC-ND 2.0) feature. A study comparing a proper PFS and syringes with vials or ampoules should be

undertaken to verify these results.

4.2.4. Other safety considerations

Contrary to multi-dose vials MDV, PFS must be used at once and not be stored once

opened. This makes the addition of conservatives in PFS useless which reduces the risks of

adverse events and allergic reactions to the conservative agents. The composition of the

preparation can further change when shifting from vial or ampoule to prefill and should be

taken into consideration. For instance, the lack of human serum albumin in Epoetin Alfa PFS

contrary to MDV removes the risk of bloodborne disease transmission and also allows

injection to Jehovah's Witnesses [79].

GLEIZE (CC BY-NC-ND 2.0) 4.3. EFFICACY

The meta-analysis also yielded several studies which explored the efficacy, using various

endpoints: pharmacokinetic endpoint with AUC for Chioato et al. [80], or clinical with

seroprotection for Talbot et al. and Song et al. [43, 81], and number of gout flares per

patients for Sundy et al. [40]. They all showed no differences between PFS and standard

syringes (OR 1.20 [0.93, 1.55]) with no heterogeneity (I²=0%) (Figure 13).

Figure 13: Forrest plot comparing efficacy.

These results showing no difference in efficacy are in striking contrast with the

results showing a difference in dose accuracy. This is mostly due to the drugs investigated

and also the study design. The drugs studied by Adapa et al. and Moreira et al. for the dose

consistency endpoint were emergency drugs in the setting of the Intensive care unit (ICU)

[41, 42], while the drugs studied for the efficacy endpoint were either vaccines (Talbot et

al., Song et al.) [43, 81] or anti interleukin 1 drugs used in prevention or treatment (Sundy

et al., Chioato et al.) [40, 80]. These drugs and the context of their use differ starkly with

GLEIZE (CC BY-NC-ND 2.0) the emergency drugs used in the ICU studied for the drug consistency. The emergency drugs administration is of course highly time-sensitive, meaning preparation time is limited which can lead to a higher frequency of errors. The difference in doses showed by Adapa et al. and Moreira et al. would most certainly have resulted in reduced efficacy or increased adverse events but, as the studies were simulated, no clinical endpoint could be explored

[41, 42]. A clinical study comparing the use of PFS and standard systems in emergency settings would be interesting to clarify this point but the emergency nature of the procedure would generate practical and ethical obstacle against a comprehensive recording of relevant parameters and would necessitate a carefully built protocol.

GLEIZE (CC BY-NC-ND 2.0) 4.4 WORKFLOW

Another objective was to explore the effects of V2P on the time to injection. This endpoint has two major implications. First of all, even if the difference is only in minutes, a delayed injection can have important repercussions on the patient, whether the patient is in pain or is in a state of vital emergency. The other implication is economic. Although a V2P shift may only lead to a small time gain per injections (from tens of seconds to a few minutes), this may build up to a great gain at the end of the day in facilities delivering a lot of injections, such as vaccination centers. The time gained for HCW can be utilized in more value added processes.

The meta-analysis yielded 4 different studies comparing either preparation time or overall procedure time which explains a high heterogeneity of results (I²=81%). As for NSI, the study by Llewellyn et al. was included as the Carpuject® system operating procedure is very similar to that of classical PFS and is expected to impact in the same fashion procedure time [39]. As shown on Figure 14, the use of PFS reduces the procedure time (OR 5.59 [3.15,

9.95]). This is especially the case when only looking at the preparation steps rather than overall procedure time because the preparation steps are the ones mostly impacted by the

V2P.

GLEIZE (CC BY-NC-ND 2.0)

Figure 14: Forest plot comparing procedure time.

GLEIZE (CC BY-NC-ND 2.0) 4.5. HEALTH ECONOMICS

At equal clinical benefits, the cheapest medication is not necessarily the one with the lowest price but rather the one which use is associated with the lowest cost [44].

