Polymer-based Pre-filled

Syringes in Combination
with aATwo-Step
PDA: Global Association
Autoinjector

William Dierick, Terumo

Luca Baraldi, PhD, Ypsomed

Basel, 05 Nov. 2013

 Companies Introduction

TERUMO
Medical Technology Company
Injection & Drug Delivery Devices
Founded 1921 - Japan
4.2 b$ sales 19000 employees
YPSOMED
Developer and manufacturer
of self-injection devices
Headquarters and manufacturing
in Switzerland since 1984
> 1000 employees
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 What you will take home today

An introduction to a silicone oil free plastic prefilled syringe system

through application of a novel coated plunger stopper

Specific performance features of this polymer-based PFS for use

with biotherapeutics and self-injection

Experimental results verifying the compatibility of this silicone oil

free polymer-based PFS with a 2-step autoinjector

Demonstration of an accurate method for measuring injection times

under defined environmental conditions

A method for modeling injection times starting from a set of

measured data points, where a complete understanding of the
stoppers friction behavior is not required

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 Parenteral Drug Market

Global Injectable market ~ 220 b$ in 2011

Strong growth in Pharmerging markets
Biologics ~225 b$ by 2015
Oncology as leading therapeutic class
Therapeutic antibodies emerging
as the market leader
Nearly 300 monoclonal antibodies
in clinical development
Note: various sources (IMS Health, Insight Pharma, Global Industry Analysts, ..)

High value biopharmaceuticals requiring

safe and appropriate primary packaging
and delivery devices
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PLAJEX COP Prefilled Syringe

COP Syringe
high break resistance
i-coating plunger stopper
Glue free needle
attachment
No Tungsten
No silicone oil
Steam sterilized
ready to fill format
ISO 11040-6:2012

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 Plunger Stopper Coating

Proprietary coating technique applied to the stopper by Terumo

Bonded to the substrate

Smooth surface

Butyl rubber non-coated

Coating thickness Smooth surface
510m

(SEM x1000)

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 Plunger Stopper Coating
Universal testing machine
200 mm/min.
Break-loose and Gliding Forces over time 1 ml Long 27G x TW
1.2 ml WFI
Absence of break-loose peaks
Consistent and predictable
Silicone Oil Free

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 Silicone Oil Free Plastic PFS
Particle analysis by Micro-Flow Imaging (MFI)
ECD5 m, AR0.85 (#/mL) ECD5 m, AR0.85 (#/mL)

Protein oil
Silicone Protein
Aggregated
related Aggregated
Particles
Particles Particles
Particle count

Silicone Oil
Silicone Oil Glass PFS
Glass PFS

Sample protein - Filling volume: 0.5 mL + Air (0.5 mL), Shaking: 30 min at 250 rpm,
Sample measured by MFI (n=5), Cut-off size (ECD): >5m
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 COP Prefilled Syringe
High resistance to breakage

Loading Pin

Syringe Holder

Test method
Universal tensile and
compression testing
machine load cell 1000 N
Test speed of 50 mm/min. Whole Flange Half Flange
support support
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 YpsoMate 2-step Autoinjector

Simple to use autoinjector

with only 2 handling steps
Clear audible click for end
of dose confirmation
Integrated needle safety
Compatible with glass and
polymer syringes 1. Remove cap 2. Push to inject
Flexible autoinjector
platform for customization
with different spring forces
and industrial designs

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 Dimensional Requirements

Syringe dimensions necessary for proper functionality

when used in the YpsoMate autoinjector

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 Dimensional Requirements

Results from dimensional measurements

Measured on
a push/pull tester
(not shown here)
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 Physical Requirements

Main objective: Align autoinjector and PFS to obtain an

injection time <10 sec for a given drug product.
Which elements affect the injection time?
Needle:
- inner diameter: d Stopper & Barrel
Drive Unit - total length: l

Barrel:
- inner diameter: D

Needle & Fluid

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 The Drive Unit

The drive unit generates the acting force, which depends

on the current plunger position only: FD = FD(x)

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 Plunger Stopper & Barrel (friction)

After overcoming the break-loose friction, the moving

plunger stopper responds to the acting force with a
gliding friction Ff = Ff (...).