4.5.1. Costs of medical errors

In 2008, medical errors cost the United States $17.1billion [82]. This cost was directly associated with additional medical cost, including: ancillary services, prescription drug services, and inpatient and outpatient care. Additional costs of $1.4 billion were attributed to increased mortality rates with $1.1 billion or 10 million days of lost productivity from missed work based on short-term disability claims [83]. However, the economic impact is much higher, perhaps nearly $1 trillion annually when quality-adjusted life years (QALYs) are applied to those that die. Using the Institute of Medicine's estimate of 98,000 deaths due to preventable medical errors annually in its 1998 report, To Err Is Human, and an average of ten lost years of life at $75,000 to $100,000 per year, there is a loss of $73.5 billion to $98 billion in QALYs for those deaths according to Andel et al. [67, 83]. While the reduction of medical errors observed with V2P will certainly have an impact on medical error associated costs, it is difficult to assess its true impact. The number of studies comparing directly PFS and standard systems is little as shown by the meta-analysis and those studies are often compartmented or simulated.

GLEIZE (CC BY-NC-ND 2.0) De Giorgi et al. [84] did a qualitative and quantitative risk assessment in order to assess the potential impact of safety tool implementation. The injectable drug process in the pediatric and neonatal ICU of their hospital was prospectively assessed using a failure modes, effects and criticality analysis (FMECA). Thirty-one failure modes were identified and criticality indexes were estimated based on their likelihood of occurrence, detection probability and potential severity. The impact of 10 safety tools on the criticality index was calculated and extrapolated to all drugs injected daily. They found that the use of PFS would greatly reduce predicted criticality index points even though they estimated only 60% of injections could be presented in PFS. As illustrated in Figure 15, it was also the third best in terms of cost-effectiveness (0.72€ for the reduction of the criticality index by one point) after the implementation of double-checking by a clinical pharmacist (0.54€ per criticality index point) or by nurses (0.71€ per criticality index point).

GLEIZE (CC BY-NC-ND 2.0)

Figure 15: The 10 safety tools are laid out in four quadrants, according to yearly costs to gain 1 quali per day and total quali gained per day. Intervals were calculated with a sensitivity analysis. (One quali was defined as a reduction of the criticality index by one point.

CPOE = Computerized Physician Order Entry. HFLA = Horizontal Laminar Flow Hood). De

Giorgi, 2010.

The results of this study are promising for V2P but it remains an estimation. It would be very interesting to have an ambitious study comparing medical errors for PFS and vials or ampoules while looking at the clinical outcome for patients. As stated above, this could answer interrogations about efficacy but would also pave the way for an economic analysis of the reduction of medical errors linked to V2P.

GLEIZE (CC BY-NC-ND 2.0)

4.5.2. Comprehensive unit price

Different studies compared the total cost of PFS use versus vials or ampoules for different drug classes and clinical environment.

Wazny et al. did so for Epoetin Alfa used in the treatment of anemia of chronic kidney disease [79]. Their institution used MDV but was concerned about potential drug wastage. A preliminary study found on visual exam that 26% of all discarded MDV had at least 0.2 ml (4,000 units) of Epoetin Alfa left over. Even considering a 10% (0.1 ml) overfilling in the MDV [85], this suggested that there was still 0.1 ml (2,000 units) of Epoetin Alfa wasted. This, as well as other safety and convenience related arguments, led to a V2P conversion for this drug and a retrospective analysis of the cost-savings. This showed that total Epoetin Alfa purchased decreased from 261,080,000 units (MDV period) to

242,681,000 units (PFS period), representing a 7.0% decrease while the total number of patient augmented by 5.7%. The average weekly cost of Epoetin Alfa was $195.71 per patient during the MDV period versus $183.23 per patient during the PFS period. This equates to a weekly cost savings of $12.48 per patient with PFS. With an average of 799 patients receiving Epoetin Alfa PFS in the 2008 evaluation period, this results in predicted cost savings of $518,519 per year for their institution.

GLEIZE (CC BY-NC-ND 2.0) Concerning overfilling, Scheifele et al. noted that PFS of influenza vaccines were slightly overfilled, yielding a mean of 0.54 mL and 0.55 mL for two different brands [86]. Ten doses vials on the other hand were slightly more over-filled with an average of 5.8 mL.