The main parameters that influence the stoppers gliding

friction include:
the acting force of the drive unit FD(x)
the elasticity of the plunger stopper
the stoppers shape and dimensions
lubrication of the plunger stopper and/or the barrel wall

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 Needle & Fluid (fluid dynamics)

The fluids friction as a response to the resulting total

force F = FD Ff can be described for Newtonian fluids
by the equation of Hagen-Poiseuille:

with and (1)

We made use of the following assumptions:

Newtonian fluid (here: PEG in water )
laminar flow (for Red = 4Q/(d) < 2300)
uniform pressure across the barrel, i.e. gravity and fluid friction in the
barrel section are neglected (F < 20 mN , pbarrel /pneedle 10-6 )
entrance effects in the needle are negligable (pcorr /pneedle < 410-5 )

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 Needle & Fluid (fluid dynamics)

Together with the continuity equation for incompressible

fluids
(2)

we obtain a differential equation describing the

movement of the plunger:

(3)

with

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 Injection Times - Measurements

Measurements in
climate chamber using
digital video recording

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 Injection Times - Measurements

Measurement results
showing ti = ti()

Recall Eqn (3): with

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 Injection Times - Modeling

Measurement results
showing ti = ti(G)

for PLAJEX 27G TW:

d = 0.261 mm
l = 22.1 mm
V = 1.04 ml

for
G 8.1776104
cp/mm3

ti 10 sec

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 Injection Times - Modeling

Modeling for silicone oil free PLAJEX syringes

The needle used

in this study.

... and theoretical data for the selected drive unit with other
PFS, assuming
a constant
gliding friction
of Ff = 2 N
D = 6.35 mm
V = 1.0 ml

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 System Verification

After the system has been specified, i.e.

the drugs viscosity is set
the drive unit has been chosen among a selection of units having different
spring forces
the PFS with an adequate needle gauge has been selected, eventually with
the help of the procedure described in this presentation

the combined product (autoinjector, PFS and drug) is

verified by successfully passing all tests required by part
1 and part 5 of ISO 11608:2012.
Following, a selection of results from Minimum Deliverable
Dose Assessments (MDDA) after various pre-treatments
are summarized.

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 System Verification

MDDA after free-

fall testing
Drop 3 x 10 samples from
a height of 1 m in the
following orientations:

The maximum allowable,

obvious syringe breakages
are 3 per orientation
Perform the MDDA with
3 x 7 samples
Observations:
No syringe breakages

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 System Verification

MDDA at 5C

Store 60 samples at 5C
for at least 4 hours
Perform the MDDA with
60 samples at 5C

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 System Verification

MDDA at 40C
and 50% RH
Store 60 samples at
40C / 50% RH for at
least 4 hours
Perform the MDDA with
60 samples at 40C /
50% RH

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 Summary

PLAJEX PFS system with i-coating has favorable functional

performance properties for use with biotherapeutics and in applications
of self-injection
i-coating allows for a silicone oil free system resulting in low sub-
visible particles related to silicone oil and protein aggregation
PLAJEX silicone oil free PFS have been shown to be fully compatible
with the YpsoMate autoinjector
A technique for accurately measuring injection times under defined
environmental conditions was presented
Using measured injection time data, predictions for alternative needles
can be made without the need of a deeper understanding of the
syringes friction behavior
With the appropriate needle gauge and drive unit, drugs with a dynamic
viscosity of up to 35 cp can be injected in 10 seconds or less

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 Acknowledgements

Terumo
Keisuke Yoshino, PhD, VP Business Development
Tsuyoshi Yoshimoto, Project Leader
Koji Nakamura, PhD, Team Leader R&D
Arisa Yamashita, R&D Division

Ypsomed
Orfeo Niedermann, Business Development Director
Nicolas Binggeli, Specialist Concept Development
Competence Center Laboratory
YpsoMate Development Team

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