However, the observed yield of vaccine from multi-dose vials was 1,011 doses from 102 vials, 0.9% short of the nominal yield of 1,020 doses. The observed figure even included recovery of partial doses remaining in vials. Another study showed that to deliver 10 doses, a mean of 1.35 ten doses vials were required (54 MDV to perform 400 doses) [87]. This means that overfill of MDV, which is higher than that of PFS, is still not sufficient in practice to ensure the drawing of all the doses.

Pereira and Bishai studied the influence of V2P on costs for the influenza vaccine comparing MDV and PFS through a time-motion study [88]. They observed 31 registered nurses with various years of experience from 7 practices in Baltimore (Maryland, USA) metropolitan area including hospitals, clinics and private medical centers. After adding to the acquisition cost of the vaccine all relevant administration costs, which included nurses’ time, syringes for MDVs only, needles, storage, alcohol and gloves per 1000 injections, the total administration costs were 8596$ for MDVs and 8920.21£ for PFSs, a difference of

324.21$ as shown by Table 5: Costs associated with vaccination using multidose vials and prefilled syringes in 2009 in the USA. Pereira 2010.. In this case, and contrary to Wazny’s study, the price balance is higher when using PFS for the buyer. However, this does not take

GLEIZE (CC BY-NC-ND 2.0) into account the clinical and safety benefits of PFS and the associated costs. Still, the authors suggest a 0.32$ price reduction of PFS doses. The savings in vaccination administration costs would then exactly offset the higher PFS purchase price and thus encourage institutions to shift to PFS.

Considering refrigerated storage, the monthly storage costs were estimated by obtaining the average market price of medical-use refrigerators of 4 cubic feet capacity, assuming a 10-year useful life and a discount rate of 5% after adjustment to inflation. The average volume for a package of five doses of PFSs was 52.6 cm3 and of ten doses of MDVs or one vial was 5.4 cm3 [88]. The increased storage volume leads to a higher storage price as shown in Table 5. The increased storage volume can also lead to the great difficulties for the implementation of V2P if the refrigerated storage capacity of an institution is overwhelmed. In developing countries, the addition of a refrigerator might not be supported by the power grid or by the local generator. It will also be a problem for vaccination campaigns in the countryside, where vaccine doses are often stored in portable coolers. In the case of the influenza vaccine studied by Pereira and Bishai, the volume of

PFS is 20 times higher than that of MDV. In this case, a nurse would have to take 20 coolers of PFS to transport as much as one cooler of MDV which is highly impractical.

GLEIZE (CC BY-NC-ND 2.0) Table 5: Costs associated with vaccination using multidose vials and prefilled syringes in 2009 in the USA. Pereira 2010.

Bellefleur et al. studied the costs of V2P for ephedrine, used for the management of arterial hypotension in obstetrical anesthesia [89]. The authors measured the drug consumption in their maternity during two different 7 day periods. During the first period, as it is an emergency drug, an ephedrine syringe was systematically prepared in advance from an ampoule by dilution in 0.9% sodium chloride and provided in each delivery room and C-section room to be readily available if need be. The syringe was replaced after administration or systematically after a 24 hour period. During the second period, a PFS syringe, still in its packaging, was provided on the anesthesia tray in each room. The packaging was opened only in necessity of use. This study only focused on the number of syringes used by the department compared to the number of syringes actually injected and

GLEIZE (CC BY-NC-ND 2.0) neither on the costs associated with preparation time nor with medical errors. As shown in

Table 6: Consumption and costs of the different packaging. Translated from Bellefleur 2009. the unit price (including dilution solution, syringes and needles needed with ampoules) for ampoules is three times lower than the unit price of PFS. However, due to the high number of prepared syringes discarded but not used, the cost per patient of ampoules is 20% higher than PFS. Moreover, the authors also observed that out of the 45 PFS used, only 30 were really injected. This difference is due to PFS packaging abusively opened from habit or excessive anticipation. However after 18 month of implementation of PFS, there was a sensible amelioration with un-used opened PFS dropping from 33% to 11% which brings the cost of PFS even lower.

Table 6: Consumption and costs of the different packaging. Translated from

Bellefleur 2009.

Another study was performed 4 years later in two similar maternity departments in another city [90]. In this maternity, the unused syringes prepared from ampoules were either discarded after each patients for delivery rooms (called S1 for strategy 1) or only discarded at the end of the day, as in Bellefleur et al. study, in the operating rooms (called S2). Here,

GLEIZE (CC BY-NC-ND 2.0) the unit costs are nearly the same but the percentage of patients requiring an epinephrine injection is much lower. As shown in Table 7, they also find that the use of PFS lead to a lower cost for the hospital, especially when the syringes are discarded after each patients.

They further calculate that the use of PFS would enable a 5590€ (57%) reduction of the epinephrine related expenses for the hospital (S1 and S2), while having the clinical and safety advantages of PFS.

Table 7: Consumption and costs of the different packaging. Translated from Cregut-

Corbaton 2013.

Murdoch et al. also performed a cost analysis on another emergency obstetric anesthetic drug: thiopental, an induction agent [91]. Once again, syringes were prepared in advance from vials in order to reduce preparation errors and save time in an emergency context. Unused syringe were also discarded at the end of the day. Table 8 shows that despite a PFS unit price twice as high, the annual overall cost was cut down by 62%. Once again this does not take into account the costs linked to medical errors.

GLEIZE (CC BY-NC-ND 2.0) Table 8: Cost comparison of daily reconstitution with prefilled syringes. Murdoch

2012.

These studies show that the higher unit price of PFS can be counterbalanced or inverted directly for the buyer. This is especially true for very expensive drugs such as

Epoetin Alfa and for drugs which must be readily available such as anesthetics as PFS reduce drug wastage. For other drugs, the bill might still be higher with PFS but this does not take into account the cost of medical errors, both for the medical institution in terms of legal liability and for society in general.

GLEIZE (CC BY-NC-ND 2.0) 5. DISCUSSION

The originality of this work is the undertaking of a meta-analysis comparing PFS with conventional systems. To the best of our knowledge, this is the first meta-analysis on this subject. However, the meta-analysis only yielded 8 studies deemed worthy of being included. This low number is quite surprising considering that early versions of PFS appeared more than 70 years ago. This number of studies is a bit disappointing but shows the relevance of our work. Although some of the advantages of PFS are empirically known, there is still a need for rational proof from peer-reviewed controlled studies. Many of the studies discussed in the review are only looking at PFS or conventional systems. Others lack a robust and reliable methodology. A lot of data was generated through the years concerning PFS and another review undertaken by BD in 2009 also found a lot of interesting studies but already only a few direct comparisons. The review of this kind of literature brings a lot of interesting elements which help shape our vision of PFS but fails to bring definitive answers or at least define a clear paradigm.

Indeed, while PFS manufacturers such as BDM-PS are convinced of the overall clinical and economical (when taking into account global health costs) superiority of PFS, no study is sufficient by itself to prove this as the subject is wide and complex. The objective of this work was to compile and leverage as much data as possible and see if the available studies could complete each other and enable us to formulate a clear answer concerning

GLEIZE (CC BY-NC-ND 2.0) the advantages and limits of PFS. However, when looking at the results of our meta-analysis, the degree of certainty does not seem always optimal. On dose errors, the meta-analysis shows a significant diminution with PFS but only two studies are included although multiple parameters are explored. For NSI, only one study was included and still leaves some unanswered questions concerning the rate of bloodborne pathologies transmission. On efficacy, 4 studies were included but as explained above, they show results contradicting the one found for medication errors. Finally, on workflow four studies were included showing a clear advantage for PFS. Nonetheless, most of these results are backed by other studies included in the review which often look only at one type of injection system. This is particularly inconvenient as such studies can give optimistic results but the lack of direct comparison make it nearly impossible to conclude one way or the other.

The meta-analysis is therefore insufficient to bring an undisputable answer due to a lack of eligible studies. The review brings a lot of elements and gives us a better understanding of the advantages and limits of PFS on a broader range of the issues at hand, but also fails to give a definite answer.

Therefore, we call for more direct comparison RCTs between PFS and conventional systems. Such studies could and will hopefully be undertaken by BDM-PS. The academic and institutional actors should also continue to actively research the matter as the patients and the medical staff and administration will also reap the benefits of a V2P conversion. Specific

GLEIZE (CC BY-NC-ND 2.0) studies would be particularly interesting. First of all, a clinical study comparing medical errors as well as efficacy and adverse events in emergency settings between PFS and conventional systems to clarify the somewhat contradictory results found for efficacy.

Another one would be exploring in details NSI differentiating pre- and post-injection NSI and of course comparing PFS and conventional systems. Indeed, as shown by Llewellyn et al. PFS lead to a reduction of pre-injection NSI which was expected but might also reduce the risk of post-injection NSI. The difference between the two is major as only post-injection

NSI bear the risk of bloodborne pathogen contamination. Concerning health economics, costs analysis should always include an estimation of overall healthcare costs as it would be a strong incentive for PFS shift. Some of the costs analyses presented in the review seem to only focus on budget aspects. While we understand the high importance of this, the patient’s safety should always stay in view, especially as it is often the driving factor for V2P.

This goes to show that although this work might be downplayed as kicking down open doors, there is in fact a strong need for more robust direct comparison between PFS and conventional systems.

GLEIZE (CC BY-NC-ND 2.0) 6. CONCLUSION

Les travaux présentés dans cette thèse ont été menés pour Becton Dickinson, une

des principales entreprises mondiales spécialisées dans les technologies médicales, et plus

précisément pour la division BD Medical – Pharmaceutical Systems qui conçoit,

manufacture et commercialise des systèmes d'administration de médicaments notamment

des seringues pré-remplies, des systèmes d’auto-injection ainsi que des systèmes de

sécurité de protection des aiguilles. L’objet de ces travaux était d’identifier de façon précise

et étayée, en s’appuyant sur les compétences méthodologiques et scientifiques du

pharmacien industriel, les avantages et inconvénients de la substitution des ampoules et

flacons, mono- ou multi-doses, par des seringues pré-remplies. L’objectif primaire était

l’évaluation des impacts sur la sécurité et la santé des patients et des personnels de santé,

ce qui comprend notamment les problèmes de contamination et de conformité des doses.

Les objectifs secondaires étaient l’étude des impacts économiques, depuis le prix unitaire

jusqu’aux aspects macroscopiques de l’économie de la santé, en passant par le gain de

temps pour chaque injection. Enfin, divers facteurs pouvant influencer la faisabilité de cette

substitution ont été explorés, comme l’interaction contenant-contenu, la facilité d’emploi

ou le stockage. Notre étude a portée sur les injections dans un cadre médical, c’est-à-dire

par des professionnels de santé ou des volontaires formés pour des campagnes de

vaccination. Nous avons ainsi exclu les injections effectuées par le patient lui-même ou par

un de ses proches. 91

GLEIZE (CC BY-NC-ND 2.0) Deux études différentes et complémentaires ont été menées : une revue de la littérature et une méta-analyse. La stratégie de recherche de la revue était basée sur le processus PICO (population, intervention, comparateur, résultat) en incluant une grande variété de publications afin d’être le plus exhaustif possible (essais contrôlés randomisés, revues de littérature, étude de cas, publications de l’Organisation Mondiale de la Santé ou d’autorités compétentes). La stratégie de recherche de la méta-analyse était dérivée de la première mais limitée aux essais contrôlés randomisés selon les recommandations de la

Cochrane afin de générer des résultats robustes et statistiquement significatifs. Les recherches ont été effectuées dans PubMed, Medline et EbscoHost en utilisant les termes

MeSH (Medical Subject Headings). Une évaluation de la qualité des études sélectionnées a

été effectuée dans les deux cas.

L’analyse de la littérature montre que l’utilisation des seringues pré-remplies au lieu des ampoules et flacons permet d’assurer une plus grande sécurité et une plus grande efficacité, notamment en assurant en réduisant le risque de contamination et le risque d’écart entre dose prescrite et dose injectée. La substitution par des seringues pré-remplies permet également de réduire le temps infirmier lié à la préparation de chaque dose, ainsi que le gaspillage de médicament injectable ce qui représente des arguments économiques minimisant ou annulant l’augmentation du prix unitaire par rapport aux ampoules et flacons.

Cependant, la spécificité de chaque système de santé doit être prise en compte afin de

GLEIZE (CC BY-NC-ND 2.0) convaincre chaque acteur de l’intérêt de cette substitution. Les travaux présentés dans cette thèse ont permis l’élaboration d’un document de référence donnant des arguments solides et étayés aux collaborateurs de BD afin qu’ils puissent promouvoir la substitution par des seringues pré-remplies auprès de leurs partenaires et clients. Ce document a pour vocation à être régulièrement mis à jour, par une veille documentaire mais également par la mise en place d’études cliniques et/ou médico-économiques afin d’apporter des comparaisons directes lorsqu’elles font défaut ou d’obtenir des données spécifiques à certains pays ou certaines régions du monde.

GLEIZE (CC BY-NC-ND 2.0)

GLEIZE (CC BY-NC-ND 2.0) BIBLIOGRAPHIE

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GLEIZE (CC BY-NC-ND 2.0) ANNEXE I: ETUDES INCLUES DANS LA META-ANALYSE

1. Llewellyn J, Giese R, Nosek LJ, Lager JD, Turco SJ, Goodell J, et al. A multicenter study of costs and nursing impact of cartridge-needle units. Nurs Econ. août 1994;12(4):208-14. 2. Chioato A, Noseda E, Colin L, Matott R, Skerjanec A, Dietz AJ. Bioequivalence of canakinumab liquid pre-filled syringe and reconstituted lyophilized formulations following 150 mg subcutaneous administration: a randomized study in healthy subjects. Clin Drug Investig. nov 2013;33(11):801-8. 3. Moreira ME, Hernandez C, Stevens AD, Jones S, Sande M, Blumen JR, et al. Color- Coded Prefilled Medication Syringes Decrease Time to Delivery and Dosing Error in Simulated Emergency Department Pediatric Resuscitations. Ann Emerg Med. août 2015;66(2):97-106.e3. 4. Adapa RM, Mani V, Murray LJ, Degnan BA, Ercole A, Cadman B, et al. Errors during the preparation of drug infusions: a randomized controlled trial. Br J Anaesth. nov 2012;109(5):729-34. 5. Talbot HK, Keitel W, Cate TR, Treanor J, Campbell J, Brady RC, et al. Immunogenicity, safety and consistency of new trivalent inactivated influenza vaccine. Vaccine. 29 juill 2008;26(32):4057-61. 6. Song JY, Cheong HJ, Lee J, Wie S-H, Park K-H, Kee SY, et al. Phase IV: randomized controlled trial to evaluate lot consistency of trivalent split influenza vaccines in healthy adults. Hum Vaccin Immunother. 2014;10(10):2958-64. 7. Kasi SG, Prabhu SV, Sanjay S, Chitkara A, Mitra M. Prefilled syringes versus vials: Impact on vaccination efficiency and patient safety in Indian private market. Pediatric Infectious Disease. 1 oct 2013;5(4):181-6.

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GLEIZE (CC BY-NC-ND 2.0) 8. Sundy JS, Schumacher HR, Kivitz A, Weinstein SP, Wu R, King-Davis S, et al. Rilonacept for gout flare prevention in patients receiving uric acid-lowering therapy: results of RESURGE, a phase III, international safety study. J Rheumatol. août 2014;41(8):1703- 11.

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GLEIZE (CC BY-NC-ND 2.0) L’ISPB - Faculté de Pharmacie de Lyon et l’Université Claude Bernard Lyon 1 n’entendent donner aucune approbation ni improbation aux opinions émises dans les thèses ; ces opinions sont considérées comme propres à leurs auteurs.

L’ISPB - Faculté de Pharmacie de Lyon est engagé dans une démarche de lutte contre le plagiat. De ce fait, une sensibilisation des étudiants et encadrants des thèses a été réalisée avec notamment l’incitation à l’utilisation d’une méthode de recherche de similitudes

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